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22653314 | CONCLUSION: This analysis provides a current evidence-based estimate of PACG prevalence in European derived populations and suggests there are 130,000 people in the UK, 1.60 million people in Europe and 581,000 people in the USA with PACG today. Accounting for ageing population structures, cases are predicted to increase by 19% in the UK, 9% in Europe and 18% in the USA within the next decade. PACG is more common than previously thought, and all primary glaucoma cases should be considered to be PACG until the anterior chamber angle is shown to be open on gonioscopy. | PURPOSE: Primarily to determine the prevalence of various types of glaucoma and ocular hypertension in Wroclaw inhabitants aged 40-79 years. The second aim of the study was to determine the number of undiagnosed glaucoma cases in this population.
METHODS: A representative group of the Wroclaw population (4853 people aged from 40 to 79 years) was recruited by a proportional simple random sampling selection with stratification. All participants underwent the first, screening-stage examination, which included a medical history interview, intraocular pressure (IOP) measurement, anterior chamber depth assessment by the Van Herrick technique, and optic nerve head (ONH) assessment by means of indirect ophthalmoscopy (Volk's lens), confocal scanning laser ophthalmoscopy with a Heidelberg Retinal Tomograph (HRT) and scanning laser polarimetry by the GDx Nerve Fiber Analyzer (GDx). The second stage, in glaucoma-suspect patients only, included best corrected visual acuity, static perimetry, 24-hour monitoring of IOP, gonioscopy, and full eye examination with mydriasis. Glaucoma was diagnosed by the presence of any two of the following: characteristic morphological changes in the optic disc, glaucomatous visual field abnormalities, and intraocular pressure greater than 21 mmHg.
RESULTS: The overall prevalence of glaucoma was 1.6% (79 subjects). The prevalence increased with age from 0.4% in subjects belonging to the age group 40-49 years to 4.6% in people aged between 70 and 79 years. The prevalence of definite primary open-angle glaucoma was 1.0% (49 subjects). Normal-pressure glaucoma was diagnosed in 13 subjects (0.3%). Ocular hypertension was diagnosed in 92 subjects (1.9%).
CONCLUSION: The prevalence of the different types of glaucoma was similar to that found in other white populations. Among the subjects examined, 79 had various forms of glaucoma and 71% of them had not previously been diagnosed. Undiagnosed glaucoma is a serious public health problem in Poland. ||||| OBJECTIVE: The purpose of the study is to assess the prevalence of various types of glaucoma and to determine the intraocular pressure (IOP) distribution in a defined population in an Italian rural community.
DESIGN: A cross-sectional epidemiologic study in a defined population was planned. After the screening examination, the subjects with suspected glaucoma were re-examined at the screening center in order to confirm the diagnosis. All cases that still proved suspect after the second examination underwent a third phase of investigations at the Ophthalmologic Division of Bolzano Hospital, and were classified as healthy or definitely glaucomatous.
PARTICIPANTS: All subjects residing in the Egna-Neumarkt area of Alto Adige region (Northern Italy) and over 40 years of age were invited to undergo an ophthalmologic examination.
INTERVENTION: Each subject was examined according to a standard protocol, including computerized perimetry, applanation tonometry, evaluation of anterior chamber depth and optic disc, and a medical history interview. The diagnosis of glaucoma was based on the presence of at least two of the following criteria: IOP > or = 22 mmHg, glaucomatous optic disc abnormalities, and glaucomatous visual field defects. Ocular hypertension was defined as IOP > or = 22 mmHg without visual field or glaucomatous optic disc abnormalities.
MAIN OUTCOME MEASURES: Participation rate, mean IOP, prevalence of glaucoma (primary open-angle glaucoma, primary angle-closure glaucoma, normal-tension glaucoma, secondary glaucoma), and ocular hypertension were determined.
RESULTS: Of a total of 5816, 4297 subjects were examined (73.9% overall participation rate). Intraocular pressure showed a Gaussian-like distribution curve skewed to the right. Mean IOP increased with age, and was slightly higher in men (15.14 mmHg) than in women (14.94 mmHg). The overall prevalences of ocular hypertension, primary open-angle glaucoma, primary angle-closure glaucoma, and normal-tension glaucoma were 2.1%, 1.4%, 0.6%, and 0.6%, respectively. Only 28 of 210 patients with glaucoma or ocular hypertension had been diagnosed prior to the screening.
CONCLUSIONS: The distribution of IOP and the prevalence of the different types of glaucoma were similar to those found in other white populations. ||||| PURPOSE: The purpose of this study was to determine the prevalence of open-angle glaucoma and ocular hypertension in an Australian community whose residents are 49 years of age or older.
SUBJECTS: There were 3654 persons, representing 82.4% of permanent residents from an area west of Sydney, Australia, who were examined. The population was identified by a door-to-door census of all dwellings and by closely matched findings from the national census.
METHODS: All participants received a detailed eye examination, including applanation tonometry, suprathreshold automated perimetry (Humphrey 76-point test), and Zeiss stereoscopic optic disc photography. Glaucoma suspects were asked to return for full threshold fields (Humphrey 30-2 test), gonioscopy, and repeat tonometry.
RESULTS: A 5-point hemifield difference on the 76-point test was found in 616 persons (19% of people tested). Humphrey 30-2 tests were performed on 336 glaucoma suspects (9.2% of population), of whom 125 had typical glaucomatous field defects. Two hundred three persons had enlarged or asymmetric cup-disc ratios (> or = 0.7 in 1 or both eyes or a cup-disc ratio difference of > or = 0.3). Open-angle glaucoma was diagnosed when glaucomatous defects on the 30-2 test matched the optic disc changes, without regard to the intraocular pressure level. This congruence was found in 87 participants (2.4%), whereas an additional 21 persons (0.6%) had clinical signs of open-angle glaucoma but incomplete examination findings. Open-angle glaucoma was thus found in 108 persons, a prevalence of 3.0% (95% confidence interval [CI], 2.5-3.6), of whom 49% were diagnosed previously. An exponential rise in prevalence was observed with increasing age. Ocular hypertension, defined as an intraocular pressure in either eye greater than 21 mmHg, without matching disc and field changes, was present in 3.7% of this population (95% CI, 3.1-4.3), but there was no significant age-related increase in prevalence. The prevalence of glaucoma was higher in women after adjusting for age (odds ratio, 1.5; CI, 1.0-2.2). There was no sex difference in the age-adjusted prevalence of ocular hypertension.
CONCLUSIONS: These data provide detailed age and sex-specific prevalence rates for open-angle glaucoma and ocular hypertension in an older Australian population. ||||| OBJECTIVE: To assess the prevalence of primary angle-closure glaucoma (PACG), the frequency of its different clinical presentations, and its association with peripheral anterior chamber depth in a defined population in Northern Italy.
DESIGN: Cross-sectional epidemiologic study in a defined population.
PARTICIPANTS: All subjects resident in the Egna-Neumarkt area of the South Tyrol Region (Northern Italy) and more than 40 years of age were invited to undergo an ophthalmologic examination.
INTERVENTION: After the screening examination, subjects with suspected glaucoma were re-examined at the screening center to confirm the diagnosis. All cases that still proved suspect after the second examination underwent a third phase of investigations and were classified as healthy or as definitely glaucomatous. Each subject was examined according to a standard protocol, including medical history interview, refraction and visual acuity determination, ocular biomicroscopy, evaluation of peripheral anterior chamber depth by means of the Van Herick method, applanation tonometry, optic disc evaluation, and computerized perimetry. Gonioscopy was not performed during initial screening but only in all selected patients in the second and third phases of investigations. The diagnosis of PACG was made on the basis of the concomitant presence of at least two of the following criteria: intraocular pressure > or = 22 mmHg, glaucomatous optic disc abnormalities, glaucomatous visual field defects. In addition, biomicroscopic or gonioscopic evidence of angle closure was also necessary.
MAIN OUTCOME MEASURES: Percentage distribution of peripheral anterior chamber depths, prevalence of angle-closure glaucoma, and frequency of the different PACG clinical presentations.
RESULTS: Four thousand two hundred ninety-seven subjects were examined (73.9% overall participation rate). The peripheral depth of the anterior chamber according to the Van Herick method was grade 2 in 14.7%, grade 1 in 2.5%, and grade 0 in 0.3% of the population. The overall prevalence of angle-closure glaucoma was 0.6% (26 cases). Five of these were cases of previous acute attacks resolved by therapy, three were cases of chronic angle-closure after acute attacks, three were intermittent angle-closure glaucomas, and 15 were chronic angle-closure cases.
CONCLUSIONS: Occludable angles were more frequent than in other white populations previously studied. The prevalence of PACG is not as low as is usually believed; this type of glaucoma accounts for more than a quarter of all glaucomas found in the Egna-Neumarkt population. The most frequent clinical presentation is chronic angle-closure glaucoma. ||||| The Baltimore Eye Survey was a population-based survey conducted from January 1985 to November 1988 among residents of east Baltimore, Maryland, who were 40 years of age or older. A total of 5,308 black subjects and white subjects received a comprehensive screening examination for glaucoma including tonometry, visual fields, stereoscopic fundus photography, and a detailed medical and ophthalmic history. Based on a definitive examination, a diagnosis of glaucoma of any type was made for 196 persons. Tonometry, cup:disc ratio, and narrowest neuroretinal rim width were evaluated for their ability to correctly classify subjects into diseased or nondiseased states. There were no cutoff values at which these variables provided a reasonable balance of sensitivity and specificity, separately or in combination. Logistic regression models were fit that included demographic and other risk factors. Sensitivities and specificities were calculated for varying cutoff levels on the distribution of predicted probabilities. There was no cutoff for which reasonable sensitivity and specificity were obtained. The authors conclude that the effectiveness of current techniques for glaucoma screening is limited. ||||| PURPOSE: The objective of this study is to assess the prevalence of primary open-angle glaucoma (POAG) in a defined population in Rotterdam, The Netherlands.
METHODS: The Rotterdam Study is a single-center prospective cohort study of a total population of more than 10,000 people, 55 years of age or older. For the current analysis, the first 3062 consecutive, unselected, noninstitutionalized participants were examined according to standard protocols, including perimetry. The diagnosis of POAG was based on the presence of a glaucomatous visual field defect combined with either a vertical cup: disc ratio of 0.5 or more or a cup:disc ratio asymmetry of 0.2 or more, or an intraocular pressure (IOP) more than 21 mmHg, with open and normal anterior chamber angles.
RESULTS: The overall prevalence of POAG in the current study was 1.10% (95% confidence interval [CI]: 1.09, 1.11). Age-specific prevalence figures increased from 0.2% (95% CI: 0.16, 0.24) in the age group of 55 to 59 years to 3.3% (95% CI: 2.57, 4.04) in the age group of 85 to 89 years. Men had a more than three times higher risk of having POAG than women (odds ratio, 3.6). In 52.9% of the patients, POAG had not been diagnosed previously. Of these patients, 38.9% had IOPs of 21 mmHg or lower. In 8.8% of the eyes (2.9% of patients), visual acuity was 20/200 or less due to POAG.
CONCLUSION: The overall prevalence of POAG in the current study was 1.1%. The prevalence of POAG was higher in men than in women. Of the untreated patients, 38.9% had IOPs of 21 mmHg or lower. ||||| The purpose of this study was to determine the prevalence of glaucoma in Ponza, Italy. The design was a population-based prevalence survey of residents of Ponza aged 40 years or older. There were 1,296 official residents identified by a house-to-house census, of whom 1,226 were identified as eligible for the study. Of these, 1,034 individuals (449 males and 585 females), or 84.3% of the eligible population, participated in the ophthalmological examination. A two-stage method was adopted to identify cases of glaucoma. All subjects underwent a standardized initial examination. Glaucoma suspects and 50% of non-suspects were referred to a definitive examination which included visual field testing. Patients were defined as glaucoma cases if they presented abnormal visual fields and at least one of the following: high 10P, large or asymmetric cup-to-disc ratio. In addition to typical glaucomatous visual field defects such as paracentral scotoma, nasal step, arcuate scotoma and temporal and/or central islands fields, a visual field defect was identified as a decrease in sensitivity greater than 6 db in at least one location of the central 10 degrees, two locations of the central 20 degrees or three locations of the central 30 degrees. Prevalence rates of 2.51% of Primary Open Angle Glaucoma (1.72%-3.66%, CI 95%), 0.97% of Primary Closed Angle Glaucoma (0.53%-1.77%, CI 95%) and 0.29% of secondary glaucoma were found. Moreover, 2.13% of probable POAG (1.41%-3.20%, CI 95%) and 6.00% of High Intraocular Pressure (4.71%-7.61%, CI 95%) were found. The prevalence rates of POAG found in the Ponza Ophthalmological Survey are consistent with the results of other studies. Minor differences are most likely due to the different criteria adopted in the assessment of glaucomatous visual field damage. ||||| OBJECTIVE: To determine the prevalence of glaucoma among black and white persons 73 years and older.
DESIGN: Participants in the fourth round of a population-based study, the Salisbury Eye Evaluation, were examined. The main outcome measure was glaucoma, based on optic nerve damage and visual field loss or obvious glaucomatous optic neuropathy without an available, reliable, reproducible visual field.
RESULTS: A total of 1250 individuals (95.9% of those eligible) participated, 1233 (98.6%) of whom agreed to screening and an eye examination. The prevalence (95% confidence interval) of open-angle glaucoma was 3.4% (0.5%-6.4%) for white individuals aged 73 and 74 years, increasing to 9.4% (7.4%-11.5%) for those 75 years and older. There was no increasing prevalence in those older than 75 years. Among black persons, the prevalence (95% confidence interval) was 5.7% (0%-11.9%) in those aged 73 and 74 years and 23.2% (17.8%-28.5%) in those 75 years and older.
CONCLUSIONS: Many older individuals have open-angle glaucoma, and black persons 75 years and older have substantially higher rates than whites. These findings have important implications for public health initiatives, in which screening programs may be of benefit. | [
{
"source_pmid": "16283988",
"source_text": "PURPOSE: Primarily to determine the prevalence of various types of glaucoma and ocular hypertension in Wroclaw inhabitants aged 40-79 years. The second aim of the study was to determine the number of undiagnosed glaucoma cases in this population.\nMETHODS: A repr... |
20665044 | CONCLUSIONS: Current data suggests that IVB is an effective short-term treatment for diabetic macular edema, and that its efficacy wanes after 6 weeks. More trials exploring the therapeutic role of intravitreal bevacizumab in DME need to be conducted to define the role of bevacizumab. | OBJECTIVE: To provide data on the short-term effect of intravitreal bevacizumab for diabetic macular edema (DME).
DESIGN: Randomized phase II clinical trial.
PARTICIPANTS: One hundred twenty-one eyes of 121 subjects (109 eligible for analysis) with DME and Snellen acuity equivalent ranging from 20/32 to 20/320.
INTERVENTIONS: Random assignment to 1 of 5 groups: (A) focal photocoagulation at baseline (n = 19), (B) intravitreal injection of 1.25 mg of bevacizumab at baseline and 6 weeks (n = 22), (C) intravitreal injection of 2.5 mg of bevacizumab at baseline and 6 weeks (n = 24), (D) intravitreal injection of 1.25 mg of bevacizumab at baseline and sham injection at 6 weeks (n = 22), or (E) intravitreal injection of 1.25 mg of bevacizumab at baseline and 6 weeks with photocoagulation at 3 weeks (n = 22).
MAIN OUTCOME MEASURES: Central subfield thickness (CST) on optical coherence tomography and best-corrected visual acuity (VA) were measured at baseline and after 3, 6, 9, 12, 18, and 24 weeks.
RESULTS: At baseline, median CST was 411 mum and median Snellen VA equivalent was 20/50. Compared with group A, groups B and C had a greater reduction in CST at 3 weeks and about 1 line better median VA over 12 weeks. There were no meaningful differences between groups B and C in CST reduction or VA improvement. A CST reduction > 11% (reliability limit) was present at 3 weeks in 36 of 84 (43%) bevacizumab-treated eyes and 5 of 18 (28%) eyes treated with laser alone, and at 6 weeks in 31 of 84 (37%) and 9 of 18 (50%) eyes, respectively. Combining focal photocoagulation with bevacizumab resulted in no apparent short-term benefit or adverse outcomes. Endophthalmitis developed in 1 eye. The following events occurred during the first 24 weeks in subjects treated with bevacizumab without attributing cause to the drug: myocardial infarction (n = 2), congestive heart failure (n = 1), elevated blood pressure (n = 3), and worsened renal function (n = 3).
CONCLUSION: These results demonstrate that intravitreal bevacizumab can reduce DME in some eyes, but the study was not designed to determine whether treatment is beneficial. A phase III trial would be needed for that purpose. ||||| PURPOSE: To evaluate the effect of three intravitreal injections of bevacizumab (IVB) alone or combined with triamcinolone (IVT) in the first injection for treatment of refractory diabetic macular edema (DME).
METHODS: In this prospective, placebo-controlled, randomized clinical trial, 115 eyes of 101 patients with refractory DME were included. Subjects were randomly assigned to one of the three study arms: 1) three injections of IVB (1.25 mg/0.05 ml) at 6-week intervals, 2) combined IVB and IVT (1.25 mg/0.05 ml and 2 mg/0.05 ml respectively) followed by two injections of IVB at 6-week intervals, and 3) sham injection (control group). The primary outcome measure was change in central macular thickness (CMT). Secondary outcome measures were change in best-corrected logMAR visual acuity (BCVA ) and incidence of potential adverse events.
RESULTS: Central macular thickness was reduced significantly in both the IVB and IVB/IVT groups. At week 24, CMT change compared to the baseline was -95.7 microm (95% CI, -172.2 to -19.26) in the IVB group, -92.1 microm (95% CI, -154.4 to -29.7) in the IVB/IVT group, and 34.9 microm (95% CI, 7.9 to 61.9) in the control group. There was a significant difference between the IVB and control groups (P = 0.012) and between the IVB/IVT and control groups (P = 0.022). Improvement of BCVA was initiated at weeks 6 and 12 in the IVB/IVT and IVB groups respectively. In terms of BCVA change compared to the baseline at 24 weeks, the differences between the IVB and control groups (P = 0.01) and also between the IVB/IVT and control groups (P = 0.006) were significant. No significant differences were detected in the changes of CMT and BCVA between the IVB and IVB/IVT groups (P = 0.99). Anterior chamber reaction was noticed in eight (19.5%) and seven (18.9%) eyes respectively in the IVB and IVB/IVT groups the day after injection, and it resolved with no sequel. Elevation of IOP occurred in three eyes (8.1%) in the IVB/IVT group.
CONCLUSION: Three consecutive intravitreal injections of bevacizumab had a beneficial effect on refractory DME in terms of CMT reduction and BCVA improvement. Addition of triamcinolone in the first injection seemed to induce earlier visual improvement; however, it did not show any significant additive effect later during follow-up. ||||| PURPOSE: To compare the results of intravitreal bevacizumab (IVB) injection alone or in combination with intravitreal triamcinolone acetonide (IVT) versus macular laser photocoagulation (MPC) as a primary treatment of diabetic macular edema (DME).
DESIGN: Randomized 3-arm clinical trial.
PARTICIPANTS: A total of 150 eyes of 129 patients with clinically significant DME and no previous treatment.
METHODS: The eyes were randomly assigned to 1 of the 3 study arms: the IVB group, patients who received 1.25 mg IVB (50 eyes); the IVB/IVT group, patients who received 1.25 mg of IVB and 2 mg of IVT (50 eyes); and the MPC group, patients who underwent focal or modified grid laser (50 eyes). Retreatment was performed at 12-week intervals whenever indicated.
MAIN OUTCOME MEASURES: Change in best-corrected visual acuity (VA) at week 24.
RESULTS: VA changes among the groups were statistically significant at 6 (P<0.001) and 24 (P = 0.012) weeks. The significant treatment effect was demonstrated in the IVB group at all follow-up visits and in the IVB/IVT group at 6 and 12 weeks. VA changes +/- standard deviation at 36 weeks were -0.28+/-0.25, -0.04+/-0.33, and +0.01+/-0.27 logarithm of minimum angle of resolution in the IVB, IVB/IVT, and MPC groups, respectively (P = 0.053). Significant central macular thickness (CMT) reduction was observed in all groups only up to 6 weeks; however, CMT changes were not significant among the groups in all visits. Overall, retreatment was required for 27 eyes up to 36 weeks (14 in the IVB group, 10 in the IVB/IVT group, and 3 in the MPC group). In the IVB group, in which a greater VA improvement was observed, only 1 injection was required in 72% of the cases. VA improvement >2 Snellen lines at 36 weeks was detected in 37%, 25%, and 14.8% of patients in the IVB, IVB/IVT, and MPC groups, respectively.
CONCLUSIONS: Intravitreal bevacizumab injection in patients with DME yielded a better visual outcome at 24 weeks compared with macular photocoagulation. A change in CMT beyond the 6-week time point that corresponded to the vision change was not detected. No adjunctive effect of IVT was demonstrated.
FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article. ||||| PURPOSE: To evaluate the additive effect of triamcinolone to bevacizumab in comparison to standard macular laser photocoagulation versus bevacizumab in the management of diabetic macular edema (DME).
METHODS: In a prospective, randomized clinical trial, 130 eyes of 110 patients with type 2 diabetes with DME were included. Eligible eyes were randomly assigned to 1.25 mg intravitreal bevacizumab (42 eyes) (IVB group) or combination of 1.25 mg bevacizumab and 2 mg triamcinolone acetonide (41 eyes) (IVB+IVT group) or macular laser photocoagulation (47 eyes) (MPC). Central macular thickness (CMT) and visual acuity changes at week 6 and 16 were assessed.
RESULTS: The mean age of the patients was 57 -/+7 years. Patients were followed 16 weeks. At week 6, all the three groups showed significant reduction in CMT but the reductions for IVB and IVB+IVT were significantly more than MPC (p<0.001). At week 16, the response was not stable for IVB (p<0.001), but IVB+IVT maintained its superior status to MPC (p<0.001). At week 16, visual acuities were essentially unchanged for the two groups of MPC and IVB and improvement for IVB+IVT was marginal and at most was 0.1 log MAR. No patient developed uveitis, endophthalmitis, or thromboembolic event.
CONCLUSIONS: Single intravitreal bevacizumab or triamcinolone plus bevacizumab injection brought about significantly greater macular thickness reduction in diabetic patients in comparison to standard laser treatment. However, the response for bevacizumab alone was short-lived. Reduction in macular thickness was only marginally associated with visual acuity improvement in the triamcinolone plus bevacizumab injection group. | [
{
"source_pmid": "17698196",
"source_text": "OBJECTIVE: To provide data on the short-term effect of intravitreal bevacizumab for diabetic macular edema (DME).\nDESIGN: Randomized phase II clinical trial.\nPARTICIPANTS: One hundred twenty-one eyes of 121 subjects (109 eligible for analysis) with DME and Snel... |
23741296 | CONCLUSION: Ex-Press was associated with equivalent efficacy to Trab in lowering IOP. Comparable proportions of patients reached the IOP target with Ex-Press and Trab. Ex-Press was better tolerated than Trab. | INTRODUCTION: The purpose of this study was to establish the efficacy and safety of the Ex-PRESS (Optonol Ltd., Neve Ilan, Israel) mini glaucoma shunt in open-angle glaucoma.
METHODS: This was a prospective, randomized trial. Eyes from enrolled patients were randomly assigned to either Ex-PRESS implantation under a scleral flap, or trabeculectomy. The main outcome measures were: mean intraocular pressure (IOP), postoperative medication use, visual acuity, and incidence of complications. Complete success was defined as an IOP of >4 mmHg and <or=18 mmHg without the use of antiglaucoma medications. A more stringent target of IOP >4 mmHg and <or=15 mmHg was also noted.
RESULTS: There were 78 patients (80 eyes) with primary open-angle, pseudoexfoliative, or pigmentary glaucoma enrolled in the study. A total of 84.6% of patients receiving Ex-PRESS and 60.0% of patients receiving trabeculectomy (P=0.0230) achieved complete success. The respective proportions of patients achieving an IOP >4 mmHg and <or=15 mmHg were 76.9% and 50.0% (P=0.0193). At 1-year follow-up, complete success rates were 81.8% for Ex-PRESS and 47.5% for trabeculectomy (P=0.0020), and 71.7% and 37.5% (P=0.0070), respectively, for the more stringent target. There was a similar level of postoperative interventions and complications for each group.
CONCLUSIONS: In open-angle glaucoma, the Ex-PRESS mini glaucoma shunt implanted under a superficial scleral flap produces significantly higher success rates, and a similar complication rate, compared with trabeculectomy. The Ex-PRESS is a safe and effective device for treating open-angle glaucoma. ||||| BACKGROUND AND OBJECTIVE: To compare the success and complication rates of patients with glaucoma who had an Ex-PRESS mini glaucoma shunt device implantation (Optonol, Ltd., Neve Ilan, Israel) to those who had conventional trabeculectomy.
PATIENTS AND METHODS: The records of 76 eyes of 69 consecutive subjects who had Ex-PRESS implants and 77 eyes of 65 consecutive controls who had trabeculectomy procedures were reviewed. All surgeries were performed by one of the authors (LWH). Success was defined as an intraocular pressure (IOP) between 5 and 21 mm Hg in patients who did not require further glaucoma surgery in the eye of note.
RESULTS: The difference in the percentage of cases of postoperative hypotony between the standard trabeculectomy group (16%) and the Ex-PRESS group (4%) was statistically significant (P = .023).
CONCLUSION: The Ex-PRESS device is at least as effective as the standard trabeculectomy in lowering the IOP of patients with glaucoma, with a significantly lower risk of postoperative hypotony. The data further suggest that the Ex-PRESS device results in an overall greater percentage reduction in IOP than with trabeculectomy, although this did not reach statistical significance. ||||| BACKGROUND: This study compared the efficacy of the EX-PRESS(®) glaucoma filtration device and trabeculectomy in primary open-angle glaucoma up to five years after surgery.
METHODS: Patients from a previously reported randomized, open-label, parallel-arm clinical trial in which 78 patients received either the EX-PRESS glaucoma filtration device or underwent a trabeculectomy were followed for up to an additional four years (five total) beyond the original study (39 eyes per treatment group). Risk-benefit data were obtained for up to five years after glaucoma surgery. Outcome variables were intraocular pressures and intraocular pressure medications. Complete success was denoted by intraocular pressure values ≤ 18 mmHg without medication.
RESULTS: The EX-PRESS glaucoma filtration device controlled intraocular pressure more effectively without medication for more patients from year 1 (86.8% versus 61.5%, P = 0.01) to year 3 (66.7% versus 41.0%, P = 0.02) than trabeculectomy. At year 1, only 12.8% of patients required intraocular pressure medication after EX-PRESS implantation, compared with 35.9% after trabeculectomy. The proportions became closer at year 5 (41% versus 53.9%). The responder rate was higher with EX-PRESS and time to failure was longer. In addition, surgical interventions for complications were fewer after EX-PRESS implantation.
CONCLUSION: This five-year analysis confirmed and extended the results reported after one year. Compared with trabeculectomy, EX-PRESS provided better intraocular pressure control in the first three years, and patients required fewer intraocular pressure medications and fewer surgical interventions during the five-year study period. For patients with primary open-angle glaucoma, the EX-PRESS glaucoma filtration device, implanted under a superficial scleral flap, produced significantly higher success rates than trabeculectomy. EX-PRESS is an effective device for long-term treatment of primary open-angle glaucoma. ||||| PURPOSE: To compare outcomes between resident-performed trabeculectomy and Ex-PRESS shunt implantation.
METHODS: A consecutive cohort of 36 Ex-PRESS shunt implantations and 57 trabeculectomies (1 eye/patient) performed by resident surgeons in their third year of ophthalmic training at the University of California, San Francisco and at the San Francisco Veterans Administration Hospital, under the supervision of a single glaucoma fellowship-trained surgeon were included in this study. Eyes with < 6 months of follow-up or previous glaucoma surgery were excluded. Preoperative and postoperative intraocular pressure (IOP), preoperative and postoperative number of ocular antihypertensive medications and complication rates were compared between the 2 procedures retrospectively.
RESULTS: No difference was found in postoperative IOP (all, P≥0.099) or proportional decrease in IOP (all, P≥0.092) between the trabeculectomy and Ex-PRESS shunt groups at all follow-up points. On average, the Ex-PRESS shunt group required significantly less ocular antihypertensive medication to control IOP at 3 months postoperative (P=0.01), but no difference was found at 6 months or 1 year (all, P≥0.28). A larger proportion of Ex-PRESS shunt patients had good IOP control without medication at 3 (P=0.057) and 6 months (P=0.076) postoperatively. No difference was found in the rates of sight-threatening complications between groups (all, P≥0.22).
CONCLUSIONS: In the hands of ophthalmology residents in their third year of training, the trabeculectomy and Ex-PRESS shunt implantation procedures perform comparably in terms of postoperative IOP control, reduction in patient dependence on ocular antihypertensive medications, and risk of complication in our population. ||||| PURPOSE: This paper compares the outcomes of the Ex-PRESS(®) Glaucoma Filtration Device (Alcon, Fort Worth, TX) implant observed in Japanese patients for 1 year with those of patients undergoing trabeculectomy.
PATIENTS AND METHODS: The subjects comprised ten eyes of ten cases with open-angle glaucoma for which filtration surgery using Ex-PRESS (P-50) was performed by one operator from February 2008 and observed for at least 1 year (Ex-PRESS Group), and eleven eyes of eleven cases for which trabeculectomy was performed by the same operator (TE Group). For both groups, mitomycin C was used and a scleral flap was created after a fornix-based incision of the conjunctiva.
RESULTS: Hypotony and choroidal detachment were observed as early postoperative complications during a 1-week period in one-third of the cases in the TE Group, and failing vision in about 45%, while these were seen in fewer cases in the Ex-PRESS Group. No significant difference in intraocular pressure (IOP) was observed during the period, but IOP variations on the day following the surgery were obviously narrower in the Ex-PRESS Group than in the TE Group. Visual acuity was significantly poorer from 1 week to 3 months in the TE Group while it was stable in the Ex-PRESS Group. The Ex-PRESS Group had fewer cases of laser suture lysis and fewer administrations of glaucoma eyedrop, and no cases of progression in the stage of visual field defect.
CONCLUSION: Filtration surgery using the Ex-PRESS is unlikely to cause early complications in Japanese patients. Similarly to the trabeculectomy, the intermediate-term control of IOP showed favorable results. ||||| PURPOSE: To evaluate postoperative outcomes and success after combined phacoemulsification and glaucoma surgery with Ex-PRESS miniature implant compared with combined surgery with standard trabeculectomy.
METHODS: In this prospective series of 40 consecutive eyes we compared 20 eyes in 17 patients treated with combined phacoemulsification and glaucoma filtering surgery with the Ex-PRESS miniature glaucoma implant under a scleral flap with 20 matched control eyes in 20 patients who underwent combined cataract and glaucoma surgery with trabeculectomy.
RESULTS: The average follow-up was 9.7 months (range 4.5 to 15) for the Ex-PRESS group and 10.3 months (range 3.5 to 14.5) for the trabeculectomy group. The mean IOP was significantly higher in the early postoperative period in the Ex-PRESS group compared with the trabeculectomy group. Complications rate in the early postoperative period was significantly higher in the trabeculectomy group. No significant differences were objectified in success between both groups after the first week.
DISCUSSION: The Ex-PRESS implant is an effective and safe alternative to standard trabeculectomy in selected cases which makes possible to reduce remarkably the classic early postoperative complications associated with trabeculectomy. ||||| PURPOSE: To compare intraocular pressure (IOP) over time after standard trabeculectomy vs Ex-PRESS implantation in patients with bilateral primary open-angle glaucoma (POAG).
DESIGN: Prospective, randomised study.
PATIENTS AND METHODS: This study included adult patients with bilateral POAG necessitating surgery. Each patient underwent trabeculectomy in one eye and Ex-PRESS implantation under a scleral flap in the other eye according to randomised contralateral allocations. Efficacy was assessed by IOP values and success rates (IOP threshold and/or need for topical glaucoma medication) during 30 months. Statistical analysis included Generalised Estimate Equation and Cox Survival models, and paired t-tests.
RESULTS: Thirty eyes of 15 patients were studied for a mean of 23.6 months (SD, ± 6.9). At the last follow-up visit, mean pre-operative IOP decreased from 31.1 (± 14.2) to 16.2 (± 1.5) mm Hg after trabeculectomy, and from 28.1 (± 9.0) to 15.7 (± 1.8) mm Hg after Ex-PRESS implantation (P=0.001). The mean number of anti-glaucoma medicines prescribed at the last follow-up decreased from 3.7 pre-operatively (both groups) to 0.9 after trabeculectomy vs 0.3 after Ex-PRESS implantation (P=0.001). Complete success rates (5<IOP<18 mm Hg without medications) were higher with Ex-PRESS compared with trabeculectomy (P=0.0024). Postoperative complications were more frequent after trabeculectomy (33%) compared with Ex-PRESS (20%), with four trabeculectomy eyes (27%) needing postoperative interventions, compared with none with Ex-PRESS.
CONCLUSIONS: Trabeculectomy and Ex-PRESS implantation provided similar IOP control, but the Ex-PRESS group had a lower rate of complications, fewer postoperative interventions, and needed less glaucoma medications. ||||| PURPOSE: To evaluate the Ex-PRESS miniature implant (Model R 50) placed under partial-thickness scleral flap compared with standard trabeculectomy.
METHODS: In this retrospective comparative series of 100 eyes, we compared 50 eyes in 49 patients treated with the Ex-PRESS miniature glaucoma implant under a scleral flap with 50 matched control eyes in 47 patients treated with trabeculectomy. Success was defined as intraocular pressure (IOP) > or =5 mm Hg and < or =21 mm Hg, with or without glaucoma medications, without further glaucoma surgery or removal of implant. Early postoperative hypotony was defined as IOP <5 mm Hg during the first postoperative week.
RESULTS: The average follow-up was 10.8 months (range 3.5 to 18) for the Ex-PRESS group and 11.2 months (range 3 to 15) for the trabeculectomy group. Although the mean IOP was significantly higher in the early postoperative period in the Ex-PRESS group compared with the trabeculectomy group, the reduction of IOP was similar in both groups after 3 months. The number of postoperative glaucoma medications in both groups was not significantly different. Kaplan-Meier survival curve analysis showed no significant difference in success between the 2 groups (P=0.594). Early postoperative hypotony and choroidal effusion were significantly more frequent after trabeculectomy compared with Ex-PRESS implant under scleral flap (P<0.001).
CONCLUSIONS: The Ex-PRESS implant under a scleral flap had similar IOP-lowering efficacy with a lower rate of early hypotony compared with trabeculectomy. | [
{
"source_pmid": "19337705",
"source_text": "INTRODUCTION: The purpose of this study was to establish the efficacy and safety of the Ex-PRESS (Optonol Ltd., Neve Ilan, Israel) mini glaucoma shunt in open-angle glaucoma.\nMETHODS: This was a prospective, randomized trial. Eyes from enrolled patients were ran... |
27846316 | CONCLUSION: The current literature suggests a possible association between GC use and the development of cataract. However, this risk cannot be accurately quantified in RA from the available evidence. RCTs have not adequately captured these outcomes and well-designed observational research is required. | OBJECTIVE: To assess the effect of 5 mg/day prednisolone on disease progression in patients with early rheumatoid arthritis (RA) receiving standardized disease-modifying antirheumatic drug (DMARD) therapy.
METHODS: Patients with active RA of <2 years' duration were randomly assigned in a double-blinded manner to receive prednisolone or placebo while starting concomitant DMARD therapy (gold sodium thiomalate or methotrexate). Hand and foot radiographs were taken at baseline and at 6, 12, and 24 months and were evaluated according to the Ratingen score and the total modified Sharp/van der Heijde score (SHS).
RESULTS: Of 192 included patients, 166 were available for the intent-to-treat analysis (ITT). Seventy-six patients completed the study per protocol (PP). Radiographic progression (increase in the Ratingen score) was significantly less with prednisolone than with placebo. The difference in the progression rate between the groups was greatest in the first 6 months. At 24 months in the ITT population, the least squares (LS) mean difference was 3.14 (95% confidence interval [95% CI] 0.94, 5.34), P = 0.006. The results were confirmed by the total SHS in the ITT population (LS mean difference 7.20 [95% CI 0.93, 13.47], P = 0.022) and with the PP population. Clinical and functional outcomes tended to be better and the rate of remissions was higher in the prednisolone group. Side effects were observed more frequently in the prednisolone group than in the control group: weight gain (4 versus 0 patients), hypertension (6 versus 2 patients), glaucoma (3 versus 0 patients), Cushing's syndrome (5 versus 0 patients), gastric distress (9 versus 4 patients), and gastric ulcers (only with concomitant nonsteroidal antiinflammatory drug therapy; 3 versus 0 patients). No new lumbar fractures were found in either group.
CONCLUSION: The very low daily dose of 5 mg prednisolone given over 2 years in combination with background DMARD therapy substantially decreased radiographic progression in early RA at low risk. ||||| BACKGROUND: Oral glucocorticoids combined with disease-modifying antirheumatic drugs are beneficial and retard radiologic joint damage in rheumatoid arthritis.
OBJECTIVE: To investigate the clinical efficacy, disease-modifying properties, and side effects of low-dose glucocorticoids as monotherapy for previously untreated patients with early active rheumatoid arthritis.
DESIGN: 2-year randomized, double-blind, placebo-controlled clinical trial.
SETTING: 2 outpatient rheumatology clinics.
PATIENTS: 81 patients with early active rheumatoid arthritis who had not been treated with disease-modifying antirheumatic drugs.
INTERVENTION: 41 patients were assigned to 10 mg of oral prednisone per day, and 40 were assigned to placebo. Nonsteroidal anti-inflammatory drugs were allowed in both groups. After 6 months, sulfasalazine (2 g/d) could be prescribed as rescue medication.
MEASUREMENTS: Clinical variables were assessed at baseline and every 3 months; radiologic studies were performed every 6 months. Adverse effects were documented every 3 months.
RESULTS: In the first 6 months, the prednisone group showed more clinical improvement than the placebo group. This effect was not seen after 6 months except in grip strength and the 28-joint score for tenderness. Use of additional therapies was significantly less common in the prednisone group, particularly in the first 6 months. More than 65% of those who completed the study were not taking sulfasalazine. After month 6, radiologic scores showed significantly less progression in the prednisone group than in the placebo group. No clinically relevant adverse effects were observed, except for a higher incidence of osteoporotic fractures in the prednisone group.
CONCLUSIONS: Prednisone, 10 mg/d, provides clinical benefit, particularly in the first 6 months, and substantially inhibits progression of radiologic joint damage in patients with early active rheumatoid arthritis and no previous treatment with disease-modifying antirheumatic drugs. Because of their limited disease-modifying effects, glucocorticoids should be combined with disease-modifying antirheumatic drugs in patients with rheumatoid arthritis. ||||| BACKGROUND: Treatment strategies for tight control of early rheumatoid arthritis (RA) are highly effective but can be improved.
OBJECTIVE: To investigate whether adding prednisone, 10 mg/d, at the start of a methotrexate (MTX)-based treatment strategy for tight control in early RA increases its effectiveness.
DESIGN: A 2-year, prospective, randomized, placebo-controlled, double-blind, multicenter trial (CAMERA-II [Computer Assisted Management in Early Rheumatoid Arthritis trial-II]). (International Standard Randomised Controlled Trial Number: ISRCTN 70365169)
SETTING: 7 hospitals in the Netherlands.
PATIENTS: 236 patients with early RA (duration <1 year).
INTERVENTION: Patients were randomly assigned to an MTX-based, tight control strategy starting with either MTX and prednisone or MTX and placebo. Methotrexate treatment was tailored to the individual patient at monthly visits on the basis of predefined response criteria aiming for remission.
MEASUREMENTS: The primary outcome was radiographic erosive joint damage after 2 years. Secondary outcomes included response criteria, remission, and the need to add cyclosporine or a biologic agent to the treatment.
RESULTS: Erosive joint damage after 2 years was limited and less in the group receiving MTX and prednisone (n = 117) than in the group receiving MTX and placebo (n = 119). The MTX and prednisone strategy was also more effective in reducing disease activity and physical disability, achieving sustained remission, and avoiding the addition of cyclosporine or biologic treatment. Adverse events were similar in both groups, but some occurred less in the MTX and prednisone group.
LIMITATION: A tight control strategy for RA implies monthly visits to an outpatient clinic, which is not always feasible.
CONCLUSION: Inclusion of low-dose prednisone in an MTX-based treatment strategy for tight control in early RA improves patient outcomes.
PRIMARY FUNDING SOURCE: Catharijne Foundation. | [
{
"source_pmid": "16255011",
"source_text": "OBJECTIVE: To assess the effect of 5 mg/day prednisolone on disease progression in patients with early rheumatoid arthritis (RA) receiving standardized disease-modifying antirheumatic drug (DMARD) therapy.\nMETHODS: Patients with active RA of <2 years' duration w... |
30030923 | This meta-analysis strongly suggests improved VA outcomes at 12 months in patients with wet AMD for 2.0 mg aflibercept, comparable to but slightly lower than landmark trials. Increased injection frequency and younger age demonstrates a trend with improved outcomes. | PURPOSE: To study visual outcome and number of annual injections in treatment-naïve patients with neovascular age-related macular degeneration (nAMD) before and after a change in first-line therapy from ranibizumab to aflibercept in a high-volume clinical practice.
METHODS: This was a retrospective chart review of routine clinical practice. The study included 1027 treatment-naïve patients, 559 of whom started intravitreal ranibizumab therapy in 2011-2012 and 468 of whom started intravitreal aflibercept therapy in 2013-2014, a fixed loading dose of three injections followed by a pro re nata treatment regimen used in both periods.
RESULTS: Snellen best-corrected visual acuity (BCVA) at baseline and after one year was 0.23 and 0.31 (p < 0.0001), respectively, for patients treated with ranibizumab and 0.25 and 0.33 (p < 0.0001) for patients treated with aflibercept, last observation carried forward. The share of patients (73%) still in treatment with ranibizumab at year 1 had a baseline BCVA of 0.26 but 0.40 at year 1 (p < 0.0001), and the patients (75%) still in treatment with aflibercept at year 1 had a baseline BCVA of 0.28 but 0.42 at year 1 (p < 0.0001). Proportional visual gains for both cohorts were comparable for one year (p = 0.14). The number of injections given within year 1 including first injection was 6.9 for ranibizumab and 5.9 for aflibercept (p < 0.0001). In patients continuing treatment through year 1, the number of injections was 8.0 for ranibizumab and 6.6 for aflibercept (p < 0.0001). The two cohorts had similar cause-of-discontinuation profiles.
CONCLUSION: Treatment of nAMD at a single centre in two sequential cohorts yielded comparable BCVA outcomes with 15% fewer injections of aflibercept compared to ranibizumab. ||||| OBJECTIVE: Two similarly designed, phase-3 studies (VEGF Trap-Eye: Investigation of Efficacy and Safety in Wet AMD [VIEW 1, VIEW 2]) of neovascular age-related macular degeneration (AMD) compared monthly and every-2-month dosing of intravitreal aflibercept injection (VEGF Trap-Eye; Regeneron, Tarrytown, NY, and Bayer HealthCare, Berlin, Germany) with monthly ranibizumab.
DESIGN: Double-masked, multicenter, parallel-group, active-controlled, randomized trials.
PARTICIPANTS: Patients (n = 2419) with active, subfoveal, choroidal neovascularization (CNV) lesions (or juxtafoveal lesions with leakage affecting the fovea) secondary to AMD.
INTERVENTION: Patients were randomized to intravitreal aflibercept 0.5 mg monthly (0.5q4), 2 mg monthly (2q4), 2 mg every 2 months after 3 initial monthly doses (2q8), or ranibizumab 0.5 mg monthly (Rq4).
MAIN OUTCOME MEASURES: The primary end point was noninferiority (margin of 10%) of the aflibercept regimens to ranibizumab in the proportion of patients maintaining vision at week 52 (losing <15 letters on Early Treatment Diabetic Retinopathy Study [ETDRS] chart). Other key end points included change in best-corrected visual acuity (BCVA) and anatomic measures.
RESULTS: All aflibercept groups were noninferior and clinically equivalent to monthly ranibizumab for the primary end point (the 2q4, 0.5q4, and 2q8 regimens were 95.1%, 95.9%, and 95.1%, respectively, for VIEW 1, and 95.6%, 96.3%, and 95.6%, respectively, for VIEW 2, whereas monthly ranibizumab was 94.4% in both studies). In a prespecified integrated analysis of the 2 studies, all aflibercept regimens were within 0.5 letters of the reference ranibizumab for mean change in BCVA; all aflibercept regimens also produced similar improvements in anatomic measures. Ocular and systemic adverse events were similar across treatment groups.
CONCLUSIONS: Intravitreal aflibercept dosed monthly or every 2 months after 3 initial monthly doses produced similar efficacy and safety outcomes as monthly ranibizumab. These studies demonstrate that aflibercept is an effective treatment for AMD, with the every-2-month regimen offering the potential to reduce the risk from monthly intravitreal injections and the burden of monthly monitoring.
FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references. ||||| PURPOSE: To evaluate a modified treat-and-extend (TAE) regimen of intravitreal aflibercept injection (IAI) for treatment-naïve patients with neovascular age-related macular degeneration (AMD).
METHODS: Thirty-six eyes (36 patients) treated with the modified TAE regimen were evaluated at 12 months retrospectively. The modified TAE regimen consisted of three steps: 1) an induction phase, during which patients were treated with ≥ 3-monthly IAIs until exudative activity disappeared, 2) an observation phase, during which patients were monitored until exudative activity appeared, and 3) a TAE phase, for which the initial treatment interval was determined based on the disease recurrence interval, followed by treatment intervals changing by 2 weeks.
RESULTS: Mean logMAR BCVA improved significantly from 0.48 ± 0.51 at baseline to 0.40 ± 0.53 at 12 months (P < 0.01), and was maintained (losing <0.3 logMAR units) in 35 eyes (97.2 %). Mean central retinal thickness and central choroidal thickness decreased significantly after 12 months. In the TAE phase, the distribution of treatment intervals was ≥8 weeks in 64.7 % (11 eyes) at 12 months. The mean number of injections was 4.53.
CONCLUSION: A modified TAE regimen of IAI for neovascular AMD produced good functional outcomes over 12 months with the small number of injections. ||||| PURPOSE: We compared 1-year outcomes of 1 + pro re nata (PRN) versus 3 + PRN of intravitreal aflibercept injection (IAI) for age-related macular degeneration (AMD).
METHODS: Forty-two eyes with naïve AMD received 3 + PRN IAI treatment and 47 eyes with naïve AMD received 1 + PRN IAI treatment. Visual acuity (VA), central retinal thickness (CRT), and central choroidal thickness (CCT) and number of administered IAIs during 12 months were compared.
RESULTS: VAs improved, and CRTs reduced significantly at any given month from baseline in both groups (p < 0.01, respectively). CCT reduced significantly at 3 months in the 3 + PRN group (p = 0.024) but not in the 1 + PRN group. The 1 + PRN group received fewer injections than the 3 + PRN group (p < 0.01).
CONCLUSIONS: Aflibercept leads to equivalent VA and morphologic retinal improvement without administering 3 injections. ||||| PURPOSE: Aflibercept has the potential advantage of reducing capacity problems by allowing 2 monthly visits for patients with neovascular macular degeneration (nAMD) compared with monthly pro re nata regimens that are the most commonly used in the United Kingdom. This study aimed to report the visual outcomes achieved in routine clinical practice using the VEGF Trap-Eye: Investigation of Efficacy and Safety in Wet AMD (VIEW) protocol at 1 year and compare with trials data and other real-world reports.
DESIGN: Retrospective data analysis from an electronic medical record.
PARTICIPANTS: Consecutive series of treatment-naïve patients initiated on aflibercept for nAMD at least 1 year before data extraction.
METHODS: Data were anonymized and remotely extracted from 16 centers in the United Kingdom that use the same electronic medical record (EMR) system (Medisoft Ophthalmology; Medisoft Limited, Leeds, UK).
MAIN OUTCOME MEASURES: The minimum data set defined before first data entry and mandated by the EMR included age, gender, visual acuity, injection episodes, and complications.
RESULTS: The mean age was 80.0 years (median, 81.0 years) and 63.7% were women. During the first year of treatment with aflibercept, 1840 treatment-naïve eyes of 1682 patients received a median of 8 (mean, 7.0) injections at a median of 8 (mean, 7.3) visits. The mean baseline visual acuity was 53.7 letters, improving to 58.8 letters (+5.1-letter gain) at 1 year. In first-treated eyes, the respective figures were 52.7 letters at baseline and 58.2 letters at 1 year, a gain of +5.5 letters. The proportion achieving 70 letters or more increased from 16.4% at baseline to 33.7% at 1 year, and 92% avoided moderate visual loss at 1 year.
CONCLUSIONS: The visual acuity outcomes are comparable to randomized trials and better than many previous real-world data collections, with a mean +5.1-letter gain at 1 year compared with +8.4 letters in the integrated analysis of the VIEW 1 and VIEW 2 studies. Early visual gains were maintained through the year. Collection of outcomes beyond clinical trials can have limitations but better reflect the full pool of patients actually treated and are important to determine whether a particular treatment is performing as expected. Such data also have the potential to improve services by setting up a mechanism to compare sites. ||||| PURPOSE: To compare the responses of intravitreal injections of bevacizumab, ranibizumab, or aflibercept for the treatment of neovascular age-related macular degeneration (nAMD).
METHODS: This retrospective study examined 232 eyes of 232 patients who received intravitreal anti-vascular endothelial growth factor (VEGF) injections due to treatment-naïve nAMD. All patients, who were followed-up for at least 1 year, were treated with intravitreal injections monthly until 3 months, and then as needed. We evaluated the effects of intravitreal injections for treatment of nAMD using the central macular thickness (CMT), subretinal fluid (SRF), pigment epithelial detachment (PED) size, and best-corrected visual acuity (BCVA).
RESULTS: CMT, SRF, PED size, and BCVA (LogMAR) were significantly decreased after treatment with all three anti-VEGF agents. Overall, the bevacizumab, ranibizumab, and aflibercept treatments showed no significant differences in their responses. However, the aflibercept injections decreased PED size more quickly than bevacizumab injections (P = 0.034).
CONCLUSIONS: Bevacizumab, ranibizumab, and aflibercept injections are effective treatments for nAMD and have similar responses, although the number of injections of aflibercept was fewer than other anti-VEGF agents. In addition, aflibercept injections may be a better choice than other anti-VEGF agents for cases of severe increases in PED height. ||||| PURPOSE: To directly compare visual acuity (VA) outcomes with ranibizumab vs. aflibercept for eyes with neovascular age-related macular degeneration (nAMD) treated in routine clinical practice.
DESIGN: Database observational study.
PARTICIPANTS: Treatment-naïve eyes with nAMD tracked by the Fight Retinal Blindness outcome registry that commenced anti-vascular endothelial growth factor therapy with ranibizumab or aflibercept between December 1, 2013, and January 31, 2015. Eyes were matched at baseline for VA, age, and choroidal neovascular membrane (CNV) size.
METHODS: Locally weighted scatterplot smoothing curves were used to display VA results. Eyes that switched or discontinued treatment were included with their last observation carried forward.
MAIN OUTCOME MEASURES: Change in mean VA (number of letters read on a logarithm of the minimum angle of resolution chart); number of injections and visits; proportion of eyes with inactive CNV over 12 months.
RESULTS: We identified 394 eyes (197 treated with ranibizumab and 197 with aflibercept) from 372 patients who received treatment from 34 practitioners. Baseline parameters were well matched. The mean (standard deviation [SD]) VA of ranibizumab-treated eyes increased from 58.6 (20.3) letters at baseline to 62.3 (23.9) (+3.7 [95% confidence interval {CI} 1.4-6.1]) letters (P = 0.001), compared with 58.9 (19.2) letters at baseline to 63.1 (21.5) (+4.26 [95% CI 2.0-6.5]) letters (P < 0.001) for eyes receiving aflibercept. The difference in change in crude VA of 0.6 letters between the 2 groups was not statistically significant (P = 0.76), nor was the difference in adjusted mean VA of the 2 groups (P = 0.26). In completers, the mean (SD) numbers of injections (8.1 [2.1] vs. 8.0 [2.3]; P = 0.27) and visits (9.6 [3.0] vs. 9.5 [3.1]; P = 0.15) did not differ between the 2 groups. The adjusted proportion of eyes in which the CNV lesion was graded as inactive during the study was similar between the eyes receiving ranibizumab and aflibercept (74% vs. 77%, respectively; P = 0.63).
CONCLUSIONS: Visual acuity outcomes at 12 months did not differ between ranibizumab and aflibercept used for nAMD in this large observational study, nor was a difference in treatment frequency found. ||||| PURPOSE: To report 2-year treatment outcomes with intravitreal aflibercept for neovascular age-related macular degeneration (nAMD) in routine clinical practice.
DESIGN: Retrospective, nonrandomized, interventional case series.
METHODS: Retrospective analysis of electronic medical record (EMR) notes (OpenEyes) and paper case notes and review of spectral-domain optical coherence tomography (SDOCT) imaging of patients with consecutively treated eyes with previously untreated nAMD. Patients were commenced on aflibercept injections in 1 or both eyes from October 1, 2013 to December 31, 2013. Data including age, sex, visual acuity (VA) measured on Early Treatment Diabetic Retinopathy Study charts, injection episodes, and complications were recorded. Additionally, SDOCT data, including presence or absence of macular fluid and automated central subfield macular thickness (CSMT) at year 1 and 2, were recorded.
RESULTS: Of the 109 eyes of 102 patients treated, data from 94 eyes of 88 patients were available at 2-year follow-up (86% of patients). In the analysis of 2-year outcomes, there were 58 women (65.9%); the mean (± standard deviation) age was 77.5 ± 8 years. Over the 2 years, these eyes received a median of 12 (mean, 11.4 ± 4) injections at a median of 100 (mean, 99.3 ± 5.3) weeks of follow-up. The mean VA changed from 55.9 ± 15 letters at baseline to 61.3 ± 16.9 letters (VA gain 5.4 letters) at 1 year and to 61 ± 17.1 letters (VA gain 5.1 ± 14.9 letters) at 2 years. The reduction in CSMT was 79 μm with absence of macular fluid in 72.7% of the 88 eyes with SDOCT data available at 2-year follow-up.
CONCLUSIONS: The VA and SDOCT results compare favorably with outcomes seen in randomized controlled trials. The results suggest that good long-term outcomes can be achieved using aflibercept for nAMD in clinical settings. ||||| PURPOSE: To compare the 12-month treatment outcome of ranibizumab with that of aflibercept in cases of neovascular age-related macular degeneration (AMD).
METHODS: This retrospective single-institution study included patients who had been diagnosed with treatment-naïve neovascular AMD and treated using either ranibizumab (ranibizumab group, n = 30) or aflibercept (aflibercept group, n = 21) monotherapy over a 12-month follow-up period. Patients initially received three monthly injections, and were re-treated when neovascularization recurred. The best-corrected visual acuity (BCVA) at diagnosis and at 12 months, as well as the number of injections, were compared between the two groups.
RESULTS: In the ranibizumab group, the mean logarithm of the minimum angle of resolution BCVA values at diagnosis and at 12 months were 0.86 ± 0.45 and 0.72 ± 0.56, respectively. The equivalent values were 0.73 ± 0.37 and 0.58 ± 0.41 in the aflibercept group. The mean number of injections was 4.5 ± 1.3 in the ranibizumab group and 4.3 ± 0.9 in the aflibercept group. There was no difference in BCVA between the two groups at either diagnosis (P = 0.560) or 12 months (P = 0.702). There was also no difference between the two groups in the number of injections (P = 0.847).
CONCLUSION: The 12-month treatment outcome of intravitreal ranibizumab was similar to that of intravitreal aflibercept, with a comparable injection frequency. Further prospective studies with a more controlled design are needed to confirm our findings. ||||| PURPOSE: To investigate the efficacy of periodic injection of aflibercept in each subtype of age-related macular degeneration (AMD) and to explore the predictive factors for visual outcome in clinical settings.
DESIGN: Prospective nonrandomized interventional case series.
METHODS: Patients with AMD were recruited and were administered aflibercept injections once a month for 3 months followed by once every 2 months for 8 months. The logarithm of the minimal angle of resolution (logMAR) at 12 months and improvement of vision from baseline were compared among polypoidal choroidal vasculopathy (PCV), retinal angiomatous proliferation (RAP), and typical AMD. Regression rate of polypoidal lesions was assessed. We also performed regression analysis with logMAR at 12 months as the dependent variable.
RESULTS: The study sample consisted of 98 patients: 46 had typical AMD, 42 had PCV, and 10 had RAP. Mean logMAR improved from 0.36 to 0.21 in 12 months. While there was no difference in visual improvement between typical AMD and PCV, final logMAR was better in PCV (0.32 ± 0.09 vs 0.08 ± 0.04, P = .016). Thirty-nine PCV patients underwent follow-up angiography, and regression of polyps was observed in 27 cases (69.2%). Multiple regression analysis showed that the presence of external limiting membrane (ELM), smaller greatest linear dimension, and the presence of polypoidal lesion were associated with better visual outcome (R(2) = 0.53, P = 2.73 × 10(-14)).
CONCLUSIONS: Periodic injection of aflibercept is effective for PCV as well as for typical AMD. The statuses of ELM, greatest linear dimension, and polypoidal lesion are predictive for visual outcome. | [
{
"source_pmid": "27535819",
"source_text": "PURPOSE: To study visual outcome and number of annual injections in treatment-naïve patients with neovascular age-related macular degeneration (nAMD) before and after a change in first-line therapy from ranibizumab to aflibercept in a high-volume clinical practic... |
26625212 | AUTHORS' CONCLUSIONS: Overall, the use of devices with standard trabeculectomy may help with greater IOP reduction at one-year follow-up than trabeculectomy alone; however, due to potential biases and imprecision in effect estimates, the quality of evidence is low. When we examined outcomes within subgroups based on the type of device used, our findings suggested that the use of an Ex-PRESS device or an amniotic membrane as an adjunct to trabeculectomy may be slightly more effective in reducing IOP at one year after surgery compared with trabeculectomy alone. The evidence that these devices are as safe as trabeculectomy alone is unclear. Due to various limitations in the design and conduct of the included studies, the applicability of this evidence synthesis to other populations or settings is uncertain. Further research is needed to determine the effectiveness and safety of other devices and in subgroup populations, such as people with different types of glaucoma, of various races and ethnicity, and with different lens types (e.g. phakic, pseudophakic). | INTRODUCTION: The purpose of this study was to establish the efficacy and safety of the Ex-PRESS (Optonol Ltd., Neve Ilan, Israel) mini glaucoma shunt in open-angle glaucoma.
METHODS: This was a prospective, randomized trial. Eyes from enrolled patients were randomly assigned to either Ex-PRESS implantation under a scleral flap, or trabeculectomy. The main outcome measures were: mean intraocular pressure (IOP), postoperative medication use, visual acuity, and incidence of complications. Complete success was defined as an IOP of >4 mmHg and <or=18 mmHg without the use of antiglaucoma medications. A more stringent target of IOP >4 mmHg and <or=15 mmHg was also noted.
RESULTS: There were 78 patients (80 eyes) with primary open-angle, pseudoexfoliative, or pigmentary glaucoma enrolled in the study. A total of 84.6% of patients receiving Ex-PRESS and 60.0% of patients receiving trabeculectomy (P=0.0230) achieved complete success. The respective proportions of patients achieving an IOP >4 mmHg and <or=15 mmHg were 76.9% and 50.0% (P=0.0193). At 1-year follow-up, complete success rates were 81.8% for Ex-PRESS and 47.5% for trabeculectomy (P=0.0020), and 71.7% and 37.5% (P=0.0070), respectively, for the more stringent target. There was a similar level of postoperative interventions and complications for each group.
CONCLUSIONS: In open-angle glaucoma, the Ex-PRESS mini glaucoma shunt implanted under a superficial scleral flap produces significantly higher success rates, and a similar complication rate, compared with trabeculectomy. The Ex-PRESS is a safe and effective device for treating open-angle glaucoma. ||||| AIM: To verify the safety and efficacy of Ologen (OLO) implant as adjuvant compared with low-dosage mitomycin-C (MMC) in trabeculectomy.
METHODS: This was a prospective randomized clinical trial with a 24-month follow-up. Forty glaucoma patients (40 eyes) were assigned to trabeculectomy with MMC or OLO. Primary outcome includes target IOP at ≤21, ≤17, and ≤15 mm Hg; complete (target IOP without medications), and qualified success (target IOP regardless of medications). Secondary outcomes include bleb evaluation, according to Moorfields Bleb Grading System (MBGS); spectral domain optical coherence tomography (SD-OCT) examination; number of glaucoma medications; and frequency of postoperative adjunctive procedures and complications.
RESULTS: The mean preoperative IOP was 26.5 (±5.2) in MMC and 27.3 (±6.0) in OLO eyes, without statistical significance. One-day postoperatively, the IOP dropped to 5.2 (±3.5) and 9.2 (±5.5) mm Hg, respectively (P=0.009). The IOP reduction was significant at end point in all groups (P=0.01), with a mean IOP of 16.0 (±2.9) and 16.5 (±2.1) mm Hg in MMC and OLO, respectively. The rates and Kaplan-Meier curves did not differ for both complete and qualified success at any target IOP. The bleb height in OLO group was higher than MMC one (P<0.05). SD-OCT analysis of successful/unsuccessful bleb in patients with or without complete success at IOP ≤17 mm Hg indicated a sensitivity of 83% and 73% and a specificity of 75% and 67%, respectively, for MMC and OLO groups. No adverse reaction to OLO was noted.
CONCLUSIONS: Our results suggest that OLO implant could be a new, safe, and effective alternative to MMC, with similar long-term success rate. ||||| PURPOSE: To compare outcomes of trabeculectomy combined with mitomycin C (MMC) and amniotic membrane transplantation (AMT) with those of trabeculectomy with MMC alone in refractory glaucoma.
METHODS: This prospective, randomized study included 37 eyes with refractory glaucoma at such high risks as neovascular, pseudophakic, and prior failure. Trabeculectomy with MMC and single-layer AMT under the scleral flap was performed in 19 eyes and trabeculectomy with MMC alone in 18 eyes. The outcome measures included intraocular pressure (IOP), number of antiglaucoma medications, and complications. All patients were followed for 12 months.
RESULTS: Complete success (IOP <22 mm Hg without glaucoma medications) was seen in 15/16 (93.7%) study eyes and 9/15 (60%) control eyes at 6 months postoperatively (P=0.03), and in 12/15 (80%) and 6/15 (40%) at 12 months after surgery, respectively (P=0.03). IOP decreased from 45.6+/-12.7 mm Hg and 44.9+/-10.7 mm Hg preoperatively in study and control groups to 15.3+/-2.3 mm Hg and 21.3+/-3.8 mm Hg, respectively, at 12 months (P<0.0001). Early postoperative hypotony developed in 3 (16.7%) control eyes owing to excessive filtration but none of study eyes (P=0.1). Encapsulated bleb occurred in 7 (38.9%) control eyes but in 1 (5.3%) study eye (P=0.02).
CONCLUSIONS: In refractory glaucoma, trabeculectomy combined with MMC and AMT compared to trabeculectomy with MMC alone has higher success rates, lower postoperative mean IOPs, and less complication rates. ||||| PURPOSE: To compare the clinical outcomes of the EX-PRESS glaucoma filtration device placed under a partial-thickness scleral flap with trabeculectomy.
DESIGN: Randomized, prospective, multicenter trial.
METHODS: A total of 120 eyes in 120 subjects were analyzed, including 59 eyes treated with EX-PRESS and 61 eyes treated with trabeculectomy. Both the EX-PRESS and the trabeculectomy groups were treated intraoperatively with mitomycin C and followed postoperatively for 2 years. Surgical success was defined as 5 mm Hg ≤ intraocular pressure ≤ 18 mm Hg, with or without medications, without further glaucoma surgery.
RESULTS: Mean intraocular pressure was significantly reduced compared with baseline in both groups (P < 0.001). Average intraocular pressure and number of medications were similar in both groups during follow-up, with mean intraocular pressure at 2 years after surgery of 14.7 ± 4.6 mm Hg and 14.6 ± 7.1 mm Hg in the EX-PRESS and trabeculectomy groups, respectively (P = 0.927). At 2 years after surgery, the success rate was 83% and 79% in the EX-PRESS and trabeculectomy groups, respectively (P = 0.563). Although visual acuity (logMAR) was significantly decreased on day 1 in both groups, the vision was not significantly different compared with baseline at 1 month after EX-PRESS implant (P = 0.285) and 3 months after trabeculectomy (P = 0.255). The variance of early postoperative intraocular pressure values was similar between groups on the first postoperative day but higher after trabeculectomy compared with EX-PRESS implant on day 7 (P = 0.003). The total number of postoperative complications was higher after trabeculectomy than after EX-PRESS implantation (P = 0.013).
CONCLUSIONS: Mean intraocular pressures, medication use, and surgical success were similar at 2 years after treatment with the EX-PRESS device and trabeculectomy. Vision recovery between groups was also similar throughout the study, although return to baseline vision was more rapid in the EX-PRESS group. Intraocular pressure variation was lower during the early postoperative period, and postoperative complications were less common after EX-PRESS implantation compared with trabeculectomy. ||||| PURPOSE: To present the preliminary results of our study comparing the outcomes of trabeculectomy with or without OloGen implant in patients requiring glaucoma surgery for uncontrolled intraocular pressure (IOP).
METHODS: Forty eyes of 40 patients were assigned randomly to undergo trabeculectomy either with OloGen implant (study group) or without implant (control group). Preoperative data included age, gender, type of glaucoma, IOP and number of preoperative glaucoma medications. Postoperative IOP, number of postoperative glaucoma medications and postoperative complications were recorded. Each patient was followed up for at least 6 months.
RESULTS: There were no significant differences between the groups in terms of age, gender, type of glaucoma, preoperative IOP and number of antiglaucoma medications. Mean IOPs for both groups were significantly lower than preoperative levels at all intervals (P < 0.05) The number of glaucoma medications used dropped from a preoperative mean of 3.5 +/- 0.7 to a 6-month postoperative mean of 0.3 +/- 0.7 (P < 0.001) in the study group and from 3.7 +/- 0.4 to 0.5 +/- 1.1 (P < 0.001) in the control group. No statistically significant differences between the two groups were observed in terms of postoperative complications.
CONCLUSION: In this pilot study it appears that trabeculectomy with OloGen does not seem to offer any significant advantages compared with trabeculectomy alone. Additionally, even though there were no statistical differences between the two groups as far as complications were concerned, one eye from the study group developed endophthalmitis 10 days after surgery and two eyes presented with positive Seidel test and flat anterior chamber and required additional suturing. Studies with larger numbers of patients and longer follow-ups are required to confirm these findings and to examine the safety and long-term outcomes of trabeculectomy with OloGen. ||||| BACKGROUND: This study compared the efficacy of the EX-PRESS(®) glaucoma filtration device and trabeculectomy in primary open-angle glaucoma up to five years after surgery.
METHODS: Patients from a previously reported randomized, open-label, parallel-arm clinical trial in which 78 patients received either the EX-PRESS glaucoma filtration device or underwent a trabeculectomy were followed for up to an additional four years (five total) beyond the original study (39 eyes per treatment group). Risk-benefit data were obtained for up to five years after glaucoma surgery. Outcome variables were intraocular pressures and intraocular pressure medications. Complete success was denoted by intraocular pressure values ≤ 18 mmHg without medication.
RESULTS: The EX-PRESS glaucoma filtration device controlled intraocular pressure more effectively without medication for more patients from year 1 (86.8% versus 61.5%, P = 0.01) to year 3 (66.7% versus 41.0%, P = 0.02) than trabeculectomy. At year 1, only 12.8% of patients required intraocular pressure medication after EX-PRESS implantation, compared with 35.9% after trabeculectomy. The proportions became closer at year 5 (41% versus 53.9%). The responder rate was higher with EX-PRESS and time to failure was longer. In addition, surgical interventions for complications were fewer after EX-PRESS implantation.
CONCLUSION: This five-year analysis confirmed and extended the results reported after one year. Compared with trabeculectomy, EX-PRESS provided better intraocular pressure control in the first three years, and patients required fewer intraocular pressure medications and fewer surgical interventions during the five-year study period. For patients with primary open-angle glaucoma, the EX-PRESS glaucoma filtration device, implanted under a superficial scleral flap, produced significantly higher success rates than trabeculectomy. EX-PRESS is an effective device for long-term treatment of primary open-angle glaucoma. ||||| PURPOSE: To compare the safety and efficacy of trabeculectomy with Ologen implant vs. trabeculectomy with Mitomycin C (MMC).
MATERIALS AND METHODS: In a prospective, randomized, pilot study, 39 eyes of 33 subjects with medically uncontrolled primary glaucoma, aged 18 years or above underwent trabeculectomy either with MMC (20 eyes) or with Ologen implant (19 eyes). The primary outcome measure was cumulative success probability, defined as complete if the intraocular pressure (IOP) was > 5 and ≤ 21 mm Hg without anti-glaucoma medications or additional surgery and qualified if an IOP was > 5 and ≤ 21 mm Hg with or without anti-glaucoma medications.
RESULTS: Mean (± standard deviation) follow-up in Ologen group was 19.1 ± 8.1 months, and in MMC group was 18.0 ± 8.4 months. Mean IOP reduction at 6 months was significantly lower (P = 0.01) in the MMC group (11.9 ± 2.9 mm Hg) as compared to Ologen group (14.6 ± 2.7 mm Hg). However, at 12 months (P = 0.81) and 24 months (P = 0.32), the mean IOP was similar between the 2 groups. Complete success probability at the end of 6 months in Ologen group was 100% (95% confidence interval: 59.1 - 99.0) was similar (P = 0.53) to that in MMC group (93.8%, 95% CI: 63.2 - 99.1). The incidences of early post-operative complications were similar in the 2 groups, except hyphema, which was significantly more in Ologen group (P = 0.02).
CONCLUSION: In this pilot study, the success of trabeculectomy and complications were similar in both Ologen and MMC groups at the end of 6 months. ||||| PURPOSE: To compare the safety and efficacy of human preserved amniotic membrane (AM) in the trabeculectomy for treatment of primary open-angle glaucoma.
METHODS: A prospective, randomized clinical trial compared primary trabeculectomy with amniotic membrane (study group) and without amniotic membrane (control group) in the treatment of the glaucoma. Intraocular pressure (IOP), number of glaucoma medications and appearance of the bleb were compared between the two groups. Thirty-two patients divided into two groups of 16 patients were followed for a period of 12 months.
RESULTS: The difference of the mean postoperative intraocular pressure between groups was not statistically significant (15.19 +/- 3.33 in the control group and 12.81 +/- 2.48 in the study group p=0.297) at one year follow-up. Postoperative number of medications decreased in both groups (p<0.001 and p=0.007, study group and control respectively). At the end of a 12-month follow-up period, nine eyes (56.25%) showed thin, avascular blebs in the study group as compared to only one eye (6.25%) in the control group.
CONCLUSIONS: Trabeculectomy with amniotic membrane and standard trabeculectomy promote lower postoperative intraocular pressure although results showed no statistically significant difference between groups regarding postoperative intraocular pressure after one year follow-up. ||||| PURPOSE: To compare the rate of visual recovery after Ex-PRESS implantation versus standard trabeculectomy.
PATIENTS AND METHODS: Subjects enrolled in a prospective randomized controlled trial comparing Ex-PRESS to trabeculectomy were analyzed for postoperative changes in visual acuity (VA). Risk factors for visual loss (split fixation, cup-disc ratio, intraocular pressure, visual field mean deviation, and hypotony) were evaluated.
RESULTS: Sixty-four subjects were enrolled (33 Ex-PRESS, 31 trabeculectomy). There was no significant difference in mean logMAR VA between groups at baseline or any study visit. VA was significantly reduced up to week 2 following surgery in both the groups. However, by month 1, VA in the Ex-PRESS group was no longer significantly different from baseline (P=0.23) and remained nonsignificant at subsequent visits up to 6 months. In the trabeculectomy group, VA remained significantly lower than baseline at each study visit. At 6 months, 47% of the trabeculectomy eyes compared with 16% of the Ex-PRESS eyes had lost ≥2 Snellen lines (P=0.01). Reasons for VA loss included cataract, central retinal vein occlusion, and diabetic retinopathy, however, in a significant number of cases no cause could be determined. None of the risk factors evaluated were associated with vision loss.
CONCLUSIONS: Although there was no difference in mean VA between the Ex-PRESS and trabeculectomy groups at any time point, trabeculectomy eyes were more likely to lose ≥2 Snellen lines. In addition, VA recovered faster in the Ex-PRESS group. ||||| PURPOSE: To assess the efficacy of trabeculectomy with a biodegradable Ologen™ implant (OLO) versus mitomycin C (MMC) in patients in a prospective randomized clinical trial.
METHODS: In the MMC group (15 patients), trabeculectomy was performed according to standard protocols. In the OLO group (15 patients) after standard trabeculectomy, the implant was positioned on top of the scleral flap, and no MMC was applied.
RESULTS: Mean preoperative intraocular pressure (IOP) levels (OLO: 28.0 ± 9.4; MMC: 23.9 ± 5.0 mm Hg; p = 0.21) and medication score (OLO: 3.4 ± 1.6; MMC: 3.6 ± 1.5; p = 0.56) were comparable in both groups. One year after surgery, the mean IOP was 15.9 ± 4.5 mm Hg in the OLO group (p < 0.01, 43% reduction) and 11.0 ± 2.6 mm Hg in the MMC group (p < 0.01, 54% reduction). The surgical success rate 12 months after surgery was 93.3% in the MMC group and 40% in the OLO group (p = 0.01).
CONCLUSIONS: With the atelocollagen-glycosaminoglycan matrix OLO it was not possible to reach the surgical success rate and pressure reduction achieved in the MMC group. ||||| PURPOSE: The aim of this study is to assess the efficacy and complications of trabeculectomy with a biodegradable implant (ologen implant) vs trabeculectomy using mitomycin C (MMC) in patients with medically uncontrolled open-angle glaucoma in a prospective randomised clinical trial.
METHODS: In the MMC group (10 patients), trabeculectomy was performed according to standard protocols. In the ologen group (10 patients) after standard trabeculectomy the implant was positioned on top of the scleral flap and no MMC was applied. Follow-up was continued for 12 months after surgery and included testing of intraocular pressure (IOP), visual acuity, visual field, ultrasound biomicroscopy, and filtering bleb score.
RESULTS: The mean preoperative IOP was 24.8+/-8.9 mm Hg for all patients enrolled. At 1 year after surgery, the mean IOP was 15.6+/-2.4mm Hg in the ologen group (P<0.01, 43% reduction) and 11.5+/-4.1 mm Hg in the MMC group (P<0.01, 50% reduction). No anti-glaucomatous medication was necessary in the MMC group in the first year of follow-up, whereas five patients in the ologen group required topical treatment. The absolute success rate was 100% in the MMC group and 50% in the ologen group (P=0.01). After 1 year, filtering blebs developed significantly more avascular areas in the MMC group (score=1.4) than in the ologen group (score=2.8; P<0.01).
CONCLUSION: The complete success rate using trabeculectomy with the ologen implant is lower than that achieved by trabeculectomy with MMC. However, the bleb morphology caused more problems in the MMC group (avascularity score). ||||| PURPOSE: To compare intraocular pressure (IOP) over time after standard trabeculectomy vs Ex-PRESS implantation in patients with bilateral primary open-angle glaucoma (POAG).
DESIGN: Prospective, randomised study.
PATIENTS AND METHODS: This study included adult patients with bilateral POAG necessitating surgery. Each patient underwent trabeculectomy in one eye and Ex-PRESS implantation under a scleral flap in the other eye according to randomised contralateral allocations. Efficacy was assessed by IOP values and success rates (IOP threshold and/or need for topical glaucoma medication) during 30 months. Statistical analysis included Generalised Estimate Equation and Cox Survival models, and paired t-tests.
RESULTS: Thirty eyes of 15 patients were studied for a mean of 23.6 months (SD, ± 6.9). At the last follow-up visit, mean pre-operative IOP decreased from 31.1 (± 14.2) to 16.2 (± 1.5) mm Hg after trabeculectomy, and from 28.1 (± 9.0) to 15.7 (± 1.8) mm Hg after Ex-PRESS implantation (P=0.001). The mean number of anti-glaucoma medicines prescribed at the last follow-up decreased from 3.7 pre-operatively (both groups) to 0.9 after trabeculectomy vs 0.3 after Ex-PRESS implantation (P=0.001). Complete success rates (5<IOP<18 mm Hg without medications) were higher with Ex-PRESS compared with trabeculectomy (P=0.0024). Postoperative complications were more frequent after trabeculectomy (33%) compared with Ex-PRESS (20%), with four trabeculectomy eyes (27%) needing postoperative interventions, compared with none with Ex-PRESS.
CONCLUSIONS: Trabeculectomy and Ex-PRESS implantation provided similar IOP control, but the Ex-PRESS group had a lower rate of complications, fewer postoperative interventions, and needed less glaucoma medications. ||||| PURPOSE: To compare the efficacy and safety of the Ex-PRESS glaucoma shunt with standard trabeculectomy.
PATIENTS AND METHODS: Consenting patients with medically uncontrolled open-angle glaucoma were prospectively randomized to trabeculectomy or Ex-PRESS shunt both with mitomycin-C. Exclusion criteria included previous ocular surgery with the exception of clear cornea phaco or 1 previous trabeculectomy, uveitis, and vitreous in the anterior chamber. Standardized data collection sheets were completed at baseline and postoperative day 1, weeks 1 and 2, and months 1, 2, 3, 6, and 12. Primary outcome was intraocular pressure (IOP). Complete success was defined as an IOP between 5 and 18 mm Hg and a 20% reduction from baseline without medication. A sample size calculation determined that 52 eyes were required to detect a 2.0 mm Hg IOP difference with a power of 80%.
RESULTS: Sixty-four subjects were enrolled, 33 in the Ex-PRESS and 31 in the trabeculectomy group. IOP was not statistically significantly different between groups. Baseline and 1-year mean IOP was 22.0±6.8 versus 22.7±10.3 mm Hg (P=0.76) and 11.6±4.5 versus 11.3±4.5 mm Hg (P=0.81) in the trabeculectomy versus Ex-PRESS groups, respectively. Complete success was 57% versus 70% (P=0.28) in the trabeculectomy versus Ex-PRESS groups, respectively. There were no statistically significant differences in surgical time, number of glaucoma medications, visual acuity, central corneal thickness, endothelial cell counts, complications, interventions, or bleb morphology between the trabeculectomy and the Ex-PRESS groups.
CONCLUSIONS: There was no statistically significant difference between the trabeculectomy and Ex-PRESS groups regarding IOP, success rates, complications, additional interventions, and bleb morphology. ||||| BACKGROUND: To investigate the effectiveness of amniotic membrane transplantation (AMT) on improving the outcomes of trabeculectomy in primary open-angle glaucoma (POAG).
METHODS: Fifty-nine eyes affected by primary open-angle glaucoma were enrolled in this prospective randomized study. Thirty-two eyes underwent amnion-shielded trabeculectomy (study group) and 27 eyes underwent trabeculectomy without any antimetabolites (control group). Success was defined as intraocular pressure (IOP) <21 mmHg without any medications at 24 months follow-up. The two groups were compared in terms of IOP, bleb morphology, bleb survival and risk of failure, glaucoma medications, and complications.
RESULTS: There was no statistically significant difference in terms of postoperative IOP between the two groups and at 24 months median IOP was 15.5 mmHg for the AMT group and 16 mmHg for the control group. IOP postoperative reduction was 8 mmHg for the AMT group versus 6 mmHg for the non AMT group (P = 0.276). Two patients from the study group developed IOP >21 mmHg in contrast to seven patients from the classic trabeculectomy group. The study group had 61.0% less risk of developing IOP >21 mmHg (P = 0.203). No major complications in the AMT group were observed. AMT blebs were diffuse with mild vascularization.
CONCLUSION: In patients with POAG, AMT showed favorable effects on bleb survival, however data failed to provide firm evidence that AMT could be used as a routine procedure in trabeculectomy. ||||| PURPOSE: To evaluate the intraocular pressure (IOP)-lowering effect of trabeculectomy with the use of amniotic membrane transplant (AMT) compared with the standard trabeculectomy with Mitomycin-C (MMC) in patients with primary open-angle glaucoma.
PATIENTS AND METHODS: This study was a patient-masked, randomized, controlled comparison trial involving 52 eyes of 52 patients with bilateral primary open-angle glaucoma. Patients were randomized to receive trabeculectomy with AMT or trabeculectomy with MMC. The main outcome for comparison was the IOP-lowering effect of both procedures. Surgical success was considered if the patient's IOP was <22 mm Hg, and the IOPs were lowered by >20% without the use of any medication.
RESULTS: All surgeries passed uneventfully without intraoperative complications, and all patients showed significantly (P<0.05) lower IOP on the first postoperative day compared with their respective preoperative IOP with nonsignificant (P>0.05) difference between both study groups. All patients, irrespective of the operative procedure maintained significantly (P<0.05) lower IOP compared with their respective preoperative IOP till the end of 24 months follow-up. Moreover, patients of the AMT group showed lower IOP compared with those included in the MMC group throughout the follow-up period; however, the difference was not statistically significant at any point of the study period.
CONCLUSIONS: AMT exhibits potential as an alternative to MMC in trabeculectomy surgery. Over 24 months of follow-up, the use of AMT with trabeculectomy was safe and effective with an IOP-lowering effect comparable to that achieved with the use of MMC, and a reduced rate of postoperative complication. ||||| PURPOSE: Ex-PRESS shunt is an alternative filtration procedure to trabeculectomy. This study aimed to compare the 1-year cost differences between the 2 operations.
METHODS: Subjects were enrolled in a randomized controlled trial comparing Ex-PRESS to trabeculectomy. Surgical cost difference and 1-year postoperative costs (follow-up visits, additional procedures, and medications) were determined and compared. The 95% confidence interval of incremental cost-effectiveness ratio was estimated using bootstrap method.
RESULTS: Forty-three subjects with 1-year follow-up were included. Success rate was not significantly different for Ex-PRESS (65%) versus trabeculectomy (55%, P=0.49). Ex-PRESS had a net surgical cost of $956 greater than trabeculectomy. There was no significant difference in the overall postoperative cost [median (interquartile range); $485 (337, 822) vs. $609 (387, 820), P=0.78], cost of follow-up visits [$303 (275, 358) vs. $317 (275, 385), P=0.75], additional procedures [$182 (0, 365) vs. $182 (0, 365), P=0.69], or glaucoma medication [$0 (0, 68) vs. $0 (0, 90), P=0.8] for Ex-PRESS versus trabeculectomy, respectively. The overall 1-year cost was significantly greater for Ex-PRESS and the incremental cost-effectiveness ratio was $9625 (95% confidence interval, $2435-548,084).
CONCLUSIONS: Ex-PRESS is associated with greater surgical cost compared with trabeculectomy. This needs to be considered in conjunction with efficacy and safety if Ex-PRESS is to supersede trabeculectomy. ||||| AIM: To observe effects of trabeculectomy with amniotic membrane transplantation (AMT) in controlling postoperative intraocular pressure (IOP) in patients with medically uncontrolled glaucoma.
METHODS: This study included adult patients with requiring bilateral glaucoma surgery. Each patient underwent trabeculectomy (Non-AMT group) in one eye and with AMT (AMT group) in the other eye according to randomized principle. Success was defined as intraocular pressure (IOP)<21mmHg without any anti-glaucoma medications at 24 months follow-up. The two groups were compared in terms of IOP, complications and success rate.
RESULTS: Thirty-four eyes of 17 patients were investigated in this study. There was no statistically signifcant difference in pre-operative IOP between the two groups. The mean IOP was lower in AMT group compared with Non-AMT group on follow up months 12, 18, and 24.Postoperative complications were more frequent in Non-AMT group (35.3%, 6/17) compared with AMT group (5.9%, 1/17). The success rate of surgery was 88.2% (15/17) in Non-AMT group and 100% (17/17) in AMT group.
CONCLUSION: Trabeculectomy with AMT is an effective procedure to reduce IOP and complications, thereby improving surgical success rates. ||||| PURPOSE: To test the expanded polytetrafluoroethylene (ePTFE) as a new adjuvant in trabeculectomy.
METHODS: Consecutive glaucoma surgical inpatients were observed at the Department of Ophthalmology of Palermo University. Sixty patients (60 eyes) were randomly assigned to undergo trabeculectomy (T), trabeculectomy with mitomycin-C (TMMC), with ePTFE (TG) or with mitomycin-C and ePTFE (TGMMC). Postoperative visits were scheduled at 24 hr, 7 days, 1, 3, 6, 12, 18 and 24 months. Complete success and qualified success were assessed at two target intraocular pressure (IOP) levels -< or =21 and < or =17 mmHg - by Kaplan-Meier curves.
RESULTS: The postoperative IOP reduction was significant (P < 0.01) at the endpoint in all groups, with a mean IOP of 16.9 (+/-2.9), 16.2 (+/-2.7), 15.3 (+/-3.4) and 15.2 (+/-4.3) mmHg in T, TMMC, TG and TGMMC eyes, respectively. No intergroup difference was found at either IOP targets. The Kaplan-Meier curves relating to either the < or =21 mmHg or the < or =17 mmHg target IOP did not show significant intergroup differences for complete and qualified success rate. When ePTFE was used, a trend favouring the medium-term survival rate was noted. No adverse reaction to the ePTFE was present, and no membrane extrusion or conjuctival erosion were noted in any cases. Hypotony was significantly more frequent (P = 0.035) in groups without ePTFE. Moreover, the late MMC-related complications were more frequent when MMC was applied.
CONCLUSION: Expanded polytetrafluoroethylene implant in trabeculectomy is well tolerated and could act as a filtration modulating device. Therefore, it is useful in reducing early hypotony-related complications and contributes to attaining medium-term IOP control that is comparable to the low-dosage MMC. ||||| PURPOSE: To compare the results of subscleral trabeculectomy (SST) augmented with mitomycin-C (MMC) versus Ologen™ implant regarding intraocular pressure (IOP) control and incidence of complications.
METHODS: Sixty eyes of 60 patients, who planned to undergo SST, were divided into 2 groups. Group I eyes (included thirty eyes) were operated upon with SST augmented with intraoperative MMC. Group II eyes (included 30 eyes) were operated upon with SST using an Ologen implant. IOP and bleb status, as well as reporting postoperative complications, were followed up.
RESULTS: The follow-up period was 12 months. At 12 months postoperatively, the mean IOP was 19.33±3.22 mmHg in group I, and 19.87±4.17 mmHg in group II, with no significant difference between groups. One case in each group had hyphema, and 4 cases in group I and 2 cases in group II had shallow anterior chamber. One case in group I and no cases in group II had blebitis. There was no significant difference regarding the complications between both groups.
CONCLUSION: We conclude that the use of the Ologen implant in SST is comparable to the use of MMC with advantage of avoiding the potential dangerous complications related to MMC use in the early (12 months) follow-up period. | [
{
"source_pmid": "19337705",
"source_text": "INTRODUCTION: The purpose of this study was to establish the efficacy and safety of the Ex-PRESS (Optonol Ltd., Neve Ilan, Israel) mini glaucoma shunt in open-angle glaucoma.\nMETHODS: This was a prospective, randomized trial. Eyes from enrolled patients were ran... |
20179632 | CONCLUSIONS: Trabeculectomy was found to have a greater pressure-lowering effect compared with viscocanalostomy. However, viscocanalostomy had a significantly better risk profile. | AIMS: To compare trabeculectomy with viscocanalostomy augmented with adjunctive antimetabolite use for the control of intraocular pressure (IOP) in open angle glaucoma (OAG).
METHODS: 45 patients (50 eyes) with uncontrolled OAG were randomised to either trabeculectomy (25 eyes) or a viscocanalostomy technique (25 eyes). Preoperatively, all eyes were graded in terms of risk factors for drainage failure and were given intraoperative antimetabolites (5-fluorouracil 25 mg/ml (5-FU), mitomycin C (MMC) 0.2 mg/ml and 0.4 mg/ml) according to a standard protocol.
RESULTS: There were no significant differences between the groups in age, sex, type of OAG, preoperative medications, risk factors for drainage failure, and preoperative IOP. Mean follow up was 20 months (range 3-24 months). It was 12 months or longer in all eyes, except two lost to follow up at 3 months. At 12 months, complete success (IOP<21 mm Hg without antiglaucoma medications) was seen in 91% of eyes undergoing trabeculectomy, but in only 60% of eyes undergoing viscocanalostomy (p<0.02). Similarly, at the last follow up visit (mean 20 months) complete success was seen in 68% of eyes undergoing trabeculectomy and 34% with viscocanalostomy (p<0.05). In terms of qualified success (IOP<21 mm Hg with or without glaucoma medications) and mean IOP measurements postoperatively there were no difference between the groups, although the mean number of antiglaucomatous medications required postoperatively was less with trabeculectomy (0.39) than viscocanalostomy (1.04) (p<0.05). Needling procedures were more commonly required after trabeculectomy (p<0.02). YAG goniotomy was required in three eyes (13%) after viscocanalostomy. Early transient complications such as anterior chamber shallowing and encysted blebs were more common in the trabeculectomy group (p<0.05). Late postoperative cataract formation was similar between the two groups.
CONCLUSION: In terms of complete success and number of antiglaucomatous medications required postoperatively, IOP control appears to be better with trabeculectomy. Viscocanalostomy is associated with fewer early transient postoperative complications. ||||| AIMS: The purpose of this randomized clinical trial was to compare the effectiveness and safety of viscocanalostomy (visco) with trabeculectomy (trab) in the management of primary open angle glaucoma (POAG).
METHODS: Patients were randomized to have a viscocanalostomy (25 eyes) or a trabeculectomy (25 eyes) performed by one surgeon (TDM) and followed up prospectively. Patients were examined preoperatively, at day 1, day 3 if required, day 6, week 2 and thereafter as near as possible to 1, 3, 6, 12, 18, 24, 30, 36, 48, 54, and 60 months. We recorded intraocular pressure (IOP), presence or absence of any complications, presence and description of any bleb, visual acuity with glasses, and full examinations as routine to monitor any progression of the glaucoma. Bleb interventions including needling and antimetabolites were allowed and recorded in both groups. YAG laser goniopuncture was allowed in the viscocanalostomy group.
RESULTS: Mean follow-up was 40 months (SD 15), with a range from 6 to 60 months. Forty-two percent (n=10) of the patients in the trabeculectomy group had a successful outcome (IOP<18 mm Hg with no treatment) at last follow-up visit, compared to 21% (n=5) in the viscocanalostomy group. IOP was lower in the trab group with differences in IOP being statistically significant at month 12 (P=<0.001), 24 (P=<0.001), 30 (P=0.030), 36 (P=<0.001), and 48 (P=0.018). The trabeculectomy group required less postoperative topical IOP-lowering medication (P=0.011).
CONCLUSION: In this study, we found trabeculectomy to be more effective at lowering IOP than viscocanalostomy in POAG patients. ||||| PURPOSE: To compare the effectiveness and safety of viscocanalostomy and trabeculectomy in adults with uncontrolled open-angle glaucoma.
DESIGN: Single-masked, parallel-group, prospective, randomized 24-month trial, with 90% power to detect a clinically important difference between groups.
PARTICIPANTS: Fifty consecutive patients (50 eyes) with primary open-angle or pseudoexfoliative glaucoma.
INTERVENTION: Eyes were assigned randomly to either viscocanalostomy (group 1) or trabeculectomy (group 2) with no intraoperative antifibrotics in the study eye. In group 1, no further intervention was allowed, whereas trabeculectomy eyes could receive subconjunctival 5-fluorouracil (5-FU) injections or laser suture lysis after surgery.
MAIN OUTCOME MEASURES: Success rate based on intraocular pressure (IOP), visual acuity, discomfort, and other complications.
RESULTS: At the end of the 24-month follow-up, IOP of 21 mmHg or less and more than 6 mmHg was achieved in 76% in group 1 (n = 19) and in 80% in group 2 (n = 20; log-rank P = 0.60); an IOP between 6 and 16 mmHg was obtained in 56% in group 1 (n = 14) and in 72% in group 2 (n = 18; log-rank P = 0.17; Kaplan-Meier cumulative probability of success). Complications of viscocanalostomy included one intraoperative conversion into trabeculectomy; microruptures in Descemet's membrane in five eyes; three cases of iris incarceration in the Decemet's window, two of which caused early failure of the procedure requiring reoperation; and a 1-mm to 2-mm transient self-resolving hyphema in three cases. Complications of trabeculectomy included one case of postoperative bleb bleeding with early transient IOP spike; one early hyphema; five cases of postoperative hypotony, two of which had a positive Seidel test from the conjunctival suture; three cases of transient choroidal detachment, two of which had shallow anterior chamber. No patient required reoperation. Two eyes required argon laser suture lysis, and nine underwent one or more 5-FU injections, which caused punctate keratopathy in three eyes.
CONCLUSIONS: Viscocanalostomy is an effective IOP-lowering procedure in white adults affected by open-angle glaucoma. Trabeculectomy with postoperative 5-FU can probably provides lower IOPs but, with more numerous complications, greater discomfort, and more intensive postoperative management. ||||| PURPOSE: To compare surgically induced corneal refractive change following trabeculectomy with the nonpenetrating trabecular filtering surgeries with and without implant.
SETTING: Department of Ophthalmology, Ege University School of Medicine, Izmir, Turkey.
METHODS: A consecutive series of 34 patients (34 eyes) with uncontrolled open-angle glaucoma had trabecular filtering surgery. Patients were assigned randomly to receive viscocanalostomy (12 patients), nonpenetrating deep sclerectomy (NPDS) with T-flux implant (10 patients), and trabeculectomy (12 patients). Autokeratometry and computerized corneal videokeratoscopy with the Topcon KR-7000P autokeratorefractometer were performed preoperatively and 1 day and 1, 3, and 6 months postoperatively to analyze surgically induced keratometric and topographic astigmatism.
RESULTS: Thirty patients (11 trabeculectomy, 11 viscocanalostomy, and 8 NPDS with nonabsorbable implant) completed the study. Mean patient age was 61.7 years +/- 10.9 (SD) (range 37 to 81) and did not differ among groups. Postoperative intraocular pressure (IOP) levels and visual acuity (logMAR values) did not differ among groups compared with preoperative levels. Average induced astigmatism was lower in the NPDS group than the trabeculectomy group at postoperative month 3 and 6 based on autokeratometry values (P =.023 and.042, respectively). Nonpenetrating surgeries resulted in less induced astigmatism in the early postoperative period and less against-the-rule shift over 6 months.
CONCLUSION: Despite larger flap size and surgical area, nonpenetrating trabecular surgeries induced less astigmatism than trabeculectomy. ||||| Results of trabeculectomy (TE) and viscocanalostomy (VCO) were compared in a prospective randomised study in two fellow eyes of 22 consecutive patients with bilateral symmetrical high-tension glaucoma. Rates of overall surgical success with intraocular pressures (IOP) < or = 18 mm Hg with or without medications were 91 for the TE, and 95 for the VCO group after a mean follow-up of 18 months. Complete success rates without medications were 64 and 59 for TE and VCO groups, respectively (p = 0.750). Both procedures significantly reduced IOP, however, IOP course following trabeculectomy was significantly lower (p = 0.026). Rates of complications were not found to be different between the two groups of eyes, except for an apparent--though not significant (p = 0.066)--increase in cataract progression with TE. Various types of conjunctival blebs were detected in all eyes with surgical success in both groups, however, diffuse, elevated or multi-cystic functional blebs appeared to be more predominant in eyes with TE, compared to the VCO group in which low-lying, localised blebs had a higher incidence (p = 0.015). Viscocanalostomy was found to be a safe and effective filtration technique in patients with uncomplicated high-tension glaucoma, though IOP decrease was more pronounced with trabeculectomy. ||||| PURPOSE: To compare the intraocular pressure-lowering effect and safety of viscocanalostomy and trabeculectomy with mitomycin C.
METHODS: Twenty-five patients with bilateral primary open-angle glaucoma were enrolled in a prospective clinical study. The eyes of each patient were randomly assigned to receive viscocanalostomy in one eye and trabeculectomy with mitomycin C in the other eye. The patients were followed up for 12 months. At each visit, best-corrected visual acuity, intraocular pressure, and the appearance of the surgical wound, anterior chamber, and indirect ophthalmoscopy were recorded.
RESULTS: The mean baseline intraocular pressure was 25.0+/-2.2 mmHg in viscocanalostomy-treated eyes and 24.8+/-2.6 mmHg in trabeculectomy-treated eyes. The mean postoperative intraocular pressure was 15.3+/-1.7 mmHg, 17.1+/-1.5 mmHg, and 17.1+/-1.5 mmHg in viscocanalostomy-treated eyes and 11.7+/-4.4 mmHg, 11.8+/-4.6 mmHg, and 12.6+/-4.3 mmHg in trabeculectomy-treated eyes at 3-, 6- and 12-month intervals, respectively. The mean intraocular pressure in viscocanalostomy-treated eyes was significantly higher than that in trabeculectomy-treated eyes at every visit (P<0.0001). At 12 months, 16 viscocanalostomy-treated eyes (64%) and 22 trabeculectomy-treated eyes (88%) achieved an intraocular pressure of less than or equal to 20 mmHg without medication; there was a significant difference between the two groups (P=0.0240). There were fewer complications in viscocanalostomy-treated eyes. Complications included four cases of shallow anterior chamber (16%) and five of hypotony (20%) in trabeculectomy-treated eyes, against intraoperative microperforation of Descemet's membrane in one of viscocanalostomy-treated eye (4%).
CONCLUSION: Trabeculectomy with mitomycin C may be more effective than viscocanalostomy in lowering intraocular pressure in patients with primary open-angle glaucoma, while eyes undergoing viscocanalostomy experience a lower incidence of complications. Further investigation of more cases is needed. ||||| AIMS: To compare trabeculectomy with viscocanalostomy for the control of intraocular pressure (IOP) in open angle glaucoma (OAG) uncontrolled by medical therapy.
METHODS: 48 patients (50 eyes) with uncontrolled OAG were randomised to either trabeculectomy (25 eyes) or a viscocanalostomy technique (25 eyes). Preoperatively, eyes were graded in terms of risk factors for drainage failure. Those undergoing trabeculectomy were given intraoperative antimetabolites (5-fluorouracil 25 mg/ml (5-FU), mitomycin C (MMC) 0.2 mg/ml and 0.4 mg/ml) according to a standard protocol. Antimetabolites were not used intraoperatively in eyes undergoing viscocanalostomy, but they were randomised to the use of viscoelastic (Healonid GV) for intraoperative intracanalicular injection.
RESULTS: There were no significant differences between the groups in age, sex, type of OAG, preoperative medications, risk factors for drainage failure, and preoperative IOP. Mean follow up was 19 months (range 6-24 months). It was 12 months or longer in all eyes, except one lost to follow up at 6 months. At 12 months, complete success (IOP <21 mm Hg without antiglaucoma medications) was seen in all eyes undergoing trabeculectomy (100%), but in only 64% of eyes undergoing viscocanalostomy (p<0.001). The mean IOP was lower at 12 months (p<0.001) with trabeculectomy and the number of eyes with IOPs of 15 mm Hg or less was greater (p<0.05). The mean IOP at 12 months was lower in eyes that had undergone viscocanalostomy using intraoperative intracanalicular Healonid GV injection compared to those where only balanced saline solution had been used (p<0.01). However, in terms of complete success there was no difference between the viscocanalostomy groups (p<0.1). With the exception of measurements at 1 week, visual recovery (logMAR acuity) was similar and laser flare and cell values showed little differences between the groups. Corneal topography and keratometry at 12 months were little different from preoperative values. Postoperative interventions (subconjunctival 5-FU and needling procedures) were similar between the groups. Transient complications such as early bleb leak and hyphaema were more common in the trabeculectomy group (p<0.05). Postoperative cataract formation was more common after trabeculectomy (p<0.05).
CONCLUSIONS: IOP control appears to be better with trabeculectomy. Viscocanalostomy is associated with fewer postoperative complications, although significant complications permanently impairing vision did not occur with either technique. ||||| PURPOSE: To assess the intraocular pressure-lowering efficacy and the postoperative complication profile of viscocanalostomy versus trabeculectomy.
PATIENTS AND METHODS: Sixty eyes of 60 patients with medically uncontrolled open-angle glaucoma were randomized either to the viscocanalostomy or to the trabeculectomy group of the trial. Viscocanalostomy was performed according to Stegmann's technique using high-molecular-weight sodium hyaluronate to fill the ostia of the Schlemm canal. For trabeculectomy, a modified Cairns-trabeculectomy was performed. Examinations were performed before surgery and postoperatively daily for 1 week. Follow-up visits were scheduled 1, 6, and 12 months after surgery.
RESULTS: The mean (SD) preoperative intraocular pressure was 27.1 (7.1) mm Hg for all patients enrolled. One day after surgery, mean (SD) intraocular pressure was 15.9 (5.2) for the trabeculectomy group (P <0.001) and 15.7 (3.6) for the viscocanalostomy group (P <0.001), respectively. The success rate, defined as an intraocular pressure lower than 22 mm Hg without medication, was 56.7% in the trabeculectomy group and 30% in the viscocanalostomy group at 12 months postoperatively (P = 0.041). The number of postoperative complications was lower in the viscocanalostomy group than in the trabeculectomy group.
CONCLUSIONS: In eyes with open-angle glaucoma, viscocanalostomy is less effective in reducing intraocular pressure than standard filtering surgery. However, postoperative complications are more frequent after filtering surgery. ||||| PURPOSE: To compare viscocanalostomy, a nonpenetrating procedure for glaucoma treatment, with trabeculectomy.
DESIGN: Randomized controlled trial.
PARTICIPANTS: Twenty white subjects (20 eyes) with open-angle glaucoma with no history of surgery were enrolled.
METHODS: Ten subjects were randomly assigned to viscocanalostomy according to Stegmann's technique and 10 subjects to a modified Cairns trabeculectomy. A complete ophthalmologic examination was performed the day before surgery and postoperatively. Further visits were scheduled monthly for 6 to 8 months after surgery.
MAIN OUTCOME MEASURES: Success was defined as intraocular pressure (IOP) between 7 and 20 mmHg, with no medication.
RESULTS: After a mean follow-up of 6 months (range, 6-8 months), success was obtained in 5 of 10 cases in the trabeculectomy group and in no case in the viscocanalostomy group. With Kaplan-Meier's method, subjects with viscocanalostomy showed shorter postoperative IOP-reduction periods than subjects undergoing trabeculectomy.
CONCLUSIONS: According to the results of this short-term study, trabeculectomy was more effective than viscocanalostomy in lowering IOP in glaucomatous eyes of white patients. ||||| PURPOSE: To compare the efficacy and safety of viscocanalostomy and trabeculectomy in patients with primary open-angle glaucoma (POAG).
SETTING: Department of Ophthalmology, Ankara Education and Research Hospital, Ankara, Turkey.
METHODS: In this prospective randomized trial, 50 eyes of 50 patients with medically uncontrolled POAG were randomized to have a trabeculectomy (25 eyes) or a viscocanalostomy (25 eyes). Visual acuity, intraocular pressure (IOP), and slitlamp examinations were performed before surgery and 1 day, 1 week, 1, 3, and 6 months, and 1, 2, and 3 years postoperatively.
RESULTS: At 3 years, the mean IOP was 16.0 mmHg +/- 7.07 (SD) in the trabeculectomy group and 17.8 +/- 4.6 mmHg in the viscocanalostomy group (P=.694). Complete success (IOP 6 to 21 mm Hg without medication) was achieved in 66.2% of eyes at 6 months and 55.1% at 3 years in the trabeculectomy group and in 52.9% and 35.3%, respectively, in the viscocanalostomy group (P>.05). Qualified success (IOP 6 to 21 mmHg with medication) was achieved in 95.8% of eyes at 6 months and 79.2% at 3 years in the trabeculectomy group and in 90.7% and 73.9%, respectively, in the viscocanalostomy group (P>.05). Postoperative hypotony and cataract formation occurred more frequently in the trabeculectomy group than in the viscocanalostomy group (P=.002).
CONCLUSIONS: Primary trabeculectomy lowered IOP more than viscocanalostomy in POAG patients. However, the complication rate was lower in the viscocanalostomy group. | [
{
"source_pmid": "15258016",
"source_text": "AIMS: To compare trabeculectomy with viscocanalostomy augmented with adjunctive antimetabolite use for the control of intraocular pressure (IOP) in open angle glaucoma (OAG).\nMETHODS: 45 patients (50 eyes) with uncontrolled OAG were randomised to either trabecul... |
30666092 | Compared with ranibizumab, corticosteroid implant did not have greater improved BCVA, but corticosteroid implant had less CST reduction. The advantages of corticosteroids are fewer injections, while the advantages of ranibizumab include fewer side effects. | PURPOSE: To evaluate whether treatment with dexamethasone intravitreal implant (DEX implant) 0.7 mg every 5 months provides a similar average change in best-corrected visual acuity (BCVA) from baseline as ranibizumab 0.5 mg administered as per its European Summary of Product Characteristics in patients with diabetic macular edema (DME).
METHODS: This was a multicenter, open-label, 12-month, randomized, parallel-group, noninferiority study in patients with DME (one eye/patient). The primary efficacy measure was BCVA using the Early Treatment Diabetic Retinopathy Study (ETDRS) method. Secondary efficacy measures included area of leakage on fluorescein angiography and central retinal thickness (CRT) on optical coherence tomography.
RESULTS: Baseline patient characteristics were similar in the two treatment groups (DEX implant, n = 181; ranibizumab, n = 182); mean DME duration was ∼33 months. The mean average BCVA change from baseline over 12 months was 4.34 letters with DEX implant and 7.60 letters with ranibizumab. The lower limit of the 95 % confidence interval of the between-group difference was -4.74 letters, and therefore, DEX was demonstrated to be noninferior to ranibizumab based on the prespecified noninferiority margin of 5 letters. At monthly follow-up visits, the percentage of patients with ≥15-letter BCVA gain from baseline ranged from 7.2 to 17.7 % with DEX implant and 4.4 to 26.9 % with ranibizumab. Both DEX implant and ranibizumab effectively reduced CRT and reduced the area of fluorescein leakage. Between-group differences in change from baseline CRT favored DEX implant at 1, 2, 6, and 7 months (p ≤ 0.007) and ranibizumab at 4, 5, 9, and 10 months (p < 0.001); the decrease in fluorescein leakage area was greater with DEX implant than ranibizumab at month 12 (p < 0.001). Ocular adverse events in the study eye were more frequent in the DEX implant group because of the occurrence of intraocular pressure (IOP) increases and cataract. IOP increases were transient and generally managed with topical medication.
CONCLUSIONS: Both DEX implant and ranibizumab were well tolerated and improved BCVA and anatomic outcomes in patients with DME. DEX implant met the a priori criterion for noninferiority to ranibizumab in average change from baseline BCVA over 12 months. Noninferiority was achieved with an average of 2.85 DEX implant injections and 8.70 ranibizumab injections per patient. ||||| PURPOSE: To compare the efficacy and safety of the European labels of ranibizumab 0.5 mg vs dexamethasone 0.7 mg in patients with macular edema secondary to central retinal vein occlusion (CRVO).
DESIGN: Phase IIIb, multicenter, double-masked, randomized clinical trial.
METHODS: Patients were randomized (1:1) to receive either monthly ranibizumab followed by pro re nata (PRN) treatment (n = 124) or 1 sustained-release dexamethasone implant followed by PRN sham injections (n = 119). Main outcomes were mean average change in best-corrected visual acuity (BCVA) from baseline to month 1 through month 6, mean change in BCVA, and adverse events (AEs).
RESULTS: Of 243 patients, 185 (76.1%) completed the study. No difference was observed in BCVA between ranibizumab and dexamethasone at months 1 and 2. From month 3 to month 6, there was significant difference in BCVA gains in favor of ranibizumab. At month 6, mean average BCVA gain was significantly higher with ranibizumab than with dexamethasone (12.86 vs 2.96 letters; difference 9.91 letters, 95% confidence interval [6.51-13.30]; P < .0001). Mean injection number of ranibizumab was 4.52. Ocular AEs were reported in more patients in the dexamethasone than in the ranibizumab group (86.6% vs 55.6%).
CONCLUSIONS: Using the European labels, similar efficacy was observed for ranibizumab and dexamethasone at months 1 and 2. However, ranibizumab maintained its efficacy throughout the study, whereas dexamethasone declined from month 3 onward. The main limitation of the study was that dexamethasone patients received only a single treatment during the 6-month study. In clinical practice, dexamethasone retreatment may be required earlier than 6 months. Safety findings were similar to those previously reported. ||||| PURPOSE: To compare the efficacy and safety of ranibizumab 0.5 mg versus dexamethasone 0.7 mg according to their European labels in macular oedema secondary to branch retinal vein occlusion (BRVO) in a 6-month, phase IIIb, randomized trial.
METHODS: Patients received either monthly ranibizumab for 3 months followed by Pro re nata (PRN) treatment (n = 126) or a sustained-release dexamethasone implant followed by PRN sham injections (n = 118). Main outcomes were mean average change in best-corrected visual acuity (BCVA) from baseline to month 1 through month 6, mean changes in BCVA and foveal centre point thickness (FCPT), and adverse events (AEs).
RESULTS: There was no difference in BCVA gains between the treatments prior to month 3. Best-corrected visual acuity (BCVA) gain with dexamethasone declined thereafter. From month 3 to month 6, mean BCVA change from baseline was significantly higher with ranibizumab than with dexamethasone [raw means (standard deviation):+16.2 (±11) letters versus +9.3 (±10.1) letters]. At month 6, the difference in BCVA gains from baseline was +17.3 letters in the ranibizumab versus +9.2 letters in the dexamethasone group. Patients in the ranibizumab group received a mean of 2.94 loading injections and 1.74 PRN retreatment injections, while those in the dexamethasone group received a single loading injection. Elevated intraocular pressure (IOP) and AEs were more frequent with dexamethasone than ranibizumab treatment.
CONCLUSION: Ranibizumab PRN resulted in greater visual acuity (VA) gains in macular oedema following BRVO compared with single-dose dexamethasone over a 6-month study period, observed from month 3, when administered according to their European label. In clinical practice, retreatment with dexamethasone may be required prior to this point. | [
{
"source_pmid": "27632215",
"source_text": "PURPOSE: To evaluate whether treatment with dexamethasone intravitreal implant (DEX implant) 0.7 mg every 5 months provides a similar average change in best-corrected visual acuity (BCVA) from baseline as ranibizumab 0.5 mg administered as per its European Summar... |
32504495 | State-of-the-art neural networks could effectively detect clinical significant DR. To further improve diagnostic accuracy of neural networks, researchers might need to develop new algorithms rather than simply enlarge sample sizes of training sets or optimize image quality. | IMPORTANCE: More than 60 million people in India have diabetes and are at risk for diabetic retinopathy (DR), a vision-threatening disease. Automated interpretation of retinal fundus photographs can help support and scale a robust screening program to detect DR.
Objective: To prospectively validate the performance of an automated DR system across 2 sites in India.
DESIGN, SETTINGS AND PARTICIPANTS: This prospective observational study was conducted at 2 eye care centers in India (Aravind Eye Hospital and Sankara Nethralaya) and included 3049 patients with diabetes. Data collection and patient enrollment took place between April 2016 and July 2016 at Aravind and May 2016 and April 2017 at Sankara Nethralaya. The model was trained and fixed in March 2016.
INTERVENTIONS: Automated DR grading system compared with manual grading by 1 trained grader and 1 retina specialist from each site. Adjudication by a panel of 3 retinal specialists served as the reference standard in the cases of disagreement.
Main Outcomes and Measures: Sensitivity and specificity for moderate or worse DR or referable diabetic macula edema.
RESULTS: Of 3049 patients, 1091 (35.8%) were women and the mean (SD) age for patients at Aravind and Sankara Nethralaya was 56.6 (9.0) years and 56.0 (10.0) years, respectively. For moderate or worse DR, the sensitivity and specificity for manual grading by individual nonadjudicator graders ranged from 73.4% to 89.8% and from 83.5% to 98.7%, respectively. The automated DR system's performance was equal to or exceeded manual grading, with an 88.9% sensitivity (95% CI, 85.8-91.5), 92.2% specificity (95% CI, 90.3-93.8), and an area under the curve of 0.963 on the data set from Aravind Eye Hospital and 92.1% sensitivity (95% CI, 90.1-93.8), 95.2% specificity (95% CI, 94.2-96.1), and an area under the curve of 0.980 on the data set from Sankara Nethralaya.
CONCLUSIONS AND RELEVANCE: This study shows that the automated DR system generalizes to this population of Indian patients in a prospective setting and demonstrates the feasibility of using an automated DR grading system to expand screening programs. ||||| Diabetic retinopathy is a leading cause of blindness among working-age adults. Early detection of this condition is critical for good prognosis. In this paper, we demonstrate the use of convolutional neural networks (CNNs) on color fundus images for the recognition task of diabetic retinopathy staging. Our network models achieved test metric performance comparable to baseline literature results, with validation sensitivity of 95%. We additionally explored multinomial classification models, and demonstrate that errors primarily occur in the misclassification of mild disease as normal due to the CNNs inability to detect subtle disease features. We discovered that preprocessing with contrast limited adaptive histogram equalization and ensuring dataset fidelity by expert verification of class labels improves recognition of subtle features. Transfer learning on pretrained GoogLeNet and AlexNet models from ImageNet improved peak test set accuracies to 74.5%, 68.8%, and 57.2% on 2-ary, 3-ary, and 4-ary classification models, respectively. ||||| PURPOSE: To increase the efficiency of retinal image grading, algorithms for automated grading have been developed, such as the IDx-DR 2.0 device. We aimed to determine the ability of this device, incorporated in clinical work flow, to detect retinopathy in persons with type 2 diabetes.
METHODS: Retinal images of persons treated by the Hoorn Diabetes Care System (DCS) were graded by the IDx-DR device and independently by three retinal specialists using the International Clinical Diabetic Retinopathy severity scale (ICDR) and EURODIAB criteria. Agreement between specialists was calculated. Results of the IDx-DR device and experts were compared using sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV), distinguishing between referable diabetic retinopathy (RDR) and vision-threatening retinopathy (VTDR). Area under the receiver operating characteristic curve (AUC) was calculated.
RESULTS: Of the included 1415 persons, 898 (63.5%) had images of sufficient quality according to the experts and the IDx-DR device. Referable diabetic retinopathy (RDR) was diagnosed in 22 persons (2.4%) using EURODIAB and 73 persons (8.1%) using ICDR classification. Specific intergrader agreement ranged from 40% to 61%. Sensitivity, specificity, PPV and NPV of IDx-DR to detect RDR were 91% (95% CI: 0.69-0.98), 84% (95% CI: 0.81-0.86), 12% (95% CI: 0.08-0.18) and 100% (95% CI: 0.99-1.00; EURODIAB) and 68% (95% CI: 0.56-0.79), 86% (95% CI: 0.84-0.88), 30% (95% CI: 0.24-0.38) and 97% (95% CI: 0.95-0.98; ICDR). The AUC was 0.94 (95% CI: 0.88-1.00; EURODIAB) and 0.87 (95% CI: 0.83-0.92; ICDR). For detection of VTDR, sensitivity was lower and specificity was higher compared to RDR. AUC's were comparable.
CONCLUSION: Automated grading using the IDx-DR device for RDR detection is a valid method and can be used in primary care, decreasing the demand on ophthalmologists. ||||| OBJECTIVE: To determine the diagnostic accuracy in a real-world primary care setting of a deep learning-enhanced device for automated detection of diabetic retinopathy (DR).
RESEARCH DESIGN AND METHODS: Retinal images of people with type 2 diabetes visiting a primary care screening program were graded by a hybrid deep learning-enhanced device (IDx-DR-EU-2.1; IDx, Amsterdam, the Netherlands), and its classification of retinopathy (vision-threatening [vt]DR, more than mild [mtm]DR, and mild or more [mom]DR) was compared with a reference standard. This reference standard consisted of grading according to the
RESULTS: A total of 1,616 people with type 2 diabetes were imaged. The hybrid deep learning-enhanced device's sensitivity/specificity against the reference standard was, respectively, for vtDR 100% (95% CI 77.1-100)/97.8% (95% CI 96.8-98.5) and for mtmDR 79.4% (95% CI 66.5-87.9)/93.8% (95% CI 92.1-94.9).
CONCLUSIONS: The hybrid deep learning-enhanced device had high diagnostic accuracy for the detection of both vtDR (although the number of vtDR cases was low) and mtmDR in a primary care setting against an independent reading center. This allows its' safe use in a primary care setting. ||||| IMPORTANCE: Deep learning is a family of computational methods that allow an algorithm to program itself by learning from a large set of examples that demonstrate the desired behavior, removing the need to specify rules explicitly. Application of these methods to medical imaging requires further assessment and validation.
OBJECTIVE: To apply deep learning to create an algorithm for automated detection of diabetic retinopathy and diabetic macular edema in retinal fundus photographs.
Design and Setting: A specific type of neural network optimized for image classification called a deep convolutional neural network was trained using a retrospective development data set of 128 175 retinal images, which were graded 3 to 7 times for diabetic retinopathy, diabetic macular edema, and image gradability by a panel of 54 US licensed ophthalmologists and ophthalmology senior residents between May and December 2015. The resultant algorithm was validated in January and February 2016 using 2 separate data sets, both graded by at least 7 US board-certified ophthalmologists with high intragrader consistency.
EXPOSURE: Deep learning-trained algorithm.
Main Outcomes and Measures: The sensitivity and specificity of the algorithm for detecting referable diabetic retinopathy (RDR), defined as moderate and worse diabetic retinopathy, referable diabetic macular edema, or both, were generated based on the reference standard of the majority decision of the ophthalmologist panel. The algorithm was evaluated at 2 operating points selected from the development set, one selected for high specificity and another for high sensitivity.
RESULTS: The EyePACS-1 data set consisted of 9963 images from 4997 patients (mean age, 54.4 years; 62.2% women; prevalence of RDR, 683/8878 fully gradable images [7.8%]); the Messidor-2 data set had 1748 images from 874 patients (mean age, 57.6 years; 42.6% women; prevalence of RDR, 254/1745 fully gradable images [14.6%]). For detecting RDR, the algorithm had an area under the receiver operating curve of 0.991 (95% CI, 0.988-0.993) for EyePACS-1 and 0.990 (95% CI, 0.986-0.995) for Messidor-2. Using the first operating cut point with high specificity, for EyePACS-1, the sensitivity was 90.3% (95% CI, 87.5%-92.7%) and the specificity was 98.1% (95% CI, 97.8%-98.5%). For Messidor-2, the sensitivity was 87.0% (95% CI, 81.1%-91.0%) and the specificity was 98.5% (95% CI, 97.7%-99.1%). Using a second operating point with high sensitivity in the development set, for EyePACS-1 the sensitivity was 97.5% and specificity was 93.4% and for Messidor-2 the sensitivity was 96.1% and specificity was 93.9%.
CONCLUSIONS AND RELEVANCE: In this evaluation of retinal fundus photographs from adults with diabetes, an algorithm based on deep machine learning had high sensitivity and specificity for detecting referable diabetic retinopathy. Further research is necessary to determine the feasibility of applying this algorithm in the clinical setting and to determine whether use of the algorithm could lead to improved care and outcomes compared with current ophthalmologic assessment. ||||| IMPORTANCE: There is a burgeoning interest in the use of deep neural network in diabetic retinal screening.
BACKGROUND: To determine whether a deep neural network could satisfactorily detect diabetic retinopathy that requires referral to an ophthalmologist from a local diabetic retinal screening programme and an international database.
DESIGN: Retrospective audit.
PARTICIPANTS: Diabetic retinal photos from Otago database photographed during October 2016 (485 photos), and 1200 photos from Messidor international database.
METHODS: Receiver operating characteristic curve to illustrate the ability of a deep neural network to identify referable diabetic retinopathy (moderate or worse diabetic retinopathy or exudates within one disc diameter of the fovea).
MAIN OUTCOME MEASURES: Area under the receiver operating characteristic curve, sensitivity and specificity.
RESULTS: For detecting referable diabetic retinopathy, the deep neural network had an area under receiver operating characteristic curve of 0.901 (95% confidence interval 0.807-0.995), with 84.6% sensitivity and 79.7% specificity for Otago and 0.980 (95% confidence interval 0.973-0.986), with 96.0% sensitivity and 90.0% specificity for Messidor.
CONCLUSIONS AND RELEVANCE: This study has shown that a deep neural network can detect referable diabetic retinopathy with sensitivities and specificities close to or better than 80% from both an international and a domestic (New Zealand) database. We believe that deep neural networks can be integrated into community screening once they can successfully detect both diabetic retinopathy and diabetic macular oedema. ||||| PURPOSE: Use adjudication to quantify errors in diabetic retinopathy (DR) grading based on individual graders and majority decision, and to train an improved automated algorithm for DR grading.
DESIGN: Retrospective analysis.
PARTICIPANTS: Retinal fundus images from DR screening programs.
METHODS: Images were each graded by the algorithm, U.S. board-certified ophthalmologists, and retinal specialists. The adjudicated consensus of the retinal specialists served as the reference standard.
MAIN OUTCOME MEASURES: For agreement between different graders as well as between the graders and the algorithm, we measured the (quadratic-weighted) kappa score. To compare the performance of different forms of manual grading and the algorithm for various DR severity cutoffs (e.g., mild or worse DR, moderate or worse DR), we measured area under the curve (AUC), sensitivity, and specificity.
RESULTS: Of the 193 discrepancies between adjudication by retinal specialists and majority decision of ophthalmologists, the most common were missing microaneurysm (MAs) (36%), artifacts (20%), and misclassified hemorrhages (16%). Relative to the reference standard, the kappa for individual retinal specialists, ophthalmologists, and algorithm ranged from 0.82 to 0.91, 0.80 to 0.84, and 0.84, respectively. For moderate or worse DR, the majority decision of ophthalmologists had a sensitivity of 0.838 and specificity of 0.981. The algorithm had a sensitivity of 0.971, specificity of 0.923, and AUC of 0.986. For mild or worse DR, the algorithm had a sensitivity of 0.970, specificity of 0.917, and AUC of 0.986. By using a small number of adjudicated consensus grades as a tuning dataset and higher-resolution images as input, the algorithm improved in AUC from 0.934 to 0.986 for moderate or worse DR.
CONCLUSIONS: Adjudication reduces the errors in DR grading. A small set of adjudicated DR grades allows substantial improvements in algorithm performance. The resulting algorithm's performance was on par with that of individual U.S. Board-Certified ophthalmologists and retinal specialists. ||||| Purpose: To compare performance of a deep-learning enhanced algorithm for automated detection of diabetic retinopathy (DR), to the previously published performance of that algorithm, the Iowa Detection Program (IDP)-without deep learning components-on the same publicly available set of fundus images and previously reported consensus reference standard set, by three US Board certified retinal specialists.
Methods: We used the previously reported consensus reference standard of referable DR (rDR), defined as International Clinical Classification of Diabetic Retinopathy moderate, severe nonproliferative (NPDR), proliferative DR, and/or macular edema (ME). Neither Messidor-2 images, nor the three retinal specialists setting the Messidor-2 reference standard were used for training IDx-DR version X2.1. Sensitivity, specificity, negative predictive value, area under the curve (AUC), and their confidence intervals (CIs) were calculated.
Results: Sensitivity was 96.8% (95% CI: 93.3%-98.8%), specificity was 87.0% (95% CI: 84.2%-89.4%), with 6/874 false negatives, resulting in a negative predictive value of 99.0% (95% CI: 97.8%-99.6%). No cases of severe NPDR, PDR, or ME were missed. The AUC was 0.980 (95% CI: 0.968-0.992). Sensitivity was not statistically different from published IDP sensitivity, which had a CI of 94.4% to 99.3%, but specificity was significantly better than the published IDP specificity CI of 55.7% to 63.0%.
Conclusions: A deep-learning enhanced algorithm for the automated detection of DR, achieves significantly better performance than a previously reported, otherwise essentially identical, algorithm that does not employ deep learning. Deep learning enhanced algorithms have the potential to improve the efficiency of DR screening, and thereby to prevent visual loss and blindness from this devastating disease. ||||| Artificial Intelligence (AI) has long promised to increase healthcare affordability, quality and accessibility but FDA, until recently, had never authorized an autonomous AI diagnostic system. This pivotal trial of an AI system to detect diabetic retinopathy (DR) in people with diabetes enrolled 900 subjects, with no history of DR at primary care clinics, by comparing to Wisconsin Fundus Photograph Reading Center (FPRC) widefield stereoscopic photography and macular Optical Coherence Tomography (OCT), by FPRC certified photographers, and FPRC grading of Early Treatment Diabetic Retinopathy Study Severity Scale (ETDRS) and Diabetic Macular Edema (DME). More than mild DR (mtmDR) was defined as ETDRS level 35 or higher, and/or DME, in at least one eye. AI system operators underwent a standardized training protocol before study start. Median age was 59 years (range, 22-84 years); among participants, 47.5% of participants were male; 16.1% were Hispanic, 83.3% not Hispanic; 28.6% African American and 63.4% were not; 198 (23.8%) had mtmDR. The AI system exceeded all pre-specified superiority endpoints at sensitivity of 87.2% (95% CI, 81.8-91.2%) (>85%), specificity of 90.7% (95% CI, 88.3-92.7%) (>82.5%), and imageability rate of 96.1% (95% CI, 94.6-97.3%), demonstrating AI's ability to bring specialty-level diagnostics to primary care settings. Based on these results, FDA authorized the system for use by health care providers to detect more than mild DR and diabetic macular edema, making it, the first FDA authorized autonomous AI diagnostic system in any field of medicine, with the potential to help prevent vision loss in thousands of people with diabetes annually. ClinicalTrials.gov NCT02963441. ||||| We have attempted to reproduce the results in Development and validation of a deep learning algorithm for detection of diabetic retinopathy in retinal fundus photographs, published in JAMA 2016; 316(22), using publicly available data sets. We re-implemented the main method in the original study since the source code is not available. The original study used non-public fundus images from EyePACS and three hospitals in India for training. We used a different EyePACS data set from Kaggle. The original study used the benchmark data set Messidor-2 to evaluate the algorithm's performance. We used another distribution of the Messidor-2 data set, since the original data set is no longer available. In the original study, ophthalmologists re-graded all images for diabetic retinopathy, macular edema, and image gradability. We have one diabetic retinopathy grade per image for our data sets, and we assessed image gradability ourselves. We were not able to reproduce the original study's results with publicly available data. Our algorithm's area under the receiver operating characteristic curve (AUC) of 0.951 (95% CI, 0.947-0.956) on the Kaggle EyePACS test set and 0.853 (95% CI, 0.835-0.871) on Messidor-2 did not come close to the reported AUC of 0.99 on both test sets in the original study. This may be caused by the use of a single grade per image, or different data. This study shows the challenges of reproducing deep learning method results, and the need for more replication and reproduction studies to validate deep learning methods, especially for medical image analysis. Our source code and instructions are available at: https://github.com/mikevoets/jama16-retina-replication. ||||| IMPORTANCE: There has been wide interest in using artificial intelligence (AI)-based grading of retinal images to identify diabetic retinopathy, but such a system has never been deployed and evaluated in clinical practice.
OBJECTIVE: To describe the performance of an AI system for diabetic retinopathy deployed in a primary care practice.
Design, Setting, and Participants: Diagnostic study of patients with diabetes seen at a primary care practice with 4 physicians in Western Australia between December 1, 2016, and May 31, 2017. A total of 193 patients consented for the study and had retinal photographs taken of their eyes. Three hundred eighty-six images were evaluated by both the AI-based system and an ophthalmologist.
MAIN OUTCOMES AND MEASURES: Sensitivity and specificity of the AI system compared with the gold standard of ophthalmologist evaluation.
RESULTS: Of the 193 patients (93 [48%] female; mean [SD] age, 55 [17] years [range, 18-87 years]), the AI system judged 17 as having diabetic retinopathy of sufficient severity to require referral. The system correctly identified 2 patients with true disease and misclassified 15 as having disease (false-positives). The resulting specificity was 92% (95% CI, 87%-96%), and the positive predictive value was 12% (95% CI, 8%-18%). Many false-positives were driven by inadequate image quality (eg, dirty lens) and sheen reflections.
CONCLUSIONS AND RELEVANCE: The results demonstrate both the potential and the challenges of using AI systems to identify diabetic retinopathy in clinical practice. Key challenges include the low incidence rate of disease and the related high false-positive rate as well as poor image quality. Further evaluations of AI systems in primary care are needed. ||||| Artificial intelligence (AI) based on deep learning (DL) has sparked tremendous global interest in recent years. DL has been widely adopted in image recognition, speech recognition and natural language processing, but is only beginning to impact on healthcare. In ophthalmology, DL has been applied to fundus photographs, optical coherence tomography and visual fields, achieving robust classification performance in the detection of diabetic retinopathy and retinopathy of prematurity, the glaucoma-like disc, macular oedema and age-related macular degeneration. DL in ocular imaging may be used in conjunction with telemedicine as a possible solution to screen, diagnose and monitor major eye diseases for patients in primary care and community settings. Nonetheless, there are also potential challenges with DL application in ophthalmology, including clinical and technical challenges, explainability of the algorithm results, medicolegal issues, and physician and patient acceptance of the AI 'black-box' algorithms. DL could potentially revolutionise how ophthalmology is practised in the future. This review provides a summary of the state-of-the-art DL systems described for ophthalmic applications, potential challenges in clinical deployment and the path forward. ||||| Diabetic retinopathy (DR) causes blindness in the working age for people with diabetes in most countries. The increasing number of people with diabetes worldwide suggests that DR will continue to be major contributors to vision loss. Early detection of retinopathy progress in individuals with diabetes is critical for preventing visual loss. Non-proliferative DR (NPDR) is an early stage of DR. Moreover, NPDR can be classified into mild, moderate and severe. This paper proposes a novel morphology-based algorithm for detecting retinal lesions and classifying each case. First, the proposed algorithm detects the three DR lesions, namely haemorrhages, microaneurysms and exudates. Second, we defined and extracted a set of features from detected lesions. The set of selected feature emulates what physicians looked for in classifying NPDR case. Finally, we designed an artificial neural network (ANN) classifier with three layers to classify NPDR to normal, mild, moderate and severe. Bayesian regularisation and resilient backpropagation algorithms are used to train ANN. The accuracy for the proposed classifiers based on Bayesian regularisation and resilient backpropagation algorithms are 96.6 and 89.9, respectively. The obtained results are compared with results of the recent published classifier. Our proposed classifier outperforms the best in terms of sensitivity and specificity. ||||| Deep learning is quickly becoming the leading methodology for medical image analysis. Given a large medical archive, where each image is associated with a diagnosis, efficient pathology detectors or classifiers can be trained with virtually no expert knowledge about the target pathologies. However, deep learning algorithms, including the popular ConvNets, are black boxes: little is known about the local patterns analyzed by ConvNets to make a decision at the image level. A solution is proposed in this paper to create heatmaps showing which pixels in images play a role in the image-level predictions. In other words, a ConvNet trained for image-level classification can be used to detect lesions as well. A generalization of the backpropagation method is proposed in order to train ConvNets that produce high-quality heatmaps. The proposed solution is applied to diabetic retinopathy (DR) screening in a dataset of almost 90,000 fundus photographs from the 2015 Kaggle Diabetic Retinopathy competition and a private dataset of almost 110,000 photographs (e-ophtha). For the task of detecting referable DR, very good detection performance was achieved: A<sub>z</sub>=0.954 in Kaggle's dataset and A<sub>z</sub>=0.949 in e-ophtha. Performance was also evaluated at the image level and at the lesion level in the DiaretDB1 dataset, where four types of lesions are manually segmented: microaneurysms, hemorrhages, exudates and cotton-wool spots. For the task of detecting images containing these four lesion types, the proposed detector, which was trained to detect referable DR, outperforms recent algorithms trained to detect those lesions specifically, with pixel-level supervision. At the lesion level, the proposed detector outperforms heatmap generation algorithms for ConvNets. This detector is part of the Messidor® system for mobile eye pathology screening. Because it does not rely on expert knowledge or manual segmentation for detecting relevant patterns, the proposed solution is a promising image mining tool, which has the potential to discover new biomarkers in images. ||||| INTRODUCTION: In April 2018, the US Food and Drug Administration (FDA) approved the world's first artificial intelligence (AI) medical device for detecting diabetic retinopathy (DR), the IDx-DR. However, there is a lack of evaluation systems for DR intelligent diagnostic technology.
METHODS: Five hundred color fundus photographs of diabetic patients were selected. DR severity varied from grade 0 to 4, with 100 photographs for each grade. Following that, these were diagnosed by both ophthalmologists and the intelligent technology, the results of which were compared by applying the evaluation system. The system includes primary, intermediate, and advanced evaluations, of which the intermediate evaluation incorporated two methods. Main evaluation indicators were sensitivity, specificity, and kappa value.
RESULTS: The AI technology diagnosed 93 photographs with no DR, 107 with mild non-proliferative DR (NPDR), 107 with moderate NPDR, 108 with severe NPDR, and 85 with proliferative DR (PDR). The sensitivity, specificity, and kappa value of the AI diagnoses in the primary evaluation were 98.8%, 88.0%, and 0.89, respectively. According to method 1 of the intermediate evaluation, the sensitivity of AI diagnosis was 98.0%, specificity 97.0%, and the kappa value 0.95. In method 2 of the intermediate evaluation, the sensitivity of AI diagnosis was 95.5%, the specificity 99.3%, and kappa value 0.95. In the advanced evaluation, the kappa value of the intelligent diagnosis was 0.86.
CONCLUSIONS: This article proposes an evaluation system for color fundus photograph-based intelligent diagnostic technology of DR and demonstrates an application of this system in a clinical setting. The results from this evaluation system serve as the basis for the selection of scenarios in which DR intelligent diagnostic technology can be applied. ||||| IMPORTANCE: A deep learning system (DLS) is a machine learning technology with potential for screening diabetic retinopathy and related eye diseases.
Objective: To evaluate the performance of a DLS in detecting referable diabetic retinopathy, vision-threatening diabetic retinopathy, possible glaucoma, and age-related macular degeneration (AMD) in community and clinic-based multiethnic populations with diabetes.
Design, Setting, and Participants: Diagnostic performance of a DLS for diabetic retinopathy and related eye diseases was evaluated using 494 661 retinal images. A DLS was trained for detecting diabetic retinopathy (using 76 370 images), possible glaucoma (125 189 images), and AMD (72 610 images), and performance of DLS was evaluated for detecting diabetic retinopathy (using 112 648 images), possible glaucoma (71 896 images), and AMD (35 948 images). Training of the DLS was completed in May 2016, and validation of the DLS was completed in May 2017 for detection of referable diabetic retinopathy (moderate nonproliferative diabetic retinopathy or worse) and vision-threatening diabetic retinopathy (severe nonproliferative diabetic retinopathy or worse) using a primary validation data set in the Singapore National Diabetic Retinopathy Screening Program and 10 multiethnic cohorts with diabetes.
EXPOSURES: Use of a deep learning system.
MAIN OUTCOMES AND MEASURES: Area under the receiver operating characteristic curve (AUC) and sensitivity and specificity of the DLS with professional graders (retinal specialists, general ophthalmologists, trained graders, or optometrists) as the reference standard.
Results: In the primary validation dataset (n = 14 880 patients; 71 896 images; mean [SD] age, 60.2 [2.2] years; 54.6% men), the prevalence of referable diabetic retinopathy was 3.0%; vision-threatening diabetic retinopathy, 0.6%; possible glaucoma, 0.1%; and AMD, 2.5%. The AUC of the DLS for referable diabetic retinopathy was 0.936 (95% CI, 0.925-0.943), sensitivity was 90.5% (95% CI, 87.3%-93.0%), and specificity was 91.6% (95% CI, 91.0%-92.2%). For vision-threatening diabetic retinopathy, AUC was 0.958 (95% CI, 0.956-0.961), sensitivity was 100% (95% CI, 94.1%-100.0%), and specificity was 91.1% (95% CI, 90.7%-91.4%). For possible glaucoma, AUC was 0.942 (95% CI, 0.929-0.954), sensitivity was 96.4% (95% CI, 81.7%-99.9%), and specificity was 87.2% (95% CI, 86.8%-87.5%). For AMD, AUC was 0.931 (95% CI, 0.928-0.935), sensitivity was 93.2% (95% CI, 91.1%-99.8%), and specificity was 88.7% (95% CI, 88.3%-89.0%). For referable diabetic retinopathy in the 10 additional datasets, AUC range was 0.889 to 0.983 (n = 40 752 images).
CONCLUSIONS AND RELEVANCE: In this evaluation of retinal images from multiethnic cohorts of patients with diabetes, the DLS had high sensitivity and specificity for identifying diabetic retinopathy and related eye diseases. Further research is necessary to evaluate the applicability of the DLS in health care settings and the utility of the DLS to improve vision outcomes. ||||| Diabetes is a globally prevalent disease that can cause visible microvascular complications such as diabetic retinopathy and macular edema in the human eye retina, the images of which are today used for manual disease screening and diagnosis. This labor-intensive task could greatly benefit from automatic detection using deep learning technique. Here we present a deep learning system that identifies referable diabetic retinopathy comparably or better than presented in the previous studies, although we use only a small fraction of images (<1/4) in training but are aided with higher image resolutions. We also provide novel results for five different screening and clinical grading systems for diabetic retinopathy and macular edema classification, including state-of-the-art results for accurately classifying images according to clinical five-grade diabetic retinopathy and for the first time for the four-grade diabetic macular edema scales. These results suggest, that a deep learning system could increase the cost-effectiveness of screening and diagnosis, while attaining higher than recommended performance, and that the system could be applied in clinical examinations requiring finer grading. | [
{
"source_pmid": "31194246",
"source_text": "IMPORTANCE: More than 60 million people in India have diabetes and are at risk for diabetic retinopathy (DR), a vision-threatening disease. Automated interpretation of retinal fundus photographs can help support and scale a robust screening program to detect DR.\... |
26966358 | CONCLUSION: This meta-analysis suggests lower cognitive function test scores in patients with AMD, especially with MMSE and Mini-Cog test. The other cognitive impairment screening tests, such as animal fluency test and TMT, need more studies to assess. | Several previous studies showed that age-related macular degeneration (AMD) and Alzheimer's disease (AD) share common risk factors and histopathology changes, and there is epidemiological evidence linking AMD to cognitive impairment. We tested this theory in 51 patients with late-stage AMD and 24 controls by analyzing their neuropsychological profiles. In this study, data showed that patients affected by late-stage AMD have a worse global cognitive function than those of the controls and, in particular, show worse performances in memory tasks. Moreover, patients affected by the dry form of AMD are significantly impaired in executive functions in addition to memory. Data support the hypothesis of a possible association between AMD and cognitive impairment. In particular, patients affected by the dry form of AMD may be at greater risk of developing subsequent dementia. ||||| BACKGROUND: Macular pigment (MP) levels correlate with brain concentrations of lutein (L) and zeaxanthin (Z), and have also been shown to correlate with cognitive performance in the young and elderly.
OBJECTIVE: To investigate the relationship between MP, serum concentrations of L and Z, and cognitive function in subjects free of retinal disease with low MP (Group 1, n = 105) and in subjects with AMD (Group 2, n = 121).
METHODS: MP was measured using customized heterochromatic flicker photometry and dual-wavelength autofluorescence; cognitive function was assessed using a battery of validated cognition tests; serum L and Z concentrations were determined by HPLC.
RESULTS: Significant correlations were evident between MP and various measures of cognitive function in both groups (r = -0.273 to 0.261, p≤0.05, for all). Both serum L and Z concentrations correlated significantly (r = 0.187, p≤0.05 and r = 0.197, p≤0.05, respectively) with semantic (animal) fluency cognitive scores in Group 2 (the AMD study group), while serum L concentrations also correlated significantly with Verbal Recognition Memory learning slope scores in the AMD study group (r = 0.200, p = 0.031). Most of the correlations with MP, but not serum L or Z, remained significant after controlling for age, gender, diet, and education level.
CONCLUSION: MP offers potential as a non-invasive clinical biomarker of cognitive health, and appears more successful in this role than serum concentrations of L or Z. ||||| BACKGROUND/AIM: To compare the cognitive functions and define the frequency of Alzheimer disease (AD) between participants with and without age-related macular degeneration (AMD).
MATERIALS AND METHODS: Fifty-nine patients with late-stage AMD (74.3 ± 7.3 years) and 49 age-, sex-, and education-matched control subjects were compared for the presence of AD according to the guidelines of the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA). Detailed neuropsychological tests were performed for all subjects.
RESULTS: Neuropsychiatric tests scores were lower in the AMD group than the control group. The frequency of AD was higher in patients with AMD (40.7% in AMD and 20.4% in control group, P = 0.03), and particularly higher in late dry (nonvascular) AMD (d-AMD) patients (71.4% in d-AMD and 31.1% in late wet (vascular) AMD, P = 0.007). d-AMD patients performed worse than controls on all tests. There was also an association between age, sex, and low education and neuropsychiatric tests scores (P < 0.01). However, there was no association between visual acuity and neuropsychiatric tests scores.
CONCLUSION: The increased frequency of AD in patients with AMD is significant. This study demonstrated the importance of cognitive assessment in patients with AMD, particularly in the d-AMD type. ||||| PURPOSE: To compare Mini-Cognitive (Mini-Cog) Screening test results between patients with age-related macular degeneration (AMD) and age-matched controls.
PARTICIPANTS: Two hundred and twenty-nine patients were included in the study. Patients were divided into 3 groups: 56 patients with exudative AMD, mean age of 76 ± 8 years; 82 patients with dry AMD, mean age of 77 ± 9 years; and 91 controls, mean age of 75 ± 8 years.
METHODS: The Mini-Cog test, used to screen patients with early cognitive impairment, was introduced to the three groups of patients at the settings of an ophthalmology outpatient clinic. Test scores were compared between the groups.
RESULTS: The mean for the Mini-Cog test scores was 3.5 (95% confidence interval, 3.15-3.85) for the dry AMD group, 3.95 (95% confidence interval, 3.51-4.39) for the exudative AMD group, and 4.63 (95% confidence interval, 4.45-4.80) for the control group. There was no statistically significant difference between the scores of AMD groups, however, both AMD groups received significantly lower scores than controls (P < 0.0001).
CONCLUSION: Patients with age-related macular degeneration in this study demonstrated lower mean scores in the Mini-Cog test than age-matched controls. The Mini-Cog test may be easily applied at an office setting of ophthalmology outpatient clinics, and may help in the early diagnosis of cognitive impairment in the patients with AMD. ||||| It is now established that vitamin A and its derivatives, retinoic acid (RA), are required for cognitive functions in adulthood. RA hyposignaling and hyperactivity of glucocorticoid (GC) pathway appear concomitantly during aging and would contribute to the deterioration of hippocampal synaptic plasticity and functions. Furthermore, recent data have evidenced counteracting effects of retinoids on GC signaling pathway. In the present study, we addressed the following issue: whether the stimulation of RA pathway could modulate intrahippocampal corticosterone (CORT) levels in middle-aged mice and thereby impact on hippocampal plasticity and cognitive functions. We firstly investigated the effects of vitamin A supplementation and RA treatment in middle-aged mice, on contextual serial discrimination task, a paradigm which allows the detection of early signs of age-related hippocampal-dependent memory dysfunction. We then measured intrahippocampal CORT concentrations by microdialysis before and after a novelty-induced stress. Our results show that both RA treatment and vitamin A supplementation improve "episodic-like" memory in middle-aged mice but RA treatment appears to be more efficient. Moreover, we show that the beneficial effect of RA on memory is associated to an increase in hippocampal PSD-95 expression. In addition, intrahippocampal CORT levels are reduced after novelty-induced stress in RA-treated animals. This effect cannot be related to a modulation of hippocampal 11β-HSD1 expression. Interestingly, RA treatment induces a modulation of RA receptors RARα and RARβ expression in middle-aged mice, a finding which has been correlated with the amplitude of intrahippocampal CORT levels after novelty-induced stress. Taken together, our results suggest that the preventive action of RA treatment on age-related memory deficits in middle-aged mice could be, at least in part, due to an inhibitory effect of retinoids on GC activity. ||||| PURPOSE: To investigate cognitive function in patients with early and late age-related macular degeneration (AMD) compared with an elderly, community-dwelling Korean population without AMD.
DESIGN: Case-control study.
PARTICIPANTS: We enrolled 170 AMD patients and 190 non-AMD community-based controls.
METHODS: A comprehensive battery for cognitive function evaluation consisting of 15 psychological tests, including a depression evaluation test, was used. Cognitive function scores were adjusted for age, gender, education, and visual acuity (VA). We categorized AMD as early AMD, exudative AMD, or geographic atrophy.
MAIN OUTCOME MEASURES: The primary outcome measure was the degree of cognitive impairment, as assessed by the Korean versions of the Consortium to Establish a Registry for Alzheimer's Disease Neuropsychological Assessment Battery, Benton Visual Retention Test, and Digit Span Test Forward and Backward.
RESULTS: Patients with AMD showed lower global cognition scores than did normal controls (mean Mini-Mental State Examination [MMSE] score, 24.97 vs 25.99; P<0.001). Among cognitive functions, visuospatial function, verbal memory, visual memory, and frontal function were impaired in AMD patients relative to normal controls. The rate of mild cognitive impairment (MCI) was higher in AMD patients than in controls (52.4% vs 26.8%; P<0.001), with an odds ratio (OR) of 3.127 (95% confidence interval, 1.855-5.271) after adjustment for age, education, and VA. Geographic atrophy was associated with the highest risk of MCI (OR, 4.431; 95% confidence interval, 1.413-13.898) and a clinically significant reduction in MMSE scores (23.42) relative to the controls. There was a trend of worsening cognitive function test scores from the controls to the early AMD, then the exudative AMD, and finally the geographic atrophy patients, after adjustment for covariates. AMD patients with poor VA (≤20/100) had 6 times the risk of MCI as AMD patients with good or moderate VA (>20/100).
CONCLUSIONS: Patients with AMD, especially those with the geographic atrophy subtype, are at greater risk for cognitive impairment than are non-AMD control subjects. In the visual rehabilitation of AMD patients, potential cognitive impairment should be taken into consideration. ||||| Starting from previous studies showing that patients with cognitive deficit present neutral lipids (NLs) accumulation in cytoplasm of their peripheral blood mononuclear cells (PBMCs) and considering that there is epidemiological evidence linking age-related macular degeneration (AMD) to cognitive deficit, the first purpose of this study was to test whether neutral lipids also accumulated in PBMCs from AMD subjects. Moreover, the impact of statin use on AMD was explored and whether such use in AMD subjects was associated with NLs accumulation in PBMCs. The study was conducted on 222 subjects: 136 AMD (36 of which - 26.5% - using statins], 48 cognitive deficit (20 of which - 41.7% - using statins) and 38 healthy controls (4 of which -10.1% - using statins), AMD lesions were assessed from color fundus photographs. Mini-mental state examination (MMSE), demographics, lifestyle factors and medical history were collected at interview. MMSE score was categorized as normal (24-30), and impaired (<24), NLs content was evaluated by oil red 0 (ORO) staining method. ORO determination showed that neutral lipids were generally absent or very low (score between 0 and 1) in healthy controls while most of PBMCs from cognitive deficit and AMD had ORO staining levels scoring 2-4. Post hoc analysis (Bonferroni) in a one-way ANOVA revealed that ORO score was significantly higher in cognitive deficit and AMD subjects compared to healthy controls and in cognitive deficit compared to AMD. Bonferroni-test also showed that AMD subjects had significantly lower total cholesterol (TC) levels compared to healthy controls while high density lipoprotein-cholesterol (HDL-C) did not reach statistical significance. The results also revealed a significant higher number of statin-users in AMD compared to healthy controls. Likewise when cognitive deficit vs healthy controls was analyzed, the number of statin users were found to be significant higher in cognitive deficit than in healthy controls. There were no significant differences in statin use between AMD and cognitive deficit. Compared to healthy controls, statin use in cognitive deficit and AMD groups was significantly associated with ORO scores of 2-4. This data supports the hypothesis that AMD and cognitive deficit share similar complex pathophysiology and risk factors including NLs accumulation in their PBMCs, although this does not necessarily imply that one disease causes the other. In addition, they provide further evidence that statin use may increase the risk of AMD. | [
{
"source_pmid": "24370621",
"source_text": "Several previous studies showed that age-related macular degeneration (AMD) and Alzheimer's disease (AD) share common risk factors and histopathology changes, and there is epidemiological evidence linking AMD to cognitive impairment. We tested this theory in 51 p... |
22307787 | The present meta-analyses indicated that there were no significantly associations between VEGF polymorphisms (rs833061, rs1413711, rs2010963) and the risk of AMD, although the association was different for each polymorphism among different populations. | Age-related macular degeneration (AMD) is the most common cause of blindness in the elderly. Linkage has been shown to the vascular endothelial growth factor (VEGF) gene and ocular levels of VEGF are raised in individuals with the neovascular form of disease. To examine the role of VEGF further, we conducted a case-control study where 45 individuals with neovascular AMD and 94 age-matched controls were genotyped for 14 single nucleotide polymorphisms (SNPs) in the VEGF promoter and gene. The single SNP +674 CC genotype was significantly associated with AMD (OR=2.40, 95%CI 1.09-5.26, P=0.027). Haplotype analysis of SNPs +674, +4618, +5092, +9162 and +9512 revealed that CTCCT and TCACC were associated with AMD (OR=15.77, 95% CI 1.91-130.24, P=0.0161 and OR=9.95, 95%CI 3.22-30.74, P=0.000053, respectively). The haplotype TCACT was associated with the control group (P=0.0001832). Furthermore, haplotype analysis of promoter SNPs revealed that possession of the -460T, -417T, -172C, -165C, -160C, -152G, -141A, -116A, +405C haplotype was strongly associated with AMD (OR=18.24, 95%CI 2.25-148.25, P=0.0074). This is the most extensive analysis of the VEGF gene in AMD, demonstrating a clear association with the exudative form of disease, thereby creating the possibility for predictive testing. Smoking, high fat intake and hypertension are negative environmental risk factors in AMD, whereas increased consumption of dietary antioxidants can have a protective effect. Identification of those at risk in the population would allow individual counselling with lifestyle advice to reduce the risks of blindness. (Genbank accession nos M63971 and AF437895). ||||| PURPOSE: To investigate the association between VEGF gene polymorphism and age-related macular degeneration (AMD) in a Brazilian cohort.
METHODS: We examined 160 affected individuals and 140 sex- and age-matched controls recruited at the Vision Institute and the Retina Department, São Geraldo Hospital, Minas Gerais Federal University, Brazil, between 2007 and 2011. Genotyping for the VEGF rs1413711 single nucleotide polymorphism (SNP) (+674C>T) was performed. The incidence rate ratios and 95% confidence interval (CI) for AMD for this genotype was calculated. The odds ratio (OR) was also assessed by using logistic regression, controlling for CFH and LOC387715 risk genotype.
RESULTS: We observed a prevalence of homozygosity (TT genotype) of 18.1% for rs1413711 among AMD cases compared with 5.8% among controls (P < 0.002). The ORs for this polymorphism were 3.6 (95%CI 1.6-8.2) for homozygous subjects and 1.5 (95%CI 1.1-2.1, P < 0.01) if the subject had at least one risk allele. When we studied separately exudative and dry AMD groups, this polymorphism was statistically significant for both groups. Controlling for CFH and LOC387715 risk genotype the OR was 3.0 for VEGF homozygous, and the OR increases if the patient is homozygous for the three genes.
CONCLUSION: The present data suggests that VEGF TT genotype is associated with AMD among Brazilian patients. ||||| PURPOSE: Age-related macular degeneration (AMD) is the leading cause of poor vision in the developed world, and its pathogenesis remains unknown. The most devastating form of end stage disease is neovascular or wet AMD, where there is abnormal growth of new blood vessels under the retina. Vascular endothelial growth factor (VEGF) is thought to be a major player in the stimulus of this abnormal growth of blood vessels. We undertook a case-control association study to investigate the VEGF-A gene, a known angiogenic gene that has previously been associated with AMD.
METHODS: We recruited 577 individuals with AMD (early, atrophic, and neovascular AMD) and 173 ethnically matched controls for our study. We employed a tag-single nucleotide polymorphisms (tSNP) approach to investigate this gene using a series of seven tSNPs that encompassed the coding region of the VEGF gene as well as its promoter. Alleles were determined by a MALDI-TOF based approach followed by statistical analysis.
RESULTS: One SNP (rs3024997) showed evidence of departure from Hardy-Weinberg equilibrium in only the AMD cases. Therefore, it was retained for further analysis. All other SNPs in our study showed no departure from Hardy-Weinberg equilibrium. No association was found between any of the VEGF tSNPs analyzed in our study and AMD nor any of its sub-types.
CONCLUSIONS: Using a tSNP approach, we found no evidence of an association of these SNPs within the VEGF-A gene being associated with either AMD or any of its subtypes in our population. ||||| The pathogenesis of age-related macular degeneration (AMD) is thought to be determined by an array of environmental and genetic factors. The association of increased expression of vascular endothelial growth factor (VEGF) with AMD, especially the wet form of AMD, was reported in several studies. The VEGF gene is highly polymorphic and some of its polymorphisms may affect its expression. In our work, we searched for an association between the -460C> (rs833061) and -634G>C (rs2010963) polymorphisms of the VEGF gene and the occurrence of AMD and its dry and wet forms. We have chosen these polymorphisms because they were shown to be significant in other studies and we previously showed their association with diabetic retinopathy. A total of 401 individuals were enrolled in this study: 136 controls, and 88 patients with dry and 177 with wet AMD. The polymorphisms were determined with DNA from peripheral blood lymphocytes by allele-specific and restriction fragment length polymorphism polymerase chain reaction. The significance of the polymorphisms was assessed by multiple logistic regression, producing odds ratios (ORs) and 95% confidence intervals (CIs). We observed a weak association (OR 2.90) between AMD occurrence and the C/T genotype of the -460C>T polymorphism. An association (OR 3.77) between the C/T genotype of the -460C>T polymorphism and the occurrence of dry AMD was observed. The T/T genotype considerably lowered the risk of dry AMD (OR 0.19). Dry AMD was associated with the C/C genotype of the -634G>C polymorphism (OR 3.68). Another weak association (OR 2.63) was found between the C/T genotype of the -460C>T polymorphism and the occurrence of wet AMD. The occurrence of AMD was correlated with the presence of the combined C/T-G/G genotype of both polymorphisms (OR 2.41), whereas the T/T-G/G and T/T-G/C genotypes exerted a protective effect against the disease (OR 0.22 and 0.48, respectively). The presence of the C/T-G/G and C/T-C/C combined genotypes increased the risk of dry AMD (OR 2.08 and 3.77, respectively), whereas the presence of the T/T-G/G and T/T-G/C genotypes decreased the risk (OR 0.15 and 0.28, respectively). In the wet form of AMD, the combined genotype C/T-G/G slightly favored the disease (OR 2.61) and the T/T-G/G genotype had a protective effect (OR 0.25). Analysis of haplotypes of both polymorphisms yielded similar results for AMD in general as well as for the dry and wet forms of the disease: the CG haplotype favored both forms of AMD, whereas the TG haplotype protected against both forms of AMD. The results obtained indicate that the -460C>T and -634G>C polymorphisms of the VEGF gene may be associated with the dry and wet forms of AMD in a Polish population. ||||| PURPOSE: To assess the association between genotypes and alleles of the C-460T polymorphism of the vascular endothelial growth factor (VEGF) gene and the risk of wet form of age-related macular degeneration (AMD).
MATERIALS AND METHODS: 100 patients with clinically diagnosed wet form of AMD and 104 healthy individuals were enrolled in this study. The patients were diagnosed by optical coherence tomography, fluorescein angiography and indocyanin green angiography. The allele-specific polymerase chain reaction was used to determine the genotypes of the C-460T polymorphism of the VEGF gene. The odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using a logistic regression model to assess the assoctiation betweeen genotypes of the C-460T polymorphism and AMD occurrence.
RESULTS: A difference was observed in the genotype distributions between patients and controls. An association (OR 3.04, 95% CI 1.65-5.60) was found between wet form of AMD and the C/T genotype. On the other hand, the T/T genotype displayed the protective effect against the disease.
CONCLUSION: The C-460T polymorphism of the endothelial growth factor can be considered as a potential marker for the wet form of age-related macular degeneration. ||||| PURPOSE: Vascular endothelial growth factor (VEGF) is an important regulator of angiogenesis and a target for inhibition therapy in wet age-related macular degeneration (AMD). The purpose of this study was to examine whether genetic variation in the VEGF gene is associated with AMD and, especially, with its wet end stage.
DESIGN: Prospective population-based cohort study.
PARTICIPANTS: Four thousand two hundred twenty-eight participants aged 55 years and older.
METHODS: AMD was classified according to a modified International Classification System using fundus color images. Genotypes and haplotypes were determined for 3 functional VEGF single nucleotide polymorphisms (SNPs): C-2578A, G-1154A, and G-634C. Cox proportional hazards regression analyses were used to investigate possible associations between the individual SNPs and incident AMD. The Haplo.Stats program was used to test the associations between VEGF gene haplotypes and incident AMD.
MAIN OUTCOME MEASURE: AMD RESULTS: Of 4228 participants at risk for incident early and late AMD for whom blood specimens were available for VEGF genotyping, incident early AMD developed in 514 and incident late AMD developed in 89 (35 dry and 54 wet) after a mean follow-up of 7.4 years. None of the SNPs showed a significant association with incident early or late AMD, especially not with incident wet AMD. Haplotype analyses also detected no associations.
CONCLUSIONS: The a priori hypothesis that 3 common SNPs in the VEGF gene would be a risk factor for AMD, especially the wet form, could not be confirmed. ||||| PURPOSE: Genetic factors influence an individual's risk for developing neovascular age-related macular degeneration (AMD), a leading cause of irreversible blindness. Previous studies on the potential genetic link between AMD and vascular endothelial growth factor (VEGF), a key regulator of angiogenesis and vascular permeability, have yielded conflicting results. In the present case-control association study, we aimed to determine whether VEGF or its main receptor tyrosine kinase VEGFR-2 is genetically associated with neovascular AMD.
METHODS: A total of 515 Caucasian patients with neovascular AMD and 253 ethically-matched controls were genotyped for polymorphisms in the VEGFA and VEGFR-2 genes. A tagging single nucleotide polymorphism (tSNP) approach was employed to cover each gene plus two kilobases on each side, spanning the promoter and 3' untranslated regions. SNPs with a minimum allele frequency of 10% were covered by seven tSNPs in VEGFA and 20 tSNPs in VEGFR-2. Two VEGFA SNPs previously linked with AMD, rs1413711 and rs3025039, were also analyzed.
RESULTS: The 29 VEGFA and VEGFR-2 SNPs analyzed in our cohort demonstrated no significant association with neovascular AMD. A single rare haplotype in the VEGFR-2 gene was associated with the presence of neovascular AMD (p=0.034).
CONCLUSIONS: This study is the first to investigate the association of VEGFR-2 polymorphisms with AMD and evaluates VEGFA genetic variants in the largest neovascular AMD cohort to date. Despite the angiogenic and permeability-enhancing effects of VEGF/VEGFR-2 signaling, we found minimal evidence of a significant link between polymorphisms in the VEGFA and VEGFR-2 genes and neovascular AMD. ||||| AIMS: To evaluate the association between vascular endothelial growth factor (VEGF) gene polymorphism and the risk of neovascular age-related macular degeneration (AMD) in a case-control study in a Chinese cohort.
METHODS: We genotyped 4 common single-nucleotide polymorphisms (SNPs), namely -460T/C (rs833061), +405C/G (rs2010963), +674C/T (rs1413711) and +936C/T (rs3025039), simultaneously detected 7 tag SNPs (tSNPs) in the VEGF gene, in 159 neovascular AMD patients and 140 age- and sex-matched control subjects. Genetic analyses for an additive, dominant and recessive model were performed on all available genotype data. All the possible haplotypes of these 11 SNPs were detected.
RESULTS: No evident association was found in the allele frequencies of any individual SNP between patients and controls; the combined p values in each genotype group were greater than 0.05. Haplotype analyses of these SNPs did not provide any evidence for an association with the risk of neovascular AMD in this Chinese cohort (p > 0.05).
CONCLUSIONS: Detection of 4 common SNPs and 7 tSNPs in the VEGF gene did not find any statistically significant association with neovascular AMD in the Chinese cohort. Further studies of comprehensive VEGF gene variations are required to characterize the susceptibility of the VEGF gene in the pathogenesis of AMD. ||||| PURPOSE: To investigate vascular endothelial growth factor (VEGF) gene polymorphisms in unrelated Taiwan Chinese patients with late age-related macular degeneration (AMD) and controls.
DESIGN: Retrospective case-control study.
METHODS: We enrolled 190 late AMD patients and 180 age-matched and gender-matched controls. Late AMD was classified as either dry (atrophic; grade 4) or wet (neovascular; grade 5) according to the International Age-Related Maculopathy Epidemiologic Study. Genomic deoxyribonucleic acid was prepared from peripheral blood obtained from all subjects. Polymerase chain reactions were used to analyze five candidate single-nucleotide polymorphisms (SNPs) in VEGF gene: +405C/G (rs2010963), -460 T/C (rs833061), +674 C/T (rs1413711), +936C/T (rs3025039), and -2578C/A (rs699947).
RESULTS: Of the 190 late AMD patients, dry AMD was diagnosed in 104 and wet AMD in 86. Among the five candidate SNPs studied, only the +936 C/T was significantly associated with wet AMD (T allele: 30% in wet AMD vs 14% in controls; P = 1.45 x 10(-5); odds ratio, 2.61; 95% confidence interval, 1.68 to 4.07). No single haplotype was significantly associated with either late AMD or controls. Based on genotypes at both VEGF +936 C/T and the complement factor H (CFH) Y402H (rs1061170), the association of VEGF +936 C/T to AMD was significant when analyzed conditional on the presence of the CFH C risk allele and vice versa (P < .0001). The VEGF +936 C/T was in strong linkage disequilibrium with CFH Y402H (D' = 0.99).
CONCLUSIONS: Both VEGF +936 C/T and CFH Y402H polymorphisms are dependently associated with wet AMD in the Taiwan Chinese population. | [
{
"source_pmid": "16940309",
"source_text": "Age-related macular degeneration (AMD) is the most common cause of blindness in the elderly. Linkage has been shown to the vascular endothelial growth factor (VEGF) gene and ocular levels of VEGF are raised in individuals with the neovascular form of disease. To ... |
19019922 | CONCLUSIONS: According to available data, the use of latanoprost is associated with a lower incidence of conjunctival hyperaemia when compared with travoprost and bimatoprost in the treatment of patients with ocular hypertension or glaucoma. | PURPOSE: To compare the intraocular pressure (IOP) lowering effect and safety of latanoprost, travoprost given every evening, and the fixed combination dorzolamide + timolol (DTFC) given twice daily in pseudoexfoliation glaucoma (PXG).
METHODS: This randomized, prospective, investigator-masked study has been conducted with 50 PXG patients. Patients were assigned to one of three groups: travoprost 0.004%, fixed combination of dorzolamide 2%+timolol 0.5%, or latanoprost 0.005% for 6 months. At baseline and 0.5, 1, 2, 3, 4, 5, and 6 months of therapy, IOP (8 am, 10 am, 4 pm), blood pressures, and pulse rates were measured, and ophthalmologic examination was performed. The side effects were recorded at each visit.
RESULTS: Forty-two of the 50 patients initially enrolled completed this study. Withdrawn patients included one (latanoprost) for lack of efficacy, five (three travoprost, one latanoprost, one DTFC) for adverse events, and two (one latanoprost, one DTFC) for loss of follow-up. Each of the three drugs considerably reduced the IOP in PXG cases throughout the 6 months. Mean IOP reduction at 6 months was -9.3+/-2.9 mmHg in the travoprost group, -8.2+/-1.2 mmHg in the latanoprost group, and 11.5+/-3.3 mmHg in the DTFC group. Comparing the groups, DTFC is more effective than latanoprost and travoprost in lowering IOP (p<0.05). There was no difference between travoprost and latanoprost. The most common treatment-related adverse event was conjunctival hyperemia. Intensity of ocular hyperemia was greater in the travoprost group compared with the latanoprost and DTFC groups (p<0.05). There were no significant effects on systemic safety parameters.
CONCLUSIONS: The results demonstrated that DTFC is more effective in reducing IOP than latanoprost and travoprost. Latanoprost and travoprost had similar ocular hypotensive effects in patients with PXG. All three drugs were well tolerated; there were fewer ocular side effects attributable in the latanoprost group. ||||| PURPOSE: This study evaluated the safety and intraocular pressure-lowering efficacy of two concentrations of travoprost (0.0015% and 0.004%) compared with latanoprost 0.005% and timolol 0.5% in patients with open-angle glaucoma or ocular hypertension.
METHODS: Eight hundred one patients with open-angle glaucoma or ocular hypertension were randomly assigned to travoprost 0.0015%, travoprost 0.004%, latanoprost 0.005%, or timolol 0.5%. The efficacy and safety of travoprost (0.0015% and 0.004%) daily was compared with latanoprost daily and timolol twice daily for a period of 12 months.
RESULTS: Travoprost was equal or superior to latanoprost and superior to timolol with mean intraocular pressure over visits and time of day ranging from 17.9 to 19.1 mm Hg (travoprost 0.0015%), 17.7 to 19.1 mm Hg (travoprost 0.004%), 18.5 to 19.2 mm Hg (latanoprost), and 19.4 to 20.3 mm Hg (timolol). For all visits pooled, the mean intraocular pressure at 4 PM for travoprost was 0.7 mm Hg (0.0015%, P =.0502) and 0.8 mm Hg (0.004%, P =.0191) lower than for latanoprost. Travoprost 0.004% was more effective than latanoprost and timolol in reducing intraocular pressure in black patients by up to 2.4 mm Hg (versus latanoprost) and 4.6 mm Hg (versus timolol). Based on a criterion of 30% or greater intraocular pressure reduction from diurnal baseline or intraocular pressure 17 mm Hg or less, travoprost 0.0015% and 0.004% had an overall response to treatment of 49.3% and 54.7%, respectively, compared with 49.6% for latanoprost and 39.0% for timolol. Iris pigmentation change was observed in 10 of 201 of patients (5.0%) receiving travoprost 0.0015%, six of 196 of patients (3.1%) receiving travoprost 0.004%, 10 of 194 of patients (5.2%) receiving latanoprost, and none of the patients receiving timolol (0 of 196). The average ocular hyperemia score was less than 1 on a scale of 0 to 3, indicating that on average patients experienced between none/trace and mild for all treatment groups. There were no serious, unexpected, related adverse events reported for any therapy.
CONCLUSIONS: Travoprost (0.0015% and 0.004%), a highly selective, potent prostaglandin F (FP) receptor agonist, is equal or superior to latanoprost and superior to timolol in lowering intraocular pressure in patients with open-angle glaucoma or ocular hypertension. In addition, travoprost 0.004% is significantly better than either latanoprost or timolol in lowering intraocular pressure in black patients. Travoprost is safe and generally well tolerated in the studied patient population. ||||| AIM: To evaluate the diurnal intraocular pressure (IOP) control and safety of bimatoprost versus latanoprost in exfoliative glaucoma (XFG).
METHODS: One eye of 129 consecutive patients with XFG (mean (SD) age 66.5 (8.3) years) was included in this prospective, observer-masked, three-centre, crossover comparison. After a 4-6 week medicine-free period patients were randomised to bimatoprost or latanoprost monotherapy for 3 months. Patients were then switched to the opposite treatment for another 3 months. At the end of the washout and the treatment periods diurnal IOP was measured at 0800, 1300, and 1800.
RESULTS: At baseline the IOP (mean (SD)) was 28.0 (4.0), 26.9 (3.6), and 25.9 (3.6) mm Hg, at the three time points, respectively. Both treatments significantly reduced mean diurnal IOP at month 3. Mean diurnal IOP was 26.9 (3.5) mm Hg at baseline, 17.6 (3.3) mm Hg with bimatoprost, and 18.6 (3.6) mm Hg with latanoprost (p<0.0001). Furthermore, lower IOP values were obtained with bimatoprost at all time points (17.9 (3.4), 17.3 (3.3), and 17.6 (3.5) mm Hg, respectively) compared with latanoprost (18.7 (3.6), 18.5 (3.6), and 18.6 (4.1) mm Hg, respectively). The corresponding mean differences (0.8, 1.1, and 1.0 mm Hg, respectively) were all significant (p<0.001 for each comparison). Significantly more patients with XFG obtained a target diurnal IOP <17 mm Hg with bimatoprost than with latanoprost, 55/123 (45%) v 34/123 (28%); (p = 0.001), and significantly fewer patients were non-responders with bimatoprost than with latanoprost (5 v 13, p = 0.021). More patients reported at least one adverse event with bimatoprost than with latanoprost (58 v 41 at 3 months; p = 0.0003).
CONCLUSION: This crossover study suggests that better diurnal IOP control is obtained with bimatoprost than with latanoprost in patients with XFG. ||||| PURPOSE: To compare the efficacy and safety of once-daily (QD) bimatoprost, latanoprost, and timolol gel-forming solution in providing 24-hour intraocular pressure (IOP) control.
DESIGN: This was a randomized, multicenter, investigator-masked, prospective, parallel-group, clinical trial.
PARTICIPANTS: Patients with open-angle glaucoma or ocular hypertension.
INTERVENTION: After washout of any previous ocular hypotensive medications, patients were randomly assigned to treatment with bimatoprost 0.03% ophthalmic solution QD (n=38) or latanoprost 0.005% ophthalmic solution QD (n=38) between 7 and 9 pm, or timolol maleate 0.5% gel-forming ophthalmic solution QD (n=39) between 7 and 9 am for 1 month.
MAIN OUTCOME MEASURES: The primary outcome measure, circadian IOP, was measured at eight time points over the course of 24 hours beginning at 8 am on day 28 and with the last measurement at 8 am on day 29. IOP was also measured at 8 am and 10 am at baseline and at 8 am on day 14. Safety measures included adverse events, biomicroscopy, visual acuity, heart rate, and blood pressure.
RESULTS: At 10 am (peak drug effect) on day 28, the mean IOP reduction from baseline was significantly greater with bimatoprost (9.3 mm Hg, 40.3%) than with timolol gel (7.1 mm Hg, 31.1%; P=.024, Wilcoxon rank sum test) or latanoprost (7.4 mm Hg, 33.3%). In the overall analysis of IOP measured over the course of 24 hours, mean IOP was significantly lower with bimatoprost or latanoprost than with timolol gel (P<.001; analysis of repeated measures). The analysis of repeated measures also showed a significant difference between bimatoprost and latanoprost (P=.003). In the area-under-the-curve analysis, bimatoprost and latanoprost were superior to timolol gel (P< or =.018) but comparable to each other (P> or =.223). All treatment regimens were well tolerated, with few discontinuations due to adverse events. There were no significant effects on systemic safety parameters.
CONCLUSION: Once-daily bimatoprost or latanoprost provided significantly better 24-hour IOP control than timolol gel in patients with glaucoma or ocular hypertension. Some measurements suggested a trend for greater efficacy of bimatoprost over latanoprost. All three treatments were well tolerated. ||||| A multicenter, randomized, investigator-masked, parallel-group trial compared bimatoprost and latanoprost for efficacy and safety in patients with glaucoma or ocular hypertension. Patients received bimatoprost 0.03% (n = 119) or latanoprost 0.005% (n = 113) once daily in the evening for 3 months. Visits were at prestudy, baseline (day 0), week 1, and months 1, 2, and 3. Primary outcome measures were mean IOP and the percentage of patients achieving IOP of 17 mm Hg or lower at 8:00 AM. Secondary outcome measures were diurnal IOP measurements (8:00 AM, 12 noon, 4:00 PM, 8:00 PM) at month 3 and safety measures including adverse events. Mean IOP was lower with bimatoprost than with latanoprost at all time points during the 3-month follow-up, although the between-group difference was not always statistically significant. At month 3 at 12 noon, mean IOP was as much as 1.0 mm Hg lower with bimatoprost (P = .021). Target pressures of < or = 17 mm Hg were reached more often with bimatoprost than with latanoprost at 8:00 AM (53% vs 43%; P = .029). Over all diurnal measurements at month 3, low target pressures of < or = 13, < or = 14, and < or = 15 mm Hg were achieved significantly more often with bimatoprost (P < or = .006). Both drugs were safe and well tolerated. Conjunctival hyperemia was more common with bimatoprost, while headache was more frequent with latanoprost. Bimatoprost provided lower mean pressures than latanoprost at every time point throughout the study and was statistically superior in achieving low target pressures. More patients reached low target pressures with bimatoprost. ||||| PURPOSE: To Internet Advance publication at ajo.com Feb 13, 2003. compare the intraocular pressure (IOP)-lowering effect and safety of latanoprost, bimatoprost, and travoprost in patients with open-angle glaucoma (OAG) or ocular hypertension (OH).
DESIGN: Interventional study.
METHODS: This 12-week, randomized, parallel-group study was conducted at 45 US sites. Previously treated patients with OAG or OH and an IOP > or =23 mm Hg in one or both eyes after washout received either latanoprost 0.005%, bimatoprost 0.03%, or travoprost 0.004% once daily in the evening. At baseline and after 6 and 12 weeks of therapy, masked evaluators measured IOP in triplicate at 8:00 AM, 12 noon, 4:00 PM, and 8:00 PM, and masked investigators graded conjunctival hyperemia before the 8:00 AM IOP measurement. The primary efficacy outcome measure was change between baseline and Week 12 in the 8:00 AM IOP (time of peak drug effect).
RESULTS: In all, 410 of 411 randomized patients were included in intent-to-treat analyses (latanoprost, 136; bimatoprost, 136; travoprost, 138). Baseline mean 8:00 AM IOP levels were similar (P =.772); by week 12, reductions were observed in all 3 groups (P <.001 for each). Adjusted (ANCOVA) reductions in mean IOP at 8:00 AM were similar (P =.128) as were those at 12 noon, 4:00 PM, and 8:00 PM. Fewer latanoprost-treated patients reported ocular adverse events (P <.001, latanoprost vs bimatoprost), fewer reported hyperemia (P =.001, latanoprost vs bimatoprost), and average hyperemia scores were lower at week 12 (P =.001, latanoprost vs bimatoprost).
CONCLUSIONS: Latanoprost, bimatoprost, and travoprost were comparable in their ability to reduce IOP in OAG and OH patients. Latanoprost exhibited greater ocular tolerability. ||||| OBJECTIVE: To evaluate 24-hour intraocular pressure (IOP) efficacy of latanoprost versus travoprost, each given every evening, in exfoliative glaucoma patients.
DESIGN: Prospective, observer-masked, crossover comparison.
PARTICIPANTS: Forty patients with exfoliation glaucoma.
METHODS: Patients with a pressure of >24 mmHg were randomized to latanoprost or travoprost for an 8-week treatment period after a 6-week medicine-free period. Patients were then switched to the opposite treatment for the second period. At untreated baseline and at the end of each treatment period the IOP was measured at 6 am, 10 am, 2 pm, 6 pm, 10 pm, and 2 am.
MAIN OUTCOME MEASURE: Diurnal IOP.
RESULTS: The mean 24-hour IOP was 25.1+/-2.5 mmHg at baseline, 17.8+/-2.1 mmHg on latanoprost, and 17.3+/-2.2 mmHg on travoprost (P = 0.001). Individual time points were similar between treatments, except at 6 pm when travoprost provided lower IOP (16.7+/-2.6 vs 17.9+/-2.5 mmHg, P<0.001). Adverse events showed more conjunctival hyperemia with travoprost (n = 15) than latanoprost (n = 6; P = 0.03).
CONCLUSIONS: Latanoprost and travoprost both significantly reduce the 24-hour IOP from baseline in exfoliative glaucoma, but travoprost may demonstrate a greater hypotensive efficacy in the late afternoon. ||||| PURPOSE: The primary objective of this study was to determine the intraocular pressure- (IOP) lowering efficacy over two consecutive 24-h periods of travoprost 0.004% ophthalmic solution (Travatan) compared to latanoprost 0.005% (Xalatan) dosed once daily in patients with primary open-angle glaucoma or ocular hypertension.
METHODS: This was a double-masked trial conducted at the Hospital Clínico San Carlos, Madrid, Spain. The primary objective of this study was to determine the IOP lowering efficacy of travoprost and latanoprost. During the eligibility visit, patients' IOP was measured throughout two consecutive 24-h periods every 4 h. Patients were then randomized to travoprost or latanoprost (one drop at 8 p.m. daily for 2 weeks). Sixty-two patients were randomized (travoprost n = 32; latanoprost n = 30). IOP was measured at week 2 every 4 h throughout two 24-h periods. All measurements were taken in both supine and sitting positions with the aid of Perkins applanation tonometry. Limitations of the study include a small sample size (due to the difficulty in recruiting patients in a study of this type) which enrolled only Caucasian patients and a short study duration. However, with 25 subjects per group, there was at least 90% power to detect a mean IOP change from baseline of 2.9 mmHg and 80% power to detect a difference of 2.5 mmHg between treatments.
RESULTS: Patients on travoprost therapy showed lower mean IOP levels than those on latanoprost. This difference was statistically significant (p < 0.05) at 12, 16, 20, 24, 36, 40, and 48 h after the last dose for the supine position. The mean IOPs in the supine position throughout the first and the second 24-h period of the week 2 visit as well as for the 48-h visit were statistically lower (p < 0.05) for the travoprost group. Adverse events were mild and included hyperemia and corneal staining. Travoprost and latanoprost were both well tolerated.
CONCLUSION: Mean IOP values were significantly lower for patients on travoprost for the majority of time points in the supine position. ||||| This multicenter, randomized, double-blind clinical trial was undertaken to compare the intraocular pressure (IOP)-lowering efficacy and safety of topical bimatoprost 0.03% with that of latanoprost 0.005% for the treatment of patients with normal-tension glaucoma. After washout of all ocular hypotensive medications, patients with normal-tension glaucoma (n=60) were randomly assigned to oncedaily bimatoprost 0.03% or latanoprost 0.005% for 3 mo. Diurnal IOP measurements were taken at each study visit. Primary outcome measures consisted of mean change from baseline IOP (8 AM, Noon, 4 PM) and change in visual field. Secondary measures included mean IOP, ophthalmologic examination findings, results of clinical evaluation, and adverse events. Mean change from baseline IOP at each study visit was statistically significant at all diurnal measurements for patients taking bimatoprost and for those taking latanoprost (P<.001). The 8 AM mean change from baseline IOP measurement showed a significant between-group difference (P< or =.033) in favor of bimatoprost at both follow-up visits. After 3 mo of treatment, mean IOP reductions from baseline ranged from 2.8 to 3.8 mm Hg (17.5%-21.6%) with bimatoprost and from 2.1 to 2.6 mm Hg (12.7%-16.2%) with latanoprost. Overall mean reduction in IOP after 3 mo of treatment was 3.4 mm Hg (19.9% rpar; with bimatoprost and 2.3 mm Hg (14.6%) with latanoprost (P=.035). No significant between-group differences were observed in incidence of adverse events, clinical success, or demographic variables. Bimatoprost was found to be more effective than latanoprost in lowering IOP in the patient with normal-tension glaucoma. Both drugs were efficacious and well tolerated. ||||| PURPOSE: To compare the intraocular pressure (IOP)-lowering efficacy and safety of topical bimatoprost 0.03% with latanoprost 0.005%.
DESIGN: Multicenter, randomized, investigator-masked clinical trial.
METHODS: After washout of glaucoma medications, ocular hypertension or glaucoma patients were randomly assigned to once-daily bimatoprost 0.03% (n = 133) or latanoprost 0.005% (n = 136) for 6 months. The primary outcome measure was mean change from baseline IOP (8 AM, 12 PM, 4 PM). Secondary measures included mean IOP, ophthalmologic examination, adverse events, and the percentage of patients reaching specific target IOPs.
RESULTS: Mean change from baseline IOP was significantly greater for bimatoprost patients than for latanoprost patients at all measurements on each study visit; 1.5 mm Hg greater at 8 AM (P <.001), 2.2 mm Hg greater at 12 PM (P <.001), and 1.2 mm Hg greater at 4 PM (P =.004) at month 6. At the end of the study, the percentage of patients achieving a > or = 20% IOP decrease was 69% to 82% with bimatoprost and 50% to 62% with latanoprost (P < or = .003). In addition, the distribution of patients achieving target pressures in each range (< or = 13 to < or = 15 mm Hg, >15 to < or = 18 mm Hg, and > 18 mm Hg) showed that bimatoprost produced lower target pressures compared with latanoprost at all times measured (P < or = .026). Few patients were discontinued for adverse events (6 on bimatoprost; 5 on latanoprost). On ophthalmologic examination, conjunctival hyperemia (P <.001) and eyelash growth (P =.064) were more common in bimatoprost patients.
CONCLUSIONS: Bimatoprost is more effective than latanoprost in lowering IOP. Both drugs were well tolerated, with few discontinuations for adverse events. ||||| PURPOSE: The aim of this study was to compare the intraocular pressure (IOP)-lowering effect of latanoprost and travoprost as primary therapy in patients with chronic angle-closure glaucoma (CACG) after peripheral iridotomy.
METHODS: Seventy-three (73) CACG patients with IOP>19 mmHg after peripheral iridotomy and without previous antiglaucoma medication were consecutively recruited. CACG was defined as the presence of chronically elevated IOP, glaucomatous optic neuropathy, and a corresponding visual field defect in eyes with occludable angle and peripheral anterior synechiae on gonioscopy. Patients were randomly assigned to 2 groups, based on daily treatment with either latanoprost 0.005% or travoprost 0.004% in the evening for 12 weeks. The IOP was measured at 9 AM and 4 PM at baseline and at 4, 8, and 12 weeks. Between-group differences in mean diurnal IOP and IOP reduction were analyzed.
RESULTS: After 12 weeks of treatment, mean IOP for both the latanoprost and travoprost groups was significantly reduced, when compared to the baseline IOP (from 21.3+/-1.8 mmHg to 16.0+/-2.3 mmHg and 21.7+/-1.7 to 16.7+/-2.2 mmHg; P<0.001 for both). There was no significant difference in IOP reduction between the 2 treatment groups (P=0.19). At 4 and 8 weeks, the IOP changes from the baseline were statistically significant at all time points for both drugs (all P<0.001).
CONCLUSIONS: Both latanoprost and travoprost significantly reduced IOP in our sample of CACG patients after peripheral iridotomy. ||||| PURPOSE: To compare the safety and efficacy of bimatoprost and latanoprost in patients with primary open-angle glaucoma or ocular hypertension.
METHODS: This was a 30-day, multicenter, double-masked, randomized, clinical trial. Patients (n = 64) diagnosed with primary open-angle glaucoma or ocular hypertension were randomly assigned to receive bimatoprost 0.03%, latanoprost 0.005%, or vehicle topically in both eyes once daily, in the evening, for 29 days. The primary endpoint was the reduction in IOP from baseline on day 14 and day 29. Secondary outcome measures included eye examinations and safety parameters.
RESULTS: Bimatoprost and latanoprost significantly lowered IOP from baseline (p <.001). Bimatoprost lowered IOP more than latanoprost at every timepoint measured (bimatoprost: 25-34% reduction, 5.9-8.9 mm Hg; latanoprost: 20-31% reduction, 4.4-7.9 mm Hg), although the between-group differences did not reach statistical significance. Over the 12-hour course of IOP measurements on day 29, bimatoprost provided better diurnal IOP control than latanoprost (p =.0378, area under the curve of diurnal IOP reductions, 1-way ANOVA with pairwise t-test). Both treatment regimens were safe and well tolerated, with no significant between-group differences in reports of specific adverse events. The most common side effect was conjunctival hyperemia, which was similarly apparent in the bimatoprost and latanoprost treatment groups.
CONCLUSIONS: At the end of this 30-day trial, once-daily bimatoprost 0.03% provided better diurnal IOP control than latanoprost and was safe and well tolerated in patients with ocular hypertension and glaucoma. ||||| OBJECTIVE: To evaluate latanoprost versus bimatoprost given each evening over the 24-hour diurnal curve.
DESIGN: Double-masked, 2-center, crossover comparison.
PARTICIPANTS: Forty-two of 44 patients with primary open-angle glaucoma (POAG) completed the study.
METHODS: Consecutive patients were not treated during a baseline 24-hour curve after a glaucoma medicine-free period. They then were randomized to either latanoprost or bimatoprost for a 7-week treatment period. Diurnal curve intraocular pressures (IOPs) were measured at treatment period end at 2 am, 6 am, 10 am, 2 pm, 6 pm, and 10 pm. After the first treatment period, patients were changed to the opposite medicine without a medicine-free period. Diurnal curve measurements were performed again at the end of the second 7-week treatment period.
MAIN OUTCOME MEASURE: The 24-hour diurnal IOP.
RESULTS: On the last day of treatment, mean 24-hour IOPs were 17.3+/-2.8 mmHg for latanoprost and 16.7+/-2.4 mmHg for bimatoprost (P = 0.01). The 6 pm individual time point for IOP was statistically lower for bimatoprost after a Bonferroni correction (P = 0.008). The largest IOP difference at any time point was 0.9 mmHg at 6 pm. The most common side effect was conjunctival hyperemia, which occurred less with latanoprost (n = 6) than with bimatoprost (n = 15) (P = 0.004). Two patients had their treatments discontinued while on bimatoprost, one due to conjunctival hyperemia and the other due to ocular intolerance.
CONCLUSION: This study indicates that the 24-hour diurnal IOP is statistically lower in POAG with bimatoprost, compared with latanoprost, among patients who tolerated bimatoprost. However, the IOP difference between groups was small and may not be clinically meaningful. In contrast, conjunctival hyperemia seems statistically greater with bimatoprost. The exact clinical importance of conjunctival hyperemia, if any, needs to be clarified further. | [
{
"source_pmid": "16496249",
"source_text": "PURPOSE: To compare the intraocular pressure (IOP) lowering effect and safety of latanoprost, travoprost given every evening, and the fixed combination dorzolamide + timolol (DTFC) given twice daily in pseudoexfoliation glaucoma (PXG).\nMETHODS: This randomized, ... |
20813751 | CONCLUSIONS: Our analysis reveals that the methodological quality of the health economic analysis of AMD therapeutic interventions in the literature is suboptimal. There is considerable variation in methodological rigour between the articles, and we have identified several attributes that are predictive of study quality. | BACKGROUND: Age-related macular degeneration (AMD) is the primary cause of vision loss in the elderly and results in significant economic and humanistic burden. The selective vascular endothelial growth factor inhibitor, pegaptanib (Macugen) is indicated for patients with neovascular AMD. Guidance is needed regarding the cost effectiveness of treatment, any variation between sub-populations of differing clinical characteristics and the optimum duration of treatment.
OBJECTIVE: To estimate the cost effectiveness of pegaptanib versus best supportive care (BSC) for AMD from the perspective of the UK government, and to evaluate the impact of patient characteristics and differing treatment discontinuation scenarios.
METHODS: A cohort of 1000 patients aged >45 years with a best-corrected visual acuity (VA) in their better-seeing eye of < or =6/12 was modelled. Patients were either treated with pegaptanib (0.3mg every 6 weeks for a maximum of 2 years in their better-seeing eye only) or received BSC (no active treatment). Supportive services were provided for patients with a VA < or =6/60. A 10-year Markov model composed of 12 VA states (defined by individual Snellen lines) and a dead state was constructed. The model reported herein was used to support submissions to the National Institute for Health and Clinical Excellence (NICE) and the Scottish Medicines Consortium (SMC). NICE guidance is expected to be available in October 2007 and the SMC advice was issued on 7 July 2006. SMC accepted pegaptanib for use in patients with visual acuity between 6/12 and 6/60 (inclusive) and should be stopped if visual acuity falls below 6/60 during treatment or where severe visual loss is experienced. Time-dependent transition probabilities for the loss and gain of Snellen lines were derived from parametric survival curves fitted to patient-level data from the VISION trials. Survival curves were fitted with treatment and baseline Snellen scores as covariates; additional curves were fitted with the addition of age, gender, lesion type or lesion size as covariates. Mortality rates were adjusted for the age, gender and VA of the population. Cost effectiveness was expressed as the incremental cost (IC) per vision-year saved and IC/QALY. Uncertainty was explored by probabilistic and univariate sensitivity analysis. Costs (year 2005 values) and outcomes were discounted at 3.5% per anum.
RESULTS: In the base-case analysis, treatment was targeted to patients with a VA of 6/12 to 6/95 and discontinued after 2 years, or earlier if VA fell below 6/95 or by > or =6 lines. The IC/QALY was estimated as 8023 pounds(upper 95% CI 20,641 pounds). Cost effectiveness varied by age (age <75 years = 2033 pounds/QALY; age > or =75 years = 11,657 pounds/QALY) and by pre-treatment VA (6/12-6/95 = 8023 pounds/QALY; 6/12-6/60 = 6664 pounds/QALY; 6/12-6/24 = 1920 pounds/QALY). Gender and lesion type or size had little effect. Cost effectiveness was not sensitive to precise rules for treatment discontinuation, but was maximised if treatment was discontinued in patients no longer likely to benefit.
CONCLUSIONS: The results suggest that pegaptanib treatment is likely to be cost effective across all groups studied, and marginally more cost effective in younger patients and those with better pre-treatment VA. Cost effectiveness appears to be optimised if treatment is discontinued after 1 year if individual patients' VA has dropped by > or =6 lines from pre-treatment levels, or at any time if it drops below 6/95. However, strict application of discontinuation rules does not appear to be necessary for pegaptanib to be cost effective. Clinical judgement and patient preference should be an important determinant in decisions about stopping treatment. ||||| AIM: To assess the cost effectiveness of high dose zinc and antioxidants for delaying and reducing the progression of early age related macular degeneration (AMD).
BACKGROUND: AMD is the leading cause of severe vision impairment and blindness in older people throughout the developed world. It currently affects around 420 000 people in the United Kingdom.
METHODS: A cost utility analysis (CUA) was conducted to estimate the cost per quality adjusted life year (QALY) for screening a cohort of men and women, aged 55 years and over, for early AMD and then treating them with zinc and antioxidants. The incremental CUA was based on a decision analytic model, comparing screening with a no screening comparator (current practice). Extensive one way sensitivity analysis of parameters was conducted to determine the robustness of the model.
RESULTS: In this model the cost effectiveness of screening for early AMD was pound 22 722 per quality adjusted life year (QALY) saved. The cost per QALY decreased to pound 18 948 if photodynamic therapy with verteporfin savings were included.
CONCLUSIONS: Screening for, and prophylactic treatment of, early AMD is estimated to cost around pound 22 700 per QALY saved. This cost falls within accepted levels to warrant further investigation. These findings have implications for ophthalmic practice and healthcare planning. ||||| OBJECTIVES: In Ontario, Canada, in a cohort of all people initially aged 50-54 years, modeling whether the Age-Related Eye Disease Study (AREDS) antioxidant supplementation for stage 3 and 4 AMD would decrease the costs of photodynamic treatment with Visudyne.
PERSPECTIVE: Third party payer, the Ontario Health Insurance Plan.
METHODS: Using reported risk reductions, prevalence data by age and sex from the Beaver Dam studies, and yearly costs: AREDS 182.50 Canadian dollars, potential savings were calculated as the difference or incremental cost between the estimated medical costs for the untreated cohort of 17,000 Canadian dollars for Visudyne treatment of individuals with neovascularization and the same cohort if stage 3 and 4 AMD patients were treated with antioxidants, decreasing progression to neovascularization. Different scenarios were explored for sensitivity analysis of direct cost savings.
RESULTS: For the Ontario cohort of approximately 788,000 aged 51-55 years in 2001, for photodynamic therapy of the untreated cohort, modeled costs were 1.7 billion Canadian dollars. AREDS treatment costs would be 513 million Canadian dollars. AREDS would reduce photodynamic therapy costs, a net saving of 431 million Canadian dollars, a saving of 547 Canadian dollars per person in the total cohort, or 6,753 Canadian dollars per stage 3 and 4 patient treated. To explore the sensitivity of this model to AMD incidence rather than prevalence data, Framingham incidence data were incorporated in the model: net savings of 70.3 million Canadian dollars were modeled using Framingham incidence data.
CONCLUSION: Under reasonable assumptions, if the case progresses to wet AMD (1) AREDS with Visudyne is less expensive than Visudyne alone in every five-year time period for the cohort that is age 50-54 right now until they become 75-79; thus, the lifetime cost is lower; (2) AREDS with Visudyne yields more QALYs than Visudyne alone in every five-year interval; (3) under all but the most extreme assumptions, the conclusions reached are robust. Even when AREDS costs a little more, it yields more QALYs at a reasonable cost per QALY. Thus, AREDS antioxidant supplementation appears to be a dominant strategy for macular degeneration. Applied to the whole Canadian population, the potential medical cost savings for Visudyne treatment of neovascular AMD are 5.6 billion Canadian dollars in direct costs. These values would be tenfold higher for the USA, because of the currency and population size differences. ||||| OBJECTIVES: Age-related macular degeneration is the leading cause of legal blindness in older people. Choroidal neovascularization (CNV) is treatable with photodynamic therapy with verteporfin (PDT) but is expensive. The aim of this study was to assess the cost-effectiveness of PDT in routine clinical practice in Switzerland.
MATERIALS AND METHODS: A Markov model was used to analyze the costs of PDT in routine clinical practice. It described patients moving between good or impaired vision (visual acuity [VA]>0.1) and highly impaired vision (VA<0.1). Costs for PDT were based on the results of the Donati open-labeled prospective clinical study. Costs for medical and social management of AMD patients were defined according to Grainer's study.
RESULTS: The cost of PDT varied from 8,800 to 10,969 euros/patient/year. Ninety percent of the patients retained a VA > or =0.1. Health costs saved by keeping patients from moving to the highly impaired vision group was 4,248 euros/patient/year. Incremental costs per vision-year saved varied from 8,239 to 10,271 euros. Cost per quality-adjusted life year (QALY) gained at 5 years was 65,150 euros.
DISCUSSION: PDT was found to be moderately cost-effective in Switzerland. The longer the follow-up, the more cost-effective Visudyne was. Cost-effectiveness is a country-dependent assessment and analyses should be done for each health care system.
CONCLUSION: PDT was found to be cost-effective in Switzerland (category C of Laupaci's classification). ||||| OBJECTIVE: The aim of this study was to estimate the public health service cost of visual acuity improvement or maintenance with photodynamic therapy in patients with age-related macular degeneration (ARMD). This illness is the most frequent cause of blindness in elderly patients in western countries.
METHODS: A cost-effectiveness analysis was carried out to compare photodynamic therapy versus no treatment. The analysis point of view was that of the health service. The improvement or maintenance of visual acuity and contrast sensitivity were considered efficacy results. Direct costs were estimated by means of cost accountancy. Quality adjusted costs per visual acuity life year gained (QACVAG) were calculated through utility values from other studies.
RESULTS: The cost per year of maintenance of visual acuity in a two-year period was 36,530 euro for women and 34,804 euro for men. If this cost was estimated for life expectancy in Asturias, it would be reduced to 4,298 euro for women and 5,354 euro for men. If costs of the QACVAG, in a two-year period, were considered, photodynamic therapy would cost 66,931 euro for women and 70,249 euro for men.
CONCLUSION: This cost-effectiveness analysis allows decisions to be made about public financing. Some research in our country suggests that public health financing should be provided for interventions whose cost-effectiveness is less than 30,000 euro of CVAQA. The treatment evaluated here far exceeds this value. It is recommended that the use of more restrictive patient selection, incorporating diagnostic criteria and patient autonomy indicators, could improve the results of this intervention. ||||| OBJECTIVE: Health economic models can assist policy-makers in determining the value of novel treatments from the viewpoint of society. In this context, value is defined as the benefit of treatment, given its cost. A new treatment for wet age-related macular degeneration (AMD), juxtascleral administration of anecortave acetate, 15 mg for depot suspension (Retaane), is now in a late-phase clinical trial. In a theoretical analysis, we sought to determine the cost at which this treatment might offer economic value to society, using incremental cost-effectiveness ratios (ICERs).
METHODS: A series of 1-year cost-utility models was created for the investigational treatment and standard treatment (photodynamic therapy [PDT] with verteporfin [Visudyne]). Value to society was defined in terms of theoretical associated ICERs (in US dollars): $100,000 per quality-adjusted life-year (QALY), $50,000/QALY, $20,000/QALY and $0/QALY, the point of economic indifference. Models were created from the societal perspective and included a patient-derived utility assessment involving regression equations to estimate time trade-off preferences, event probabilities derived from a randomized clinical trial comparing the safety and efficacy of anecortave administration and PDT with verteporfin, decision analysis and relevant costing information.
RESULTS: An ICER of $100,000/QALY would be associated with an anecortave cost of $3022/vial, an ICER of $50,000/QALY with an anecortave cost of $2986/vial and an ICER of $20,000/QALY with an anecortave cost of $2964/vial. The point of economic indifference between anecortave administration and standard therapy would occur with an anecortave cost of $2950/vial.
INTERPRETATION: In theory, an anecortave cost of $2986/vial is associated with an ICER of $50,000/QALY, the threshold used by many health technology assessment and reimbursement agencies. ||||| OBJECTIVE: To perform a value-based medicine analysis of clinical trials that evaluate the interventions of laser photocoagulation, intravitreal pegaptanib therapy, and photodynamic therapy (PDT) with verteporfin for the treatment of classic subfoveal choroidal neovascularization.
DESIGN: Reference case cost-utility analysis using value-based medicine principles, which use patient-based utility values and standardized, input variable criteria.
PARTICIPANTS: Data from participants in the Macular Photocoagulation Study, Pegaptanib for Neovascular Age-Related Macular Degeneration Study, and the Treatment of Age-Related Macular Degeneration with Photodynamic Therapy Study.
METHODS: Visual data were converted to a value-based format using time tradeoff utility analysis values from patients with macular degeneration. Costs were obtained from 2005 Medicare data. Outcomes (quality-adjusted life-years [QALYs]) and costs were discounted at a 3% annual rate.
MAIN OUTCOME MEASURES: Interventional QALYs gained, percent improvement in quality of life, and dollars spent per QALY gained.
RESULTS: Laser photocoagulation confers a 4.4% (P = 0.03 versus pegaptanib therapy) improvement in quality of life for the reference case, whereas pegaptanib therapy confers a 5.9% improvement and PDT confers an 8.1% (P = 0.0002 versus pegaptanib therapy) improvement. The cost-utility associated with laser photocoagulation is $8179, that for pegaptanib therapy is $66978, and that for PDT is $31544. All sensitivity analyses remain within the conventional standards of cost-effectiveness.
CONCLUSIONS: Photodynamic therapy confers greater patient value than intravitreal pegaptanib therapy and laser photocoagulation for the treatment of classic subfoveal choroidal neovascularization. Despite the fact that laser photocoagulation is the most cost-effective intervention, both PDT and pegaptanib therapy deliver greater value, and thus are both preferred over laser photocoagulation. Using an economic measure, photodynamic therapy is the preferred treatment among these 3 interventions. ||||| Two new drugs provide startling benefits in the treatment of age-related macular degeneration (AMD). The clinical and cost effectiveness of ranibizumab (Lucentis) was compared to that of bevacizumab (Avastin), which costs up to 100 times less. A cost effectiveness model was developed to assess the cost per quality adjusted life year (QALY) over 10 years. For predominantly classic AMD, the efficacy of bevacizumab relative to ranibizumab would have to be around 40% for the latter to achieve 30 k pounds per QALY, a NICE threshold. Similar but worse results applied to the other main forms of AMD, minimally occult and occult with no classic lesions. The price of ranibizumab would have to be drastically reduced for it to be cost effective. Continued unlicensed use of bevacizumab raises ethical, legal and policy questions. Public pressure may be the most potent weapon in persuading Genentech to license bevacizumab for AMD. ||||| OBJECTIVE: To determine the cost-effectiveness of vitamin therapy (antioxidants plus zinc) for all indicated patients diagnosed with age-related macular degeneration (AMD).
DESIGN: We compared the impacts of vitamin therapy with those of no vitamin therapy using a computerized, stochastic, agent-based model. The model simulated the natural history of AMD and patterns of ophthalmic service use in the United States in a cohort from age 50 years until 100 or death.
PARTICIPANTS AND/OR CONTROLS: The model created 20 million simulated individuals. These individuals each received both the intervention (vitamin therapy after diagnosis) and the control (no vitamin therapy). Expected outcomes generated when vitamins were taken after diagnosis were compared with the expected outcomes generated when they were not.
METHODS: The model created individuals representative of patients in the U.S. Incidence of early AMD was based on published studies, as was vision loss and response to choroidal neovascularization therapies. Post-incident disease progression was governed by previously unpublished data drawn from the Age-Related Eye Disease Study.
MAIN OUTCOME MEASURES: Extent of disease progression, years and severity of visual impairment, cost of ophthalmic care and nursing home services, and quality-adjusted life years (QALYs). Costs and benefits were considered from the health care perspective and discounted using a 3% rate. The analysis was run for 50 years starting in 2003.
RESULTS: Compared with no therapy, vitamin therapy yielded a cost-effectiveness ratio of $21,387 per QALY gained and lowered the percentage of patients with AMD who ever developed visual impairment in the better-seeing eye from 7.0% to 5.6%.
CONCLUSIONS: Our model demonstrates that vitamin therapy for AMD improves quality of life at a reasonable cost. ||||| PURPOSE: Photodynamic therapy (PDT) has recently been demonstrated to be beneficial for the treatment of subfoveal choroidal neovascularization secondary to age-related macular degeneration (AMD). Herein, we determine the cost-effectiveness of PDT for the treatment of subfoveal choroidal neovascularization (CNV) in patients with disciform degeneration in one eye and whose second and better-seeing eye develops visual loss secondary to predominantly classic subfoveal CNV. The analysis was performed from the perspective of a for-profit third-party insurer.
DESIGN: Cost-utility Markov models were created to determine the cost-effectiveness of PDT under two different scenarios, by using efficacy data derived from the Treatment of Age-Related Macular Degeneration with Photodynamic Therapy (TAP) Study and patient-based utilities.
METHODS: Decision analyses were performed by incorporating data from the TAP Study, expected longevity data, and patient-based utilities. Cost-effective models were then created by incorporating incremental medical costs. Various sensitivity analyses were carried out to determine the robustness of our models. A Monte Carlo simulation was also used to determine whether there was a significant difference in quality-of-life adjusted years (QALYs) gained between PDT therapy and the placebo.
RESULTS: For the hypothetical patient whose second and better-seeing eye becomes affected and who has 20/40 vision at baseline in this affected eye (base case 1), PDT was associated with a 10.7% relative increase in their quality-of-life (treatment conferred an additional undiscounted 0.1342 QALYs over a 2-year period). For the hypothetical patient whose second and better-seeing eye becomes affected and who has 20/200 vision at baseline in this affected eye (base case 2), PDT was associated with a 7.8% relative increase in their quality-of-life (treatment conferred an additional undiscounted 0.0669 QALYs over a 2-year period). Sensitivity analysis showed our models were robust and that PDT was usually the dominant treatment choice. Our cost-effective model demonstrated that the cost for a QALY was $86,721 (US dollars discounted at 3%) for base case 1, assuming 5.5 treatments; and $173,984 (USD discounted at 3%) for base case 2.
CONCLUSIONS: PDT will cost a third-party insurer $86,721 for an AMD patient with 20/40 vision in the better-seeing eye to obtain one QALY and $173,984 for an AMD patient with 20/200 vision in the better-seeing eye to obtain one QALY. PDT can be considered to be a treatment that is of only minimal cost-effectiveness for AMD patients who have subfoveal CNV in their second and better-seeing eyes and who have good presenting visual acuity at baseline. It is a cost-ineffective treatment for AMD patients who have poor visual acuities in their affected better-seeing eyes. ||||| AIM: To estimate the potential cost effectiveness of photodynamic therapy (PDT) with verteporfin in the UK setting.
METHODS: Using data from a variety of sources a Markov model was built to produce estimates of the cost effectiveness (incremental cost per quality adjusted life year (QALY) and incremental cost per vision year gained) of PDT for two cohorts of patients (one with starting visual acuity (VA) of 20/40 and one at 20/100) with predominantly classic choroidal neovascular disease over a 2 year and 5 year time horizon. A government perspective and a treatment cost only perspective were considered. Probabilistic and one way sensitivity analyses were undertaken.
RESULTS: From the government perspective, over the 2 year period, the expected incremental cost effectiveness ratios range from 286 000 (starting VA 20/100) to 76 000 UK pounds (starting VA 20/40) per QALY gained and from 14 000 (20/100) to 34 000 UK pounds (20/40) per vision year gained. A 5 year perspective yields incremental ratios less than 5000 UK pounds for vision years gained and from 9000 (20/40) to 30 000 UK pounds (20/100) for QALYs gained. Without societal or NHS cost offsets included, the 2 year incremental cost per vision year gained ranges from 20 000 (20/100) to 40 000 UK pounds (20/40), and the 2 year incremental cost per QALY gained ranges from 412 000 (20/100) to 90 000 UK pounds (20/40). The 5 year time frame shows expected costs of 7000 (20/40) to 10 000 UK pounds (20/100) per vision year gained and from 38 000 (20/40) to 69 000 UK pounds (20/100) per QALY gained.
CONCLUSION: This evaluation suggests that early treatment (that is, treating eyes at less severe stages of disease) with PDT leads to increased efficiency. When considering only the cost of therapy, treating people at lower levels of visual acuity would probably not be considered cost effective. However, a broad perspective that incorporates other NHS treatment costs and social care costs suggests that over a long period of time, PDT may yield reasonable value for money. ||||| BACKGROUND/AIM: Age related macular degeneration (AMD) is the leading cause of severe vision impairment and blindness in older people throughout the developed world and currently affects around 420 000 UK citizens. Choroidal neovascularisation (CNV) is treatable with photodynamic therapy (PDT) but is expensive at over pound 1200 per treatment. The aim of this study was to assess the cost utility of PDT for better eye, predominantly classic, subfoveal choroidal neovascular lesions secondary to AMD.
METHODS: Cost utility analysis (CUA) was conducted to estimate the cost effectiveness of PDT for scenarios involving reasonable (6/12) and poor (6/60) visual acuity. The models incorporated data from the Treatment of Age-related Macular Degeneration with PDT (TAP) Study and patient based utilities. The incremental CUA was based on decision analytical models, comparing treatment to a placebo comparator. Extensive one way sensitivity analysis of parameters was conducted to determine the robustness of the model. A discount rate of 6% was used for costs and quality adjusted life years (QALY).
RESULTS: Model 1: in people with reasonable initial visual acuity, the cost utility of treating applicable neovascular AMD lesions was pound 31 607 per QALY saved, with a sensitivity analysis range from pound 25 285 to pound 37 928. Model 2: in people with poor initial visual acuity, the cost utility was pound 63 214 per QALY saved, with a sensitivity analysis range from pound 54 183 to pound 75 856.
CONCLUSIONS: PDT treatment is the only available treatment for some forms of neovascular ("wet") AMD. Under these assumptions, PDT can be considered moderately cost effective for those with reasonable visual acuity but less cost effective for those with initial poor visual acuity. These findings have implications for ophthalmic practice and healthcare planning. ||||| PURPOSE: The purpose of this study was to perform a reference case (average case), cost-utility analysis of laser photocoagulation for extrafoveal choroidal neovascularization associated with age-related macular degeneration using a model incorporating patient preferences.
METHODS: Visual acuity data for patients treated and observed over a 5-year period were obtained from previously reported studies by the Macular Photocoagulation Study Group. The results from this prospective, randomized trial were incorporated in a cost-utility model using time-trade-off utility analysis and decision analysis with Markov modeling according to the recommendations of the Panel on Cost-Effectiveness in Health and Medicine. Expenditures and health care benefits were each discounted at a 3% yearly rate.
RESULTS: Laser photocoagulation therapy for extrafoveal choroidal neovascularization in age-related macular degeneration, compared with observation, resulted in a mean gain of 0.0740 quality-adjusted life-year per patient treated. The mean cost of treatment for the average patient totaled 1,715 US dollars. The cost divided by the health care benefit resulted in 23,176 year 2001 US dollars per quality-adjusted life-year gained for this procedure for a reference case. Sensitivity analyses, varying the cost, utility values, and discount parameters, resulted in dollars per quality-adjusted life-year gained ranging from 16,117 to 49,766 US dollars.
CONCLUSION: Laser photocoagulation for extrafoveal choroidal neovascularization associated with age-related macular degeneration appears to be cost-effective when compared with interventions across multiple medical specialties. ||||| PURPOSE: To assess the value conferred by photodynamic therapy (PDT) and the cost-utility of PDT for the treatment of classic, subfoveal choroidal neovascularization associated with age-related macular degeneration (ARMD).
DESIGN: Average cost-utility analysis utilizing clinical trial data, patient-based time tradeoff utility preferences, and a third party insurer cost perspective.
METHODS: Five-year visual acuity data from the TAP (Treatment of Age-related Macular Degeneration With Photodynamic Therapy) Investigation were modeled into a 12-year, value-based, reference case, cost-utility model utilizing year 2004 Medicare costs and an outcome of dollar/QALY (dollars/quality-adjusted life-year). Discounting of outcomes and costs using net present value analysis with a 3% annual rate was performed as recommended by the Panel for Cost-Effectiveness in Health and Medicine.
RESULTS: PDT with verteporfin (Visudyne) dye for classic subfoveal choroidal neovascularization confers an 8.1% quality of life (value) improvement over the 12-year life expectancy of the reference case, while during the last 8 years the value improvement is 9.5%. The average cost-utility of the intervention is dollar 31,103/QALY (quality-adjusted life-year). Extensive one-way sensitivity analysis values range from dollar 20,736/QALY if treatment efficacy is increased by 50% to dollar 62,207 if treatment efficacy is decreased by 50%, indicating robustness of the model.
CONCLUSIONS: PDT using verteporfin dye to treat classic subfoveal choroidal neovascularization is a very cost-effective treatment by conventional standards. The marked improvement in cost-effectiveness compared with a previous report results from the facts that the treatment benefit increasingly accrues during 5 years of follow-up while the number of yearly treatments diminishes markedly during that time. ||||| The cost-effectiveness of photodynamic therapy with verteporfin in the treatment of patients with predominantly classic subfoveal choroidal neovascularization secondary to age-related macular degeneration was investigated by a Markov Model over a time horizon of three years in Switzerland. This model describes patients moving between three levels of visual acuity (e.g., good vision, impaired vision, highly impaired vision) and death in terms of transition probabilities. Transition probabilities as well as effectiveness values were derived from a randomized, controlled, double-masked clinical trial. Effectiveness for verteporfin therapy and for placebo was calculated in terms of vision years: 1.068 and 0.494, respectively. Cost per level of visual acuity was assessed in ascending order by expert panels from a societal perspective. Cost strongly increased parallel with vision loss on a patient-per-year basis from 4683 CHF at good vision to 8443 CHF at impaired vision, and was highest with 15231 CHF at highly impaired vision. The model-calculated cost per visionyear were 14907 CHF for patients in the verteporfin therapy group, versus 21047 CHF for patients in the placebo group. The incremental cost per vision-year additionally saved through verteporfin therapy was 9624 CHF. The study demonstrated that greater effectiveness of verteporfin therapy versus placebo compensated for the cost of the therapy so that verteporfin therapy was clearly costeffective. Therefore, for the indicated patients with AMD that causes severe vision loss, verteporfin therapy can be recommended as the therapy of choice, on both clinical and economic grounds. ||||| AIMS: To re-evaluate the cost-effectiveness of photodynamic therapy with verteporfin (Visudyne, Novartis AG, Switzerland) in patients with predominantly classic and classic choroidal neovascularization (CNV) owing to age-related macular degeneration (AMD), using new evidence on the impact of contrast sensitivity on health status.
METHOD: A health economic model is used to synthesise the evidence on contrast sensitivity and treatment rates from the TAP Investigation with health state utilities and costs. Impairment of visual function is estimated using a Markov model to predict transitions between states of contrast sensitivity. Each state is associated with costs and a health state utility. Total expected costs and benefits for a cohort of patients over a defined number of cycles are calculated. The expected health state utility for each disease state was estimated using results from a study of 209 patients with AMD in Sheffield. The model includes the costs associated with treatment and monitoring in the verteporfin treatment arm and costs offset by delaying the deterioration of visual function.
RESULTS: Beyond 3 years, the annual costs of the verteporfin arm are estimated to be less than the annual costs of the control arm, owing to the cost associated with higher blindness prevalence in the control arm. Over time, the results show that both the incremental utility and cost decreases. By 10 years, the estimated incremental cost-effectiveness is approximately pound20 996 per Quality-Adjusted Life Years.
CONCLUSION: The results of this study suggest that the verteporfin therapy in the treatment for patients with predominantly classic and classic CNV owing to AMD is encouraging. | [
{
"source_pmid": "17887807",
"source_text": "BACKGROUND: Age-related macular degeneration (AMD) is the primary cause of vision loss in the elderly and results in significant economic and humanistic burden. The selective vascular endothelial growth factor inhibitor, pegaptanib (Macugen) is indicated for pati... |
30325017 | AUTHORS' CONCLUSIONS: Anti-VEGF drugs are effective at improving vision in people with DMO with three to four in every 10 people likely to experience an improvement of 3 or more lines VA at one year. Aflibercept may confer some advantage over ranibizumab and bevacizumab in people with DMO at one year in visual and anatomic terms but it is unclear whether this applies to the long-term. There is a need for more evidence on the long-term (greater than two years) comparative effects of these anti-VEGF agents. Evidence from RCTs may not apply to real-world practice, where people in need of antiangiogenic treatment are often under-treated and under-monitored.We found no signals of differences in overall safety between the three antiangiogenic drugs that are currently available to treat DMO, but our estimates are imprecise for cardiovascular events and death. | PURPOSE: To compare the functional and structural effects of ranibizumab versus macular laser therapy in patients with center-involving diabetic macular edema.
DESIGN: Prospective, randomized, single-masked clinical trial.
METHODS: None
SETTING: Single center.
STUDY POPULATION: Thirty-three eyes of 33 patients with center-involving diabetic macular edema, with best corrected visual acuity of 55 to 79 Early Treatment Diabetic Retinopathy Study letters at baseline, completing the 48-week study period.
INTERVENTION: Subjects were randomized 2:1 to 3 loading doses of ranibizumab then retreatment every 4 weeks as required; or macular laser therapy at baseline, repeated as required every 12 weeks. Exploratory Outcome Measures: Structural imaging studies included greatest linear dimension and area of foveal avascular zone, perifoveal capillary dropout grade, and presence of morphologic features of diabetic macular edema on Spectralis optical coherence tomography (Heidelberg Engineering GmbH, Heidelberg, Germany). Functional measures: Visual acuity, retinal sensitivity in the central 4 and 12 degrees on microperimetry, color contrast sensitivity protan and tritan thresholds, pattern and full-field electroretinogram amplitudes and implicit times, and multifocal electroretinogram amplitude distribution. These were reported at 12, 24, and 48 weeks.
RESULTS: Ranibizumab-treated subjects gained 6.0 vs 0.9 letters lost for laser, demonstrated improved tritan and protan color contrast thresholds, and improved retinal sensitivity. Electrophysiologic function also improved after ranibizumab therapy. No safety issues were evident. Better retinal thickness reduction and structural improvement in optical coherence tomography features of diabetic macular edema were seen with ranibizumab therapy than in the laser group. There was no evidence of progressive ischemia with ranibizumab therapy.
CONCLUSIONS: Ranibizumab therapy in the treatment of diabetic macular edema seems to improve retinal function and structure as demonstrated by this evaluation of different assessment methods. ||||| OBJECTIVES: To determine the long-term effects of ranibizumab (RBZ) in patients with diabetic macular edema (DME).
DESIGN: Prospective, randomized, interventional, multicenter clinical trial.
PARTICIPANTS: One hundred twenty-six patients with DME.
METHODS: Subjects were randomized 1:1:1 to receive 0.5 mg RBZ at baseline and months 1, 3, and 5 (group 1), focal or grid laser photocoagulation at baseline and month 3 if needed (group 2), or a combination of 0.5 mg RBZ and focal or grid laser at baseline and month 3 (group 3). Starting at month 6, if retreatment criteria were met, all subjects could be treated with RBZ.
MAIN OUTCOME MEASURES: The mean change from baseline in best-corrected visual acuity (BCVA) at month 24.
RESULTS: After the primary end point at month 6, most patients in all groups were treated only with RBZ, and the mean number of injections was 5.3, 4.4, and 2.9 during the 18-month follow-up period in groups 1, 2, and 3, respectively. For the 33 patients in group 1, 34 patients in group 2, and 34 patients in group 3 who remained in the study through 24 months, the mean improvement in BCVA was 7.4, 0.5, and 3.8 letters at the 6-month primary end point, compared with 7.7, 5.1, and 6.8 letters at month 24, and the percentage of patients who gained 3 lines or more of BCVA was 21, 0, and 6 at month 6, compared with 24, 18, and 26 at month 24. The percentage of patients with 20/40 or better Snellen equivalent at month 24 was 45% in group 1, 44% in group 2, and 35% in group 3. Mean foveal thickness (FTH), defined as center subfield thickness, at month 24 was 340 μm, 286 μm, and 258 μm for groups 1, 2, and 3, respectively, and the percentage of patients with center subfield thickness of 250 μm or less was 36%, 47%, and 68%, respectively.
CONCLUSIONS: Intraocular injections of RBZ provided benefit for patients with DME for at least 2 years, and when combined with focal or grid laser treatments, the amount of residual edema was reduced, as were the frequency of injections needed to control edema.
FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references. ||||| BACKGROUND: In spite of laser being the gold standard treatment for Diabetic Macular edema (DME), some patients do not respond to laser. Various treatment modalities are being tried in the management of refractory diffuse DME (DDME).
PURPOSE: To compare the efficacy of intravitreal bevacizumab (IVB), intravitreal triamcinolone acetonide (IVTA), and macular grid augmentation in the management of refractory DDME.
SETTINGS AND DESIGN: Prospective randomized study in a tertiary eye care center.
MATERIALS AND METHODS: SIXTY PATIENTS WITH REFRACTORY DDME WERE RANDOMLY ASSIGNED TO THREE GROUPS: Group 1 received IVB (1.25 mg/0.05 ml), Group 2 received IVTA (4 mg/0.1ml), and Group 3 underwent laser augmentation. Primary outcome measures were best corrected visual acuity (BCVA) and central macular thickness (CMT) at the end of 6 months.
STATISTICS: Analysis was performed using SPSS 14.0
RESULTS: Group 1 and 2 showed significant improvement in mean BCVA from 20/160 at baseline to 20/80 and from 20/125 to 20/63, respectively, at 6 months (P < 0.05). These groups also showed a significant reduction in the mean CMT from 457 ± 151 μ at baseline to 316 ± 136 μ and from 394 ± 61 μ to 261 ± 85 μ, respectively, at 6 months (P < 0.05). Group 3 showed only small improvement in mean BCVA from 20/100 to 20/80 (P = 1.0) while mean CMT increased from 358 ± 89 μ at baseline to 395 ± 127 μ at 6 months (P = 0.191). Eight (40%) eyes in Group 2 had intraocular pressure (IOP) rise and 10 (50%) eyes developed cataract.
CONCLUSIONS: Both IVB and IVTA may be effective in the treatment of refractory DDME compared with macular grid augmentation. IVTA may be associated with side effects such as IOP rise and cataract formation. | [
{
"source_pmid": "24531025",
"source_text": "PURPOSE: To compare the functional and structural effects of ranibizumab versus macular laser therapy in patients with center-involving diabetic macular edema.\nDESIGN: Prospective, randomized, single-masked clinical trial.\nMETHODS: None\nSETTING: Single center.... |
20671613 | CONCLUSIONS: There is evidence of a modest positive association only between T34T polymorphism and POAG in Asians and adults. The M98K and R545Q polymorphisms have no association with POAG susceptibility. However, this meta-analysis exploring combinations of the polymorphisms may help us better understand the genetics of POAG. | PURPOSE: To evaluate the association of myocilin (MYOC), optineurin (OPTN), and apolipoprotein E (APOE) genes and their interactions in primary open angle glaucoma (POAG).
METHODS: A cohort of 400 unrelated POAG patients (294 high tension glaucoma, HTG, and 106 normal tension glaucoma, NTG) and 281 unrelated control subjects were recruited. All coding exons and splicing junctions in MYOC and OPTN were screened for sequence alterations. Common polymorphisms in APOE were genotyped. Single genes were investigated by univariate and haplotype analysis, and gene-gene interactions by logistic regression and stratified analysis. Multiple comparisons were corrected by the Bonferroni method. Bioinformatics analysis was performed to assess the conservation of mutation sites across species and to predict putative motifs and secondary structures in mutated proteins.
RESULTS: Disease-causing mutations in MYOC and OPTN were identified in 1.75% and 1% of POAG patients, respectively. Most of these mutations were highly conserved across species, many predicted to create new motifs or change protein secondary structures. No individual MYOC polymorphisms significantly contributed to HTG or NTG. A haplotype containing the minor allele of the MYOC IVS2+35A>G increased NTG risk (p=0.0001). Three OPTN polymorphisms, T34T, IVS5+38T>G, and IVS8-53T>C increased NTG risk (p<0.0008), while IVS5+38T>G increased HTG risk (p=0.0006). One haplotype that contains the minor alleles of 3 OPTN polymorphisms, T34T, IVS5+38T>G, and IVS7+24G>A, increased NTG risk (p=0.0002). APOE epsilon4 carriers had a decreased NTG risk (p=0.007). Possible gene-gene interactions were found between MYOC, OPTN, and APOE.
CONCLUSIONS: Disease-causing mutations in MYOC and OPTN accounted for only a small proportion of Chinese POAG patients. Common polymorphisms in MYOC, OPTN, and APOE might interactively contribute to POAG, indicating a polygenic etiology. ||||| PURPOSE: Primary open-angle glaucoma (POAG) is the second most common cause of blindness. It has been linked to mutations in the myocilin (MYOC) and optineurin (OPTN) genes, although mutations have been found in <5% of patients. The pathologic mechanism(s) of POAG remain unknown but may include retinal ganglion cell apoptosis, which causes progressive damage to axons at the optic nerve head.
METHODS: In 27 patients with definite POAG, the MYOC and OPTN genes were sequenced, the entire mitochondrial (mt)DNA coding region was sequenced, relative mtDNA content was investigated, and mitochondrial respiratory function was assessed.
RESULTS: Only three benign polymorphisms were identified in MYOC and OPTN in patients with POAG and in control subjects. Conversely, 27 different novel nonsynonymous mtDNA changes were found, only in patients with POAG (not control subjects), 22 of which (found in 14 patients) were potentially pathogenic. Unlike Leber hereditary optic neuropathy, most mtDNA sequence alterations in patients with POAG were transversions-sequence changes that alter the purine/pyrimidine orientation and imply oxidative stress. mtDNA content was relatively increased in 17 patients with POAG compared with age-matched control subjects, also implying a possible response to oxidative stress. Mean mitochondrial respiratory activity was decreased by 21% in patients with glaucoma compared with control subjects (P<0.001).
CONCLUSIONS: These results reveal a spectrum of mitochondrial abnormalities in patients with POAG, implicating oxidative stress and implying that mitochondria dysfunction may be a risk factor for POAG. This concept may open up new experimental and therapeutic opportunities. ||||| PURPOSE: Juvenile open-angle glaucoma (JOAG) differs from primary open-angle glaucoma in that it is usually a more severe phenotype and has an earlier age of onset. Optineurin was recently associated with a variant of POAG that is characterized by intraocular pressure within normal limits: normal-tension glaucoma. The present study tested whether OPTN sequence changes play a role in early-onset glaucoma characterized by elevated intraocular pressure.
METHODS: Sixty-six patients with JOAG characterized by high intraocular pressure were screened for mutations. Mutational analysis was performed with a combination of restriction enzyme digestion, single-strand conformation polymorphism, and direct sequencing. The effects of select changes on exon splicing were assessed using bioinformatic modeling approaches and RT-PCR.
RESULTS: Ten sequence changes were identified, of which H486R was strongly suggestive of pathogenicity. H486R represents the first reported OPTN mutation associated with JOAG. Also, L41L is proposed to confer an increased susceptibility to the development of JOAG. Most of the other sequence changes observed were not thought to be biologically significant. The frequency of the previously reported M98K allele was not increased in the JOAG population studied but showed the previously reported skewed distribution in the POAG study population. The changes identified were not shown to affect the splicing machinery.
CONCLUSIONS: The results of this work support the hypothesis that mutations in OPTN are not specifically associated with low-pressure glaucoma, but can play a role in JOAG. ||||| PURPOSE: To investigate sequence variations in the optineurin (OPTN) gene and their association with TNF-alpha polymorphisms in Japanese patients with glaucoma.
METHODS: The OPTN gene was analyzed in blood samples from 629 Japanese subjects. There were 194 patients with primary open-angle glaucoma (POAG), 217 with normal-tension glaucoma (NTG), and 218 with no eye disease (control subjects). The gene was screened for mutations by denaturing high-performance liquid chromatography. Genotyping of three polymorphisms of -308G-->A, -857C-->T, and -863C-->A in the TNF-alpha promoter region was performed. The associations between the genotypes and age, intraocular pressure (IOP), and visual field defects at the time of diagnosis were examined.
RESULTS: A possible glaucoma-causing mutation, His26Asp, was identified in 1 of the 411 Japanese patients with glaucoma. A c.412G-->A (Thr34Thr) polymorphism in the OPTN gene was significantly associated with POAG (genotype frequency, P = 0.011; allele frequency, P = 0.003). The frequency of TNF-alpha/-857T and optineurin/412A carriers was significantly higher (P = 0.006) in patients with POAG than in control subjects. Among the patients with POAG who were carriers of TNF-alpha/-857T, the optineurin/412A carriers had significantly worse (P = 0.020) visual field scores than the non-optineurin/412A ones. The frequency of TNF-alpha/-863A and optineurin/603A (or Lys98) carriers was significantly higher in patients with POAG (P = 0.008) or NTG (P = 0.027) than in control subjects. Among the patients with POAG who were carriers of TNF-alpha/-863A, the ones with optineurin/603A (or Lys98) had significantly worse (P = 0.026) visual field scores than did those with non-optineurin/603A (or Lys98).
CONCLUSIONS: These findings demonstrated that the OPTN gene is associated with POAG rather than NTG in the Japanese. Statistical analysis showed a possible interaction between polymorphisms in the OPTN and the TNF-alpha genes that would increase the risk for glaucoma. ||||| OBJECTIVE: To determine whether mutations in the optineurin gene contribute to susceptibility to adult-onset primary open-angle glaucoma.
METHODS: The optineurin gene was screened in 86 probands with adult-onset primary open-angle glaucoma and in 80 age-matched control subjects. Exons 4 and 5, containing the recurrent mutations identified in patients with normal-tension glaucoma, were sequenced in all individuals studied, while the remaining exons were screened for DNA sequence variants with denaturing high-performance liquid chromatography.
RESULTS: The recurrent mutation, Met98Lys, previously found to be associated with an increased risk of disease was found in 8 (9%) of 86 probands. We also found the Met98Lys mutation in 10% of individuals from a control population of similar age, sex, and ethnicity. Consistent segregation of the mutation with the disease was not demonstrated in any of the 8 families. No other DNA changes altering the amino acid structure of the protein were found.
CONCLUSION: The mutations in the optineurin gene associated with normal-tension glaucoma are not associated with adult-onset primary open-angle glaucoma in this patient population. Clinical Relevance Genetic abnormalities that render the optic nerve susceptible to degeneration are excellent candidates for genetic factors that could contribute to adult-onset primary open-angle glaucoma. Mutations in optineurin have been associated with normal-tension glaucoma, but are not associated with disease in patients with adult-onset primary open-angle glaucoma. This result may indicate that normal-tension glaucoma is not necessarily part of the phenotypic spectrum of adult open-angle glaucoma. ||||| The optineurin gene (OPTN) was identified as a gene that causes primary open-angle glaucoma (POAG) and normal tension glaucoma (NTG). To investigate the frequency of sequence changes in OPTN in Japanese glaucoma patients, single-strand conformation polymorphism analysis and subsequent sequence analysis were performed for genotyping OPTN in 165 unrelated Japanese patients with POAG and 148 patients with NTG, with 196 control subjects without glaucoma as reference subjects. Out of four mutations reported to be associated with risk and to cause disease in Caucasian patients, sequence alterations in 458G > A and 691_692insAG were not detected in any investigated Japanese patients with glaucoma, and alterations in 1944G > A and 603T > A, were present in similar frequencies in glaucoma patients and control subjects. The current results suggest that there may be certain racial differences between Japanese and Caucasians with respect to OPTN genotypes. ||||| PURPOSE: To evaluate the noelin 2 gene as a disease-causing factor for open-angle glaucoma (OAG) and the interactions between the noelin 2 (OLFM2), optineurin (OPTN), and myocilin (MYOC) genes.
METHODS: OLFM2 was analyzed in 770 Japanese subjects including 215 patients with elevated intraocular pressure (IOP), 277 with normal IOP, 38 with juvenile open-angle glaucoma, and 240 control subjects. Two single-nucleotide polymorphisms (SNPs) in OPTN (c.412G-->A and c.603T-->A) and one SNP in MYOC (c.227G-->A) were examined. Single genes were investigated by univariate analysis and the gene-gene interactions by logistic regression analysis. Associations between genotypes and clinical characteristics at the time of diagnosis were examined.
RESULTS: In OLFM2, 12 sequence variants were identified in 770 Japanese subjects. Arg144Gln (exon 4) was identified in two (0.3%) of the patients and in none of the control subjects. Combinations of OLFM2/317A and OPTN/412A or OLFM2/1281T and OPTN/412A were associated with patients with elevated IOP (P = 0.018 or P = 0.012, respectively). The combination of OLFM2/317G and OPTN/603A was significantly associated with elevated IOP (P = 0.018). No significant association was detected between SNPs in OLFM2 and in MYOC. Patients with normal IOP and with OLFM2/678A+OPTN/412G or OLFM2/1281C+OPTN/412G had significantly worse visual field scores (P = 0.022 or 0.030, respectively).
CONCLUSIONS: The Arg144Gln mutation in OLFM2 is a possible disease-causing mutation in Japanese patients with OAG. Common polymorphisms in OLFM2 and OPTN may interactively contribute to the development of OAG, indicating a polygenic etiology. ||||| A collection of DNA samples obtained from primary open-angle glaucoma (POAG) patients from St. Petersburg was analyzed for single-strand conformation polymorphism (SSCP) to reveal sequence variants in exon 3 of the myocilin gene (MYOC/TIGR) and in exons 4 and 5 of the optineurin gene (OPTN), where most of the mutations revealed worldwide are located. The Q368X mutation (c. 1102 C --> T) in exon 3 of MYOC/TIGR was detected in 1.2% (2/170) of the POAG patients from St. Petersburg, i.e., with the frequency close to that observed in other world populations. Three known polymorphisms in exon 3 of MYOC/TIGR, Y347Y (c. 1041 T --> C) (12.4%), T325T (c. 975 G --> A) (0.6%), and K398R (c. 1193 A --> G) (0.6%) were also detected. No statistically significant differences in frequencies of these polymorphisms were revealed between the POAG patient and control groups. The L41L polymorphism (c. 433 G --> A) in exon 4 of OPTN was detected in 2.9% of probands and in 1% of controls. The frequency of heterozygotes for the M98K polymorphism (c. 603 T --> A) in the OPTN exon 5 was statistically significantly higher (P = 0.036; Fisher's exact test) among the POAG patients (6.5%) than among the controls (1%). In the sample examined the E50K mutation, typical of the patients with pseudonormal intraocular pressure glaucoma, was not found. ||||| PURPOSE: To evaluate the extent to which mutations in the optineurin (OPTN) glaucoma gene play a role in glaucoma in different populations.
METHODS: Case-controlled study of OPTN sequence variants in individuals with or without glaucoma in populations of different ancestral origins and evaluate previous OPTN reports. We analyzed 314 subjects with African, Asian, Caucasian and Hispanic ancestries included 229 cases of primary open-angle glaucoma, 51 cases of juvenile-onset open-angle glaucoma, 33 cases of normal tension glaucoma, and 371 controls. Polymerase chain reaction-amplified OPTN coding exons were resequenced and case frequencies were compared to frequencies in controls matched for ancestry.
RESULTS: The E50K sequence variant was identified in one individual from Chile with normal tension glaucoma, and the 691_692insAG variant was found in one Ashkenazi Jewish individual from Russia. The R545Q variant was found in two Asian individuals with primary open-angle glaucoma; one of Filipino ancestry and one of Korean ancestry. In addition to presenting OPTN allele frequencies for Caucasian and Asian populations that have been the subject of previous reports, we also present information for populations of Hispanic and black African ancestries.
CONCLUSIONS: Our study contributes additional evidence to support the previously reported association of the OPTN E50K mutation with glaucoma. After finding an additional 691_692insAG OPTN variant, we can still only conclude that this variant is rare. Combined analysis of our data with data from more than a dozen other studies indicates no association of R545Q with glaucoma in most populations. Those same studies disagree in their conclusions regarding the role of M98K in glaucoma. Our analysis of the combined data provides statistically significant evidence of association of M98K with normal tension glaucoma in Asian populations, but not in Caucasian populations; however, the validity of this conclusion is questionable because of large differences in allele frequencies between and within populations. It is currently not possible to tell how much of the underlying cause of the allele frequency difference is attributable to demographic, technical, or ascertainment differences among the studies. ||||| PURPOSE: To evaluate the role of the optineurin gene (OPTN) in Indian primary open angle glaucoma (POAG) patients from different parts of the country.
METHODS: Two hundred patients with POAG and 200 ethnically matched normal controls were recruited from various parts of India for the study. The entire coding region of OPTN along with the intron-exon boundaries were screened by PCR and single strand conformation polymorphism (SSCP) followed by direct sequencing. A rapid screening method was developed for some of the observed variants by denaturing high performance liquid chromatography (dHPLC). Four variants were also confirmed by digesting the amplicon with appropriate restriction enzymes.
RESULTS: Seven nucleotide changes were observed in OPTN of which one was a putative mutation in exon 16 (Arg545Gln) that was observed in six POAG patients and not in the controls (p<0.05). The remaining variants comprised four single nucleotide polymorphisms (SNPs) in the coding region (Thr34Thr, Met98Lys, Arg149Arg, and Asn303Lys) and two in intron 6 (879-10G>A and 879-5C>T). But frequencies of the minor allele were not significantly different among the patients and controls. The Met98Lys variant that was identified to be a potential risk factor for NTG and POAG in some Asian populations and also for modulating IOP in Caucasian populations, did not exhibit any significant association to the disease phenotype.
CONCLUSIONS: Despite a putative mutation (Arg545Gln) in some patients, the present study does not suggest a significant involvement of OPTN in POAG patients of Indian origin. ||||| PURPOSE: To verify the frequencies of T34T, E50K, M98K, 691_692insAG, and R545Q variants in the optineurin (OPTN) gene in Brazilian subjects with primary open-angle glaucoma (POAG) and controls.
PATIENTS AND METHODS: Ninety-nine patients with POAG and 100 normal controls were enrolled in this study. The frequency of alterations in the OPTN gene was analyzed by direct sequencing and enzymatic digestion of PCR products.
RESULTS: None of the five alterations evaluated was significantly associated with POAG when compared to controls. However, the T34T silent change was present in greater frequency in POAG patients (37.37% vs. 23.00% in controls), while the R545Q change was more prevalent in controls (23.00% vs. 10.10% in POAG). The M98K and 691_692insAG presented with low frequencies in POAG patients (1.01% and 2.02%, respectively) and controls (2.00% and 2.00%, respectively). The E50K substitution was not observed.
CONCLUSION: Our data show no association between the five evaluated variants and POAG in the Brazilian population. ||||| AIMS: To investigate the role of the common OPTN Met98Lys variant as a risk allele in open-angle glaucoma (OAG), autosomal dominant optic atrophy (ADOA) and Leber's hereditary optic neuropathy (LHON).
METHODS: The presence of the Met98Lys variant was determined in a total of 498 (128 with normal-tension glaucoma (NTG)) patients with OAG, 29 patients who had myocilin-related OAG, 101 patients from ADOA pedigrees, 157 patients from LHON pedigrees and 218 examined OAG age-matched normal controls.
RESULTS: 17 of 218 (7.8%) controls had the Met98Lys variant. 28 (5.6%) patients with OAG were Met98Lys positive. More Met98Lys carriers were found in the NTG group than in the high-tension glaucoma (HTG) group (p = 0.033). However, no significant difference was observed between the NTG and control cohorts (p = 0.609). Two MYOC mutation carriers were found to have the variant. The variant was found in 1 of 10 pedigrees with ADOA and in 8 of 35 pedigrees with LHON.
CONCLUSION: Data from this study do not support a strong role for the OPTN Met98Lys variant in glaucoma, ADOA or LHON. However, a weak association was observed of the variant with NTG compared with that with HTG. Meta-analysis of all published data on the variant and glaucoma confirmed that the association, although weak, is highly statistically significant in the cohort with glaucoma versus controls. ||||| OBJECTIVE: To detect the single nucleotide polymorphisms (SNPs) of the myocilin (MYOC) and optineurin (OPTN) genes, and to investigate their associations with high tension glaucoma (HTG) and normal tension glaucoma (NTG).
METHODS: SNPs were detected using polymerase chain reaction (PCR), followed by conformation sensitive gel electrophoresis (CSGE) and fluorescent labeling automated DNA sequencing among 94 unrelated patients with HTG, 48 unrelated patients with NTG, and 77 unrelated control subjects.
RESULTS: Fourteen MYOC sequence alterations were identified, five of them: V53A, I304I, T347T, 1-126T > C, and IVS2 + 172C > A, were novel. Among them, V53A was for the first time found in primary open angle glaucoma (POAG) patient. R76K usually occurred with the promoter polymorphism 1-83G > A. No sequence alterations in the MYOC gene showed significant differences among the HTG, NTG and control subjects (all P > 0.05). A total of 12 sequence alterations were identified in the OPTN gene, and three of them: V161M, I407T and L211L, were novel. Among them, I407T and L211L were found only in the HTG patients. The allele and genotype frequencies of T34T in the NTG patients were significantly higher than those of the controls (P = 0.001 and 0.004 respectively). In HTG, only the allele frequency of T34T was 24% (23/96), significantly higher than those of the NTG group (16.5%, 31/188) and the control group (9.1%, 14/154) (both P < 0.05). In addition, IVS8 + 20G > A was found only in the HTG (3.1%, 3/96) and NTG patients (3.7%, 7/188), and had significantly higher frequencies in the HTG and NTG patients when compared with the controls (P = 0.016 and 0.014, and P = 0.027 and 0.026).
CONCLUSION: Polymorphisms in the MYOC and OPTN genes are associated with POAG in Chinese people. Moreover, sequence alterations not causing amino acid changes may play a role in the pathogenesis of POAG. ||||| PURPOSE: To retrospectively investigate the contribution of myocilin (MYOC) and optineurin (OPTN) sequence variations to adult-onset ocular hypertension (OHT) and primary open-angle glaucoma (POAG) in Spanish patients.
METHODS: The promoter region and the three exons of MYOC were analyzed by direct PCR DNA sequencing in 40 OHT and 110 POAG unrelated patients. We used 98 subjects in whom OHT or glaucoma had been ruled out as controls. We also screened the complete coding region of the OPTN gene (exons 4-16) in all subjects by single-stranded conformational polymorphisms (SSCPs).
RESULTS: We identified six common single nucleotide polymorphisms (SNPs) in the promoter region of MYOC (-1000C>G, -387C>T, -306G>A, -224T>C, -126T>C and -83G>A) and a polymorphic GT microsatellite (-339(GT)11-19). In addition, we detected four novel, rare DNA polymorphisms. None of these DNA sequence variations were associated with either OHT or POAG. We also found three (2.7%) POAG patients with MYOC pathogenic mutations. Two of these pathogenic mutations (Gln368Stop and Ala445Val) were previously described whereas the third (Tyr479His) was novel. Transient expression of the novel mutation in 293T cells supported its pathogenicity. Only two OPTN polymorphisms, which are not associated with the disease, were detected.
CONCLUSIONS: Overall, our data show that in Spain a minority of adult-onset high-pressure POAG patients carry heterozygous disease-causing mutations in the MYOC gene and that OPTN is not involved in either OHT or POAG. ||||| PURPOSE: To investigate sequence variants in the optineurin (OPTN) gene in patients with juvenile-onset open-angle glaucoma (JOAG) in Taiwan.
METHODS: We analyzed the sequence variants of OPTN in 51 unrelated Taiwanese probands with JOAG and in 51 control group subjects who did not have JOAG. Genomic DNA was extracted from the individuals and subjected to polymerase chain reaction (PCR) to amplify all 16 exons and flanking introns of OPTN. The amplified products were then screened for base variants by autosequence. Data from the two study groups were then compared using Fisher's exact test and Armitage's trend test.
RESULTS: Fifteen variants of OPTN were found in the 51 JOAG patients and 51 unrelated normal controls. Two were missense variants (M98K and K322E), one was a synonymous codon change (T34T), and 12 were changes in the noncoding sequences. Seven of the variants have been reported and eight were novel. All of the sequence changes were found in patients with JOAG and in the normal controls except for variant c.-233+25C>G, which was found only in the control group. Allelic frequencies of these sequence changes did not differ significantly between patients and controls (p>0.05) except for the variant c.-233+25C>G (p<0.001). Genotype frequencies of c.-233+25C>G was shown to be significant between the two groups using Fisher's two-tailed exact test (p<0.001) and Armitage's trend test (p=6.815e(-06)).
CONCLUSIONS: Our data indicate that none of the mutations in OPTN are associated with JOAG. The variant M98K is not a risk factor and the variant c.-233+25C>G may be protective against glaucoma in Taiwanese. ||||| PURPOSE: Coding variants in the optineurin gene (OPTN, GLC1E) have been reported to play a role in primary open-angle glaucoma (POAG) in various populations. This study investigated the role of OPTN sequence variants in patients with POAG in Ghana (West Africa).
METHODS: This is a case-control study of unrelated Ghanaian POAG cases and non-glaucomatous controls. Ascertainment criteria for POAG included the presence of glaucomatous optic nerve neuropathy, associated visual field loss, and elevated intraocular pressure (IOP) in both eyes, all in the absence of secondary causes of glaucoma. Controls had normal optic nerves, visual fields, and IOP. All the coding exons of OPTN were polymerase chain reaction (PCR) amplified and sequenced in all 140 cases and 130 controls using an ABI 3730 DNA analyzer.
RESULTS: All the coding exons of OPTN were sequenced in 140 POAG patients and 130 controls. Several coding variants were identified including M98K, A134A, V147L, P292P, A301G, S321S, and E322K. Three coding variants (V147L, P292P, and A301G) have not been reported previously. There were no significant differences on the frequencies of all the identified variants between POAG cases and controls in this population.
CONCLUSIONS: This is the first comprehensive study of OPTN in a single West African population. Our results suggest that coding variants in OPTN may not contribute to the risk for POAG in persons of West African descent. ||||| PURPOSE: To investigate the association of sequence variations in the optineurin (OPTN) gene in patients with open-angle glaucoma.
DESIGN: Prospective case control study.
METHODS: The OPTN gene was screened for sequence variations using a combination of single-strand conformational polymorphism analysis and automated DNA sequencing. A total of 1,299 subjects (1048 glaucoma patients and 251 controls) were screened for variations in the four portions of the gene that had been previously associated with glaucoma. A subset of these subjects (376 patients and 176 controls) was screened for variations in the entire coding sequence. Twenty-four percent of the patients and 35% of the controls were Japanese, whereas the remainder were predominantly Caucasian. Allele frequencies were compared with the Fisher exact test.
RESULTS: The OPTN sequence variations were not significantly associated with any form of high-tension open-angle glaucoma. One proband with familial normal-tension glaucoma was found to harbor the previously reported Glu50Lys variation. Another previously reported change, Met98Lys, was associated with normal-tension glaucoma in Japanese but not in Caucasian patients.
CONCLUSIONS: This study provides some additional evidence for the association of the Glu50Lys OPTN sequence variation with familial normal tension glaucoma. However, because familial normal-tension glaucoma is so rare, this change seems to be responsible for less than 0.1% of all open-angle glaucoma. The Arg545Gln variation is likely to be a nondisease-causing polymorphism. The Met98Lys change may be associated with a fraction of normal-tension glaucoma in patients of Japanese ethnicity. ||||| OBJECTIVE: Glaucoma, a leading cause of blindness in the world, is characterized by neuropathy of the retinal ganglion cells and the optic nerve. Recently, sequence alterations in the optineurin gene were shown to be associated with the disease in families with primarily normal tension glaucoma.
METHODS: In the present study, 200 patients with primary open-angle glaucoma, 200 patients with exfoliative glaucoma, and 200 matched controls were tested for alterations in the coding sequences using denaturing high-performance liquid chromatography and sequencing. In addition, single nucleotide polymorphisms distributed throughout the gene were typed and haplotypes were constructed.
RESULTS: No disease-causing alterations were found in either of the patient cohorts. The risk-associated allele M98K was found in equal amounts in both patients and controls. Analysis of haplotype frequencies and distribution revealed high haplotype diversity but no differences between patients and controls.
CONCLUSION: These experiments show no association between optineurin and our Swedish cohorts of high-pressure glaucoma cases, either in coding sequence or in haplotype frequency and distribution. ||||| Glaucoma represents one of the most common eye diseases and is characterized by progressive loss of visual fields. In the more advanced stages bilateral blindness may result, due to optic nerve atrophy and an excavated optic nerve head. Open-angle glaucoma is one of the main disease subsets, which may be further divided into high tension primary open-angle glaucoma (POAG) and normal tension glaucoma (NTG). Recently, the optineurin ( OPTN) gene was identified as a causative factor for NTG. Alterations in this gene were found in Caucasian families with NTG. In particular, c.458G>A, c.691-692insAG and c.1944G>A were shown to be risk factors. Since NTG is reported to be the most common form of glaucoma in Japan, and to identify if the OPTN gene plays a role in POAG, the DNAs from 148 unrelated Japanese patients with NTG, 165 patients with POAG and 196 unrelated controls who were not suffering glaucoma were investigated by appropriate genotyping techniques. No glaucoma-specific mutations were found in the OPTN gene in Japanese glaucoma patients. However, some novel single-nucleotide polymorphisms (SNPs) in the exons and introns are reported in this paper for the first time. ||||| PURPOSE: To evaluate the individual and interactive effects of polymorphisms in the myocilin (MYOC),optineurin (OPTN), WD repeat domain 36 (WDR36), and apolipoprotein E (APOE) genes on primary open-angle glaucoma (POAG) in northern Chinese.
METHODS: Northern Chinese study subjects, 176 POAG patients and 200 controls, were recruited for screening of the coding exons and splicing regions of MYOC. Five single nucleotide polymorphisms (SNPs) in OPTN (M98K, R545Q, IVS5+38T>G, IVS8-53T>C, and IVS15+10G>A), one SNP in WDR36 (IVS5+30C>T) as well as the APOE promoter and epsilon2/epsilon3/epsilon4 polymorphisms were also examined. Association analysis was performed by using chi(2) analysis. High-order gene-gene interaction was also analyzed using the multifactor dimensionality reduction (MDR) method.
RESULTS: In MYOC, 22 variants were identified. Four of them were novel but found in controls only. The missense mutation, Val53Ala, is likely a glaucoma causing mutation, accounting for 0.6% of cases. No individual polymorphism in OPTN, WDR36, or APOE was associated with POAG. MDR analysis identified a best 6-factor model for POAG: MYOC IVS2+35A>G, OPTN Met98Lys, OPTN IVS5+38T>G, OPTN IVS8-53T>C, WDR36 IVS5+30C>T, and APOE -491A>T.
CONCLUSIONS: The association pattern between the genes, MYOC, OPTN, WDR36, and APOE, and POAG in northern Chinese is different from that of southern Chinese. Disease-causing mutations in MYOC accounted for a small proportion of northern Chinese POAG patients. Common polymorphisms in these genes were not associated with POAG individually but might interactively contribute to the disorder, supporting a polygenic etiology. ||||| PURPOSE: Optineurin gene (OPTN) mutations are reported in primary open angle glaucoma patients (POAG) from different populations. The coding and noncoding regions of OPTN were screened for mutations in 100 Indian high tension glaucoma patients (HTG). The frequency of the OPTN M98K mutation in an additional 120 patients (70 HTG and 50 normal tension glaucoma [NTG]) was analyzed by restriction enzyme digestion.
METHODS: The HTG patients (about 40 years of age) were characterized by open angles on gonioscopy, with raised intraocular pressure (IOP) more than 21 mmHg (<21 mmHg on office diurnal phasing for NTG), and typical glaucomatous disc changes with corresponding visual field defects in the absence of any secondary cause. One hundred HTG patients and controls were screened for OPTN mutations by direct sequencing using an ABI prism 310/3100 Avant genetic analyzer. The M98K status was analyzed by restriction enzyme digestion with StuI. A genotype/phenotype correlation was also attempted for OPTN sequence alterations with clinical parameters such as age at diagnosis, intraocular pressure, cup:disc ratio, etc. The putative change in the transcription factor binding site for the IVS7 +24G>A polymorphism was attempted with AliBaba software (version 2.1).
RESULTS: Six sequence alterations were observed in the 100 POAG patients by direct sequencing. The M98K substitution was observed in a total of 10 patients (7/170 HTG and 3/50 NTG) contributing to 4.1% in HTG and 6% in the NTG group and not in the controls. The IVS7+24G>A nucleotide change showed a significant difference in the HTG group (7/100) when compared to the control group (0/100) and found to be associated with increased IOP at diagnosis (p=0.03). The IVS7+24G>A polymorphism resulted in the creation of binding sites for transcription factors NF-1 and CPE that were not present in the wild type.
CONCLUSIONS: The current study suggests a possible role of SNPs rather than mutations in OPTN in POAG pathology in the Indian population. ||||| PURPOSE: To study the clinical relevance of sequence alterations in the optineurin gene (OPTN) among Japanese patients with open-angle glaucoma, including both primary open-angle glaucoma (POAG) and normal tension glaucoma (NTG).
METHODS: Genomic DNA was isolated from 83 patients with open-angle glaucoma (55 with POAG and 28 with NTG) and 58 control subjects. The 13 exons of OPTN corresponding to the coding region were amplified by polymerase chain reaction and directly sequenced. Clinical factors were compared between glaucoma patients with and without a certain nucleotide change.
RESULTS: The reported heterozygous mutations, c.458G > A(Glu50Lys) in exon 4 and c.691_692insAG in exon 6, were not found in any glaucoma patients or control subjects. The reported c.603T > A(Met98Lys) in exon 5 was significantly more prevalent in the POAG (8/55, 14.5%, p=0.0147) and NTG (4/28, 14.2%, p=0.0369) patients, and even in both the POAG and NTG patients combined (12/83, 14.4%, p=0.0149, Fisher exact probability test), than in the control subjects (1/58, 1.7%). The rates of the reported c.1944G > A(Arg545Gln) in exon 16 were not significantly different between open-angle glaucoma patients (3/83, 3.6%) and control subjects (4/58, 6.8%). In addition, a heterozygous change, c.412G > A(Thr34Thr) in exon 4 was found in 18 (21.6%) open-angle glaucoma patients and seven (12.0%) control subjects. Another heterozygous change, c.457C > T(Thr49Thr), in exon 4 was found only in three POAG patients. The 18 open-angle glaucoma patients with c.412G > A showed significantly larger cup-to-disc ratios (p=0.0178, Mann-Whitney U test), significantly more deteriorated mean deviations of the visual field in the left eye at the final visit (p=0.0076), and a significantly higher rate of surgery and/or laser history (p=0.0321, Fisher exact probability test) than the 65 open-angle glaucoma patients without the nucleotide change.
CONCLUSIONS: Met98Lys is a risk-associated alteration for open-angle glaucoma, including POAG and NTG, in the Japanese population as initially reported. The amino acid-preserving polymorphism, c.412G > A, may be a genetic risk factor for the progression of open- angle glaucoma in this Japanese population. ||||| PURPOSE: To determine whether mutations in the optineurin (OPTN) gene are associated with the incidence of primary open-angle glaucoma (POAG) and normal tension glaucoma (NTG) in the Japanese.
METHODS: Eighty-nine unrelated Japanese patients with POAG and 65 unrelated patients with NTG were studied. Genomic DNA was extracted from leukocytes of the peripheral blood, and thirteen exons of the OPTN gene were amplified by polymerase chain reaction (PCR) and directly sequenced.
RESULTS: Sequence alterations in exons 4 (His26Asp), 5 (Met98Lys), and 16 (Arg545Gln) were found. The His26Asp and Arg545Gln mutations were not detected in 100 ethnically matched controls. The frequency of the missense Met98Lys variant was higher in the POAG and NTG groups than in the control group (16.9% versus 5%, 15.4% versus 5%; P = 0.009 and P = 0.029, and odds ratio 3.85 and 3.45, respectively, for the dominant effect of the OPTN A allele). Polymorphisms in exons 4 and 12, and in introns 6 and 7 were also detected.
CONCLUSIONS: The association of the allelic variation (Met98Lys) in the OPTN gene and the prevalence of POAG and NTG in unrelated Japanese patients suggest that they are involved in the pathogenesis of POAG and NTG. | [
{
"source_pmid": "16148883",
"source_text": "PURPOSE: To evaluate the association of myocilin (MYOC), optineurin (OPTN), and apolipoprotein E (APOE) genes and their interactions in primary open angle glaucoma (POAG).\nMETHODS: A cohort of 400 unrelated POAG patients (294 high tension glaucoma, HTG, and 106 ... |
23440797 | AUTHORS' CONCLUSIONS: Based on the included trials, we found no evidence that antiangiogenic steroids prevent visual loss in patients with neovascular AMD. With the emergence of anti-vascular endothelial growth factor modalities, based on evidence summarized in this review, it is unclear what role steroids have in treating patients with neovascular AMD. | OBJECTIVE: To determine the safety of a single intravitreal injection of triamcinolone acetonide (4 mg) in patients with subfoveal choroidal neovascularization caused by age-related macular degeneration.
METHODS: A double-masked, placebo-controlled, randomized clinical trial was conducted at a public tertiary referral eye hospital. Patients participating had age-related macular degeneration with evidence of choroidal neovascularization, any part of which was classic; age older than 59 years; and best-corrected visual acuity of 20/200 or better. Eyes were assigned to active study treatment or to placebo. Intraocular pressure and cataract grading were performed every 6 months for 3 years. Adverse events, from mild to vision-threatening or life-threatening, were recorded as procedure-related or corticosteroid-related.
RESULTS: Seventy-five eyes were assigned to study treatment and 76 eyes to placebo. There were no moderate or severe adverse events related to the surgical procedure in either group. Triamcinolone-treated eyes had a significantly increased risk of developing mild or moderate elevation of the intraocular pressure. Topical glaucoma medication reduced intraocular pressure to acceptable levels in all patients. There was significant progression of cataract in the triamcinolone-treated eyes.
CONCLUSION: Despite a significant adverse event profile, intravitreal triamcinolone is generally well tolerated by the human eye as long as patients are carefully followed up by their surgeon and treated appropriately, when necessary. ||||| PURPOSE: To evaluate safety and efficacy of the angiostatic agent anecortave acetate, compared with a placebo, for treatment of subfoveal choroidal neovascularization (CNV).
DESIGN: Ongoing masked, randomized, placebo-controlled, parallel evaluation of anecortave acetate (30 mg, 15 mg, and 3 mg) versus a placebo.
PARTICIPANTS: There were 128 eyes of 128 patients with subfoveal CNV secondary to age-related macular degeneration who were enrolled and treated, with 80% (102/128) of eyes presenting with predominantly classic lesions at baseline.
METHODS: All eyes received a posterior juxtascleral depot application of masked study medication or a placebo, with retreatment at 6-month intervals if the masked investigator believed the patient could benefit. Patients received periodic detailed ophthalmic examinations with both fluorescein and indocyanine green angiography, general physical examinations with electrocardiograms, and hematology/serum chemistry/urinalysis. All ophthalmic and systemic safety data were periodically reviewed by the Independent Safety Committee overseeing the study.
MAIN OUTCOME MEASURES: Best-corrected logarithm of the minimum angle of resolution (logMAR) vision and fluorescein angiographic lesion characteristics were compared over time and among treatment groups.
RESULTS: At month 12, anecortave acetate (15 mg) administered at 6-month intervals was statistically superior to the placebo for 3 measures of clinical efficacy: mean change from baseline vision (P = 0.0131), stabilization of vision (<3 logMAR line change; P = 0.0323), and prevention of severe vision loss (decrease of > or = 6 logMAR lines from baseline; P = 0.0224). Subgroup analysis of predominantly classic lesions revealed that anecortave acetate (15 mg) was also superior to the placebo at 1 year for each of these 3 measures of visual outcome (Ps = 0.0022, 0.0100, and 0.0299, respectively). Anecortave acetate (15 mg) trended toward significance over the placebo at month 12 for inhibition of total lesion growth and for inhibition of both the total CNV component and the classic CNV component in both the overall and subgroup analyses. The Independent Safety Committee identified no clinically relevant treatment-related safety issues.
CONCLUSIONS: Anecortave acetate (15 mg) is safe and clinically efficacious at 1 year for maintaining vision, preventing severe vision loss, and inhibiting subfoveal CNV lesion growth. ||||| BACKGROUND: Anecortave acetate is a synthetic derivative of cortisol, but very specific and irreversible chemical modifications to the cortisol structure have resulted in the creation of a potent inhibitor of blood vessel growth with no evidence non-clinically or clinically of glucocorticoid receptor-mediated bioactivity. The clinical safety of Anecortave Acetate administered as a posterior juxtascleral depot every 6 months for up to 4 years is reviewed in this manuscript.
METHODS: Clinical safety and efficacy of the novel angiostatic agent Anecortave Acetate for Depot Suspension was evaluated in patients with subfoveal exudative age-related macular degeneration (AMD) in a masked, randomized, dose-duration clinical trial completed in June 2003. This safety and efficacy study enrolled and treated 128 patients at 18 clinical sites in the US and EU. This was the first clinical trial of Anecortave Acetate for Depot Suspension administered as a posterior juxtascleral depot. Assessments of clinical safety were made with general physical examinations including electrocardiograms and hematology/serum chemistry/urinalysis, detailed ophthalmic evaluations with fluorescein/indocyanine green angiography and assessments of best-corrected logMAR visual acuity. All safety reports have been reviewed periodically by an Independent Safety Committee responsible for overseeing these activities.
RESULTS: No clinically relevant safety issues related to either Anecortave Acetate for Depot Suspension or the administration procedure have been identified by an Independent Safety Committee. The most frequent safety issues reported were cataractous changes, decreased visual acuity, ptosis, ocular pain, abnormal vision and subconjunctival hemorrhage, but the majority of these were assessed as unrelated to treatment.
CONCLUSIONS: Anecortave Acetate for Depot Suspension (3, 15 and 30 mg) is clinically safe following administration and re-administration at 6-month intervals as a posterior juxtascleral depot using a specially designed curved cannula. ||||| PURPOSE: To compare 1-year safety and efficacy of anecortave acetate 15 mg with photodynamic therapy (PDT) with verteporfin in patients eligible for initial PDT treatment.
DESIGN: Prospective, masked, randomized, multicenter, parallel group, active control, noninferiority clinical trial.
PARTICIPANTS: Five hundred thirty patients with predominantly classic subfoveal choroidal neovascularization secondary to age-related macular degeneration were randomized to treatment with either anecortave acetate 15 mg or PDT.
METHODS: In the anecortave acetate group, the drug was administered under the Tenon's capsule as a periocular posterior juxtascleral depot (PJD) at the beginning of the study and at month 6. Before the first administration of anecortave acetate, patients in this treatment group received a sham PDT treatment, and sham PDT treatments were repeated every 3 months if there was evidence of leakage on fluorescein angiography (FA). Patients assigned to PDT received up to 4 PDT treatments at 3-month intervals, as needed based upon FA, and a sham PJD procedure at the beginning of the study and at month 6. Best-corrected visual acuity was determined at baseline and all follow-up visits. Safety data were regularly reviewed by an independent safety committee.
MAIN OUTCOME MEASURE: Percent responders (patients losing <3 lines of vision) at month 12.
RESULTS: Percent responders in the anecortave acetate and PDT groups were 45% and 49%, respectively (not statistically different, P = 0.43). The confidence interval (CI) for the difference ranged from -13.2% favoring PDT to +5.6% favoring anecortave acetate. The month 12 clinical outcome for anecortave acetate was improved in patients for whom reflux was controlled and who were treated within the 6-month treatment window (57% vs. 49%; 95% CI, -4.3% favoring PDT to +21.7% favoring anecortave acetate). No serious adverse events related to the study drug were reported in either treatment group.
CONCLUSIONS: The safety and efficacy outcomes in this study demonstrate that the benefits of anecortave acetate for the treatment of choroidal neovascularization outweigh the risks associated with either the drug or the PJD administration procedure. ||||| OBJECTIVE: To determine if a single intravitreal injection of 4 mg of triamcinolone acetonide in patients with classic choroidal neovascularization associated with age-related macular degeneration can safely reduce the risk of severe visual loss.
METHODS: A double-masked, placebo-controlled, randomized clinical trial was performed in patients 60 years or older who had choroidal neovascularization with any classic component, a duration of symptoms of less than 1 year, and a visual acuity of 20/200 or better. Best-corrected visual acuity, intraocular pressure, and cataract grading were performed before the injection and then at 3, 6, and 12 months.
MAIN OUTCOME MEASURE: The development of severe loss of vision (30 letters) by survival analysis on an intention-to-treat basis.
RESULTS: One hundred fifty-one eyes were randomized into the study, and follow-up data were obtained for 73 (97%) of the 75 eyes in the treated group and for 70 (92%) of the 76 eyes in the control group. There was no difference between the 2 groups for the development of severe visual loss during the first year of the study (log-rank chi 2(1) = 0.03, P =.90). In both groups, the 12-month risk of severe visual loss was 35%, with a hazard ratio of 1.05 (95% confidence interval, 0.59-1.86). The change in size of the neovascular membranes, however, was significantly less in eyes receiving triamcinolone than in those receiving placebo 3 months after treatment (P =.01), although no difference was noted after 12 months. After 12 months, treated eyes had a significantly higher risk of an elevated intraocular pressure (31/75 [41%] vs 3/76 [4%]; P<.001), but not of cataract progression (P =.29).
CONCLUSIONS: A single dose of intravitreal triamcinolone had no effect on the risk of loss of visual acuity during the first year of the study in eyes with age-related macular degeneration and classic choroidal neovascularization, despite a significant antiangiogenic effect found 3 months after treatment. This biological effect warrants further study. ||||| PURPOSE: Anecortave acetate is a novel angiostatic cortisene being evaluated clinically for treatment of exudative age-related macular degeneration (ARMD). A randomized, placebo-controlled, efficacy and safety dose duration study of anecortave acetate for depot suspension (3 mg, 15 mg, 30 mg) in this patient population was completed in June 2003. As part of this trial, 128 patients with subfoveal choroidal neovascularization (CNV) secondary to ARMD were enrolled and treated for up to 2 years by 18 clinical sites in the United States and European Union.
METHODS: Study patients were evaluated clinically with detailed ophthalmic examinations, general physical examinations, assessments of best-corrected logMAR visual acuity, and angiographic evaluations. The Digital Angiography Reading Center (New York City, NY) assessed lesion eligibility while the clinical investigators assessed overall patient eligibility prior to treatment. As part of this study, study medication was delivered as a posterior juxtascleral depot using a specially designed curved cannula at 6-month intervals if in the masked investigator's opinion the patient's lesion could benefit from additional treatment.
RESULTS: The 2-year efficacy results of this placebo-controlled study demonstrated that RETAANE 15 mg (anecortave acetate for depot suspension) was statistically superior to placebo for stabilization of vision (<3 logMAR line change from baseline) and for inhibition of neovascular lesion growth. There were no serious treatment-related safety issues associated with either the study medication or the procedure for administration.
CONCLUSIONS: Anecortave acetate 15 mg for depot suspension is clinically efficacious compared to placebo for treatment of subfoveal exudative ARMD lesions when administered at 6-month intervals as a posterior juxtascleral depot. | [
{
"source_pmid": "15006845",
"source_text": "OBJECTIVE: To determine the safety of a single intravitreal injection of triamcinolone acetonide (4 mg) in patients with subfoveal choroidal neovascularization caused by age-related macular degeneration.\nMETHODS: A double-masked, placebo-controlled, randomized c... |
31428642 | Conclusion: The meta-analysis highlighted that certain mutations of some TLR4 polymorphisms might increase the susceptibility of OAG. However, TLR4 polymorphisms are still far from being candidate genetic biomarkers for OAG. Additional researches involving larger scale epidemiological studies are warranted to validate our results. | PURPOSE: To evaluate the association of Toll-like receptor 4 (TLR4) gene polymorphisms with normal tension glaucoma (NTG) in the South Korean population.
METHODS: A total of 147 normal tension glaucoma patients in South Korea were recruited from April, 2007 to August, 2008. Allele, genotype, and haplotype of 8 different types of TLR4 single nucleotide polymorphisms were analyzed: rs10759930, rs1927914, rs1927911, rs12377632, rs2149356, rs11536889, rs7037117, and rs7045953. Three hundred eighty healthy, unrelated South Korean adults were enrolled as controls.
RESULTS: Frequencies of the TLR4 allele did not show any statistically significant difference between normal tension glaucoma patients and the control group (p>0.00625). The same results were observed in genotype frequency analysis. In addition, no statistically significant difference was observed in the frequency of haplotypes in cases of normal tension glaucoma when compared with controls.
CONCLUSIONS: TLR4 single nucleotide polymorphisms are not associated with normal tension glaucoma. Findings from this study suggest that TLR4 polymorphisms may not play an important role in NTG pathogenesis in the South Korean population. ||||| BACKGROUND: To investigate whether SNP rs4986790 in toll-like receptors (TLRs) is a risk factor for primary open angle glaucoma (POAG) in a Saudi population.
MATERIALS AND METHODS: A cohort of 85 unrelated POAG patients and 95 unrelated control subjects from Saudi Arabia were genotyped utilizing Taq-Man® assay. The association between mutant genotypes and various clinical indices important for POAG was investigated.
RESULTS: Among cases, the normal pattern (A/A) was detected in 70 (82.4%) of the subjects, A/G in 14 (16.5%) and G/G in one subject only (1.2%). Among controls, prevalence of the genotype (A/A) was detected in 86 (90.5%), the (A/G) genotype in 8 (8.4%) and homozygous mutated genotype (G/G) in 1 (1.1%) subjects. Comparing cases to controls, the odds ratio of having heterozygous mutation (A/G) was 2.15 [95% CI: 0.853-5.417], which was not significant (p = 0.114). The odds ratio of having homozygous mutation (G/G) was 1.22 [95% CI: 0.075-19.99], which was statistically non-significant (p = 0.568). Likewise, the presence of the mutated allele (G) was non-significantly different between cases and controls (p = 0.154). Comparing cases to controls as regards co-morbidity with other systemic diseases, there were no statistically significant differences between groups in all assessed diseases except for a family history of glaucoma (p = 0.014)
CONCLUSIONS: In conclusion, we could not detect any direct link between genotypes or allele frequencies of SNP rs4986790 in the TLR4 gene and POAG. In contrast, genotype (A/A) may be protective against POAG especially among individuals with no family history of glaucoma. ||||| PURPOSE: Toll-like receptor 4 (TLR4) is a transmembrane receptor that mediates immune responses to exogenous and endogenous ligands. Previously, non-coding single nucleotide polymorphisms (SNPs) in the TLR4 gene were related to primary open angle glaucoma (POAG). This study was undertaken to investigate whether coding TLR4 Asp299Gly (rs4986790 A/G) and Thr399Ile (rs4986791 C/T) are associated with POAG in a Mexican population.
METHODS: One hundred and eighty-seven unrelated Mexican patients with POAG (94 men and 95 women; mean age 66.49 ± 14.3 years) and 109 control subjects (40 men and 69 women; age, 63.28 ± 7.93 years) were included. SNPs Asp299Gly (rs4986790 A/G) and Thr399Ile (rs4986791 C/T) were genotyped by a Taqman® Allelic Discrimination Assayand. Allelic, genotypic, haplotypic, and model-based (dominant, recessive, and codominant) associations of the SNPs with POAG were analyzed using Chi-squared tests or Fisher exact tests and logistic regression.
RESULTS: Strong linkage disequilibrium was observed among the SNPs (D' = 0.8692), which were located in one haplotype block. With respect to allelic diversity, the minor allele of both SNPs generates a significantly increased risk of POAG. The minor allele of Asp299Gly conferred the highest increased risk of POAG (P = 0.0054, OR = 4.47, 95% CI = 1.46-13.70). With regard to genotypic diversity, individuals carrying the minor allele of Asp299Gly and Thr399Ile had a significant increased risk for POAG with OR of 4.47 (P = 0.054, 95% CI = 1.30-15.35) and 3.5, respectively (P = 0.012, 95% CI = 1.17-10.44). Haplotype analysis was non-significant.
CONCLUSIONS: TLR4 coding SNPs Asp299Gly and Thr399Ile might be used as genetic susceptibility alleles for POAG in Mexican population. Our findings support the role of TLR4 in the pathophysiology of glaucoma. ||||| BACKGROUND: Toll-like receptor 4 (TLR4) non-coding polymorphisms are associated to primary open angle glaucoma (POAG), normal tension glaucoma, and pseudoexfoliation glaucoma. This study was performed to determine whether non-coding single nucleotide polymorphisms (SNPs) in the TLR4 gene contribute to POAG in a Mexican population.
MATERIAL AND METHODS: A total of 187 unrelated Mexican patients with POAG and 109 control subjects were included. Allelic, genotypic, and haplotypic diversity was assessed for the non-coding polymorphisms rs11536889, rs1927911, rs12377632, and rs2149356 of the TLR4 gene. Genotyping of target SNPs was performed by 5' exonuclease allelic discrimination assays.
RESULTS: Strong linkage disequilibrium was observed among the SNPs (D' > 0.818), which were located in one haplotype block. The rs11536889 polymorphism was not associated to POAG in any case. The frequency of the minor allele of rs2149356 was significantly higher in the glaucoma group, conferring an increased risk of POAG (p = 0.0018, OR = 1.803, 95% CI 1.2556-2.5890) whereas minor allele of rs12377632 was significantly lower, attributing a protective effect (p = 0.0001, OR = 0.6662, 95% CI 0.4753-0.9339). Subjects with genotypes carrying the minor allele of rs1927911 and rs2149356 shown an increased risk for POAG (p = 0.03, OR = 1.78, 95% CI 1.10-2.87, and p < 0.0004, OR =2.62, 95%CI 1.61-4.27 respectively). Finally, we found significant risk haplotypes. The GTT haplotype (constituted by rs1927911, rs12377632, and rs2149356) reached the higher OR (p = 0.0026, OR = 4.70, 95% CI 1.73-12.77).
CONCLUSIONS: We have identified intronic TLR4 SNPs as genetic susceptibility alleles for POAG in a Mexican population. Our findings support the association of the TLR4 gene with POAG. ||||| AIMS: To investigate whether single nucleotide polymorphism (SNP) rs4986791 (C>T) in the toll-like receptor 4 (TLR4) gene is a risk factor for primary open-angle glaucoma (POAG) in the Saudi population.
METHOD: A case-control study was performed to genotype a cohort of 85 POAG patients and 95 matched healthy controls utilizing TaqMan(®). The association between mutant genotypes and various POAG clinical indices were investigated.
RESULTS: The wild-type (C/C), heterozygous (C/T), and homozygous (T/T) genotypes were observed in 85.9%, 12.9%, and 1.2% POAG cases, respectively, compared to 91.6%, 8.4%, and none, respectively, among controls. The minor allele frequency was 0.076 in cases and 0.042 in controls. Both the genotype and allele frequency among POAG cases and controls did not vary significantly. With the exception of family history of glaucoma (p = 0.032), no significant association of genotypes was seen with age, intraocular pressure, cup/disc ratio, number of antiglaucoma medications, and other systemic comorbidities among the POAG cases.
CONCLUSION: We did not detect any direct association between genotypes or allele frequencies of SNP rs4986791 in the TLR4 gene and POAG. ||||| PURPOSE: Toll-like receptor 4 (TLR4) is a transmembrane receptor that mediates immune responses to exogenous and endogenous ligands and interacts with heat shock proteins, which are reportedly involved in normal tension glaucoma (NTG). This study was undertaken to investigate whether TLR4 polymorphisms are associated with NTG.
METHODS: Two hundred fifty Japanese patients with NTG and 318 Japanese healthy control subjects were recruited. Eight single-nucleotide polymorphisms (SNPs) in the TLR4 gene were genotyped, and allelic and phenotypic diversity was assessed between cases and control subjects.
RESULTS: Strong linkage disequilibrium was observed among all SNPs (D' >or= 0.85), which were located in one haplotype block. With respect to allelic diversity, the minor allele of three SNPs (rs10759930, rs1927914, and rs7037117) carried a significantly increased risk of NTG. With regard to genotypic diversity, individuals with the minor allele of six SNPs (rs10759930, rs1927914, rs1927911, rs12377632, rs2149356, and rs7037117) had a 1.47- to 1.65-fold increased risk of NTG. rs7037117, located in the 3'-untranslated region of TLR4, was most strongly associated with NTG, and when incorporated into a haplotype with rs10759930, the strongest association was detected (P = 0.0038, P(c) = 0.0095).
CONCLUSIONS: Multiple SNPs in the TLR4 gene are associated with the risk of NTG. This finding suggests that the ligands and/or cytokines involved in the TLR4 signaling network may be risk factors for the development of NTG. ||||| PURPOSE: To investigate the associations between gene variants in cholesterol 24S-hydroxylase (CYP46A1), LIM homeobox transcription factor 1-beta (LMX1B), plexin domain containing 2 (PLXDC2), toll-like receptor 4 (TLR4), transmembrane and tetratricopeptide repeat containing 2 (TMTC2), zona pellucida glycoprotein 4 (ZP4), chromosome 2p16.3, and primary open-angle glaucoma (POAG).
METHODS: We studied 462 POAG patients and 577 controls from three cohorts (Hong Kong, Shantou, and Beijing, China). Twelve single-nucleotide polymorphisms (SNPs) were genotyped in the Hong Kong cohort using TaqMan genotyping assay. Significant associations were validated in the Shantou and Beijing cohorts.
RESULTS: Association of POAG with TLR4 rs7037117, in a recessive model, was identified in the Hong Kong and Shantou cohorts (both southern Chinese, p(rec)=0.0019) but not the Beijing cohort (northern Chinese). rs1533428 at chromosome 2p16.3 showed a consistent trend of age-specific association in all three cohorts. Genotypes TT + CT conferred a 2.16 fold of significantly increased risk to late-onset POAG (p(dom)=0.00025), but no significant risk to POAG of younger ages of onset in the combined cohort. A joint effect was found between rs7037117 and rs1533428, with carriers of both higher-risk genotypes having a 4.53 fold of increased disease risk (p=0.00028).
CONCLUSIONS: Our study reveals discrepant association patterns of 12 candidate SNPs in 7 genes/loci with POAG in Chinese, provides positive replications for POAG markers rs1533428 at 2p16.3 and TLR4 rs7037117, and suggests that rs1533428 is a putative risk variant for late-onset POAG. The identification of an age-specific association between rs1533428 and late-onset POAG highlights a new genotype-phenotype association in POAG. Further studies are warranted to confirm the age-specific association. ||||| PURPOSE: To determine whether polymorphisms in the Toll-like receptor 4 (TLR4) gene are associated with primary open-angle glaucoma (POAG), normal-tension glaucoma (NTG), and exfoliation glaucoma (XFG) in Japanese individuals.
DESIGN: Genetic association study.
METHODS: None
SETTING: Multicenter study.
STUDY POPULATION: One hundred eighty-four unrelated Japanese patients with POAG, 365 unrelated patients with NTG, and 109 unrelated patients with XFG from 5 hospitals.
PROCEDURES: Genomic DNA was extracted from leukocytes of the peripheral blood, and 8 polymorphisms in the TLR4 genes were amplified by polymerase chain reaction (PCR) and directly sequenced. Allele and genotype frequencies and the inferred haplotypes were estimated.
MAIN OUTCOME MEASURES: Differences in allele and genotype frequencies and haplotypes between subjects with POAG, NTG, and XFG.
RESULTS: The allele frequency of rs2149356 of the TLR4 gene in the POAG, NTG, and XFG groups was the most significantly different from that of the control group (minor allele frequency 0.446, 0.395, 0.404, vs 0.308; P = .000058, P = .0030, and P = .015). The allele frequencies of the 5 TLR4 SNPs were higher in all of the glaucoma groups than that in the control group. The statistics of genotypes of TLR4 were approximately the same for all allele frequencies. The haplotypic frequencies with Tag SNPs studied earlier showed that only POAG was statistically significant. Other haplotypes, such as rs10759930, rs1927914, rs1927911, and rs2149356, had higher statistical significance (overall P = .00078 in POAG, overall P = .018 in NTG, and overall P = .014 in XFG).
CONCLUSIONS: This study demonstrated that TLR4 polymorphisms are associated with NTG in the Japanese, and they also play a role in the pathogenesis of POAG and XFG. | [
{
"source_pmid": "21921986",
"source_text": "PURPOSE: To evaluate the association of Toll-like receptor 4 (TLR4) gene polymorphisms with normal tension glaucoma (NTG) in the South Korean population.\nMETHODS: A total of 147 normal tension glaucoma patients in South Korea were recruited from April, 2007 to A... |
16235305 | AUTHORS' CONCLUSIONS: Intraoperative MMC reduces the risk of surgical failure in eyes that have undergone no previous surgery and in eyes at high risk of failure. Compared to placebo it reduces mean IOP at 12 months in all groups of participants in this review. Apart from an increase in cataract formation following MMC, there was insufficient power to detect any increase in other serious side effects such as endophthalmitis. | OBJECTIVE: This study aimed to investigate whether previously failed glaucoma filtration surgery is a risk factor for filtration failure of subsequent trabeculectomy combined with cataract surgery and to determine the role of adjunctive mitomycin C (MMC) in the secondary glaucoma triple procedure (SGTP) as compared to primary glaucoma triple procedure (PGTP).
DESIGN: A prospective, controlled study that was randomized with respect to assignment to adjunctive MMC and a case-control design with respect to comparisons between SGTP and PGTP was studied.
PARTICIPANTS: The SGTP group consisted of 49 eyes of 49 consecutive patients with primary open-angle glaucoma with a history of glaucoma filtration surgery requiring glaucoma medical therapy and in need of cataract surgery, randomized to adjunctive MMC (SGTP MMC subgroup of 21 eyes) and no adjunctive MMC (SGTP control subgroup of 28 eyes). The PGTP group consisted of 49 PGTP cases closely matched to the SGTP cases with respect to age, race, gender, MMC use, C:D ratio, and systemic diseases.
INTERVENTION: Trabeculectomy combined with phacoemulsification and a small incision (5 x 6 mm), all polymethylmethacrylate posterior chamber intraocular lens implantation with or without adjunctive MMC (0.5 mg/ml for 1 minute), was performed.
MAIN OUTCOME MEASURES: Surgery failure was defined as the need of an additional intraocular procedure or the need of more than one medication to achieve intraocular pressure control to the target level. Intragroup and intergroup comparisons were made with respect to filtration outcome among the SGTP and PGTP patients.
RESULTS: Without adjunctive MMC, filtration success was significantly less in SGTP than in PGTP (P = 0.03). Adjunctive MMC significantly increased the success rate of SGTP (P = 0.02) but not that of PGTP (P = 0.89) over the average follow-up period of 2 years.
CONCLUSIONS: Previously failed glaucoma filtration surgery is a significant risk factor for the filtration failure of combined surgery. Intraoperative use of adjunctive MMC significantly improves the filtration success rate of SGTP. ||||| PURPOSE: The purpose of this study was to analyze the efficacy and safety of low-dose (0.2 mg/ml) intraoperative mitomycin C in primary trabeculectomy.
METHODS: Twenty-eight eyes of 28 patients with advanced primary open-angle glaucoma undergoing primary trabeculectomy were randomized to either mitomycin C (0.2 mg/ml) or saline solution intraoperatively for 3 min. Intraocular pressure was measured at 1 day; 1 week; 1, 3, and 6 months postoperatively; and at the final visit.
RESULTS: Mean follow-up was 17.0 +/- 5.6 months for the mitomycin C group and 15.7 +/- 5.1 months for the control group. Mean intraocular pressures were significantly lower in the treated group on the first postoperative day (p = 0.021), at the 6-month interval (p = 0.001), and at the final visit (p = 0.001). At the last follow-up examination, intraocular pressure was < or = 15 mm Hg in 12 (85.7%) of the mitomycin C-treated eyes and in four (28.6%) of the control eyes (p = 0.002). Life table analysis showed a significantly higher probability of intraocular pressure control in the mitomycin C group than in the control group (p = 0.0065). Choroidal effusion was observed in five (35.7%) treated eyes and two (14.3%) control eyes, whereas shallow anterior chamber were present in five (35.7%) treated eyes and one control eye (7.1%).
CONCLUSION: Despite inducing a higher short-term complication rate, low-dose mitomycin C may be an alternative in the treatment of eyes with advanced glaucomatous damage requiring low final intraocular pressures. ||||| This prospective, randomized clinical trial assessed the effects of mitomycin C and cyclosporin A used as antimetabolites in trabeculectomy on the post-operative IOP and success rate. Eighty-six consecutive patients were randomly allocated to three treatment groups. There were 30 patients in the mitomycin C group, 28 in the cyclosporin A group and 28 in the control group. The follow-up periods were different for the three groups and ranged from 6 to 30 months. The treatment groups consisted of primary open-angle glaucoma, closed-angle glaucoma, various secondary glaucomas and prior failed trabeculectomy. There were no significant differences pre-operatively with respect to IOP and number of medications used (p > 0.05). Postoperative IOP was considered to be successfully reduced when it was reduced by more than 25% from baseline or when it was lower than 20 mmHg. According to these criteria, IOP was under control in 90% of the mitomycin C treated eyes, 85.7% of cyclosporin A treated eyes and 71.4% of the control eyes. Postoperatively there was a significant decrease in IOP (p < 0.01) and in the number of medications need to control IOP (p < 0.01) in the mitomycin C and cyclosporin A groups. Post-operative IOP and number of medications in the mitomycin C and cyclosporin A group were similar. Complications encountered in the three groups were similar. There were no serious complications like hypotonus maculopathy. Our study highlights the utility of mitomycin C as an adjunct in glaucoma filtering surgery and indicated that cyclosporin A may also be used as an antimetabolite. ||||| PURPOSE: This study was performed to determine if adjunctive use of mitomycin C (MMC) would increase the success of combined phacoemulsification, intraocular lens implantation, and trabeculectomy surgery with releasable sutures.
METHODS: Seventy-two eyes with cataract and glaucoma, requiring surgery for decreased vision, uncontrolled intraocular pressure, or to obtain a better view of the optic nerve, were randomized to receive a 2.5-minute subconjunctival exposure to either MMC (0.5 mg/ml) or placebo balanced salt solution. Postoperative evaluations at 3, 6, and 12 months were performed by a masked observer who recorded visual acuity, intraocular pressure, glaucoma medications, presence of filtering blebs, and complications. Endothelial cell counts were measured before and 3 months after surgery.
RESULTS: The MMC group had significantly greater reduction in mean intraocular pressure through the first 12 months of follow-up (7.05-7.65 mmHg versus 2.62-3.84 mmHg; P = 0.001-0.028). In addition, through the first 6 months of follow-up, the MMC group required significantly fewer medications (0.4-0.5 versus 1.1-1.2; P = 0.002-0.004). Requirements for additional glaucoma surgery were less in the MMC group (4/ 36) than in the placebo group (7/35) (P = 0.301). Filtering blebs were significantly larger at 6 and 12 months (P = 0.002 and P = 0.001, respectively), and would leaks were more common (P = 0.101) in the MMC group. The mean decrease in endothelial cell count at month 3 was slightly, although not significantly, greater in the MMC treatment group (206.9 versus 91.3 cells/mm2* P = 0.377).
CONCLUSION: The increased success of the glaucoma procedure in the MMC group together with relatively minor toxicity, suggests its use is beneficial in combined glaucoma-cataract surgery. ||||| OBJECTIVE: To determine the anticicatrization effect of mytomycin C (MMC).
METHODS: We randomly divided 30 cases (40 eyes) into two groups: 21 eyes in MMC group and 19 eyes in control group. Intra-operatively, 0.4 mg/ml MMC was used in the trabeculectomy in MMC group, and no MMC was used in the control group. The post-operative follow-up periods ranged from 6 to 25 months (mean, 10.0 months).
RESULTS: The successful rate of the operation of MMC group was 90.4% and that of the control group, 26.3% (P < 0.0001). The rate of eyes with functional filtering blebs was 17/21 and that of the control group, 4/19 (P = 0.002). Macular edema occurred in 3 eyes of MMC group and none in the eyes in the control group. There were no corneal complication and leakage of the wound.
CONCLUSION: The results show that MMC can promote the formation of functional filtering bleb and elevate the successful rate of filtration surgery. ||||| PURPOSE: To assess the advantages and adverse effects of intraoperative low-dose Mitomycin C in filtering glaucoma surgery.
METHODS: Sixty eyes of 48 patients undergoing surgery for uncontrolled glaucoma were randomized to two groups: one underwent standard trabeculectomy, the other had trabeculectomy with intraoperative application of 0.1 mg/ml mitomycin C. Follow-up was at least one year.
RESULTS: The success rate (IOP < 18 mmHg) was 96.6% in the mitomycin C group and 73.3% in the control group. Mean IOP at one year of successful cases was 11.1 +/- 3.1 mmHg in the mitomycin C group and 16.4 +/- 6.1 mmHg in controls (p < 0.0001). Two patients in the mitomycin C group (6.6%) and six (20%) in the control group needed antiglaucomatous drugs to keep IOP below 18 mmHg.
CONCLUSIONS: Mitomycin C is a useful adjunct to glaucoma surgery. Adverse effects at the dosage used are mainly due to hypotony and are preventable with two-layer suture. Low-dose mitomycin C may be useful in standard primary trabeculectomy. ||||| The aim of the study was to evaluate the effect of mitomycin-C (MMC) in a second antiglaucoma operation after failure of the first operation. We assessed 46 patients (26 male, 20 female, mean age 64.2 years) with high intraocular pressure (IOP) (mean 32.4 +/- 5.2 mmHg) despite previous trabeculectomy (Tr-Ec) one to three years earlier and topical or systemic medical treatment. All patients underwent a second Tr-Ec and were randomly divided into two groups: group A, 24 patients, underwent a second Tr-Ec with MMC and group B, 22 patients, also underwent a second Tr-Ec but without MMC. Postoperative complications included: shallow anterior chamber (duration > 1 week), group A 29.2%, group B 13.6%; chroidal effusion, group A 8.3%, group B 0%; cystic degeneration of conjunctiva, group A 16.6%, group B 4.5%; transient maculopathy, group A 12.5%, group B 0%. IOP control (< or = 20 mmHg after 18 months) was: group A 20 patients (83.3%) with mean 12.5 +/- 3.2 mmHg and group B 13 patients (63.6%) with mean 19.6 +/- 6.1 mmHg. In conclusion, the use of MMC in re-operation for primary open-angle glaucoma is associated with a higher rate of and more severe postoperative complications than Tr-Ec alone. However, it achieves significantly lower IOP in a larger number of patients. ||||| The aim of the study was to determine the corneal endothelial permeability coefficient (Pac) in subjects after trabeculectomies using different concentrations of Mitomycin-C (MMC). MMC, a highly toxic drug, is not without drawbacks and complications such as corneal damage. To ascertain a possible relationship between a level of endothelial permeability (Pac) and concentrations of MMC used, we performed, in a prospective study, trabeculectomies in cases of primary open-angle glaucoma (POAG), younger than 50 years, with either concentrations of 0.5 mg/ml of MMC (group 1: 11 eyes) or 0.2 mg/ml of MMC (group 2: 10 eyes). Group 3 consisted of 8 patients after a typical trabeculectomy without MMC and served as a control group (8 eyes). In all groups, before surgery and again 1, 3 and 6 months after surgery, corneal endothelial permeability (Pac) was determined by using anterior segment fluorophotometry (Fluorotron Master). The thickness of the cornea (CT) was measured with a DGH Technology ultrasonic pachymeter. One month after surgery the mean values of Pac were statistically significantly higher in groups 1 and 2 (group 1: 4.78 x 10(-4) cm/min, group 2: 4.67 x 10(-4) cm/min) in comparison with the control group (group 3: 3.37 x 10(-4) cm/min), but the differences between groups 1 and 2 were not statistically significant (p = 0.05). Six months after operation the mean values of Pac in all groups were normalized. In eyes that underwent trabeculectomy with MMC, higher concentrations of MMC were likely to have a transient adverse effect on corneal endothelial permeability. In light of the resulting toxic intraocular effect of MMC, the damage in the function of the corneal endothelial barrier is greater with greater concentrations of MMC. ||||| PURPOSE: The purpose of the study is to determine whether the intraoperative application of subconjunctival mitomycin C (MMC), during combined phacoemulsification and trabeculectomy, is an effective means of improving filtration, defined as overall lower intraocular pressure (IOP) and less antiglaucoma medication use.
METHODS: Twenty-nine patients with a visually significant cataract and glaucoma were randomized, in a double-masked fashion, to receive intraoperative MMC (0.5 mg/ml) or placebo.
RESULTS: Follow-up ranged from 6 to 30 months (mean, 20 months). Postoperative visual acuity at 1 year was 20/40 or better in 14 of 15 eyes operated on in the placebo group and 13 of 14 eyes operated on in the MMC group. Intraocular pressure at 8 months averaged 15.2 +/- 1.5 mmHg in the placebo-treated eyes versus 12.3 +/- 1.6 mmHg in the MMC-treated eyes. At 12 months, IOPs averaged 16.2 +/- 1.5 mmHg in the placebo-treated eyes versus 12.6 +/- 1.0 mmHg in the MMC-treated eyes. On average, the MMC group had postoperative IOP levels 3.0 mmHg lower than did the placebo group (P = 0.04) throughout the study. In the placebo group, laser suture lysis was required in a greater number of patients (80% versus 43%) and to a greater extent (mean = 2.0 versus 0.7 suture lysed) (P < 0.05). At 12 months, 5 of the 15 patients in the placebo group required an average of 1.8 medications for IOP control, whereas 0 of the 14 patients in the MMC group needed IOP-lowering medications. A late endophthalmitis developed through an intact bleb in one patient in the MMC group; otherwise, complications were minimal in each group.
CONCLUSION: These results suggest that intraoperative MMC application, during combined phacoemulsification and trabeculectomy surgery, does improve early filtration as shown by overall lower IOPs and less antiglaucoma medication use. ||||| PURPOSE: To evaluate the potential benefit of adjunctive subconjunctival mitomycin in patients with primary open-angle glaucoma undergoing primary trabeculectomy combined with phacoemulsification and intraocular lens implantation.
METHODS: Seventy-eight eyes of 78 patients with primary open-angle glaucoma with visually symptomatic cataracts and no previous incisional surgery were randomized to receive either no mitomycin C or a subconjunctival application of 1-, 3-, or 5-minute mitomycin C (0.5 mg/ml).
RESULTS: Follow-up (mean +/- standard deviation) was 21.0 +/- 7.7 months. The mean postoperative intraocular pressures were significantly lower with significantly less medications than the preoperative values at each follow-up time (1, 3, 6, 9, 12, 15 months, and last follow-up) for all groups (P < 0.05 for each). However, there was no significant difference at each follow-up time in intraocular pressure, medications, or best-corrected visual acuity among the four groups or between the control and the total mitomycin C group.
CONCLUSION: Adjunctive subconjunctival mitomycin C did not further improve the final intraocular pressure outcome of the primary trabeculectomy combined with phacoemulsification and intraocular lens implantation in patients with primary open-angle glaucoma. Future studies will determine the appropriate role, if any, for adjunctive mitomycin C in selected primary glaucoma triple procedures. ||||| OBJECTIVE: To establish the long-term, dose-response relationship between the concentration of and duration of exposure to mitomycin to a decrease in intraocular pressure (IOP) and fewer complications.
METHODS: We performed a prospective double-masked, placebo-controlled, 1-year study evaluating the decrease in IOP and fewer complications of fornix-based trabeculectomy surgery in 300 eyes equally divided among therapy with placebo; mitomycin, 0.2 mg/ mL, applied for 2 minutes; mitomycin, 0.4 mg/mL, applied for 4 minutes; or mitomycin, 0.4 mg/mL, applied for 2 minutes. All of the eyes had vertical and horizontal cup-disc ratios greater than 0.7.
RESULTS: We observed significant treatment-related differences in IOP, with a decrease in IOP in all 3 mitomycin-treated groups for all of the times beyond 1 month. The number of eyes achieving strict IOP control and the development of cataract suggest a possible dose-response effect for concentration and time of exposure. Progressive lens opacification was the most frequent complication in 54 eyes (18.1%). The incidence of progressive lens changes markedly increased in subjects receiving 4 minutes of mitomycin therapy. Cataract formation was unrelated to IOP. Other complications were rare. Macular folds developed in 6 patients, with visual acuity returning to better than 20/40 in all but 1 patient.
CONCLUSIONS: A possible dose-response relationship seemed to exist between the concentration of and duration of exposure to mitomycin. Length of exposure seems to be more important than concentration. The benefits of additional decreases in IOP must be weighed against the potential for increases in the risk of complications. | [
{
"source_pmid": "9544650",
"source_text": "OBJECTIVE: This study aimed to investigate whether previously failed glaucoma filtration surgery is a risk factor for filtration failure of subsequent trabeculectomy combined with cataract surgery and to determine the role of adjunctive mitomycin C (MMC) in the se... |
26651305 | CONCLUSIONS: This meta-analysis suggested that CX3CR1 T280M and V249I polymorphisms may not be associated with an increased risk of AMD based on current published data. Given the limited sample size, the finding on CX3CR1 polymorphisms needs further investigation. | Major genetic factors for age-related macular degeneration (AMD) have recently been identified as susceptibility risk factors. The CX3CR1 gene has been shown to be associated with AMD in some studies. Our purpose was to analyze the role of the T280M polymorphism of the CX3CR1 gene in a large French population, in a case-control study. 1093 patients with exudative AMD and 396 controls have been recruited and genotyped for the Y402H of CFH, rs10490924 of ARMS2 and T280M of the CX3CR1 gene. The distribution of the Y402H of CFH and of the rs10490924 of ARMS2 was significantly different between cases and controls (p < 0.0001). The distribution of the T280M genotypes was not significantly different in the AMD patients compared to controls (p = 0.99). The Odds Ratio compared to TT individuals was 1.0 (95% CI 0.8-1.3) for TM individuals and 1.0 (95% CI 0.5-2.1) for MM individuals. The M allele frequency was 0.157 in cases and 0.154 in controls (p = 0.87). Our study exclude an association between the T280M of the CX3CR1 gene and exudative AMD in a French population. ||||| BACKGROUND/AIMS: Single nucleotide polymorphisms (SNPs) in Complement Factor H (CFH), HTRA1 and CX3CR1 are associated with age-related macular degeneration (AMD) in Caucasian population. We aimed to determine whether, and of what magnitude, these AMD susceptibility SNPs are associated with exudative AMD in Han Chinese.
METHODS: Exudative AMD cases and age-matched controls were recruited from Nantong University Hospital (109 cases, 150 controls). Six SNPs in CFH, HTRA1 and CX3CR1 were genotyped. The allele/genotype frequencies were compared between the case and the control. Interactions of SNP-SNP or SNP-smoking status were assessed.
RESULTS: The CFH rs800292 showed significant associations with a reduced risk for exudative AMD. CX3CR1 V249I and T280M and the HTRA1 promoter SNP were significantly associated with the risk of exudative AMD. The two SNPs in CX3CR1 were in complete linkage disequilibrium. None of the AMD-susceptibility SNPs had interactions with each other or with smoking status to confer an altered AMD risk.
CONCLUSIONS: We have replicated the associations of the CFH and HTRA1 SNPs and report for the first time the association of CX3CR1 with exudative AMD in Han Chinese. There was no interaction among the SNPs from different genes, indicating that they might alter the AMD risk independently. ||||| This study examined the association between the sequence variation/expression of CX3CR1, a chemokine receptor, and age-related macular degeneration (AMD). Peripheral blood from 85 AMD patients and 105 subjects without AMD (controls), as well as ocular tissue from 40 pathological sections with AMD and two normal eye sections, were screened for V249I and T280M, two single nucleotide polymorphisms (SNPs) in CX3CR1. An increased prevalence, with the highest odds ratio of 3.57, of the I249 and M280 carriers was found among the AMD cases as compared with the controls. When comparing CX3CR1 expression in the archived eye sections, CX3CR1 transcripts were not detectable in the maculae of AMD eyes bearing T/M280; however, transcripts were detected in the maculae of normal eyes bearing T/T280 or T/M280 as well as in the AMD maculae bearing T/T280. Furthermore, lower CX3CR1 protein expression was observed in the maculae of AMD eyes bearing T/M280 compared with the controls bearing T/T280. The I249 and M280 alleles result in a lowered number of receptor binding sites and a decreased ligand affinity. Our data suggest that a decrease, caused by sequence variation and/or lower CX3CR1 expression, in CX3CR1-induced cellular activities could contribute to AMD development. ||||| IMPORTANCE: The CX3CR1 gene is implicated as a candidate gene for age-related macular degeneration (AMD) through several lines of evidence. There is uncertainty, however, as to whether common genetic variants in CX3CR1 alter risk of AMD, since prior studies have been inconsistent and mostly limited to evaluation of 2 nonsynonymous variants, T280M (rs3732378) and V249I (rs3732379).
OBJECTIVE: To determine if common variants in CX3CR1 predict future risk of AMD.
DESIGN, SETTING, AND PARTICIPANTS: Prospective nested case-control study within 5 large study populations with long-term follow-up. We measured genotypes for T280M, V249I, and 13 other common single-nucleotide polymorphisms (SNPs) of the CX3CR1 gene among people who developed AMD (n = 1110, including 369 with neovascular AMD) and 2532 age- and sex-matched controls.
MAIN OUTCOMES AND MEASURES: We determined the incidence rate ratios (RR) and 95% CIs for incidence of AMD for each variant and examined interactions with other AMD-associated variants and modifiable risk factors.
RESULTS: In additive genetic models, we identified nonsignificant associations with AMD for T280M (RR, 0.87; P = .07) and 3 other SNPs, rs2853707 (RR, 0.88; P = .07), rs12636547 (RR, 0.85; P = .10), and rs1877563 (RR, 0.84; P = .06), 1 of which, rs2853707, is positioned in the CX3CR1 promoter region and was associated with neovascular AMD (RR, 0.75; P = .03). We observed that a recessive model was a better fit to the data for some SNPs, with associations between rs11715522 and AMD (RR, 1.27; P = .03) and between rs2669845 (RR, 3.10; P = .04), rs2853707 (RR, 0.48; P = .050), and rs9868689 (RR, 0.31; P = .02) and neovascular AMD. Moreover, in exploratory analyses, we identified a number of possible interactions including between V249I and rs2669845 and dietary intake of ω-3 fatty acids (P = .004 and P = .009, respectively) for AMD; between rs2669845 and obesity (P = .03) for neovascular AMD; between T280M and complement component 3 (C3) R102G for AMD (P = .03); between rs2669845 and Y402H in complement factor H for AMD (P = .04); and between rs2669845, rs2853707, and V249I and C3 R102G for neovascular AMD (P = .008; .04; and .002, respectively).
CONCLUSIONS AND RELEVANCE: This study failed to identify significant associations between common CX3CR1 variants and AMD after considering the number of SNPs analyzed and multiple comparisons. However, we observed evidence consistent with recessive modes of association and that an effect of CX3CR1 variants may depend on other factors including dietary intake of ω-3 fatty acids, obesity, and genotypes at CFH Y402H and C3 R102G. If replicated in other populations, these findings would support a role for CX3CR1 in AMD but also suggest that its role may involve mechanisms that are independent of the T280M/V249I variations. ||||| BACKGROUND AND AIMS: Age-related macular degeneration (AMD) is an important cause of visual impairment in elderly persons. AMD is a multifactorial disease in which both environmental and genetic factors have been implicated. Various single nucleotide polymorphisms (SNPs) have been found to be associated with AMD. This study aimed to investigate the association of polymorphisms in CX3CR1, PLEKHA1 and VEGF genes with AMD in Indian patients.
METHODS: Genotyping for the CX3CR1 T280M (C>T) and V249I (G>A), PLEKHA1 A320T (G>A) &VEGF +674 (C>T) and +936 (C>T) was performed in 121 AMD patients and 100 controls by polymerase chain reaction, restriction fragment length polymorphism (PCR-RFLP) and sequencing method.
RESULTS: The genotype analysis of VEGF gene polymorphisms (+674 and +936) showed a significant association with AMD. Odds ratios for VEGF (+674) and VEGF (+936) were 2.37 and 2.50 with a p value 0.0029 and 0.0358 for the autosomal dominant model. CX3CR1 (T280M and V249I) and PLEKHA1 (A320T) polymorphisms were not found to be associated with AMD. Odds ratios for mutant alleles of T280M and V249I polymorphisms in CX3CR1 gene were 0.95 and 0.83, respectively, compared to the wild-type alleles. Odds ratio for the polymorphism in the PLEKHA1 gene was 0.63.
CONCLUSIONS: The present study suggests that both polymorphisms in VEGF gene are risk factors for AMD in the Indian population. Detection of individuals at risk could lead to strategies for prevention, early diagnosis and management of AMD. ||||| The role of retinal microglial cells (MCs) in age-related macular degeneration (AMD) is unclear. Here we demonstrated that all retinal MCs express CX3C chemokine receptor 1 (CX3CR1) and that homozygosity for the CX3CR1 M280 allele, which is associated with impaired cell migration, increases the risk of AMD. In humans with AMD, MCs accumulated in the subretinal space at sites of retinal degeneration and choroidal neovascularization (CNV). In CX3CR1-deficient mice, MCs accumulated subretinally with age and albino background and after laser impact preceding retinal degeneration. Raising the albino mice in the dark prevented both events. The appearance of lipid-bloated subretinal MCs was drusen-like on funduscopy of senescent mice, and CX3CR1-dependent MC accumulation was associated with an exacerbation of experimental CNV. These results show that CX3CR1-dependent accumulation of subretinal MCs evokes cardinal features of AMD. These findings reveal what we believe to be a novel pathogenic process with important implications for the development of new therapies for AMD. | [
{
"source_pmid": "21621535",
"source_text": "Major genetic factors for age-related macular degeneration (AMD) have recently been identified as susceptibility risk factors. The CX3CR1 gene has been shown to be associated with AMD in some studies. Our purpose was to analyze the role of the T280M polymorphism ... |
27111565 | CONCLUSIONS: There is no evidence to indicate an inverse association between serum vitamin D levels and any stages and subtypes of AMD risk, but opposite results from the United States and Korea resulted in this nonsignificance. Potential difference across various study designs might exist, based on few studies reporting in heterogeneous manners so far. More studies are needed to further confirm the causality of vitamin D and AMD, especially longitudinal studies. | PURPOSE: To investigate the association of 25-hydroxyvitamin D with AMD.
METHODS: A population-based, cross-sectional study using a nationwide, systemic-stratified, multistage-clustered sampling method involved a total of 17,045 subjects older than 40 years who participated in the Korean National Health and Nutrition Examination Survey 2008 to 2012. All participants underwent standardized interviews, evaluation of blood 25-hydroxyvitamin D levels, and comprehensive ophthalmic examinations. A 45° digital fundus photograph of both eyes was taken under physiologic mydriasis. All fundus photographs were graded using the international classification and grading system.
RESULTS: Blood 25-hydroxyvitamin D levels were 17.5 ng/mL in women and 20.0 ng/mL in men. After adjusting for potential confounders including age, sex, smoking status, hypertension, heart problems, stroke, and sunlight-exposure time, the odds ratio (OR) for late AMD significantly decreased in the highest blood 25-hydroxyvitamin D quintile (OR, 0.32; 95% confidence interval [CI], 0.12-0.81; P for trend = 0.018) compared with the lowest quintile in men, but not in women. Early AMD was not associated with blood 25-hydroxyvitamin D levels in either sex.
CONCLUSIONS: High level of blood 25-hydroxyvitamin D was inversely associated with late AMD in men but not women. Considering antiangiogenic and antifibrotic action of vitamin D, association between two variables warrants further studies. ||||| OBJECTIVE: The relationship between serum 25-hydroxyvitamin D (25[OH]D) concentrations (nmol/L) and the prevalence of early age-related macular degeneration (AMD) was investigated in participants of the Carotenoids in Age-Related Eye Disease Study.
METHODS: Stereoscopic fundus photographs, taken from 2001 to 2004, assessed AMD status. Baseline (1994-1998) serum samples were available for 25(OH)D assays in 1313 women with complete ocular and risk factor data. Odds ratios (ORs) and 95% confidence intervals (CIs) for early AMD (n = 241) of 1287 without advanced disease were estimated with logistic regression and adjusted for age, smoking, iris pigmentation, family history of AMD, cardiovascular disease, diabetes, and hormone therapy use.
RESULTS: In multivariate models, no significant relationship was observed between early AMD and 25(OH)D (OR for quintile 5 vs 1, 0.79; 95% CI, 0.50-1.24; P for trend = .47). A significant age interaction (P = .002) suggested selective mortality bias in women aged 75 years and older: serum 25(OH)D was associated with decreased odds of early AMD in women younger than 75 years (n = 968) and increased odds in women aged 75 years or older (n = 319) (OR for quintile 5 vs 1, 0.52; 95% CI, 0.29-0.91; P for trend = .02 and OR, 1.76; 95% CI, 0.77-4.13; P for trend = .05, respectively). Further adjustment for body mass index and recreational physical activity, predictors of 25(OH)D, attenuated the observed association in women younger than 75 years. Additionally, among women younger than 75 years, intake of vitamin D from foods and supplements was related to decreased odds of early AMD in multivariate models; no relationship was observed with self-reported time spent in direct sunlight.
CONCLUSIONS: High serum 25(OH)D concentrations may protect against early AMD in women younger than 75 years. ||||| OBJECTIVE: To evaluate the associations between levels of vitamin D (25-hydroxyvitamin D) in serum and prevalent age-related macular degeneration (AMD).
METHODS AND DESIGN: Cross-sectional associations of serum vitamin D and early and advanced AMD, assessed from nonmydriatic fundus photographs, were evaluated in the third National Health and Nutrition Examination Survey, a multistage nationally representative probability sample of noninstitutionalized individuals (N = 7752; 11% with AMD).
RESULTS: Levels of serum vitamin D were inversely associated with early AMD but not advanced AMD. The odds ratio (OR) and 95% confidence interval (CI) for early AMD among participants in the highest vs lowest quintile of serum vitamin D was 0.64 (95% CI, 0.5-0.8; P trend <.001). Exploratory analyses were conducted to evaluate associations with important food and supplemental sources of vitamin D. Milk intake was inversely associated with early AMD (OR, 0.75; 95% CI, 0.6-0.9). Fish intake was inversely associated with advanced AMD (OR, 0.41; 95% CI, 0.2-0.9). Consistent use vs nonuse of vitamin D from supplements was inversely associated with early AMD only in individuals who did not consume milk daily (early AMD: OR, 0.67; 95% CI, 0.5-0.9).
CONCLUSION: This study provides evidence that vitamin D may protect against AMD. Additional studies are needed to confirm these findings. ||||| PURPOSE: To investigate the prevalence and risk factors of age-related macular degeneration (AMD) in the general Korean adult population.
METHODS: The study involved a nationally representative Korean population from the 2010 to 2011 Korea National Health and Nutrition Examination Survey. A total of 7899 subjects ≥ 40 years old participated in health interviews, physical examinations, and ophthalmologic assessment including fundus photography.
RESULTS: The overall prevalence of early AMD was estimated at 6.7% (95% confidence interval [CI], 6.1-7.4), and that of late AMD was estimated at 0.7% (95% CI, 0.5-0.9), which included 0.5% prevalence of neovascular AMD and 0.2% prevalence of geographic atrophy. The prevalence rates of early and late AMD among participants aged ≥ 65 years were 16.9% and 1.8%, respectively. Hyperopia was positively associated with the presence of any AMD type (odds ratio [OR], 1.08 for every 1 diopter increase). In multivariate analyses, significant risk factors for the presence of any AMD type were age, serum high-density lipoprotein (HDL) level, serum gamma-glutamyl transferase (GGT) level, and hepatitis B surface antigen (HBsAg) serum positivity (OR, 2.26). The risk factors for late AMD included age, ever-smoking history (OR, 2.18), serum GGT level, and systolic blood pressure.
CONCLUSIONS: The prevalence of AMD in Korea was similar to the prevalence of pooled Asian and Western populations. Age and serum GGT level were strongly associated with both the presence of any AMD and late AMD. Additionally, serum HDL level, HBsAg serum positivity, ever-smoking history, and systolic blood pressure were identified as risk factors for AMD. ||||| PURPOSE: Recent evidence has suggested a correlation between reduced vitamin D levels and delayed angiogenesis and reduced inflammatory response, which are known to have a major role in the development and progression of age-related macular degeneration (AMD).
DESIGN: Cross-sectional study.
PARTICIPANTS: Members of the Maccabi Healthcare Services (MHS, one of the four largest Israeli Health Maintenance Organization) aged ≥60 years, whose vitamin D levels were taken as part of routine examinations between 2000 and 2008.
METHODS: All data for this study were obtained from MHS databases that include medical information on 1.8 million subscribers.
MAIN OUTCOME MEASURES: Serum 25-OH vitamin D levels.
RESULTS: The total study population comprised of 1045 members diagnosed as having AMD, and 8124 as non-AMD, for whom there was information on vitamin D levels. The mean±SD level of 25-OH vitamin D was 24.1±9.41 ng/ml (range 0.8-120) for the AMD patients and 24.13±9.50 ng/ml (range 0.0-120) for the controls (P=ns). One-third (33.6%) of the AMD patients and 32.86% of the controls had a 25-OH vitamin D level <16 ng/ml, and the proportions of tests in which the 25-OH vitamin D level was >74 ng/ml were 0.19 and 0.14%, respectively (P=ns).
CONCLUSIONS: No association was detected between vitamin D levels and the presence of AMD in this cross-sectional study. These results raise some doubt about an association between reduced vitamin D levels and the prevalence of AMD. ||||| OBJECTIVES: To evaluate potential differences in plasma 25-hydroxyvitamin in subtypes of age-related macular degeneration (AMD), and in patients in Clinical Age-Related Maculopathy Staging (CARMS) group 5 with or without subretinal fibrosis.
METHODS: This single-center cross-sectional study included 178 participants during a period of 20 months. Ninety-five patients belonged to CARMS 5; twelve belonged to CARMS 4; twenty-two belonged to CARMS 2 or 3; and 49 individuals did not have AMD (CARMS 1). Following a structured interview, a detailed bilateral retinal examination was performed and participants were allocated to their respective subgroups in accordance with the Clinical Age-Related Maculopathy Staging system. Plasma 25-hydroxyvitamin D2 and D3 were analyzed using liquid chromatography-tandem mass spectrometry. Genomic DNA was extracted from leukocytes and genotyped for single nucleotide polymorphisms (SNPs) in the vitamin D metabolism. Differences in plasma 25-hydroxyvitamin D were determined in the subgroups as well as between patients in CARMS 5 with or without subretinal fibrosis.
RESULTS: Plasma 25-hydroxyvitamin D was comparable in patients across CARMS groups 1 to 5 (p = 0.83). In CARMS 5, the presence of subretinal fibrosis was associated with significantly lower concentrations of 25-hydroxyvitamin D as compared to the absence of subretinal fibrosis (47.2 versus 75.6 nmol/L, p<0.001). Patients in CARMS 5 with subretinal fibrosis were more likely to have insufficient levels of 25-hydroxyvitamin D compared to patients without subretinal fibrosis (p = 0.006). No association was found between the SNPs rs10877012, rs2228570, rs4588, or rs7041 and AMD subgroups or plasma 25-hydroxyvitamin levels.
CONCLUSIONS: This study suggests that the presence of subretinal fibrosis in patients belonging to CARMS 5 may be associated with a poor vitamin D status. Our observations warrant further investigation into the role of vitamin D in the development of subretinal fibrosis. ||||| Vitamin D has been shown to have anti-angiogenic properties and to play a protective role in several types of cancer, including breast, prostate and cutaneous melanoma. Similarly, vitamin D levels have been shown to be protective for risk of a number of conditions, including cardiovascular disease and chronic kidney disease, as well as numerous autoimmune disorders such as multiple sclerosis, inflammatory bowel diseases and type 1 diabetes mellitus. A study performed by Parekh et al. was the first to suggest a role for vitamin D in age-related macular degeneration (AMD) and showed a correlation between reduced serum vitamin D levels and risk for early AMD. Based on this study and the protective role of vitamin D in diseases with similar pathophysiology to AMD, we examined the role of vitamin D in a family-based cohort of 481 sibling pairs. Using extremely phenotypically discordant sibling pairs, initially we evaluated the association of neovascular AMD and vitamin D/sunlight-related epidemiological factors. After controlling for established AMD risk factors, including polymorphisms of the genes encoding complement factor H (CFH) and age-related maculopathy susceptibility 2/HtrA serine peptidase (ARMS2/HTRA1), and smoking history, we found that ultraviolet irradiance was protective for the development of neovascular AMD (p = 0.001). Although evaluation of serum vitamin D levels (25-hydroxyvitamin D [25(OH)D]) was higher in unaffected individuals than in their affected siblings, this finding did not reach statistical significance. Based on the relationship between ultraviolet irradiance and vitamin D production, we employed a candidate gene approach for evaluating common variation in key vitamin D pathway genes (the genes encoding the vitamin D receptor [VDR]; cytochrome P450, family 27, subfamily B, polypeptide 1 [CYP27B1]; cytochrome P450, family 24, subfamily A, polypeptide 1 [CYP24A1]; and CYP27A1) in this same family-based cohort. Initial findings were then validated and replicated in the extended family cohort, an unrelated case-control cohort from central Greece and a prospective nested case-control population from the Nurse's Health Study and Health Professionals Follow-Up Studies, which included patients with all subtypes of AMD for a total of 2,528 individuals. Single point variants in CYP24A1 (the gene encoding the catabolising enzyme of the vitamin D pathway) were demonstrated to influence AMD risk after controlling for smoking history, sex and age in all populations, both separately and, more importantly, in a meta-analysis. This is the first report demonstrating a genetic association between vitamin D metabolism and AMD risk. These findings were also supplemented with expression data from human donor eyes and human retinal cell lines. These data not only extend previous biological studies in the AMD field, but further emphasise common antecedents between several disorders with an inflammatory/immunogenic component such as cardiovascular disease, cancer and AMD. ||||| PURPOSE: To compare 25-hydroxyvitamin D (25OHD) levels in patients with neovascular age-related macular degeneration (NVAMD) with patients with nonneovascular age-related macular degeneration and control patients.
METHODS: Medical records of all patients diagnosed with age-related macular degeneration and tested for serum 25OHD level at a single medical center were reviewed. Control patients were selected from patients diagnosed with pseudophakia but without age-related macular degeneration. The lowest 25OHD level available for each patient was recorded.
RESULTS: Two hundred sixteen patients with nonneovascular age-related macular degeneration, 146 with NVAMD, and 100 non-age-related macular degeneration control patients were included. The levels of 25OHD (mean ± SD) were significantly lower in NVAMD patients (26.1 ± 14.4 ng/mL) versus nonneovascular age-related macular degeneration (31.5 ± 18.2 ng/mL, P = 0.003) and control (29.4 ± 10.1 ng/mL, P = 0.049) patients. The prevalence of vitamin D insufficiency (<30 ng/mL 25OHD), deficiency (<20 ng/mL), and severe deficiency (<10 ng/mL) were highest in the NVAMD group. The highest quintile of 25OHD was associated with a 0.35 (95% confidence interval, 0.18-0.68) odds ratio for NVAMD.
CONCLUSION: This is the largest study to compare 25OHD levels in patients with the different clinical forms of age-related macular degeneration. Mean 25OHD levels were lower and vitamin D deficiency was more prevalent in NVAMD patients. These associations suggest that further research is necessary regarding vitamin D deficiency as a potentially modifiable risk factor for the development of NVAMD. | [
{
"source_pmid": "25015360",
"source_text": "PURPOSE: To investigate the association of 25-hydroxyvitamin D with AMD.\nMETHODS: A population-based, cross-sectional study using a nationwide, systemic-stratified, multistage-clustered sampling method involved a total of 17,045 subjects older than 40 years who ... |
23827458 | CONCLUSIONS: The present meta-analysis suggested that there might be a significant association of GSTM1 null genotype with POAG risk in East Asians. | BACKGROUND: Genetic factors and oxidative damage have been shown to have a role in the development of primary open angle glaucoma (POAG).
AIM: To determine the effects of genetic polymorphisms of glutathione S transferase (GST)M1 and GSTT1 on the risk of POAG in a Turkish population.
METHODS: Using a multiplex polymerase chain reaction (PCR), GSTM1 and GSTT1 gene polymorphisms were analysed in 144 patients with POAG and in 121 otherwise healthy controls of similar age.
RESULTS: The GSTM1 positive genotype and the GSTT1 null genotype had an increased risk of developing POAG (p<0.001, OR 2.93, 95% CI 1.66 to 5.20 and OR 4.25, 95% CI 2.30 to 7.80, respectively). The risk of glaucoma also increased significantly in subjects with a combination of GSTM1 positive and GSTT1 null genotypes (p<0.001, OR 3.46, 95% CI 1.64 to 7.38).
CONCLUSION: The GSTM1 positive genotype and GSTT1 null genotype or the combination of both may be associated with the increased risk of development of POAG in the Turkish population. ||||| PURPOSE: To evaluate the distribution of GSTM1, GSTP1, and GSTT1 gene polymorphisms in exfoliation syndrome (XFS) and the possible associations between the presence of exfoliation syndrome and glutathione S-transferase (GST) gene polymorphisms.
METHODS: Using a real-time polymerase chain reaction, GSTM1, GSTP1, and GSTT1 gene polymorphisms were detected in 60 patients with exfoliation syndrome, among which 71.7% had exfoliative glaucoma (43 patients), 16.7% had XFS with elevated intraocular pressure (IOP) (10 patients), and 11.7% had XFS only (7 cases), and in 65 otherwise healthy control group of similar age.
RESULTS: Although the exfoliation syndrome group presented a higher prevalence of the GSTM1 null and GSTP1 Ile/Val genotypes than the control group, this increase was not statistically significant. GSTT1 null and GSTP1 Val/Val polymorphisms were also not different among groups. The risk of exfoliation syndrome was not increased as the number of putative high-risk genotypes increase (p = 0.73).
CONCLUSIONS: GSTM1, GSTP1, and GSTT1 gene polymorphisms were not different among exfoliation syndrome patients, with or without glaucoma, and the controls therefore GSTM1, GSTP1, and GSTT1 gene polymorphisms did not seem to be associated with the risk of development of exfoliation syndrome. ||||| The Glutathione S-transferase M1 (GSTM1) gene is reported to be involved in glaucoma, an eye disease with a largely unknown mechanism. The gene is polymorphic and three alleles have been characterized. These are one complete deletion of the gene, GSTM1*0, and two alleles differing only in a single amino acid substitution, GSTM1*A and *B. The two latter alleles seem to have equivalent function. Approximately 45% of the European populations are GSTM1 positive. An Estonian study has found that 60% of the glaucoma patients are GSTM1 positive as compared to 45% of controls (P=0.002). We genotyped 200 primary open angle glaucoma patients (POAG), 188 exfoliative glaucoma patients and 200 matched controls using multiplex PCR and pyrosequencing. Forty four per cent of the POAG patients and exfoliative glaucoma patients, and 44.5% of the matched controls were GSTM1 positive. Using pyrosequencing we were able to determine if the patients were homo- or hemizygous for the GSTM1 gene. Five per cent of the POAG patients, 7.4% of the exfoliative glaucoma patients and 4.6% of the controls were homozygous for the presence of the GSTM1 gene. There is no evidence of association between GSTM1 and glaucoma in the Swedish population. ||||| PURPOSE: Glutathione S-transferases (GSTs) are a family of enzymes that inactivate xenobiotics and endogenous end products formed as secondary metabolites during oxidative stress. In humans, GSTT1 and GSTM1 deletion genotypes (T0M1, T1M0, and T0M0) are associated with a variety of pathologic processes including certain ophthalmologic diseases.
METHODS: We compared the prevalence of GSTT1 and GSTM1 deletion genotypes, which were determined by multiplex polymerase chain reaction, in 107 Arab patients with glaucoma (49 with primary open-angle glaucoma, 29 with pseudoexfoliation glaucoma, and 29 with primary angle-closure glaucoma) to 120 age, sex, and ethnically matched controls.
RESULTS: All three GST polymorphisms were significantly more common in the entire glaucoma group (p<0.0167) than in controls. However, when patients were stratified by glaucoma type, the deletion genotype, T0M0, was not particularly associated with any type of glaucoma tested. The T1MO genotype was more common among patients with each type of glaucoma than among controls whereas T0M1 genotype was more common among pseudoexfoliation glaucoma (PEG) and primary open-angle glaucoma (POAG) patients than controls.
CONCLUSIONS: The overall results indicate a possible variable association between various GSTT1 and GSTM1 genotypes and glaucoma in this population. Decreased GST function might interfere with the metabolism of oxidative intermediates and exacerbate the direct or indirect damaging effects of oxidative stress on the optic nerve. It is possible that these GST polymorphisms may be risk factors for glaucoma. ||||| Primary open-angle glaucoma (POAG) is characterized by loss of retinal ganglion cells, optic nerve damage and irreversible loss of visual field. Glaucoma is the second leading cause of blindness worldwide. It was estimated that in 2010 there were about 60.5 million glaucoma cases worldwide; among these patients, 4.5 million will become bilaterally blind. Glutathione S-transferases (GST) are a group of drug-metabolizing enzymes of phase-II that act in the detoxification of xenobiotics and inactivate end-products formed as secondary metabolites during oxidative stress. Through PCR amplification, we analyzed the GSTM1 gene in DNA samples from 25 patients with POAG and 25 controls; 14 of the patients presented the GSTM1 gene null polymorphism while only eight of the control group had this gene.Although the POAG patients had a higher frequency of GSTM1, the difference was not significant (P = 0.0874); this lack of significance could be due to the small sample size. ||||| PURPOSE: To evaluate the variants of 10 genes for association with primary open-angle glaucoma (POAG) in a Chinese population.
METHODS: A total of 405 unrelated patients with POAG (255 high-tension glaucoma [HTG], 100 normal-tension glaucoma [NTG], and 50 juvenile-onset open-angle glaucoma [JOAG]) and 201 control subjects were recruited. Seventeen variants in 10 genes with reported association with POAG were genotyped for analysis of allele and haplotype frequencies between cases and control subjects. These genes included CDH1 (cadherin 1, type 1, E-cadherin), CDKN1A (cyclin-dependent kinase inhibitor 1A), CYP1B1 (cytochrome P450, family 1, subfamily B, polypeptide 1), GSTM1 (glutathione S-transferase mu 1), GSTT1 (glutathione S-transferase theta 1), MTHFR (5,10-methylenetetrahydrofolate reductase), NOS3 (nitric oxide synthase 3), OPA1 (optic atrophy 1), TNF (tumor necrosis factor), and TP53 (tumor protein p53).
RESULTS: One SNP (-308G>A; rs1800629) in TNF demonstrated a significant association with HTG (P = 0.012). The allele G frequency was higher in HTG patients than in control subjects (94.6% vs. 90.3%; OR = 1.89). One haplotype consisting of rs1799724 and rs1800629 was significantly associated with HTG (P = 0.015, corrected P = 0.045). One SNP (R72P; rs1042522) in TP53 was significantly associated with NTG (P = 0.018). The allele G frequency was higher in NTG patients than in control subjects (56.1% vs. 45.8%; OR = 1.52). The significance of these associations survived the Bonferroni correction (corrected P < 0.024). Other gene variants were not significantly associated with HTG (P > 0.063) or NTG (P > 0.13). None of the studied variants was significantly associated with JOAG (P > 0.17).
CONCLUSIONS: The findings suggest that variants in TNF and TP53 are risk factors for POAG, whereas variants in other studied genes are not major risk factors for POAG, at least in the Chinese population. ||||| PURPOSE: To find out whether the polymorphism at GSTM1, GSTT1 and GSTP1 loci is associated with increased susceptibility to glaucoma.
METHODS: We genotyped 153 primary open angle patients and 159 healthy controls. Genomic DNA from peripheral blood was examined using polymerase chain reaction and defined for the genetic polymorphisms of glutathione S-transferase.
RESULTS: The frequency of the GSTM1 null genotype individuals among the glaucoma patients was significanlty higher than in controls (54.9 vs 40.9%) with odds ratio of 1.64 (95% CI: 1.10-2.59). The frequency of the GSTT1 and GSTP1 in both groups were not statistically different.
CONCLUSION: The present study suggests that the GSTM1 null genotype may be a genetic risk factor for development of primary open angle glaucoma. Further associations studies in other polymorphic genes for xenobiotic-metabolizing enzymes are needed to elucidate the environmental-genetic interaction in the underlying cause of primary open angle glaucoma. ||||| BACKGROUND: Little is known about the molecular mechanisms responsible for the development of glaucoma, the leading cause of irreversible blindness worldwide. Some investigators have hypothesized that oxidative damage may be involved. We evaluated oxidative deoxyribonucleic acid (DNA) damage, in terms of 8-hydroxy-2'-deoxyguanosine (8-OH-dG), in the eyes of glaucoma patients.
METHODS: Levels of 8-OH-dG were measured in the trabecular meshwork region from 42 patients with glaucoma and 45 controls of similar age and sex. Genotypes of glutathione S-transferase isoenzymes (GSTM1 and GSTT1) were assessed by polymerase chain reaction in the same DNA samples.
RESULTS: Levels of 8-OH-dG were significantly higher in glaucoma patients than in controls. Oxidative DNA damage in patients with glaucoma correlated significantly with intraocular pressure; in patients with primary open-angle glaucoma, it also correlated with visual field defects. GSTT1 was similar in the two groups, and had no effect on 8-OH-dG levels. Conversely, 8-OH-dG levels were significantly higher in GSTM1-null than in GSTM1-positive subjects. The GSTM1-null genotype was significantly more common in patients with primary open-angle glaucoma than in controls.
CONCLUSION: Oxidative DNA damage is significantly increased in the trabecular meshwork of glaucoma patients. GSTM1 gene deletion, which has been associated with an increased risk of cancer at various sites and molecular lesions in atherosclerosis, predisposes to more severe oxidative DNA damage in glaucoma patients. These findings may contribute to understanding the pathogenesis of glaucoma and may be useful in the prevention and treatment of this disease. ||||| Primary open-angle glaucoma, the most common form of glaucoma is a slowly progressive atrophy of the optic nerve, characterized by loss of peripheral visual function and is usually associated with elevated intraocular pressure. The etiology and genetic risk factors of primary open-angle glaucoma are mostly unknown. The aim of this study was to find out whether the polymorphism at GSTM1, GSTM3, GSTT1 and GSTP1 loci is associated with increased susceptibility to glaucoma, because these polymorphic enzymes are susceptibility candidates for several diseases, including such eye disease as cataract. The phenotype of GSTM1 and GSTT1 was determined by ELISA and the genotype of GSTM3 and GSTP1 was detected by polymerase chain reaction. Four hundred and fifty two Estonians (250 glaucomas and 202 controls) participated in a case-control study. A significant association of the GSTM1 polymorphism with glaucoma was observed. The frequency of the GSTM1 positive individuals among the glaucoma group was significantly higher than in controls (60 vs. 45.0%) with odds ratio of 1.83 (95% CI 1.26-2.66;P = 0.002). The risk among the GSTM1 positive individuals of developing glaucoma was even higher in the case of smoking: 62.7% of smokers were GSTM1 positive in the glaucoma group while only 33.3% of smokers had GSTM1 positive phenotype in controls (OR = 3.36; 95% CI 1.49-7.56;P = 0.012). An association with a lower level of significance was also found with the GSTM3 gene. Four% of the 250 patients with POAG were identified as carriers of the GSTM3 BB genotype, a proportion which was slightly higher than the 1.0% for the controls (OR = 4.17; 95% CI 0. 90-19.24;P = 0.144). The frequencies of the GSTT1 and GSTP1 genotypes in both groups were not statistically different. The present study suggests that the GSTM1 polymorphism may be associated with increased risk of development of primary open-angle glaucoma. ||||| PURPOSE: To investigate the association of glutathione S-transferase (GST) GSTM1, GSTT1, and GSTP1 genes with the risk of primary open angle glaucoma (POAG) and clinical features of the disease.
METHODS: We conducted a case-control study that included 87 Brazilian patients with POAG and 85 healthy controls matched for age, ethnicity, and sex, whose blood samples were genotyped for polymorphisms in GST genes using polymerase chain reaction (PCR) based methods.
RESULTS: The GSTM1 null polymorphism was significantly more common in the POAG than in the controls group (OR: 2.1, 95% CI: 1.13-3.9; p=0.018). The combined GSTM1 null/GSTT1+ genotype and GSTM1 null/GSTP1 Ile/Val or Val/Val was more prevalent in POAG patients, being a risk factor for POAG (OR: 2.4, 95% CI: 1.16-4.9; p=0.016 and OR: 2.7, 95% CI: 1.07-6.74; p=0.033, respectively). The GSTM1 null/GSTT1+ genotype were associated with higher levels of IOP of both eyes and with more severe defect of the right eye optic nerve. The GSTM1 null/GSTP1 Ile/Val or Val/Val genotypes were associated with higher levels of IOP and more advanced defect of the right eye optic nerve and visual field.
CONCLUSIONS: We demonstrate that GSTM1 null polymorphism is associated with POAG in the Brazilian population. | [
{
"source_pmid": "16973661",
"source_text": "BACKGROUND: Genetic factors and oxidative damage have been shown to have a role in the development of primary open angle glaucoma (POAG).\nAIM: To determine the effects of genetic polymorphisms of glutathione S transferase (GST)M1 and GSTT1 on the risk of POAG in... |
26658620 | These results demonstrated that statin use was protective for early and exudative AMD. Additional large prospective cohort studies and RCTs are required to determine the potential effect of statins on AMD prevention. | OBJECTIVE: To investigate the relationship of subclinical atherosclerotic cardiovascular disease (CVD) and its risk factors with age-related macular degeneration (AMD) in the Multiethnic Study of Atherosclerosis.
METHODS: This study included 6176 white, black, Hispanic, and Chinese participants aged 44 to 84 years from 6 communities in the United States. Measurements of subclinical CVD were performed according to standardized protocols. Fundus images were graded using the Wisconsin Age-Related Maculopathy Grading System.
RESULTS: In analyses controlled for age, sex, race/ethnicity, and study location, early AMD was associated with a higher serum high-density lipoprotein cholesterol level (odds ratio per 15 mg/dL, 1.16; 95% confidence interval, 1.01-1.36) and the presence of echolucent carotid artery plaque (odds ratio for present vs no plaque, 0.37; 95% confidence interval, 0.18-0.74) in the whole cohort. Interactions of race/ethnicity and early AMD were found for carotid intima-media thickness, increasing severity of maximum carotid artery stenosis, serum triglyceride level, subclinical CVD severity, and Agatston calcium score.
CONCLUSION: Few associations were found between subclinical CVD and CVD risk factors with early AMD. The findings of associations of early AMD with some signs of subclinical atherosclerotic CVD are different among the 4 racial/ethnic groups, which suggests that care must be taken in generalizing from one racial/ethnic group to another. ||||| AIMS: To evaluate the association between age related maculopathy (ARM) and statin use.
METHODS: A nested case-control study among patients at the Veterans Affairs Medical Center in Birmingham, Alabama, with newly diagnosed ARM (cases) between 1997 to 2001 were selected and age matched to non-ARM controls.
RESULTS: 550 incident cases of ARM were identified and matched to 5500 controls. Overall, cases were 70% (OR 0.30, 95% CI 0.21 to 0.45) less likely to have received and filled a statin prescription relative to the controls. This association was present among both current and past (OR 0.34, 95% CI 0.21 to 0.53 and OR 0.26, 95% CI 0.14 to 0.47, respectively) statin users. When considering use of statin and/or non-statin lipid lowering medications, a significant risk reduction was observed for statin only users (OR 0.30, 95% CI 0.20 to 0.45) and combined statin and non-statin users (OR 0.20, 95% CI 0.06 to 0.64); there was no significant association for non-statin only users (OR 0.47, 95% CI 0.20 to 1.13).
CONCLUSIONS: The results of this study suggest that subjects with ARM were significantly less likely to have filled a statin prescription. Future clinical research initiatives should include a clinical trial to provide direct evidence of the effectiveness of statins in lowering the incidence and progression of ARM. ||||| BACKGROUND: Lipid metabolism and particularly high-density lipoprotein (HDL) may be involved in the pathogenic mechanism of age-related macular degeneration (AMD). However, conflicting results have been reported in the associations of AMD with plasma HDL and other lipids, which may be confounded by the recently reported associations of AMD with HDL-related genes. We explored the association of AMD with plasma lipid levels and lipid-lowering medication use, taking into account most of HDL-related genes associated with AMD.
METHODS: The Alienor study is a population-based study on age-related eye diseases performed in 963 elderly residents of Bordeaux (France). AMD was graded from non mydriatic color retinal photographs in three exclusive stages: no AMD (n = 430 subjects, 938 eyes); large soft distinct drusen and/or large soft indistinct drusen and/or reticular drusen and/or pigmentary abnormalities (early AMD, n = 176, 247); late AMD (n = 40, 61). Associations of AMD with plasma lipids (HDL, total cholesterol (TC), Low-density lipoprotein (LDL), and triglycerides (TG)) were estimated using Generalized Estimating Equation logistic regressions. Statistical analyses included 646 subjects with complete data.
RESULTS: After multivariate adjustment for age, sex, educational level, smoking, BMI, lipid-lowering medication use, cardiovascular disease and diabetes, and for all relevant genetic polymorphisms (ApoE2, ApoE4, CFH Y402H, ARMS2 A69S, LIPC rs10468017, LIPC rs493258, LPL rs12678919, ABCA1 rs1883025 and CETP rs3764261), higher HDL was significantly associated with an increased risk of early (OR = 2.45, 95%CI: 1.54-3.90; P = 0.0002) and any AMD (OR = 2.29, 95%CI: 1.46-3.59; P = 0.0003). Association with late AMD was far from statistical significance (OR = 1.58, 95%CI: 0.48-5.17; p = 0.45). No associations were found for any stage of AMD with TC, LDL and TG levels, statin or fibrate drug use.
CONCLUSIONS: This study suggests that elderly patients with high HDL concentration may be at increased risk for AMD and, further, that HDL dysfunction might be implicated in AMD pathogenesis. ||||| OBJECTIVE: To evaluate both the use of cholesterol-lowering medications as a group and the use of statins specifically with regard to the risk of age-related macular degeneration (AMD).
METHODS: A case-control study was conducted using data from the Cardiovascular Health Study, a population-based prospective study of adults enrolled from 4 communities in the United States in 1989 and 1990. Individuals with AMD (cases) and those without AMD (controls) were compared with regard to their use of cholesterol-lowering medications and statins.
RESULTS: Nearly equal proportions of cases and controls used cholesterol-lowering medications, both before adjustment (odds ratio, 0.92; 95% confidence interval, 0.70-1.21) and after adjustment for selected confounding variables (age, sex, and race) (odds ratio, 1.35; 95% confidence interval, 0.98-1.87). Statin use was also found to be similar among cases and controls (odds ratio, 0.98; 95% confidence interval, 0.73-1.30). After controlling for the aforementioned 3 confounders (odds ratio, 1.40; 95% confidence interval, 0.99-1.98), we noted a modest trend for statin users to have an increased risk of AMD.
CONCLUSION: The results suggest that no association exists between having used cholesterol-lowering medications and AMD. However, there was a suggestion that statin use might increase the risk of AMD. ||||| PURPOSE: To determine the association of hydroxymethylglutarylcoenzyme A (HMG Co-A) reductase inhibitor (statin) use with the prevalence of age-related macular degeneration (AMD).
METHODS: This cross-sectional study included 5604 participants in the National Health and Nutrition Examination Survey (NHANES) from 2005 to 2008, ≥ 40 years of age, who were ascertained with regard to the diagnosis of AMD, the use of statins, and comorbidities and health-related behaviors such as smoking.
RESULTS: The mean age of participants denying or confirming a history of AMD was 68 (SEM 0.90) and 55 (SEM 0.36) years, respectively. Individuals 68 years of age or older who were classified as long-term users of statins had statistically significant less self-reported AMD (odds ratio (OR) 0.64, 95% confidence interval (CI) 0.49-0.84; P=0.002), after adjusting for potential confounding variables. No significant association was found between the prevalence of AMD and statin consumption among subjects between 40 and 67 years of age (OR 1.61, 95% CI 0.85-3.03; P=0.137).
CONCLUSIONS: Our results suggest a possible beneficial effect of statin intake for the prevention of AMD in individuals 68 years of age or older. ||||| AIMS: Age related macular degeneration (AMD) is the leading cause of blindness in industrialised countries. Previous studies have suggested that statins may have a protective effect against the disease; however, existing studies have had limited power to reliably detect or exclude an effect and have produced conflicting results. The authors assessed the risk of AMD associated with the use of statins.
METHODS: Population based case control study using the United Kingdom General Practice Research Database. 18 007 people with diagnosed AMD were compared with 86 169 controls matched on age, sex, and general practice. The primary outcome was the odds ratio for the association between exposure to statins and AMD.
RESULTS: The crude odds ratio for the association between any recorded exposure to statins and AMD was 1.32 (95% CI 1.17 to 1.48), but this reduced to 0.93 (95% CI 0.81 to 1.07, p=0.33) after adjustment for consultation rate, smoking, alcohol intake, body mass index, atherosclerotic disease, hyperlipidaemia, heart failure, diabetes mellitus, hypertension, use of other cardiovascular drugs, and use of fibrates. There was no evidence that the risk varied by dose of statin, duration of use, or that the risk varied for individual statins.
CONCLUSION: In the short and medium term statin use is not associated with a decreased risk of AMD. Whether subgroups of patients with specific forms of AMD (particularly choroidal neovascularisation) benefit from statin therapy remains a possibility. ||||| OBJECTIVE: To examine the association of hydroxymethyl glutaryl coenzyme A reductase inhibitors (statins) with the 5-year incidence of age-related maculopathy (ARM).
DESIGN: Population-based cohort study. Participants included persons 48 to 91 years old examined March 1, 1993, through June 14, 1995, living in Beaver Dam, Wis (N = 3684), of whom 2780 participated in a follow-up 5 years later.
METHODS: Standardized procedures were used for physical examinations, blood sample collection, and questionnaire administration. Age-related maculopathy was determined by grading images of the posterior pole using a standard protocol. Standard univariate and multivariate analyses were performed.
MAIN OUTCOME MEASURES: Incidence and progression of ARM was measured over the 5-year interval.
RESULTS: While controlling for age and sex, statin use was not found to be associated with the 5-year incidence of early ARM (odds ratio [OR], 1.12; 95% confidence interval [CI], 0.47-2.67), progression of ARM (OR, 1.22; 95% CI, 0.54-2.76), or incidence of late ARM (OR, 0.41; 95% CI, 0.12-1.45).
CONCLUSIONS: These findings do not suggest an association between statin use and incident ARM over a 5-year period. Further investigation of these relationships in larger studies over a longer period is needed. ||||| PURPOSE: To assess associations between smoking and cardiovascular risk factors and prevalent age-related macular degeneration (AMD) in the Singapore Malay population.
DESIGN: Population-based, cross-sectional study.
METHODS: A total of 3,280 Malay adults age 40 to 80 years were included in the study. Early and late AMD signs were graded from retinal photographs following Wisconsin system. All participants had interview, systemic examination, and laboratory investigations to determine smoking status and cardiovascular risk factors.
RESULTS: A total of 3,265 participants had gradable photos, 21 (0.6%) with late AMD and 169 (5.2%) with early AMD. After adjusting for age and gender, current smokers were significantly more likely to have late AMD (odds ratio [OR], 3.79; 95% confidence interval [CI], 1.40 to 10.23). This association was stronger among those who currently smoked >5 packs of cigarettes per week (OR, 9.35; 95% CI, 2.49 to 35.08).
CONCLUSIONS: Smoking was associated with a higher late AMD prevalence in Malays, consistent with findings from studies in White populations. ||||| BACKGROUND: Age related macular degeneration (AMD) is a progressive degenerative disease affecting central vision. Recent studies have shown that that statins may lower the risk of AMD potentially due to statins' anti-inflammatory and anti-oxidative properties. We sought to further explore this association and also explore the role of angiotensin-converting enzyme inhibitors (ACE-Is) with respect to the development of AMD.
METHODS: We conducted a nested case-control study within a cardiovascular cohort that had undergone revascularization interventions in the Province of Quebec, Canada. Cases were identified as those with an ICD-9 code for AMD. For each case, four controls were randomly chosen from the cohort and matched to the cases by age and calendar time. Conditional logistic regression was used to estimate rate ratios and adjust for potential confounders.
RESULTS: Our nested case-control study consisted of 2,867 cases and 11,468. Current users of ACE-Is or statins were at a slightly higher risk of developing AMD (1.19 [1.07-1.33]) and (1.30 [1.17-1.44]) respectively. The results were similar for those using these drugs in the year prior.
CONCLUSIONS: Based on the results of our study, statin and ACE-I use may be associated with an increase in the risk of AMD. Given that our study is an observational study, further studies are required to confirm or refute these findings. ||||| Since the introduction of HMG-CoA reductase inhibitors (statins) for lowering lipids, a large amount of data has been published demonstrating their potential benefits in conditions as varied as cancer, osteoporosis, and Alzheimer's dementia. We reviewed the published literature on MEDLINE from articles between 1950 and 2008 on the non-atheroprotective effects of statins and noted consistent benefits of statin use in improving outcomes of ventricular arrhythmias, sudden cardiac death, cardiac transplant rejection, chronic obstructive pulmonary disease, and sepsis. However, for these conditions, the level of evidence was inadequate to recommend statin use. The evidence for improving outcomes in atrial fibrillation, mortality in heart failure, contrast-induced nephropathy, cataract, age-related macular degeneration, sub-arachnoid hemorrhage, osteoporosis, dementia, and cancer incidence was conflicting and inconclusive. Furthermore, we found that most of the literature consists of small observational studies and their conclusions are often not corroborated by results from larger or randomized studies. Pending large, well designed, randomized trials, we conclude that there is no definite evidence for the use of statins in any condition besides hyperlipidemia and atherosclerosis. ||||| OBJECTIVE: To evaluate the impact of statin use on the incidence of advanced age-related macular degeneration (AMD) and its components, choroidal neovascularization (CNV) and geographic atrophy (GA), among patients with bilateral large drusen.
DESIGN: Cohort study within a multicenter, randomized, clinical trial.
PARTICIPANTS: Patients enrolled in the Complications of Age-related Macular Degeneration Prevention Trial (CAPT).
METHODS: Eligibility criteria for the clinical trial required that participants have >or=10 large (>125 microm) drusen and visual acuity >or=20/40 in each eye. Patients scheduled for their final CAPT visit after May 2005 were interviewed on their history of use of cholesterol-lowering medications, including statins. Trained readers identified CNV and end point GA (>1 Macular Photocoagulation Study disc area of GA) based on review of fluorescein angiograms and fundus photographs taken at annual follow-up visits and when patients reported symptoms. The risk ratio for participants developing CNV or developing GA associated with statin use was estimated with time-dependent Cox proportional hazards models.
MAIN OUTCOME MEASURES: Development of advanced AMD, CNV, and end point GA.
RESULTS: Among 764 patients eligible for the interview, 744 (97.4%) patients completed the interview on medication use. Statin use was reported by 296 (39.8%) of those interviewed, with the majority, 187 (63.2%) of the 296, beginning use after enrollment in CAPT. Among 744 patients, advanced AMD developed in 332 (22.5%) eyes of 242 (32.5%) patients, CNV in 222 (15%) eyes of 176 (23.7%) patients, and GA in 114 (7.7%) eyes of 80 (10.8%) patients. With adjustment for other risk factors, the estimated risk ratio for eyes (95% confidence interval) associated with statin use was 1.15 (0.87-1.52) for advanced AMD, 1.35 (0.99-1.83) for CNV, and 0.80 (0.46-1.39) for GA.
CONCLUSIONS: The CAPT data are not consistent with a strong protective effect (risk ratio, <or=0.85) of statins on the development of advanced AMD among patients with bilateral large drusen. ||||| PURPOSE: To assess the relationship between statin use and the long-term incidence of age-related macular degeneration (AMD).
DESIGN: Population-based cohort study.
METHODS: Of 3,654 baseline (1992 to 1994) participants in the Blue Mountains Eye Study initially aged 49+ years, 2,335 were reexamined after five years (1997 to 1999) and 1,952 after 10 years (2002 to 2004). Stereoscopic macular photographs were graded using the Wisconsin Age-related Maculopathy Grading System. History, physical examination, and fasting blood samples provided data on possible risk factors. Discrete linear logistic models were used to assess risk of incident AMD.
RESULTS: After controlling for age, gender, and other confounding factors, compared with nonusers, statin users had a reduced risk of developing indistinct soft drusen, the principal late AMD precursor lesion (hazard ratio, 0.33; 95% confidence interval, 0.13 to 0.84).
CONCLUSIONS: Statin use was not significantly associated with overall early AMD incidence, but was protective for indistinct soft drusen, a key late AMD precursor lesion. ||||| Age-related macular degeneration (AMD) is a complex, degenerative and progressive disease involving the multiple genetic and environmental factors that can result in severe visual loss. The etiology of AMD is not well understood. Many theories exist and feature mechanisms of oxidative stress, atherosclerotic-like changes, genetic predisposition and inflammation. The most recent clinical studies appointed to a great role of inflammation and C-reactive protein (CRP) in the pathogenesis of AMD. There is a large body of evidence indicating the association of CRP with endothelial dysfunction, oxidative stress and production of reactive oxygen species (ROS), as well as with lipid status disorder in AMD patients. According to recent studies, CRP is definitely not only the inflammatory marker but also a mediator of development of the vascular disorders in the retinal circulation. The results obtained from the present studies may help our understanding the pathogenesis of the retinal vascular disease associated with high levels of CRP. ||||| AIMS: To assess the effect of statins on a range of health outcomes.
METHODS: We undertook a population-based cohort study to assess the effect of statins on a range of health outcomes using a propensity score-based method to control for differences between people prescribed and not prescribed statins. We validated our design by comparing our results for vascular outcomes with the effects established in large randomized trials. The study was based on the United Kingdom Health Improvement Network database that includes the computerized medical records of over four and a half million patients.
RESULTS: People who initiated treatment with a statin (n = 129,288) were compared with a matched sample of 600,241 people who did not initiate treatment, with a median follow-up period of 4.4 years. Statin use was not associated with an effect on a wide range of outcomes, including infections, fractures, venous thromboembolism, gastrointestinal haemorrhage, or on specific eye, neurological or autoimmune diseases. A protective effect against dementia was observed (hazard ratio 0.80, 99% confidence interval 0.68, 0.95). There was no effect on the risk of cancer even after > or =8 years of follow-up. The effect sizes for statins on vascular end-points and mortality were comparable to those observed in large randomized trials, suggesting bias and confounding had been well controlled for.
CONCLUSIONS: We found little evidence to support wide-ranging effects of statins on health outcomes beyond their established beneficial effect on vascular disease. | [
{
"source_pmid": "17420374",
"source_text": "OBJECTIVE: To investigate the relationship of subclinical atherosclerotic cardiovascular disease (CVD) and its risk factors with age-related macular degeneration (AMD) in the Multiethnic Study of Atherosclerosis.\nMETHODS: This study included 6176 white, black, H... |
25185256 | This study shows an association between A69S polymorphism in the ARMS2 gene and the anti-angiogenesis treatment response. A69S could be considered predictive of the anti-angiogenic effects, especially in Asian populations. | PURPOSE: To determine if prespecified genetic polymorphisms influence responsiveness to vascular endothelial growth factor (VEGF) inhibition in neovascular age-related macular degeneration (nAMD). The objectives were to replicate 3 reported pharmacogenetic associations of response in nAMD and to test for novel associations.
DESIGN: Cohort study, combining information about patients' genotypes with information from a randomized controlled trial about responsiveness to anti-VEGF therapy for nAMD.
PARTICIPANTS: Five hundred nine participants with nAMD, enrolled in the Alternative Treatments to Inhibit VEGF in Patients with Age-Related Choroidal Neovascularisation (IVAN) trial.
METHODS: Participants were classified as responders or nonresponders to VEGF inhibition based on the optical coherence tomography (OCT) metric of total retinal thickness (TRT). We computed the change in TRT from baseline to the latest time point for which OCT data were available (3, 6, 9, or 12 months). Eyes with changes in TRT greater than or equal to the 75th percentile or more were classified as responders, and those with changes less than or equal to the 25th percentile or lower were classified as non-responders. Three previously reported associations of response to VEGF inhibition in nAMD involving single nucleotide polymorphisms (SNPs) at the CFH, FZD4, and HTRA1/ARMS2 loci were tested for replication. An additional 482 SNPs also were tested using a candidate gene approach. Associations were estimated as odds ratios (ORs) with confidence intervals (CIs).
MAIN OUTCOME MEASURES: The primary outcome was evidence of a genetic association with response to VEGF inhibition as measured by change in TRT.
RESULTS: One hundred twenty-six participants were classified as responders and 128 were classified as nonresponders. The SNP rs10490924 in HTRA1/ARMS2 showed a borderline association with responsiveness after Bonferroni correction (OR, 1.53; CI, 0.99-2.36; P = 0.055, Bonferroni correction). None of the other 484 additional SNPs tested for association was significant after Bonferroni correction for multiple testing. The smallest corrected P value was 0.84 (P = 0.002, uncorrected) for rs9679290 in the EPAS1 (HIF2A) gene on chromosome 2. Four of the 10 most significant results were in this gene.
CONCLUSIONS: We estimated pharmacogenetic associations using high-quality phenotype data from a randomized controlled clinical trial of nAMD. No significant association or replication of previous associations were observed. Further investigation of the EPAS1 (HIF2A) gene, however, may, be merited. ||||| PURPOSE: To study the association of single-nucleotide polymorphisms of interleukin 8, vascular endothelial growth factor, erythropoietin, complement factor H, complement component C3, and LOC387715 genes with the response to bevacizumab treatment in exudative age-related macular degeneration.
METHODS: Clinical records, smoking history, optical coherence tomography, and angiographies of 96 bevacizumab-treated exudative age-related macular degeneration patients were analyzed retrospectively. Blood DNA was collected. Based on the disappearance of intra- or subretinal fluid in optical coherence tomography, patients were graded as responders, partial responders, or nonresponders after 3 initial treatment visits and a median time of 3.5 months.
RESULTS: Interleukin 8 promoter polymorphism -251A/T was significantly associated with persisting fluid in optical coherence tomography. The A allele was more frequent in nonresponders than in responders (P = 0.033). In multivariate modeling, the AA genotype of -251A/T (P = 0.043) and occult (P = 0.042) or predominantly classic (P = 0.040) lesions predicted poorer outcome. Visual acuity change was better in responders than in nonresponders (P = 0.006). Baseline lesion size (P = 0.006) and retinal cysts after the treatment (P < 0.001) correlated with less visual acuity gain.
CONCLUSION: The A allele and the homozygous AA genotype of interleukin 8 -251A/T were associated with anatomical nonresponse to bevacizumab treatment. ||||| PURPOSE: To determine the association of genetic variants in known age-related macular degeneration (AMD) risk-associated genes with outcome of anti-vascular endothelial growth factor (VEGF) treatment in neovascular AMD.
DESIGN: Prospective cohort study.
PARTICIPANTS: We enrolled 224 consecutive patients with neovascular AMD at the Royal Victorian Eye and Ear Hospital, Australia.
METHODS: Patients were treated with 3 initial monthly ranibizumab or bevacizumab injections followed by 9 months of "as required" injections based on clinician's decision at each follow-up visit according to retreatment criteria. Seventeen single nucleotide polymorphisms (SNPs) in known AMD risk-associated genes including CFH (rs800292, rs3766404, rs1061170, rs2274700 and rs393955), HTRA1 (rs11200638), CFHR1-5 (rs10922153, rs16840639, rs6667243, and rs1853883), LOC387715/ARMS2 (rs3793917 and rs10490924), C3 (rs2230199 and rs1047286), C2 (rs547154), CFB (rs641153) and F13B (rs6003) were examined. Multivariate analysis was used to determine the role of each SNP in treatment outcome.
MAIN OUTCOME MEASURES: The influence of selected SNPs on mean change in visual acuity (VA) at 12 months.
RESULTS: Mean baseline VA was 51 ± 16.8 Early Treatment Diabetic Retinopathy Study letters. Overall, the mean change in VA from baseline was +3.2 ± 14.9 letters at 12 months. The AA (homozygote risk) genotype at rs11200638 - HTRA1 promoter SNP (P = 0.001) and GG (homozygote risk) genotype at rs10490924 (A69S) in LOC387715/ARMS2 (P = 0.002) were each significantly associated with poorer VA outcome at 12 months after multiple correction. Mean ± standard deviation change in VA from baseline in patients with AA genotype at rs11200638 was -2.9 ± 15.2 letters after 12 months compared with +5.1 ± 14.1 letters in patients with AG or GG genotypes at this SNP. Patients with either of these genotypes were also significantly more likely to lose >15 letters after 12 months. SNPs rs11200638 and rs10490924 were in high linkage disequilibrium (r(2) = 0.92). None of the other examined SNPs was associated with outcome.
CONCLUSIONS: The HTRA1 promoter SNP (rs11200638) and A69S at LOC387715/ARMS2 were associated with a poorer visual outcome for ranibizumab or bevacizumab treatment in neovascular AMD, suggesting strong pharmacogenetic associations with anti-VEGF treatment. This finding could aid in applying more individualized treatment regimens based on patients' genotype to achieve optimal treatment response in AMD.
FINANCIAL DISCLOSURE(S): The authors have no proprietary or commercial interest in any materials discussed in this article. ||||| PURPOSE: To evaluate the pharmacogenetic relationship between genotypes of single nucleotide polymorphisms (SNPs) known to be associated with age-related macular degeneration (AMD) and response to treatment with ranibizumab (Lucentis; Genentech, South San Francisco, CA) or bevacizumab (Avastin; Genentech) for neovascular AMD.
DESIGN: Clinical trial.
PARTICIPANTS: Eight hundred thirty-four (73%) of 1149 patients participating in the Comparison of AMD Treatments Trials (CATT) were recruited through 43 CATT clinical centers.
METHODS: Each patient was genotyped for SNPs rs1061170 (CFH), rs10490924 (ARMS2), rs11200638 (HTRA1), and rs2230199 (C3), using TaqMan SNP genotyping assays (Applied Biosystems, Foster City, CA).
MAIN OUTCOMES MEASURES: Genotypic frequencies were compared with clinical measures of response to therapy at one year, including mean visual acuity (VA), mean change in VA, 15-letter or more increase in VA, retinal thickness, mean change in total foveal thickness, presence of fluid on OCT, presence of leakage on fluorescein angiography (FA), mean change in lesion size, and mean number of injections administered. Differences in response by genotype were evaluated with tests of linear trend calculated from logistic regression models for categorical outcomes and linear regression models for continuous outcomes. To adjust for multiple comparisons, P≤0.01 was considered statistically significant.
RESULTS: No statistically significant differences in response by genotype were identified for any of the clinical measures studied. Specifically, there were no high-risk alleles that predicted final VA or change in VA, the degree of anatomic response (fluid on OCT or FA, retinal thickness, change in total foveal thickness, change in lesion size), or the number of injections. Furthermore, a stepwise analysis failed to show a significant epistatic interaction among the variants analyzed; that is, response did not vary by the number of risk alleles present. The lack of association was similar whether patients were treated with ranibizumab or bevacizumab or whether they received monthly or pro re nata dosing.
CONCLUSIONS: Although specific alleles for CFH, ARMS2, HTRA1, and C3 may predict the development of AMD, they did not predict response to anti-vascular endothelial growth factor therapy. ||||| PURPOSE: To investigate whether there is an association between known age-related macular degeneration genetic risk variants in the CFH, ARMS2, and HTRA1 genes and response to anti-vascular endothelial growth factor (VEGF) (ranibizumab or bevacizumab) treatment for wet age-related macular degeneration.
METHODS: A retrospective review of 150 patients with documented wet age-related macular degeneration based on clinical examination and fluorescein angiogram was performed. Patients received anti-VEGF therapy with ranibizumab and/or bevacizumab. Patients were genotyped for the single-nucleotide polymorphism rs1061170, rs10490924, rs3750848, rs3793917, rs11200638, and rs932275 and for the indel del443ins54 spanning the CFH, ARMS2, and HTRA1 genes.
RESULTS: There were 57 patients who were characterized as negative responders to anti-VEGF therapy, and 93 patients who were characterized as positive responders. There was no significant difference in mean baseline visual acuity between the groups. Negative responders were followed for a mean duration of 24.0 months, while positive responders were followed for a mean duration of 22.0 months. Although the frequency of the at-risk alleles was higher in the positive responders when compared with the negative responder, this did not reach statistical significance. Additionally, there was no significant association between genotype and the number of injections or absolute change in visual acuity in both groups of responders.
CONCLUSION: In our patient cohort, there was no statistically significant association between response to anti-VEGF therapy and the genotype in both positive-responder and negative-responder groups. Larger studies with more power are necessary to further determine whether a pharmacogenetic association exists between wet age-related macular degeneration and anti-VEGF therapy. ||||| Purpose. To identify the predictors of visual response to the bevacizumab treatment of neovascular age-related macular degeneration (AMD). Design. A cohort study within the Neovascular AMD Treatment Trial Using Bevacizumab (NATTB). Methods. This was a multicenter trial including 144 participants from the NATTB study. Visual outcomes measured by change in visual acuity (VA) score, proportion gaining ≥15 letters, and change in central retinal thickness (CRT) were compared among groups according to the baseline, demographic, and ocular characteristics and genotypes. Results. Mean change in the VA score was 9.2 ± 2.3 SD letters with a total of 46 participants (31.9%) gaining ≥15 letters. Change in median CRT was -81.5 μ m. Younger age, lower baseline VA score, shorter duration of neovascular AMD, and TT genotype in rs10490924 were significantly associated with greater VA score improvement (P = 0.028, P < 0.001, P = 0.02, and P = 0.039, resp.). Lower baseline VA score and TT genotype in rs10490924 were significantly associated with a higher likelihood of gaining ≥15 letters (P = 0.028, and P = 0.021, resp.). Conclusions. Baseline VA and genotype of rs10490924 were both important predictors for visual response to bevacizumab at 6 months. This trial is registered with the Registration no. NCT01306591. ||||| PURPOSE: To investigate whether there is an association between complement factor H (CFH) or LOC387715 genotypes with response to treatment with intravitreal bevacizumab for exudative age-related macular degeneration (AMD).
DESIGN: Retrospective cohort study.
PARTICIPANTS: The study cohort consisted of 86 patients being treated for neovascular AMD with bevacizumab alone.
METHODS: Genotype determination for the CFH Y402H and LOC387715 A69S polymorphisms was performed by allele-specific digestion of polymerase chain reaction products. All patients were treated with 1.25 mg intravitreal bevacizumab at 6-week intervals until choroidal neovascularization was no longer active.
MAIN OUTCOME MEASURES: CFH Y402H and LOC387715 A69S polymorphisms. Choroidal neovascular lesion characteristics were ascertained by fluorescein angiography. Snellen visual acuity (VA) was measured before and after treatment.
RESULTS: For the CFH Y402H polymorphism, patients with the CFH TT genotype had the largest choroidal neovascular lesions (P = 0.02). With treatment, VA improved from 20/248 to 20/166 for the CFH TT genotype and from 20/206 to 20/170 for the TC genotype, but fell from 20/206 to 20/341 for the CFH CC genotype (P = 0.016). Only 10.5% of patients with the CFH CC genotype demonstrated improved VA with treatment, compared with 53.7% of CFH TT and TC genotypes (P = 0.004). For the LOC387715 A69S variant, patients with the TT genotype had the largest choroidal neovascular lesions (P = 0.012). There was no significant difference in response to bevacizumab treatment according to LOC387715 genotype.
CONCLUSIONS: The AMD-associated CFH Y402H and LOC387715 A69S variants were associated with differences in choroidal neovascular lesion size in this study. Patients with the CFH CC genotype fared significantly worse with intravitreal bevacizumab than did those with the CFH TC and TT genotypes, suggesting a potential pharmacogenetic relationship. Prospective studies to confirm or refute this observation should be considered. ||||| PURPOSE: To ascertain whether single nucleotide polymorphisms (SNPs) in the Vascular Endothelial Growth factor (VEGFA), Complement Factor H (CFH), and LOC387715 genes could predict outcome to anti-VEGF therapy for patients with age related macular degeneration (AMD).
METHODS: Patients with "wet" AMD were identified by chart review. Baseline optical coherence tomography (OCT) and visual acuity (VA) data, and at least 6 months of clinical follow up after 3 initial monthly injections of bevacizumab or ranibizumab were required for inclusion. Based on OCT and VA, patients were categorized into two possible clinical outcomes: (a) responders and (b) non-responders. DNA was extracted from saliva and genotyped for candidate SNPs in the VEGFA, LOC387715, and CFH genes. Clinical outcomes were statistically compared to patient genotypes.
RESULTS: 101 patients were recruited, and one eye from each patient was included in the analysis. 97% of samples were successfully genotyped for all SNPs. We found a statistically significant association between the LOC387715 A69S TT genotype and outcome based on OCT.
CONCLUSION: Genetic variation may be associated with outcome in patients receiving anti-VEGF therapy. ||||| AIM: This study was conducted to evaluate the possible clinical and genetic indicators for an early response to intravitreal ranibizumab (IVR) in exudative age-related macular degeneration (AMD).
PATIENTS & METHODS: The records of 120 eyes from 120 Japanese patients with treatment-naive exudative AMD were retrospectively reviewed. Three consecutive IVR treatments were performed every month. Achievement of anatomical resolution was evaluated by ophthalmoscopy and optical coherence tomography. Multivariable logistic regression analysis was conducted by analyzing SNPs in the ARMS2 locus (A69S) and in the CFH gene (I62V and Y402H), in addition to clinical factors.
RESULTS: The mean central retinal thickness of overall patients was significantly decreased (-120.1 ± 122.8 µm, p = 2.7 × 10(-19)) at 3 months after the initial treatment. In the logistic regression analysis, the poor anatomical resolution of the lesion at 3 months was associated with the combination of CFH I62V + CFH Y402H variants (p = 0.0021), and the polypoidal choroidal vasculopathy lesions (p = 0.044).
CONCLUSION: The CFH variants and the polypoidal choroidal vasculopathy lesion may influence the early anatomical resolution with IVR in exudative AMD. ||||| PURPOSE: To investigate factors affecting patient response to intravitreal ranibizumab treatment for age-related macular degeneration (AMD).
DESIGN: Retrospective chart review.
METHODS: We reviewed medical records of 105 consecutive eyes with AMD treated with intravitreal ranibizumab injections and followed for more than 1 year after treatment. Response to ranibizumab treatment was compared between typical neovascular AMD and polypoidal choroidal vasculopathy (PCV). Furthermore, we investigated associations of age, lesion size, and single nucleotide polymorphisms (SNPs) in CFH and ARMS2 genes with treatment response.
RESULTS: Forty-nine eyes were diagnosed with typical neovascular AMD and 56 eyes with PCV. Serous retinal detachment and retinal edema resolved similarly in both typical neovascular AMD and PCV after treatment. However, visual acuity (VA) significantly improved in eyes with PCV, whereas VA was maintained in typical neovascular AMD. At the third and twelfth months after injection, VA was better in PCV than in typical neovascular AMD (P = .027 and P = .044, respectively), although there were no differences in baseline VA between the 2 groups. Age and size of greatest linear dimension were significantly associated with visual prognosis in typical neovascular AMD but not in PCV. There was no clear association between 3 SNPs and responsiveness to ranibizumab treatment.
CONCLUSIONS: Although exudative changes were equivalent following ranibizumab treatment in both typical neovascular AMD and PCV, there was a significant increase in VA in PCV compared to typical neovascular AMD. Age and greatest linear dimension correlated with visual prognosis only in typical neovascular AMD and not in PCV. ||||| PURPOSE: To investigate whether there was an association with the LOC387715/HTRA1 variants and a response to combined photodynamic therapy with intravitreal bevacizumab for polypoidal choroidal vasculopathy.
METHODS: Combined photodynamic therapy with intravitreal bevacizumab was repeated every 3 months until the disappearance of angiographic signs in the active lesions of 51 eyes with polypoidal choroidal vasculopathy who were followed-up for at least 12 months. Patients were genotyped for LOC387715 and HTRA1 polymorphisms.
RESULTS: Although there was no significant difference in the baseline best-corrected visual acuity and fluorescein angiography-guided greatest linear dimension among the 3 genotypes in both genes, there was a significant difference at 12 months (P < 0.05, respectively). For LOC387715, the TT genotype showed greater fluorescein angiography-guided greatest linear dimension than the TG and GG genotypes (P = 0.035 and 0.006, respectively). The best-corrected visual acuity of the GG genotype was better than the TT and TG (P = 0.029 and 0.045, respectively). For HTRA1, the AA genotype showed greater fluorescein angiography-guided greatest linear dimension than AG and GG (P = 0.042 and 0.017, respectively). The best-corrected visual acuity of GG genotype was better than AA and AG (P = 0.018 and 0.040, respectively).
CONCLUSION: After combined photodynamic therapy with intravitreal bevacizumab treatment, LOC387715 TT and HTRA1 AA genotype had poorer outcomes at 12 months, suggesting a pharmacogenetic relationship. ||||| PURPOSE: To investigate the association between genetic risk variants for age-related macular degeneration (AMD) and response to intravitreal ranibizumab in Korean patients with neovascular AMD.
METHODS: This prospective study included 273 treatment-naive patients (273 eyes) who underwent 5 monthly injections (Months 0, 1, 2, 3, and 4) of intravitreal ranibizumab for neovascular AMD. Patients were genotyped for 23 single-nucleotide polymorphisms within 12 AMD-relevant genes. For each polymorphism, genotypic association with good response at Month 5, predetermined as visual improvement of ≥ 8 Early Treatment Diabetic Retinopathy Study letters from baseline, was investigated with logistic regression analysis adjusted for age, gender, smoking, baseline Early Treatment Diabetic Retinopathy Study letter, central retinal thickness, lesion area, and type of choroidal neovascularization.
RESULTS: At Month 5, visual acuity improved by 9.1 ± 17.6 letters from baseline, and 136 patients (49.8%) were classified as good responders. In logistic regression, no tested polymorphism showed statistically significant association with favorable visual outcome at Month 5. When unadjusted for multiple tests, AA genotype for VEGF rs699947 had an increased chance of good response compared with other genotypes (odds ratio, 3.61; 95% confidence interval, 1.42-9.18; P = 0.0071).
CONCLUSION: In this Korean neovascular AMD cohort, there was no statistically significant effect of genotype on early visual outcome after ranibizumab treatment. | [
{
"source_pmid": "24070809",
"source_text": "PURPOSE: To determine if prespecified genetic polymorphisms influence responsiveness to vascular endothelial growth factor (VEGF) inhibition in neovascular age-related macular degeneration (nAMD). The objectives were to replicate 3 reported pharmacogenetic associ... |
26872021 | To sum up, our data indicate that rs17576 polymorphism is not related to glaucoma and rs3918249 polymorphism might be a protective factor against glaucoma. | PURPOSE: To evaluate the influence of topographic profiles (i.e., inner directional angle and angular width) of localized retinal nerve fiber layer (RNFL) defects on the diagnostic performance of macular ganglion cell-inner plexiform layer (GCIPL) thickness in discriminating preperimetric glaucoma (PPG) eyes from normal control eyes.
METHODS: The ganglion cell analysis algorithm in Cirrus OCT was performed to determine the macular GCIPL thickness. Areas under the receiver operating characteristic curves (AUROCs) and the sensitivities/specificities based on an internal normative database were evaluated. The effect of the inner directional angle and the angular width of localized RNFL defects on the diagnostic performance of macular GCIPL parameters were evaluated by using linear-by-linear association analysis and logistic regression analysis.
RESULTS: Ninety-two patients with PPG and 92 age-matched healthy control subjects were enrolled in this study. The AUROC of the best parameters in macular GCIPL was 0.823 (inferotemporal sector), which showed no significant difference in comparison to the best parameters of peripapillary RNFL (7 o'clock sector, 0.764) and optic nerve head (rim area, 0.767) (for all comparisons, P > 0.05). A significant linear association was observed between the inner directional angle of RNFL defects and the sensitivity of macular GCIPL parameters for detecting RNFL defects. The angular width of RNFL defects was not significantly associated with the sensitivity of macular GCIPL parameters.
CONCLUSIONS: The diagnostic ability of macular GCIPL parameters was comparable to that of peripapillary RNFL and ONH parameters in PPG. The inner directional angle of RNFL defects, but not the angular width, affects the diagnostic sensitivity of macular GCIPL parameters. ||||| PURPOSE: To evaluate the usefulness of the spectral-domain optical coherence tomography (SD OCT)-determined ganglion cell complex thickness to total retinal thickness ratio (G/T ratio) in diagnosing glaucoma.
METHODS: A total of 99 eyes with primary open-angle glaucoma and 35 normal eyes were enrolled in the study. SD OCT (RTVue-100) was used to measure the macular ganglion cell complex thickness, total retinal thickness, outer retinal thickness, and circumpapillary retinal nerve fiber layer (RNFL) thickness. A new macular parameter, the G/T ratio, was also calculated. The ability of each parameter to diagnose glaucoma was examined by analyzing the area under the receiver operating characteristics curve (AUROC) and the sensitivity at fixed specificity.
RESULTS: The G/T ratio was 36.0 ± 1.5% in normal eyes, 31.8 ± 1.7% in early glaucoma, and 30.2 ± 2.6% in advanced glaucoma. These decreases in the ratio were statistically significant. For the AUROC, the individual SD OCT parameters were 0.982 for the G/T ratio, 0.968 for the macular ganglion cell complex thickness, 0.942 for the RNFL thickness, and 0.841 for the total retinal thickness. The AUROC for the G/T ratio was significantly higher than that seen for the total retinal and RNFL thicknesses (P<0.05). Analyses of the sensitivity at a specificity of >90% indicated that the G/T ratio (sensitivity, 93.94%) was the best diagnostic parameter.
CONCLUSIONS: Decreases in the G/T ratio occur during the early stages of glaucoma. When using SD OCT to diagnose glaucoma, the G/T ratio may improve the diagnostic ability of the macular parameter. ||||| AIMS: To evaluate the glaucoma discriminating ability of macular retinal layers as measured by spectral domain optical coherence tomography (SD-OCT).
METHODS: Healthy, glaucoma suspect and glaucomatous subjects had a comprehensive ocular examination, visual field testing and SD-OCT imaging (Cirrus HD-OCT; Carl Zeiss Meditec, Dublin, California, USA) in the macular and optic nerve head regions. OCT macular scans were segmented into macular nerve fibre layer (mNFL), ganglion cell layer with inner plexiform layer (GCIP), ganglion cell complex (GCC) (composed of mNFL and GCIP), outer retinal complex and total retina. Glaucoma discriminating ability was assessed using the area under the receiver operator characteristic curve (AUC) for all macular parameters and mean circumpapillary retinal nerve fibre layer (cpRNFL).
RESULTS: Analysis was performed on 51 healthy, 49 glaucoma suspect and 63 glaucomatous eyes. The median visual field MD was -2.21 dB (IQR: -6.92 to -0.35) for the glaucoma group, -0.32 dB (IQR: -1.22 to 0.73) for the suspect group and -0.18 dB (IQR: -0.92 to 0.71) for the healthy group. Highest age adjusted AUCs were found for average GCC and GCIP (AUC=0.901 and 0.900, respectively) and their sectoral measurements: infero-temporal (0.922 and 0.913), inferior (0.904 and 0.912) and supero-temporal (0.910 and 0.897). These values were similar to the discriminating ability of the mean cpRNFL (AUC=0.913). Comparison of these AUCs did not yield any statistically significant difference (all p>0.05).
CONCLUSIONS: SD-OCT GCIP and GCC measurements showed similar glaucoma diagnostic ability and were comparable with that of cpRNFL. ||||| PURPOSE: We determined the diagnostic performance of ganglion cell-inner plexiform layer (GCIPL) parameters of high definition optical coherence tomography (HD-OCT) in perimetric and preperimetric glaucoma, and compared it to optic nerve head (ONH) and peripapillary retinal nerve fiber layer (RNFL) parameters.
METHODS: In a cross-sectional study, 53 eyes of normal subjects and 83 eyes of glaucoma patients (62 perimetric and 21 preperimetric) from the Longitudinal Glaucoma Evaluation Study (LOGES) underwent HD-OCT imaging with Optic Disc and Macular Cube protocols. Diagnostic abilities of GCIPL, ONH, and RNFL parameters were determined using area under receiver operating characteristic curves (AUC) and likelihood ratios (LR).
RESULTS: The AUCs of GCIPL parameters to diagnose perimetric glaucoma ranged from 0.84 to 0.90. The same of ONH and RNFL parameters ranged from 0.88 to 0.97 and 0.56 to 0.94, respectively. The AUCs of GCIPL, ONH, and RNFL parameters to diagnose preperimetric glaucoma ranged from 0.55 to 0.63, 0.77 to 0.92, and 0.39 to 0.80, respectively. For diagnosing preperimetric glaucoma, AUCs of all GCIPL parameters were significantly lower (P < 0.05) than those of the global ONH (vertical cup-to-disc ratio [CDR]; AUC, 0.92) and RNFL (average RNFL; AUC, 0.79) parameters. Outside normal limits category of GCIPL parameters also were associated with significantly smaller effects on the posttest probability of perimetric and preperimetric glaucoma.
CONCLUSIONS: The diagnostic ability of GCIPL parameters was similar to that of ONH and peripapillary RNFL parameters in perimetric glaucoma. However, in preperimetric glaucoma, the diagnostic ability of GCIPL parameters was significantly lower than that of ONH and RNFL parameters. ||||| PURPOSE: To evaluate the performance of ganglion cell layer/inner plexiform layer (GCL/IPL) measurements with spectral-domain optical coherence tomography (Cirrus HD-OCT) for detection of early glaucoma and to compare results to retinal nerve fiber layer (RNFL) measurements.
DESIGN: Cross-sectional prospective diagnostic study.
METHODS: We enrolled 99 subjects, including 59 eyes with glaucoma (47 subjects) (mean deviation >-6.0 dB) and 91 normal eyes (52 subjects). Patients underwent biometry and peripapillary and macular OCT imaging. Performance of the GCL/IPL and RNFL algorithms was evaluated with area under receiver operating characteristic curves (AUC), likelihood ratios, and sensitivities/specificities adjusting for covariates. Combination of best parameters was explored.
RESULTS: Average (SD) mean deviation in the glaucoma group was -2.5 (1.9) dB. On multivariate analyses, age (P < 0.001) and axial length (P = 0.03) predicted GC/IPL measurements in normal subjects. No significant correlation was found between average or regional GC/IPL thickness and respective outer retina (OR) thickness measurements (P > 0.05). Average RNFL thickness performed better than average GCL/IPL measurements for detection of glaucoma (AUC = 0.964 vs 0.937; P = 0.04). The best regional measures from each algorithm (inferior quadrant RNFL vs minimum GCL/IPL) had comparable performances (P = 0.78). Entering the GC/IPL to OR ratio into prediction models did not enhance the performance of the GCL/IPL measures. Combining the best parameters from each algorithm improved detection of glaucoma (P = 0.04).
CONCLUSIONS: Regional GCL/IPL measures derived from Cirrus HD-OCT performed as well as regional RNFL outcomes for detection of early glaucoma. Using the GC/IPL to OR ratio did not enhance the performance of GCL/IPL parameters. Combining the best measures from the 2 algorithms improved detection of glaucoma. ||||| PURPOSE: To compare the diagnostic abilities of peripapillary retinal nerve fiber layer (RNFL) and macular inner retina (MIR) measurements by spectral domain optical coherence tomography (SD-OCT) in Indian eyes early glaucoma.
METHODS: In an observational, cross-sectional study, 125 eyes of 64 normal subjects and 91 eyes of 59 early glaucoma patients underwent RNFL and MIR imaging with SD-OCT. Glaucomatous eyes had characteristic optic nerve and RNFL abnormalities and correlating visual field defects and a mean deviation of better than or equal to -6 dB on standard automated perimetry. Areas under the receiver operating characteristic curves (AUC), sensitivities at a fixed specificity and likelihood ratios (LRs) were estimated for all RNFL and MIR parameters.
RESULTS: The AUCs for the RNFL parameters ranged from 0.537 for the temporal quadrant thickness to 0.821 for the inferior quadrant RNFL thickness. AUCs for the MIR parameters ranged from 0.603 for the superior minus inferior MIR thickness average to 0.908 for ganglion cell complex focal loss volume (GCC-FLV). AUC for the best MIR parameter (GCC-FLV) was significantly better (P<0.001) than that of the best RNFL parameter (inferior quadrant thickness). The sensitivities of these parameters at high specificity of 95%, however, were comparable (52.7% vs58.2%). Evaluation of the LRs showed that outside normal limits results of most of the RNFL and MIR parameters were associated with large effects on the post-test probability of disease.
CONCLUSION: MIR parameters with RTVue SD-OCT were as good as the RNFL parameters to detect early glaucoma. ||||| PURPOSE: To compare the ability of spectral-domain optical coherence tomography (SDOCT) retinal nerve fiber layer (RNFL), optic nerve head (ONH), and macular measurements to detect preperimetric glaucomatous damage.
METHODS: The study included 142 eyes from 91 patients suspected of having the disease based on the appearance of the optic disc. All eyes had normal visual fields before the imaging session. Forty-eight eyes with progressive glaucomatous damage were included in the preperimetric glaucoma group. Ninety-four eyes without any evidence of progressive glaucomatous damage and followed untreated for 12.8 ± 3.6 years were used as controls. Areas under the receiver operating characteristic curves (AUC) were calculated to summarize diagnostic accuracies of the parameters.
RESULTS: The three RNFL parameters with the largest AUCs were average RNFL thickness (0.89 ± 0.03), inferior hemisphere average thickness (0.87 ± 0.03), and inferior quadrant average thickness (0.85 ± 0.03). The three ONH parameters with the largest AUCs were vertical cup-to-disc ratio (0.74 ± 0.04), rim area (0.72 ± 0.05), and rim volume (0.72 ± 0.05). The three macular parameters with the largest AUCs were GCC average thickness (0.79 ± 0.04), GCC inferior thickness (0.79 ± 0.05), and GCC superior thickness (0.76 ± 0.05). Average RNFL thickness performed better than vertical cup-to-disc ratio (0.89 vs. 0.74; P = 0.007) and GCC average thickness (0.89 vs. 0.79; P = 0.015).
CONCLUSIONS: SDOCT RNFL measurements performed better than ONH and macular measurements for detecting preperimetric glaucomatous damage in a cohort of glaucoma suspects. (ClinicalTrials.gov number, NCT00221897.). ||||| BACKGROUND: With the advent of spectral domain optical coherence tomography (SDOCT), there has been a renewed interest in macular region for detection of glaucoma. However, most macular SDOCT parameters currently are thickness parameters which evaluate thinning of the macular layers but do not quantify the extent of area over which the thinning has occurred. We therefore calculated a new macular parameter, "ganglion cell complex surface abnormality ratio (GCC SAR)" that represented the surface area over which the macular thickness was decreased.
PURPOSE: To evaluate the ability of SAR in detecting perimetric and preperimetric glaucoma.
DESIGN: Retrospective image analysis.
MATERIALS AND METHODS: 68 eyes with perimetric glaucoma, 62 eyes with preperimetric glaucoma and 165 control eyes underwent GCC imaging with SDOCT. SAR was calculated as the ratio of the abnormal to total area on the GCC significance map.
STATISTICAL ANALYSIS: Diagnostic ability of SAR in glaucoma was compared against that of the standard parameters generated by the SDOCT software using area under receiver operating characteristic curves (AUC) and sensitivities at fixed specificities.
RESULTS: AUC of SAR (0.91) was statistically significantly better than that of GCC average thickness (0.86, P = 0.001) and GCC global loss volume (GLV; 0.88, P = 0.01) in differentiating perimetric glaucoma from control eyes. In differentiating preperimetric glaucoma from control eyes, AUC of SAR (0.72) was comparable to that of GCC average thickness (0.70, P > 0.05) and GLV (0.72, P > 0.05). Sensitivities at specificities of 80% and 95% of SAR were comparable (P > 0.05 for all comparisons) to that of GCC average thickness and GLV in diagnosing perimetric and preperimetric glaucoma.
CONCLUSION: GCC SAR had a better ability to diagnose perimetric glaucoma compared to the SDOCT software provided global GCC parameters. However, in diagnosing preperimetric glaucoma, the ability of SAR was similar to that of software provided global GCC parameters. ||||| PURPOSE: To evaluate retinal nerve fiber layer (RNFL), optic nerve head (ONH), and macular thickness measurements for glaucoma detection using the RTVue spectral domain optical coherence tomograph.
DESIGN: Diagnostic, case-control study.
PARTICIPANTS: One hundred forty eyes of 106 glaucoma patients and 74 eyes of 40 healthy subjects from the Diagnostic Innovations in Glaucoma Study (DIGS).
METHODS: All patients underwent ocular imaging with the commercially available RTVue. Optic nerve head, RNFL thickness, and macular thickness scans were obtained during the same visit. Receiver operating characteristic (ROC) curves and sensitivities at fixed specificities (80% and 95%) were calculated for each parameter.
MAIN OUTCOME MEASURES: Areas under the ROC curves (AUC) and sensitivities at fixed specificities of 80% and 95%.
RESULTS: The AUC for the RNFL parameter with best performance, inferior quadrant thickness, was significantly higher than that of the best-performing ONH parameter, inferior rim area (0.884 vs 0.812, respectively; P = 0.04). There was no difference between ROC curve areas of the best RNFL thickness parameters and the best inner macular thickness measurement, ganglion cell complex root mean square (ROC curve area = 0.870).
CONCLUSIONS: The RTVue RNFL and inner retinal macular thickness measurements had good ability to detect eyes with glaucomatous visual field loss and performed significantly better than ONH parameters. ||||| PURPOSE: To evaluate the diagnostic accuracy of Topcon 3D spectral-domain optical coherence tomography (SD-OCT) for measuring the macular inner retinal layers and the circumpapillary retinal nerve fiber layer (cpRNFL) in order to detect preperimetric glaucoma.
METHODS: Two hundred four eyes, including 64 healthy eyes, 68 eyes with preperimetric glaucoma, and 72 eyes with early glaucoma were analyzed. Patients had a comprehensive ocular examination including visual field testing and SD-OCT imaging (3D OCT-2000; Topcon Corporation, Tokyo, Japan) in the macular and peripapillary regions. OCT macular scans were segmented into the macular nerve fiber layer (mNFL), ganglion cell layer with the inner plexiform layer (GCIP), and ganglion cell complex (GCC) (composed of the mNFL and GCIP). Ability to discriminate preperimetric glaucoma was assessed using the area under the receiver operating curve for all macular parameters and the cpRNFL.
RESULTS: The median visual field MD was -0.78 ± 1.19 dB for the healthy group, -1.02 ± 1.29 dB for the preperimetric glaucoma group, and -3.08 ± 1.61 dB for the early glaucoma group. There were significant differences between the preperimetric and healthy groups for GCIP and GCC and for almost all cpRNFL thickness parameters (P < 0.05), except for the mNFL and cpRNFL (nasal, 3, 4, 8, 9, and 10 o'clock sectors). The comparisons among the AUCs of the cpRNFL parameters (0.772), the GCIP parameters (0.727) and the GCC parameters (0.720) showed no significant differences in their abilities to detect preperimetric glaucoma.
CONCLUSIONS: The capacity of Topcon 3D-OCT macular intraretinal parameters (GCIP and GCC measurements, not mNFL measurements) to diagnose preperimetric glaucoma is similar to that of the cpRNFL. ||||| PURPOSE: To compare perimacular ganglion cell complex (GCC) parameters between patients with normal tension glaucoma (NTG) and primary open-angle glaucoma (POAG).
METHODS: Participants, consecutively enrolled from January 2009 to June 2009, underwent optical coherence tomographic imaging with RTVue-100 (Optovue Inc, Fremont, CA). Optic nerve head (ONH) parameters, retinal nerve fiber layer (RNFL) parameters, and GCC parameters were acquired. Mean measurements of ONH, RNFL, and GCC parameters among the normal, NTG, and POAG groups were compared using analysis of variance. Area under the receiver operator characteristic curve was used to assess the ability of each parameter to detect glaucomatous changes.
RESULTS: Fifty-eight normal controls, 51 patients with NTG, and 52 patients with POAG were included. Mean measurements of ONH parameters were similar between the NTG and POAG groups (all P>0.05). Average RNFL thickness did not differ between the NTG and POAG groups (P=0.053), whereas average GCC thickness significantly differed between the NTG and POAG groups (P=0.001). In terms of pattern-based parameters of GCC, focal loss volume did not differ between the NTG and POAG groups (P=0.165), whereas global loss volume was significantly higher in the POAG group (P<0.001). There were no statistically significant differences between RNFL and GCC measurements with respect to the ability to detect glaucomatous changes.
CONCLUSIONS: GCC loss in the NTG group was more localized compared with diffuse GCC loss in the POAG group. Perimacular GCC parameters could be a good alternative or supplement to peripapillary RNFL measurements for diagnosis and research in patients with NTG. ||||| PURPOSE: To evaluate and compare the diagnostic ability of spectral domain optical coherence tomography (SD-OCT) for detecting localized retinal nerve fiber layer (RNFL) defects in topographic RNFL maps and circumpapillary RNFL (cpRNFL) thickness measurements.
METHODS: Sixty-four eyes with localized RNFL defects in red-free RNFL photographs and 72 healthy eyes were included. All participants were imaged with SD-OCT. The area and angular width of the localized RNFL defects were measured with ImageJ software on RNFL thickness map, significance map (yellow pixels, <5% level), and red-free RNFL photographs. The sensitivity, specificity, and area under the receiver operating characteristic curves (AUCs) were calculated for cpRNFL thickness, macular inner retina thickness, and RNFL maps (thickness, significance) according to the quantitative measurements and a <5% level of classification to distinguish eyes with localized RNFL defects from healthy eyes.
RESULTS: RNFL thickness map (sensitivity 96.9-98.4%, specificity 86.1-98.6%, and AUCs 0.915-0.992) and significance map (sensitivity 96.9-98.4%, specificity 88.9-95.8%, and AUCs 0.937-0.983) showed superior performance in detecting localized RNFL defects compared with other parameters (P-value 0.001-0.024) except for 36 sector cpRNFL thickness (sensitivity 92.2%, specificity 87.5%, and AUCs 0.898; P-value 0.080-0.545). The sensitivity for detecting RNFL defects was related to the angular width, area, and depth of the RNFL defects in the cpRNFL (4 sector, 12 sector) and macular inner retinal measurements. RNFL thickness and significance maps showed a constant sensitivity regardless of variations in angular width, area, and depth of the RNFL defects.
CONCLUSION: RNFL thickness and significance maps could be used to distinguish eyes with localized RNFL defects from healthy eyes more effectively than cpRNFL thickness and macular inner retina thickness measurements. ||||| PURPOSE: To compare the glaucoma detection ability of macular ganglion cell-inner plexiform layer (GCIPL) thickness measured with Cirrus spectral-domain optical coherence tomography (SD-OCT) with that of peripapillary retinal nerve fiber layer (RNFL) thickness in high myopia.
METHODS: In 49 highly myopic and 54 nonhighly myopic glaucoma patients--along with 78 healthy myopic subjects--two scans, including one macular scan and one peripapillary RNFL scan, were obtained using Cirrus SD-OCT. For 44 randomly selected glaucoma patients, three macular scans were taken for reproducibility measurements. The glaucoma detection abilities of macular GCIPL and peripapillary RNFL thicknesses were compared between the highly myopic and nonhighly myopic groups. Diagnostic power was assessed by area under the receiver operating characteristic (AUROC) curves and sensitivity. Repeatability was assessed by intraclass correlation coefficient (ICC) and coefficient of variation (CV).
RESULTS: All of the macular GCIPL and peripapillary RNFL thickness measurements excepting the 3 o'clock peripapillary RNFL sector showed an AUROC over 0.5. The best parameters for discriminating normal from glaucomatous eyes were inferior RNFL (0.906) and inferotemporal GCIPL (0.852) thickness in the highly myopic group, and average RNFL (0.920) and minimum GCIPL (0.908) thickness in the nonhighly myopic group. The best peripapillary RNFL and macular GCIPL thickness parameters showed no statistically significant differences. All of the ICCs of the macular GCIPL ranged between 0.96 and 0.99, and the CV was <3%.
CONCLUSIONS: In cases of high myopia, the glaucoma detection ability of macular GCIPL thickness was high and comparable with that of peripapillary RNFL thickness. ||||| PURPOSE: We compared the ability of circumpapillary retinal nerve fiber layer (cpRNFL) thickness and macular parameters obtained by three spectral-domain optical coherence tomography (SD-OCT) instruments to detect glaucoma.
METHODS: We enrolled 87 normal eyes and 145 glaucomatous eyes (75 early glaucomatous eyes (EGs), mean deviation > -6 dB). Each participant was imaged using Cirrus, RTVue, and 3D-OCT to evaluate the average and quadrant cpRNFL thicknesses. The macular retinal nerve fiber layer (mRNFL), ganglion cell layer plus inner plexiform layer (GCL/IPL), and mRNFL + GCL/IPL (ganglion cell complex [GCC]) thicknesses were analyzed. The areas under the receiver operating characteristic curves (AUCs) were compared among the instruments.
RESULTS: These instruments revealed similar AUCs for the average cpRNFL and GCC thicknesses in EGs, and total all-stage glaucomatous eyes (TGs). RTVue showed better performance in the nasal cpRNFL thickness than Cirrus and 3D-OCT, and better performance in the temporal cpRNFL thickness than 3D-OCT in TGs. RTVue had a higher AUC for the superior GCC thickness compared to Cirrus and 3D-OCT in EGs, and TGs. Cirrus had higher AUCs for GCL/IPL parameters in TGs, and lower AUCs for the mRNFL parameters in EGs and TGs compared to 3D-OCT.
CONCLUSIONS: The average cpRNFL and GCC thicknesses measured using these OCT instruments exhibited similar abilities in the diagnosis of glaucoma, and RTVue exhibited better diagnostic abilities than Cirrus and 3D-OCT for nasal cpRNFL, and superior GCC thicknesses. The diagnostic performance of Cirrus and 3D-OCT was different for GCL/IPL and mRNFL parameters. (http://www.umin.ac.jp/ctr number, UMIN000006900.) ||||| PURPOSE: To evaluate the influence of a control group on the diagnostic accuracy of spectral-domain optical coherence tomography (SD-OCT) in early glaucoma.
METHODS: In a diagnostic, case-control study, 119 eyes of 60 normal subjects with no findings suspicious for glaucoma (control cohort 1); 76 eyes of 41 subjects referred by general ophthalmologists as glaucoma suspects based on optic disc morphology, but found by glaucoma experts to be normal but with physiological variations in their optic nerves (control cohort 2); and 65 eyes of 46 early-glaucoma patients (cases) underwent imaging of the optic nerve head (ONH), retinal nerve fiber layer (RNFL), and ganglion cell complex (GCC) by SD-OCT.
RESULTS: Areas under the receiver operating characteristic curves (AUC) of ONH parameters discriminating glaucomatous eyes from normal eyes of control cohort 2 were significantly lesser (P < 0.001) than those discriminating glaucomatous eyes from normal eyes of control cohort 1. AUCs of RNFL parameters discriminating glaucomatous eyes from normal eyes of control cohorts 2 and 1 were comparable. Although the AUCs of GCC thickness parameters were comparable, AUCs of GCC focal and global loss volume in control cohort 2 (0.684 and 0.671. respectively) were significantly less (P < 0.05) than in control cohort 1 (0.881 and 0.841, respectively).
CONCLUSIONS: The effectiveness of most SD-OCT parameters in detecting glaucoma significantly decreased when evaluated against a clinically relevant control group with suspicious-looking optic nerves compared with that against a control group consisting of normal subjects with no findings suspicious for glaucoma. ||||| BACKGROUND: To assess the ability of retinal nerve fiber layer (RNFL) thickness measurements obtained using GDx-enhanced corneal compensation (ECC) or spectral-domain optical coherence tomography (RTVue), and that of ganglion cell complex (GCC) scan available on RTVue, to detect glaucoma.
METHODS: One randomly selected eye of 205 subjects (70 normal, 65 ocular hypertension, and 70 glaucoma) underwent a complete clinical and instrumental examination. RTVue spectral-domain optical coherence tomography was used to assess RNFL thickness and GCC parameters, GDx ECC to assess RNFL thickness. Areas under the receiver operating characteristic curves (AUCs) and sensitivity of the RNFL and GCC parameters were calculated at a fixed specificity of 95%, and the diagnostic abilities of the RNFL values obtained using the 2 instruments were compared. We also compared the results obtained in the normal, ocular hypertensive, and glaucomatous subjects.
RESULTS: Best GDx RNFL parameter was nerve fiber indicator (NFI) (AUC 0.99, sensitivity 96%); the best RTVue parameters were average (AUC 0.98, sensitivity 90%), inferior-temporal (AUC 0.97, sensitivity 89%), and superior-temporal RNFL thickness (AUC 0.96, sensitivity 87%). There were no significant differences between the 2 devices (P>0.05). Best GCC parameters were focal loss volume (AUC 0.98, sensitivity 91%) and global loss volume (AUC 0.96, sensitivity 87%).
CONCLUSIONS: GDx ECC and RTVue show a very good diagnostic ability to detect glaucoma. Most of the RNFL parameters had high AUCs and sensitivities. The diagnostic validity of GCC was comparable with that of the RNFL parameters, and they may be very useful in detecting RNFL damage. ||||| OBJECTIVE: We sought to compare the glaucoma discrimination ability of macular inner retinal layer (MIRL) thickness with that of conventional peripapillary retinal nerve fiber layer (pRNFL) thickness as measured by spectral-domain optical coherence tomography (SD-OCT) in patients with early glaucoma.
DESIGN: Cross-sectional study.
PARTICIPANTS: We studied 67 patients with early glaucoma (visual field mean deviation index ≥-6 dB), and 56 healthy subjects were prospectively enrolled.
METHODS: All patients underwent MIRL thickness measurement (ganglion cell complex [GCC] scan) and pRNFL thickness measurement (3.45 mm scan) by SD-OCT. Whenever both eyes were eligible, one was randomly selected. Receiver operating characteristic curves and sensitivities at fixed specificities were generated for different parameters. The areas under the receiver operating characteristic curves (AUCs) of each parameter were compared.
RESULTS: The average mean deviation for the glaucomatous eyes was -2.5 ± 1.6 dB. The AUCs for average (0.815); superior (0.807); and inferior (0.788) MIRL thicknesses were not significantly different (p ≥ 0.18). The AUCs for average (0.735); superior (0.728); and inferior (0.697) pRNFL thicknesses were also similar (p ≥ 0.15). Average MIRL thickness had a significantly larger AUC compared to average pRNFL thickness analysis (0.815 vs 0.735; p = 0.03). Sensitivities at 80% specificity for average MIRL and pRNFL thicknesses were 66.7% (cutoff, 89.9 μm) and 62.9% (cutoff, 111.8 μm), respectively.
CONCLUSIONS: The GCC scan showed a similar or even a slightly better ability to discriminate between healthy and early glaucomatous eyes compared to the pRNFL scan. Different from previous analyses considering total macular thickness, the GCC macular scan seems to be a useful tool for identification of early structural damage in patients with glaucoma. ||||| PURPOSE: To evaluate the diagnostic accuracy of retinal nerve fibre layer thickness (RNFLT), ganglion cell complex (GCC), and optic disc measurements made with the RTVue-100 Fourier-domain optical coherence tomography (OCT) to detect glaucoma in a Caucasian referral population.
METHODS: One randomly selected eye of 286 Caucasian patients (93 healthy, 36 ocular hypertensive, 46 preperimetric glaucoma, and 111 perimetric glaucoma eyes) was evaluated.
RESULTS: Using the software-provided classification, for the total population sensitivity did not exceed 73.6% for the optic nerve head parameters, and 62.7% for the other parameters. Specificity was high (94.6-100%) for most RNFLT and GCC parameters, but low (72.0-76.3%) for the optic disc parameters. Positive predictive value varied between 98.1 and 100% for the main RNFLT parameters, 92.6 and 100% for the 16 RNFLT sectors, 92.4 and 99.0% for the GCC parameters, but did not exceed 86.3% for any of the optic disc parameters. Positive likelihood ratio (PLR) was higher than 10 for average, inferior and superior RNFLT (25.5 to infinite), 12 of the 16 RNFLT sectors (12.6 to infinite), and three of the four GCC parameters (40.0 to 48.6). No optic disc parameter had a PLR higher than 3.0.
CONCLUSIONS: RNFLT and GCC parameters of the RTVue-100 Fourier-domain OCT showed moderate sensitive but high specificity, positive predictive value and PLR for detection of glaucoma. The optic disc parameters had lower diagnostic accuracy than the RNFLT and GCC parameters. ||||| PURPOSE: To evaluate the glaucoma diagnostic performance of ganglion cell inner-plexiform layer (GCIPL) parameters used individually and in combination with retinal nerve fiber layer (RNFL) or optic nerve head (ONH) parameters measured with Cirrus HD-OCT (Carl Zeiss Meditec, Inc, Dublin, CA).
DESIGN: Prospective cross-sectional study.
PARTICIPANTS: Fifty patients with early perimetric glaucoma and 49 age-matched healthy subjects.
METHODS: Three peripapillary RNFL and 3 macular GCIPL scans were obtained in 1 eye of each participant. A patient was considered glaucomatous if at least 2 of the 3 RNFL or GCIPL scans had the average or at least 1 sector measurement flagged at 1% to 5% or less than 1%. The diagnostic performance was determined for each GCIPL, RNFL, and ONH parameter as well as for binary or-logic and and-logic combinations of GCIPL with RNFL or ONH parameters.
MAIN OUTCOME MEASURES: Sensitivity, specificity, positive likelihood ratio (PLR), and negative likelihood ratio (NLR).
RESULTS: Among GCIPL parameters, the minimum had the best diagnostic performance (sensitivity, 82.0%; specificity, 87.8%; PLR, 6.69; and NLR, 0.21). Inferior quadrant was the best RNFL parameter (sensitivity, 74%; specificity, 95.9%; PLR, 18.13; and NLR, 0.27), as was rim area (sensitivity, 68%; specificity, 98%; PLR, 33.3; and NLR, 0.33) among ONH parameters. The or-logic combination of minimum GCIPL and average RNFL provided the overall best diagnostic performance (sensitivity, 94%; specificity, 85.7%; PRL, 6.58; and NLR, 0.07) as compared with the best RNFL, best ONH, and best and-logic combination (minimum GCIPL and inferior quadrant RNFL; sensitivity, 64%; specificity, 100%; PLR, infinity; and NPR, 0.36).
CONCLUSIONS: The binary or-logic combination of minimum GCIPL and average RNFL or rim area provides better diagnostic performances than those of and-logic combinations or best single GCIPL, RNFL, or ONH parameters. This finding may be clinically valuable for the diagnosis of early glaucoma. ||||| PURPOSE: To evaluate the diagnostic validity of macular ganglion cell-inner plexiform layer (mGCIPL) thickness deviation map algorithm using Cirrus high definition-optical coherence tomography to discriminate between normal controls and patients with preperimetric or early glaucoma.
PATIENTS AND METHODS: Seventy-two normal controls, 37 patients with preperimetric glaucoma and 70 patients with early glaucoma were enrolled. mGCIPL thickness and peripapillary retinal nerve fiber layer (pRNFL) thickness were measured by Cirrus high definition-optical coherence tomography. Areas showing abnormal color coding were obtained by customized Image J software calculating the number of abnormal superpixels at 1% and 5% level in each deviation map of measurements (GCIPL-DM1, GCIPL-DM5, RNFL-DM1, RNFL-DM5). The area under the receiver operating characteristic curve (AROC) of each parameter was calculated to provide diagnostic ability between normal controls and patients with preperimetric or early glaucoma.
RESULTS: AROCs of the deviation map algorithms were higher than those of other parameters. Parameter with the best AROC was the GCIPL-DM5 (0.920 and 0.968) in both preperimetric and early glaucoma. The sensitivities of the GCIPL-DM5 at 80% and 95% specificities were 92% and 68% in preperimetric glaucoma and 98% and 90% in early glaucoma, respectively. Pairwise comparisons between AROCs of parameters from deviation map algorithms did not show statistically significant differences.
CONCLUSIONS: mGCIPL thickness deviation map showed good diagnostic ability in detecting preperimetric and early glaucoma, and it was comparable with pRNFL thickness deviation map. Our findings suggest that it can be an important parameter in detecting subtle glaucomatous structural change. ||||| PURPOSE: To evaluate the diagnostic ability of macular parameters and peripapillary retinal nerve fiber layer (RNFL) parameters for early glaucoma using spectral domain optical coherence tomography (SD-OCT).
MATERIALS AND METHODS: One eye from 32 early glaucoma patients (including preperimetric glaucoma) and 32 normal participants underwent macular scans and peripapillary RNFL scans with SD-OCT 3 times on the same day. The discrimination power of each parameter to detect early glaucoma was determined by areas under receiver operating characteristics curve (AROC) and sensitivity at fixed specificity. Correlation of OCT data with visual field defects was evaluated by linear regression analysis. Reproducibility was also evaluated.
RESULTS: Significant differences between early glaucoma and normal participants were found for all parameters except fovea in macular scans and in the superior and inferior quadrants, at 12, 3, 6, 7, 11 o'clock, and average RNFL thickness in RNFL scans. The best parameters based on AROC and sensitivity at a specificity of >90% were temporal outer macula thickness (AROC, 0.79; sensitivity, 63%) in macular parameters and inferior quadrant (AROC, 0.82; sensitivity, 53%) in RNFL parameters. The highest correlation with mean deviation was found in inferior inner macular volume (r=0.50, P<0.001). The mean intraclass correlation coefficient was 0.96 in macular scans and 0.84 in RNFL scans. Test-retest variability ranged from 2.3 to 10.1 μm in macular thickness, 0 to 0.06 mm in macular volume, and 5.8 to 18.9 μm in RNFL thickness.
CONCLUSION: For the diagnosis of early glaucoma by SD-OCT, macular parameters had high discriminating power and high reproducibility comparable with peripapillary RNFL parameters. ||||| AIMS: To evaluate the capability of Fourier-domain optical coherence tomography (FD-OCT) to detect structural damage in patients with preperimetric glaucoma.
METHODS: A total of 178 Caucasian subjects were enrolled in this cohort study: 116 preperimetric glaucoma patients and 52 healthy subjects. Using three-dimensional FD-OCT, the participants underwent imaging of the ganglion cell complex (GCC) and the optic nerve head. Sensitivity, specificity, likelihood ratios, and predictive values were calculated for all parameters at the first and fifth percentiles. Areas under the curves (AUCs) were generated for all parameters and were compared (Delong test). For both the GCC and the optic nerve head protocols, the OR logical disjunction (Boolean logic operator) was calculated.
RESULTS: The AUCs didn't significantly differ. Macular global loss volume had the largest AUC (0.81). Specificities were high at both the fifth and first percentiles (up to 97%), but sensitivities were low, especially at the first percentile (55%-27%).
CONCLUSION: Macular and papillary diagnostic accuracies did not differ significantly based on the 95% confidence interval. The computation of the Boolean OR operator has been found to boost diagnostic accuracy. Using the software-provided classification, sensitivity and diagnostic accuracy were low for both the retinal nerve fiber layer and the GCC scans. FD-OCT does not seem to be decisive for early detection of structural damage in patients with no functional impairment. This suggests that there is a need for analysis software to be further refined to enhance glaucoma diagnostic capability. ||||| PURPOSE: To evaluate the ability of the optic nerve head (ONH), retinal nerve fiber layer (RNFL), and ganglion cell complex (GCC) parameters of spectral domain optical coherence tomograph (SDOCT) in detecting preperimetric glaucoma.
METHODS: In a cross-sectional study, 34 preperimetric glaucoma eyes (34 patients) and 72 control eyes (72 subjects) with large physiologic optic disc cupping underwent ONH, RNFL, and GCC imaging with SDOCT. Preperimetric glaucoma was diagnosed in the presence of glaucomatous optic neuropathy on masked evaluation of optic disc photographs by two glaucoma experts and normal visual fields. The ability of SDOCT parameters to discriminate preperimetric glaucoma eyes from eyes with large physiologic cups was evaluated by areas under the receiver operating characteristic curves (AUC), sensitivities at fixed specificities, and likelihood ratios (LR).
RESULTS: All SDOCT parameters were significantly different (P < 0.05) between the two groups. The ONH, RNFL, and GCC parameters with best AUCs to differentiate preperimetric glaucoma from eyes with large physiologic cups were vertical cup to disc ratio (0.76), inferior quadrant RNFL thickness (0.76), and inferior quadrant GCC thickness (0.75), respectively. Sensitivities at 95% specificity of SDOCT parameters ranged between 15% and 29%. Likelihood ratios of outside normal limits category of parameters ranged between 3 and 11, and within normal limits category between 0.5 and 0.8.
CONCLUSIONS: Diagnostic abilities of ONH, RNFL, and GCC parameters of SDOCT to differentiate preperimetric glaucoma eyes from control eyes with large physiologic cupping were only moderate. ||||| BACKGROUND: Optical coherence tomography (OCT) is a high resolution noncontact imaging modality which can quantitatively detect the optic disc and retinal structure. This study was designed to evaluate the diagnostic capability of parameters of the optic disc, retinal nerve fiber layer thickness, and ganglion cell complex (GCC) using a new technology called Fourier-domain OCT (FD-OCT) for early primary open angle glaucoma (POAG) patients.
METHODS: Two groups of patients, early perimetric damage POAG and normal subjects were included in this observational cross-sectional study. All patients underwent FD-OCT and visual field examination in addition to full ophthalmic examinations. Receiver operating characteristic curves (ROC) were studied for all parameters. The sensitivity and specificity for distinguishing between normal and early glaucomatous eyes, the areas under the receiver operating characteristic curves (AROC) and positive, negative likelihood ratios were evaluated for all the single parameters and selected combined parameters using arbitrary cutoffs.
RESULTS: Thirty-four eyes of 34 early POAG patients and 42 eyes of 42 normal subjects were analyzed. Cup/disc (C/D) vertical ratio presented the best sensitivity and positive likelihood ratio for selected specificities (95% and 85%) which were 79.4% and 88.2%, 33.4 and 7.4, respectively. Among all single parameters, the C/D vertical ratio demonstrated the highest AROC which was at 0.930. The average thickness of circumpapillary RNFL on 3.45 mm showed the highest AROC among all of the peripapillary RNFL parameters. The sensitivity at selected specificity and AROC of GCC were not as high as C/D vertical ratio and RNFL AT on 3.45 mm. When the C/D vertical ratio, RNFL AT on 3.45 mm, and rim area were combined using a logistical diagnostic model, the AROC was raised to 0.949 but not significantly different from the top single parameter, C/D vertical ratio.
CONCLUSIONS: The key parameters obtained by FD-OCT were able to show the significant differences of optic discs, thickness of RNFL and GCC between POAG patients and normal subjects. According to sensitivity, specificity, likelihood ratio and AROC, the top three parameters from FD-OCT for early diagnosis of POAG were C/D vertical ratio, RNFL AT on 3.45 mm, and the rim area. ||||| PURPOSE: To investigate the relationship between macular ganglion cell-inner plexiform layer (mGCIPL) thickness and estimated macular retinal ganglion cell (RGC) counts in glaucoma.
DESIGN: Observational cohort study.
PARTICIPANTS: Cross-sectional study of 77 healthy, 154 glaucoma suspect, and 159 glaucomatous eyes from the Diagnostic Innovations in Glaucoma Study.
METHODS: All eyes underwent 24-2 standard automated perimetry (SAP) and optic nerve and macular imaging using high-definition optical coherence tomography (OCT). The total number of RGCs was estimated using a previously described model that uses SAP and OCT circumpapillary retinal nerve fiber layer (cpRNFL) measurements. The number of macular RGCs was estimated from the temporal cpRNFL and SAP test points within the central 10°.
MAIN OUTCOME MEASURES: The correlation between mGCIPL thickness and estimates of macular RGC counts.
RESULTS: The average estimated macular RGC count in glaucomatous eyes was 306 010 ± 109 449 cells, which was significantly lower than the estimate of 520 678 ± 106 843 cells in healthy eyes (P < 0.001). Glaucomatous eyes had 41% fewer estimated macular RGCs than healthy eyes and suspects had 21% fewer estimated macular RGCs. There was strong correlation between estimated macular RGC counts and mGCIPL thickness (R(2) = 0.67; P < 0.001). Macular RGC counts performed better than average mGCIPL thickness in discriminating healthy and glaucomatous eyes with receiver operating characteristic curve areas of 0.873 and 0.775, respectively (P = 0.015).
CONCLUSIONS: The strong association between estimated macular RGC counts and mGCIPL thickness and the better diagnostic performance of the macular RGC counts compared with mGCIPL thickness provides further evidence that estimates of RGC number from cpRNFL thickness and SAP sensitivity can be used to assess neural losses in glaucoma. ||||| BACKGROUND: To evaluate and compare the utility of ganglion cell complex with peripapillary retinal nerve fibre layer and optic nerve head measurements for detection of localized defects in patients with preperimetric glaucoma using spectral-domain optical coherence tomography.
DESIGN: Prospective study.
PARTICIPANTS: Preperimetric glaucoma patients.
METHODS: A total of 105 eyes with preperimetric glaucoma and 68 age- and refractive error-matched control eyes were enrolled. The ability to detect localized retinal nerve fibre layer defects by RTVue-100 spectral-domain optical coherence tomography (Optovue, Inc., Fremont, CA, USA) was assessed calculating the areas under receiver operating characteristic curves.
MAIN OUTCOME MEASURES: The ability to detect localized retinal nerve fibre layer defects by spectral-domain optical coherence tomography.
RESULTS: Global volume loss and superior ganglion cell complex thickness showed the largest area under receiver operating characteristic curve values (both areas under receiver operating characteristic curves 0.84, P < 0.001) among ganglion cell complex parameters. Average peripapillary retinal nerve fibre layer thickness afforded the best diagnostic capability (area under receiver operating characteristic curve 0.89, P < 0.001), whereas among optic nerve head parameters, the horizontal cup:disc ratio yielded the highest area under receiver operating characteristic curve (0.85, P < 0.001). No statistical difference was evident between the areas under receiver operating characteristic curves of the most informative parameters when the data were gathered from the three different sites (ganglion cell complex, peripapillary retinal nerve fibre layer, and optic nerve head) (P > 0.02).
CONCLUSIONS: Ganglion cell complex thickness was significantly reduced in eyes with preperimetric glaucoma. Ganglion cell complex imaging using spectral-domain optical coherence tomography may be a useful ancillary modality for detection of early macular changes in glaucomatous eyes with localized retinal nerve fibre layer defects. ||||| PURPOSE: We evaluated the diagnostic accuracy of macular ganglion cell-inner plexiform layer (GCIPL) measurements using a high-definition optical coherence tomography (Cirrus HD-OCT) ganglion cell analysis algorithm for detecting early and moderate-to-severe glaucoma.
METHODS: Totals of 119 normal subjects and 306 glaucoma patients (164 patients with early glaucoma and 142 with moderate-to-severe glaucoma) were enrolled from the Macular Ganglion Cell Imaging Study. Macular GCIPL, peripapillary retinal nerve fiber layer (RNFL) thickness, and optic nerve head (ONH) parameters were measured in each subject. Areas under the receiver operating characteristic curves (AUROCs) were calculated and compared. Based on the internal normative database, the sensitivity and specificity for detecting early and moderate-to-severe glaucoma were calculated.
RESULTS: There was no statistically significant difference between the AUROCs for the best OCT parameters. For detecting early glaucoma, the sensitivity of the Cirrus GCIPL parameters ranged from 26.8% to 73.2% and that of the Cirrus RNFL parameters ranged from 6.1% to 61.6%. For the early glaucoma group, the best parameter from the GCIPL generally had a higher sensitivity than those of the RNFL and ONH parameters with comparable specificity (P < 0.05, McNemar's test).
CONCLUSIONS: There were no significant differences between the AUROCs for Cirrus GCIPL, RNFL, and ONH parameters, indicating that these maps have similar diagnostic potentials for glaucoma. The minimum GCIPL showed better glaucoma diagnostic performance than the other parameters at comparable specificities. However, other GCIPL parameters showed performances comparable to those of the RNFL parameters. ||||| AIM: To compare the diagnostic ability to detect glaucomatous changes between peripapillary retinal nerve fibre layer (RNFL) thickness and the macular ganglion cell complex (GCC) in highly myopic patients using Fourier domain optical coherence tomography.
METHODS: Participants, consecutively enrolled from January 2009 to June 2009, were imaged with RTVue-100 (NHM4 and MM7 scan). The sensitivity and specificity of a colour code less than 5% (red or yellow) for glaucoma diagnosis were calculated. Area under the receiver operator characteristic (AUROC) curves were generated to assess the ability of each parameter to detect glaucomatous changes.
RESULTS: 73 normal controls and 77 glaucoma patients were included. Participants were categorised as 105 non-high myopes (spherical equivalent >-6.0 dioptres) and 45 high myopes (Spherical equivalent ≤-6.0 dioptres). The GCC thickness showed a strong correlation with RNFL thickness (correlation coefficient=0.763, p<0.001) in all participants. The sensitivity from superior GCC colour code was significantly higher than that from superior RNFL (p=0.019). The ability to detect glaucomatous changes in the highly myopic group by examining the average GCC thickness (AUROC, GCC; 0.889) was higher than when examining RNFL thickness (AUROC, RNFL; 0.825); however, there was no statistical significance (p=0.442).
CONCLUSIONS: The ability to diagnose glaucoma with macular GCC thickness was comparable with that with peripapillary RNFL thickness in high-myopia patients. Macular GCC thickness measurements may be a good alternative or a complementary measurement to RNFL thickness assessment in the clinical evaluation of glaucoma in patients with high myopia. ||||| PURPOSE: To create a multivariable predictive model for glaucoma with early visual field loss using a combination of spectral-domain optical coherence tomography (SD-OCT) parameters, and to compare the results with single variable models.
METHODS: Two hundred fifty-three subjects (149 healthy controls and 104 with early glaucoma) underwent optic disc and macular scanning using SD-OCT in one randomly selected eye per subject. Sixteen parameters (rim area, cup-to-disc area ratio, vertical cup-to-disc diameter ratio, average and quadrant RNFL thicknesses, average, minimum, and sectoral ganglion cell inner-plexiform layer [GCIPL] thicknesses) were collected and submitted to an exploratory factor analysis (EFA) followed by logistic regression with the backward elimination variable selection technique. Area under the curve (AUC) of the receiver operating characteristic (ROC), sensitivity, specificity, Akaike's information criterion (AIC), predicted probability, prediction interval length (PIL), and classification rates were used to determine the performances of the univariable and multivariable models.
RESULTS: The multivariable model had an AUC of 0.995 with 98.6% sensitivity, 96.0% specificity, and an AIC value of 43.29. Single variable models yielded AUCs of 0.943 to 0.987, sensitivities of 82.6% to 95.7%, specificities of 88.0% to 94.0%, and AICs of 113.16 to 59.64 (smaller is preferred). The EFA logistic regression model correctly classified 91.67% of cases with a median PIL of 0.050 in the validation set. Univariable models correctly classified 80.62% to 90.48% of cases with median PILs 1.9 to 3.0 times larger.
CONCLUSIONS: The multivariable model was successful in predicting glaucoma with early visual field loss and outperformed univariable models in terms of AUC, AIC, PILs, and classification rates. ||||| PURPOSE: To compare the detection of localized retinal nerve fiber layer (RNFL) defects by two different spectral domain optical coherence tomography (SD-OCT) devices.
METHODS: Eyes of 42 normal control subjects and 48 patients with a localized RNFL defect on red-free fundus photographs were imaged by the Cirrus (Carl Zeiss Meditec, Dublin, CA, USA) and 3D OCT (Topcon, Tokyo, Japan) devices. We compared sensitivities, specificities, and area under the receiver operating characteristic curves (AUCs) of circumpapillary RNFL (cpRNFL) thickness and ganglion cell complex (GCC) parameters between the two devices.
RESULTS: The devices provided different cpRNFL thickness measurements. The highest sensitivities at fixed specificities of 80 % (Cirrus: 83.3 %; 3D OCT: 77.1 %) and 95 % (Cirrus: 69.8 %; 3D OCT: 68.8 %) and the largest AUCs (Cirrus: 0.90; 3D OCT: 0.88) obtained by the cpRNFL parameters of the two devices were similar. Based on the internal normative database, the deviation-from-normal map of the Cirrus OCT device and the 36-segment map of the 3D OCT device had the highest sensitivity (89.6 and 91.7 %, respectively). Among the macular GCC parameters of the 3D OCT device, inferior macular RNFL thickness had the highest sensitivity (81.2 % at a specificity of 80 %) and the largest AUC (0.89).
CONCLUSIONS: Although the two SD-OCT devices have different measurement protocols, they showed similar abilities for the detection of a localized RNFL defect. ||||| PURPOSE: To determine the diagnostic performance of macular ganglion cell-inner plexiform layer (GCIPL) thickness measured with the Cirrus high-definition optical coherence tomography (HD-OCT) ganglion cell analysis (GCA) algorithm (Carl Zeiss Meditec, Dublin, CA) to discriminate normal eyes and eyes with early glaucoma and to compare it with that of peripapillary retinal nerve fiber layer (RNFL) thickness and optic nerve head (ONH) measurements.
DESIGN: Evaluation of diagnostic test or technology.
PARTICIPANTS: Fifty-eight patients with early glaucoma and 99 age-matched normal subjects.
METHODS: Macular GCIPL and peripapillary RNFL thicknesses and ONH parameters were measured in each participant, and their diagnostic abilities were compared.
MAIN OUTCOME MEASURES: Area under the curve (AUC) of the receiver operating characteristic.
RESULTS: The GCIPL parameters with the best AUCs were the minimum (0.959), inferotemporal (0.956), average (0.935), superotemporal (0.919), and inferior sector (0.918). There were no significant differences between these AUCs and those of inferior quadrant (0.939), average (0.936), and superior quadrant RNFL (0.933); vertical cup-to-disc diameter ratio (0.962); cup-to-disc area ratio (0.933); and rim area (0.910), all P>0.05.
CONCLUSIONS: The ability of macular GCIPL parameters to discriminate normal eyes and eyes with early glaucoma is high and comparable to that of the best peripapillary RNFL and ONH parameters.
FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references. ||||| PURPOSE: To determine whether the thicknesses of the different parameters of the ganglion cell complex (GCC) and peripapillary retinal nerve fiber layer can be used to differentiate eyes with glaucoma from normal eyes.
METHODS: Two hundred sixty-one eyes, including 68 normal eyes and 32 preperimetric glaucoma, 81 early glaucoma, and 80 advanced glaucoma were analyzed in the present study. The thicknesses of the GCC and retinal nerve fiber layer were measured using RTVue spectral-domain optical coherence tomographic (SD-OCT) images. The area under the receiver operating characteristic (AUROC) curve and sensitivities at fixed specificities were calculated for each parameter. A logistic regression analysis was used to determine the risk factors for glaucoma.
RESULTS: The 2 largest AUROC curves for all glaucoma stages were those for the GCC parameters. The global loss volume (GLV) was always one of the 2 highest values of the AUROC curve. The GLV also had the highest sensitivity at a fixed specificity to identify glaucoma at early and advanced stage. The focal loss volume (FLV) had the largest AUROC curve value and the highest sensitivity at a fixed specificity for advanced glaucoma. The logistic regression analysis showed that the GLV was one of the factors that predicted preperimetric glaucoma [odds ratio (OR)=1.74] and early glaucoma (OR=1.22), whereas the FLV was useful for detecting advanced glaucoma (OR=2.32).
CONCLUSIONS: The SD-OCT-derived macular GCC parameters can be used to detect preperimetric and perimetric glaucoma. The new GCC parameters, GLV and FLV, performed well in discriminating glaucomatous eyes from normal eyes. ||||| PURPOSE: To evaluate the capability of the optic disc, peripapillary retinal nerve fiber layer (P-RNFL), macular inner retinal layer (M-IRL) parameters, and their combination obtained by Fourier-domain optical coherent tomography (OCT) in differentiating a glaucoma suspect from perimetric glaucoma.
METHODS: Two hundred and twenty eyes from 220 patients were enrolled in this study. The optic disc morphology, P-RNFL, and M-IRL were assessed by the Fourier-domain OCT (RTVue OCT, Model RT100, Optovue, Fremont, CA). A linear discriminant function was generated by stepwise linear discriminant analysis on the basis of OCT parameters and demographic factors. The diagnostic power of these parameters was evaluated with receiver operating characteristic (ROC) curve analysis. The diagnostic power in the clinically relevant range (specificity ≥ 80%) was presented as the partial area under the ROC curve (partial AROC).
RESULTS: The individual OCT parameter with the largest AROC and partial AROC in the high specificity (≥ 80%) range were cup/disc vertical ratio (AROC = 0.854 and partial AROC = 0.142) for the optic disc parameters, average thickness (AROC = 0.919 and partial AROC = 0.147) for P-RNFL parameters, inferior hemisphere thickness (AROC = 0.871 and partial AROC = 0.138) for M-IRL parameters, respectively. The linear discriminant function further enhanced the ability in detecting perimetric glaucoma (AROC = 0.970 and partial AROC = 0.172).
CONCLUSIONS: Average P-RNFL thickness is the optimal individual OCT parameter to detect perimetric glaucoma. Simultaneous evaluation on disc morphology, P-RNFL, and M-IRL thickness can improve the diagnostic accuracy in diagnosing glaucoma. ||||| PURPOSE: To evaluate and compare the glaucoma discrimination ability of macular inner retinal layer (MIRL) thickness with that of peripapillary retinal nerve fiber layer (pRNFL) thickness measured by spectral-domain optical coherence tomography (RTVue-100; Optovue Inc, Fremont, CA) in patients with normal-tension glaucoma (NTG).
METHODS: Sixty-five healthy subjects and 102 with NTG were enrolled. MIRL thickness provided by a ganglion cell complex (GCC) scan and two RNFL thicknesses measured by the NHM4 (RNFL1) and RNFL 3.45 (RNFL2) modes of the RTVue-100 system were analyzed. The areas under the receiver operating characteristic curves (AUCs) of MIRL and pRNFL thicknesses for discriminating patients with NTG from control subjects were determined. The AUCs were compared between patients with central visual field (VF) defects (VF; <or=10 degrees of fixation) and peripheral VF defects (>10 degrees from fixation).
RESULTS: The average MIRL thickness showed a strong correlation with both RNFL1 and -2 thicknesses (R(2) = 0.773, 0.774, both P < 0.0001). The AUCs for average MIRL, RNFL1, and RNFL2 thicknesses were not significantly different at 0.945, 0.973, and 0.976, respectively. However, the AUCs of the average and superior MIRL thicknesses were significantly less than that of the pRNFL thickness in eyes with moderate-to-advanced glaucoma and eyes with peripheral VF defects.
CONCLUSIONS: The average MIRL thickness showed a strong correlation with pRNFL thickness, because patients with NTG at an early stage showed paracentral VF defects near the fixation point. MIRL thickness showed glaucoma discrimination ability comparable to that of pRNFL thickness in patients with NTG with early VF defects. In eyes with advanced or peripheral VF defect, pRNFL measurement showed a better glaucoma diagnostic ability than did MIRL measurement. | [
{
"source_pmid": "24576877",
"source_text": "PURPOSE: To evaluate the influence of topographic profiles (i.e., inner directional angle and angular width) of localized retinal nerve fiber layer (RNFL) defects on the diagnostic performance of macular ganglion cell-inner plexiform layer (GCIPL) thickness in di... |
30352574 | CONCLUSION: In our meta-analysis, C3 genetic polymorphisms unveiled a positive effect on the risk of advanced AMD, especially in Caucasians. Furthermore, numerous well-designed studies with large sample-size are required to validate this conclusion. | Age-related macular degeneration (AMD) is the leading cause of blindness in the elderly in the developed world. Numerous genetic factors contribute to the development of the multifactorial disease. We performed a case-control study to assess the risk conferred by known and candidate genetic polymorphisms on the development of AMD. We searched for genetic interactions and for differences in dry and wet AMD etiology. We enrolled 213 patients with exudative, 67 patients with dry AMD and 106 age and ethnically matched controls. Altogether 12 polymorphisms in Apolipoprotein E, complement factor H, complement factor I, complement component 3, blood coagulation factor XIII, HTRA1, LOC387715, Gas6 and MerTK genes were tested. No association was found between either the exudative or the dry form and the polymorphisms in the Apolipoprotein E, complement factor I, FXIII and MerTK genes. Gas6 c.834+7G>A polymorphism was found to be significantly protective irrespective of other genotypes, reducing the odds of wet type AMD by a half (OR = 0.50, 95%CI: 0.26-0.97, p = 0.04). Multiple regression models revealed an interesting genetic interaction in the dry AMD subgroup. In the absence of C3 risk allele, mutant genotypes of both CFH and HTRA1 behaved as strongly significant risk factors (OR = 7.96, 95%CI: 2.39 = 26.50, p = 0.0007, and OR = 36.02, 95%CI: 3.30-393.02, p = 0.0033, respectively), but reduced to neutrality otherwise. The risk allele of C3 was observed to carry a significant risk in the simultaneous absence of homozygous CFH and HTRA1 polymorphisms only, in which case it was associated with a near-five-fold relative increase in the odds of dry type AMD (OR = 4.93, 95%CI: 1.98-12.25, p = 0.0006). Our results suggest a protective role of Gas6 c.834+7G>A polymorphism in exudative AMD development. In addition, novel genetic interactions were revealed between CFH, HTRA1 and C3 polymorphisms that might contribute to the pathogenesis of dry AMD. ||||| Genome-wide association studies (GWASs) assess correlation between traits and DNA sequence variation using large numbers of genetic variants such as single nucleotide polymorphisms (SNPs) distributed across the genome. A GWAS produces many trait-SNP associations with low p-values, but few are replicated in subsequent studies. We sought to determine if characteristics of the genomic loci associated with a trait could be used to identify initial associations with a higher chance of replication in a second cohort. Data from the age-related eye disease study (AREDS) of 100,000 SNPs on 395 subjects with and 198 without age-related macular degeneration (AMD) were employed. Loci highly associated with AMD were characterized based on the distribution of genotypes, level of significance, and clustering of adjacent SNPs also associated with AMD suggesting linkage disequilibrium or multiple effects. Forty nine loci were highly associated with AMD, including 3 loci (CFH, C2/BF, LOC387715/HTRA1) already known to contain important genetic risks for AMD. One additional locus (C3) reported during the course of this study was identified and replicated in an additional study group. Tag-SNPs and haplotypes for each locus were evaluated for association with AMD in additional cohorts to account for population differences between discovery and replication subjects, but no additional clearly significant associations were identified. Relying on a significant genotype tests using a log-additive model would have excluded 57% of the non-replicated and none of the replicated loci, while use of other SNP features and clustering might have missed true associations. ||||| Age-related macular degeneration (AMD) is the leading cause of blindness in the elderly in the developed world. We conducted a genome-wide association study in a series of families enriched for AMD and completed a meta-analysis of this new data with results from reanalysis of an existing study of a late-stage case-control cohort. We tested the top findings for replication in 1896 cases and 1866 controls and identified two novel genetic protective factors for AMD. In addition to the complement factor H (CFH) (P=2.3 × 10⁻⁶⁴) and age-related maculopathy susceptibility 2 (ARMS2) (P=1.2 × 10⁻⁶⁰) loci, we observed a protective effect at rs429608, an intronic SNP in SKIV2L (P=5.3 × 10⁻¹⁵), a gene near the complement component 2 (C2)/complement factor B (BF) locus, that indicates the protective effect may be mediated by variants other than the C2/BF variants previously studied. Haplotype analysis at this locus identified three protective haplotypes defined by the rs429608 protective allele. We also identified a new potentially protective effect at rs2679798 in MYRIP (P=2.9 × 10⁻⁴), a gene involved in retinal pigment epithelium melanosome trafficking. Interestingly, MYRIP was initially identified in the family-based scan and was confirmed in the case-control set. From these efforts, we report the identification of two novel protective factors for AMD and confirm the previously known associations at CFH, ARMS2 and C3. ||||| PURPOSE: Intermediate and large drusen usually precede advanced age-related macular degeneration (AMD). There is little information about which genes influence drusen accumulation. Discovery of genetic variants associated with drusen may lead to prevention and treatments of AMD in its early stages.
METHODS: A total of 3066 subjects were evaluated on the basis of ocular examinations and fundus photography and categorized as control (n = 221), intermediate drusen (n = 814), large drusen (n = 949), or advanced AMD (n = 1082). SNPs in the previously identified CFH, C2, C3, CFB, CFI, APOE, and ARMS2/HTRA1 genes/regions and the novel genes LIPC, CETP, and ABCA1 in the high-density lipoprotein (HDL) cholesterol pathway were genotyped. Associations between stage of AMD and SNPs were assessed using logistic regression.
RESULTS: Controlling for age, sex, education, smoking, body mass index, and antioxidant treatment, the number of minor (T) alleles of the genes LIPC and ABCA1 were significantly associated with a reduced risk of intermediate drusen (LIPC [P trend = 0.045], ABCA1 [P = 4.4 × 10(-3)]), large drusen (LIPC [P = 0.041], ABCA1 [P = 7.7 × 10(-4)]), and advanced AMD (LIPC [P = 1.8 × 10(-3)], ABCA1 [P = 3 × 10(-4)]). After further adjustment for known genetic factors, the protective effect of the TT genotype was significant for intermediate drusen (LIPC [odds ratio (OR), 0.56; 95% confidence interval (CI), 0.33-0.94], ABCA1 [OR, 0.48; 95% CI, 0.27-0.85]), large drusen (LIPC [OR, 0.58; 95% CI, 0.34-0.98)], ABCA1 [OR, 0.41; 95% CI, 0.23-0.74)]), and advanced AMD (LIPC [OR, 0.39; 95% CI, 0.21-0.74)], ABCA1 [OR, 0.35; 95% CI, 0.17-0.71)]). CFH, C3, C2, and ARMS2/HTRA1 were associated with large drusen and advanced AMD.
CONCLUSIONS: LIPC and ABCA1 are related to intermediate and large drusen, as well as advanced AMD. CFH, C3, C2, and ARMS2/HTRA1 are associated with large drusen and advanced AMD. Genes may have varying effects on different stages of AMD. ||||| BACKGROUND: Age-related macular degeneration (AMD) is a prevalent cause of blindness in Western societies. Variants in the genes encoding complement factor H (CFH), complement component 3 (C3) and age-related maculopathy susceptibility 2 (ARMS2) have repeatedly been shown to confer significant risks for AMD; however, their role in disease progression and thus their potential relevance for interventional therapeutic approaches remains unknown.
METHODOLOGY/PRINCIPAL FINDINGS: Here, we analyzed association between variants in CFH, C3 and ARMS2 and disease progression of geographic atrophy (GA) due to AMD. A quantitative phenotype of disease progression was computed based on longitudinal observations by fundus autofluorescence imaging. In a subset of 99 cases with pure bilateral GA, variants in CFH (Y402H), C3 (R102G), and ARMS2 (A69S) are associated with disease (P = 1.6x10(-9), 3.2x10(-3), and P = 2.6x10(-12), respectively) when compared to 612 unrelated healthy control individuals. In cases, median progression rate of GA over a mean follow-up period of 3.0 years was 1.61 mm(2)/year with high concordance between fellow eyes. No association between the progression rate and any of the genetic risk variants at the three loci was observed (P>0.13).
CONCLUSIONS/SIGNIFICANCE: This study confirms that variants at CFH, C3, and ARMS2 confer significant risks for GA due to AMD. In contrast, our data indicate no association of these variants with disease progression which may have important implications for future treatment strategies. Other, as yet unknown susceptibilities may influence disease progression. ||||| OBJECTIVE: To evaluate if adult-onset foveomacular vitelliform dystrophy (AOFVD) and butterfly-shaped pigment dystrophy (BSPD) are associated with risk single-nucleotide polymorphisms (SNPs) for age-related macular degeneration (AMD).
METHODS: This was a tertiary referral center-based cross-sectional study including 35 consecutive patients with BSPD and AOFVD, 317 patients with AMD, and 159 unaffected individuals. Demographics, clinical information, and ophthalmic imaging studies were collected. Sequencing was performed for the peripherin/RDS and BEST1 genes, and genotyping was performed for SNPs in the genes for complement factor H (CFH) (rs1061170), HTRA1 (rs11200638), and complement component 3 (C3) (rs2231099).
RESULTS: Adult-onset foveomacular vitelliform dystrophy and BSPD were diagnosed in 24 (68.6%) and 11 (31.4%) of the 35 patients, respectively. The mean (SD) age of patients with pattern dystrophy (PD) was 75.3 (10) years and median visual acuity was 0.7. Pattern dystrophy was associated with the HTRA1 risk allele compared with unaffected individuals (odds ratio, 1.72; 95% CI, 1.11-2.66; P = .03). The HTRA1 SNP showed similar prevalence in patients with AMD and PD. The CFH risk allele was significantly less common in patients with PD compared with patients with AMD (odds ratio, 0.47; 95% CI, 0.28-0.76; P = .002). No mutations in peripherin/RDS or BEST1 were detected.
CONCLUSIONS: The AOFVD and BSPD phenotypes are associated with an HTRA1 risk SNP. These phenotypes often present in elderly individuals who do not carry peripherin/RDS gene mutations and are associated with retinal pigment epithelium alterations and increased risk for choroidal neovascularization. Further research is required to evaluate if AOFVD and BSPD phenotypes in aged individuals are associated with AMD. ||||| PURPOSE: Nonsynonymous coding single nucleotide polymorphisms (nsSNPs) in complement component 3 (C3) alter the risk of age-related macular degeneration (AMD). This was a study of the effect of haplotypes across C3 on AMD risk.
METHODS: Nine SNPs tagging haplotypes across C3 were genotyped on 738 subjects at the Mayo Clinic. Haplotype analyses were performed with and without conditioning on individual SNPs. Replication studies were performed using 1541 subjects from the age-related eye disease study (AREDS).
RESULTS: Two nsSNPs located 5125 bp apart in the 5' end of C3 showed the highest association (rs1047286 or P314L, P = 9.2E-05; rs2230199 or R102G, P = 4.1E-05) with AMD. The minor alleles of both SNPs tagged a single risk haplotype. The effects of the two nsSNPs could not be distinguished due to high linkage disequilibrium. The risk SNPs preferentially promoted the development of advanced AMD relative to early AMD in both the Mayo and AREDS subjects. Haplotypes in the 3' end of the C3 locus were associated with AMD in both the Mayo and AREDS subjects. The effect persisted after conditioning on the nsSNPs only in the Mayo subjects. No interaction was found between rs2230199 and smoking or other AMD loci.
CONCLUSIONS: nsSNPs in C3 increased the risk of developing AMD 1.8-fold for 1 risk allele or 2.4-fold for two risk alleles and were preferentially associated with advanced AMD. Further study is needed to determine whether haplotypes in the 3' end of C3 have an independent association with AMD. ||||| Predictive tests for estimating the risk of developing late-stage neovascular age-related macular degeneration (AMD) are subject to unique challenges. AMD prevalence increases with age, clinical phenotypes are heterogeneous and control collections are prone to high false-negative rates, as many control subjects are likely to develop disease with advancing age. Risk prediction tests have been presented previously, using up to ten genetic markers and a range of self-reported non-genetic variables such as body mass index (BMI) and smoking history. In order to maximise the accuracy of prediction for mainstream genetic testing, we sought to derive a test comparable in performance to earlier testing models but based purely on genetic markers, which are static through life and not subject to misreporting. We report a multicentre assessment of a larger panel of single nucleotide polymorphisms (SNPs) than previously analysed, to improve further the classification performance of a predictive test to estimate the risk of developing choroidal neovascular (CNV) disease. We developed a predictive model based solely on genetic markers and avoided inclusion of self-reported variables (eg smoking history) or non-static factors (BMI, education status) that might otherwise introduce inaccuracies in calculating individual risk estimates. We describe the performance of a test panel comprising 13 SNPs genotyped across a consolidated collection of four patient cohorts obtained from academic centres deemed appropriate for pooling. We report on predictive effect sizes and their classification performance. By incorporating multiple cohorts of homogeneous ethnic origin, we obtained >80 per cent power to detect differences in genetic variants observed between cases and controls. We focused our study on CNV, a subtype of advanced AMD associated with a severe and potentially treatable form of the disease. Lastly, we followed a two-stage strategy involving both test model development and test model validation to present estimates of classification performance anticipated in the larger clinical setting. The model contained nine SNPs tagging variants in the regulators of complement activation (RCA) locus spanning the complement factor H (CFH), complement factor H-related 4 (CFHR4), complement factor H-related 5 (CFHR5) and coagulation factor XIII B subunit (F13B) genes; the four remaining SNPs targeted polymorphisms in the complement component 2 (C2), complement factor B (CFB), complement component 3 (C3) and age-related maculopathy susceptibility protein 2 (ARMS2) genes. The pooled sample size (1,132 CNV cases, 822 controls) allowed for both model development and model validation to confirm the accuracy of risk prediction. At the validation stage, our test model yielded 82 per cent sensitivity and 63 per cent specificity, comparable with metrics reported with earlier testing models that included environmental risk factors. Our test had an area under the curve of 0.80, reflecting a modest improvement compared with tests reported with fewer SNPs. ||||| PURPOSE: To investigate whether the previously reported noncoding variant of the complement factor H (CFH) gene and two coding variants of the complement component 3 (C3) gene are associated with exudative age-related macular degeneration (AMD) in Chinese patients.
METHODS: One hundred fifty Chinese patients with exudative AMD and 161 control individuals without AMD were recruited for the study. Genomic DNA was extracted from blood leukocytes. The noncoding variant of the CFH gene (rs1410996) and two coding variants of the C3 gene (rs2230199 and rs1047286) were genotyped by polymerase chain reaction (PCR) followed by allele-specific restriction enzyme digestion and direct sequencing.
RESULTS: Significant association was detected for exudative AMD with the CFH noncoding variant rs1410996. Frequencies of the risk C allele at rs1410996 were 72.0% in AMD cases versus 55.6% in controls (P < 0.001). The odds ratio for risk of AMD was 1.71 (95% confidence interval [CI], 0.82-3.54) for heterozygous TC genotype and 3.85 (95% CI, 1.84-8.05) for homozygous CC genotype compared with the wild TT genotype. In contrast, the C3 variants rs2230199 and rs1047286 were not associated with exudative AMD in the studied subjects. Frequencies of the risk G allele at rs2230199 and of the risk T allele at rs1047286 were 0.3% to 1.0% in both cases and controls.
CONCLUSIONS: The data suggest that the noncoding variant rs1410996 of the CFH gene moderately increased the risk of exudative AMD in a Chinese population. The C3 variants were rare and not associated with exudative AMD in this Chinese cohort. ||||| BACKGROUND: Age related macular degeneration (AMD) is the leading cause of irreversible blindness in the elderly population. Inflammatory mediators play an important role in AMD pathogenesis and immune-related gene polymorphisms are shown to increase the risk. Complement system is an important mediator of the immunity system and several genes encoding proteins involved in this system are associated with susceptibility to AMD. The central element of the complement cascade, C3 has been a plausible candidate since its cleavage product C3a was found in drusen. This study was planned to evaluate the association of C3-rs2230199 (R102G) variants with advanced type AMD in this cohort.
MATERIALS AND METHODS: In this case-control study, 494 participants consisting of 266 AMD patients (187 wet AMD and 79 advanced dry AMD) and 228 samples from unrelated healthy controls were enrolled for evaluation. Extracted-DNA samples were amplified to obtain fragments including the polymorphic region.
RESULTS: The distribution of the R102G genotypes was significantly different in the AMD patients compared to controls (p = 0.001).The Odds Ratio compared to CC individuals was 1.69 (95% CI 1.15-2.49) for GC individuals and 6.48 (95% CI1.87-22.43) for GG individuals. The Odds Ratio compared to the C allele was 2.31 (95% CI 0.48-11) for the G allele. GG and GC genotypes and G allele were significantly associated with both types of advanced-AMD. Individuals carrying GG genotype have over a six-fold risk of developing AMD in comparison to those carrying the CC genotype in this cohort. Our meta-analysis pooled data showed that our homozygous individuals for GG have a higher risk of AMD compared to previous publications in different nations (p = 0.017).
CONCLUSIONS: Our study shows C3 to be a relatively strong susceptibility gene for advanced-type-AMD (exudative-and-geographic-atrophy) in an Iranian population. ||||| PURPOSE: We explored associations between age-related macular degeneration (AMD) and genetic variants of 10 genes in a nationwide Chinese population.
METHODS: In this multicenter case-control study, 535 AMD patients and 469 controls were recruited from 16 centers that spread from the north to the south of China. All participants underwent comprehensive eye examinations, and 40 single nucleotide polymorphisms (SNPs) of 10 genes were selected. DNA samples were genotyped with the MassArray system. The effect of the genotypes and haplotypes on AMD was assessed with logistic regression analysis, adjusted for age, sex, long-term residence, and family origin.
RESULTS: In our study, 11 SNPs in complement H (CFH), 2 in age-related maculopathy susceptibility 2 (ARMS2), and 2 in high-temperature requirement factor A1 (HTRA1) were associated significantly with AMD. They were rs551397, rs800292, rs1329424, rs1061170, rs10801555, rs12124794, rs10733086, rs10737680, rs2274700, rs1410996, and rs380390 in CFH; rs10490924 and rs2736912 in ARMS2; and rs11200638 and rs3793917 in HTRA1. Three haplotypes in CFH, predisposed the patients significantly to AMD (P<0.001, P=0.001, and P<0.001, respectively). With the sample size of our study, no relationship was found for AMD and the SNPs tested in complement 3 (C3); serpin peptidase inhibitor, clade G, member 1 (SERPING1); vascular endothelial growth factor (VEGF); cholesterol ester transfer protein (CETP); lipoprotein lipase (LPL); hepatic lipase (LIPC); and metallopeptidase inhibitor 3 (TIMP3) genes.
CONCLUSIONS: Gene variants in CFH, ARMS2, and HTRA1 contribute to AMD in the Chinese population. ||||| BACKGROUND: Age related macular degeneration (AMD) is a leading cause of blindness. AMD is a complex disorder caused by genetic and environmental factors in which single nucleotide polymorphisms (SNPs) in the genes CFH and LOC387715/HTRA1/ARMS2 have prognostic importance for progression to advanced AMD (with visual loss). CFH may also have a pharmacogenetic role by affecting treatment response to widely used nutritional supplements. This paper examines other AMD susceptibility genes to determine if these genotypes influenced disease progression and treatment response.
METHODS: Three cohorts, totalling 3137 individuals, were genotyped for SNPs in 13 genes previously published to be associated with advanced AMD (other than CFH and LOC387715/ARMS2/HTRA1). Those genes found associated were then evaluated for their involvement in disease progression. Interactions between the genes and with AREDS (Age-Related Eye Disease Study) nutritional supplements were investigated.
RESULTS: Positive independent associations were noted in SNPs in the genes C2 (p = 0.0001, odds ratio (OR) 0.35, 95% confidence interval (CI) 0.2 to 0.6), CFB (p = 0.0001, OR 0.35, 95% CI 0.2 to 0.6), C3 (p = 0.0001, OR 3.91, 95% CI 1.94 to 7.88), APOE (epsilon4, p = 0.01, OR 0.50, 95% CI 0.29 to 0.86) and VEGFA (p = 0.01, OR 2.23, 95% CI 1.06 to 4.68). C2/CFB and C3 were independently related to progression from early/intermediate to advanced AMD with OR 0.32 (95% CI 0.14 to 0.73) and 3.32 (95% CI 1.46 to 7.59), respectively. Gene-gene and pharmacogenetic interactions were not observed. No preferential associations were observed with geographic atrophy or choroidal neovascularisation.
CONCLUSION: This study provides insights into the genetic pathogenesis of AMD. Five genes have now been shown to be independently involved in progression from intermediate disease (before vision loss has occurred) to advanced disease in which blindness is frequent. ||||| PURPOSE: Genes in the complement pathway, including complement factor H (CFH), C2/BF, and C3, have been reported to be associated with age-related macular degeneration (AMD). Genetic variants, single-nucleotide polymorphisms (SNPs), in these genes were geno-typed for a case-control association study in a mainland Han Chinese population.
METHODS: One hundred and fifty-eight patients with wet AMD, 80 patients with soft drusen, and 220 matched control subjects were recruited among Han Chinese in mainland China. Seven SNPs in CFH and two SNPs in C2, CFB', and C3 were genotyped using the ABI SNaPshot method. A deletion of 84,682 base pairs covering the CFHR1 and CFHR3 genes was detected by direct polymerase chain reaction and gel electrophoresis.
RESULTS: Four SNPs, including rs3753394 (P = 0.0276), rs800292 (P = 0.0266), rs1061170 (P = 0.00514), and rs1329428 (P = 0.0089), in CFH showed a significant association with wet AMD in the cohort of this study. A haplotype containing these four SNPs (CATA) significantly increased protection of wet AMD with a P value of 0.0005 and an odds ratio of 0.29 (95% confidence interval: 0.15-0.60). Unlike in other populations, rs2274700 and rs1410996 did not show a significant association with AMD in the Chinese population of this study. None of the SNPs in CFH showed a significant association with drusen, and none of the SNPs in CFH, C2, CFB, and C3 showed a significant association with either wet AMD or drusen in the cohort of this study. The CFHR1 and CFHR3 deletion was not polymorphic in the Chinese population and was not associated with wet AMD or drusen.
CONCLUSION: This study showed that SNPs rs3753394 (P = 0.0276), rs800292 (P = 0.0266), rs1061170 (P = 0.00514), and rs1329428 (P = 0.0089), but not rs7535263, rs1410996, or rs2274700, in CFH were significantly associated with wet AMD in a mainland Han Chinese population. This study showed that CFH was more likely to be AMD susceptibility gene at Chr.1q31 based on the finding that the CFHR1 and CFHR3 deletion was not polymorphic in the cohort of this study, and none of the SNPs that were significantly associated with AMD in a white population in C2, CFB, and C3 genes showed a significant association with AMD. ||||| The association of variants in complement factors H and B with age-related macular degeneration has led to more intense genetic and functional analysis of the complement pathway. We identify a nonsynonymous coding change in complement factor 3 that is strongly associated with risk of age-related macular degeneration in a large case-control sample. ||||| We executed a genome-wide association scan for age-related macular degeneration (AMD) in 2,157 cases and 1,150 controls. Our results validate AMD susceptibility loci near CFH (P < 10(-75)), ARMS2 (P < 10(-59)), C2/CFB (P < 10(-20)), C3 (P < 10(-9)), and CFI (P < 10(-6)). We compared our top findings with the Tufts/Massachusetts General Hospital genome-wide association study of advanced AMD (821 cases, 1,709 controls) and genotyped 30 promising markers in additional individuals (up to 7,749 cases and 4,625 controls). With these data, we identified a susceptibility locus near TIMP3 (overall P = 1.1 x 10(-11)), a metalloproteinase involved in degradation of the extracellular matrix and previously implicated in early-onset maculopathy. In addition, our data revealed strong association signals with alleles at two loci (LIPC, P = 1.3 x 10(-7); CETP, P = 7.4 x 10(-7)) that were previously associated with high-density lipoprotein cholesterol (HDL-c) levels in blood. Consistent with the hypothesis that HDL metabolism is associated with AMD pathogenesis, we also observed association with AMD of HDL-c-associated alleles near LPL (P = 3.0 x 10(-3)) and ABCA1 (P = 5.6 x 10(-4)). Multilocus analysis including all susceptibility loci showed that 329 of 331 individuals (99%) with the highest-risk genotypes were cases, and 85% of these had advanced AMD. Our studies extend the catalog of AMD associated loci, help identify individuals at high risk of disease, and provide clues about underlying cellular pathways that should eventually lead to new therapies. ||||| Age-related macular degeneration (AMD) is a late onset vision disorder. Recent studies demonstrate that alterations in complement cascade genes are associated with AMD. Of the three identified complement loci, variants in complement factor H (CFH) have the highest impact as does an independent locus at 10q26. Our matched case-control study using the Age-Related Eye Disease Study (AREDS) cohort confirms and extends the associations in these loci. Subjects were genotyped for single nucleotide polymorphisms (SNPs) from CFH, complement component 2 (C2), complement component 3 (C3), complement factor B (CFB), age-related maculopathy susceptibility (ARMS2), HtrA serine peptidase 1 (HTRA1), and apolipoprotein E (APOE). Individual SNPs, and haplotypes showed risk trends consistent with those seen in other population studies for CFH, C3, C2, and CFB. SNP rs10490924 on chromosome 10 in exon 1 of the ARMS2 gene showed a highly significant association with an odds ratio (OR) of 3.2 (95% CI 2.4-4.2) for the risk allele and rs11200638 located in the proximal promoter region of HTRA1 showed a higher significant association with an OR of 3.4 (95% CI 2.5-4.6) with our AMD cases. We found that APOE haplotypes were not significantly associated with disease status. Adjustments for other risk factors did not significantly alter the observed associations. This study validates the complement pathway's involvement in AMD and suggests that allelic variants in complement genes have a direct role in disease. These results also support previous findings that variants in the region of 10q26 exert an independent risk for AMD. ||||| PURPOSE: Major genetic factors for age-related macular degeneration (AMD) have recently been identified as susceptibility risk factors, underlying the role of the complement pathway in AMD. Our purpose was to analyze the role of the R102G polymorphism of the complement component (C3) gene in a French population, in a case-control study.
METHODS: A total of 1,080 patients with exudative AMD and 406 controls were recruited and genotyped for Y402H of complement factor H (CFH), rs10490924 of age-related maculopathy susceptibility 2 (ARMS2), and R102G of the C3 gene.
RESULTS: The distribution of the R102G genotypes was significantly different in the AMD patients compared to controls (p=0.02). The Odds Ratio compared to C/C individuals was 1.4 (95% CI 1.1-1.8) for C/G individuals and 1.4 (95% CI 0.8-2.4) for G/G individuals. In a dominant model, the adjusted Odds Ratio for carriers of the G allele is 1.4 (95% CI 1.0-1.9; p=0.03).
CONCLUSIONS: Our study shows C3 to be a moderate susceptibility gene for exudative AMD in the French population. ||||| PURPOSE: To evaluate the contribution of genetic variants of complement factor H (CFH), complement component 2 and 3 (C2 and C3), complement factor B (CFB), and age-related maculopathy susceptibility 2 (ARMS2) to age-related macular degeneration (AMD) risk in the Mexican Mestizo population.
METHODS: Analysis included 282 unrelated Mexican patients with advanced AMD, 205 healthy controls, and 280 population controls. Stereoscopic fundus images were graded on the Clinical Age-Related Maculopathy System (CARMS). We designed a resequencing strategy using primers with M13 adaptor for the 23 exons of the CFH gene in a subgroup of 96 individuals clinically evaluated: 48 AMD cases and 48 age- and sex-matched healthy controls. Single nucleotide polymorphisms (SNPs) in C3 (Arg80Gly and Pro292Leu), C2 (rs547154), CFB (Leu9His), and ARMS2 (Ala69Ser) were genotyped in all patients, healthy and population controls using TaqMan assay.
RESULTS: All evaluated individuals were Mexican Mestizos, and their genetic ancestry was validated using 224 ancestry informative markers and calculating F(st) values. The CFH resequencing revealed 19 SNPs and a common variant in the intron 2 splice acceptor site; three CFH haplotypes inferred from individual genotypes, showed significant differences between cases and controls. The risk alleles in C3 (rs1047286, odds ratio [OR]=2.48, 95% confidence interval [CI]=1.64-3.75, p=1.59E-05; rs2230199, OR=2.15, 95% CI=1.48-3.13, p=6.28E-05) and in ARMS2 (rs10490924, OR=3.09, 95% CI=2.48-3.86, p=5.42E-23) were strongly associated with risk of AMD. The protective effect of alleles in C2 (rs547154) and CFB (rs4151667) showed a trend but was not significantly associated after correction for multiple testing.
CONCLUSIONS: Our results show that ARMS2 and C3 are major contributors to advanced AMD in Mexican patients, while the contributions of CFH, C2, and CFB are minor to those of other populations, reveling significant ethnic differences in minor allele frequencies. We provide evidence that two specific common haplotypes in the CFH gene predispose individuals to AMD, while another may confer reduced risk of disease in this admixed population. ||||| OBJECTIVE: To explore the association between polymorphisms in the complement component 3 (C3) gene and age-related macular degeneration (AMD), and to investigate the modifying effect of complement factor H (CFH) Y402H, LOC387715 A69S and smoking.
DESIGN: Pooled data from the prospective, population-based Rotterdam Study (enrolment between 1990 and 1993, and 3 follow-up examinations between September 1, 1993, and December 31, 2004) and an independent case-control study from the Netherlands.
PARTICIPANTS: The Rotterdam Study comprised a total of 6418 persons aged >or=55 years who had gradable fundus photographs. The case-control study consisted of 357 unrelated AMD patients and 173 control individuals aged >or=55 years.
METHODS: The variants R102G and P314L of the C3 gene, CFH Y402H and LOC387715 A69S, were genotyped in all study participants. Information on cigarette smoking was obtained by interview at baseline.
MAIN OUTCOME MEASURES: Early and late stages of prevalent and incident AMD, graded according to the international classification and grading system for AMD.
RESULTS: We found a population frequency of 0.217 for R102G and 0.211 for P314L in the Rotterdam Study. Both alleles significantly increased the risk of early AMD and all subtypes of late AMD, and this risk seemed to be independent of CFH Y402H, LOC387715 A69S, and smoking. Detailed analysis showed that the haplotype carrying both alleles had the highest frequency difference between cases and controls (P=0.006). We estimated a total population-attributable risk of 14.6%. A meta-analysis of all currently available data yielded a pooled odds ratio (OR) of 1.61 (95% confidence interval [CI], 1.46-1.78) for the R102G allele, and an OR of 1.50 (95% CI, 1.31-1.71) for the P314L allele.
CONCLUSIONS: Our study showed a significant association between variants in the C3 gene and AMD and further highlights the crucial role of the complement pathway in the etiology of AMD. ||||| Neovascular age-related macular degeneration (AMD) and polypoidal choroidal vasculopathy (PCV) are leading causes of irreversible blindness in developed countries. In this study, we investigated the associations of haplotype-tagging single nucleotide polymorphisms (SNPs) in the complement component 3 (C3) gene with both neovascular AMD and PCV, and potential epistatic effects on C3. Eight tagging SNPs in C3 were genotyped in 708 unrelated study subjects: 200 neovascular AMD patients, 233 PCV patients and 275 controls. Among the eight C3 SNPs, rs17030 was associated with PCV after adjusted for gender and SNP-gender interaction (P = 0.008, OR = 2.94; 95% CI: 1.32-6.52). Moreover, an interaction between rs17030 and gender was identified in PCV (P = 0.02). After stratification by gender, the rs17030 G allele was found to confer an increased risk for PCV in male (P = 0.010, OR = 1.56) but not in female. The haplotype AG defined by the major alleles of rs17030 and rs344555 was also associated with PCV in male (P = 0.010, OR = 0.64). In contrast to PCV, none of the eight SNPs was significantly associated with neovascular AMD. This study shows an association of C3 rs17030 with PCV in male, indicating that C3 may have an epistatic effect with gender in the pathogenesis of PCV. ||||| BACKGROUND: Age-related macular degeneration is the most common cause of blindness in Western populations. Susceptibility is influenced by age and by genetic and environmental factors. Complement activation is implicated in the pathogenesis.
METHODS: We tested for an association between age-related macular degeneration and 13 single-nucleotide polymorphisms (SNPs) spanning the complement genes C3 and C5 in case subjects and control subjects from the southeastern region of England. All subjects were examined by an ophthalmologist and had independent grading of fundus photographs to confirm their disease status. To test for replication of the most significant findings, we genotyped a set of Scottish cases and controls.
RESULTS: The common functional polymorphism rs2230199 (Arg80Gly) in the C3 gene, corresponding to the electrophoretic variants C3S (slow) and C3F (fast), was strongly associated with age-related macular degeneration in both the English group (603 cases and 350 controls, P=5.9x10(-5)) and the Scottish group (244 cases and 351 controls, P=5.0x10(-5)). The odds ratio for age-related macular degeneration in C3 S/F heterozygotes as compared with S/S homozygotes was 1.7 (95% confidence interval [CI], 1.3 to 2.1); for F/F homozygotes, the odds ratio was 2.6 (95% CI, 1.6 to 4.1). The estimated population attributable risk for C3F was 22%.
CONCLUSIONS: Complement C3 is important in the pathogenesis of age-related macular degeneration. This finding further underscores the influence of the complement pathway in the pathogenesis of this disease. ||||| PURPOSE: To study the association of the single nucleotide polymorphism (SNP) rs4073 in the interleukin-8 (IL-8) promoter region with the diagnosis and age of onset of exudative age-related macular degeneration (AMD) in association with the known genetic risk factors for AMD and tobacco smoking.
METHODS: Medical records, smoking history and angiograms or fundus photographs of 301 patients with exudative AMD, 72 patients with dry AMD and 119 control subjects were analysed retrospectively. The associations of IL-8 rs4073 A→T, CFH rs1061170 T→C, ARMS2 rs10490924 G→T and C3 rs2230199 C→G SNPs with the presence of AMD and with the age of onset of exudative AMD were analysed.
RESULTS: Younger age of exudative AMD onset was associated with the homozygous AA genotype of IL-8 rs4073 (p = 0.009, Mann-Whitney U-test), CC genotype of CFH rs1061170 (p = 0.016), TT genotype of ARMS2 rs10490924 (p = 0.001) and with current smoking (p = 0.002). The risk alleles C in CFH rs1061170 (p < 0.0001, Pearson chi-square) and T in ARMS2 rs10490924 (p < 0.0001), as well as smoking (p < 0.0001), were more prevalent in AMD patients compared with controls. No association was found between the IL-8 rs4073 genotype and the presence of AMD.
CONCLUSION: Out of the factors associated with the earlier onset of exudative AMD, only the genotype of IL-8 rs4073 did not appear as a risk factor for AMD in general. IL-8 may have a role in accelerating the development of the choroidal neovascularization in exudative AMD. ||||| PURPOSE: Systemic complement activation is associated with age-related macular degeneration (AMD) and has mainly been attributed to a risk allele in the complement factor H (CFH) gene. Whether other important AMD genes also influence complement activation is unclear. In the present case-control study, complement activity and concentrations of complement components and their activation products are measured in AMD patients and in unaffected controls and correlated with genetic variants in the CFH, ARMS2, C3, CFI, and CFB genes.
DESIGN: Case-control study.
PARTICIPANTS: A cohort of 197 confirmed AMD patients and 150 unaffected age-matched controls were recruited prospectively for the study.
METHODS: Hemolytic complement assays (AP50, CP50, and LP50), complement components (C3, CFB, CFI, and CFH), and the activation products (C3d, C5a, and SC5b-9) were analyzed in serum or plasma. The DNA samples were genotyped for 5 single nucleotide polymorphisms (SNPs) previously associated with AMD in the CFH, ARMS2, C3, CFB, and CFI genes.
MAIN OUTCOME MEASURES: Complement concentrations and their associations with SNPs in the CFH, ARMS2, C3, CFB, and CFI genes.
RESULTS: The AMD patients had increased activation of the alternative complement pathway (P = 0.003) and elevated levels of complement activation components C3d (P<0.0001) and C5a (P<0.0001), CFB (P<0.0001), and an increased C3d/C3 ratio (P<0.0001) calculated as a measure of C3 activation. While the CFH risk genotype was significantly associated with the elevated C3d/C3 ratios obtained, in the absence of CFH risk alleles the ARMS2 risk genotype also showed significantly increased levels of complement activation (P = 0.013). Furthermore, the carriers of the CFB protective allele had lower CFB concentrations.
CONCLUSIONS: The current study found evidence showing that in AMD risk alleles in CFH and ARMS2 are independently associated with complement activation. Especially the C3d/C3 ratio seems to be a strong marker for AMD. The findings suggest that CFH and ARMS2 share a common pathway in the pathogenesis of AMD. ||||| Through whole-genome sequencing of 2,230 Icelanders, we detected a rare nonsynonymous SNP (minor allele frequency = 0.55%) in the C3 gene encoding a p.Lys155Gln substitution in complement factor 3, which, following imputation into a set of Icelandic cases with age-related macular degeneration (AMD) and controls, associated with disease (odds ratio (OR) = 3.45; P = 1.1 × 10(-7)). This signal is independent of the previously reported common SNPs in C3 encoding p.Pro314Leu and p.Arg102Gly that associate with AMD. The association of p.Lys155Gln was replicated in AMD case-control samples of European ancestry with OR = 4.22 and P = 1.6 × 10(-10), resulting in OR = 3.65 and P = 8.8 × 10(-16) for all studies combined. In vitro studies have suggested that the p.Lys155Gln substitution reduces C3b binding to complement factor H, potentially creating resistance to inhibition by this factor. This resistance to inhibition in turn is predicted to result in enhanced complement activation. ||||| OBJECTIVES: To evaluate the independent and joint effects of genetic factors and environmental variables on advanced forms of age-related macular degeneration (AMD), including geographic atrophy and choroidal neovascularization, and to develop a predictive model with genetic and environmental factors included.
METHODS: Demographic information, including age at onset, smoking status, and body mass index, was collected for 1844 participants. Genotypes were evaluated for 8 variants in 5 genes related to AMD. Unconditional logistic regression analyses were performed to generate a risk predictive model.
RESULTS: All genetic variants showed a strong association with AMD. Multivariate odds ratios were 3.52 (95% confidence interval, 2.08-5.94) for complement factor H, CFH rs1061170 CC, 4.21 (2.30-7.70) for CFH rs2274700 CC, 0.46 (0.27-0.80) for C2 rs9332739 CC/CG, 0.44 (0.30-0.66) for CFB rs641153 TT/CT, 10.99 (6.04-19.97) for HTRA1/LOC387715 rs10490924 TT, and 2.66 (1.43-4.96) for C3 rs2230199 GG. Smoking was independently associated with advanced AMD after controlling for age, sex, body mass index, and all genetic variants.
CONCLUSION: CFH confers more risk to the bilaterality of geographic atrophy, whereas HTRA1/LOC387715 contributes more to the bilaterality of choroidal neovascularization. C3 confers more risk for geographic atrophy than choroidal neovascularization. Risk models with combined genetic and environmental factors have notable discrimination power.
CLINICAL RELEVANCE: Early detection and risk prediction of AMD could help to improve the prognosis of AMD and to reduce the outcome of blindness. Targeting high-risk individuals for surveillance and clinical interventions may help reduce disease burden. ||||| PURPOSE: Age-related macular degeneration (AMD) has a strong genetic component with a major locus at 1q31, including the complement factor H (CFH) gene. Detailed analyses of this locus have demonstrated the existence of one SNP haplotype block, carrying the CFH 402His allele, which confers increased risk for AMD, and two protective SNP haplotypes, one of them carrying a deletion of the CFHR1 and CFHR3 genes (ΔCFHR3-CFHR1). The purpose of these studies was to evaluate the contribution of newly described CFHR1 alleles to the association of the 1q31 locus with AMD.
METHODS: Two hundred fifty-nine patients and 191 age-matched controls of Spanish origin were included in a transversal case-control study using multivariate logistic regression analysis and ROC (receiver operating characteristic) statistics to generate and test models predictive of the development of AMD.
RESULTS: This study showed for the first time that a particular CFHR1 allotype, CFHR1*A, is strongly associated with AMD (odds ratio, 2.08; 95% confidence interval, 1.59-2.73; P<0.0001) and illustrate a peculiar genotype-phenotype correlation between the CFHR1 alleles and different diseases that may have important implications for understanding the pathophysiology of AMD. It also shows that CFHR1*A is in strong linkage disequilibrium with the CFH 402His allele, which provides additional candidate variants within the major risk haplotype at 1q31, promoting its association with AMD. Further, using the Spanish population as a model, the results showed that analysis of the CFHR1 genotypes provide sufficient information to delineate the individual risk of developing AMD.
CONCLUSIONS: The results support a relevant role of CFHR1 in the pathogenesis of AMD. ||||| Inflammation has long been suspected to play a role in the pathogenesis of age-related macular degeneration (AMD). Association of variants in the complement factor H (CFH) and complement factor B (CFB) genes has targeted the search for additional loci to the alternative complement cascade, of which C3 is a major component. Two non-synonymous coding polymorphisms within C3, R102G and L314P, have previously been strongly associated with increased risk. These variants are in strong linkage disequilibrium (LD), making the contribution of this locus to AMD even more difficult to ascertain. We sought to determine whether the C3 association resulted primarily from only one of these two variants or from a combined effect of both in 223 families and an independent dataset of 701 cases and 286 unrelated controls. The C3 polymorphisms were in strong LD (r(2) = 0.85), and both were associated in the family-based and case-control datasets (R102G genoPDT P = 0.02, case-control genotypic P = 0.004; L314P genoPDT P = 0.001, case-control genotypic P = 0.04). In conditional analyses in the case-control dataset, R102G remained associated with disease in the L314P risk allele carriers (P = 0.01), but there was no effect of L314P in the R102G risk allele carriers (P = 0.2). After adjusting for age, smoking, CFH Y402H, LOC387715 A69S, and CFB R32Q, the effect of R102G remained strong [P = 0.015, odds ratio = 1.55, 95% confidence interval 1.09 to 2.21, adjusted PAR(population attributable risk) = 0.17]. Therefore, while the strong LD between R102G and L314P makes it difficult to disentangle their individual effects on disease risk, the R102G polymorphism acting alone provides the best model for disease in our data. ||||| Age-related macular degeneration (AMD) is a leading cause of visual loss in Western populations. Susceptibility is influenced by age, environmental and genetic factors. Known genetic risk loci do not account for all the heritability. We therefore carried out a genome-wide association study of AMD in the UK population with 893 cases of advanced AMD and 2199 controls. This showed an association with the well-established AMD risk loci ARMS2 (age-related maculopathy susceptibility 2)-HTRA1 (HtrA serine peptidase 1) (P =2.7 × 10(-72)), CFH (complement factor H) (P =2.3 × 10(-47)), C2 (complement component 2)-CFB (complement factor B) (P =5.2 × 10(-9)), C3 (complement component 3) (P =2.2 × 10(-3)) and CFI (P =3.6 × 10(-3)) and with more recently reported risk loci at VEGFA (P =1.2 × 10(-3)) and LIPC (hepatic lipase) (P =0.04). Using a replication sample of 1411 advanced AMD cases and 1431 examined controls, we confirmed a novel association between AMD and single-nucleotide polymorphisms on chromosome 6p21.3 at TNXB (tenascin XB)-FKBPL (FK506 binding protein like) [rs12153855/rs9391734; discovery P =4.3 × 10(-7), replication P =3.0 × 10(-4), combined P =1.3 × 10(-9), odds ratio (OR) = 1.4, 95% confidence interval (CI) = 1.3-1.6] and the neighbouring gene NOTCH4 (Notch 4) (rs2071277; discovery P =3.2 × 10(-8), replication P =3.8 × 10(-5), combined P =2.0 × 10(-11), OR = 1.3, 95% CI = 1.2-1.4). These associations remained significant in conditional analyses which included the adjacent C2-CFB locus. TNXB, FKBPL and NOTCH4 are all plausible AMD susceptibility genes, but further research will be needed to identify the causal variants and determine whether any of these genes are involved in the pathogenesis of AMD. ||||| IMPORTANCE: Identification of the genetic risk factors that contribute to geographic atrophy (GA) could lead to advancements in interventional trials and/or therapeutic approaches for combating vision loss.
OBJECTIVE: To investigate whether single-nucleotide polymorphisms (SNPs) are associated with the presence and progression of established GA in age-related macular degeneration (AMD).
DESIGN, SETTING, AND PARTICIPANTS: Prospective, controlled, multicenter study of 154 patients with GA/AMD and 141 age-matched control participants at 8 Spanish hospitals.
MAIN OUTCOMES AND MEASURES: Samples of DNA were collected to analyze SNPs within AMD-related genes (CFH, CFB, C3, FHR1-3, and ARMS2). Fundus autofluorescence imaging was used to evaluate GA progression during a 2-year period in 73 patients with GA/AMD. Finally, logistic regression was used to analyze the associations of SNPs, age, body mass index, and cigarette smoking with the rate of progression and relative growth of GA.
RESULTS: This case-control analysis revealed a significant (P < .05) association between the presence of GA and SNPs within CFH, ARMS2, and FHR1-3. Moreover, logistic regression analysis identified significant associations of the rate of progression with genetic polymorphisms (CFH-402His [P = .04] and CFH-62Ile [P = .04]) and demographic factors (sex [P = .02] and age [P = .02]), whereas relative growth was associated with 1 polymorphism (CFB-32Gln [P = .04]).Conclusions and Relevance Taken together, our findings confirm that genetic risk factors related to the presence of GA are not identical to those associated with GA progression. In fact, we demonstrate that gene variants of CFH and CFB, as well as demographic risk factors, confer significant risk for GA progression (both rate of progression and relative growth) within a Spanish population. ||||| AIMS: Age-related macular degeneration (AMD) is a multifactorial disease, in which complement-mediated inflammation plays a pivotal role. A positive family history is an important risk factor for developing AMD. Certain lifestyle factors are shown to be significantly associated with AMD in non-familial cases, but not in familial cases. This study aimed to investigate whether the contribution of common genetic variants and complement activation levels differs between familial and sporadic cases with AMD.
METHODS AND RESULTS: 1216 AMD patients (281 familial and 935 sporadic) and 1043 controls (143 unaffected members with a family history of AMD and 900 unrelated controls without a family history of AMD) were included in this study. Ophthalmic examinations were performed, and lifestyle and family history were documented with a questionnaire. Nine single nucleotide polymorphisms (SNPs) known to be associated with AMD were genotyped, and serum concentrations of complement components C3 and C3d were measured. Associations were assessed in familial and sporadic individuals. The association with risk alleles of the age-related maculopathy susceptibility 2 (ARMS2) gene was significantly stronger in sporadic AMD patients compared to familial cases (p = 0.017 for all AMD stages and p = 0.003 for advanced AMD, respectively). ARMS2 risk alleles had the largest effect in sporadic cases but were not significantly associated with AMD in densely affected families. The C3d/C3 ratio was a significant risk factor for AMD in sporadic cases and may also be associated with familial cases. In patients with a densely affected family this effect was particularly strong with ORs of 5.37 and 4.99 for all AMD and advanced AMD respectively.
CONCLUSION: This study suggests that in familial AMD patients, the common genetic risk variant in ARMS2 is less important compared to sporadic AMD. In contrast, factors leading to increased complement activation appear to play a larger role in patients with a positive family history compared to sporadic patients. A better understanding of the different contributions of risk factors in familial compared to non-familial AMD will aid the development of reliable prediction models for AMD, and may provide individuals with more accurate information regarding their individual risk for AMD. This information is especially important for individuals who have a positive family history for AMD. ||||| PURPOSE: A non-synonymous single nucleotide polymorphism (SNP) in complement component 3 has been shown to increase the risk of age-related macular degeneration (AMD). We assess its effect on AMD risk in a Northern Irish sample, test for gene-gene and gene-environment interaction, and review a risk prediction model.
METHODS: SNP rs2230199 was genotyped in 1,358 samples, which comprised 437 cases, 436 no-disease controls, and 485 participants randomly sampled from the Northern Ireland population. Allele frequencies were assessed in cases and controls. Logistic regression analysis was used to assess interaction and develop a risk prediction model.
RESULTS: We report a minor allele frequency of 0.248 for rs2230199 in the population (n=485), 0.296 in cases (n=437), and 0.221 in controls (n=436; odds ratio [OR]=1.48; confidence interval [CI]: 1.19-1.85; p=0.0003). The significant association is retained following multivariate analysis with adjustment for age, smoking status, Complement Factor H (CFH), Age-Related Maculopathy Susceptibility 2 (ARMS2), Complement Component 2 (CC2), and Complement Factor B (CFB; OR=1.45; CI: 1.10-1.91; p=0.009). No evidence to support an interaction between any of the covariates within the regression model was found. The area under the receiver operator characteristic curve calculated for the fully adjusted model, including all variables, was 0.86 for late AMD.
CONCLUSIONS: Our study confirmed the association between Complement Component 3 (C3) and late-stage AMD. There was no evidence for an interaction with environmental exposures, nor did we find data to support a gene-gene effect. ||||| PURPOSE: To investigate the association of age-related macular degeneration (AMD)-high risk alleles of the complement factor H (CFH), complement factor B (CFB), complement component 2 (C2), complement component 3 (C3), and age-related maculopathy susceptibility 2 (ARMS2) genes in a Mexican population for the first time.
METHODS: Genotyping was performed for the Y402H variant of CFH, for the L9H, R32Q, and K565E variants of CFB, the E318D variant of C2, the A69S variant of ARMS2, and the R102G variant of C3 in 159 Mexican mestizo patients at advanced stages of AMD, i.e., CARMS (Clinical Age-Related Maculopathy Staging System) grade 4 or 5. The frequency of these variants was also investigated in a group of 152 control subjects without AMD. Genomic DNA was extracted from blood leukocytes, and genotyping was performed using PCR followed by direct sequencing. Allele-specific restriction enzyme digestion was used to detect the R102G polymorphism in C3.
RESULTS: There were significant differences in the allelic distribution between the two groups for CFH Y402H (p=1×10(-5)), ARMS A69S (p=4×10(-7)), and CFB R32Q (p=0.01). The odds ratios (95% confidence interval) obtained for the risk alleles of these three variants were 3.8 (2.4-5.9), 3.04 (2.2-4.3), and 2.5 (1.1-5.7), respectively. Haplotype analysis including the two most significantly associated alleles (CFH Y402H and ARMS A69S) indicated that the C-T combination conferred an odds ratio (95% confidence interval) of 6.9 (3.2-14.8). The exposed attributable risk for this particular haplotype was 85.5%.
CONCLUSIONS: This is the first case-control investigation of AMD-high risk alleles in a Latino population. Our results support that CFH, ARMS2, and CFB AMD-risk alleles are consistently associated with the disease, even in ethnic groups with a complex admixture of ancestral populations such as Mexican mestizos. ||||| PURPOSE: To assess whether established and newly reported genetic variants, independent of known lifestyle factors, are associated with the risk of age-related macular degeneration (AMD) among women participating in the Women's Health Initiative Sight Exam (WHI-SE) Genetic Ancillary Study.
DESIGN: Multicenter case-control study.
METHODS: One hundred and forty-six women with intermediate and late stages of AMD and 1269 subjects without AMD underwent ocular examinations and fundus photography to determine stage of AMD. Fourteen polymorphisms at or near 11 genes, including previously confirmed genes CFH, ARMS2/HTRA1, C2, C3, and CFI; recently reported AMD genes in the high-density lipoprotein cholesterol (HDL) pathway LIPC, ABCA1, CETP, and LPL; TIMP3/SYN3, a known ocular gene recently linked with AMD; and APOE, were assessed using logistic regression analysis.
RESULTS: After adjustment for demographic, behavioral, and other genetic factors, a protective effect was detected among TT carriers compared with non-carriers for the HDL pathway gene, LIPC rs493258, for intermediate and late AMD (OR [95% confidence interval]: 0.3 [0.2-0.7], P = .003). Variants in CFH rs1410996, ARMS2/HTRA1 A69S, and C3 R102G were significantly associated with an increased risk of AMD. Individuals with the homozygous CFI rs10033900 TT genotype had a 2.9 [1.2-7.2]-fold increased risk, and those with the CFH Y402H GG genotype had a 2.2 [1.0-4.8]-fold higher risk of developing AMD compared with non-carriers. APOE4 carriers may have a reduced risk of intermediate/late AMD (OR = 0.5 [0.3-0.9], P = .015. Suggestive associations were seen between AMD and the HDL pathway genes CETP and LPL.
CONCLUSION: In this unique national cohort of women, we found associations with established AMD-related genetic factors and the recently reported LIPC gene in the HDL pathway. These findings may help develop novel therapeutic targets to treat or delay the onset of the disease. ||||| BACKGROUND: Genetic variants in the complement component 3 gene (C3) have been shown to be associated with age-related macular degeneration (AMD) in Caucasian populations of European descent. In particular, a nonsynonymous coding variant, rs2230199 (R102G), is presumed to be the most likely causal variant in the C3 locus based on strong statistical evidence for disease association and mechanistic functional evidence. However, the risk allele is absent or rare (<1%) in Japanese and Chinese populations, and the association of R102G with AMD has not been reported in Asian populations. Genetic heterogeneity of disease-associated variants among different ethnicities is common in complex diseases. Here, we sought to examine whether other common variants in C3 are associated with wet AMD, a common advanced-stage manifestation of AMD, in a Japanese population.
METHODOLOGY/PRINCIPAL FINDINGS: We genotyped 13 tag single nucleotide polymorphisms (SNPs) that capture the majority of common variations in the C3 locus and tested for associations between these SNPs and wet AMD in a Japanese population comprising 420 case subjects and 197 controls. A noncoding variant in C3 (rs2241394) exhibited statistically significant evidence of association (allelic P = 8.32 × 10(-4); odds ratio = 0.48 [95% CI = 0.31-0.74] for the rs2241394 C allele). Multilocus logistic regression analysis confirmed that the effect of rs2241394 was independent of the previously described loci at ARMS2 and CFH, and that the model including variants in ARMS2 and CFH plus C3 rs2241394 provided a better fit than the model without rs2241394. We found no evidence of epistasis between variants in C3 and CFH, despite the fact that they are involved in the same biological pathway.
CONCLUSIONS: Our study provides evidence that C3 is a common AMD-associated locus that transcends racial boundaries and provides an impetus for more detailed genetic characterization of the C3 locus in Asian populations. ||||| PURPOSE: We assessed the association between complement pathway genes and age-related macular degeneration (AMD) in a Chinese population.
METHODS: In a case-control study, 165 AMD patients and 216 unrelated controls were recruited from two hospitals in central China. We selected and genotyped six single nucleotide polymorphisms (SNPs) of four complement pathway genes, including rs800292 and rs1410996 of complement H (CFH), rs9332739 of complement 2 (C2), rs4151667 of complement factor B (CFB), and rs2241394 and rs2230199 of complement 3 (C3). The associations between SNPs and AMD, adjusted by age and sex, were assessed by using logistic regression models and haplotype association analysis.
RESULTS: In our study, two SNPs of CFH and their haplotypes were associated significantly with AMD, and the adjusted odd ratios (ORs) were 2.45 (95% confidence interval [CI] 1.25-4.79) for rs800292 (genotype GG versus AA), 2.49 (95% CI 1.24-5.00) for rs1410996 (genotype TT versus CC), and 4.45 (95% CI 2.32-8.55) for haplotype block of rs800292-rs1410996 (haplotype G-C versus A-C), respectively. The haplotype of C2/CFB also was associated significantly with AMD, and the adjusted OR was 8.86 (95% CI 1.88-41.69) for the haplotype block of rs9332739-rs4151667 (haplotype G-A versus G-T), though no relationship was found in genotype association analysis of the two SNPs of C2/CFB. With the sample size of our study, no relationship was found for AMD and the two SNPs of C3.
CONCLUSIONS: Gene variants in CFH and C2/CFB contribute to AMD in the Chinese population. ||||| PURPOSE: The purpose of this study was to determine whether the genetic polymorphisms of complement factor 3 (C3) are associated with neovascular age-related macular degeneration (AMD) in the Chinese population.
METHODS: A total of 123 unrelated Chinese Han patients with neovascular AMD and 130 control subjects were recruited. Their six single-nucleotide polymorphisms (SNPs) in the C3 gene, one in the complement factor H (CFH) gene and two in the complement factor B (CFB) gene were characterized. Their genotypes, allele frequencies, and odds ratios were analyzed.
RESULTS: The G allele of the C3 IVS2 rs2250656, but not other tested C3 SNPs of rs2230205, rs10411506, rs2230199, rs339392, and rs163913, was significantly associated with a reduced risk for AMD in the Chinese population (OR 0.605, 95% CI 0.39-0.93, p = 0.023), even after adjusting for age, gender, smoking status, CFH rs1061170, CFB rs4151667, and CFB rs641153 allele status (OR 0.58, 95% CI 0.35-0.96, p = 0.033). However, the C3 haplotype of A-A-C-A-T-T was identified as a statistically significant risk factor for neovascular AMD (OR 1.41, 95% CI 1.02-1.94). Furthermore, the C allele of the CFH rs1061170, but not the CFB rs4151667 and rs641153, was significnatly associated with increased risk for AMD (OR 3.09, 95% CI 1.55-6.15, p < 0.001).
CONCLUSION: The G allele of C3 IVS2 rs2250656 may be a significantly protective factor for neovascular AMD in the Chinese population. This, together with low MAF of C3 R102G, may be partially responsible for the low prevalence of AMD in the Chinese population. ||||| PURPOSE: Several genes encoding complement system components and fragments are associated with age-related macular degeneration (AMD). This study was conducted to determine whether alterations in circulating levels of these markers of complement activation and regulation are also independently associated with advanced AMD and whether they are related to AMD genotypes.
METHODS: Plasma and DNA samples were selected from individuals in our AMD registry who had progressed to or developed the advanced stages of AMD, including 58 with geographic atrophy and 62 with neovascular disease. Subjects of similar age and sex, but without AMD, and who did not progress were included as controls (n = 60). Plasma complement components (C3, CFB, CFI, CFH, and factor D) and activation fragments (Bb, C3a, C5a, iC3b, and SC5b-9) were analyzed. DNA samples were genotyped for seven single-nucleotide polymorphisms in six genes previously shown to be associated with AMD: CFB, CFH, C2, C3, and CFI and the LOC387715/ARMS2 gene region. The association between AMD and each complement biomarker was assessed by using logistic regression, controlling for age, sex, and proinflammatory risk factors: smoking and body mass index (BMI). Functional genomic analyses were performed to assess the relationship between the complement markers and genotypes. Concordance, or C, statistics were calculated to assess the effect of complement components and activation fragments in an AMD gene-environment prediction model.
RESULTS: The highest quartiles of Bb and C5a were significantly associated with advanced AMD, when compared with the lowest quartiles. In multivariate models without genetic variants, the odds ratio (OR) for Bb was 3.3 (95% confidence interval [CI] = 1.3-8.6), and the OR for C5a was 3.6 (95% CI = 1.2-10.3). With adjustment for genetic variants, these ORs were substantially higher. The alternative pathway regulator CFH was inversely associated with AMD in the model without genotypes (OR = 0.3; P = 0.01). Positive associations were found between BMI and plasma C3, CFB, CFH, iC3b, and C3a. There were also significant associations between C5a fragment and LOC387715/ARMS2 and C3 genotypes (P for trend = 0.02, 0.04), respectively. C statistics for models with behavioral and genetic factors increased to 0.94 +/- 0.20 with the addition of C3a, Bb, and C5a.
CONCLUSIONS: Increased levels of activation fragments Bb and C5a are independently associated with AMD. Higher BMI is related to increased levels of complement components. C5a is associated with AMD genotypes. C statistics are stronger with the addition of C3a, Bb, and C5a in predictive models. Results implicate ongoing activation of the alternative complement pathway in AMD pathogenesis. | [
{
"source_pmid": "23209669",
"source_text": "Age-related macular degeneration (AMD) is the leading cause of blindness in the elderly in the developed world. Numerous genetic factors contribute to the development of the multifactorial disease. We performed a case-control study to assess the risk conferred by... |
23029558 | CONCLUSIONS: There is strong evidence that myocilin polymorphisms are associated with POAG susceptibility, and the prevalence of myocilin mutations might be ethnicity-dependent in Caucasians for Q368X and in Asians for T353I. | PURPOSE: To evaluate the association of myocilin (MYOC), optineurin (OPTN), and apolipoprotein E (APOE) genes and their interactions in primary open angle glaucoma (POAG).
METHODS: A cohort of 400 unrelated POAG patients (294 high tension glaucoma, HTG, and 106 normal tension glaucoma, NTG) and 281 unrelated control subjects were recruited. All coding exons and splicing junctions in MYOC and OPTN were screened for sequence alterations. Common polymorphisms in APOE were genotyped. Single genes were investigated by univariate and haplotype analysis, and gene-gene interactions by logistic regression and stratified analysis. Multiple comparisons were corrected by the Bonferroni method. Bioinformatics analysis was performed to assess the conservation of mutation sites across species and to predict putative motifs and secondary structures in mutated proteins.
RESULTS: Disease-causing mutations in MYOC and OPTN were identified in 1.75% and 1% of POAG patients, respectively. Most of these mutations were highly conserved across species, many predicted to create new motifs or change protein secondary structures. No individual MYOC polymorphisms significantly contributed to HTG or NTG. A haplotype containing the minor allele of the MYOC IVS2+35A>G increased NTG risk (p=0.0001). Three OPTN polymorphisms, T34T, IVS5+38T>G, and IVS8-53T>C increased NTG risk (p<0.0008), while IVS5+38T>G increased HTG risk (p=0.0006). One haplotype that contains the minor alleles of 3 OPTN polymorphisms, T34T, IVS5+38T>G, and IVS7+24G>A, increased NTG risk (p=0.0002). APOE epsilon4 carriers had a decreased NTG risk (p=0.007). Possible gene-gene interactions were found between MYOC, OPTN, and APOE.
CONCLUSIONS: Disease-causing mutations in MYOC and OPTN accounted for only a small proportion of Chinese POAG patients. Common polymorphisms in MYOC, OPTN, and APOE might interactively contribute to POAG, indicating a polygenic etiology. ||||| PURPOSE: Mutations in the CYP1B1, MYOC, OPTN, and WDR36 genes result in glaucoma. Given its expression in the optic nerve, it is likely a mutation in the OPTC gene is also involved in initiating glaucoma. This study was designed to evaluate the involvement of the CYP1B1, MYOC, OPTN, and OPTC genes in the etiology of adult-onset primary open-angle glaucoma (POAG) found in 251 Indian patients.
METHODS: Blood samples were obtained from individuals for DNA isolation. A combination of polymerase chain reaction-single strand conformation polymorphism, allele-specific PCR, and DNA sequencing techniques were used to detect mutations in four genes. Four microsatellite markers from the CYP1B1 candidate region and three intragenic CYP1B1 single nucleotide polymorphisms (SNPs) were used to determine the origin of the most common CYP1B1 mutations.
RESULTS: Three previously known mutations (Pro193Leu, Glu229Lys, and Arg368His) and one novel (Met292Lys) mutation were found in the CYP1B1 gene. Frequencies of the most common mutations, Glu229Lys and Arg368His, in patients were 5.12% and 3.98%, respectively. The Glu229Lys and Arg368His mutations were also found in normal controls at frequencies of 5% and 2%, respectively, suggesting that these mutations might be polymorphic variants in our population. The absence of allele sharing for D2S177, D2S1346, D2S2974, and D2S2331 markers and three intragenic CYP1B1 SNPs in patients suggested multiple origins for the Glu229Lys and Arg368His variants. Two of 251 (0.8%) patients had the Gln48His mutation in MYOC. There was no difference in the frequency of a MYOC -83G>A promoter polymorphism between patients and controls. A novel OPTN mutation, Thr202Arg, was detected in one of 251 (0.4%) patients. The OPTN variant Met98Lys was detected in similar frequencies in patients and controls. No mutation was detected in OPTC. Taken together, 3.59% (9/251) of our POAG patients had mutations in the CYP1B1, MYOC, and OPTN genes.
CONCLUSIONS: This is the first report to document the involvement of the CYP1B1, MYOC, and OPTN genes in the etiology of POAG in the same set of Indian patients. Our study shows that mutations in these genes are rare in Indian POAG patients. ||||| Primary open-angle glaucoma (POAG) is a prevalent optic neuropathy with complex genetics. A small number of patients carry a mutation in the coding region of the myocilin (MYOC) gene. The nature and the frequency of these mutations, however, vary substantially, notably with the age at onset and the ethnic origin of the patients. Here, we showed that denaturing high performance liquid chromatography (DHPLC) is an appropriate method for screening carriers of MYOC mutations. We have applied the method to a group of 237 POAG patients and 108 control subjects from France. Mutations were found in 17 (7.5%) patients and in none of the controls. A single mutation, Q368X (c.1102C>T), accounted for the majority (12/17) of these mutations, corresponding to a frequency of 5% among POAG patients, the highest ever reported for this mutation. Furthermore, analysis of allelic associations at closely linked microsatellite markers indicated that most, if not all, patients inherited Q368X from a same ancestor. Five other patients carried four distinct mutations, including N480K (c.1440C>A) (2 cases), I499F (c.1495A>T), G367R (c.1099G>A) and T438I (c.1313C>T), which is reported here for the first time. Altogether, MYOC mutations in French patients were associated with a significantly increased intraocular pressure at diagnosis. In addition, the age at diagnosis of patients with a mutation other than Q368X was significantly younger than that of Q368X carriers or of patients with a normal MYOC. Based on these observations, a screening strategy of MYOC mutations in French POAG patients is briefly outlined. ||||| PURPOSE: To evaluate the noelin 2 gene as a disease-causing factor for open-angle glaucoma (OAG) and the interactions between the noelin 2 (OLFM2), optineurin (OPTN), and myocilin (MYOC) genes.
METHODS: OLFM2 was analyzed in 770 Japanese subjects including 215 patients with elevated intraocular pressure (IOP), 277 with normal IOP, 38 with juvenile open-angle glaucoma, and 240 control subjects. Two single-nucleotide polymorphisms (SNPs) in OPTN (c.412G-->A and c.603T-->A) and one SNP in MYOC (c.227G-->A) were examined. Single genes were investigated by univariate analysis and the gene-gene interactions by logistic regression analysis. Associations between genotypes and clinical characteristics at the time of diagnosis were examined.
RESULTS: In OLFM2, 12 sequence variants were identified in 770 Japanese subjects. Arg144Gln (exon 4) was identified in two (0.3%) of the patients and in none of the control subjects. Combinations of OLFM2/317A and OPTN/412A or OLFM2/1281T and OPTN/412A were associated with patients with elevated IOP (P = 0.018 or P = 0.012, respectively). The combination of OLFM2/317G and OPTN/603A was significantly associated with elevated IOP (P = 0.018). No significant association was detected between SNPs in OLFM2 and in MYOC. Patients with normal IOP and with OLFM2/678A+OPTN/412G or OLFM2/1281C+OPTN/412G had significantly worse visual field scores (P = 0.022 or 0.030, respectively).
CONCLUSIONS: The Arg144Gln mutation in OLFM2 is a possible disease-causing mutation in Japanese patients with OAG. Common polymorphisms in OLFM2 and OPTN may interactively contribute to the development of OAG, indicating a polygenic etiology. ||||| A collection of DNA samples obtained from primary open-angle glaucoma (POAG) patients from St. Petersburg was analyzed for single-strand conformation polymorphism (SSCP) to reveal sequence variants in exon 3 of the myocilin gene (MYOC/TIGR) and in exons 4 and 5 of the optineurin gene (OPTN), where most of the mutations revealed worldwide are located. The Q368X mutation (c. 1102 C --> T) in exon 3 of MYOC/TIGR was detected in 1.2% (2/170) of the POAG patients from St. Petersburg, i.e., with the frequency close to that observed in other world populations. Three known polymorphisms in exon 3 of MYOC/TIGR, Y347Y (c. 1041 T --> C) (12.4%), T325T (c. 975 G --> A) (0.6%), and K398R (c. 1193 A --> G) (0.6%) were also detected. No statistically significant differences in frequencies of these polymorphisms were revealed between the POAG patient and control groups. The L41L polymorphism (c. 433 G --> A) in exon 4 of OPTN was detected in 2.9% of probands and in 1% of controls. The frequency of heterozygotes for the M98K polymorphism (c. 603 T --> A) in the OPTN exon 5 was statistically significantly higher (P = 0.036; Fisher's exact test) among the POAG patients (6.5%) than among the controls (1%). In the sample examined the E50K mutation, typical of the patients with pseudonormal intraocular pressure glaucoma, was not found. ||||| BACKGROUND: Primary open-angle glaucoma (POAG) is characterized by optic nerve damage and consists of a group of genetically heterogeneous disorders. This study was to investigate the associations of genetic and environmental factors with POAG in a hospital-based Chinese population.
METHODS: Thirty-two adult onset POAG patients and 96 age-sex matched control subjects were studied by multivariable logistic regression analysis for the relationships between POAG and its risk factors including family history, diabetes, hypertension, cardiovascular diseases, cigarette smoking, alcohol consumption and polymorphisms of the myocilin and the optineurin genes.
RESULTS: Univariate analysis showed that POAG was related to family history, cardiovascular disease, alcohol consumption and a myocilin sequence alteration (T353I) (P < 0.04). Multivariable logistic regression analysis confirmed that POAG was significantly associated with family history (OR = 20.2), hypertension (OR = 3.58), cigarette smoking (OR = 10.8), alcohol consumption (OR = 0.028) and T353I (OR = 6.03, all P < 0.05).
CONCLUSIONS: Family history, hypertension, cigarette smoking and T353I in the myocilin gene are risk factors for POAG. Alcohol consumption, however, has a protective effect. ||||| A glaucoma locus, GLC1A, was identified previously on chromosome 1q. A gene within this locus (encoding the protein myocilin) subsequently was shown to harbor mutations in 2-4% of primary open angle glaucoma patients. A total of 1703 patients was screened from five different populations representing three racial groups. There were 1284 patients from primarily Caucasian populations in Iowa (727), Australia (390) and Canada (167). A group of 312 African American patients was from New York City and 107 Asian patients from Japan. Overall, 61 different myocilin sequence variations were identified. Of the 61 variations, 21 were judged to be probable disease-causing mutations. The number of probands found to harbor such mutations in each population was: Iowa 31/727 (4.3%), African Americans from New York City 8/312 (2.6%), Japan 3/107 (2.8%), Canada 5/167 (3.0%), Australia 11/390 (2.8%) and overall 58/1703 (3. 4%). Overall, 16 (76%) of 21 mutations were found in only one population. The most common mutation observed, Gln368Stop, was found in 27/1703 (1.6%) glaucoma probands and was found at least once in all groups except the Japanese. Studies of genetic markers flanking the myocilin gene suggest that most cases of the Gln368Stop mutations are descended from a common founder. Although the specific mutations found in each of the five populations were different, the overall frequency of myocilin mutations was similar ( approximately 2-4%) in all populations, suggesting that the increased rate of glaucoma in African Americans is not due to a higher prevalence of myocilin mutations. ||||| PURPOSE: To investigate the coding exons in the trabecular meshwork-induced glucocorticoid response protein (TIGR) gene for mutations in primary open-angle glaucoma (POAG) in Chinese subjects.
METHODS: Ninety-one Chinese patients with POAG and 113 of their family members without glaucoma were screened for sequence alterations in the TIGR gene by polymerase chain reaction, conformation-sensitive gel electrophoresis, and DNA sequencing. One hundred thirty-two unrelated individuals without glaucoma, aged 50 years or more, were studied as control subjects.
RESULTS: Five sequence variants that lead to amino acid changes were identified. One was novel: Arg91Stop in one patient with POAG. Four had been reported: Arg46Stop in subjects with and without POAG, including an unaffected 77-year-old woman homozygous for Arg46Stop; Gly12Arg in subjects without glaucoma; and Asp208Glu and Thr353Ile in subjects with and without POAG. The previously reported 1-83(G-->A) and Arg76Lys polymorphisms were detected in both patients and controls and always occurred together.
CONCLUSIONS: A different pattern of TIGR sequence variants exists in the Chinese than in non-Chinese populations. No common TIGR mutation that causes POAG was found. The occurrence of subjects without glaucoma who are heterozygous or homozygous for Arg46Stop suggests that reduction in the amount of TIGR protein does not cause glaucoma. Thus, the TIGR missense mutations known to cause POAG probably do not cause glaucoma by inactivating a normal TIGR function, but rather through the gain of a pathologic function. ||||| PURPOSE: To screen for mutations in the MYOC gene in Japanese patients with primary open-angle glaucoma (POAG) using denaturing high-performance liquid chromatography (DHPLC).
PATIENTS AND METHODS: Blood samples were collected from 171 patients with POAG and 100 controls from seven institutions in Japan. For high-throughput analysis, seven exonic regions were amplified by polymerase chain reaction using DNA pooled from three patients; each DNA pool was then analyzed chromatographically. For analysis of a small number of samples, 7 exonic regions were amplified separately but simultaneously with annealing at 58 degrees C in each patient and then chromatographed, using 7 wells of the same 96-well plate per sample. When chromatographic patterns were abnormal by either method, the PCR products of the individual samples were sequenced.
RESULTS: Four glaucoma-causing mutations were identified in five POAG patients (2.9%). One missense mutation, Phe369Leu, is new; and three others, Ile360Asn, Ala363Thr, and Thr448Pro, have been reported in Japanese patients. Phe369Leu was associated with adult onset POAG.
CONCLUSIONS: Mutations in the MYOC gene were demonstrated chromatographically in 2.9% of our Japanese POAG patients. The use of pooled DNAs with DHPLC analysis is a time- and labor-saving technique. All mutations detected appear to be specific to Japanese patients. ||||| OBJECTIVE: To detect the single nucleotide polymorphism (SNP) of trabecular meshwork-induced glucocorticoid response protein (TIGR) gene and to investigate the association between SNP and primary open-angle glaucoma (POAG) in Chinese Han population.
METHODS: High throughput conformation sensitive gel electrophoresis (HTCSGE) and fluorescent labeling automated sequencing method were used to screen and identify the SNPs of TIGR in 82 unrelated patients with POAG. Restriction endonuclease analysis was used to detect the SNPs of TIGR in 150 sex-and age-matched unrelated control subjects without POAG. The frequencies of genotypes and alleles of each SNP between the two groups were compared by chi-square test.
RESULTS: A total of six SNPs were identified in TIGR gene with a length of 2172 bp, including all coding regions and part of promoter, introns and 3'UTR region: 1-83(G --> A), G12R, R46X, R76K, IVS2 + 35(A --> G), and T353I. Significant differences were found in frequencies of the genotype TC and the allele T of T353I between POAG patients and control subjects. The frequency of heterozygote TC was 12.20% in POAG patients, significantly higher than that in control subjects (3.33%, kappa(2) = 6.885, P = 0.009, OR = 4.028, OR95% CI = 1.327 approximately 12.223). The frequency of the allele T was 6.10% in POAG patients, significantly higher than that in control subjects (1.67%, kappa(2) = 6.655, P = 0.010). No significant difference was found between the two groups in frequencies of genotypes and alleles of the other SNPs.
CONCLUSION: The T353I polymorphism of TIGR gene is associated with POAG in Chinese Han population. ||||| PURPOSE: To investigate the role of MYOC and CYP1B1 in Iranian juvenile open angle glaucoma (JOAG) patients.
METHODS: Twenty-three JOAG probands, their available affected and unaffected family members, and 100 ethnically matched control individuals without history of ocular disease were recruited. Clinical examinations of the probands included slit lamp biomicroscopy, intraocular pressure (IOP) measurement, gonioscopic evaluation, fundus examination, and perimetry measurement. Familial cases were classified according to the mode of inheritance. Exons of MYOC and CYP1B1 were sequenced, and novel variations assessed in the control individuals. Potential disease-associated variations were tested for segregation with disease status in available family members.
RESULTS: The mode of inheritance of the disease in the families of four probands (17.4%) appeared to be autosomal dominant and in at least eight (34.8%) to be autosomal recessive. Four patients carried MYOC mutations, and an equal number carried CYP1B1 mutations. The MYOC mutations were heterozygous; two of them (p.C8X and p.L334P) are novel, and one codes for the shortest truncated protein so far reported. Autosomal recessive inheritance was consistent with inheritance observed in families of patients carrying CYP1B1 mutations. All these patients carried homozygous mutations.
CONCLUSIONS: MYOC and CYP1B1 contributed equally to the disease status of the Iranian JOAG patients studied. The contribution of the two genes appeared to be independent in that no patient carried mutations in both genes. The fraction of Iranian patients carrying MYOC mutations was comparable to previously reported populations. ||||| PURPOSE: To discover sequence alterations in the TIGR/MYOC gene associated with primary open-angle glaucoma (POAG) in Chinese subjects.
METHODS: Two hundred one unrelated Chinese patients with POAG and 291 unrelated individuals without glaucoma, aged 50 years or more, were screened for sequence alterations in the TIGR/MYOC gene by polymerase chain reaction, conformation sensitive gel electrophoresis, and DNA sequencing. Up to 111 more control subjects were screened for some of the alterations.
RESULTS: Fourteen sequence variants that lead to amino acid changes were identified. Seven were novel: Pro16Leu, Ala17Ser, Leu95Pro, Leu215Pro, Glu300Lys, Glu414Lys, and Tyr471Cys. Of these, Glu300Lys and Tyr471Cys were found only in POAG. Arg46Stop was found in 4 patients with POAG (2.0%) and 9 of 402 control subjects (2.2%); one control subject was homozygous. IOP showed a trend (P = 0.11) toward a decrease of 1.5 mm Hg among the control subjects, with Arg46Stop compared with matched control subjects without Arg46Stop. Gly12Arg occurred four times as frequently in control subjects as in patients, but the difference was not statistically significant.
CONCLUSIONS: Gly12Arg might be negatively associated with POAG, suggesting a protective effect. Three patients with POAG had a sequence change not found in control subjects, for a frequency of possible disease-causing TIGR/MYOC mutations of 1.5% (95% confidence interval [CI] = 0.3%-4.3%). Arg46Stop occurred with similar frequency in patients with POAG and control subjects, suggesting that the reduced amount of TIGR/MYOC predicted to result from this truncation does not dramatically increase or decrease risk of glaucoma. ||||| Myocilin (MYOC) mutations are associated with juvenile- and adult-onset primary open-angle glaucoma (POAG). The purpose of this study was to determine whether MYOC gene mutations are associated with normal-tension glaucoma (NTG). The prevalence of MYOC mutations was determined in 80 Japanese NTG patients and 100 control subjects. In addition, the expression of mutant MYOC was determined by transforming COS-1 cells with five myocilin variants (R158Q, D208E, I360N, A363T, and I477S) and examining whether myocilin was present in the cultured cells and/or the culture medium by western blotting. Six different nucleotide sequence variants, R46Stop, R76K, R158Q, D208E, A488A, and one in the 3' non-coding region, were identified in 80 NTG patients. Variants in codon 46 (R46Stop), codon 158 (R158Q), and codon 488 (A488A) were not found in the 100 normal controls. The frequency of other sequence changes (R76K, D208E, and 3' non-coding) in NTG patients did not differ significantly from the frequencies in the control subjects. COS-1 cells transfected with the wild type, R158Q, or D208E variants secreted myocilin into the culture medium. On the other hand, the detected myocilin was significantly reduced in the medium of cells transfected with the I360N, A363T, or I477S variants that were previously identified as mutations for POAG. Definitive evidence of MYOC variants associated with NTG was not found. ||||| Primary open-angle glaucoma (POAG) is a complex disorder characterized by a progressive and treatable degeneration of the optic nerve. TIGR/myocilin (MYOC) gene mutations are found in approximately 4% of all POAG patients. Populations with frequent founder effects, such as the French-Canadians, offer unique advantages to implement genetic testing for the disorder. To assess molecular diagnosis for POAG in this population, we determined the prevalence of TIGR/MYOC mutations in 384 unrelated glaucoma patients, 38 ocular hypertensive subjects and 18 affected families (180 patients). We further analyzed the clinical features associated with these variations. Nine coding sequence variants were defined as mutations causing mostly, but not exclusively, POAG. Four families segregated distinct mutations (Gly367Arg, Gln368Stop, Lys423Glu and Pro481Leu), while 14 unrelated glaucoma patients harbored six known mutations (Thr293Lys, Glu352Lys, Gly367Arg, Gln368Stop, Lys423Glu and Ala445Val) and two novel (Ala427Thr and Arg126Trp). The frequencies of these mutations were respectively 3.8% and 22.2% in the unrelated and family studies. The Gly367Arg and Lys423Glu variants caused the earliest ages at onset. When achievable, assessment of relatives of unrelated mutation carriers showed the Arg126Trp and Gly367Arg to be familial. Characteristic allele signatures, indicative of specific founder effects, were observed for five of the six mutations conveyed by at least two patients. Recombination probability estimates suggested that the French-Canadian population had most probably inherited these six mutations from 7-10 Québec settlers. Our data demonstrated that genetic screening for TIGR/MYOC mutations should be offered to glaucoma families and to close relatives of unrelated patients aware of a family history for the disorder. ||||| OBJECTIVE: To detect the single nucleotide polymorphisms (SNPs) of the myocilin (MYOC) and optineurin (OPTN) genes, and to investigate their associations with high tension glaucoma (HTG) and normal tension glaucoma (NTG).
METHODS: SNPs were detected using polymerase chain reaction (PCR), followed by conformation sensitive gel electrophoresis (CSGE) and fluorescent labeling automated DNA sequencing among 94 unrelated patients with HTG, 48 unrelated patients with NTG, and 77 unrelated control subjects.
RESULTS: Fourteen MYOC sequence alterations were identified, five of them: V53A, I304I, T347T, 1-126T > C, and IVS2 + 172C > A, were novel. Among them, V53A was for the first time found in primary open angle glaucoma (POAG) patient. R76K usually occurred with the promoter polymorphism 1-83G > A. No sequence alterations in the MYOC gene showed significant differences among the HTG, NTG and control subjects (all P > 0.05). A total of 12 sequence alterations were identified in the OPTN gene, and three of them: V161M, I407T and L211L, were novel. Among them, I407T and L211L were found only in the HTG patients. The allele and genotype frequencies of T34T in the NTG patients were significantly higher than those of the controls (P = 0.001 and 0.004 respectively). In HTG, only the allele frequency of T34T was 24% (23/96), significantly higher than those of the NTG group (16.5%, 31/188) and the control group (9.1%, 14/154) (both P < 0.05). In addition, IVS8 + 20G > A was found only in the HTG (3.1%, 3/96) and NTG patients (3.7%, 7/188), and had significantly higher frequencies in the HTG and NTG patients when compared with the controls (P = 0.016 and 0.014, and P = 0.027 and 0.026).
CONCLUSION: Polymorphisms in the MYOC and OPTN genes are associated with POAG in Chinese people. Moreover, sequence alterations not causing amino acid changes may play a role in the pathogenesis of POAG. ||||| PURPOSE: To retrospectively investigate the contribution of myocilin (MYOC) and optineurin (OPTN) sequence variations to adult-onset ocular hypertension (OHT) and primary open-angle glaucoma (POAG) in Spanish patients.
METHODS: The promoter region and the three exons of MYOC were analyzed by direct PCR DNA sequencing in 40 OHT and 110 POAG unrelated patients. We used 98 subjects in whom OHT or glaucoma had been ruled out as controls. We also screened the complete coding region of the OPTN gene (exons 4-16) in all subjects by single-stranded conformational polymorphisms (SSCPs).
RESULTS: We identified six common single nucleotide polymorphisms (SNPs) in the promoter region of MYOC (-1000C>G, -387C>T, -306G>A, -224T>C, -126T>C and -83G>A) and a polymorphic GT microsatellite (-339(GT)11-19). In addition, we detected four novel, rare DNA polymorphisms. None of these DNA sequence variations were associated with either OHT or POAG. We also found three (2.7%) POAG patients with MYOC pathogenic mutations. Two of these pathogenic mutations (Gln368Stop and Ala445Val) were previously described whereas the third (Tyr479His) was novel. Transient expression of the novel mutation in 293T cells supported its pathogenicity. Only two OPTN polymorphisms, which are not associated with the disease, were detected.
CONCLUSIONS: Overall, our data show that in Spain a minority of adult-onset high-pressure POAG patients carry heterozygous disease-causing mutations in the MYOC gene and that OPTN is not involved in either OHT or POAG. ||||| PURPOSE: Glaucoma is the second leading cause of blindness worldwide after cataract. Defects in the myocilin gene (MYOC) have been shown to be associated with Primary Open Angle Glaucoma (POAG), the most common form of the disease, especially in its juvenile form. Most of the reported mutations in MYOC are in POAG patients of Caucasian origin. A few studies have been reported on Asian patients (such as Chinese, Japanese, and Koreans) but none from the Indian subcontinent. The purpose of this study was to investigate the molecular basis of POAG among Indians, using MYOC as the candidate gene, and broaden our understanding on the pathogenesis caused by MYOC.
METHODS: Fifty-six unrelated POAG patients, comprising 39 sporadic cases and 17 patients having familial history for POAG were enrolled in this study. The coding sequence of the gene was amplified by polymerase chain reaction (PCR) using genomic DNA from 30 POAG patients, followed by sequencing of the PCR products. Nucleotide changes were detected by identifying double peaks in the chromatogram due to heterozygosity and pairwise BLAST analysis of the sequence output data against the normal copy of the MYOC cDNA. Alteration of restriction sites due to nucleotide changes was identified. Twenty-six patients (not sequenced) and controls were screened for nucleotide changes by allele specific restriction digestion of the PCR products followed by separation of the digested DNA fragments by polyacrylamide gel electrophoresis.
RESULTS: From a pool of 56 unrelated POAG patients two mutations were identified. A putative novel mutation (144 G->T; Gln48His) of a conserved amino acid was detected in the exon 1 of MYOC from three unrelated patients but none in the 51 control samples examined. The other mutation (1109 C->T; Pro370Leu), located in exon 3 and detected in a family affected with POAG, cosegregated with the disease and was not present in control samples. Two single nucleotide polymorphisms (SNPs) were identified; one in the promoter region (-83 G->A) and the other in the coding sequence (227 G->A; Arg76Lys). These two SNPs were found to be highly heterozygous both in the control (0.480) and the patient (0.477) populations, and were observed to be in linkage disequilibrium.
CONCLUSIONS: The presence of a novel non-conservative change in codon 48 of MYOC in 3 POAG patients, but none in the healthy controls, suggests a causal association of the mutation with the disease, either singly or in combination with other genetic loci. The other point mutation (Pro370Leu) detected in the members of an affected POAG family represents a hotspot of mutation in the gene. Two identified SNPs (-83 G->A and 227 G->A) are not associated with the disease phenotype but could be used as highly informative markers in POAG affected families to determine any causal association of MYOC with the disease, and for identification of presymptomatic carriers in the family, where applicable. A comparison of our data with other studies revealed that these two polymorphisms are in complete linkage disequilibrium among Asians, but not among other ethnic groups studied so far. ||||| OBJECTIVE: To study the mutations in the trabecular meshwork induced-glucocorticoid response protein gene (TIGR/MYOC) in Chinese POAG patients.
METHODS: It was a case-control study. One hundred and eighteen Chinese patients with POAG and 150 control subjects without POAG were screened for coding sequence of the MYOC gene by polymerase chain reaction, single-strand conformation polymorphism (SSCP) and DNA sequence. Restriction endonuclease analysis was used to detect the SSCP in 150 gender- and aged-matched controls. Statistical significance of the difference in frequencies of MYOC mutations between POAG patients and the controls was determined by the chi-squared test.
RESULTS: Three coding sequence variants that lead to amino acid changes were identified in MYOC gene. One mutation of MYOC gene was novel, I288M, which was present in one patient with POAG and 3 control subjects. G12R and Y353I have been reported previously. I288M and Y353I were found in both the subjects with and without POAG, the difference of the frequency of these two mutations between POAG and the controls was χ(2) = 0.07, P = 0.791 and χ(2) = 0.56, P = 0.453, respectively. Coding sequence mutations of MYOC were found in 4.23% POAG patients. Frequency of G12R mutation in POAG patients was significantly greater than that in the controls (χ(2) = 4.37, P = 0.037).
CONCLUSIONS: One novel variant locus in the MYOC/TIGR (I288M) was found in the present study, but this mutation is not associated with POAG. G12R is the most common mutation in MYOC locus in Chinese subjects with POAG. Approximately 4.23% sporadic POAG patients have mutation in the exon 1 in MYOC/TIGR. ||||| PURPOSE: Myocilin (MYOC) mutations are associated with primary open-angle glaucoma (POAG) in multiple populations. Here we examined the role of MYOC mutations in a black South African population with primary open-angle glaucoma (POAG).
METHODS: Unrelated black South African subjects with POAG and unaffected controls were recruited from the St. John Eye Hospital (Soweto, Johannesburg, South Africa) and East London Hospital Complex (Eastern Cape, South Africa). A complete eye examination including visual field assessment was performed in all subjects. Blood samples were obtained for DNA extraction. The complete coding region of MYOC was sequenced using the PCR-based Sanger method. Identified mutations were compared to known MYOC mutations.
RESULTS: One hundred-thirteen POAG cases and 131 controls were recruited for analysis. A total of 19 variants were observed. Probable glaucoma-causing mutations were observed in 4.4% of POAG cases. A previously reported glaucoma-causing mutation, Tyr453MetfsX11, was observed in three cases and one control. Two other sequence variants, Gly374Val and Lys500Arg, occurred only in cases. Other sequence variants, including 6 novel variants, occurred in at least one control.
CONCLUSIONS: A small minority of black South Africans with POAG carry MYOC mutations. The Gly374Val mutation might represent a novel glaucoma-causing mutation. The Tyr453MetFSX11 mutation appears to be a glaucoma-causing mutation with incomplete penetrance. ||||| BACKGROUND: A substantial proportion of cases of glaucoma have a genetic basis. Mutations causing glaucoma have been identified in the chromosome 1 open-angle glaucoma gene (GLC1A), which encodes a 57-kd protein known as myocilin. The normal role of this protein and the mechanism by which mutations cause glaucoma are not known.
METHODS: We screened 716 patients with primary open-angle glaucoma and 596 control subjects for sequence changes in the GLC1A gene.
RESULTS: We identified 16 sequence variations that met the criteria for a probable disease-causing mutation because they altered the predicted amino acid sequence and they were found in one or more patients with glaucoma, in less than 1 percent of the control subjects. These 16 mutations were found in 33 patients (4.6 percent). Six of the mutations were found in more than 1 subject (total, 99). Clinical features associated with these six mutations included an age at diagnosis ranging from 8 to 77 years and maximal recorded intraocular pressures ranging from 12 to 77 mm Hg.
CONCLUSIONS: A variety of mutations in the GLC1A gene are associated with glaucoma. The spectrum of disease can range from juvenile glaucoma to typical late-onset primary open-angle glaucoma. ||||| One of the leading causes of blindness in the world is glaucoma. The most common form is primary open-angle glaucoma (POAG). The only gene identified so far as being associated with POAG is the MYOC gene; 2-4% of the patients have been reported to carry mutations in this gene. Exfoliative glaucoma is a secondary glaucoma, in which one of the symptoms is exfoliations on the lens capsule and anterior segment of the eye. No gene has been identified as being associated with this variant. The aim of the present study was to analyze Swedish patient material for allelic variants and mutations in the coding region of the MYOC gene. Two hundred patients with POAG and 200 with exfoliative glaucoma were analyzed using enzymatic cleavage assay and denaturing high-performance liquid chromatography (dHPLC). An age-matched control group (n = 200), in whom glaucoma had been excluded, was also analyzed using dHPLC. Eight allele variants were identified, two of which were determined to be disease-causing mutations. These two disease-causing mutations were only found in POAG patients, indicating a prevalence of 1% in this patient group. This frequency is lower than that reported in other studies of other populations. No disease-causing mutations were found in the exfoliative glaucoma patients, indicating a fundamentally different genetic basis for that glaucoma variant. ||||| PURPOSE: To investigate the Myocilin (MYOC) gene for mutations and polymorphisms in patients with primary open-angle glaucoma (POAG) in Morocco.
METHODS: Fifty-seven patients with severe POAG, who suffered from complete or almost complete visual field loss, were included in the study. The MYOC coding region, including exon I, exon II, and the coding part of exon III, were screened for sequence alteration using denaturing high-performance liquid chromatography (DHPLC). Variant amplicons were sequenced bidirectionally. The control group consisted of 60 subjects from the general population.
RESULTS: One disease-causing mutation, T377M, was observed in one POAG patient. In addition, 10 polymorphisms, namely P13P, R76K, R82H, G122G, T135I, L159L (often associated with P13P), T285T, T325T, Y347Y, and E396E, were detected in patients or in controls. The Q368X mutation that has been documented in Caucasian POAG patients was absent.
CONCLUSIONS: MYOC is an infrequent genetic cause of severe POAG in Morocco. The absence of the POAG-associated Q368X mutation and the presence of particular polymorphisms, including P13P + L159L and T325T, could be specific features of the MYOC sequence in African populations. ||||| PURPOSE: To determine MYOC gene mutation frequency in patients with primary open-angle glaucoma (POAG) from Western Switzerland.
METHODS: A total of 117 unselected index patients with primary open-angle glaucoma were submitted to a full eye examination. DNA was extracted from blood and PCR amplicons of MYOC exon 3 were screened for mutations by single-strand conformation polymorphism (SSCP) analysis. Abnormal conformers were analyzed both by direct bidirectional sequencing and by enzymatic mutation detection (EMD) assay.
RESULTS: Ten occurrences of four different sequence changes were detected, including: 1) five times the same disease-causing mutation (Q368X) in five unrelated POAG patients and 2) three distinct polymorphisms in five patients. The patients carrying an MYOC mutant allele were characterized by a broad clinical variability in terms of age of onset (34-77 years) and highest intraocular pressure (IOP) values (23-47 mmHg).
CONCLUSIONS: A pathogenic MYOC mutation (Q368X) was identified in 4.27% (5/117) of the studied population from Western Switzerland, which corresponds to the highest frequency yet reported for this mutation. ||||| OBJECTIVE: To detect single nucleotide polymorphisms (SNPs) of the myocilin (MYOC) gene and to investigate their associations with primary open-angle glaucoma (POAG).
METHODS: One hundred and fifty-seven sporadic patients with POAG and 155 unrelated control subjects without POAG were recruited from staff and visitors to the Prince of Wales Hospital between 1998 and 2000. All study subjects are ethnic Chinese living in Hong Kong. The two populations were matched in frequencies of gender and age. The SNPs of the MYOC gene in POAG patients and control subjects were screened and identified by high throughout conformation sensitive gel electrophoresis and fluorescent labeling automated sequencing. The genotype frequencies of each SNP in the two groups were compared by the Chi2 test or Fisher's exact 2-tailed test.
RESULTS: A total of seventeen SNPs were identified from 2172 bp long of the MYOC gene, including all 3 exons and adjacent non-coding regions. The identified SNPs were 1-83G --> A, G12R, P16L, A17S, R46X, R76K, R91X, T123T, D208E, L215P, 730+35A --> G, A260A, I288I, E300K, T353I, Y471C and 1515+73G --> C, respectively. Of these, R91X, E300K and Y471C were found only in POAG patients. A significant difference between POAG patients and control subjects was found in the genotype frequencies of 1515+73G --> C. The frequency of the heterozygote (CG) was 0.6% in POAG patients, significantly less than the 4.5% in control subjects (Fisher's exact 2-tailed test, P=0.036, OR=0.136, 95%CI=0.022-0.828). No significant difference was found between the two populations in genotype frequencies of all other SNPs.
CONCLUSION: The polymorphisms of the MYOC gene may be related to POAG. ||||| PURPOSE: To evaluate the individual and interactive effects of polymorphisms in the myocilin (MYOC),optineurin (OPTN), WD repeat domain 36 (WDR36), and apolipoprotein E (APOE) genes on primary open-angle glaucoma (POAG) in northern Chinese.
METHODS: Northern Chinese study subjects, 176 POAG patients and 200 controls, were recruited for screening of the coding exons and splicing regions of MYOC. Five single nucleotide polymorphisms (SNPs) in OPTN (M98K, R545Q, IVS5+38T>G, IVS8-53T>C, and IVS15+10G>A), one SNP in WDR36 (IVS5+30C>T) as well as the APOE promoter and epsilon2/epsilon3/epsilon4 polymorphisms were also examined. Association analysis was performed by using chi(2) analysis. High-order gene-gene interaction was also analyzed using the multifactor dimensionality reduction (MDR) method.
RESULTS: In MYOC, 22 variants were identified. Four of them were novel but found in controls only. The missense mutation, Val53Ala, is likely a glaucoma causing mutation, accounting for 0.6% of cases. No individual polymorphism in OPTN, WDR36, or APOE was associated with POAG. MDR analysis identified a best 6-factor model for POAG: MYOC IVS2+35A>G, OPTN Met98Lys, OPTN IVS5+38T>G, OPTN IVS8-53T>C, WDR36 IVS5+30C>T, and APOE -491A>T.
CONCLUSIONS: The association pattern between the genes, MYOC, OPTN, WDR36, and APOE, and POAG in northern Chinese is different from that of southern Chinese. Disease-causing mutations in MYOC accounted for a small proportion of northern Chinese POAG patients. Common polymorphisms in these genes were not associated with POAG individually but might interactively contribute to the disorder, supporting a polygenic etiology. ||||| Myocilin is a gene responsible for juvenile onset primary open angle glaucoma (POAG) mapped as the GLC1A locus and, many mutations have been reported worldwide. Some mutations were found not only in patients with juvenile onset POAG, but also in patients with late onset POAG and in patients with normal tension glaucoma. To investigate the mutation prevalence in Japan, we performed a mutation analysis in 140 unrelated Japanese patients. We have identified the 10 sequence variants, of which four were highly probable for disease-causing mutations (Arg46ter, Arg158Gln, Ile360Asn, and Ala363Thr), and six polymorphisms (Gln19His, Arg76Lys, Asp208Glu, Val439Val, Arg470His, and Ala488Ala). Thus, myocilin mutations were found at the rate of 4/140 (2.9%) probands, similar to previous reports with other ethnic populations. ||||| The myocilin gene was identified as a gene (MYOC) that caused primary open-angle glaucoma (POAG). Although a normal tension glaucoma (NTG) patient with the myocilin gene mutation was previously reported, no study using large numbers of patients with NTG has been reported. Single-strand conformation polymorphism analysis and subsequent sequence analysis were performed for genotyping the myocilin gene in 114 unrelated Japanese patients with NTG. One hundred and nineteen patients with POAG and 100 control subjects without glaucoma were studied as reference subjects. Five amino acid sequence changes of the myocilin were identified: Arg46Stop (one NTG), Arg76Lys (four NTG, 10 POAG, seven control), Arg158Gln (one NTG, one POAG, one control) found in only Japanese, Asp208Glu (four NTG, three POAG, one control), Pro481Ser (one control). Pro481Ser was novel. Arg76Lys always occurred with 1-83 from G to A in the promoter as it was reported in Chinese. Although some Japanese patients with NTG had sequence changes of the myocilin gene, there were no apparent specific mutations in patients with NTG. ||||| PURPOSE: To investigate mutations in the promoter and coding regions of the myocilin (MYOC) gene in Taiwanese patients suffering from juvenile-onset open-angle glaucoma (JOAG).
METHODS: MYOC was analyzed for mutations in 48 unrelated Taiwanese probands with JOAG and in 100 healthy control subjects. Genomic DNA was extracted from peripheral blood leukocytes and then subjected to PCR to amplify exons, flanking introns and promoter regions of the MYOC gene. The amplified products were screened for base mutations by autosequence. Data from the two groups were then compared using the chi(2) test. Finally, the levels of MYOC transcripts were predicted by a neural network prediction system to study whether the intron mutations have any effect on the level of mRNA expression.
RESULTS: The analysis revealed four MYOC mutations and six polymorphisms. The prevalence of MYOC gene mutations in this study was 12.5% (6/48). The mutations included one nonsense mutation (Arg46Stop; 3/6), one missense mutation (Val56Ala; 1/6), one intron mutation (c.604+228A>T; 1/6) as well as one mutation in the 3'-untranslated region (c.1515+73G>C; 1/6). In addition, although c.604+228A>T is an intron mutation and does not alter the content of the amino acid residue, the neural network prediction system revealed that it can potentially create a novel accept splice site during transcription. This mutation might affect the protein structure and consequently the normal function of myocilin.
CONCLUSIONS: Our results indicate that the c.136C>T (Arg46Stop), c.158T>C (Val56Ala), c.604+228A>T, and c.1515+73G>C mutations of MYOC may be associated with JOAG. In addition, we suggest that the c.136C>T (Arg46Stop) mutation of MYOC is a hot spot in Taiwanese patients with JOAG. ||||| PURPOSE: To investigate the prevalence of myocilin (MYOC) mutations in a population-based sample of open-angle glaucoma (OAG) cases and to describe a family with both juvenile and adult onset OAG caused by a mutation in MYOC.
METHODS: MYOC was screened in cases derived from the Rotterdam Study in the Netherlands. Definite OAG was defined as a glaucomatous optic neuropathy together with a glaucomatous visual field defect. Upon the identification of the Asn480Lys mutation in one case, seven additional family members were studied. To test for a founder effect with earlier reported families with this mutation, the haplotypes of MYOC flanking markers D1S2851, D1S242, D1S218, and D1S1165 were compared.
RESULTS: Seven sequence alterations in MYOC were found in 14 of 47 OAG cases; six of these were also found in controls. In one case, an Asn480Lys mutation was found. In relatives of the latter patient, the phenotype ranged from a glaucomatous optic neuropathy without visual field defect in a 70-year-old patient to severely affected optic discs and a remaining temporal remnant in a 34-year-old patient; those without the mutation had no signs of OAG. Haplotype analysis suggested a different origin of the mutation.
CONCLUSIONS: The prevalence of MYOC mutations (2.2%) was similar to that found in hospital-based studies. Although mutations in MYOC are rare, relatives carrying this mutation run a high risk of developing the disease. Instead of submitting all members of a family with the Asn480Lys mutation to frequent follow-up, medical care can be restricted to those carrying the mutation. ||||| OBJECTIVE: To identify and evaluate MYOC variant alleles among patients with primary open-angle glaucoma (POAG) and age-matched control subjects in an Indian population.
METHODS: Three hundred fifteen patients with POAG and 100 unrelated control subjects from the same ethnic background were enrolled in the study. The coding sequence of MYOC was amplified by polymerase chain reaction using genomic DNA, followed by sequencing of the polymerase chain reaction products. Four single nucleotide polymorphisms were genotyped in different Indian subpopulations comprising 1466 individuals using SEQUENOM's homogeneous MassEXTEND assay.
RESULTS: One novel mutation (Gly399Asp), 6 reported mutations (Gln48His, Thr256Met, Thr353Ile, Gln368Stop, Pro370Leu, and Ala427Thr), and 6 single nucleotide polymorphisms were identified in MYOC. Ala427Thr was identified in a patient with POAG and Parkinson disease. Four single nucleotide polymorphisms genotyped in control subjects were highly heterozygous and displayed a similar pattern of linkage disequilibrium among all linguistic groups.
CONCLUSIONS: MYOC mutations account for 2.2% of POAG cases. The Gln368Stop mutation (common among persons of the white race) found in 2 families does not seem to be of white race origin. Identification of a MYOC mutation (Ala427Thr) in a patient with POAG and Parkinson disease is interesting with respect to reported interaction of myocilin with synucleins.
CLINICAL RELEVANCE: Studying the genetics of POAG is helpful for preclinical identification and for better disease management. ||||| Primary open angle glaucoma (POAG) is the second most common cause of blindness in developed countries. It is an optic neuropathy in which a degeneration of the retinal ganglion cells causes a characteristic excavation in the optic disc. Several loci have been identified to be responsible for different types of glaucoma, including the MYOC gene located on chromosome 1. In this work, six mutations have been identified in the third exon of the MYOC gene in patients with POAG. We studied 79 Galician patients with chronic POAG glaucoma and 90 control individuals from the same general population. We identified six mutations, including three novel ones. Two of the six mutations were considered to be polymorphisms, while the other four met the criteria for pathogenicity in this disease as they altered the amino acid sequence and were found in one or more patients with glaucoma and in less of 1% of the control population. These mutations were detected in eight patients suffering from POAG (7.5%) and in two people from the control population (2.2%). POAG can be due to mutations in the myocilin gene (MYOC) on chromosome 1. The glaucoma phenotype associated with this gene may vary from a juvenile severe form to a late-onset chronic open angle glaucoma. | [
{
"source_pmid": "16148883",
"source_text": "PURPOSE: To evaluate the association of myocilin (MYOC), optineurin (OPTN), and apolipoprotein E (APOE) genes and their interactions in primary open angle glaucoma (POAG).\nMETHODS: A cohort of 400 unrelated POAG patients (294 high tension glaucoma, HTG, and 106 ... |
29390407 | The limited evidence suggests that vitreomacular interface configuration have a significant influence on the visual acuity gain and CMT reduction at 1 year, injection numbers at 2 years in neovascular AMD patients treated with anti-VEGF agents. However, the results of this meta-analysis should be interpreted with caution because of the heterogeneity among study designs. Eyes with VMA/VMT on optical coherence tomography at baseline may require more intensive treatment with decreased response to anti-VEGF agents. | PURPOSE: To investigate the effects of vitreomacular adhesion (VMA) on intravitreal ranibizumab treatment in Japanese patients with exudative age-related macular degeneration (AMD).
METHODS: This was a retrospective comparative study that included 123 eyes from 123 patients with exudative AMD. The presence or absence of VMA was examined by spectral domain optical coherence tomography. The association of VMA with best-corrected visual acuity (BCVA) and central retinal thickness (CRT) at 3, 6, and 12 months after ranibizumab treatment was evaluated.
RESULTS: In the group of eyes without VMA [VMA(-)], the mean BCVA was 0.41 logMAR at baseline and significantly improved to 0.28, 0.30, and 0.29 logMAR at 3, 6, and 12 months following the initiation of treatment (P < 0.0001, <0.0001, <0.0001), respectively. In the group of eyes with VMA [VMA(+)], the mean BCVA was 0.42 logMAR at baseline, and there was no improvement at any of the measurement time-points during the follow-up period [0.39, 0.40, and 0.39 logMAR at 3, 6, and 12 months (P = 0.53, 0.75, 0.67), respectively]. The mean baseline CRT in the VMA(-) and VMA(+) groups was 326 and 370 µm, respectively, decreasing to 195 and 293 µm (P < 0.0001 and P = 0.0070), respectively, at 12 months. A better baseline BCVA was associated with poor visual response to intravitreal ranibizumab.
CONCLUSIONS: Our study of Japanese patients with AMD managed in real-world clinical practice revealed that both VMA and BCVA at baseline were associated with a poor visual response to intravitreal ranibizumab. These results are in agreement with previously reported findings for other ethnic groups. ||||| OBJECTIVE: To evaluate the effect of posterior vitreomacular adhesion (VMA), documented by optical coherence tomography (OCT), on the outcome of anti-vascular endothelial growth factor (VEGF) treatment for exudative age-related macular degeneration (AMD).
DESIGN: Retrospective comparative series.
PARTICIPANTS: A total of 148 patients (148 eyes) who were newly diagnosed with exudative AMD and were treated by anti-VEGF in 1 eye from 2005 to 2008 with a minimum of 12 months follow-up.
METHODS: We retrospectively reviewed OCT and medical records of 148 patients with exudative AMD and categorized them according to the presence of posterior VMA into 2 subgroups: VMA (+) group (38 eyes) and VMA (-) group (110 eyes). Best-corrected visual acuity (BCVA) and central retinal thickness (CRT) after anti-VEGF treatment were compared between the 2 groups at baseline; at 1, 3, 6, and 12 months; and at the last visit (mean = 21 months).
MAIN OUTCOME MEASURES: Mean changes in BCVA, which was converted to logarithm of the minimum angle of resolution (logMAR) values and CRT after anti-VEGF treatment.
RESULTS: Mean BCVA significantly decreased over time in the VMA (+) group compared with the VMA (-) group (P = 0.039). At the last follow-up, mean BCVA had deteriorated from 0.87 logMAR (20/149 Snellen equivalent; baseline) to 0.98 logMAR (20/189 Snellen equivalent) in the VMA (+) group, but improved from 0.82 logMAR (20/132 Snellen equivalent, baseline) to 0.72 logMAR (20/104, Snellen equivalent) in the VMA (-) group (P = 0.028). In paired comparisons of BCVA between baseline and each follow-up visit, the VMA (-) group showed significant improvement of BCVA at every follow-up visit (P < 0.05); however, the VMA (+) group did not show significant visual improvement at any follow-up visit despite anti-VEGF treatment (P > 0.05). Comparison of mean CRT between baseline and each follow-up visit showed a statistically significant decrease at every follow-up in both groups (P < 0.05).
CONCLUSIONS: Posterior VMA was associated with an inferior visual outcome after intravitreal anti-VEGF treatment for exudative AMD. Our results suggest that chronic tractional forces may antagonize the effect of anti-VEGF treatment, resulting in poor response to anti-VEGF treatment with patients with VMA. ||||| PURPOSE: The purpose of the present study is to compare the responses to ranibizumab between wet age-related macular degeneration patients, with and without accompanying vitreomacular traction syndrome.
METHODS: Our database of optical coherence tomography files was searched for eyes of age-related macular degeneration patients that had been treated with ranibizumab, and that had evidence of vitreomacular traction. A control group was selected from the same database for comparison. The case history of each selected individual was reviewed for data regarding the evolution of visual acuity in that patient, and the number of intravitreal injections that had been required to date.
RESULTS: From a database of 373 eyes, clear images of vitreomacular traction were obtained for a total of 18 eyes. The mean follow-up period was 20.6 months (SD=10.6, range=10.4-31.7). Patients in the vitreomacular traction group had been given an average of 5.1 injections versus an average of 4.2 injections in patients in the control group. The mean changes in visual acuity (which was measured using ETDRS charts) were -15 letters and -4 letters in the vitreomacular traction and control groups (P=.07), respectively.
CONCLUSIONS: After ranibizumab treatment, age-related macular degeneration patients with accompanying vitreomacular traction showed a tendency to have a poorer prognosis in terms of visual acuity than patients without this finding. In addition, higher numbers of intravitreal injections were required to obtain clinical responses in patients with vitreomacular traction. ||||| PURPOSE: To investigate the influence of the vitreomacular interface (VMI) on the functional and anatomic efficacy of ranibizumab therapy in patients with neovascular age-related macular degeneration (AMD).
DESIGN: Subanalysis of a prospective, 12-month, multicenter, phase IIIb trial.
PARTICIPANTS: A total of 353 treatment-naïve patients with subfoveal choroidal neovascularization (CNV) receiving quarterly or monthly ranibizumab therapy.
METHODS: On monthly optical coherence tomography (OCT) scan sets, the VMI configuration was graded by a certified reading center into one of the following conditions: continuous posterior vitreoretinal attachment (PVA), vitreomacular adhesion (VMA), partial vitreous detachment without vitreomacular contact, or complete posterior vitreous detachment (PVD). Best-corrected visual acuity (BCVA) and central retinal thickness (CRT) measurements were performed at monthly intervals. Analysis included patients with a minimum of 10 OCT examinations, including baseline and month 12 (n = 251). After integration of the VMI configuration over 12 months, patients were divided into one of the following categories: PVD (n = 162), release of vitreomacular contact (RELEASE; n = 48), VMA (n = 37), or PVA (n = 4). General estimation equation analyses were applied to test for noninferiority of quarterly versus monthly treatment.
MAIN OUTCOME MEASURES: The BCVA and CRT changes at month 12.
RESULTS: Mean BCVA changes in letters were +4.7 (PVD), +3.2 (RELEASE), and -0.2 (VMA) in the quarterly regimen and +4.9 (PVD), +12.7 (RELEASE), and +7.5 (VMA) in the monthly regimen. No difference in therapeutic efficiency between monthly and quarterly intervention was found in eyes with PVD, and quarterly treatment was noninferior to monthly treatment (P = 0.001). However, monthly treatment was superior to quarterly treatment in the RELEASE (P = 0.008) and VMA (P = 0.043) groups. Mean CRT changes were -98 and -96 μm (PVD), -117 and -136 μm (RELEASE), and -93 and -87 μm (VMA) in the monthly and quarterly regimens, respectively, without statistically significant differences.
CONCLUSIONS: The configuration of the VMI seems to have an important effect on visual outcomes and need for retreatment. In patients with PVD, a lower treatment frequency may be feasible, whereas patients with RELEASE or VMA may benefit from intensive retreatment. These findings may serve as a basis for individualized treatment decisions in anti-angiogenic therapy of neovascular AMD and perhaps other indications. ||||| PURPOSE: To evaluate the effect of vitreomacular traction (VMT) on visual acuity outcomes and central retinal thickness (CRT) measurements after intravitreal anti-vascular endothelial growth factor (anti-VEGF) therapy for treatment of exudative age-related macular degeneration (AMD).
METHODS: In this retrospective series, the authors evaluate the clinical records and optical coherence tomography of 34 eyes of 32 patients, with VMT confirmed on optical coherence tomography at baseline, to assess the effects of VMT on anti-VEGF therapy for newly diagnosed exudative wet AMD. Best-corrected visual acuity at baseline, 1, 3, 6, 9, and 12 months and CRT at baseline, 3, 6, and 12 months were assessed. Comparison was made with a control group of 29 eyes of 28 patients with wet AMD and no VMT on optical coherence tomography and with key variable-dosing studies for anti-VEGF in exudative AMD (CATT, HARBOR, PrONTO, SUSTAIN, and Gupta et al).
RESULTS: Best-corrected visual acuity results showed a visual acuity improvement that peaked at 3 months with 2.47 letters, well below other variable-dosing studies for anti-VEGF therapy in exudative AMD. This was then followed by a steady decline with mean best-corrected visual acuity at 12 months ending below the baseline level (-1.00 letters) compared with a gain of 9.39 letters in the control group at 12 months. Comparison of the mean CRT in the VMT group between baseline and 12 months showed no significant difference (P = 0.67), whereas the PrONTO study and control groups showed a highly significant difference at 12 months compared with baseline (P < 0.001). Mean CRT values at 6 months and 12 months were essentially at baseline levels (0.26 μm, -0.62 μm, respectively).
CONCLUSION: Vitreomacular traction at baseline, existing concurrently with newly diagnosed exudative AMD treated with intravitreal anti-VEGF therapy on a variable-dosing regime, was associated with poorer visual outcomes and a decreased response to reduction in CRT, compared with a control group of wet AMD without VMT and compared with major variable-dosing studies for intravitreal anti-VEGF in exudative AMD. ||||| OBJECTIVE: To assess the association of the vitreomacular interface with outcomes of eyes treated with anti-vascular endothelial growth factor drugs for neovascular age-related macular degeneration (AMD).
DESIGN: Prospective cohort study within a multicenter, randomized clinical trial.
PARTICIPANTS: Patients enrolled in the Comparison of AMD Treatments Trials (CATT).
METHODS: Treatment was assigned randomly as either ranibizumab or bevacizumab and as 3 different regimens for dosing over a 2-year period. Masked readers at a reading center assessed optical coherence tomography (OCT) scans at baseline and follow-up for vitreomacular traction (VMT) and vitreomacular adhesion (VMA), fluid, and central thickness. Visual acuity (VA) was measured by masked, certified examiners.
MAIN OUTCOME MEASURES: Anatomic features and VA at baseline and 1 and 2 years and number of treatments.
RESULTS: At baseline, 143 patient eyes (12.8%) had VMT or VMA. Compared with those with neither (n = 972), patients with VMT or VMA were younger (mean ± standard error, 75.5 ± 0.6 vs. 79.7 ± 0.24 years; P < 0.0001) and more likely to be male (52.4% vs. 36.2%; P = 0.0003), to be cigarette smokers (68.5% vs. 55.3%; P = 0.003), and to have subretinal fluid on OCT (86.7% vs. 81.0%; P = 0.047). Vitreomacular interface status was not associated with VA at baseline or follow-up. Among eyes treated as needed (n = 598) and followed up for 2 years (n = 516), the mean number of injections was 15.4 ± 0.9 for eyes having VMT at baseline or during follow-up (n = 60), 13.8 ± 0.7 for eyes with VMA at baseline or follow-up (n = 79), and 12.9 ± 0.4 (P = 0.02) for eyes without VMT or VMA (n = 377). In addition, the mean number of injections in eyes treated as needed increased from 13.0 ± 0.3 when VMT was not observed to 13.6 ± 1.3 when observed once and to 17 ± 1.2 when observed more than once during follow-up. At 2 years, geographic atrophy developed in a lower percentage of eyes with VMT or VMA at baseline (11.7%) than with neither condition (22.5%; P = 0.005).
CONCLUSIONS: In eyes in the CATT, VMT and VMA were infrequent. At baseline and follow-up, VMT or VMA were not associated with VA. Eyes with VMT or VMA treated as needed required on average 2 more injections over 2 years. ||||| PURPOSE: To determine the influence of vitreomacular adhesion (VMA) on treatment outcomes in patients with neovascular age-related macular degeneration who were treated with anti-vascular endothelial growth factor agents using a treat and extend treatment regimen.
METHODS: A retrospective consecutive case series of 204 eyes from 181 patients with a minimum of 1 year of follow-up at Wills Eye Hospital Retina Service. Vitreomacular interface characteristics were determined by spectral domain optical coherence tomography. One hundred and fifty-three eyes (75%) had no signs of VMA (non-VMA), and 51 (25%) had VMA.
RESULTS: Baseline mean visual acuity was 20/133 with a mean central retinal thickness of 350.5 μm in the non-VMA group and was 20/145 with 371.8 μm in the VMA group. Mean visual acuity in the non-VMA group was 20/83 and 20/64 at Years 1 and 2, respectively (P < 0.01 to baseline). Mean visual acuity in the VMA group was 20/81 and 20/85 at Years 1 and 2, respectively (P < 0.01 to baseline). The central retinal thickness was 289.71 μm and 267 μm at Years 1 and 2, respectively (P < 0.01 to baseline) in the non-VMA group and was 305.3 μm and 289.24 μm (P < 0.01 to baseline) in the VMA group. The mean total number of injections at Year 1 for non-VMA was 7.4 compared with 8.4 in VMA (P = 0.001) and 5.5 versus 6.7 for the 2 groups in Year 2 (P = 0.027). The mean longest extension at Year 1 was 11.8 weeks compared with 10.1 week (P = 0.005) and for Year 2 was 14.1 weeks compared with 12 weeks (P = 0.041).
CONCLUSION: The vitreomacular interface seems to have a significant influence on anti-vascular endothelial growth factor treatment intervals but not visual acuity or exudative control outcomes. Eyes with VMA on spectral domain optical coherence tomography at baseline may require more intensive treatment with decreased ability to extend treatment intervals. ||||| PURPOSE: The aim of this study was to determine the effect of posterior vitreous detachment on outcome of anti-vascular endothelial growth factor injection.
METHODS: Sixty-one eyes with age-related macular degeneration that had received intravitreal bevacizumab or ranibizumab injections were retrospectively reviewed. The vitreomacular interface was evaluated, and eyes were grouped according to the presence of posterior vitreous detachment (Group 1, n = 25) or vitreomacular adhesion (Group 2, n = 36). All patients received three loading doses of intravitreal anti-vascular endothelial growth factor injections at monthly intervals, and subsequently, pro re nata regimen was performed. Best-corrected visual acuity and central foveal thickness measurement at follow-up were evaluated. The development of posterior vitreous detachment during the follow-up was also reported.
RESULTS: The best-corrected visual acuity changes at each visit compared with baseline were significantly better in Group 1 (P = 0.01, 0.02, 0.02, 0.009, 0.009, respectively at third, sixth, ninth, 12th month, and last visit). When best-corrected visual acuity was classified according to the change in visual acuity of 10 letters or more, the rate of improved or stable best-corrected visual acuity was greater in Group 1 (P = 0.02). During the follow-up, 5 eyes (14.3%) developed posterior vitreous detachment.
CONCLUSION: Vitreomacular adhesion seems to have an adverse effect on the visual prognosis of anti-vascular endothelial growth factor treatment for age-related macular degeneration. | [
{
"source_pmid": "25096269",
"source_text": "PURPOSE: To investigate the effects of vitreomacular adhesion (VMA) on intravitreal ranibizumab treatment in Japanese patients with exudative age-related macular degeneration (AMD).\nMETHODS: This was a retrospective comparative study that included 123 eyes from ... |
27116511 | CONCLUSIONS: The results of this meta-analysis clearly indicate that intravitreal anti-VEGF injection therapy is capable of maintaining visual acuity on a long-term basis of at least 4-5 years. | PURPOSE: To analyse a 3-year clinical patient cohort of ranibizumab treatment of exudative age-related macular degeneration (AMD), to investigate the impact on visual outcome of carrying forward the last acuity observation in drop-outs and to explore possible differences between the early and the late phase of the study.
METHODS: A retrospective study of 312 eyes with neovascular AMD. The patients were followed up monthly, received three initial monthly injections of 0.5 mg ranibizumab and were re-treated pro re nata (PRN). Time-domain optical coherence tomography (TD-OCT) was used until spectral-domain (SD)-OCT was introduced during the last year of enrolment. Sixty-five patients were discontinued from the study.
PRIMARY OUTCOME: change in best corrected visual acuity (BCVA).
RESULTS: Best corrected visual acuity was 58.4 (CI 56.9-59.9) ETDRS (Early Treatment Diabetic Retinopathy Study) letters. At three months, it had increased by 4.1 letters (p=0.0004), at 12 months by 1.8 letters, at 24 months by 1.0 letter and at 36 months by 0.1 letter. However, if the last available acuity of drop-outs was carried forward one step and included, acuity had increased by 3.9 letters at 3 months (p<0.0001) and by 1.0 letter at 12 months but had decreased by 3.8 letters at 24 months (p=0.019) and by 4.1 letters (p=0.003) at 36 months. At 24 months, the result was significantly (p=0.030) less favourable when drop-outs were included. In patients enrolled during the late phase, BCVA was 59.3 (CI 56.7-62.0). It had increased by 5.7 letters (p<0.0001) at three months and by 5.8 letters at 12 months (p=0.0016). In patients enrolled during the early phase, BCVA was 57.9 (CI 55.0-60.8). At three months, it had increased by 3.5 letters (p=0.0008), but at 12 months, it had decreased by 2.3 letters (ns). The result at 12 months was significantly (p=0.0033) better for the late than for the early phase. The number of injections was also significantly (p=0.011) higher in the late phase. Adverse events were similar to those in earlier clinical trials.
CONCLUSIONS: The results of this 3-year cohort showed that the initial average acuity could be maintained over 36 months, which was comparable to those of many other clinical cohorts. However, if the last available acuity of drop-outs was carried forward one step and included, the acuity figures would have fallen significantly. The results in patients enrolled during the late phase of the study were fairly similar to those in clinical trials. ||||| PURPOSE: To evaluate 3-year follow-up treatment outcomes with ranibizumab (Lucentis(®)) 0.5 mg administered either monthly or quarterly on a pro re nata (PRN) basis according to a disease activity-guided monitoring and treatment algorithm.
METHODS: A total of 316 treatment-naive eyes of 316 patients with exudative age-related macular degeneration met the criteria for inclusion in this retrospective, interventional case series. Patients were treated with ranibizumab 0.5 mg according to a disease activity-guided algorithm with monthly monitoring. Optical coherence tomography and fluorescein angiography were routinely used to assess disease activity: active lesions were treated with a series of three monthly injections, whereas inactive lesions were treated with quarterly injections.
RESULTS: Mean Early Treatment Diabetic Retinopathy Study best-corrected visual acuity improved from 52 letters at baseline to 59 letters at 12 months, achieved with a mean of 7.1 injections, 61 letters at 24 months with a mean of 5.0 injections administered in the second year and 60 letters at 36 months with a mean number of 5.2 injections.
CONCLUSIONS: Monthly visits and a morphology-driven PRN regimen with 3 injections in case of recurrence plus quarterly injections in case of inactive CNV resulted in an average VA gain of 7-9 letters that could be maintained over 3 years. ||||| BACKGROUND: Randomized controlled phase III studies have shown that intravitreal anti-VEGF therapy is effective for exsudative age-related macular degeneration (AMD) over two years. Recently, the seven-year outcomes in ranibizumab-treated patients of the ranibizumab phase III studies have been published. Only a few other studies with such a long follow-up for intravitreal anti-VEGF therapy in patients with exsudative AMD have been published so far. We report on the outcome of patients receiving intravitreal anti-VEGF therapy for exudative AMD at the Department of Ophthalmology, University Hospital of Zurich with follow-up of 3 to 7 years.
PATIENTS: Retrospective chart review of all patients treated at our institution for exudative AMD with begin of treatment since 2006.
RESULTS: The numbers of patients with a follow-up of 3 to 4, 4 to 5, 5 to 6, 6 to 7, and more than 7 years were 430, 277, 151, 87, and 47, respectively. Mean follow-up time was 4.9 years, and median was 4.6 years. Changes in visual acuity for these patients were -5.0, -7.8, -11.7, -12.8, and -19.2 ETDRS letters, respectively.
CONCLUSIONS: Whereas in patients with exudative AMD during the first two years of intravitreal anti-VEGF treatment visual acuity can at least be stabilised, after three and more years visual acuity decreases in spite of continued treatment. ||||| OBJECTIVE: To investigate the visual outcome, pattern of discontinuation, ocular complications, and mortality of patients treated with a variable ranibizumab dosing regimen for neovascular age-related macular degeneration (AMD) for 4 years.
DESIGN: Retrospective chart review supplemented with clinical examination.
PARTICIPANTS: Six hundred eyes of 555 patients initiated intravitreal treatment with vascular endothelial growth factor inhibition for neovascular AMD in 2007 in a community-based hospital.
METHODS: Patient data from a database were retrieved from 2007 through 2011. Descriptive evaluation of the main outcome measures was carried out for the cohort of patients. A group of patients who had been discontinued because of apparent disease inactivity was reexamined.
MAIN OUTCOME MEASURES: Best-corrected visual acuity (BCVA; Snellen), number of intravitreal injections, causes of discontinuations, ocular complications, and standardized mortality rate.
RESULTS: One hundred ninety-two eyes (32%) were still receiving active treatment after 4 years. The mean BCVA in the 192 eyes was unchanged from the start (baseline, 0.30; 4-year follow-up, 0.32; P>0.3). Visual acuity after the third loading dose was associated significantly with the outcome (P<0.0001) and was a better predictor than baseline acuity. The mean number of injections was 5.5 per year. For 408 eyes (68%), discontinuation of treatment was motivated by the following 4 reasons: lack of apparent treatment response (28%), failure to appear at follow-up (11%), death (9%), and disease inactivity (20%, 120 eyes). Treatment was resumed later in 18% of patients discontinued because of inactivity. Sixty-seven eyes were reexamined in 2012 from the group of patients with disease inactivity. The final visual acuity by then had decreased significantly from the time of discontinuation, from 0.38 to 0.15 (P = 0.001). Endophthalmitis occurred in 2 eyes of 7584 injections. A total of 125 patients had died, corresponding to 75% of the mean mortality in the community.
CONCLUSIONS: One third of the eyes were still receiving active treatment after 4 years and had stable visual acuity. One third of fellow eyes (eyes at risk) started treatment during the 4 years. One fifth of discontinued eyes resumed treatment, indicating that close follow-up should be maintained for patients discontinued because of disease inactivity. The ocular complication rate was 0.2%, and the mortality rate was below expected. ||||| AIMS: To evaluate patient visual acuity outcomes and blindness rates attributable to wet AMD with a potential 5-year follow-up from intravitreal ranibizumab treatment (IVTR) in south-east Scotland.
METHODS: Data was analysed from 104 eyes of 96 patients who initiated treatment prior to September 2008. The main outcome measures were LogMAR visual acuity, number of clinic visits and the number of injections. Annual blind registration data in south-east Scotland were analysed using blind certifications recorded by the Royal National Institute of Blind People.
RESULTS: Patients had a mean clinical follow-up of 4 years and 1 month and a mean loss of 5.5 letters over the study period. Of the treated eyes 9.6% gained ≥ 15 letters whilst 24.0% lost ≥ 15 letters during this period. An average of 9.56 injections were administered per patient. The age-sex standardised incidence of legal blindness attributable to wet AMD in south-east Scotland peaked at 9.1 cases per 100,000 of the population in 2006 in either eye. Following the introduction of IVTR there were annual decreases in the incidence of blindness attributable to AMD falling to a trough of 4.8 cases per 100,000 of the population in 2011.
CONCLUSIONS: This study demonstrates that the majority of patients in a south-east Scotland maintain their vision following IVTR in wet AMD in the real-world setting. Our study also suggests that the introduction of IVTR has had population wide benefits in reducing the blindness attributable to wet AMD in the south-east Scotland population. ||||| PURPOSE: To assess long-term outcomes 7 to 8 years after initiation of intensive ranibizumab therapy in exudative age-related macular degeneration (AMD) patients.
DESIGN: Multicenter, noninterventional cohort study.
PARTICIPANTS: Sixty-five AMD patients originally treated with ranibizumab in the phase 3 Anti-VEGF Antibody for the Treatment of Predominantly Classic Choroidal Neovascularization in AMD (ANCHOR) trial, Minimally Classic/Occult Trial of the Anti-VEGF Antibody Ranibizumab in the Treatment of Neovascular AMD (MARINA) trial, and Open-Label Extension Trial of Ranibizumab for Choroidal Neovascularization Secondary to Age-Related Macular Degeneration (HORIZON).
METHODS: Fourteen clinical trial sites recruited their original subjects for a return evaluation. Individual subject comparisons were obtained from the ANCHOR, MARINA, and HORIZON databases.
MAIN OUTCOME MEASURES: The primary end point was percentage with best-corrected visual acuity (BCVA) of 20/70 or better; secondary outcomes included mean change in letter score compared with previous time points and anatomic results on fluorescein angiography, spectral-domain ocular coherence tomography (OCT), and fundus autofluorescence (FAF).
RESULTS: At a mean of 7.3 years (range, 6.3-8.5 years) after entry into ANCHOR or MARINA, 37% of study eyes met the primary end point of 20/70 or better BCVA, with 23% achieving a BCVA of 20/40 or better. Thirty-seven percent of study eyes had BCVA of 20/200 or worse. Forty-three percent of study eyes had a stable or improved letter score (≥0-letter gain) compared with ANCHOR or MARINA baseline measurements, whereas 34% declined by 15 letters or more, with overall a mean decline of 8.6 letters (P<0.005). Since exit from the HORIZON study, study eyes had received a mean of 6.8 anti-vascular endothelial growth factor (VEGF) injections during the mean 3.4-year interval; a subgroup of patients who received 11 or more anti-VEGF injections had a significantly better mean gain in letter score since HORIZON exit (P<0.05). Active exudative disease was detected by spectral-domain OCT in 68% of study eyes, and 46% were receiving ongoing ocular anti-VEGF treatments. Macular atrophy was detected by FAF in 98% of eyes, with a mean area of 9.4 mm(2); the area of atrophy correlated significantly with poor visual outcome (P<0.0001).
CONCLUSIONS: Approximately 7 years after ranibizumab therapy in the ANCHOR or MARINA trials, one third of patients demonstrated good visual outcomes, whereas another third had poor outcomes. Compared with baseline, almost half of eyes were stable, whereas one third declined by 15 letters or more. Even at this late stage in the therapeutic course, exudative AMD patients remain at risk for substantial visual decline. ||||| BACKGROUND: To evaluate the long-term outcome of bevacizumab therapy for neovascular age related macular degeneration (NVAMD) in the setting of a clinic.
METHODS: Consecutive group of NVAMD patients who were treated in a single 3(rd) referral center with bevacizumab using a loading dosage of 3 monthly injections followed by variable dosing for at least 48 months were retrospectively evaluated. Genotyping was performed for CFH (rs1061170), HTRA1 (rs1200638), and C3 (rs2230199). Main outcome measures included functional and morphological treatment outcomes as well as their risk allele associations.
RESULTS: Out of 128 patients who started bevacizumab treatment over 4 years before the study endpoint [mean (± SD): 60 ± 10.9 months], 75 eyes of 67 (52.3%) patients, were still followed. Mean best corrected visual acuity (BCVA) (LogMAR ± SEM) improved from 0.66 ± 0.07 at baseline to 0.48 ± 0.05 (p = 0.012) at 1 year, but deteriorated from the 3(rd) year on and at the final exam reduced to 0.69 ± 0.07 (p = 0.6, compared with initial BCVA). Macular thickness mirrored visual acuity (VA) changes showing initial thinning followed by thickening from the 3(rd) year on. Individuals carrying the CFH risk -allele had a mean thickening (microns ± SEM) of 66.9 ± 70.4 versus a mean thinning of 76.8 ± 22 in non-carriers (p = 0.015).
CONCLUSIONS: Bevacizumab therapy for NVAMD using a flexible treatment algorithm in a "real life" clinical setting initially obtained VA gain and thinning of the macula that were maintained for two years, but were lost later on. ||||| AIMS: To study long-term, whole population 'real-world' clinical outcomes of ranibizumab therapy in treatment-naïve eyes for neovascular age-related macular degeneration.
METHODS: Data collected prospectively from a single centre serving a defined population using an electronic medical record included: demographics, Early Treatment Diabetic Retinopathy Study visual acuity (ETDRS VA) at all visits, injection dates, central 1 mm retinal thickness, and operative and postoperative complications.
RESULTS: 1483 eyes from 1278 patients were included in this study. The median age at the time of the patient's first injection was 82.5 years, 64.9% of patients were female, and another ocular pathology was present in 7.3% eyes. The baseline VA was 23-39, 40-54, 55-70 and >70 ETDRS letters for 17.3%, 23.1%, 42.7% and 16.9% of eyes, respectively. The median VA in all baseline VA groups improved after the loading phase but declined back to the baseline level by 2-5 years. The rate of endophthalmitis following intravitreal injection was 1 in 2124 injections.
CONCLUSIONS: These long-term real-world data demonstrate that in general VA increases during the loading phase but returns to near baseline levels after 2-5 years of treatment for each baseline VA category. Patients should be identified and treated as early as possible, since presenting VA predicts the VA maintained after 5 years of treatment. National Institute of Health and Care Excellence guidance advising treatment only for eyes with vision below 70 letters does not promote best long-term VA outcomes for patients. ||||| PURPOSE: To analyze the long-term outcomes of eyes with neovascular age-related macular degeneration (AMD) starting treatment with vascular endothelial growth factor (VEGF) inhibitors at least 5 years earlier.
DESIGN: Database observational study.
PARTICIPANTS: Treatment-naïve eyes with neovascular AMD tracked by the Fight Retinal Blindness outcome registry that received at least 1 anti-VEGF injection.
METHODS: Locally weighted scatterplot smoothing curves were used to display visual acuity (VA) results.
MAIN OUTCOME MEASURES: Change in mean VA and number of injections and visits from baseline up to 7 years after initiating treatment.
RESULTS: The mean follow-up time of all 1212 identified eyes was 53.5 months, and 549 (45%) continued attending after 60 months. Mean VA improved from 55.1 to 61.4 letters after 6 months and remained above the mean presenting VA for approximately 6 years. After 7 years, mean VA was 2.6 letters lower than baseline for the 131 eyes still being followed; 40% had VA ≥70 (20/40) letters, and 18% had VA ≤35 letters (20/200). Of those with 20/40 VA before treatment, 40% had lost it after 7 years. Geographic atrophy affecting the fovea was thought to be the cause of a ≥10-letter loss after 6.5 years in 37% of a subset of such eyes that were retrospectively analyzed. A median of 6 injections and 9 visits were recorded over the first 12 months, and then 5 treatments and 7 to 9 visits per annum thereafter through 7 years. Treatment was discontinued for 663 eyes (53%) within the first 5 years. Despite initial gains in vision, the mean VA of these eyes had deteriorated to baseline or worse around the time treatment was discontinued. The rate of serious adverse events was low.
CONCLUSIONS: Good long-term outcomes of VEGF inhibition for neovascular AMD were found in this study. These results may be better than other reports because more injections were given to our patients, possibly associated with a greater incentive for the physician to treat. Further studies to determine how to maximize the proportion of eyes that retain the initial VA gains of anti-VEGF are warranted. ||||| OBJECTIVE: To evaluate long-term safety of intravitreal ranibizumab 0.5-mg injections in neovascular age-related macular degeneration (nAMD).
DESIGN: Twenty-four-month, open-label, multicenter, phase IV extension study.
PARTICIPANTS: Two hundred thirty-four patients previously treated with ranibizumab for 12 months in the EXCITE/SUSTAIN study.
METHODS: Ranibizumab 0.5 mg administered at the investigator's discretion as per the European summary of product characteristics 2007 (SmPC, i.e., ranibizumab was administered if a patient experienced a best-corrected visual acuity [BCVA] loss of >5 Early Treatment Diabetic Retinopathy Study letters measured against the highest visual acuity [VA] value obtained in SECURE or previous studies [EXCITE and SUSTAIN], attributable to the presence or progression of active nAMD in the investigator's opinion).
MAIN OUTCOME MEASURES: Incidence of ocular or nonocular adverse events (AEs) and serious AEs, mean change in BCVA from baseline over time, and the number of injections.
RESULTS: Of 234 enrolled patients, 210 (89.7%) completed the study. Patients received 6.1 (mean) ranibizumab injections over 24 months. Approximately 42% of patients had 7 or more visits at which ranibizumab was not administered, although they had experienced a VA loss of more than 5 letters, indicating either an undertreatment or that factors other than VA loss were considered for retreatment decision by the investigator. The most frequent ocular AEs (study eye) were retinal hemorrhage (12.8%; 1 event related to study drug), cataract (11.5%; 1 event related to treatment procedure), and increased intraocular pressure (6.4%; 1 event related to study drug). Cataract reported as serious due to hospitalization for cataract surgery occurred in 2.6% of patients; none was suspected to be related to study drug or procedure. Main nonocular AEs were hypertension and nasopharyngitis (9.0% each). Arterial thromboembolic events were reported in 5.6% of the patients. Five (2.1%) deaths occurred during the study, none related to the study drug or procedure. At month 24, mean BCVA declined by 4.3 letters from the SECURE baseline.
CONCLUSIONS: The SECURE study showed that ranibizumab administered as per a VA-guided flexible dosing regimen recommended in the European ranibizumab SmPC at the investigator's discretion was well tolerated over 2 years. No new safety signals were identified in patients who received ranibizumab for a total of 3 years. On average, patients lost BCVA from the SECURE study baseline, which may be the result of disease progression or possible undertreatment.
FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references. ||||| With the advent of anti-vascular endothelial growth factor (VEGF) therapy, clinicians are now focused on various treatment strategies to better control neovascular age-related macular degeneration (NVAMD), a leading cause of irreversible blindness. Herein, we retrospectively reviewed consecutive patients with treatment-naïve NVAMD initially classified based on fluorescein angiography (FA) alone or with an anatomic classification utilizing both FA and optical coherence tomography (OCT) and correlated long-term visual outcomes of these patients treated with an anti-VEGF Treat-and-Extend Regimen (TER) with baseline characteristics including neovascular phenotype. Overall, 185 patients (210 eyes) were followed over an average of 3.5 years (range 1-6.6) with a retention rate of 62.9%, and visual acuity significantly improved with a TER that required a mean number of 8.3 (±1.6) (± standard deviation) intravitreal anti-VEGF injections/year (range 4-13). The number of injections and the anatomic classification were independent predictors of visual acuity at 6 months, 1, 2, 3 and 4 years. Patients with Type 1 neovascularization had better visual outcomes and received more injections than the other neovascular subtypes. There were no serious adverse events. A TER provided sustained long-term visual gains. Eyes with Type 1 neovascularization had better visual outcomes than those with other neovascular subtypes. ||||| Advanced functional hybrids based on carbon materials (CMs) represent one of the main achievements of scientific communities. To achieve the hybridization, pristine CMs have to be chemically modified, or surfactants, which are nonfunctional for the performances of the hybrids, have to be employed as a cross-linkage. The construction of pristine CM-based hybrids using dual-functional coupling reagents, which work not only as a glue for hybridization but also as a functional component for enhanced performance, is strongly desired. Here, we report that pristine graphdiyne (GD), a recently synthesized new carbon allotrope, can be facilely hybridized with Ag/AgBr using graphene oxide (GO) as a cross-linkage. We demonstrate that compared to Ag/AgBr, Ag/AgBr/GO, and Ag/AgBr/GD, our Ag/AgBr/GO/GD exhibits an enhanced photocatalytic performance toward the degradation of methyl orange (MO) pollutant under visible light irradiation. In our Ag/AgBr/GO/GD, GO serves not only as a glue for a successful hybridization, but also as a functional component for enhanced catalytic performance. Beyond GD, our work likely paves a new avenue for the fabrication of advanced functional hybrids based on pristine carbon allotropes, wherein desired functions or properties might be achieved by choosing desired CMs and desired hybridized components. ||||| AIM: To analyse the benefit of intravitreal ranibizumab over 4 years for patients with neovascular age-related macular degeneration (AMD).
METHODS: A retrospective case note review of all patients who started treatment between August 2007 and September 2009 in our unit, minimum follow-up 2 years, maximum 4 years. The main outcome measures were: numbers of patients with different levels of vision, changes in visual acuity, number of treatments and numbers remaining under follow-up.
RESULTS: 1086 eyes of 1017 patients received treatment. Numbers of patients remaining under follow-up were 892/1017 (87.71%) at 12 months, 730/1017 (71.78%) at 24 months, 468/730 (64.11%) at 36 months and 110/217 (50.69%) at 48 months. The main reasons for patients no longer being under follow-up were the consequences of old age or transfer of care. 50% of patients had 6/18 or better over 4 years. Patients received on average 5.79 ± 2.53, 9.15 ± 3.79, 11.22 ± 4.92 and 13.7 ± 7.84 injections by 12, 24, 36 and 48 months, respectively.
CONCLUSIONS: We suggest that the numbers of patients with a particular level of vision may best reflect the actual benefit of AMD treatment provided by a service. Long-term follow-up is required as only 72/730 (10%) had been discharged at 36 months, half of whom had good vision of greater than 60 letters. 83% and 65% of patients needed treatment in the third and fourth year. Follow-up may be for the rest of the patients' life or at some point they may no longer be well enough to attend. | [
{
"source_pmid": "23452436",
"source_text": "PURPOSE: To analyse a 3-year clinical patient cohort of ranibizumab treatment of exudative age-related macular degeneration (AMD), to investigate the impact on visual outcome of carrying forward the last acuity observation in drop-outs and to explore possible dif... |
27905339 | In summary, these results indicate that p53 codon 72 polymorphism is likely an important genetic factor contributing to susceptibility of POAG. However, more case-controls studies based on larger sample size and stratified by ethnicity are suggested to further clarify the relationship between p53 codon 72 polymorphism and POAG. | PURPOSE: Glaucoma is a complex neurodegenerative disorder of the eye. Primary Open Angle Glaucoma (POAG) is the most common type, accounting for over half of the total cases. Recently, a significant difference in the distribution of the codon 72 polymorphism of the tumor suppressor gene p53 between control subjects and POAG patients of Chinese origin (p=0.00782) was demonstrated. The proline residue at codon 72 of the p53 gene was significantly over represented in the POAG patients relative to healthy controls. The purpose of this study was to investigate whether the reported association between the p53 polymorphism and POAG is a common phenomenon irrespective of geographical location or ethnicity of the population.
METHODS: Sixty seven unrelated POAG patients, ranging from 10-65 years of age (mean+/-SD of 41.16+/-18.52 years), and 112 control subjects having a similar age range of 18-63 years (mean+/-SD of 36.64+/-14.65 years) were enrolled in this study. A region of the p53 gene encompassing two polymorphic sites, a 16 bp duplication in intron 3 and a BstU I RFLP in exon 4, were amplified by polymerase chain reaction from Indian POAG patients and normal healthy controls. A single base change (G to C) in codon 72 alters the amino acid residue from arginine to proline and removes the polymorphic BstU I site mentioned above. The amplified DNA fragments were digested with the restriction enzyme and the digestion patterns of the fragments were used to identify the alleles for both the polymorphic sites.
RESULTS: No significant association between p53 alleles and Indian POAG patients were observed by analyzing either codon 72 polymorphism (p=0.5627) or the intronic 16 bp duplication polymorphism (p=0.059). Haplotype analysis, reported to be a better predictor of association of the p53 gene with different types of cancer, was also performed and no association of any haplotype was detected with POAG (p=0.1831).
CONCLUSIONS: Association between the p53 gene encoding for proline at codon 72 and POAG presumably exists in some ethnic populations but cannot be used as a predictor for the role of the gene as a common regulator of cell death of retinal ganglions leading to POAG. ||||| PURPOSE: To investigate the association between Apolipoprotein E (APOE), tumor suppressor protein p53 (p53), and cyclin-dependent kinase inhibitor 1A (p21) genes and primary open-angle glaucoma (POAG) in a cohort of Turkish subjects.
METHODS: Seventy-five POAG patients (49 women, 26 men) and 119 healthy subjects (67 women, 52 men) were genotyped with polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Allele and genotype frequencies between healthy subjects and glaucoma patients were compared by the chi(2) test, and intraocular pressure (IOP), cup/disc ratio (C/D) and visual field indices (MD and PSD) were compared among different APOE, p53, and p21 genotypes in POAG group. A p value <0.05 was considered as statistically significant.
RESULTS: The mean ages were 63.8+/-9.5 and 61.8+/-10.2 years in POAG and control groups, respectively (p=0.18). There were no significant differences in the distribution of APOE, p53, and p21 genotypes between the healthy subjects and POAG patients (p=0.38, p=0.12, and p=0.2, respectively). There were no significant differences in maximum IOP, MD, and PSD values among different groups of p53 and p21 genotypes (p>0.05). POAG subjects with the epsilon2epsilon3 genotype had a worse PSD value (median=2.2) than those with the epsilon3epsilon4 genotype (median=1.77; p=0.01) and POAG subjects with the epsilon3epsilon3 genotype had worse MD and PSD values (median= -7.4 and 3.4, respectively) than those with the epsilon3epsilon4 genotype (median= -4.1 and 1.77, respectively; p=0.034 and 0.028, respectively).
CONCLUSIONS: Our study found no link between polymorphisms in APOE, p53, and p21 genes and POAG in Turkish patients, although a larger sample is required to elucidate the role of these polymorphisms in the pathogenesis and course of glaucoma. ||||| PURPOSE: To evaluate the variants of 10 genes for association with primary open-angle glaucoma (POAG) in a Chinese population.
METHODS: A total of 405 unrelated patients with POAG (255 high-tension glaucoma [HTG], 100 normal-tension glaucoma [NTG], and 50 juvenile-onset open-angle glaucoma [JOAG]) and 201 control subjects were recruited. Seventeen variants in 10 genes with reported association with POAG were genotyped for analysis of allele and haplotype frequencies between cases and control subjects. These genes included CDH1 (cadherin 1, type 1, E-cadherin), CDKN1A (cyclin-dependent kinase inhibitor 1A), CYP1B1 (cytochrome P450, family 1, subfamily B, polypeptide 1), GSTM1 (glutathione S-transferase mu 1), GSTT1 (glutathione S-transferase theta 1), MTHFR (5,10-methylenetetrahydrofolate reductase), NOS3 (nitric oxide synthase 3), OPA1 (optic atrophy 1), TNF (tumor necrosis factor), and TP53 (tumor protein p53).
RESULTS: One SNP (-308G>A; rs1800629) in TNF demonstrated a significant association with HTG (P = 0.012). The allele G frequency was higher in HTG patients than in control subjects (94.6% vs. 90.3%; OR = 1.89). One haplotype consisting of rs1799724 and rs1800629 was significantly associated with HTG (P = 0.015, corrected P = 0.045). One SNP (R72P; rs1042522) in TP53 was significantly associated with NTG (P = 0.018). The allele G frequency was higher in NTG patients than in control subjects (56.1% vs. 45.8%; OR = 1.52). The significance of these associations survived the Bonferroni correction (corrected P < 0.024). Other gene variants were not significantly associated with HTG (P > 0.063) or NTG (P > 0.13). None of the studied variants was significantly associated with JOAG (P > 0.17).
CONCLUSIONS: The findings suggest that variants in TNF and TP53 are risk factors for POAG, whereas variants in other studied genes are not major risk factors for POAG, at least in the Chinese population. ||||| PURPOSE: Apoptosis has been implicated as the mechanism for retinal ganglion cell death in primary open-angle glaucoma (POAG), a complex neurodegenerative disease. There have been inconsistent reports regarding increased risk of POAG and a polymorphism (Arg72Pro) within the tumor suppressor gene, p53. The goal of this study was to examine the role of this polymorphism in susceptibility to POAG in a Caucasian population from the United States.
METHODS: We generated genotypes in 191 unrelated Caucasian POAG patients and 167 unrelated Caucasian controls for the following polymorphisms within p53: rs1042522 (Arg72Pro), rs17878362 (16 bp Ins/Del), and rs1800371 (Pro47Ser) by PCR amplification followed by restriction digestion and sequence analysis.
RESULTS: There was a significant difference in genotypic frequencies for rs1042522 (Arg72Pro) between POAG patients and controls (chi(2)= 9.56, p=0.008). Individuals who were homozygous for the arginine allele have a 1.9 fold significantly increased risk of developing glaucoma (95%CI: 1.16-2.82, p=0.01). Interestingly, we found that the frequency of the arginine allele was even higher in the normal-tension glaucoma (NTG) subtype compared to high-tension POAG (0.81 versus 0.76).
CONCLUSIONS: Our preliminary results indicate that the arginine variant of rs1042522 within p53 is associated with increased risk of POAG. This variant has increased apoptotic potential, thus the retinal ganglion cells in carriers of the arginine allele may have greater susceptibility to apoptosis. ||||| PURPOSE: To assess whether tumor protein p53 gene (p53) polymorphisms are associated with primary open angle glaucoma (POAG) in the Japanese population.
METHODS: Four hundred and twenty-five Japanese patients with POAG, including normal tension glaucoma (NTG, n=213) and high tension glaucoma (HTG, n=212) and 189 control subjects without glaucoma were analyzed for two p53 polymorphisms (rs1042522; a G-->C substitution at codon 72 in exon 4 and rs59758982; a 16 base pair insertion in intron 3) using allele specific primer PCR and a pyrosequencing technique respectively. The genotypic and allelic frequencies were compared between NTG or HTG patients and control subjects.
RESULTS: No significant difference (NTG versus control, p=0.99, and HTG versus control, p=0.69, chi(2) test) was observed regarding the p53 genotype frequencies at codon 72 between the NTG (GG: 43.2%, GC: 44.6%, CC: 12.2%) or HTG (GG: 40.1%, GC: 48.1%, CC: 11.8%) patients and the control subjects (GG: 43.9%, GC: 43.9%, CC: 12.2%). In addition, there was no significant difference (NTG versus control, p=0.94; and HTG versus control, p=0.66, Fisher's exact test) in the p53 allele frequencies at codon 72 between the NTG (G allele: 65.5%, C allele: 34.5%) or HTG (G allele: 64.2%, C allele: 35.8%) patients and the control subjects (G allele: 65.9%, C allele: 34.1%). No 16 base pair insertion in intron 3 was found in this study.
CONCLUSION: p53 polymorphisms were not associated with POAG in the Japanese population. Further studies in the other ethnic populations should therefore be performed to elucidate whether the p53 intron 3 insertion polymorphism is a genetic risk factor for POAG, because the intron 3 insertion polymorphism occurs very rarely in the Japanese population. ||||| PURPOSE: To investigate the role of WDR36 and P53 sequence variations in POAG susceptibility.
METHODS: The authors performed a case-control genetic association study in 268 unrelated Spanish patients (POAG1) and 380 control subjects matched for sex, age, and ethnicity. WDR36 sequence variations were screened by either direct DNA sequencing or denaturing high-performance liquid chromatography. P53 polymorphisms p.R72P and c.97-147ins16bp were analyzed by single-nucleotide polymorphism (SNP) genotyping and PCR, respectively. Positive SNP and haplotype associations were reanalyzed in a second sample of 211 patients and in combined cases (n = 479).
RESULTS: The authors identified almost 50 WDR36 sequence variations, of which approximately two-thirds were rare and one-third were polymorphisms. Approximately half the variants were novel. Eight patients (2.9%) carried rare mutations that were not identified in the control group (P = 0.001). Six Tag SNPs were expected to be structured in three common haplotypes. Haplotype H2 was consistently associated with the disease (P = 0.0024 in combined cases). According to a dominant model, genotypes containing allele P of the P53 p.R72P SNP slightly increased glaucoma risk. Glaucoma susceptibility associated with different WDR36 genotypes also increased significantly in combination with the P53 RP risk genotype, indicating the existence of a genetic interaction. For instance, the OR of the H2 diplotype estimated for POAG1 and combined cases rose approximately 1.6 times in the two-locus genotype H2/RP.
CONCLUSIONS: Rare WDR36 variants and the P53 p.R72P polymorphism behaved as moderate glaucoma risk factors in Spanish patients. The authors provide evidence for a genetic interaction between WDR36 and P53 variants in POAG susceptibility, although this finding must be confirmed in other populations. ||||| Primary open angle glaucoma (POAG) is the most common type of glaucoma. The p53 codon 72 Arg-Pro (CGC to CCC) polymorphism of exon 4 affects various biological properties; recently, it was reported that this polymorphism affects the ability to induce apoptosis in vitro. Various genotypes have been found to be significantly associated with POAG. We examined the distribution of this polymorphism in 104 unrelated POAG patients and in 58 normal healthy individuals without history of POAG at the Pronto Clínica de Olhos in Goiânia, Brazil. The controls were recruited among individuals undergoing ophthalmological examination. Their genomic DNA was analyzed for p53 gene codon 72 polymorphism by polymerase chain reaction. The Arg72 allele was more common than the Pro72 allele in both groups. There was no significant difference in the distribution of the codon 72 polymorphism between groups (p= 0.3311). The genotype distribution in the POAG group was 23.07 Arg homozygote, 75 heterozygote, and 1.93% Pro homozygote, while in the control group it was 31.04 Arg homozygote, 68.96 heterozygote, and 0% Pro homozygote. We concluded that the p53 codon 72 Arg/Pro polymorphism is not associated with glaucoma in Brazilian patients. ||||| BACKGROUND: Glaucomatous neuropathy is a type of cell death due to apoptosis. The p53 gene is one of the regulatory genes of apoptosis. Recently, the association between the p53 gene encoding for proline at codon 72 and primary open-angle glaucoma (POAG) has been studied in some ethnic groups. This study is the first association analysis of POAG and p53 codon 72 polymorphism in Iranian patients.
METHODS: A cohort of 65 unrelated patients with POAG (age range from 12-62 years, mean ± SD of 40.16 ± 17.51 years) and 65 unrelated control subjects (without glaucoma, age range of 14-63 years, mean ± SD of 35.64 ± 13.61 years) were selected. In Iranian POAG patients and normal healthy controls, the p53 codon 72 polymorphism in exon 4 was amplified using polymerase chain reaction. The amplified DNA fragments were digested with the BstUI restriction enzyme, and the digestion patterns were used to identify the alleles for the polymorphic site.
RESULTS: Comparisons revealed significant differences in allele and genotype frequencies of Pro72Arg between POAG patients and control group. A higher risk of POAG was associated with allele Pro (OR = 2.1, 95% CI = 1.2-3.4) and genotype Pro/Pro (OR = 3.9, 95% CI = 0.13-12.7).
CONCLUSION: The p53 Pro72 allele was more frequent in Iranian POAG patients than in the control group (P<0.05). The present findings show that the individuals with the Pro/Pro genotype may be more likely to develop POAG. However, additional studies are necessary to confirm this association. ||||| BACKGROUND: Glaucomatous neuropathy is a type of cell death by apoptosis. The p53 gene is one of the regulatory genes of apoptosis. Recently, p53 codon 72 polymorphism has been extensively studied to determine the risk factors responsible for many diseases. In the p53 gene, a single base change from G to C causes the alternation of amino acid residue 72 from arginine to proline. In this study the association between p53 codon 72 polymorphism and primary open angle glaucoma (POAG) patients was evaluated.
METHODS: 58 POAG patients and 59 healthy volunteers were enrolled in this study. Polymerase chain reaction based analysis was used to resolve the p53 codon 72 polymorphism.
RESULTS: There were significant differences in the distribution of the polymorphism between the control subjects and the POAG patients (p = 0.00782) The proline form of p53 gene codon 72 appears to be a significant risk factor in the development of POAG (odds ratio 2.389, 95% confidence interval: 1.14 to 5.01).
CONCLUSIONS: Retinal ganglion cells die during POAG by apoptosis. The tumour suppressor protein, p53, is one of the primary regulators steps of apoptosis, and the results of our study are compatible with this concept. ||||| BACKGROUND: The final common pathway for open angle glaucoma (OAG) is retinal ganglion cell apoptosis. Polymorphisms in p53, a major regulator of apoptosis, affect the efficiency of cell death induction. Association studies of p53 haplotypes and OAG have had conflicting results.
OBJECTIVE: To examine the association between p53 haplotypes and OAG in a larger white population than in previous reports, and extend the analysis to normal tension glaucoma.
METHODS: 345 unrelated people with OAG were recruited (283 subjects with high tension glaucoma and 62 with normal tension glaucoma) and compared with 178 age matched controls. Genomic DNA was analysed for the p53 codon 72 Arg/Pro polymorphism as well as for the presence or absence of a 16 bp intron 3 insertion.
RESULTS: In this white cohort no association was found between glaucoma (high or normal tension) and either sequence variant or haplotype.
CONCLUSIONS: The p53 codon 72 Arg/Pro polymorphism is not associated with age of onset or severity of glaucoma. ||||| BACKGROUND: Loss of vision in glaucoma is due to apoptotic retinal ganglion cell loss. While p53 modulates apoptosis, gene association studies between p53 variants and glaucoma have been inconsistent. In this study we evaluate the association between a p53 variant functionally known to influence apoptosis (codon 72 Pro/Arg) and the subset of primary open angle glaucoma (POAG) patients with early loss of central visual field.
METHODS: Genotypes for the p53 codon 72 polymorphism (Pro/Arg) were obtained for 264 POAG patients and 400 controls from the U.S. and in replication studies for 308 POAG patients and 178 controls from Australia (GIST). The glaucoma patients were divided into two groups according to location of initial visual field defect (either paracentral or peripheral). All cases and controls were Caucasian with European ancestry.
RESULTS: The p53-PRO/PRO genotype was more frequent in the U.S. POAG patients with early visual field defects in the paracentral regions compared with those in the peripheral regions or control group (p=2.7 × 10(-5)). We replicated this finding in the GIST cohort (p =7.3 × 10(-3), and in the pooled sample (p=6.6 × 10(-7)) and in a meta-analysis of both the US and GIST datasets (1.3 × 10(-6), OR 2.17 (1.58-2.98 for the PRO allele).
CONCLUSIONS: These results suggest that the p53 codon 72 PRO/PRO genotype is potentially associated with early paracentral visual field defects in primary open-angle glaucoma patients. | [
{
"source_pmid": "12368717",
"source_text": "PURPOSE: Glaucoma is a complex neurodegenerative disorder of the eye. Primary Open Angle Glaucoma (POAG) is the most common type, accounting for over half of the total cases. Recently, a significant difference in the distribution of the codon 72 polymorphism of t... |
24465860 | CONCLUSION: In OAG, Ex-PRESS and trabeculectomy provided similar IOP control, but Ex-PRESS was more likely to achieve complete success, with fewer postoperative interventions. Complication rates were similar for the two types of surgery, except for a lower frequency of hyphema in the Ex-PRESS group. | BACKGROUND: This study compared the efficacy of the EX-PRESS(®) glaucoma filtration device and trabeculectomy in primary open-angle glaucoma up to five years after surgery.
METHODS: Patients from a previously reported randomized, open-label, parallel-arm clinical trial in which 78 patients received either the EX-PRESS glaucoma filtration device or underwent a trabeculectomy were followed for up to an additional four years (five total) beyond the original study (39 eyes per treatment group). Risk-benefit data were obtained for up to five years after glaucoma surgery. Outcome variables were intraocular pressures and intraocular pressure medications. Complete success was denoted by intraocular pressure values ≤ 18 mmHg without medication.
RESULTS: The EX-PRESS glaucoma filtration device controlled intraocular pressure more effectively without medication for more patients from year 1 (86.8% versus 61.5%, P = 0.01) to year 3 (66.7% versus 41.0%, P = 0.02) than trabeculectomy. At year 1, only 12.8% of patients required intraocular pressure medication after EX-PRESS implantation, compared with 35.9% after trabeculectomy. The proportions became closer at year 5 (41% versus 53.9%). The responder rate was higher with EX-PRESS and time to failure was longer. In addition, surgical interventions for complications were fewer after EX-PRESS implantation.
CONCLUSION: This five-year analysis confirmed and extended the results reported after one year. Compared with trabeculectomy, EX-PRESS provided better intraocular pressure control in the first three years, and patients required fewer intraocular pressure medications and fewer surgical interventions during the five-year study period. For patients with primary open-angle glaucoma, the EX-PRESS glaucoma filtration device, implanted under a superficial scleral flap, produced significantly higher success rates than trabeculectomy. EX-PRESS is an effective device for long-term treatment of primary open-angle glaucoma. ||||| PURPOSE: To compare the rate of visual recovery after Ex-PRESS implantation versus standard trabeculectomy.
PATIENTS AND METHODS: Subjects enrolled in a prospective randomized controlled trial comparing Ex-PRESS to trabeculectomy were analyzed for postoperative changes in visual acuity (VA). Risk factors for visual loss (split fixation, cup-disc ratio, intraocular pressure, visual field mean deviation, and hypotony) were evaluated.
RESULTS: Sixty-four subjects were enrolled (33 Ex-PRESS, 31 trabeculectomy). There was no significant difference in mean logMAR VA between groups at baseline or any study visit. VA was significantly reduced up to week 2 following surgery in both the groups. However, by month 1, VA in the Ex-PRESS group was no longer significantly different from baseline (P=0.23) and remained nonsignificant at subsequent visits up to 6 months. In the trabeculectomy group, VA remained significantly lower than baseline at each study visit. At 6 months, 47% of the trabeculectomy eyes compared with 16% of the Ex-PRESS eyes had lost ≥2 Snellen lines (P=0.01). Reasons for VA loss included cataract, central retinal vein occlusion, and diabetic retinopathy, however, in a significant number of cases no cause could be determined. None of the risk factors evaluated were associated with vision loss.
CONCLUSIONS: Although there was no difference in mean VA between the Ex-PRESS and trabeculectomy groups at any time point, trabeculectomy eyes were more likely to lose ≥2 Snellen lines. In addition, VA recovered faster in the Ex-PRESS group. ||||| PURPOSE: To compare intraocular pressure (IOP) over time after standard trabeculectomy vs Ex-PRESS implantation in patients with bilateral primary open-angle glaucoma (POAG).
DESIGN: Prospective, randomised study.
PATIENTS AND METHODS: This study included adult patients with bilateral POAG necessitating surgery. Each patient underwent trabeculectomy in one eye and Ex-PRESS implantation under a scleral flap in the other eye according to randomised contralateral allocations. Efficacy was assessed by IOP values and success rates (IOP threshold and/or need for topical glaucoma medication) during 30 months. Statistical analysis included Generalised Estimate Equation and Cox Survival models, and paired t-tests.
RESULTS: Thirty eyes of 15 patients were studied for a mean of 23.6 months (SD, ± 6.9). At the last follow-up visit, mean pre-operative IOP decreased from 31.1 (± 14.2) to 16.2 (± 1.5) mm Hg after trabeculectomy, and from 28.1 (± 9.0) to 15.7 (± 1.8) mm Hg after Ex-PRESS implantation (P=0.001). The mean number of anti-glaucoma medicines prescribed at the last follow-up decreased from 3.7 pre-operatively (both groups) to 0.9 after trabeculectomy vs 0.3 after Ex-PRESS implantation (P=0.001). Complete success rates (5<IOP<18 mm Hg without medications) were higher with Ex-PRESS compared with trabeculectomy (P=0.0024). Postoperative complications were more frequent after trabeculectomy (33%) compared with Ex-PRESS (20%), with four trabeculectomy eyes (27%) needing postoperative interventions, compared with none with Ex-PRESS.
CONCLUSIONS: Trabeculectomy and Ex-PRESS implantation provided similar IOP control, but the Ex-PRESS group had a lower rate of complications, fewer postoperative interventions, and needed less glaucoma medications. ||||| PURPOSE: Ex-PRESS shunt is an alternative filtration procedure to trabeculectomy. This study aimed to compare the 1-year cost differences between the 2 operations.
METHODS: Subjects were enrolled in a randomized controlled trial comparing Ex-PRESS to trabeculectomy. Surgical cost difference and 1-year postoperative costs (follow-up visits, additional procedures, and medications) were determined and compared. The 95% confidence interval of incremental cost-effectiveness ratio was estimated using bootstrap method.
RESULTS: Forty-three subjects with 1-year follow-up were included. Success rate was not significantly different for Ex-PRESS (65%) versus trabeculectomy (55%, P=0.49). Ex-PRESS had a net surgical cost of $956 greater than trabeculectomy. There was no significant difference in the overall postoperative cost [median (interquartile range); $485 (337, 822) vs. $609 (387, 820), P=0.78], cost of follow-up visits [$303 (275, 358) vs. $317 (275, 385), P=0.75], additional procedures [$182 (0, 365) vs. $182 (0, 365), P=0.69], or glaucoma medication [$0 (0, 68) vs. $0 (0, 90), P=0.8] for Ex-PRESS versus trabeculectomy, respectively. The overall 1-year cost was significantly greater for Ex-PRESS and the incremental cost-effectiveness ratio was $9625 (95% confidence interval, $2435-548,084).
CONCLUSIONS: Ex-PRESS is associated with greater surgical cost compared with trabeculectomy. This needs to be considered in conjunction with efficacy and safety if Ex-PRESS is to supersede trabeculectomy. | [
{
"source_pmid": "21607021",
"source_text": "BACKGROUND: This study compared the efficacy of the EX-PRESS(®) glaucoma filtration device and trabeculectomy in primary open-angle glaucoma up to five years after surgery.\nMETHODS: Patients from a previously reported randomized, open-label, parallel-arm clinica... |
18412600 | The conclusion is that both drugs are equally effective in lowering IOP. Brimonidine is associated with a higher rate of allergy. | OBJECTIVE: Brimonidin tartrate is a highly selective alpha 2-agonist. This study investigates the safety and efficacy of 0.2% brimonidine administered twice daily for 1 year in patients with glaucoma or ocular hypertension.
METHODS: The study design was a multicenter, double-masked, randomized, parallel-group, active-controlled comparison clinical trial. Subjects instilled 0.2% brimonidine or 0.5% timolol maleate twice daily for 12 months. Subjects were examined at baseline, week 1, and months 1, 2, 3, 6, 9, and 12. A subset of subjects was examined at week 2.
RESULTS: Of 443 subjects enrolled in this study, 374 met the entry criteria; 186 received brimonidine and 188 received timolol. Brimonidine-treated subjects showed an overall mean peak reduction in intraocular pressure (IOP) of 6.5 mm Hg; timolol-treated subjects had a mean peak reduction in IOP of 6.1 mm Hg. Brimonidine lowered mean peak IOP significantly more than timolol at week 2 and month 3 (P < .03); no significant difference was observed between the groups for this variable at other visits throughout the 1-year course of the study. No evidence of tachyphylaxis was seen in either group. Allergy was seen in 9% of subjects treated with brimonidine. Dry mouth was more common in the brimonidine-treated group than in the timolol-treated group (33.0% vs 19.4%), but complaints of burning and stinging were more common in the timolol-treated group (41.9%) than in the brimonidine-treated patients (28.1%). Headache, fatigue, and drowsiness were similar in the 2 groups. In general, the tolerance to medication was acceptable.
CONCLUSIONS: Brimonidine is safe and effective in lowering IOP in glaucomatous eyes. Brimonidine provides a sustained long-term ocular hypotensive effect, is well tolerated, and has a low rate of allergic response. ||||| PURPOSE: Latanoprost, a new prostaglandin analogue, was compared with timolol for ocular hypotensive efficacy and side effects.
METHODS: In a multicenter, randomized, double-masked, parallel group study, 268 patients with ocular hypertension or early primary open-angle glaucoma received either 0.005% latanoprost once daily or 0.5% timolol twice daily for 6 months. All except ten patients from each group successfully completed the study.
RESULTS: Intraocular pressure (IOP) was significantly (P<0.001) reduced and maintained by both medications without evidence of a long-term drift over 6 months. Comparing 6-month with baseline diurnal IOP values, the IOP reduction (mean +/- standard deviation) achieved with latanoprost (-6.7 +/- 3.4 mmHg) was significantly (P<0.001) greater than that produced with timolol (4.9 +/- 2.9 mmHg). Four patients treated with timolol and none treated with latanoprost were withdrawn from the study because of inadequate IOP control. Pulse rate was significantly reduced with timolol, but not with latanoprost. Slightly more conjunctival hyperemia appeared in latanoprost-treated compared with timolol-treated eyes. Fewer subjective side effects occurred in latanoprost-treated eyes. Both eyes of a patient with a characteristic, concentric iris heterochromia (darker centrally) at baseline showed a definite, photographically documented increase in pigmentation during latanoprost treatment, making the irides uniformly darker. Three additional patients treated with latanoprost were suspects for this color change. Otherwise, no significant difference between treatment groups occurred visual acuity, slit-lamp examination, blood pressure, and laboratory values.
CONCLUSION: Latanoprost has the potential for becoming a new first-line treatment for glaucoma. ||||| OBJECTIVE: To evaluate the intraocular pressure (IOP)-reducing effect and the side effects of latanoprost (PhXA41), a new phenyl-substituted prostaglandin F2 alpha-isopropyl ester analogue, in patients with elevated IOP, using timolol maleate as the reference drug.
METHODS: A total of 184 patients with primary open-angle glaucoma or ocular hypertension at 35 medical centers participated in this randomized double-masked study. The patients were randomized to receive either 0.005% latanoprost once daily or 0.5% timolol maleate twice daily, for a period of 12 weeks. Intraocular pressure was measured 24 hours after the administration of timolol, at 2, 4, 8, and 12 weeks of treatment.
RESULTS: Latanoprost reduced IOP at the end of 12 weeks by 6.2 +/- 2.7 mm Hg (mean +/- SD) (26.8%), while timolol reduced IOP by 4.4 +/- 2.3 mm Hg (19.9%). At all visits latanoprost reduced IOP significantly more than timolol did. The main ocular side effects observed in both groups were conjunctival hyperemia and smarting. The main systemic side effect was a reduced pulse rate, which occurred in patients treated with timolol.
CONCLUSIONS: The results of this study demonstrated that 0.005% latanoprost taken once daily is well tolerated and more effective in reducing IOP than 0.5% timolol taken twice daily. Thus, latanoprost may become an important choice for the medical treatment of glaucoma. ||||| PURPOSE: To compare the intraocular pressure (IOP)-reducing effect and side effects of 0.005% latanoprost administered once daily with 0.5% timolol administered twice daily in patients with open-angle glaucoma or ocular hypertension.
METHODS: This was a randomized, double-masked study with two parallel groups and a treatment period of 6 months. The primary objective of the study is to compare the IOP-reducing effect of lantanoprost with that of timolol at the end of the 6-month treatment period. A total of 294 patients were included: 149 were in the latanoprost group and 145 were in timolol group. Latanoprost was administered in the evening.
RESULTS: Diurnal IOP (9:00 am, 1:00 pm, 5:00 pm) was reduced from 25.2 to 16.7 mmHg (33.7%) with lantanoprost and from 25.4 to 17.1 mmHg (32.7%) with timolol as determined at the end of the 6-month treatment period. No upward drift in IOP occurred with either drug during the treatment period. Latanoprost caused a somewhat more conjunctival hyperemia than timolol and more corneal punctuate epithelial erosions. However, both drugs were generally well tolerated. The most significant side effect of latanoprost was increased pigmentation of the iris which was observed in 15 patients (10.1%). Timolol caused more systemic side effects than latanoprost.
CONCLUSIONS: Latanoprost 0.005% administered once daily in the evening reduced IOP at least as well as timolol 0.5% administered twice daily. Latanoprost was generally well tolerated systemically and in the eye. However, the drug has an unusual side effect of increasing the pigmentation of the iris, particularly in individuals with green-brown or blue-brown eyes. ||||| OBJECTIVE: To compare the long-term safety and ocular-hypotensive efficacy of brimonidine tartrate 0.2% with timolol maleate 0.5% administered twice daily in patients with glaucoma or ocular hypertension.
DESIGN: A double-masked, parallel-group, active-controlled, multicenter clinical trial of 12 months' duration.
PARTICIPANTS: Four hundred eighty-three patients with glaucoma or ocular hypertension were enrolled. Of these, 463 were evaluated according to the protocol criteria (280 in the brimonidine tartrate group and 183 in the timolol group).
INTERVENTIONS: Brimonidine tartrate 0.2% or timolol maleate 0.5% was administered twice daily.
MAIN OUTCOME MEASURES: The primary efficacy variable was intraocular pressure (IOP).
RESULTS: Brimonidine and timolol produced significant (P < 0.001) and sustained mean reductions in IOP throughout the 1-year follow-up when measured at hour 0 (trough) and at hour 2 (peak). At weeks 1 and 2 and month 12, significantly greater mean decreases in IOP measured at peak (P < or = 0.007) were observed in patients treated with brimonidine as compared to timolol, whereas the mean decreases in IOP measured at trough was significantly greater in patients treated with timolol as compared to brimonidine (P < 0.001) at all follow-up visits. Both drugs were well-tolerated. The incidence of adverse events was similar in both treatment groups, except for ocular allergy, oral dryness, and conjunctival follicles, which occurred more frequently in the brimonidine group, and burning-stinging, which occurred more frequently in the timolol group. Patients receiving timolol experienced significant decreases in heart rate at all follow-up visits.
CONCLUSIONS: Topically applied twice daily for 12 months, brimonidine tartrate 0.2% was safe and effective in lowering IOP in patients with glaucoma or ocular hypertension. ||||| OBJECTIVE: To compare the efficacy and side effects and the effect on aqueous humor dynamics of 0.005% latanoprost applied topically once daily with 0.5% timolol given twice daily for 12 months to patients with pigmentary glaucoma.
DESIGN: Prospective, randomized, double-masked, clinical study.
PARTICIPANTS: Thirty-six patients affected with bilateral pigmentary glaucoma controlled with no more than a single hypotensive medication were enrolled in the study.
INTERVENTION: The sample population was randomly divided into 2 age- and gender-matched groups each of 18 patients. Group 1 received 0.005% latanoprost eyedrops once daily and the vehicle (placebo) once daily; group 2 was assigned to timolol 0.5% eyedrops twice daily.
MAIN OUTCOME MEASURES: Diurnal curves of intraocular pressure (IOP) were performed on the baseline day and after 0.5, 3, 6, and 12 months of treatment. The IOP measurements were performed at 8:00 AM, 12:00 noon, 4:00 PM, and 8:00 PM. Outflow facility ("C") was measured on the baseline day and on the last day of the study with a Schiotz electronic tonometer. A two-tailed Student's t test for paired or unpaired data was used for statistical evaluation of differences between treatment and baseline values or between the latanoprost and timolol group. Diurnal IOP measurements were compared hour by hour. Mean values of the two eyes IOP and "C" were used for analysis.
RESULTS: Compared with baseline measurements, both latanoprost and timolol caused a significant (P < 0.001) reduction of IOP at each hour of diurnal curve throughout the duration of therapy. Reduction of IOP was 6.0 +/- 4.5 and 5.9 +/- 4.6 with latanoprost and 4.8 +/- 3.0 and 4.6 +/- 3.1 with timolol after 6 and 12 months, respectively. Comparison of mean diurnal measurements with latanoprost and timolol showed a statistical significant (P < 0.001) difference at 3, 6, and 12 months. Mean "C" was found to be significantly enhanced (+30%) only in the latanoprost-treated group compared with the baseline (P = 0.017). Mean conjunctival hyperemia was graded at 0.3 in latanoprost-treated eyes and 0.2 in timolol-treated eyes. A remarkable change in iris color was observed in both eyes of 1 of the 18 patients treated with latanoprost and none of the 18 patients who received timolol. Darkening of the peripheral iris stroma was suspected in two patients treated with latanoprost. In the timolol group, heart rate was significantly reduced from 72 +/- 9 at baseline to 67 +/- 10 beats per minute at 12 months.
CONCLUSIONS: Although further studies may need to confirm these data on a larger sample and to evaluate the side effect of increased iris pigmentation on long-term follow-up, in patients with pigmentary glaucoma, 0.005% latanoprost taken once daily was well tolerated and more effective in reducing IOP than 0.5% timolol taken twice daily. ||||| The safety and ocular hypotensive efficacy of twice-daily administration of brimonidine 0.2% solution or betaxolol 0.25% suspension were compared in subjects with open-angle glaucoma or ocular hypertension. A total of 206 adult patients were enrolled in a prospective, 3-month, multicentered, randomized, double-masked, parallel-group study. Both drugs significantly (p < 0.001) reduced peak and trough intraocular pressure (IOP) at every scheduled follow-up visit over the 3-month study. At peak, the overall mean decrease from baseline IOP was greater (p = 0.004) in the brimonidine-treated group (5.8 mm Hg) than in the betaxolol-treated group (3.8 mm Hg). At trough, the overall mean decrease from baseline (p < 0.001) was 3.9 mm Hg in the brimonidine-treated group and 3.2 mm Hg in the betaxolol-treated group. The IOP-lowering effect of brimonidine was sustained throughout the 3-month study period. Terminations from the study due to lack of efficacy included 2.9% (3/103) of patients in the brimonidine group and 4.2% (4/96) of those in the betaxolol group. The overall incidence of adverse events was similar in both treatment groups, with the only significant (p = 0.027) between-group difference being that ocular blurring was reported more often by patients receiving betaxolol suspension than by those receiving brimonidine treatment. Instillation of drug was reported to be comfortable (p = 0.036) by more brimonidine-treated patients than betaxolol-treated patients. Overall, brimonidine 0.2% solution was well-tolerated, safe and clinically and statistically more effective than betaxolol 0.25% suspension in lowering intraocular pressure in patients with open-angle glaucoma or ocular hypertension. ||||| PURPOSE: To compare the effect on intraocular pressure (IOP) and side effects of 0.005% latanoprost applied once daily, morning or evening, with 0.5% timolol applied twice daily.
METHODS: A 6-month randomized, double-masked, multicenter study with three parallel groups was undertaken. Two hundred sixty-seven patients were randomized, 84 to timolol, 89 to latanoprost in the morning for 3 months and then in the evening for another 3 months, and 94 to latanoprost with the treatment schedule reversed.
RESULTS: After 6 months, timolol reduced diurnal IOP from 24.6 to 17.9 mmHg (27%); latanoprost applied in the morning, from 25.5 to 17.7 mmHg (31%); and latanoprost applied in the evening, from 24.8 to 16.2 mmHg (35%). The efficacy of latanoprost applied in the evening was statistically superior to latanoprost applied in the morning and to timolol (P < 0.001). Latanoprost induced a slight increase in conjunctival hyperemia in 31.4% of treated patients, compared with 15.9% for timolol. Sporadic episodes of mild punctate corneal epithelial erosions were three times as frequent in latanoprost-treated eyes as in timolol-treated eyes. The most significant ocular side effect was increased pigmentation of the iris observed in five and suspected in seven more latanoprost-treated eyes. All these eyes had a mixed green-brown or blue/gray-brown iris color. Timolol reduced heart rate by 3 beats/minute (P < 0.005).
CONCLUSIONS: The effect on diurnal IOP of latanoprost applied once daily in the evening is superior to that of timolol. The main difference in side effects is increased pigmentation of the iris induced by latanoprost, most likely due to stimulation of melanogenesis in iris stromal melanocytes. | [
{
"source_pmid": "9230823",
"source_text": "OBJECTIVE: Brimonidin tartrate is a highly selective alpha 2-agonist. This study investigates the safety and efficacy of 0.2% brimonidine administered twice daily for 1 year in patients with glaucoma or ocular hypertension.\nMETHODS: The study design was a multice... |
28211200 | Based on these meta-analyses, there seems to be an association between hypothyroidism and glaucoma, which does not seem to be the case between glaucoma and hypothyroidism. However, larger scale studies with better phenotype classification, longer follow-up and taking comorbidity and other biases into consideration are needed to address a potential causal relationship. | PURPOSE: To determine if hypothyroidism is associated with an increased risk of glaucoma using a large cohort of patients.
DESIGN: Nested case-control study.
PARTICIPANTS: Patients seen at the Veterans Affairs Medical Center in Birmingham, Alabama with newly diagnosed glaucoma between 1997 and 2001 were selected (n = 590) and age-matched to nonglaucoma controls (n = 5897).
METHODS: Patient information was extracted from the Birmingham Veterans Affairs Medical Center data files containing demographic, clinical, and medication information. An index date was assigned to the glaucoma subjects corresponding to the time of diagnosis. Patients who had a glaucoma diagnosis before the observation period of the study were excluded. Ten controls were randomly selected for each patient and matched on age (+/-1 year) and an encounter on or before the index date of the matched case.
MAIN OUTCOME MEASURES: Odds ratios (ORs) for the association between the prior diagnosis of hypothyroidism and the risk of developing glaucoma with adjustment for the presence of diabetes, lipid metabolism disorders, hypertension, cardiovascular disease, cerebrovascular disease, arterial disease, and migraines.
RESULTS: After adjustment for the other potential risk factors, patients were significantly more likely to have prior hypothyroidism than controls (OR, 1.40; 95% confidence interval, 1.01-1.97).
CONCLUSIONS: Our study has demonstrated a significantly greater risk of subjects with a preexisting diagnosis of hypothyroidism developing glaucoma, compared with controls, in a large Veterans Affairs Medical Center population. ||||| PURPOSE: To investigate the risk factors for primary open-angle glaucoma (POAG) in the Namil study population.
METHODS: A cross-sectional, population-based epidemiological study of residents aged ≥40 years from Namil-myon, South Korea, was conducted. Fifty-five subjects with POAG and 1,409 controls were enrolled in this study. Univariate and multivariate logistic regression analyses were performed to identify ocular and systemic factors associated with POAG.
RESULTS: Multivariate logistic regression analysis demonstrated that older age, a history of thyroid disease and higher IOP were associated with an increased risk of POAG. Subgroup analysis showed that older age (OR 1.033, 95 % CI 1.003-1.063 per year), a history of thyroid disease (OR 7.373, 95 % CI 1.407-38.636) and higher IOP (OR 1.132, 95 % CI 1.011-1.268 per mmHg) were risk factors for normal tension glaucoma (NTG, POAG with IOP ≤21 mmHg).
CONCLUSIONS: In the Namil study, higher IOP, older age and a history of thyroid disease were significant risk factors for POAG. ||||| OBJECTIVE: To test if there is an association between hypothyroidism and primary open-angle glaucoma (POAG) and the utility of routine study of thyroid function in these patients.
METHODS: The study was conducted in a case-control fashion. Seventy-five consecutive patients with a previous diagnosis of POAG and 75 control patients were prospectively evaluated for hypothyroidism. The levels of thyroid-stimulating hormone and free thyroxin were measured.
RESULTS: Hypothyroidism was revealed in only 2 patients with previous diagnosis of POAG (2.67%) and 3 patients of the control group (4%).
CONCLUSIONS: As we have not been able to demonstrate the previously reported relationship between hypothyroidism and POAG, we cannot recommend the systematic screening for hypothyroidism in patients with POAG. ||||| To examine the hypothesis that glaucoma may be a manifestation of unrecognized hypothyroidism, we studied 25 consecutive patients with newly diagnosed hypothyroidism who presented to an endocrinology clinic. Using tonography and tonometry, we demonstrated a reduction in facility of outflow in the hypothyroid state. With treatment of the hypothyroidism alone there was a statistically significant improvement in facility of outflow, intraocular pressure and Po/C (p < 0.002). Our results support the hypothesis that secondary open-angle glaucoma may be a manifestation of hypothyroidism and that the glaucoma will resolve on treatment of the primary disease. ||||| OBJECTIVE: To investigate the risk of open-angle glaucoma (OAG) after a diagnosis of hypothyroidism.
DESIGN: A retrospective, population-based follow-up study using an administrative database.
PARTICIPANTS: The study group comprised 257 hypothyroidism patients. The comparison group included 2056 subjects.
METHODS: Data were retrospectively collected from the Taiwan Longitudinal Health Insurance Database. The study cohort comprised patients aged ≥ 60 who received a first diagnosis of hypothyroidism (International Classification of Diseases, Ninth Revision, Clinical Modification code 244.9) from 1997 to 2001 (n = 257). The comparison cohort consisted of randomly selected patients without hypothyroidism who were aged ≥ 60 and had no diagnosis of glaucoma before 2001 (8 for every OAG patient; n = 2056). Each sampled patient was tracked for 5 years from their index visit. Cox proportional hazard regressions were used to compute the 5-year OAG-free survival rate, after adjusting for possible confounding factors.
MAIN OUTCOME MEASURES: The risk of developing OAG during the 5-year follow-up period.
RESULTS: Open-angle glaucoma developed in 7.4% of patients with hypothyroidism and 3.8% of patients in the comparison cohort during the follow-up period. Hypothyroid patients had a significantly lower 5-year OAG-free survival rate than patients in the comparison cohort. After adjusting for patients' age, gender, monthly income, urbanization level, and comorbid medical disorders, hypothyroidism patients were found to have a 1.78-fold (95% confidence interval [CI], 1.04-3.06) greater risk of developing OAG than the comparison cohort. This association remained significant in untreated hypothyroidism patients (adjusted hazard ratio [HR], 2.37; 95% CI, 1.10-5.09) and became statistically nonsignificant in patients treated with levothyroxine (adjusted HR, 1.73; 95% CI, 0.89-3.38).
CONCLUSIONS: Hypothyroid patients had a significantly increased risk of OAG development during the 5-year follow-up period. Levothyroxine seemed to be protective. ||||| The prevalence of hypothyroidism in British patients with primary open angle glaucoma (POAG) was examined. A recently reported study from Montreal had shown a significant increase (p < 0.004) in biochemical hypothyroidism (23.4%) in a population of 64 POAG patients compared with controls (4.7%). Mechanisms for a possible causal association between the two diseases are discussed, including mucopolysaccharide deposition in the trabecular meshwork and vasculopathy altering ocular bloodflow. Reports of improved glaucoma control following treatment of hypothyroidism are discussed. This study examined 100 consecutive patients with POAG in a specialist glaucoma clinic. All patients were questioned regarding symptoms of thyroid dysfunction and previous thyroid disease. All patients not already taking thyroxine underwent an assay of thyroid stimulating hormone. The 4% (95% CI 1.1-9.4%) prevalence of overt hypothyroidism in our study shows no clinically significant increase either over controls in the Montreal study or over our local population. We conclude that in our local population there is no evidence for a clinically important association of hypothyroidism with glaucoma. ||||| OBJECTIVE: To determine the prevalence of selected comorbidities in patients with open-angle glaucoma (OAG) and whether these comorbidities are more prevalent among individuals with OAG than those without OAG.
DESIGN: A retrospective, nationwide, case-control study using an administrative database.
PARTICIPANTS: The study group comprised 76,673 OAG patients. The comparison group comprised 230,019 subjects matched to the study cohort.
METHODS: Data were collected retrospectively from the Taiwan National Health Insurance Research Database. The study cohort comprised all patients with a diagnosis of OAG (International Classification of Diseases, 9th Revision, Clinical Modification codes 365.1-365.11) in 2005 (n = 76,673). The comparison cohort comprised randomly selected patients (3 for every 1 OAG patient; n = 230,019) matched with the study group in terms of age, gender, urbanization level, and monthly income. In total, 31 medical comorbidities were selected based mainly on the Elixhauser Comorbidity Index. Separate conditional logistic regression analyses were used to estimate the adjusted odds ratio for each of the medical comorbidities between patients with and without OAG.
MAIN OUTCOME MEASURES: The prevalences of selected comorbidities.
RESULTS: More than half (50.5%) of the OAG patients had hypertension, and more than 30% had hyperlipidemia or diabetes (30.5% and 30.2%, respectively). The prevalences of 28 of 31 comorbidities were significantly higher for OAG patients than subjects without glaucoma after adjusting for age, gender, urbanization level, and monthly income. The adjusted odds ratio was more than 1.50 for hypertension, hyperlipidemia, systemic lupus erythematosus, diabetes, hypothyroidism, fluid and electrolyte disorders, depression, and psychosis. Among the studied comorbidities, the prevalence difference of the OAG group minus the control group was 3% or higher for hypertension, hyperlipidemia, stroke, diabetes, liver disease, and peptic ulcer.
CONCLUSIONS: Open-angle glaucoma patients are significantly more likely to have comorbidities, many of which can be life threatening or can affect the quality of life appreciably.
FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussedin this article ||||| PURPOSE: To investigate the association between hypothyroidism and glaucomatous disease.
METHODS: This cross-sectional study included all subjects above the age of 40 years from two nationwide surveys: the 2008 National Health Interview Survey (NHIS) as well as the 2007 and 2008 National Health and Nutrition Examination Survey (NHANES). The presence or absence of glaucoma, thyroid disease and other demographic and health-related information including comorbidities was ascertained via interview. Blood samples were collected from NHANES subjects and analyzed for thyrotropin (TSH).
RESULTS: A total of 13,599 and 3,839 NHIS and NHANES participants respectively were analyzed to assess for a possible relationship between self-reported glaucoma, and self-reported hypothyroidism as well as self-reported thyroid disease. The unadjusted odds ratio (OR) for NHIS showed a significant association between self-reported glaucoma and self-reported hypothyroidism (OR 1.46, 95% confidence interval [CI] 1.07-1.99). Multivariate logistic regression analysis adjusted for age, gender, race, comorbidities, and health-related behavior, however, showed no association between self-reported glaucoma and hypothyroidism or thyroid disease in both surveys (OR 1.60, 95%CI 0.87-2.95 for NHIS; OR 1.05, 95%CI 0.59-1.88 for NHANES).
CONCLUSION: A previously reported association between hypothyroidism and glaucomatous disease was not confirmed in two large U.S. health survey populations. While such an association was noted in the univariate analysis for the NHIS survey, such a relationship was not found in the multivariate analysis after adjustment for potential confounding variables. ||||| PURPOSE: To assess whether thyroid disease is independently associated with open-angle glaucoma (OAG), using history of thyroid disease and current thyroxine use.
METHODS: The Blue Mountains Eye Study examined 3654 persons, aged 49-97 years. Interviewers collected self-reported history of diagnosis and treatment for thyroid disease. Eye examinations included applanation tonometry, stereoscopic optic disc photography and automated perimetry. OAG was diagnosed from the presence of matching typical glaucomatous field changes and optic disc cupping, independent of intraocular pressure. Associations between thyroid disease (history and treatment) and OAG were assessed in a multivariate model.
RESULTS: Of 324 participants (8.9%) reporting history of thyroid disease, 147 (4.0%) were currently using thyroxine. Although we could not accurately categorize the thyroid disorder for all cases, current use of thyroxine suggests a prior hypothyroid state. All thyroid disease subgroups affected women more frequently than men, P=0.001. OAG was diagnosed in 108 subjects (3.0%) and was more frequent in those reporting past thyroid disease (4.6 vs 2.8%). This relationship was not statistically significant after adjusting for potential confounders, multivariate odds ratio (OR) 1.6; 95% confidence interval (95% CI) 0.9-2.9. OAG was significantly more frequent, however, in subjects reporting current thyroxine use (6.8 vs 2.8%), multivariate OR 2.1; 95% CI 1.0-4.4, or history of thyroid surgery (6.5 vs 2.8%), multivariate OR 2.5; 95% CI 1.0-6.2.
CONCLUSIONS: This population-based study suggests that thyroid disease, indicated by current thyroxine use or past thyroid surgery, could be independently related to OAG. ||||| PURPOSE: There have been conflicting reports pertaining to the association between hypothyroidism and open-angle glaucoma (OAG). The purpose of this study was to assess the hypothesized association between preexisting hypothyroidism and development of OAG in a population-based setting.
DESIGN: Case-control study.
PARTICIPANTS: The study population and controls were taken from all patients in a large US managed care database aged >or=60 years with 4 years of continuous eligibility dating from January 1, 2001, through December 31, 2004.
METHODS: A total of 4728 newly diagnosed OAG patients were matched with 14 184 controls (3:1 matching) based on age and gender.
MAIN OUTCOME MEASURES: Conditional logistic regression was used to assess the relationship between hypothyroidism and OAG while controlling for various risk factors (ischemic heart disease, cerebrovascular disease, hyperlipidemia, hypertension, arterial disease, diabetes, and migraines).
RESULTS: Based on a diagnosis of hypothyroidism or use of a thyroid replacement therapy, prior hypothyroidism was found in 815 (17.2%) OAG subjects and in 2498 (17.6%) control subjects. After adjusting for the specified risk factors, patients with OAG were not found to be associated with a prior hypothyroid diagnosis when compared with control subjects (odds ratio, 0.93; 95% confidence interval, 0.85-1.01).
CONCLUSIONS: An association between prior hypothyroidism and OAG development was not found. The large proportion of patients receiving thyroid replacement therapy may have negated any OAG-related consequences of hypothyroidism. ||||| We reviewed the charts of 67 patients with the diagnosis of normal-tension glaucoma listed in the Bascom Palmer Eye Institute computer database. These patients were matched with respect to age, race, and sex with an equal number of patients having ocular hypertension. All medical diagnoses in the charts for both groups were tabulated and classified as either immune-related or non-immune-related. Twenty (30%) patients with normal-tension glaucoma had one or more immune-related disease(s) compared with five (8%) patients in the comparison group (P = .00134, McNemar statistic with continuity correction). ||||| AIMS: To evaluate the association between thyroid problems and glaucoma.
METHODS: A population-based cross-sectional sample with 12,376 participants from the 2002 National Health Interview Survey. Odds ratios (OR) and 95% confidence intervals (CIs) were used to quantify the association between a self-reported diagnosis of glaucoma and a self-reported history of thyroid problems, controlling for demographic characteristics and smoking status.
RESULTS: The overall prevalence of glaucoma was 4.6%; 11.9% reported a history of thyroid problems. The prevalence of glaucoma among those who did and did not report thyroid problems was 6.5% and 4.4%, respectively (p = 0.0003). Following adjustment for differences in age, gender, race and smoking status, the association between glaucoma and thyroid problems remained (OR 1.38, 95% CI 1.08 to 1.76).
CONCLUSIONS: The results of this study lend support to the hypothesis that thyroid disorders may increase the risk of glaucoma. Research should continue evaluating potential mechanisms underlying this relationship and whether the treatment of thyroid problems reduces subsequent glaucoma risk. | [
{
"source_pmid": "15350317",
"source_text": "PURPOSE: To determine if hypothyroidism is associated with an increased risk of glaucoma using a large cohort of patients.\nDESIGN: Nested case-control study.\nPARTICIPANTS: Patients seen at the Veterans Affairs Medical Center in Birmingham, Alabama with newly di... |
31102206 | Our review showed a clear anatomical benefit after the switch in terms of central retinal thickness and pigment epithelium detachment characteristics, whereas the functional outcomes were variable. Remarkable heterogeneity was documented among the relevant studies with regard to several factors including the baseline characteristics of the cohorts, the non-response definition and previous treatment protocols. Larger prospective trials with appropriate control arms are therefore required to elucidate the potential benefit when switching between anti-VEGF agents in refractory nAMD. | Purpose: To investigate whether tolerance to the anti-VEGF drug, ranibizumab, develops after drug exposure and to determine whether the history of treatment with ranibizumab prior to refractoriness can predict the post-switching responses to aflibercept.
Methods: We retrospectively investigated neovascular age-related macular degeneration patients refractory to ranibizumab (intra- or subretinal fluid despite monthly injections for ≥6 months) who were switched to aflibercept and were followed up for at least 12 months on each of ranibizumab and aflibercept. Baseline characteristics and ranibizumab and aflibercept treatment history (number of injections during the first year and central retinal thickness [CRT]) were analyzed by univariate and multivariate correlation analyses.
Results: Ninety-eight eyes (88 patients, 70% females, mean age 77.5 years), including a high proportion of eyes with pigment epithelium detachment (63%), were treated with a mean of 26.2 injections during 36.8 months before switching to aflibercept. The number of ranibizumab injections required in the first year (
Conclusion: Ranibizumab treatment history before switching to aflibercept correlates with the post-switching response in terms of the number of drug injections needed and CRT. Thus, drug tolerance does indeed exist and this might help to identify switching candidates. ||||| PURPOSE: To compare the effects of converting to aflibercept therapy with continuing ranibizumab therapy in eyes with neovascular age-related macular degeneration requiring monthly ranibizumab treatment.
METHODS: Patients were selected from the 104 patients (115 eyes) already enrolled in an "Observe and Plan" prospective case series that included treating neovascular age-related macular degeneration with ranibizumab for 24 months. Patients who still needed monthly retreatment at the end of a 2-year study were randomized to either continue ranibizumab therapy or to convert to aflibercept therapy. Outcome measures included average interval between treatments, resolution of exudative signs, number of retreatments, and change in visual acuity over 12 months (the third treatment year).
RESULTS: Nineteen patients (21 eyes) met the inclusion criteria. Ten eyes were randomized to receive aflibercept, and 11 eyes remained on ranibizumab. Groups were balanced for baseline characteristics. Outcomes were similar in the 2 groups over a 12-month study duration, with no statistical difference.
CONCLUSION: This comparative pilot study suggests that neovascular age-related macular degeneration requiring monthly retreatment with ranibizumab may respond in similar ways to both ranibizumab and aflibercept treatment. Larger sample sizes would be needed to confirm this observation. ||||| PurposeTo evaluate the effects of aflibercept administered according to a pro re nata (PRN) or Fixed Regimen to patients with neovascular AMD and persistent intraretinal/subretinal fluid (IRF/SRF) despite three consecutive ranibizumab injections.MethodsPatients were switched to aflibercept injection (IVA) administered according to a PRN or to a fixed regimen for 1 year in two different retina centers. At baseline each patient underwent a complete ophthalmologic evaluation, including best-corrected visual acuity assessment (BCVA ETDRS chart), fluorescein, and indocyanine green angiography and OCT.ResultsEach group included 36 eyes. After 1 year the PRN group showed BCVA stabilization (63 vs 60 letters, P=0.33), whereas fixed regimen group showed significant BCVA improvement (68 vs 71, P=0.008). The median central retinal thickness decreased by 94 μm in the PRN (P=0.002) and by 148 μm in the fixed regimen group (P≤0.001). Complete IRF/SRF reabsorption was found in 58% of eyes in the PRN and in 42% of eyes in the fixed regimen group. At 1-year visit, the percentage of eyes with pigment epithelium detachment did not significantly decrease, but a height reduction was recorded in both groups. The median number of IVA was 3.5 in the PRN and 7 in the fixed regimen group.ConclusionThe switch to aflibercept with both treatment strategies enabled improvement in morphological parameters and stabilization of visual acuity. BCVA improvement and reduction in vision loss with reduction in retinal thickness, fluid and PED height was achieved with the fixed regimen in previously treated nAMD after 1 year. ||||| BACKGROUND AND OBJECTIVE: To evaluate the effects of switching to aflibercept in eyes with neovascular age-related macular degeneration (AMD) requiring frequent re-treatment with bevacizumab or ranibizumab.
PATIENTS AND METHODS: Retrospective review of 73 eyes of 65 patients with neovascular AMD switched to aflibercept due to persistent or recurrent macular fluid after at least 1 year of intravitreal bevacizumab or ranibizumab with re-treatment at least every 6 weeks. Minimum post-switch follow-up was 6 months. All patients were treated using a treat-and-extend strategy. The treatment intervals immediately after and before the switch were the same.
RESULTS: The mean pre-switch anti-VEGF therapy duration was 45 months, and the mean number of injections was 31. In the 6 months after the switch, the average number of injections was reduced by 0.6 compared with the 6 months before the switch (P < .001). Visual acuity was unchanged during this period (P = .78). Central retinal thickness (CRT) decreased by 19 µm after the switch (P < .001). Seventy eyes had vascularized retinal pigment epithelial detachments (PEDs). The decrease in the PED cube-root volume during the 6 months after the switch was statistically significant (-0.07 mm; P = .007).
CONCLUSION: The number of injections, CRT, and PED volume decreased significantly after the switch to aflibercept, but visual acuity was unchanged. ||||| PURPOSE: To analyze the efficacy of aflibercept switch treatment for regression of pigment epithelial detachment (PED) in patients previously treated with ranibizumab.
METHODS: Multicenter, prospective, nonrandomized clinical trial. One eye of patients presenting neovascular age-related macular degeneration with PED of more than 250 μm in height, with persistent fluid, was included. Patients had to have received at least six ranibizumab intravitreal injections during the 12 months before enrollment. Patients were switched from ranibizumab pro re nata to aflibercept (fixed regimen, 3 monthly intravitreal injections, and then Q6). Main outcome measure was change in PED height from baseline to Week 12 after switch. Secondary outcomes were best-corrected visual acuity and PED volume changes.
RESULTS: Eighty four patients were included. Mean delay between last ranibizumab intravitreal injection and switch was 44.7 days. Mean maximal PED height at baseline visit was 347 μm (±109) and reduced to a mean of 266 μm (±114) at Week 12 (P < 0.001) and 288.2 μm at Week 32 (P < 0.001). Mean PED volume was reduced from 1.3 mm to 0.98 mm at Week 12 (P < 0.001). Best-corrected visual acuity improved by 3.3 Early Treatment Diabetic Retinopathy Study letters at Week 32 (P = 0.003).
CONCLUSION: Aflibercept switch therapy seems to be effective on large PED in patients previously treated with pro re nata ranibizumab. ||||| PURPOSE: To report the results of switching treatment to vascular endothelial growth factor (VEGF) Trap-Eye (aflibercept) in neovascular age-related macular degeneration (AMD) and polypoidal choroidal vasculopathy (PCV) refractory to anti-VEGF (ranibizumab and bevacizumab).
METHODS: This is a retrospective study involving 32 eyes from 29 patients; 18 were cases of neovascular AMD and 14 were cases of PCV. The best-corrected visual acuity (BCVA) and central macular thickness (CMT) of spectral-domain optical coherence tomography were evaluated.
RESULTS: BCVA and CMT improved from 0.58 to 0.55 (p = 0.005) and from 404 to 321 µm (p < 0.001), respectively, after switching to aflibercept. The 14 eyes that received 6 or more aflibercept injections remained stable at 0.81 to 0.81 and 321 to 327 µm (p = 1.0, 0.29), respectively, after 3 aflibercept injections. The 10 eyes that received 3 or more bevacizumab injections after 3 or more aflibercept injections worsened, from 0.44 to 0.47 and from 332 to 346 µm (p = 0.06, 0.05), respectively. The results showed similar improvement of BCVA and CMT in neovascular AMD and PCV.
CONCLUSIONS: Aflibercept seems to be effective for improvement and maintenance of BCVA and CMT for neovascular AMD and PCV refractory to anti-VEGF. Switching from aflibercept back to bevacizumab treatment may not be a proper strategy. ||||| BACKGROUND AND OBJECTIVE: To quantitatively evaluate the change in pigment epithelial detachment (PED) morphology on spectral-domain optical coherence tomography (SD-OCT) 18 months after the transition to intravitreal aflibercept in patients with neovascular age-related macular degeneration (AMD) with PED recalcitrant to monthly intravitreal bevacizumab or ranibizumab.
PATIENTS AND METHODS: Retrospective case series examining patients with neovascular AMD who had a persistent fibrovascular or serous PED on SD-OCT. PED volume was calculated by manually outlining the PED on individual OCT slices of the raster scan and multiplying by the pixel dimensions.
RESULTS: Eleven eyes of 10 patients who had received an average of 25.7 ± 20.1 (range: 6 to 70) prior bevacizumab or ranibizumab injections over a period of 26.6 ± 19.8 months (range: 4 to 63) were included. PED volume decreased with aflibercept from 0.687 ± 0.837 mm(3) to 0.562 ± 0.705 mm(3) (P = .02), a decrease of 19% ± 12.27%.
CONCLUSION: After 18 months of aflibercept, recalcitrant PED volumes were reduced by 19% while preserving visual acuity in eyes with neovascular AMD. ||||| PURPOSE: To describe the efficacy of intravitreal aflibercept on 12-month visual and anatomical outcomes in patients with neovascular age-related macular degeneration (AMD) recalcitrant to prior monthly intravitreal bevacizumab or ranibizumab.
METHODS: Non-comparative case series of 21 eyes of 21 AMD patients with evidence of persistent exudation (intraretinal fluid/cysts, or subretinal fluid (SRF), or both) on spectral domain OCT despite ≥6 prior intravitreal 0.5 mg ranibizumab or 1.25 mg bevacizumab (mean 29.8±17.1 injections) over 31.6±17.4 months who were transitioned to aflibercept.
RESULTS: At baseline, best-corrected visual acuity (BCVA) was 0.42±0.28 logarithm of minimum-angle of resolution (logMAR), central foveal thickness (CFT) was 329.38±102.67 μm and macular volume (MV) was 7.71±1.32 mm(3). After 12 months of aflibercept (mean 10.2±1.2 injections), BCVA was 0.40±0.28 logMAR (P=0.5), CFT decreased to 292.71±91.35 μm (P=0.038) and MV improved to 7.33±1.27 mm(3) (P=0.003). In a subset of 15 eyes with a persistent fibrovascular or serous pigment epithelial detachment (PED), mean baseline PED greatest basal diameter (GBD) was 2350.9±1067.6 μm and mean maximal height (MH) was 288.7±175.9 μm. At 12 months, GBD improved to 1896.3±782.3 μm (P=0.028), while MH decreased to 248.27±146.2 μm (P=0.002).
CONCLUSION: In patients with recalcitrant AMD, aflibercept led to anatomic improvement at 12 months, reduction in proportion of eyes with SRF and reduction in PED, while preserving visual acuity. ||||| PURPOSE: To study the effects of converting to aflibercept in accordance with a treat and extend (T&E) strategy in eyes with treatment resistant exudative age-related macular degeneration (AMD).
METHODS: Two-year prospective study of eyes with exudative AMD and persistent macular fluid despite monthly treatment with ranibizumab or bevacizumab. Eyes were converted to 2.0 mg aflibercept in accordance with a T&E protocol.
RESULTS: Fifty eyes from 47 patients were included. At baseline, the mean central retinal thickness (CRT) was 273 μm and mean best-corrected visual acuity (BCVA) 0.25 logarithm of the minimal angle of resolution (logMAR). The mean number of aflibercept injections the first year was 9.2. After 1 year, there was a reduction in mean CRT to 228 μm (p < 0.001); 22 eyes (44%) had a dry macula; and the mean BCVA was 0.24 logMAR (p = 0.531). The mean number of aflibercept injections the second year was 8.0 (p = 0.013 compared to first year). After 2 years, 24 eyes (48%) received treatment more frequently than every eighth week. The mean CRT was 225 μm (p < 0.001 compared to baseline); 31 eyes (62%) had a dry macula; and mean BCVA was 0.32 logMAR (p = 0.005 compared to baseline). Five eyes did not complete 2 years of aflibercept treatment after failing to improve.
CONCLUSION: A majority of eyes showed improved anatomic outcomes. There was a small decrease in mean BCVA after the second year of treatment. About half of the eyes required treatment more frequently than the recommended aflibercept label of an 8-week interval. ||||| PURPOSE: To determine the efficacy of monthly (0.1 mL/4 mg) aflibercept for refractory neovascular age-related macular degeneration (wet age-related macular degeneration).
METHODS: This was a retrospective interventional case series in which patients with wet age-related macular degeneration were treated with stepwise dose escalation. Nonvitrectomized patients resistant to monthly (Q4W) ranibizumab/bevacizumab were switched to 2 mg aflibercept every 8 weeks. With resistance, they were escalated to Q4W 2 mg aflibercept, then Q4W 4 mg (high dose high frequency, 4Q4W) aflibercept. Resistance was defined as ≥2 recurrences after being dry following ≥3 injections or persistent exudation on treatment of ≥5 injections.
RESULTS: Thirty-three eyes of 28 patients were treated with 4Q4W aflibercept and followed for a mean of 16 months. A dry retina (no intraretinal or subretinal fluid) was achieved after initiating 4Q4W aflibercept treatment at a mean of 3.8 months. Central foveal thickness, maximum foveal thickness, intraretinal fluid, subretinal fluid, and retinal pigment detachment height decreased significantly at 1 month after initiating the 4Q4W aflibercept, and the morphologic therapeutic effect was sustained until the last visit. Forty-five percent of eyes had one or more lines of vision improvement. New geographic atrophy developed in 9% of eyes during follow-up. No ocular or systemic adverse events occurred after initiating 4Q4W aflibercept.
CONCLUSION: Intravitreal high-dose high-frequency aflibercept is an effective treatment for patients with refractory wet age-related macular degeneration. ||||| SUMMARY STATEMENT: In subjects with active exudative age-related macular degeneration, treating with a fixed intravitreal aflibercept injection dosing regimen for 12 months demonstrated improved anatomic and vision endpoints from baseline.
PURPOSE: Switching therapies in neovascular age-related macular degeneration (AMD) may offer an advantage for some patients. This study evaluates the efficacy of intravitreal aflibercept injection (IAI) in subjects previously treated with ranibizumab and/or bevacizumab.
METHODS: Subjects (n=26) were given monthly 2 mg of IAI for 3 months, followed by 2 mg once in every 2 months for up to 12 months. The mean absolute change from baseline in central subfield thickness (CST) measured by optical coherence tomography and the mean change from baseline in best-corrected visual acuity (BCVA) early treatment in diabetic retinopathy study (ETDRS) letter score were obtained. Additionally, the percentage of subjects who gained or lost ≥15 letters of vision and the percentage of subjects who are 20/40 or better or 20/200 or worse were evaluated.
RESULTS: There was a mean decrease in CST of -50.3 μm (P<0.001) and a mean increase in ETDRS BCVA of +9.2 letters (P<0.001). Twenty-seven percent of subjects experienced a ≥15-letter improvement in visual acuity, and no subject lost ≥3 lines of vision from baseline. Fifty percent of subjects were 20/40 or better, and 11.5% of subjects were 20/200 or worse at month 12.
CONCLUSION: Fixed IAI dosing regimen for 12 months demonstrated improved anatomic and vision endpoints in subjects with active exudative AMD. ||||| PURPOSE: To assess the efficacy of intravitreal aflibercept (2.0 mg) in patients with treatment-resistant neovascular age-related macular degeneration.
METHODS: Retrospective analysis of eyes treated with aflibercept with persistent subretinal and/or intraretinal fluid despite previous treatments with intravitreal ranibizumab (0.5 mg). All patients were switched to intravitreal aflibercept (2.0 mg) and analyzed after 3 consecutive injections and after 6 months of treatment. Main outcome measures included change in visual acuity, central foveal thickness, and the height and diameter of the pigment epithelial detachment on the subfoveal scan on optical coherence tomography.
RESULTS: Thirty-four eyes of 33 patients were analyzed. Mean duration of symptoms and average number of previous injections with anti-vascular endothelial growth factor agents was 44.7 ± 29.8 months (interquartile range [IQR] 24-76 months) and 28.6 ± 20.1 (IQR 10-47), respectively. At the 6-month follow-up, mean visual acuity and central foveal thickness improved significantly from 20/75 (logarithm of minimum angle of resolution 0.57 ± 0.36; IQR 0.30-1.0) and 416 ± 217 μm (IQR 263-487 μm) at baseline to 20/60 (logarithm of minimum angle of resolution 0.47 ± 0.32; IQR 0.30-0.60) (P = 0.004) and 248 ± 171 μm (IQR 235-419 μm) (P < 0.001), respectively. Maximum pigment epithelial detachment height improved significantly from 260 ± 162 μm (IQR 129-368 μm) to 214 ± 142 μm (IQR 111-305 μm) (P < 0.001) and PED diameter decreased significantly from 3,265 ± 1,622 μm (IQR 2,353-4,555 μm) to 2,949 ± 1,653 μm (IQR 1,721-4,484 μm) (P = 0.04).
CONCLUSION: Intravitreal injections of aflibercept resulted in a significant improvement in visual and anatomical outcomes in eyes with persistent subfoveal fluid despite previous treatment with ranibizumab. ||||| PURPOSE: To assess the efficacy of intravitreal injection of aflibercept for treating choroidal neovascularization due to age-related macular degeneration unresponsive to ranibizumab.
METHODS: Prospective noncomparative study. Indication for conversion to aflibercept (2.0 mg) was a failed response to ranibizumab, defined as persistent or recurrent subretinal and/or intraretinal fluid on spectral domain optical coherence tomography. Best-corrected visual acuity (Early Treatment Diabetic Retinopathy Study letter score), fluorescein angiography, indocyanine green angiography, and spectral domain optical coherence tomography were performed at baseline. Patients were followed up monthly, and retreatment was considered at physician discretion based on functional and morphological patterns.
RESULTS: Ninety-two eyes were included in the study. At 12 months, mean best-corrected visual acuity (±SD) change was +1.8 (±10.3), Early Treatment Diabetic Retinopathy Study letters and central retinal thickness (±SD) decreased on average by 112 (±173) μm. Patients received a mean of 3.5 ± 1.8 injections. No significant adverse event was observed during the follow-up.
CONCLUSION: A low number of intravitreal aflibercept injections reversed the preswitching trend toward losing vision and produced stable visual acuity and morphological improvements for up to 12 months in patients with neovascular age-related macular degeneration, not responding to ranibizumab. ||||| PURPOSE: To evaluate frequency of injections, visual and anatomical outcomes of neovascular age-related macular degeneration (nAMD) patients transitioned to intravitreal aflibercept after failure to extend treatment interval beyond 8 weeks with prior intravitreal bevacizumab or ranibizumab.
METHODS: Retrospective review of patients with nAMD switched to aflibercept following ≥ 6 prior intravitreal ranibizumab or bevacizumab injections at 4-8-week intervals. Three monthly aflibercept injections were given followed by a treat-and-extend dosing regimen.
RESULTS: Twenty-one eyes of 18 patients who had received a mean of 23.8 ± 18.8 (mean ± SD; range 6-62) prior ranibizumab or bevacizumab injections were included. Over a mean follow-up of 24 months after the transition, 9.2 ± 2.9 (range 4-21) aflibercept injections were required. Interval between aflibercept injections increased to 57.3 days (range 35-133 days), as compared with 37 ± 6.1 days (range 29-54 days) with the prior agents (P = 0.01). Mean best-corrected visual acuity was preserved (0.42 ± 0.31 vs 0.42 ± 0.23 logMAR; P = 0.2). Mean OCT central subfoveal thickness (292.1 ± 83.2 μm to 283.6 ± 78.6 μm; P = 0.4) and mean macular volume (7.9 ± 0.95 mm(3) to 7.67 ± 0.94 mm(3); P = 0.16) remained stable.
CONCLUSION: Patients requiring treatment more frequently than every 8 weeks with ranibizumab and bevacizumab were transitioned to > 8-week treatment interval with aflibercept while maintaining the anatomic and visual gains. ||||| The purpose of the study was to assess the efficacy and safety of transition from ranibizumab to aflibercept intravitreal injections in treatment-resistant retinal pigment epithelial detachment (PED). The data of intravitreal ranibizumab treatment-resistant patients who have been switched to aflibercept treatment were reviewed retrospectively. After three monthly injections, bimonthly regimen was performed. The changes of PED height and radius, and the best-corrected visual acuity (BCVA) were analyzed retrospectively. Mean baseline PED height decreased from 297 ± 151 to 122 ± 42 µm at month 12 (P = 0.0007). Mean baseline PED radius decreased from 2371 ± 882 to 1859 ± 779 µm at month 12 (P = 0.0007). No complete PED resolution occurred in any of the patients at the end of the 12 months. Baseline BCVA improved from 0.63 ± 0.21 to 0.43 ± 0.17 logMar at month 12 (P = 0.0049). Mean BCVA gain was 1.4 decimal chart lines (7 letters) at month 12. Switching to aflibercept seems to have promising functional and anatomical outcomes with a reasonable complication rate in treatment-resistant PED. ||||| BACKGROUND: To evaluate changes in central macular thickness (CMT) and visual outcome in patients with neovascular age-related macular degeneration (AMD) treated initially with bevacizumab and subsequently switched to either aflibercept or ranibizumab.
METHODS: Observational clinical study was performed. We measured the structural outcome (CMT on SD-OCT; μm) and the visual outcome (best corrected visual acuity (BCVA); logMAR), as follows: before treatment (at baseline), following bevacizumab treatment (switch follow-up) and after switching from bevacizumab to aflibercept- or ranibizumab treatment (final follow-up, AG/, RG).
RESULTS: From a total of 96 eyes treated with intravitreal injections of bevacizumab (10.5 ± 7.6 (mean ± SD)), 58 eyes switched to aflibercept (6.5 ± 3.9; AG) and 38 eyes switched to ranibizumab (7.1 ± 5.3; RG) (≥ 3 injections, each). In addition, these eyes were compared to 37 eyes under bevacizumab monotherapy.
PRIMARY OUTCOME: In the AG, the CMT decreased slightly from 430 ± 220 μm at baseline to 419 ± 212 μm at switch follow-up (p = 0.86), but decreased significantly to 318 ± 159 μm at final follow-up, AG (p < 0.0001). In the ranibizumab group (RG), the CMT increased from 396 ± 174 μm at baseline to 499 ± 333 μm at switch follow-up (p = 0.012), but decreased significantly to 394 ± 202 μm at final follow-up, RG (p = 0.007). Secondary outcome: In the AG, the mean BCVA worsened from logMAR 0.57 ± 0.33 at baseline to 0.63 ± 0.30 at switch follow-up and improved slightly to 0.53 ± 0.71 at final follow-up, AG (p = 0.46). In the RG, mean BCVA worsened from 0.57 ± 0.28 at baseline to 0.64 ± 0.31 at switch follow-up and improved slightly to 0.60 ± 0.36 at final follow-up, RG (p = 0.64).
CONCLUSION: Switching from bevacizumab to either aflibercept, or ranibizumab, has a strong anatomical effect in eyes with neovascular AMD. Nevertheless, even if the switch to aflibercept shows a minimal functional benefit over that to ranibizumab, visual prognosis remains limited. ||||| PURPOSE: To evaluate the effect of aflibercept on anatomic and visual outcomes in patients with choroidal neovascularization (CNV) previously treated with intravitreal ranibizumab with persistent fluid on optical coherence tomography (OCT).
DESIGN: Prospective, open-label study.
METHODS: Eighteen patients (19 eyes) with CNV being treated with monthly ranibizumab, with persistent fluid on OCT, were switched to intravitreal aflibercept injections at intervals of up to 8 weeks. The primary outcome was the proportion of patients maintaining vision [<5 letter loss in visual acuity (VA)] at week 48. Secondary outcomes included the change in VA and central macular thickness (CMT) and the frequency of treatment necessary along with the safety of intravitreal aflibercept.
RESULTS: Forty-eight weeks after switching to aflibercept, 16/19 eyes had maintained VA. There was a median increase in vision of 5 letters [interquartile range (IQR): 0, 15;
CONCLUSIONS: In this small cohort of eyes, switching to aflibercept seemed beneficial. The majority maintained or improved vision and eyes with IRF or SRF had significant reductions in macular edema. However, visual improvement was not always indicative of anatomical improvement. ||||| OBJECTIVE: To describe the 1-year efficacy of aflibercept in Japanese patients with age-related macular degeneration (AMD) who were resistant to ranibizumab treatment.
DESIGN: Retrospective case series.
PARTICIPANTS: Fourteen consecutive eyes of 14 patients with AMD were enrolled who had no substantial response or developed resistance to intravitreal ranibizumab injections.
METHODS: All patients were subcategorized into one of two subtypes of AMD: seven patients with occult choroidal neovascularization (CNV) and seven with polypoidal choroidal vasculopathy (PCV). Serial intravitreal aflibercept (IVA) injections were administered. Comprehensive ophthalmic examinations, including optical coherence tomography, were conducted at baseline and at follow-up examinations at 1, 3, 6, and 12 months after the initial IVA injection. The best-corrected visual acuity converted to logarithm of the minimum angle of resolution (logMAR) and central macular thickness (CMT) at each follow-up visit were compared with the baseline values. The anatomic response was also assessed with absorption or reduction of fluid in the subretina or subretinal pigment epithelial space.
RESULTS: The logMAR best-corrected visual acuity improved significantly at 3, 6, and 12 months in the total cohort: at 3 and 6 months in patients with occult CNV and at 3 and 12 months in patients with PCV. The CMT decreased significantly at all follow-up visits in the total cohort as well as in both subtypes, except for the CMT at 6 months in PCV patients. The anatomic improvement was also demonstrated in all cases, and pigment epithelial detachments tended to be resolved more rapidly in patients with PCV than in patients with occult CNV.
CONCLUSION: Conversion to IVA was effective in patients with AMD resistant to ranibizumab, showing rapid morphologic improvement. The logMAR visual acuity was raised significantly within 12 months, and the clinical course of visual acuity improvement may differ according to the AMD subtypes. ||||| PURPOSE: To investigate anatomical responses and visual changes in cases of exudative age-related macular degeneration (AMD) with choroidal vascular hyperpermeability (CVH) that responded poorly to multiple ranibizumab injections and were treated with intravitreal aflibercept.
DESIGN: Retrospective comparative study.
PARTICIPANTS: Twenty-five consecutive patients attending the outpatient clinic of the University of Tokyo Hospital who showed an insufficient response to multiple intravitreal ranibizumab injections and were switched to intravitreal aflibercept injections between March and June 2013. All patients were treated with intravitreal aflibercept in a treat-and-extend regimen and followed up for at least 12 months.
METHODS: Presence or absence of CVH was determined by indocyanine green angiography. Changes of best-corrected visual acuity (BCVA) and central retinal thickness (CRT) at 12 months were compared between the CVH (+) AMD and CVH (-) AMD eyes.
RESULTS: The improvement in logMAR BCVA at 12 months was larger in the CVH (-) AMD eyes than in the CVH (+) AMD eyes (-0.18 vs -0.026; P = 0.0089, t-test). The changes in CRT did not differ significantly between the groups (-122 ± 101 μm in the CVH (-) AMD eyes and -159 ± 118 μm in the CVH (+) AMD eyes; P = 0.44, t-test). The proportion of the eyes without intraretinal or subretinal fluid or hemorrhage was 88% in the CVH (-) AMD and 67% in the CVH (+) AMD (P = 0.21, t-test).
CONCLUSIONS: Compared with AMD without CVH, AMD with CVH showed poorer visual gain resulting from intravitreal aflibercept treatment. ||||| PURPOSE: To evaluate 6-month and 1-year outcomes of every-8-weeks (Q8W) aflibercept in patients with resistant neovascular age-related macular degeneration (AMD).
DESIGN: Retrospective, interventional, consecutive case series.
METHODS: Retrospective review of patients with resistance (multiple recurrences or persistent exudation) to every-4-weeks (Q4W) ranibizumab or bevacizumab that were switched to Q8W aflibercept.
RESULTS: Sixty-three eyes of 58 patients had a median of 13 (interquartile range [IQR], 7-22) previous anti-vascular endothelial growth factor (anti-VEGF) injections. At 6 months after changing to aflibercept, 60.3% of eyes were completely dry, which was maintained up to 1 year. The median maximum retinal thickness improved from 355 μm to 269 μm at 6 months (P < .0001) and 248 μm at 1 year (P < .0001). There was no significant improvement in ETDRS visual acuity at 6 months (P = .2559) and 1 year follow-up (P = .1081) compared with baseline. The mean difference in ETDRS visual acuity compared to baseline at 6 months was -0.05 logMAR (+2.5 letters) and 0.04 logMAR at 1 year (-2 letters).
CONCLUSION: Sixty percent of eyes with resistant AMD while on Q4W ranibizumab or bevacizumab were completely dry after changing to Q8W aflibercept at the 6-month and 1-year follow-ups, but visual acuity did not significantly improve. Only a third of eyes needed to be switched from Q8W to Q4W aflibercept owing to persistence of fluid; Q8W dosing of aflibercept without the initial 3 monthly loading doses may be a good alternative in a select group of patients who may have developed ranibizumab or bevacizumab resistance. ||||| PURPOSE: To assess changes in vision-related quality of life (VR-QoL) among patients with treatment-resistant neovascular age-related macular degeneration (nAMD) following intravitreal aflibercept treatment over 48 weeks.
METHODS: We conducted a prospective study in which 49 patients with nAMD resistant to anti-vascular endothelial growth factor therapy were switched to intravitreal aflibercept. Patients were treated with three loading doses every 4 weeks followed by injections every 8 weeks, for a total of 48 weeks. Ophthalmic examinations performed at each visit included best-corrected visual acuity (BCVA) and central macular thickness (CMT) measurement. The National Eye Institute Visual Functioning Questionnaire 25 (NEI VFQ-25) was used to assess VR-QoL at baseline and weeks 24 and 48. Changes in NEI VFQ-25 composite and subscale scores were analyzed using paired t tests. The relationship between the change in VR-QoL and changes in BCVA and CMT, and the impact of the better-seeing eye (BSE, defined as the eye reading the greater number of letters at baseline) vs. the worse-seeing eye (WSE, the fellow eye to the BSE) were assessed.
RESULTS: Mean NEI VFQ-25 composite scores improved significantly at weeks 24 and 48 compared to baseline (4.5 ± 9.2 and 4.4 ± 11.8, respectively, all p < 0.01). Among subscales, general vision and near and distance activities showed significant improvements at weeks 24 and 48 (all p < 0.05). Improvement in the NEI VFQ-25 composite score was significantly associated with increased BCVA at week 48 (β coefficient = 0.43, p = 0.029), but not with change in CMT (β coefficient = -0.007, p = 0.631). There was no association between VR-QoL changes and BSE or WSE.
CONCLUSION: Despite previous anti-VEGF treatment in this cohort, overall VR-QoL improved following aflibercept therapy over 48 weeks. This improvement was related to improved vision in treatment eyes regardless of whether they were the BSE or WSE. ||||| PURPOSE: To report the clinical outcomes of intravitreal aflibercept therapy in eyes with refractory and recurrent neovascular age-related macular degeneration (AMD) switched from intravitreal bevacizumab or ranibizumab.
METHODS: This is a retrospective review of eyes with neovascular AMD switched to intravitreal aflibercept with at least 1 year of follow-up after the switch. All patients had had a minimum of 3 injections of bevacizumab or ranibizumab before the switch. Aflibercept was used in patients considered refractory to bevacizumab (group 1) and in recurrent patients on therapy with ranibizumab due to an institutional policy decision (group 2). Changes in best-corrected visual acuity, fluid on optical coherence tomography (OCT), central retinal thickness (CRT) and the frequency of injections were compared.
RESULTS: Eighty-five eyes of 69 patients were analyzed, 39 eyes in group 1 and 46 in group 2. The mean follow-up time was 31.6 months prior to the switch and 14.7 months on treatment with aflibercept. One year after the switch, there was a nonsignificant mean decrease of 2 letters in visual acuity in both groups (group 1: from 58.2 to 55.8 letters, p = 0.086; group 2: from 56.4 to 54.5 letters, p = 0.168), but the mean number of injections per month was significantly lower (from 0.76 to 0.57, p < 0.001). With the switch, 90.6% of the patients showed anatomic improvement with a reduction of fluid on OCT, and both groups presented significant improvement in CRT (group 1: 65.3 µm, p = 0.051; group 2: 91.0 µm, p < 0.001).
CONCLUSION: Aflibercept appears to be a valuable tool for the management of patients with poor responses to other anti-vascular endothelial growth factor drugs. These patients could have anatomic improvement, and the injection intervals could be extended. ||||| PURPOSE: To determine the 24-month results of patients who had pro re nata (PRN) aflibercept treatment owing to recurrent or resistant neovascular macular degeneration.
DESIGN: Retrospective, interventional, consecutive case series.
METHODS: Eighty-one eyes of 78 patients with resistant or multiple recurrences of intraretinal or subretinal fluid while receiving monthly bevacizumab or ranibizumab injections and were switched to strict, as-needed aflibercept treatment with every-8-weeks spectral-domain optical coherence tomography (SDOCT)-guided monitoring were included. If there was a persistence of fluid despite this treatment, more frequent aflibercept injections were considered. Anatomic outcomes including maximum retinal thickness, central macular thickness, maximum pigment epithelial detachment height, maximum fluid height, and visual acuity (VA) were assessed at given follow-ups.
RESULTS: All anatomic endpoints significantly improved following 3 consecutive aflibercept injections, which were maintained through 24 months (P < .05 for all endpoints at all visits). Thirty-seven eyes (45.6%) required more frequent injections with monthly SDOCT-guided monitoring at a median of 37 weeks (interquartile range, 30-62 weeks) to adequately treat the retinal fluid. Seventy-one of 81 eyes (87.7%) became completely dry on at least 1 follow-up visit; however, there was no significant improvement in VA during the study period.
CONCLUSION: Aflibercept injection with an as-needed regimen was effective in many eyes previously treated with monthly bevacizumab or ranibizumab injections that had persistent or recurrent fluid. Despite significant improvement in anatomic outcomes, vision remained stable throughout the 2-year follow-up, likely because this cohort of patients had advanced choroidal neovascular membrane upon enrollment (recurrent or resistant). ||||| PurposeThe purpose of this study is to evaluate an early switch to aflibecept in eyes with neovascular age-related macular degeneration (nvAMD) showing partial or lack of response for initial therapy with bevacizumab.MethodsThe Aflibercept as a Second Line Therapy for Neovascular Age Related Macular Degeneration in Israel (ASLI) was a prospective, multicenter, single-arm clinical trial. Eyes with nvAMD having incomplete response to 3-9 prior bevacizumab injections were recruited. Three monthly intravitreal aflibercept (2 mg) injections were administered, followed by two bi-monthly injections and a final examination at week 28. An optional injection was allowed at week 20.ResultsForty-seven eyes of 46 patients (mean±SD age 76±8 years) were recruited. The mean number of prior bevacizumab injections was 5.5±2.9. The mean visual acuity improved from 60.3±10 ETDRS letters at baseline to 63.1±15 letters at week 28 (P=0.02, paired t-test). The central subfield thickness (CST) reduced from 409±127 micron at baseline to 330±110 microns at week 4 (P=0.0002; paired t-test), and 277±70 microns at week 28 (P=0.00002; paired t-test). Twenty-two eyes had three to five prior bevacizumab injections (mean 5.1±0.7), and 25 eyes had six to nine prior injections (7.32±1.2). Both groups had reduced CST from baseline to week 28 (P=0.0004 and P=0.0007; paired t-test, respectively). Thirty-five (75%) eyes required the optional additional aflibercept injection at week 20.ConclusionsThe ASLI study demonstrated improved BCVA and reduced CST following an early switch to aflibercept therapy in eyes with prior incomplete response to initial therapy with three to nine bevacizumab injections. ||||| BACKGROUND: Age-related macular degeneration (AMD) is a degenerative process that leads to severe vision loss. Wet AMD is defined by choroidal neovascularisation, leading to the accumulation of subretinal fluid (SRF), macular oedema (ME), and pigment epithelium detachments (PED). Purpose To evaluate the initial clinical experience of conversion from bevacizumab or ranibizumab to aflibercept in wet AMD patients.
METHODS: Records of 250 consecutive wet AMD patients were retrospectively reviewed. Of 250 patients, 29 were naive (with no previous treatment), and 221 were previously treated with bevacizumab (1/3) or ranibizumab (2/3). On average, converted patients received 14 injections every 6 weeks on a treat-and-extend regimen with Avastin or Lucentis before being converted to aflibercept every 7 weeks on average (no loading dose) for three doses. For the purposes of this study, we concentrated on the patients converted to aflibercept since the number of naive patients was too small to draw any conclusion from. Snellen (as logMar) visual acuities, and optical coherence tomography (OCT) were compared predrug and postdrug conversion.
RESULTS: Converted patients did not show a significant difference in visual acuity or average OCT thickness from preconversion values; however, small improvements in ME (p=0.0001), SRF (p=0.0001), and PED (p=0.008) grading were noted on average after conversion to aflibercept.
CONCLUSIONS: No significant difference in visual outcome or average OCT thickness was observed when switched from bevacizumab or ranibizumab q6 week to aflibercept 7-week dosing, on average. Mild anatomic improvements did occur in converted patients with regard to ME, SRF and PED improvement, on average, after conversion to aflibercept, and aflibercept was injected less frequently. No serious adverse reactions, including ocular infections or inflammation, as well as ocular and systemic effects were noted. ||||| BACKGROUND/AIM: To evaluate the clinical, anatomic and functional effects of conversion to aflibercept following ranibizumab and/or bevacizumab in patients with neovascular age-related macular degeneration (AMD).
METHODS: A retrospective review of patients with neovascular AMD treated with intravitreal ranibizumab and/or bevacizumab who were switched to aflibercept was performed. The primary outcome was change in injection frequency in the year following the change. Secondary outcomes included change in central macular thickness (CMT) at 6 months and 1 year, presence of intraretinal and subretinal fluid at 6 months and visual acuity at 1 year.
RESULTS: A total of 109 eyes with neovascular AMD were switched to aflibercept and met inclusion criteria. Overall, aflibercept injection frequency was unchanged with patients receiving 7.4 antivascular endothelial growth factor (VEGF) injections the year prior to conversion compared with 7.2 aflibercept injections in the year following (p=0.47). However, the change to aflibercept was associated with improvement in CMT from 324 to 295 μm (p=0.0001) at 6 months and 299 μm (p=0.0047) at 1 year. There was no effect on visual acuity at 1 year. In a subgroup analysis, patients who had received ≥10 anti-VEGF injections in the year prior had fewer injections (11.1 to 8.4, p<0.0001) and clinic visits (13.9 to 9.6, p<0.0001) as well as a significant decrease in CMT (-35 μm, p=0.02).
CONCLUSIONS: In our population, switching to aflibercept therapy was not associated with a change in injection frequency nor improved visual acuity, but was associated with improved CMT at 6 months and 1 year. In patients who received at least 10 anti-VEGF injections in the year prior, transitioning to aflibercept was associated with a reduced injection frequency and CMT, suggesting potential cost savings in this population. ||||| PURPOSE: To report the response of participants switching from ranibizumab to aflibercept treatment for neovascular age-related macular degeneration (nAMD) requiring further anti-vascular endothelial growth factor treatment.
METHODS: In this retrospective case review of 68 participants treated in a single hospital, all participants, prior to switching, received ranibizumab injections only. Best-corrected visual acuity (BCVA), clinical examination, and optical coherence tomography (OCT) were performed at each visit. Active nAMD was defined as persistent intraretinal or subretinal fluid on OCT. Participants had their first aflibercept injection at baseline and 2 more injections at 2 monthly intervals. Afterwards, they were followed up every 6-8 weeks and given injections as needed. The main outcome measures were visual acuity and the OCT central retinal thickness (CRT), average thickness (AT), and total macular volume (TMV).
RESULTS: The BCVA at baseline visit was 0.57 ± 0.33 log MAR and the final BCVA was 0.54 ± 0.37 log MAR (p = 0.215). The CRT mean change was -75.6 ± 85.6 (p = 0.001), the AT mean change was -24.2 ± 27.2 (p = 0.001), and TMV mean change was -0.69 ± 0.78 (p = 0.001). There were no significant ophthalmic complications related to treatments.
CONCLUSIONS: Intravitreal aflibercept improved anatomic outcomes (as measured by OCT) in eyes with nAMD that were previously treated with intravitreal ranibizumab and were still active. There was no statistically significant difference in logMAR visual acuity in participants who switched to aflibercept with a follow-up of at least 6 months. ||||| AIMS: To examine 12-month outcomes of eyes switching from intravitreal ranibizumab to aflibercept for neovascular age-related macular degeneration (nAMD).
METHODS: Database observational study of eyes with nAMD tracked by the Fight Retinal Blindness outcome registry that received ranibizumab for at least 12 months before switching to aflibercept and followed for at least 12 months after the switch. Visual acuity (VA) recorded at 12 months after the switch was analysed using locally weighted scatterplot smoothing curves. Lesion activity was graded according to a prospectively identified definition. Main outcomes were change in VA and treatment intervals 12 months after the treatment switch. Secondary outcomes included change in activity grading, effect of duration of treatment before switching and analysis of eyes that switched back.
RESULTS: A total of 384 eyes switched from ranibizumab to aflibercept after a mean duration of 39.8 months on the original treatment. The mean VA did not change from the time of switching treatment (63.4, SD 15.9 logarithm of the minimum angle of resolution letters) to 12 months later (63.3, SD 16.7). While 10% of eyes gained 10 or more letters 12 months after the switch, 13% lost the same amount. The mean number of injections decreased by around one injection in the 12 months after switching (p<0.001), with a decrease in the proportion of choroidal neovascular membrane lesions that were graded as active. Eyes that had been treated for the longest time (49 or more months) before switching had worse vision at the point of switch but neither change in VA nor treatment interval was different between groups. The small proportion (6.9%) of eyes that switched back again to ranibizumab had already lost a mean of 5.2 letters from the first switch to the switch back and continued to lose vision at a similar rate for at least 6 months.
CONCLUSIONS: The mean VA of eyes that switched treatments from ranibizumab to aflibercept was not different 12 months later. There was a modest increase in treatment intervals and a somewhat greater proportion of eyes that were graded as inactive after the switch. ||||| BACKGROUND: To investigate visual and anatomical outcomes in eyes with exudative age-related macular degeneration treated with intravitreal aflibercept following prior treatment with intravitreal ranibizumab.
MATERIALS AND METHODS: Retrospective, single-center study of 192 eyes treated with 0.5 mg intravitreal ranibizumab every 4 weeks for three consecutive doses followed by a variable dose schedule. After more than 12 months of ranibizumab treatment, eyes that required ranibizumab injections at 4-week or 6-week intervals were switched to aflibercept therapy.
RESULTS: After 12-69 months (42 months ± 18 months, mean ± standard deviation [SD]) of treatment with intravitreal ranibizumab, 80 eyes were changed to 2 mg intravitreal aflibercept treatment with follow-up after 12-18 months (16 months ± 1 month, mean ± SD). Thirty-nine eyes had persistent macular fluid after treatment with ranibizumab. Mean logMAR visual acuity (VA) in eyes treated with ranibizumab changed by - 0.089 ± 0.310 (mean ± SD; P = 0.0003), which correlates to an approximate gain of 4.5 letters. The number of eyes with macular fluid decreased from 39 to 23 after aflibercept treatment. Mean logMAR VA in eyes with intraretinal macular fluid treated with aflibercept changed by -0.079 ± 0.134 (mean ± SD; P = 0.006), which correlates to an approximate gain of 4 letters. Mean logMAR VA in eyes with submacular fluid was not significantly different after aflibercept treatment.
CONCLUSION: Eyes with persistent intraretinal macular fluid had visual and anatomic response after changing from ranibizumab to aflibercept treatment. ||||| AIM: To determine the efficacy of 2.0 mg aflibercept in the management of patients with recalcitrant exudative age-related macular degeneration (AMD).
METHODS: In this prospective, open-label, single-arm clinical trial, patients were seen monthly and given mandatory 2.0 mg aflibercept at baseline, months 1, 2 and 4. Pro re nata (PRN) retreatment at months 3 and 5 was performed upon evidence of disease on spectral domain-optical coherence tomography (SD-OCT). End point at month 6: mean change in Early Treatment Diabetic Retinopathy Study best corrected visual acuity (ETDRS BCVA) and central subfield thickness (CST), mean number of aflibercept injections, percentage of PRN injections required, patients with no fluid on SD-OCT and patients losing >15 letters.
RESULTS: At baseline, 46 patients with a mean of 42 prior antivascular endothelial growth factor-A (anti-VEGF) intravitreal treatments had a mean of 74.2 letters (Snellen equivalent 20/32) and mean CST of 347 µm. ETDRS letters remained stable throughout the trial; at month 6, mean BCVA change was +0.2 letters (range -10 to +13, p=0.71). Anatomically, mean CST improved significantly from baseline at each study visit including -23.6 µm at month 1 and -27.3 µm at month 6 (p=0.018). Seventy-one of 90 (79%) possible PRN injections were required and a mean of 5.6 aflibercept injections out of the maximum six were administered. Ten of 45 (22%) patients had no retinal fluid on SD-OCT at month 6. No patient lost >15 letters.
CONCLUSIONS: Aflibercept 2.0 mg treatment maintained mean visual acuity improvements previously achieved with high-dose 2.0-mg ranibizumab injections in recalcitrant wet AMD patients. Aflibercept 2.0 mg treatment led to significant anatomic improvement and was required monthly in most patients.
CLINICAL TRIALS REGISTRATION: FDA IND#12462. NCT 01543568.
TRIAL DETAILS: IND 12462, NCT 01543568 http://clinicaltrials.gov/show/NCT01543568. ||||| OBJECTIVE: To investigate the effect of aflibercept 2.0 mg in cases resistant to ranibizumab 0.5 mg and/or bevacizumab 1.25 mg treatment.
PURPOSE: To evaluate the anatomic and visual effect of intravitreal aflibercept 2.0 mg in cases of exudative age-related macular degeneration (AMD) with persistent fluid on optical coherence tomography (OCT) despite regular ranibizumab 0.5 mg and/or bevacizumab 1.25 mg treatment at 1 and 6 months.
METHODS: Retrospective review at Ophthalmic Consultants of Boston, Boston, Massachusetts, USA of exudative AMD cases with persistent fluid on regular ranibizumab 0.5 mg and/or bevacizumab 1.25 mg treatment switched to intravitreal aflibercept 2.0 mg treatment and followed for 6 months. Tabulated data included details of prior treatments, best available visual acuity, central subfoveal thickness on registered spectral domain OCT before and after aflibercept injection centred on the anatomic fovea and macular description before and after aflibercept injection.
RESULTS: A total of 353 eyes with exudative AMD were switched to aflibercept during the study period. Of these, 28 eyes in 28 patients had persistent fluid after an average of 20 regular ranibizumab/bevacizumab injections (range 7-37). At 1 month, 89% (25 eyes) showed anatomic improvement and 18% (five eyes) were dry after a single aflibercept injection. Central subfoveal thickness improved from 295 to 272 microns (p<0.001) after one aflibercept injection. After an average of 4.4 aflibercept injections (range 3-6) over 6 months, the central subfoveal thickness remained improved (274 microns, p=0.008); 64% (18 eyes) showed anatomic improvement and a quarter of eyes (25%, seven eyes) were dry. Visual acuity did not improve at 1 month (logarithm of minimum angle of resolution (logMAR) 0.54, Snellen 20/69, p=0.64) or 6 months (logMAR 0.57, Snellen 20/76, p=0.49). Treatment was well tolerated with no adverse events reported.
CONCLUSIONS: A significant proportion of exudative AMD cases with persistent fluid on OCT despite regular ranibizumab 0.5 mg and/or bevacizumab 1.25 mg treatment respond anatomically to aflibercept 2.0 mg. Visual acuity did not improve. Aflibercept may be beneficial anatomically in cases of exudative AMD treated with persistent fluid on ranibizumab and/or bevacizumab. ||||| PURPOSE: To prospectively assess the safety and efficacy of intravitreal aflibercept for treatment-resistant neovascular age-related macular degeneration (nAMD).
METHODS: This prospective, non-randomized clinical trial included 49 patients with treatment-resistant nAMD who received 2 mg intravitreal aflibercept as 3 monthly loading doses, followed by injections every 2 months over 12 months. Inclusion criteria included active nAMD on fluorescein angiography at baseline and persistent intra- or subretinal fluid on optical coherence tomography (OCT) for ≥ 6 months prior to baseline with a minimum of 4 injections of bevacizumab and/or ranibizumab. Patients were assessed monthly for best-corrected visual acuity (BCVA), central retinal thickness (CRT) measured with OCT and occurrence of adverse events. Retinal pigment epithelium atrophy (RPEA) was assessed at baseline and at 12 months.
RESULTS: Mean BCVA improved by 4.7 letters (95% CI: 2.1-7.3, p < 0.001) and CRT decreased by 97.2 µm (95% CI: 54.4-140.1, p < 0.001) at 12 months compared to baseline. Median RPEA area increased by 0.48 mm2 (range = -0.1 to 19.9, p < 0.001). There was 1 arterial thromboembolic event and 2 cases of submacular haemorrhage.
CONCLUSION: In this cohort of treatment-resistant nAMD patients, intravitreal aflibercept was effective in improving vision and reducing exudation. Early visual and anatomic outcomes may predict longer-term response to treatment, but further assessment is required. ||||| PURPOSE: The purpose of this study was to evaluate the outcomes over 12 months in patients with neovascular age-related macular degeneration (nAMD) with insufficient response to ranibizumab who were switched directly to 8-weekly fixed dosing of aflibercept without a loading phase.
DESIGN: Retrospective interventional study.
PARTICIPANTS: Consecutive patients with nAMD who were switched from pro re nata (PRN) intravitreal ranibizumab to 8-weekly fixed aflibercept because of persistent disease activity from November 1, 2013, to September 30, 2014, were included.
METHODS: Demographic data, visual acuity (VA), and spectral-domain optical coherence tomography characteristics over time were evaluated to determine the prognostic indicators of final visual outcome at 12 months.
MAIN OUTCOME MEASURES: The VA, central subfield thickness (CST), presence of macular fluid at month 12 compared with baseline, and the definition of prognostic indicators of final visual outcome at month 12.
RESULTS: A total of 431 patients (447 eyes) were included in this study. There was no statistically significant difference in VA between baseline and month 12 (P = 0.79), whereas the CST significantly decreased at month 12 compared with baseline (P < 0.001). At the 12-month follow-up, 48.3% of eyes had no macular fluid compared with 8.5% at baseline. The mean number of injections at month 12 was 6.8±1.75. Poor prognostic indicators included increasing age, increasing CST, the presence of intraretinal fluid, pigment epithelial detachment, and subfoveal thickening.
CONCLUSIONS: Patients who have not yet "responded" to PRN ranibizumab seem to exhibit retinal dehydration after switching to aflibercept, whereas there was no demonstration of VA benefit. Baseline features at the point of switching can independently predict outcomes. ||||| PURPOSE: To study optical coherence tomographic (OCT) results and vision at 6 months after transition (post-Tx) from intravitreal bevacizumab and/or ranibizumab to aflibercept for treatment of neovascular age-related macular degeneration (nAMD). The null hypothesis was the lack of improvements in OCT metrics and vision outcome in study eyes at 6 months after transitioning from bevacizumab or ranibizumab to aflibercept.
METHODS: This retrospective study assessed 6 monthly OCT (Cirrus) data after transitioning to aflibercept for eyes on prior Legacy-ranibizumab, Legacy-bevacizumab, or mixed treatment for nAMD. Outcome measures were subretinal fluid (SRF), cystoid macular edema (CME), pigment epithelial detachment (PED) heights and volumes, central 1- and 3-mm subfield, Macular Volume, and best spectacle and pinhole visual acuity (VA). A single masked investigator performed all OCT measurements.
RESULTS: One hundred eighty-nine eyes in 172 patients in Legacy-bevacizumab (95 eyes), Legacy-ranibizumab (84 eyes), or Mixed Group(10 eyes) were switched to aflibercept and followed for 6 months. Significant post-Tx reductions were noted in SRF/CME heights and volumes (all P<.001). Similar findings were noted for PED heights (122.8 μm vs 79.4 μm) and PED volumes (all P<.001). Post-Tx VA was better (20/43 vs 20/51, P<.001). There were no differences between Legacy-bevacizumab and Legacy-ranibizumab groups in OCT and VA changes. Post-Tx VA, SRF/CME, and PED heights and volumes were improved for Nonresponders (suboptimal response to bevacizumab/ranibizumab) (P=.001 to <.001), but not Responders (good responses to same). The only adverse event was a retinal pigment epithelial tear in one eye.
CONCLUSIONS: Significant improvements in vision and OCT metrics developed in Nonresponders but not in Responders. Post-Tx VA and OCT measures were similar for eyes on prior bevacizumab or ranibizumab. Post-Tx adverse events were uncommon. ||||| PURPOSE: To investigate the time course of pigment epithelium detachment (PED) height and its change after anti-vascular endothelial growth factor switch from ranibizumab to aflibercept in neovascular age-related macular degeneration.
METHODS: This retrospective study included 60 eyes of 50 consecutive patients with neovascular age-related macular degeneration who showed refractory intraretinal or subretinal fluid (≥9 months) despite monthly ranibizumab treatment and an associated PED (height ≥150 μm). The treatment was switched to aflibercept, and patients were followed-up for at least 9 months. Data on the height and type of PED, exudative fluid, and best-corrected visual acuity were collected at four different time points (two before and two after the drug switch).
RESULTS: The maximal PED height was significantly decreased over time, both under ranibizumab and aflibercept treatment. However, the reduction was significantly greater during the 3 months after the switch to aflibercept, due to two outliers. Visual acuity remained stable. Complete resolution of intraretinal or subretinal fluid was observed in 9 cases (15%) at 3 months after switch, allowing for treatment interval extension.
CONCLUSION: Maximal PED height continuously decreased over time. Switching the intravitreal anti-vascular endothelial growth factor medication from ranibizumab to aflibercept had a significantly stronger short-term effect on PED height reduction, without changes in visual acuity. ||||| PURPOSE: To study the visual outcomes and change in central macular thickness (CMT) in patients with neovascular age-related macular degeneration (AMD) who were previously treated with ranibizumab (Lucentis) and/or bevacizumab (Avastin) and were subsequently switched to aflibercept (VEGF Trap-Eye; Eylea).
METHODS: Retrospective study of patients who received intravitreal aflibercept from December 2011 to December 2012 and had previous anti-vascular endothelial growth factor treatment for AMD. The main outcome measures were best-corrected visual acuity (BCVA) and CMT as measured by optical coherence tomography.
RESULTS: The study population included 30 patients aged 80.4±1.45 (mean±SEM) who received 6.27±0.37 (range 4-11) aflibercept injections. Eighteen patients had previously received only bevacizumab (12.4±2.18 injections), 2 had received only ranibizumab (19±6 injections), and 10 had received both ranibizumab and bevacizumab (mean 19.3 injections). BCVA logMAR at the initial visit (aflibercept initiation) was 0.506±0.054 (mean VA 20/64), and then, follow ups at 1-month 0.504±0.055 (20/64) P=0.903, 3-months 0.458±0.061 (20/57) P=0.112, 6-months 0.413±0.071 (20/52) P=0.036, and 12-months 0.521±0.076 (20/66) P=0.836. CMT at the initial visit was 261±10.9, and then, at 1-month 238±12.4 P=0.021, 3-months 245±10.6 P=0.102, 6-months 245±10.4 P=0.099, and 12-months 237±10.2 P=0.012. Results were similar in a subset of patients (n=15) with central macular edema or submacular fluid at aflibercept initiation. While on aflibercept, 2 patients developed intraocular pressure increases that required treatment.
CONCLUSIONS: These findings demonstrate a significant decrease in CMT but no statistically significant improvement in BCVA through the 12-month follow up in patients previously treated who were switched to aflibercept for AMD. Patients may develop ocular hypertension after multiple aflibercept injections. ||||| A retrospective chart review of patients with persistent subretinal and/or intraretinal fluid, despite previous treatment with intravitreal ranibizumab (0.5 mg), who were switched to aflibercept injections, was performed. Treatment was three monthly aflibercept (2 mg) injections followed by dosing on pro re nata basis. Main outcome measures included changes in best corrected visual acuity (BCVA), 1 mm central subfield (CSF) retinal thickness, the height of the pigment epithelial detachment (PED), and subfoveal choroidal thickness on optical coherence tomography at 6 months. Thirty-one eyes of 30 patients were analyzed. The mean number of injections before aflibercept conversion was 34.4 ± 11.9. After an average of 4.5 aflibercept injections (range 3 to 6) over 6 months, no significant change in BCVA was observed (P > 0.05). Compared with baseline, there was a significant reduction of the CSF retinal thickness (449 ± 179 versus 269 ± 145 μ m, P < 0.001), maximum PED height (262 ± 134 versus 183 ± 100 μ m, P < 0.001), and choroidal thickness (192 ± 67 versus 167 ± 51 μ m, P < 0.01). Stable visual acuity and anatomical improvement were obtained for up to 6 months after aflibercept conversion. However, choroidal thinning related to treatment was observed. | [
{
"source_pmid": "29636594",
"source_text": "Purpose: To investigate whether tolerance to the anti-VEGF drug, ranibizumab, develops after drug exposure and to determine whether the history of treatment with ranibizumab prior to refractoriness can predict the post-switching responses to aflibercept.\nMethods... |
20577107 | CONCLUSIONS: The use of intraoperative MMC is a safe and effective additional step during nonpenetrating filtering surgery. | AIMS: To investigate the comparative efficacy and safety of deep sclerectomy with and without intraoperative mitomycin C (MMC) application for lowering the intraocular pressure (IOP).
METHODS: A total of 71 eyes of 71 consecutive patients who had routine deep sclerectomy (DS), nonaugmented (DS-noMMC) or with mitomycin C (DS-MMC) augmentation (0.2 mg/ml for 2 min) and follow-up of 4 months or more were identified from an ongoing prospective database on glaucoma surgery. Indications for MMC use were the presence of risk factors for subconjunctival scarring and low target IOPs. MMC 0.2 mg/ml was applied in the sub-Tenons space for 2 min.
RESULTS: There were 19 eyes in the DS-noMMC group and 52 eyes in the DS-MMC group. In 11 eyes (15.5%), the procedure was complicated by intraoperative perforation of the trabeculo-Descemet's window. Eyes in the DS-MMC group had significantly lower IOPs (MANOVA, P = 0.04). Kaplan-Meier survival curve analysis showed that the probability of maintaining IOP below target IOP level, below 18 mmHg and below 14 mmHg at 1 year was 51, 67, and 35% for the DS-noMMC group and 80, 86, and 74% for the DS-MMC group. The survival rates of the DS-MMC group were not statistically significant (P = 0.06) when the success criterion was maintaining an IOP less than 18 mmHg but were significant for the other criteria, namely IOP less than target levels (P = 0.03) and less than 14 mmHg (P = 0.03). Nd:YAG goniopuncture to lower IOP to target levels was done more frequently in the DS-noMMC group (13 eyes, 81%) than the DS-MMC group (20 eyes, 45%) and this difference was significant (P = 0.03). The prevalence of avascular areas within filtration blebs and transconjunctival oozing of aqueous was significantly higher in the DS-MMC group (P < 0.01).
CONCLUSIONS: The use of intraoperative MMC during deep sclerectomy has a significant effect on the postoperative IOP and increases the probability of achieving target IOPs. However, our current technique of MMC application is associated with a higher incidence of avascular blebs and transconjunctival oozing. ||||| BACKGROUND AND OBJECTIVE: To determine whether adjunctive use of mitomycin C (MMC) would increase the success rate of primary nonpenetrating deep sclerectomy with collagen implant.
PATIENTS AND METHODS: Twenty-six patients (26 eyes) with primary open-angle glaucoma uncontrolled with maximally tolerated medical therapy were randomly assigned to undergo nonpenetrating deep sclerectomy and collagen implant, either with (13 eyes) or without (13 eyes) 0.3 mg/mL of adjunctive MMC for 3 minutes. Intraocular pressure (IOP), number of glaucoma medications, and visual acuity were assessed before and 12 and 24 months after surgery.
RESULTS: The mean age of the study patients was similar in both groups (MMC = 68.1 +/- 8 years, control = 65.8 +/- 6.8 years). At the 12- and 24-month follow-up visits, the mean IOP with or without medications was lower in the MMC group than in the control group (15.6 +/- 3.5 vs 17.2 +/- 3.9 mm Hg at 12 months and 15.8 +/- 5.6 vs 17.8 +/- 2.8 mm Hg at 24 months, respectively). The IOP with or without medications significantly decreased after surgery in both groups (P < .05). Twelve months after surgery, the IOP decreased by 48% in the MMC group and by 35% in the control group. At the end of follow-up (24 months), the IOP decreased by 48% in the MMC group and by 32% in the control group (P = .01). The mean number of glaucoma medications decreased after surgery, there was no significant difference in complications (hyphema and suprachoroidal hemorrhage), and visual acuity was unchanged throughout the study in both groups.
CONCLUSION: The use of MMC in nonpenetrating deep sclerectomy with collagen implant is safe and improves surgical results. ||||| AIM: To study the efficacy and safety of deep sclerectomy (DS) augmented with intraoperative low dose mitomycin C (MMC) in a west African population.
METHODS: Prospective, randomised, controlled trial. Trial participants were Nigerian patients with medically uncontrolled primary open angle glaucoma undergoing primary surgery at Maja Hospital, Lagos, Nigeria. 39 eyes of 39 patients undergoing DS were randomised into receiving intraoperative MMC 0.25 mg/ml for 2 minutes at the end of procedure (DS-MMC) and a control group (DS-noMMC).
RESULTS: There were 21 patients in the DS-noMMC and 18 in the DS-MMC group with no difference in the preoperative characteristics of the groups. Mean follow up was 16.4 (SD 11.3) months. The probability of maintaining an intraocular pressure less than 18 mm Hg with or without additional medications (95% confidence intervals) at 1 year was 70% (47-92%, 95%) and 79% (57-100%), and at 18 months was 35% (8-62%) and 38% (7-69%) for the DS-noMMC and DS-MMC groups, respectively, with no difference in success rates (p = 0.6). An IOP of less than 18 mm Hg without additional medication was maintained in 65% (41-89%) and 73% (49-96%) at 1 year and 24% (8-48%) and 13% (13-46%) at 18 months for the DS-noMMC and DS-MMC groups, respectively (p = 0.5). There were no serious complications related to the procedure.
CONCLUSIONS: The success rates of DS in black west African glaucoma patients, as performed in this study, were low. The study did not achieve sufficient power to detect whether low dose intraoperative MMC application can increase success rates of DS. ||||| PURPOSE: To compare the results of viscocanalostomy with and without mitomycin-C (MMC).
METHODS: Retrospective results of 15 standard viscocanalostomy (VCO) operations (Group 1) were compared with the prospective results of 15 VCO operations performed with intraoperative adjunctive MMC (Group 2). MMC (0.2 mg/mL) was applied over and under the superficial scleral flap for 3 minutes in Group 2 before the deep flap was prepared. Each patient was followed up for at least 1 year, and results of examinations in the first 12 months were used in the statistical comparison of the two groups. Surgical success was defined as intraocular pressure (IOP) < or = 18 mmHg.
RESULTS: Preoperative mean intraocular pressures (IOP) in Group 1 and Group 2 were 35.3+/-11.0 and 39.1+/-8.9, respectively. Mean IOP levels at the 12th month were 14.4+/-2.6 and 11.9+/-4.0, respectively, showing a significant decrease in both groups (p<0.001). Postoperative IOP course appeared to be lower in the MMC group, however, the difference was not statistically significant (p=0.554). Complete success rates without medications were 40% in Group 1 and 67% in Group 2. No significant difference was found between the two groups in terms of early and late postoperative complications, pre- and postoperative number of antiglaucoma medications, and surgical success rates at the end of the study period (p>0.05 for all). A significant difference was verified between the two groups of eyes considering the conjunctival bleb types, as low-lying, localized blebs were the most frequent type in Group 1 and thin-walled, avascular blebs were more predominant in the MMC group (p=0.004).
CONCLUSIONS: Intraoperative adjunctive MMC use might improve the long-term results of viscocanalostomy by facilitating subconjunctival filtration and might widen the indication range of the technique. ||||| AIM: To report the safety and efficacy of intraoperative mitomycin (MMC) augmentation of combined phacoemulsification and deep sclerectomy (PDS).
METHODS: Retrospective, non-randomized, comparative, interventional case series of 119 eyes (63 with and 56 without MMC augmentation) of 119 patients who had PDS between September 2001 and April 2004.
RESULTS: The mean follow-up was 23 months (range 12-41 months). There were no differences in the baseline characteristics of the two groups except that patients from the phacoemulsification and deep sclerectomy with mitomycin C (PDS-MMC) group were on average, younger by 3 years (P=0.01). Two years after surgery, the probability of maintaining an IOP below 19 and 15 mmHg without glaucoma medications or needle revision was 76 and 62% in the PDS-MMC group and 62 and 45% in the PDS-no MMC group (P=0.02 and 0.04, respectively). Nd:YAG laser goniopuncture was performed in 71.4% of eyes in the PDS-no MMC and 61.9% of the PD-MMC group (P=0.33). Needle revision was performed in 21.4% of the PDS-no MMC and 17.4% of the PDS-MMC group (P=0.65). Ten patients (8.4%) lost more than two lines of Snellen's visual acuity during follow-up, with no difference between the groups. There were few serious complications related to MMC use (hypotony in one eye after laser goniopuncture). The overall incidence of transconjunctival oozing in the PDS-MMC group was 9.5% compared with 5.4% in the PDS-no MMC group.
CONCLUSION: This study demonstrates that augmentation of PDS with MMC is safe. MMC augmentation appears to increase the probability of achieving lower target intraocular pressures after combined PDS. ||||| PURPOSE: To prospectively study and compare the effectiveness and the safety of primary deep sclerectomy with and without the use of mitomycin C in eyes with open-angle glaucoma.
PATIENTS AND METHODS: A total of 90 eyes of 90 patients with primary open-angle glaucoma or pseudoexfoliative glaucoma underwent deep sclerectomy. Patients were enrolled consecutively and assigned randomly to undergo deep sclerectomy without the use of mitomycin C (DS group) and deep sclerectomy with the application of mitomycin C (DSMMC group) in a concentration of 0.2 mg/mL for 2.5 minutes, before the superficial scleral flap formation.
RESULTS: The intraocular pressure was significantly decreased by 7.13 mm Hg or 27.59% in the DS group and by 11.68 mm Hg or 42.25% in the DSMMC group at the end of the follow-up period. The intraocular pressure reduction in the DSMMC group was statistically significant when compared with that in the DS group (P <0.05). The complete (IOP <22 mm Hg without medication) and qualified (IOP < 22 mm Hg with or without medication) success rates at the end of the follow-up period were 42.5% and 72.5% in the DS group and 50% and 95% in the DSMMC group. The qualified success rate in the DSMMC group was statistically significant when compared with that in the DS group. Differences in complications (choroidal detachment, hyphema, leakage) seen between the two groups were statistically nonsignificant. A hemorrhagic detachment of the Descemet membrane was observed in one eye in the DSMMC group.
CONCLUSIONS: The use of intraoperative mitomycin C during deep sclerectomy significantly reduced the postoperative IOP and increased the success rate of the procedure. | [
{
"source_pmid": "15746961",
"source_text": "AIMS: To investigate the comparative efficacy and safety of deep sclerectomy with and without intraoperative mitomycin C (MMC) application for lowering the intraocular pressure (IOP).\nMETHODS: A total of 71 eyes of 71 consecutive patients who had routine deep sc... |
30336463 | CONCLUSIONS: The overall results support a positive association between CKD and AMD, although some limitations exist. Given the risk that AMD is increased in CKD, regular eye screenings for the CKD population is recommended for an early detection and intervention. | OBJECTIVE: To describe the prevalence and risk factors for age-related macular degeneration (AMD) in a multiethnic Asian cohort of Chinese, Malay, and Indian persons.
DESIGN: Population-based cross-sectional study.
PARTICIPANTS: A total of 10 033 persons (3280 Malay, 3400 Indian, and 3353 Chinese; response rate, 75%) 40 years of age or older residing in Singapore.
METHODS: We performed comprehensive systemic and ocular examinations, retinal photography, and laboratory investigations for all participants. We graded early and late AMD signs from retinal photographs using the modified Wisconsin AMD grading scale. We calculated the age-standardized prevalence of AMD using the 2010 Singapore adult population and analyzed risk factors for AMD using logistic regression models.
MAIN OUTCOME MEASURES: Early and late AMD.
RESULTS: Of the 9799 participants with gradable photographs, 588 had early AMD and 60 had late AMD. The age-standardized prevalence was 5.1% (95% confidence interval [CI], 4.6-5.5) for early AMD and 0.5% (95% CI, 0.4-0.6) for late AMD. The prevalence of early AMD was similar between Chinese (5.7%) and Indian (4.5%; P = 0.27) persons and lower in Malays (3.5%; P = 0.002 compared with Chinese; P = 0.09 compared with Indians); in contrast, the prevalence for late AMD was similar across ethnic groups (Chinese, 0.6%; Indian, 0.3%; and Malay, 0.3%; P = 0.20). Risk factors for early AMD were older age (odds ratio [OR], 1.40 per 5-year increase in age; 95% CI, 1.33-1.47), male gender (OR, 1.81; 95% CI, 1.43-2.29), hypertension (OR, 1.28; 95% CI, 1.02-1.61), and hyperopic refraction (OR, 1.17 per 1-diopter increase in spherical equivalent; 95% CI, 1.11-1.24). Risk factors for late AMD include older age (OR, 1.87 per 5-year increase in age; 95% CI, 1.54-2.19), smoking more than 5 packs per week (OR, 3.63; 95% CI, 1.34-9.80), and presence of chronic kidney disease (OR, 2.17; 95% CI, 1.22-3.88).
CONCLUSIONS: Early AMD is more common in Chinese and Indians than in Malays, but there were no racial variations in the prevalence of late AMD. ||||| PURPOSE: Age-related macular degeneration (AMD) and renal impairment are both associated with cardiovascular risk factors and with alterations in the complement pathways. There are few data on the association of AMD with chronic kidney disease.
METHODS: People who were visually impaired (binocular acuity < 6/18) due to AMD (ascertained from review of medical notes; n = 516) were compared to people with normal vision (6/6 or better; n = 2755). Cases with AMD and controls derive from a population-based cross-sectional study of people aged 75 years and over registered with 49 family practices in Britain. Glomerular filtration rate (eGFR) was estimated with the Modification of Diet in Renal Disease formula and proteinuria assessed by dipsticks.
RESULTS: After adjusting for a wide range of confounding factors, the presence of proteinuria was positively associated with AMD among men (odds ratio (OR) 2.06, 95% confidence interval (CI) 1.05, 4.04) but not in women (OR 0.62 95%CI 0.36,1.08). Among men, eGFR < 45 ml/min/1.73 m(2) was associated with AMD but not after adjusting for proteinuria. This was not observed for women. Both proteinuria and eGFR showed different associations with AMD by sex (p-values for interaction < 0.05).
CONCLUSIONS: Proteinuria appears to be a risk factor for AMD among men but not among women, possibly due to measurement errors in detecting proteinuria in women. ||||| BACKGROUND AND OBJECTIVES: Retinal abnormalities are common in inherited and acquired renal disease. This study determined the prevalence of retinal abnormalities in chronic kidney disease (CKD) stages 3 to 5.
DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: One hundred fifty patients with CKD stages 3 to 5 and 150 age- and gender-matched hospital patients with CKD stages 1 to 2 underwent bilateral retinal photography. These images were reviewed for incidental abnormalities, microvascular (Wong and Mitchell classification) and diabetic retinopathy (Airlie House criteria), and macular degeneration (Seddon classification).
RESULTS: Three (2%) patients with CKD stages 3 to 5 had retinal features characteristic of inherited renal disease (atrophy in Myopathy, Encephalopathy, Lactic Acidosis, Stroke-like episodes [MELAS] syndrome; and 2 with drusen in dense deposit disease). Fifty-nine (39%) patients had moderate-severe microvascular retinopathy (hemorrhages, exudates, etc.) compared with 19 (13%) with CKD stages 1 to 2. Forty-one (28%) had moderate-severe diabetic retinopathy (microaneurysms, exudates, etc.) compared with 16 (11%) with CKD stages 1 to 2. Ten (7%) had severe macular degeneration (geographic atrophy, hemorrhage, exudates, membranes) compared with one (1%) with CKD stages 1 to 2. Renal failure was an independent risk factor for microvascular retinopathy, diabetic retinopathy, and macular degeneration. Eleven (7.3%) patients with renal failure and one (0.7%) with CKD stages 1 to 2 had previously unrecognized vision-threatening retinal abnormalities that required immediate ophthalmologic attention.
CONCLUSIONS: Retinal abnormalities are common in CKD stages 3 to 5, and are more severe and more likely to threaten vision than in hospital patients with CKD stages 1 to 2. ||||| Age-related macular degeneration is the leading cause of irreversible blindness in the United States and often coexists with chronic kidney disease. Both conditions share common genetic and environmental risk factors. A total of 1183 participants aged 54+ were examined in the population-based, prospective cohort Blue Mountains Eye Study (Australia) to determine if chronic kidney disease increases the risk of age-related macular degeneration. Moderate chronic kidney disease (estimated glomerular filtration rate < 60 ml/min per 1.73 m(2) based on the Cockcroft-Gault equation) was present in 24% of the population (286 of 1183). The 5-yr incidence of early age-related macular degeneration was 3.9% in participants with no/mild chronic kidney disease (35 of 897) and 17.5% in those with moderate chronic kidney disease (50 of 286). After adjusting for age, sex, cigarette smoking, hypertension, complement factor H polymorphism, and other risk factors, persons with moderate chronic kidney disease were 3 times more likely to develop early age-related macular degeneration than persons with no/mild chronic kidney disease (odds ratio = 3.2; 95% confidence interval, 1.8 to 5.7, P < 0.0001). Each SD (14.8 ml/min per 1.73 m(2)) decrease in Cockcroft-Gault estimated glomerular filtration rate was associated with a doubling of the adjusted risk for early age-related macular degeneration (odds ratio = 2.0; 95% confidence interval, 1.5 to 2.8, P < 0.0001). In conclusion, persons with chronic kidney disease have a higher risk of early age-related macular degeneration, suggesting the possibility of shared pathophysiologic mechanisms between the two conditions. ||||| OBJECTIVE: To examine the associations of the serum cystatin C level and chronic kidney disease with the incidence of age-related macular degeneration (AMD) over 15 years.
METHODS: In this population-based cohort study of 4926 individuals aged 43 to 86 years at baseline, 3779 participated in 1 or more follow-up examinations. Age-related macular degeneration was determined by grading photographs of the macula. Individuals were defined as having mild or moderate to severe chronic kidney disease based on a value of more than 45 mL/min/1.73 m(2) to 60 mL/min/1.73 m(2) or less and 45 mL/min/1.73 m(2) or less, respectively, according to the Modification of Diet in Renal Disease Study equation.
RESULTS: While controlling for age and other risk factors, the level of serum cystatin C at baseline was associated with the incidence of early AMD (odds ratio per log standard deviation [95% confidence interval], 1.16 [1.01-1.35]) and exudative AMD (1.42 [1.03-1.96]) but not geographic atrophy (0.89 [0.56-1.41]) or progression of AMD (1.02 [0.88-1.18]). Mild chronic kidney disease was associated with the 15-year cumulative incidence of early AMD (odds ratio per log standard deviation, 1.36 [95% confidence interval, 1.00-1.86]) but not the incidence of other AMD end points.
CONCLUSION: There is a relationship between the level of serum cystatin C and chronic kidney disease with the incidence of AMD. The underlying biological processes remain to be determined. ||||| BACKGROUND: Chronic kidney disease (CKD) has been shown to be associated with diabetic retinopathy (DR) and age-related macular degeneration (AMD), leading causes of blindness in elderly adults in previous studies. However, the association of CKD with visual impairment (VI) is not clear. We aimed to examine the association of CKD with VI and other age-related ocular diseases in a population-based sample of Asian adults.
METHODS: We analyzed data from 10,033 adults aged 40-80 years who participated in the Singapore Epidemiology of Eye Diseases (SEED, 2004-11) Study. CKD was defined as an estimated glomerular filtration rate (eGFR) < 60 ml/min/1.73 m(2) from serum creatinine. VI was defined as best-corrected visual acuity < 20/40 in the better eye. Cataract, retinopathy, DR, glaucoma and AMD were assessed using standardized ocular examination, retinal photography and visual field assessments. The associations of CKD with VI and ocular conditions were examined using logistic regression models adjusted for age, sex, race, smoking, alcohol intake, education status, body mass index, systolic blood pressure, diabetes mellitus, cholesterol levels and cardiovascular disease.
FINDINGS: The prevalence of VI and ocular disease were significantly higher in participants with CKD (36.1% and 84.7%) than in those without (12.9% and 54.3%, both p < 0.001). In multivariable models, CKD was significantly associated with VI (odds ratio [95% confidence interval] = 1.34 [1.14-1.58]), any ocular disease (1.28 [1.03-1.61]), cataract (1.24 [1.01-1.52]), any retinopathy (1.77 [1.45-2.15]), and DR (1.94 [1.47-2.54]).
INTERPRETATION: The burden of VI and eye diseases is high among persons with CKD. Our findings suggest that it may be useful to screen for ocular disease and VI in persons with CKD. ||||| PURPOSE: To evaluate the association between chronic kidney disease (CKD) and early age-related macular degeneration (AMD) and peripheral retinal drusen in Korean adults 50 years and older.
METHODS: This study included 3008 participants aged 50-87 years. Early AMD was assessed from retinal photographs based on modified Wisconsin AMD grading system and peripheral retinal drusen were assessed with a standardized examination. We defined CKD as estimated glomerular filtration rate of 60mL/min/1.73m(2) and below according to the Modification of Diet in Renal Disease equation. Logistic regression was used to examine the association between early AMD, peripheral retinal drusen, and CKD.
RESULTS: There were 88 subjects with early AMD and 42 subjects with peripheral retinal drusen. After adjusting for age, gender, body mass index, smoking status, hypertension, and diabetes mellitus, a significant association was found between CKD and peripheral retinal drusen as well as early AMD. Subjects with CKD were more likely to have early AMD (OR, 1.68; 95% CI, 1.04-2.72) and peripheral retinal drusen (OR, 2.01; 95% CI, 1.02-3.99) than those without CKD.
CONCLUSIONS: CKD was associated with peripheral retinal drusen as well as early AMD in Korean adults 50 years and older. ||||| Chronic kidney disease (CKD) and macular degeneration (MD) are 2 grave diseases leading to significant disability secondary to renal failure and blindness. The 2 diseases share not only common risk factors but also similar pathogenic mechanisms to renal and retinal injuries. Previous epidemiological studies indicated association between these 2 diseases. However, this concept is challenged by recent investigations. Patients with mild to moderate CKD (n = 30,696) between January 1, 1995 and December 31, 2005 were selected from the Taiwan National Health Insurance Database. Controls (n = 122,784) were matched by age, gender, diabetes mellitus type 2, and hypertension status (1:4 ratios). The risk of MD was compared between the 2 groups. The mean age of patients was 54.9 ± 15.7 years. The proportion of MD was 2.7% in mild to moderate CKD patients and 1.9% in normal controls (P < 0.001); and, 0.39% and 0.26% (P < 0.001) in advanced MD. Mild to moderate CKD patients had higher risk for MD [adjusted odds ratio (OR), 1.301; 95% confidence interval (CI), 1.200-1.411; P < 0.001] than normal renal function subjects. The association was more pronounced for advanced MD. From all age strata (10 years increase), the presence of CKD in those patients aged less than 40 years had highest OR for all MD (OR = 2.125, 95% CI: 1.417-3.186, P < 0.001). The results were consistent in interaction terms, highlighting the importance of CKD in young age patient for risk of MD. The high risk for MD in mild to moderate CKD patients remains significant after adjustment for personal habits (alcohol drinking and smoking, model 1; OR: 1.371; 95% CI: 1.265-1.486; P < 0.001), comorbidities (dyslipidemia, cerebrovascular disease, and peripheral vascular disease, model 2; OR: 1.369; 95% CI: 1.264-1.484; P < 0.001) and all these factors (model 3; OR: 1.320, 95% CI: 1.218-1.431, P < 0.001). This association was consistent in the subanalysis, excluding those patients with diabetic retinopathy. Proper diagnosis and timely intervention should be warranted to retard visual loss of these patients. ||||| BACKGROUND: Age-related macular degeneration (AMD) and kidney disease may have shared risk factors, including cardiovascular disease risk factors; additionally AMD and dense deposit disease share a common causal link, with both associated with polymorphisms in the complement pathway. Accordingly, we explored a population-based cohort of US adults to examine if markers of kidney disease identify a higher risk population for prevalent AMD.
METHODS: A cross-sectional nested case-control study matching on age, sex and race was performed using data on adult participants in the Third National Health and Nutrition Examination Survey. Predictor variables included urine albumin-to-creatinine ratio and estimated glomerular filtration rate (eGFR). Study outcomes included late AMD, defined as neovascular disease or geographic atrophy (5:1 matching), and a composite of both early AMD, defined as soft drusen or pigment irregularities with or without any drusen, and late AMD (1:1 matching).
RESULTS: There were 51 participants with late AMD and 865 with any AMD. In conditional logistic regression adjusting for diabetes, hypertension and total cholesterol, lower eGFR was independently associated with late AMD [odds ratio (OR) = 3.05, 95% confidence interval (CI): 1.51-6.13], while albuminuria was not significant. For any AMD, neither albuminuria nor eGFR were significant in adjusted models. In sensitivity analyses excluding diabetics, albuminuria was associated with any AMD (OR = 1.56, 95% CI: 1.11-1.29 and 1.57, 95% CI: 0.61-3.69 for micro- and macroalbuminuria, respectively, P = 0.03).
CONCLUSIONS: Late AMD is more common among individuals with reduced kidney function. Whether this association reflects a common causal pathway or shared risk factors such as hypertension requires additional investigation. ||||| PURPOSE: Age-related macular degeneration (AMD) and chronic kidney disease both involve immune dysregulation and may share underlying pathophysiologic changes to systemic homeostasis. Hence, we aim to evaluate associations between impaired kidney function and early AMD, in a search for urinary biomarkers for AMD.
METHODS: A population-based, cross-sectional analysis of persons aged 45 to 84 years was conducted with renal function measured using serum creatinine and cystatin C levels and the estimated glomerular filtration rate (eGFR) calculated. Age-related macular degeneration status was ascertained from retinal photographs.
RESULTS: Of 5874 participants, 221 had early AMD. High serum cystatin C and low eGFR (≤60 ml/min/1.73 m) were not associated with early AMD in our multivariate analyses. Among normotensive persons, however, highest versus other deciles of cystatin C were associated with an increased prevalence of early AMD (odds ratio, 1.80; 95% confidence interval, 1.00 to 3.23).
CONCLUSIONS: Results could not confirm an association between kidney function and early AMD. The borderline association between cystatin C and early AMD in normotensive persons require further verification. ||||| PURPOSE: This study investigated the risk of age-related macular degeneration (AMD) in patients with end-stage renal disease (ESRD) receiving long-term dialysis and compared the risk between various dialysis modalities using propensity score-matching methods.
METHODS: From the National Health Insurance Research Database of Taiwan, the authors identified 27,232 patients with ESRD newly diagnosed from 2000 to 2010, including 9,287 patients on peritoneal dialysis (PD) and 17,945 patients on hemodialysis (HD). A total of 108,928 controls without kidney disease were randomly selected and frequency matched by age, sex, and index year of ESRD patients. The authors established an additional HD cohort matched by propensity scores of PD patients (N = 9,256 each). All cohorts were followed up until the end of 2011 to measure the incidence of AMD.
RESULTS: The incidences of AMD were 1.84, 4.03, 5.37, and 3.50 per 1,000 person-years in the control, ESRD (PD and HD), PD, and HD cohorts, respectively. The hazard ratios for AMD were 1.72, 2.47, and 1.43 for the ESRD, PD, and HD cohorts, with 95% confidence intervals of 1.50 to 1.97, 2.05 to 2.98, and 1.22 to 1.68, respectively, compared with the control cohort. The patients on PD exhibited a hazard ratio of 1.74 (95% confidence interval = 1.27-2.38) for developing AMD compared with propensity score-matched patients on HD.
CONCLUSION: Patients with ESRD may exhibit a higher risk of AMD than people without kidney disease. Patients on PD may be more likely to develop AMD than patients on HD. ||||| BACKGROUND: Previous study indicated a high prevalence of ocular fundus pathology among patients with chronic kidney disease (CKD), while the relationship between them has never been explored in a Chinese Population.
METHODS: This cross-sectional study included 9 670 participants enrolled in a medical screening program. Ocular fundus examination was performed by ophthalmologists using ophthalmoscopes. The presence of eGFR less than 60 mL/min/1.73 m(2) and/or proteinuria was defined as CKD.
RESULTS: Compared to participants without CKD, participants with CKD had higher prevalence of retinopathy (28.5% vs. 16.3%, P < 0.001), glaucoma suspect (3.1% vs. 1.8%, P = 0.004), age-related macular degeneration (1.7% vs. 0.9%, P = 0.01) and overall eye pathology (32.0% vs. 19.4%, P < 0.001). After adjusting for potential confounders, the odds ratio of proteinuria for overall eye pathology and retinopathy was 1.29 (95% confidence interval [CI] 1.07-1.55) and 1.37 (95% CI 1.12-1.67), respectively. The results were robust after excluding participants with hypertension or with diabetes.
CONCLUSIONS: Ocular fundus pathology is common among Chinese patients with CKD. Regular eye exam among persons with proteinuria is warranted. | [
{
"source_pmid": "24661862",
"source_text": "OBJECTIVE: To describe the prevalence and risk factors for age-related macular degeneration (AMD) in a multiethnic Asian cohort of Chinese, Malay, and Indian persons.\nDESIGN: Population-based cross-sectional study.\nPARTICIPANTS: A total of 10 033 persons (3280 ... |
24635444 | WHAT IS NEW AND CONCLUSION: This is the first meta-analysis to systematically evaluate the efficacy of different treatment regimens for anti-VEGF therapy. Ranibizumab 0·3 or 0·5 mg monthly treatment was more effective for neovascular AMD than non-anti-VEGF treatments but is no better than bevacizumab. | OBJECTIVE: To describe effects of ranibizumab and bevacizumab when administered monthly or as needed for 2 years and to describe the impact of switching to as-needed treatment after 1 year of monthly treatment.
DESIGN: Multicenter, randomized clinical trial.
PARTICIPANTS: Patients (n = 1107) who were followed up during year 2 among 1185 patients with neovascular age-related macular degeneration who were enrolled in the clinical trial.
INTERVENTIONS: At enrollment, patients were assigned to 4 treatment groups defined by drug (ranibizumab or bevacizumab) and dosing regimen (monthly or as needed). At 1 year, patients initially assigned to monthly treatment were reassigned randomly to monthly or as-needed treatment, without changing the drug assignment.
MAIN OUTCOME MEASURES: Mean change in visual acuity.
RESULTS: Among patients following the same regimen for 2 years, mean gain in visual acuity was similar for both drugs (bevacizumab-ranibizumab difference, -1.4 letters; 95% confidence interval [CI], -3.7 to 0.8; P = 0.21). Mean gain was greater for monthly than for as-needed treatment (difference, -2.4 letters; 95% CI, -4.8 to -0.1; P = 0.046). The proportion without fluid ranged from 13.9% in the bevacizumab-as-needed group to 45.5% in the ranibizumab monthly group (drug, P = 0.0003; regimen, P < 0.0001). Switching from monthly to as-needed treatment resulted in greater mean decrease in vision during year 2 (-2.2 letters; P = 0.03) and a lower proportion without fluid (-19%; P < 0.0001). Rates of death and arteriothrombotic events were similar for both drugs (P > 0.60). The proportion of patients with 1 or more systemic serious adverse events was higher with bevacizumab than ranibizumab (39.9% vs. 31.7%; adjusted risk ratio, 1.30; 95% CI, 1.07-1.57; P = 0.009). Most of the excess events have not been associated previously with systemic therapy targeting vascular endothelial growth factor (VEGF).
CONCLUSIONS: Ranibizumab and bevacizumab had similar effects on visual acuity over a 2-year period. Treatment as needed resulted in less gain in visual acuity, whether instituted at enrollment or after 1 year of monthly treatment. There were no differences between drugs in rates of death or arteriothrombotic events. The interpretation of the persistence of higher rates of serious adverse events with bevacizumab is uncertain because of the lack of specificity to conditions associated with inhibition of VEGF. ||||| PURPOSE: To assess the efficacy and adverse-events profile of combined treatment with ranibizumab and verteporfin photodynamic therapy (PDT) in patients with predominantly classic choroidal neovascularization (CNV) secondary to neovascular age-related macular degeneration.
DESIGN: Two-year, multicenter, randomized, single-masked, controlled study.
METHODS: Patients received monthly intravitreal injections of ranibizumab 0.5 mg (n = 106) or sham injections (n = 56). All patients received PDT on day zero, then quarterly as needed. Efficacy assessment included changes in visual acuity (VA) and lesion characteristics and PDT frequency. Adverse events were summarized by incidence and severity.
RESULTS: At month 24, 88% of ranibizumab + PDT patients had lost <15 letters from baseline VA (vs 75% for PDT alone), 25% had gained >or=15 letters (vs 7% for PDT alone), and the two treatment arms differed by 12.4 letters in mean VA change (P < .05 for all between-group differences). The VA benefit of adding ranibizumab to PDT in year one persisted through year two. On average, ranibizumab + PDT patients exhibited less lesion growth and greater reduction of CNV leakage and subretinal fluid accumulation, and required fewer PDT retreatments, than PDT-alone patients (mean = 0.4 vs 3.0 PDT retreatments). Endophthalmitis and serious intraocular inflammation occurred, respectively, in 2.9% and 12.4% of ranibizumab + PDT patients and 0% of PDT-alone patients. Incidences of serious nonocular adverse events were similar in the two treatment groups.
CONCLUSIONS: Through two years, ranibizumab + PDT was more effective than PDT alone and had a low rate of associated adverse events. ||||| OBJECTIVE: The 2-year, phase III trial designated Anti-vascular endothelial growth factor (VEGF) Antibody for the Treatment of Predominantly Classic Choroidal Neovascularization (CNV) in Age-related Macular Degeneration (ANCHOR) compared ranibizumab with verteporfin photodynamic therapy (PDT) in treating predominantly classic CNV.
DESIGN: Multicenter, international, randomized, double-masked, active-treatment-controlled clinical trial.
PARTICIPANTS: Patients with predominantly classic, subfoveal CNV not previously treated with PDT or antiangiogenic drugs.
INTERVENTION: Patients were randomized 1:1:1 to verteporfin PDT plus monthly sham intraocular injection or to sham verteporfin PDT plus monthly intravitreal ranibizumab (0.3 mg or 0.5 mg) injection. The need for PDT (active or sham) retreatment was evaluated every 3 months using fluorescein angiography (FA).
MAIN OUTCOME MEASURES: The primary, intent-to-treat efficacy analysis was at 12 months, with continued measurements to month 24. Key measures included the percentage losing <15 letters from baseline visual acuity (VA) score (month 12 primary efficacy outcome measure), percentage gaining >or=15 letters from baseline, and mean change over time in VA score and FA-assessed lesion characteristics. Adverse events were monitored.
RESULTS: Of 423 patients (143 PDT, 140 each in the 2 ranibizumab groups), the majority (>or=77% in each group) completed the 2-year study. Consistent with results at month 12, at month 24 the VA benefit from ranibizumab was statistically significant (P<0.0001 vs. PDT) and clinically meaningful: 89.9% to 90.0% of ranibizumab-treated patients had lost <15 letters from baseline (vs. 65.7% of PDT patients); 34% to 41.0% had gained >or=15 letters (vs. 6.3% of PDT group); and, on average, VA was improved from baseline by 8.1 to 10.7 letters (vs. a mean decline of 9.8 letters in PDT group). Changes in lesion anatomic characteristics on FA also favored ranibizumab (all comparisons P<0.0001 vs. PDT). Overall, there was no imbalance among groups in rates of serious ocular and nonocular adverse events. In the pooled ranibizumab groups, 3 of 277 (1.1%) patients developed presumed endophthalmitis in the study eye (rate per injection = 3/5921 [0.05%]).
CONCLUSIONS: In this 2-year study, ranibizumab provided greater clinical benefit than verteporfin PDT in patients with age-related macular degeneration with new-onset, predominantly classic CNV. Rates of serious adverse events were low.
FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references. ||||| PURPOSE: To report 1-year visual and anatomic outcomes of a prospective, double-masked randomised clinical trial comparing bevacizumab with ranibizumab for the treatment of age-related macular degeneration (AMD).
METHODS: Patients who met inclusion criteria were randomised 2 : 1 to bevacizumab or ranibizumab. All subjects and investigators (except for the pharmacist responsible for study assignments) were masked to treatment arms. Visual acuity was taken on Early Treatment Diabetic Retinopathy Study chart. Patients were given either bevacizumab or ranibizumab every month for the first 3 months, followed by an optical coherence tomography-guided, variable-dosing treatment schedule. Main outcomes measured included visual acuity, foveal thickness, and total number of injections over the 1-year treatment period.
RESULTS: In total, 15 patients received bevacizumab and 7 patients received ranibizumab. The average pre-operative visual acuity was 34.9 letters in the bevacizumab group, and 32.7 letters in the ranibizumab group. At 1-year follow-up, mean vision was 42.5 letters in the bevacizumab group, and 39.0 letters in the ranibizumab group. Two-tailed t-test failed to showed statistical significance between the two groups (P=0.5). Patients in the bevacizumab group underwent an average of eight injections, whereas patients in the ranibizumab group underwent a mean of four injections (P=0.001).
CONCLUSION: The 1-year outcomes of a prospective, double-masked, randomised clinical trial comparing bevacizumab with ranibizumab failed to show a difference in visual and anatomic outcomes between the two treatments for choroidal neovascularisation in AMD. Total injections given over the treatment period were significantly different between the two groups. Further studies with larger sample sizes are warranted. ||||| PURPOSE: To evaluate efficacy and safety of quarterly (and then monthly) ranibizumab during the 2-year Phase IIIb, multicenter, randomized, double-masked, sham injection-controlled study of the efficacy and safety of ranibizumab in subjects with subfoveal CNV with or without classic CNV secondary to AMD (PIER) study.
DESIGN: Phase IIIb, multicenter, randomized, double-masked, sham injection-controlled trial in patients with choroidal neovascularization (CNV) secondary to age-related macular degeneration (AMD).
METHODS: Patients were randomized 1:1:1 to sham injection (n = 63) or 0.3 mg (n = 60) or 0.5 mg (n = 61) intravitreal ranibizumab monthly for 3 months and then quarterly. During study year 2, eligible sham-group patients crossed over to 0.5 mg ranibizumab quarterly. Later in year 2, all eligible randomized patients rolled over to 0.5 mg ranibizumab monthly. Key efficacy and safety outcomes of the 2-year trial are reported.
RESULTS: At month 24, visual acuity (VA) had decreased an average of 21.4, 2.2, and 2.3 letters from baseline in the sham, 0.3 mg, and 0.5 mg groups (P < .0001 for each ranibizumab group vs sham). VA of sham patients who crossed over (and subsequently rolled over) to ranibizumab decreased across time, with an average loss of 3.5 letters 10 months after crossover. VA of 0.3 mg and 0.5 mg group patients who rolled over to monthly ranibizumab increased for an average gain of 2.2 and 4.1 letters, respectively, 4 months after rollover. The ocular safety profile of ranibizumab was favorable and consistent with previous reports.
CONCLUSIONS: Ranibizumab provided significant VA benefit in patients with AMD-related CNV compared with sham injection. Ranibizumab appeared to provide additional VA benefit to treated patients who rolled over to monthly dosing, but not to patients who began receiving ranibizumab after >14 months of sham injections. ||||| OBJECTIVE: To evaluate the safety and efficacy of intravitreal ranibizumab in a large population of subjects with neovascular age-related macular degeneration (AMD).
DESIGN: Twelve-month randomized (cohort 1) or open-label (cohort 2) multicenter clinical trial.
PARTICIPANTS: A total of 4300 subjects with angiographically determined subfoveal choroidal neovascularization (CNV) secondary to AMD.
METHODS: Cohort 1 subjects were randomized 1:1 to receive 0.3 mg (n = 1169) or 0.5 mg (n = 1209) intravitreal ranibizumab for 3 monthly loading doses. Dose groups were stratified by AMD treatment history (treatment-naïve vs. previously treated). Cohort 1 subjects were retreated on the basis of optical coherence tomography (OCT) or visual acuity (VA) criteria. Cohort 2 subjects (n = 1922) received an initial intravitreal dose of 0.5 mg ranibizumab and were retreated at physician discretion. Safety was evaluated at all visits.
MAIN OUTCOME MEASURES: Safety outcomes included the incidence of ocular and nonocular adverse events (AEs) and serious adverse events (SAEs). Efficacy outcomes included changes in best-corrected VA over time.
RESULTS: Some 81.7% of cohort 1 subjects and 49.9% of cohort 2 subjects completed the 12-month study. The average total number of ranibizumab injections was 4.9 for cohort 1 and 3.6 for cohort 2. The incidence of vascular and nonvascular deaths during the 12-month study was 0.9% and 0.7% in the cohort 1 0.3 mg group, 0.8% and 1.5% in the cohort 1 0.5 mg group, and 0.7% and 0.9% in cohort 2, respectively. The incidence of death due to unknown cause was 0.1% in both cohort 1 dose groups and cohort 2. The number of vascular deaths and deaths due to unknown cause did not differ across cohorts or dose groups. Stroke rates were 0.7%, 1.2%, and 0.6% in the 0.3 mg and 0.5 mg groups and cohort 2, respectively. At month 12, cohort 1 treatment-naïve subjects had gained an average of 0.5 (0.3 mg) and 2.3 (0.5 mg) VA letters and previously treated subjects had gained 1.7 (0.3 mg) and 2.3 (0.5 mg) VA letters.
CONCLUSIONS: Intravitreal ranibizumab was safe and well tolerated in a large population of subjects with neovascular AMD. Ranibizumab had a beneficial effect on VA. Future investigations will seek to establish optimal dosing regimens for persons with neovascular AMD.
FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references. ||||| OBJECTIVE: To demonstrate noninferiority of a quarterly treatment regimen to a monthly regimen of ranibizumab in patients with subfoveal choroidal neovascularization (CNV) secondary to age-related macular degeneration (AMD).
DESIGN: A 12-month, multicenter, randomized, double-masked, active-controlled, phase IIIb study.
PARTICIPANTS: Patients with primary or recurrent subfoveal CNV secondary to AMD (353 patients), with predominantly classic, minimally classic, or occult (no classic component) lesions.
INTERVENTION: Patients were randomized (1:1:1) to 0.3 mg quarterly, 0.5 mg quarterly, or 0.3 mg monthly doses of ranibizumab. Treatment comprised of a loading phase (3 consecutive monthly injections) followed by a 9-month maintenance phase (either monthly or quarterly injection).
MAIN OUTCOME MEASURES: Mean change in best-corrected visual acuity (BCVA) and central retinal thickness (CRT) from baseline to month 12 and the incidence of adverse events (AEs).
RESULTS: In the per-protocol population (293 patients), BCVA, measured by Early Treatment Diabetic Retinopathy Study-like charts, increased from baseline to month 12 by 4.9, 3.8, and 8.3 letters in the 0.3 mg quarterly (104 patients), 0.5 mg quarterly (88 patients), and 0.3 mg monthly (101 patients) dosing groups, respectively. Similar results were observed in the intent-to-treat (ITT) population (353 patients). The mean decrease in CRT from baseline to month 12 in the ITT population was -96.0 μm in 0.3 mg quarterly, -105.6 μm in 0.5 mg quarterly, and -105.3 μm in 0.3 mg monthly group. The most frequent ocular AEs were conjunctival hemorrhage (17.6%, pooled quarterly groups; 10.4%, monthly group) and eye pain (15.1%, pooled quarterly groups; 20.9%, monthly group). There were 9 ocular serious AEs and 3 deaths; 1 death was suspected to be study related (cerebral hemorrhage; 0.5 mg quarterly group). The incidences of key arteriothromboembolic events were low.
CONCLUSIONS: After 3 initial monthly ranibizumab injections, both monthly (0.3 mg) and quarterly (0.3 mg/0.5 mg) ranibizumab treatments maintained BCVA in patients with CNV secondary to AMD. At month 12, BCVA gain in the monthly regimen was higher than that of the quarterly regimens. The noninferiority of a quarterly regimen was not achieved with reference to 5.0 letters. The safety profile was similar to that reported in prior ranibizumab studies. ||||| BACKGROUND: Ranibizumab--a recombinant, humanized, monoclonal antibody Fab that neutralizes all active forms of vascular endothelial growth factor A--has been evaluated for the treatment of neovascular age-related macular degeneration.
METHODS: In this multicenter, 2-year, double-blind, sham-controlled study, we randomly assigned patients with age-related macular degeneration with either minimally classic or occult (with no classic lesions) choroidal neovascularization to receive 24 monthly intravitreal injections of ranibizumab (either 0.3 mg or 0.5 mg) or sham injections. The primary end point was the proportion of patients losing fewer than 15 letters from baseline visual acuity at 12 months.
RESULTS: We enrolled 716 patients in the study. At 12 months, 94.5% of the group given 0.3 mg of ranibizumab and 94.6% of those given 0.5 mg lost fewer than 15 letters, as compared with 62.2% of patients receiving sham injections (P<0.001 for both comparisons). Visual acuity improved by 15 or more letters in 24.8% of the 0.3-mg group and 33.8% of the 0.5-mg group, as compared with 5.0% of the sham-injection group (P<0.001 for both doses). Mean increases in visual acuity were 6.5 letters in the 0.3-mg group and 7.2 letters in the 0.5-mg group, as compared with a decrease of 10.4 letters in the sham-injection group (P<0.001 for both comparisons). The benefit in visual acuity was maintained at 24 months. During 24 months, presumed endophthalmitis was identified in five patients (1.0%) and serious uveitis in six patients (1.3%) given ranibizumab.
CONCLUSIONS: Intravitreal administration of ranibizumab for 2 years prevented vision loss and improved mean visual acuity, with low rates of serious adverse events, in patients with minimally classic or occult (with no classic lesions) choroidal neovascularization secondary to age-related macular degeneration. (ClinicalTrials.gov number, NCT00056836 [ClinicalTrials.gov].). | [
{
"source_pmid": "22555112",
"source_text": "OBJECTIVE: To describe effects of ranibizumab and bevacizumab when administered monthly or as needed for 2 years and to describe the impact of switching to as-needed treatment after 1 year of monthly treatment.\nDESIGN: Multicenter, randomized clinical trial.\nPA... |
16856103 | AUTHORS' CONCLUSIONS: There is no evidence from good quality randomized trials or non-randomized studies of the effectiveness of lens extraction for chronic primary angle-closure glaucoma. | PURPOSE: To evaluate the long-term effects of extraction of incipient cataracts or clear lenses on glaucoma control in patients with subacute or chronic angle-closure glaucoma.
SETTING: Department of Ophthalmology, University of Amsterdam, The Netherlands.
METHODS: This retrospective analysis comprised 22 extracapsular lens extractions with implantation of a posterior chamber intraocular lens in 18 patients with chronic or subacute angle-closure glaucoma (Group 1). The effect of glaucoma control was evaluated using visual field examination, diurnal intraocular pressure (IOP) curves, gonioscopic appearance, and number of antiglaucoma medications. The results were compared with those in 25 eyes of 19 patients with chronic angle-closure glaucoma in whom a filtering procedure was performed (Group 2).
RESULTS: Glaucoma control was achieved in 15 eyes (68%) in Group 1 and in 17 eyes (68%) in Group 2. Mean preoperative IOP was 27.9 mm Hg +/- 8.1 (SD) and 29.0 +/- 7.7 mm Hg, respectively. Mean postoperative IOP was 17.1 +/- 2.9 mm Hg (Group 1) and 14.8 +/- 6.6 mm Hg (Group 2) after a mean follow-up of 52.6 and 58.9 months, respectively. Mean number of ocular hypotensive medications preoperatively was 2.3 +/- 0.8 in Group 1 and 2.2 +/- 0.8 in Group 2 and at last follow-up, 1.3 +/- 0.7 and 0.52 +/- 0.8, respectively. Twenty eyes (91%) in Group 1 had the same or better final visual acuity than before surgery. In Group 2, the final visual acuity was unchanged or better in 13 eyes (52%) and worse in 12 eyes (48%); subsequent cataract surgery was performed in 9 (75%) of these 12 eyes. Additional incisional surgery was done or recommended in 6 eyes (27%) in Group 1 and 20 eyes in Group 2 (80%).
CONCLUSION: Drainage surgery in patients with angle-closure glaucoma proved to be associated with multiple surgical interventions and deterioration in visual function. The choice of first a cataract procedure with the option of a future trabeculectomy may be a more attractive approach in patients with subacute or chronic angle-closure glaucoma than trabeculectomy followed by an optional cataract procedure. ||||| PURPOSE: We studied the surgical outcomes of phacoemulsification and intraocular lens (IOL) implantation for cataract and/or uncontrolled intraocular pressure (IOP) in eyes with angle closure glaucoma.
SETTING: Department of Ophthalmology, National Nagasaki Medical Center, Nagasaki, Japan.
METHODS: Eighteen eyes from 15 patients after laser iridotomy (17 eyes) or peripheral iridectomy (1 eye) had undergone surgery and were studied. We used an iris retractor in 7 eyes due to insufficient mydriasis and a capsular tension ring in 2 eyes due to phacodonesis during the operation. The patients were followed up for at least 6 months (13.8 +/- 7.2 months; range: 6-36 months).
RESULTS: The mean IOP significantly decreased from 17.4 +/- 8.1 to 13.5 +/- 3.3 mm Hg at 6 months after surgery. The IOP was below 21 mm Hg in all eyes. The visual acuity was not worsened in any eyes and became better than 2 Snellen lines in 14 eyes. The corneal endothelial cell count decreased from 2,365 +/- 517 to 1,960 +/- 661/mm2 (18.3 +/- 17.2%).
CONCLUSIONS: Phacoemulsification and IOL implantation is useful in IOP control for angle closure glaucoma after relief of pupillary block. However, we should take care of operative complications because of a shallow anterior chamber, poor mydriasis and zonular weakness. | [
{
"source_pmid": "9795850",
"source_text": "PURPOSE: To evaluate the long-term effects of extraction of incipient cataracts or clear lenses on glaucoma control in patients with subacute or chronic angle-closure glaucoma.\nSETTING: Department of Ophthalmology, University of Amsterdam, The Netherlands.\nMETHO... |
26505407 | In conclusion, our meta-analysis provides evidence that the rs2230199 polymorphism contributes to the development of AMD. Further large-scale multicenter epidemiological studies are warranted to confirm this finding. | Dysregulation of the alternative pathway (AP) of complement cascade has been implicated in the pathogenesis of age-related macular degeneration (AMD), the leading cause of blindness in the elderly. To further test the hypothesis that defective control of complement activation underlies AMD, parameters of complement activation in blood plasma were determined together with disease-associated genetic markers in AMD patients. Plasma concentrations of activation products C3d, Ba, C3a, C5a, SC5b-9, substrate proteins C3, C4, factor B and regulators factor H and factor D were quantified in patients (n = 112) and controls (n = 67). Subjects were analyzed for single nucleotide polymorphisms in factor H (CFH), factor B-C2 (BF-C2) and complement C3 (C3) genes which were previously found to be associated with AMD. All activation products, especially markers of chronic complement activation Ba and C3d (p<0.001), were significantly elevated in AMD patients compared to controls. Similar alterations were observed in factor D, but not in C3, C4 or factor H.
Logistic regression analysis revealed better discriminative accuracy of a model that is based only on complement activation markers Ba, C3d and factor D compared to a model based on genetic markers of the complement system within our study population. In both the controls' and AMD patients' group, the protein markers of complement activation were correlated with CFH haplotypes. This study is the first to show systemic complement activation in AMD patients. This suggests that AMD is a systemic disease with local disease manifestation at the ageing macula. Furthermore, the data provide evidence for an association of systemic activation of the alternative complement pathway with genetic variants of CFH that were previously linked to AMD susceptibility. ||||| PURPOSE: Intermediate and large drusen usually precede advanced age-related macular degeneration (AMD). There is little information about which genes influence drusen accumulation. Discovery of genetic variants associated with drusen may lead to prevention and treatments of AMD in its early stages.
METHODS: A total of 3066 subjects were evaluated on the basis of ocular examinations and fundus photography and categorized as control (n = 221), intermediate drusen (n = 814), large drusen (n = 949), or advanced AMD (n = 1082). SNPs in the previously identified CFH, C2, C3, CFB, CFI, APOE, and ARMS2/HTRA1 genes/regions and the novel genes LIPC, CETP, and ABCA1 in the high-density lipoprotein (HDL) cholesterol pathway were genotyped. Associations between stage of AMD and SNPs were assessed using logistic regression.
RESULTS: Controlling for age, sex, education, smoking, body mass index, and antioxidant treatment, the number of minor (T) alleles of the genes LIPC and ABCA1 were significantly associated with a reduced risk of intermediate drusen (LIPC [P trend = 0.045], ABCA1 [P = 4.4 × 10(-3)]), large drusen (LIPC [P = 0.041], ABCA1 [P = 7.7 × 10(-4)]), and advanced AMD (LIPC [P = 1.8 × 10(-3)], ABCA1 [P = 3 × 10(-4)]). After further adjustment for known genetic factors, the protective effect of the TT genotype was significant for intermediate drusen (LIPC [odds ratio (OR), 0.56; 95% confidence interval (CI), 0.33-0.94], ABCA1 [OR, 0.48; 95% CI, 0.27-0.85]), large drusen (LIPC [OR, 0.58; 95% CI, 0.34-0.98)], ABCA1 [OR, 0.41; 95% CI, 0.23-0.74)]), and advanced AMD (LIPC [OR, 0.39; 95% CI, 0.21-0.74)], ABCA1 [OR, 0.35; 95% CI, 0.17-0.71)]). CFH, C3, C2, and ARMS2/HTRA1 were associated with large drusen and advanced AMD.
CONCLUSIONS: LIPC and ABCA1 are related to intermediate and large drusen, as well as advanced AMD. CFH, C3, C2, and ARMS2/HTRA1 are associated with large drusen and advanced AMD. Genes may have varying effects on different stages of AMD. ||||| PURPOSE: To investigate whether the previously reported noncoding variant of the complement factor H (CFH) gene and two coding variants of the complement component 3 (C3) gene are associated with exudative age-related macular degeneration (AMD) in Chinese patients.
METHODS: One hundred fifty Chinese patients with exudative AMD and 161 control individuals without AMD were recruited for the study. Genomic DNA was extracted from blood leukocytes. The noncoding variant of the CFH gene (rs1410996) and two coding variants of the C3 gene (rs2230199 and rs1047286) were genotyped by polymerase chain reaction (PCR) followed by allele-specific restriction enzyme digestion and direct sequencing.
RESULTS: Significant association was detected for exudative AMD with the CFH noncoding variant rs1410996. Frequencies of the risk C allele at rs1410996 were 72.0% in AMD cases versus 55.6% in controls (P < 0.001). The odds ratio for risk of AMD was 1.71 (95% confidence interval [CI], 0.82-3.54) for heterozygous TC genotype and 3.85 (95% CI, 1.84-8.05) for homozygous CC genotype compared with the wild TT genotype. In contrast, the C3 variants rs2230199 and rs1047286 were not associated with exudative AMD in the studied subjects. Frequencies of the risk G allele at rs2230199 and of the risk T allele at rs1047286 were 0.3% to 1.0% in both cases and controls.
CONCLUSIONS: The data suggest that the noncoding variant rs1410996 of the CFH gene moderately increased the risk of exudative AMD in a Chinese population. The C3 variants were rare and not associated with exudative AMD in this Chinese cohort. ||||| PURPOSE: We explored associations between age-related macular degeneration (AMD) and genetic variants of 10 genes in a nationwide Chinese population.
METHODS: In this multicenter case-control study, 535 AMD patients and 469 controls were recruited from 16 centers that spread from the north to the south of China. All participants underwent comprehensive eye examinations, and 40 single nucleotide polymorphisms (SNPs) of 10 genes were selected. DNA samples were genotyped with the MassArray system. The effect of the genotypes and haplotypes on AMD was assessed with logistic regression analysis, adjusted for age, sex, long-term residence, and family origin.
RESULTS: In our study, 11 SNPs in complement H (CFH), 2 in age-related maculopathy susceptibility 2 (ARMS2), and 2 in high-temperature requirement factor A1 (HTRA1) were associated significantly with AMD. They were rs551397, rs800292, rs1329424, rs1061170, rs10801555, rs12124794, rs10733086, rs10737680, rs2274700, rs1410996, and rs380390 in CFH; rs10490924 and rs2736912 in ARMS2; and rs11200638 and rs3793917 in HTRA1. Three haplotypes in CFH, predisposed the patients significantly to AMD (P<0.001, P=0.001, and P<0.001, respectively). With the sample size of our study, no relationship was found for AMD and the SNPs tested in complement 3 (C3); serpin peptidase inhibitor, clade G, member 1 (SERPING1); vascular endothelial growth factor (VEGF); cholesterol ester transfer protein (CETP); lipoprotein lipase (LPL); hepatic lipase (LIPC); and metallopeptidase inhibitor 3 (TIMP3) genes.
CONCLUSIONS: Gene variants in CFH, ARMS2, and HTRA1 contribute to AMD in the Chinese population. ||||| PURPOSE: Genes in the complement pathway, including complement factor H (CFH), C2/BF, and C3, have been reported to be associated with age-related macular degeneration (AMD). Genetic variants, single-nucleotide polymorphisms (SNPs), in these genes were geno-typed for a case-control association study in a mainland Han Chinese population.
METHODS: One hundred and fifty-eight patients with wet AMD, 80 patients with soft drusen, and 220 matched control subjects were recruited among Han Chinese in mainland China. Seven SNPs in CFH and two SNPs in C2, CFB', and C3 were genotyped using the ABI SNaPshot method. A deletion of 84,682 base pairs covering the CFHR1 and CFHR3 genes was detected by direct polymerase chain reaction and gel electrophoresis.
RESULTS: Four SNPs, including rs3753394 (P = 0.0276), rs800292 (P = 0.0266), rs1061170 (P = 0.00514), and rs1329428 (P = 0.0089), in CFH showed a significant association with wet AMD in the cohort of this study. A haplotype containing these four SNPs (CATA) significantly increased protection of wet AMD with a P value of 0.0005 and an odds ratio of 0.29 (95% confidence interval: 0.15-0.60). Unlike in other populations, rs2274700 and rs1410996 did not show a significant association with AMD in the Chinese population of this study. None of the SNPs in CFH showed a significant association with drusen, and none of the SNPs in CFH, C2, CFB, and C3 showed a significant association with either wet AMD or drusen in the cohort of this study. The CFHR1 and CFHR3 deletion was not polymorphic in the Chinese population and was not associated with wet AMD or drusen.
CONCLUSION: This study showed that SNPs rs3753394 (P = 0.0276), rs800292 (P = 0.0266), rs1061170 (P = 0.00514), and rs1329428 (P = 0.0089), but not rs7535263, rs1410996, or rs2274700, in CFH were significantly associated with wet AMD in a mainland Han Chinese population. This study showed that CFH was more likely to be AMD susceptibility gene at Chr.1q31 based on the finding that the CFHR1 and CFHR3 deletion was not polymorphic in the cohort of this study, and none of the SNPs that were significantly associated with AMD in a white population in C2, CFB, and C3 genes showed a significant association with AMD. ||||| BACKGROUND: Age-related macular degeneration is the most common cause of blindness in Western populations. Susceptibility is influenced by age and by genetic and environmental factors. Complement activation is implicated in the pathogenesis.
METHODS: We tested for an association between age-related macular degeneration and 13 single-nucleotide polymorphisms (SNPs) spanning the complement genes C3 and C5 in case subjects and control subjects from the southeastern region of England. All subjects were examined by an ophthalmologist and had independent grading of fundus photographs to confirm their disease status. To test for replication of the most significant findings, we genotyped a set of Scottish cases and controls.
RESULTS: The common functional polymorphism rs2230199 (Arg80Gly) in the C3 gene, corresponding to the electrophoretic variants C3S (slow) and C3F (fast), was strongly associated with age-related macular degeneration in both the English group (603 cases and 350 controls, P=5.9x10(-5)) and the Scottish group (244 cases and 351 controls, P=5.0x10(-5)). The odds ratio for age-related macular degeneration in C3 S/F heterozygotes as compared with S/S homozygotes was 1.7 (95% confidence interval [CI], 1.3 to 2.1); for F/F homozygotes, the odds ratio was 2.6 (95% CI, 1.6 to 4.1). The estimated population attributable risk for C3F was 22%.
CONCLUSIONS: Complement C3 is important in the pathogenesis of age-related macular degeneration. This finding further underscores the influence of the complement pathway in the pathogenesis of this disease. ||||| BACKGROUND: Variants in the complement cascade genes and the LOC387715/HTRA1, have been widely reported to associate with age-related macular degeneration (AMD), the most common cause of visual impairment in industrialized countries.
METHODS/PRINCIPAL FINDINGS: We investigated the association between the LOC387715 A69S and complement component C3 R102G risk alleles in the Finnish case-control material and found a significant association with both variants (OR 2.98, p = 3.75 x 10(-9); non-AMD controls and OR 2.79, p = 2.78 x 10(-19), blood donor controls and OR 1.83, p = 0.008; non-AMD controls and OR 1.39, p = 0.039; blood donor controls), respectively. Previously, we have shown a strong association between complement factor H (CFH) Y402H and AMD in the Finnish population. A carrier of at least one risk allele in each of the three susceptibility loci (LOC387715, C3, CFH) had an 18-fold risk of AMD when compared to a non-carrier homozygote in all three loci. A tentative gene-gene interaction between the two major AMD-associated loci, LOC387715 and CFH, was found in this study using a multiplicative (logistic regression) model, a synergy index (departure-from-additivity model) and the mutual information method (MI), suggesting that a common causative pathway may exist for these genes. Smoking (ever vs. never) exerted an extra risk for AMD, but somewhat surprisingly, only in connection with other factors such as sex and the C3 genotype. Population attributable risks (PAR) for the CFH, LOC387715 and C3 variants were 58.2%, 51.4% and 5.8%, respectively, the summary PAR for the three variants being 65.4%.
CONCLUSIONS/SIGNIFICANCE: Evidence for gene-gene interaction between two major AMD associated loci CFH and LOC387715 was obtained using three methods, logistic regression, a synergy index and the mutual information (MI) index. ||||| Inflammation has long been suspected to play a role in the pathogenesis of age-related macular degeneration (AMD). Association of variants in the complement factor H (CFH) and complement factor B (CFB) genes has targeted the search for additional loci to the alternative complement cascade, of which C3 is a major component. Two non-synonymous coding polymorphisms within C3, R102G and L314P, have previously been strongly associated with increased risk. These variants are in strong linkage disequilibrium (LD), making the contribution of this locus to AMD even more difficult to ascertain. We sought to determine whether the C3 association resulted primarily from only one of these two variants or from a combined effect of both in 223 families and an independent dataset of 701 cases and 286 unrelated controls. The C3 polymorphisms were in strong LD (r(2) = 0.85), and both were associated in the family-based and case-control datasets (R102G genoPDT P = 0.02, case-control genotypic P = 0.004; L314P genoPDT P = 0.001, case-control genotypic P = 0.04). In conditional analyses in the case-control dataset, R102G remained associated with disease in the L314P risk allele carriers (P = 0.01), but there was no effect of L314P in the R102G risk allele carriers (P = 0.2). After adjusting for age, smoking, CFH Y402H, LOC387715 A69S, and CFB R32Q, the effect of R102G remained strong [P = 0.015, odds ratio = 1.55, 95% confidence interval 1.09 to 2.21, adjusted PAR(population attributable risk) = 0.17]. Therefore, while the strong LD between R102G and L314P makes it difficult to disentangle their individual effects on disease risk, the R102G polymorphism acting alone provides the best model for disease in our data. ||||| PURPOSE: A non-synonymous single nucleotide polymorphism (SNP) in complement component 3 has been shown to increase the risk of age-related macular degeneration (AMD). We assess its effect on AMD risk in a Northern Irish sample, test for gene-gene and gene-environment interaction, and review a risk prediction model.
METHODS: SNP rs2230199 was genotyped in 1,358 samples, which comprised 437 cases, 436 no-disease controls, and 485 participants randomly sampled from the Northern Ireland population. Allele frequencies were assessed in cases and controls. Logistic regression analysis was used to assess interaction and develop a risk prediction model.
RESULTS: We report a minor allele frequency of 0.248 for rs2230199 in the population (n=485), 0.296 in cases (n=437), and 0.221 in controls (n=436; odds ratio [OR]=1.48; confidence interval [CI]: 1.19-1.85; p=0.0003). The significant association is retained following multivariate analysis with adjustment for age, smoking status, Complement Factor H (CFH), Age-Related Maculopathy Susceptibility 2 (ARMS2), Complement Component 2 (CC2), and Complement Factor B (CFB; OR=1.45; CI: 1.10-1.91; p=0.009). No evidence to support an interaction between any of the covariates within the regression model was found. The area under the receiver operator characteristic curve calculated for the fully adjusted model, including all variables, was 0.86 for late AMD.
CONCLUSIONS: Our study confirmed the association between Complement Component 3 (C3) and late-stage AMD. There was no evidence for an interaction with environmental exposures, nor did we find data to support a gene-gene effect. ||||| PURPOSE: To assess whether established and newly reported genetic variants, independent of known lifestyle factors, are associated with the risk of age-related macular degeneration (AMD) among women participating in the Women's Health Initiative Sight Exam (WHI-SE) Genetic Ancillary Study.
DESIGN: Multicenter case-control study.
METHODS: One hundred and forty-six women with intermediate and late stages of AMD and 1269 subjects without AMD underwent ocular examinations and fundus photography to determine stage of AMD. Fourteen polymorphisms at or near 11 genes, including previously confirmed genes CFH, ARMS2/HTRA1, C2, C3, and CFI; recently reported AMD genes in the high-density lipoprotein cholesterol (HDL) pathway LIPC, ABCA1, CETP, and LPL; TIMP3/SYN3, a known ocular gene recently linked with AMD; and APOE, were assessed using logistic regression analysis.
RESULTS: After adjustment for demographic, behavioral, and other genetic factors, a protective effect was detected among TT carriers compared with non-carriers for the HDL pathway gene, LIPC rs493258, for intermediate and late AMD (OR [95% confidence interval]: 0.3 [0.2-0.7], P = .003). Variants in CFH rs1410996, ARMS2/HTRA1 A69S, and C3 R102G were significantly associated with an increased risk of AMD. Individuals with the homozygous CFI rs10033900 TT genotype had a 2.9 [1.2-7.2]-fold increased risk, and those with the CFH Y402H GG genotype had a 2.2 [1.0-4.8]-fold higher risk of developing AMD compared with non-carriers. APOE4 carriers may have a reduced risk of intermediate/late AMD (OR = 0.5 [0.3-0.9], P = .015. Suggestive associations were seen between AMD and the HDL pathway genes CETP and LPL.
CONCLUSION: In this unique national cohort of women, we found associations with established AMD-related genetic factors and the recently reported LIPC gene in the HDL pathway. These findings may help develop novel therapeutic targets to treat or delay the onset of the disease. ||||| PURPOSE: We assessed the association between complement pathway genes and age-related macular degeneration (AMD) in a Chinese population.
METHODS: In a case-control study, 165 AMD patients and 216 unrelated controls were recruited from two hospitals in central China. We selected and genotyped six single nucleotide polymorphisms (SNPs) of four complement pathway genes, including rs800292 and rs1410996 of complement H (CFH), rs9332739 of complement 2 (C2), rs4151667 of complement factor B (CFB), and rs2241394 and rs2230199 of complement 3 (C3). The associations between SNPs and AMD, adjusted by age and sex, were assessed by using logistic regression models and haplotype association analysis.
RESULTS: In our study, two SNPs of CFH and their haplotypes were associated significantly with AMD, and the adjusted odd ratios (ORs) were 2.45 (95% confidence interval [CI] 1.25-4.79) for rs800292 (genotype GG versus AA), 2.49 (95% CI 1.24-5.00) for rs1410996 (genotype TT versus CC), and 4.45 (95% CI 2.32-8.55) for haplotype block of rs800292-rs1410996 (haplotype G-C versus A-C), respectively. The haplotype of C2/CFB also was associated significantly with AMD, and the adjusted OR was 8.86 (95% CI 1.88-41.69) for the haplotype block of rs9332739-rs4151667 (haplotype G-A versus G-T), though no relationship was found in genotype association analysis of the two SNPs of C2/CFB. With the sample size of our study, no relationship was found for AMD and the two SNPs of C3.
CONCLUSIONS: Gene variants in CFH and C2/CFB contribute to AMD in the Chinese population. ||||| PURPOSE: The purpose of this study was to determine whether the genetic polymorphisms of complement factor 3 (C3) are associated with neovascular age-related macular degeneration (AMD) in the Chinese population.
METHODS: A total of 123 unrelated Chinese Han patients with neovascular AMD and 130 control subjects were recruited. Their six single-nucleotide polymorphisms (SNPs) in the C3 gene, one in the complement factor H (CFH) gene and two in the complement factor B (CFB) gene were characterized. Their genotypes, allele frequencies, and odds ratios were analyzed.
RESULTS: The G allele of the C3 IVS2 rs2250656, but not other tested C3 SNPs of rs2230205, rs10411506, rs2230199, rs339392, and rs163913, was significantly associated with a reduced risk for AMD in the Chinese population (OR 0.605, 95% CI 0.39-0.93, p = 0.023), even after adjusting for age, gender, smoking status, CFH rs1061170, CFB rs4151667, and CFB rs641153 allele status (OR 0.58, 95% CI 0.35-0.96, p = 0.033). However, the C3 haplotype of A-A-C-A-T-T was identified as a statistically significant risk factor for neovascular AMD (OR 1.41, 95% CI 1.02-1.94). Furthermore, the C allele of the CFH rs1061170, but not the CFB rs4151667 and rs641153, was significnatly associated with increased risk for AMD (OR 3.09, 95% CI 1.55-6.15, p < 0.001).
CONCLUSION: The G allele of C3 IVS2 rs2250656 may be a significantly protective factor for neovascular AMD in the Chinese population. This, together with low MAF of C3 R102G, may be partially responsible for the low prevalence of AMD in the Chinese population. ||||| PURPOSE: Several genes encoding complement system components and fragments are associated with age-related macular degeneration (AMD). This study was conducted to determine whether alterations in circulating levels of these markers of complement activation and regulation are also independently associated with advanced AMD and whether they are related to AMD genotypes.
METHODS: Plasma and DNA samples were selected from individuals in our AMD registry who had progressed to or developed the advanced stages of AMD, including 58 with geographic atrophy and 62 with neovascular disease. Subjects of similar age and sex, but without AMD, and who did not progress were included as controls (n = 60). Plasma complement components (C3, CFB, CFI, CFH, and factor D) and activation fragments (Bb, C3a, C5a, iC3b, and SC5b-9) were analyzed. DNA samples were genotyped for seven single-nucleotide polymorphisms in six genes previously shown to be associated with AMD: CFB, CFH, C2, C3, and CFI and the LOC387715/ARMS2 gene region. The association between AMD and each complement biomarker was assessed by using logistic regression, controlling for age, sex, and proinflammatory risk factors: smoking and body mass index (BMI). Functional genomic analyses were performed to assess the relationship between the complement markers and genotypes. Concordance, or C, statistics were calculated to assess the effect of complement components and activation fragments in an AMD gene-environment prediction model.
RESULTS: The highest quartiles of Bb and C5a were significantly associated with advanced AMD, when compared with the lowest quartiles. In multivariate models without genetic variants, the odds ratio (OR) for Bb was 3.3 (95% confidence interval [CI] = 1.3-8.6), and the OR for C5a was 3.6 (95% CI = 1.2-10.3). With adjustment for genetic variants, these ORs were substantially higher. The alternative pathway regulator CFH was inversely associated with AMD in the model without genotypes (OR = 0.3; P = 0.01). Positive associations were found between BMI and plasma C3, CFB, CFH, iC3b, and C3a. There were also significant associations between C5a fragment and LOC387715/ARMS2 and C3 genotypes (P for trend = 0.02, 0.04), respectively. C statistics for models with behavioral and genetic factors increased to 0.94 +/- 0.20 with the addition of C3a, Bb, and C5a.
CONCLUSIONS: Increased levels of activation fragments Bb and C5a are independently associated with AMD. Higher BMI is related to increased levels of complement components. C5a is associated with AMD genotypes. C statistics are stronger with the addition of C3a, Bb, and C5a in predictive models. Results implicate ongoing activation of the alternative complement pathway in AMD pathogenesis. | [
{
"source_pmid": "18596911",
"source_text": "Dysregulation of the alternative pathway (AP) of complement cascade has been implicated in the pathogenesis of age-related macular degeneration (AMD), the leading cause of blindness in the elderly. To further test the hypothesis that defective control of compleme... |
27966830 | Our meta-analysis indicates that there is some weak evidence that increased tHcy might be associated with wet AMD; however, this result should be interpreted cautiously, because of a marked between-study heterogeneity and the possible effect of publication bias. Future studies, preferably of cohort design, are necessary before any firm conclusions on the putative role of increased tHcy on AMD can be drawn. | PURPOSE: Exudative age-related macular degeneration (ARMD) is one of the debilitating ocular complications, which results in permanent blindness. Elevated homocysteine (Hcys) levels have been associated in the development of several vascular diseases. Vascular and oxidative stress theories have been implicated for the development of choroidal neovascularization in exudative ARMD. The aim of the present study was to investigate the possible role of plasma Hcys and thiol content (tSH) as a risk factor for the development of exudative ARMD.
METHOD: A total of 16 patients with exudative ARMD and 20 age-matched controls were recruited for the study. Plasma Hcys levels were analysed using Reverse Phase High Performance Liquid Chromatography. Plasma glutathione (GSH) content was determined using o-phthalaldehyde (OPA) derivatization and subsequent detection by fluorimeter. Plasma tSH levels were determined by using thiol-specific reagent dithionitrobenzoic acid (DTNB) spectrophotometrically.
RESULTS: Plasma Hcys levels in exudative ARMD were elevated three-fold (18+/-5.0 microM) when compared to healthy controls (6.7+/-1.8 microM). There was a two-fold decrease in the GSH and tSH in exudative ARMD when compared with controls. Negative correlation was observed between diminished tSH and Hcys levels (r=-0.4837, P=0.05). Similarly plasma Hcys levels negatively correlated with GSH content (r=-0.6620, P<0.05).
CONCLUSION: Results from our present study revealed that there is an elevated Hcys level and diminished thiol pool content in exudative ARMD that are significant. ||||| OBJECTIVE: To assess combined effects on the risk of age-related macular degeneration (AMD) by the LOC387715 polymorphism, smoking, and inflammatory or hemostatic factors.
DESIGN: Population-based case-control study.
PARTICIPANTS: Two hundred seventy-eight AMD cases (224 early, 54 late) and 557 controls matched for age, gender, and smoking, drawn from the Blue Mountains Eye Study cohort.
METHODS: Subjects were genotyped for the LOC387715 Ala69Ser polymorphism (rs# 10490924). Smoking was self-reported. Serum high-sensitivity C-reactive protein (CRP), interleukin 6 (IL-6), soluble intercellular adhesion molecule 1 (sICAM-1), fibrinogen, homocysteine, plasminogen activator inhibitor 1 (PAI-1), von Willebrand factor, and white cell count (WCC) were measured. Combined effects of this genetic variant plus any of these study factors on AMD risk were assessed using logistic regression models, adjusted for age and smoking. We defined interaction if the influence of 2 factors departed from the multiplicative scale, confirmed by a statistically significant interaction term. Otherwise, the combined effect was used.
MAIN OUTCOME MEASURES: Age-related macular degeneration was graded using the Wisconsin grading system.
RESULTS: Combined effects on the likelihood of early or late AMD were demonstrated for the LOC387715 Ala69Ser G/T and T/T genotypes with the markers high-sensitivity CRP (odds ratios [ORs], 1.2 for the highest tertile alone, 1.6 for G/T and T/T genotypes alone, and 2.2 for both G/T and T/T genotypes plus the highest tertile, compared with the G/G genotype with the 2 lower tertiles), IL-6 (corresponding ORs, 1.1, 1.6, and 2.2), sICAM-1 (ORs, 1.0, 1.5, and 2.3, respectively), and PAI-1 (ORs, 1.3, 1.7, and 2.3, respectively), but not with WCC, fibrinogen, homocysteine, and von Willebrand factor. Findings were similar for early and late AMD separately. Current smokers with G/T and T/T genotypes had strong combined effects on late AMD risk compared with those who never smoked or past smokers with the G/G genotype (ORs, 1.2 for current smokers alone, 1.8 for G/T and T/T genotypes alone, and 6.1 for current smokers plus G/T and T/T genotypes).
CONCLUSIONS: We found no significant interaction but combined effects for the LOC387715 genotypes with 3 inflammatory markers and PAI-1 on the risk of early or late AMD, and with current smoking on the risk of late AMD. ||||| PURPOSE: The purpose of this study was to investigate the association of age-related macular degeneration (AMD) with plasma homocysteine, vitamin B12, and folate levels.
METHODS: Sixty patients diagnosed with AMD at our clinic between March 2004 and September 2004 were assessed in a prospective cross-sectional study. Plasma homocysteine, vitamin B12, and folate levels taken after 8 h of fasting from 30 patients with exudative AMD and 30 patients with dry AMD were compared with the results of 30 age- and sex-matched healthy participants.
RESULTS: Patients with both exudative and dry types of AMD had significantly higher plasma homocysteine levels (mean 14.19+/-3.11 micromol/l; 13.07+/-2.90 micromol/l respectively) compared with the controls (mean 10.79+/-2.56 micromol/l; (p=0.000 and p=0.008 respectively). Homocysteine levels were higher in the exudative AMD group compared with the dry AMD group, but the difference was not statistically significant (p=0.290). Plasma vitamin B12 levels were found to be significantly lower in the exudative AMD group (289.14+/-113.44 pg/l) compared with the controls (436.17+/-204.12 pg/l) and dry AMD group (443.47+/-190.83 pg/l; (p=0.000). Plasma folate levels were comparable among groups (p=0.106).
CONCLUSION: This study suggests an association between elevated plasma homocysteine and AMD regardless of the subtype. Further controlled prospective studies are needed to investigate the possible role of homocysteine in AMD and the effect of vitamin B12 and folate supplementation in this process. ||||| Age-related macular degeneration (AMD) is one of the most common causes of vision loss. AMD has been classified into two forms: atrophic and exudative forms. The exudative form is associated with choroidal neovascularization of the subretinal macular region, resulting in a sudden loss of central vision. However, the exact cause of AMD remains unknown. Several risk factors have been postulated, including smoking, atherosclerosis, and low levels of antioxidant enzymes. Malondialdehyde (MDA), a lipid peroxidation product, is used as a marker of oxidative stress. Paraoxonase 1 (PON1) metabolizes lipid peroxides and prevents oxidation of low-density lipoprotein. Increased levels of homocysteine may cause vascular endothelial injury by releasing free radicals. The purpose of this study is to investigate the relationships between serum PON1 activity and the serum levels of homocysteine and MDA in AMD. Forty patients with exudative-type AMD (63.3 +/- 5 years) and 40 controls (61+/- 4 years) were assessed in a cross-sectional study. The serum PON1 activity was significantly lower in the patients with AMD than that in the controls (p < 0.001). In contrast, the serum levels of MDA and homocysteine were significantly higher in the patients than those in the controls (p < 0.001, for both). In AMD patients, significant negative correlation was found between PON1 activity and MDA level (r = -0.493, p < 0.05) and between PON1 activity and homocysteine level (r = -0.557, p < 0.05). Increased serum homocysteine and MDA levels may be responsible for the decreased PON1 activity in patients with AMD. ||||| PURPOSE: To assess the relationship between plasma homocysteine levels and exudative neovascular age-related macular degeneration (AMD).
DESIGN: Cross-sectional study.
METHODS: A prospective comparative cross-sectional study was conducted in outpatient ophthalmology clinics in a university-affiliated medical institution. The cohort consisted of 59 patients (25 male, 34 female) with a mean age of 78 years (standard deviation [SD] = 8.4) with neovascular AMD who were candidates for photodynamic treatment. Patients were compared for plasma homocysteine levels with 58 patients who had dry AMD (24 male, 34 female) with a mean age of 76.3 years (SD = 8.4) and with a control group of 56 age-matched subjects (27 male, 29 female), with a mean age of 77.3 years (SD = 8.2). A 3-ml venous blood sample was obtained from each participant after an 8-hour fast. Levels of plasma homocysteine were measured by high performance liquid chromatography. The main outcome measure was hyperhomocysteinemia, defined as a plasma homocysteine level above 15 micromol/l.
RESULTS: Homocysteine levels were higher by 27.9% in the neovascular AMD than in the dry AMD group, and by 21.9% than in the control group (P <.02). Hyperhomocysteinemia was found in 44.1% of the study group, in 22.4% of the dry AMD group, and in 21.4% of the control group (P =.011).
CONCLUSIONS: This study suggests an association between an elevated plasma level of homocysteine and exudative neovascular AMD but not dry AMD. ||||| PURPOSE: To assess the relationship between plasma levels of homocysteine and age-related macular degeneration (AMD).
DESIGN: Cross-sectional, case-control study.
METHODS: Fasting plasma homocysteine levels were measured at two centers in 934 individuals who were participating in an ancillary study of the Age-Related Eye Disease Study. There were 547 cases and 387 control subjects, who were determined by fundus photography. Conditional logistic regression analyses were conducted to assess the association of homocysteine with AMD.
RESULTS: Median values of homocysteine were higher among advanced AMD cases (9.51 mmol/l) compared with persons with no AMD (8.81 mmol/l; P = .01). Values of >12 mmol/l vs < or =12 mmol/l were also associated with an increased risk of AMD (P = .023), when controlled for other covariates.
CONCLUSION: Results are consistent with a possible small, independent association between higher homocysteine levels and AMD. Homocysteine may be a modifiable risk factor for AMD. ||||| PURPOSE: Hyperhomocysteinemia is considered an independent risk factor for atherosclerosis and thrombosis. The purpose of this study was to evaluate plasma homocysteine, red blood cell folate, plasma folate, and plasma vitamin B12 concentration in patients with exudative age-related macular degeneration (ARMD).
METHODS: The participants of this study included 30 patients aged 60 to 71 years (mean age 66.2+/-3.6) with exudative ARMD. Plasma homocysteine levels were determined by high performance liquid chromatography (HPLC). Red blood cell folate, plasma folate, and plasma vitamin B12 concentration were determined using a standard kit (Dualcount Solid Phase No Boill radioassay kit for B12/folic acid, DPC Diagnostic, USA) by radioassay method.
RESULTS: The plasma concentration of Hcy (14.88+/-6.23 micromol/L) in ARMD patients was significantly increased (p<0.0001) compared with the control group (8.72+/-3.34 micromol/L). We found not a significant decrease of the plasma vitamin B12 concentration in the ARMD group (476.88+/-220.91 pg/mL) compared with the control group (527.08+/-208.97 pg/mL). Red blood cell folate (158.44+/-56.30 ng/mL) and plasma folate (6.5+/-3.4 ng/mL) in ARMD patients were also not significantly decreased when compared with the control group (183.86+/-59.33 ng/mL and 7.93+/-5.05 ng/mL).
CONCLUSIONS: Hyperhomocysteinemia might be one of the risk factors for the exudative form of ARMD. ||||| UNLABELLED: Age-related macular degeneration (AMD) is the leading cause of irreversible visual impairment and blindness among persons aged 60 years and older and many theories exist and feature mechanisms of oxidative stress, atherosclerotic-like changes, genetic predisposition, and inflammation in development of AMD. The aim of this study was to evaluate the association between markers of inflammation and cardiovascular risk with age-related macular degeneration.
METHODS: Case-control study that includes 163 patients with wet AMD (age group of 55-82 years with the mean age of 71 years and 170 age-matched healthy controls in the age group of 55-78 years with the mean age of 71 years. The following parameters were determined: lipidic profile (Total Cholesterol, Triglycerides, HDL-c, LDL-c), CRP (C-Reactive Protein), homocysteine and fibrinogen.
RESULTS: We found significant differences between AMD patients and control group in baseline values of homocysteine, CRP and fibrinogen, although we do not observed differences in levels of lipidic profile.
CONCLUSION: Our data support the role of chronic inflammation in the development of AMD, however, further studies are needed to determine which common disease mechanisms of chronic inflammation and atherosclerosis contribute to the pathogenesis of AMD. ||||| INTRODUCTION: Age-related macular degeneration (AMD) related to adverse vascular changes is the most frequent cause of irreversible visual impairment in the elderly. Elevated plasma concentrations of serum homocysteine have been shown to increase the risk of vascular disease.
OBJECTIVE: To assess the relationship between plasma homocysteine level and age related macular degeneration.
MATERIALS AND METHODS: A case control study was conducted in a tertiary eye care hospital with 32 diagnosed AMD patients. The patients were compared for plasma homocysteine levels with a control group of 32 patients without AMD. A 1.5 ml of fasting venous blood sample was obtained from each participant. Plasma homocysteine level was measured by high performance liquid chromatography. The main outcome measure was hyperhomocysteinemia, defined as a plasma homocysteine level above 15 μmol/l.
RESULTS: Hyperhomocysteinemia was found in 10 blood samples (83.3 %) of patients in the wet AMD group, in 16 (80 %) blood samples in the dry AMD group, and in 12 blood samples (37%) of controls. The mean ± SD homocysteine level in the AMD group was 16.86 ± 3.52 μmol/L, while in the non-AMD control group it was 14.53 ± 4.08 μmol/L. This difference was statistically significant (p-value = 0.0186). In the individual analysis, it was also found out that the homocysteine level differed significantly between cases and controls in only the wet variety of AMD.
CONCLUSION: Hyperhomocysteinemia was significantly associated with the wet AMD variety but not with the dry AMD. Thus, homocysteine by oxidative stress and vascular dysfunction can be an important risk factor in the pathogenesis of AMD. ||||| BACKGROUND: We investigated concentrations of total homocysteine (tHcy) in elderly people without and those with age-related macular degeneration (AMD). In addition, we tested the association between plasma tHcy and one glycation marker in aqueous humor.
METHODS: People with cataract only (n=48), patients with dry AMD (n=38) and those with wet AMD (n=31) were studied. Blood concentrations of tHcy, and methylation and vitamin markers were measured in 116 blood samples. The concentrations of the extracellular soluble receptor for advanced glycated end products (esRAGE) were measured in 77 aqueous humor samples.
RESULTS: Mean aqueous humor concentration of esRAGE and that of plasma tHcy did not differ significantly between the groups. Arterial hypertension but not eye disease explained the tHcy elevation in plasma in this study. In the cataract group, a significant negative correlation was found between plasma tHcy and that of esRAGE in aqueous humor (r=-0.483, p=0.006). In patients with dry AMD, the concentration of esRAGE in aqueous humor correlated negatively to tHcy and positively to serum folate.
CONCLUSIONS: Plasma tHcy levels were positively associated with hypertension, but not with AMD in this study. Higher esRAGE in aqueous humor was related to higher folate and lower tHcy in blood. Following studies may assess whether B-vitamins can protect against age-related ocular diseases by reducing glycation. ||||| PURPOSE: It was proposed that total thiols (tSH) as powerful reducing agents and oxidized low-density lipoprotein (OX-LDL) may be associated with development of choroidal neovascularization in exudative age-related macular degeneration (E-ARMD).
METHODS: In a case-control study, 45 patients with E-ARMD were compared with 45 sex- and age-matched healthy controls. The levels of plasma homocysteine (Hcy) and OX-LDL as oxidant agents, and of tSH and glutathione (GSH) as antioxidant markers, were estimated in E-ARMD patients and controls.
RESULTS: The levels of Hcy (15.4±7.2 μM versus 10.7±3.7 μM; p=0.001) and OX-LDL (52.2±13.8 U/l versus 37.8±10.8 U/l; p=0.001) were statistically higher, while GSH (1.10±0.97 μM versus 2.09±1.04 μM; p=0.001) and tSH (0.31±0.06 mM versus 0.35±0.05 mM; p=0.001) were statistically lower, in the patients with E-ARMD than in the control group, respectively. The plasma OX-LDL concentration also exhibited a positive and significant correlation with Hcy (r=0.719, p=0.001) in patients with E-ARMD.
CONCLUSIONS: Lower GSH and tSH as antioxidant and higher Hcy levels as oxidant agents in E-ARMD patients may have resulted in an oxidative environment that was associated with OX-LDL. Further studies with more cases are required to confirm the hypothesis. | [
{
"source_pmid": "15803172",
"source_text": "PURPOSE: Exudative age-related macular degeneration (ARMD) is one of the debilitating ocular complications, which results in permanent blindness. Elevated homocysteine (Hcys) levels have been associated in the development of several vascular diseases. Vascular an... |
24013816 | Our study provides evidence of the joint contribution of genetic variants in PLEKHA1/ARMS2/HTRA1 to AMD risk, in addition to the two widely studied genetic variants whose association with AMD was well established. | PURPOSE: Single nucleotide polymorphisms (SNPs) in the LOC387715 (rs10490924), HTRA1 (rs11200638), and CFH (rs1061170) genes have been implicated in age-related macular degeneration (AMD). The present study was undertaken to determine the involvement of the LOC387715 and HTRA1 in an AMD cohort from India.
METHODS: The coding region of LOC387715 (exon 1) and the promoter of HTRA1 were screened by resequencing in AMD cases and normal controls. Odds ratios were calculated to assess the risk of individual genotypes. Linkage disequilibrium (LD) and haplotype frequencies were estimated with Haploview software. Population attributable risk (PAR %) for the associated SNPs and their combined effects were calculated.
RESULTS: Resequencing revealed seven different SNPs in these genes, of which significant associations were noted with the risk alleles of rs10490924 (T allele; P = 5.34 x 10(-12)) in LOC387715, and rs11200638 (A allele; P = 4.32 x 10(-12)) and rs2672598 (C allele; P = 3.39 x 10(-11)) in HTRA1 among the cases. Correspondingly, the homozygous risk genotypes TT, AA, and CC in these SNPs exhibited higher disease odds and PAR %. rs10490924 and rs11200638 were in tight LD (D', 0.90; 95% CI, 0.84-0.93). G-C-T-A-C was the risk haplotype (P = 8.04 x 10(-15)), whereas the G-C-G-G-T haplotype was protective (P = 2.01 x 10(-4)). The combined effect of the CFH (CC) and LOC387715 (TT) risk genotypes exhibited a PAR of 93.7% (OR, 73.89; 95% CI, 8.69-628.13).
CONCLUSIONS: The present data provided an independent validation of the association of LOC387715 and HTRA1 SNPs, along with their risk estimates among Indian patients with AMD. These associations underscore their significant involvement in AMD susceptibility, which may be useful for predictive testing. ||||| A common haplotype on 10q26 influences the risk of age-related macular degeneration (AMD) and encompasses two genes, LOC387715 and HTRA1. Recent data have suggested that loss of LOC387715, mediated by an insertion/deletion (in/del) that destabilizes its message, is causally related with the disorder. Here we show that loss of LOC387715 is insufficient to explain AMD susceptibility, since a nonsense mutation (R38X) in this gene that leads to loss of its message resides in a protective haplotype. At the same time, the common disease haplotype tagged by the in/del and rs11200638 has an effect on the transcriptional upregulation of the adjacent gene, HTRA1. These data implicate increased HTRA1 expression in the pathogenesis of AMD and highlight the importance of exploring multiple functional consequences of alleles in haplotypes that confer susceptibility to complex traits. ||||| BACKGROUND: To examine if the significantly associated SNPs derived from the genome wide allelic association study on the AREDS cohort at the NEI (dbGAP) specifically confer risk for neovascular age-related macular degeneration (AMD). We ascertained 134 unrelated patients with AMD who had one sibling with an AREDS classification 1 or less and was past the age at which the affected sibling was diagnosed (268 subjects). Genotyping was performed by both direct sequencing and Sequenom iPLEX system technology. Single SNP analyses were conducted with McNemar's Test (both 2 x 2 and 3 x 3 tests) and likelihood ratio tests (LRT). Conditional logistic regression was used to determine significant gene-gene interactions. LRT was used to determine the best fit for each genotypic model tested (additive, dominant or recessive).
RESULTS: Before release of individual data, p-value information was obtained directly from the AREDS dbGAP website. Of the 35 variants with P < 10-6 examined, 23 significantly modified risk of neovascular AMD. Many variants located in tandem on 1q32-q22 including those in CFH, CFHR4, CFHR2, CFHR5, F13B, ASPM and ZBTB were significantly associated with AMD risk. Of these variants, single SNP analysis revealed that CFH rs572515 was the most significantly associated with AMD risk (P < 10-6). Haplotype analysis supported our findings of single SNP association, demonstrating that the most significant haplotype, GATAGTTCTC, spanning CFH, CFHR4, and CFHR2 was associated with the greatest risk of developing neovascular AMD (P < 10-6). Other than variants on 1q32-q22, only two SNPs, rs9288410 (MAP2) on 2q34-q35 and rs2014307 (PLEKHA1/HTRA1) on 10q26 were significantly associated with AMD status (P = .03 and P < 10-6 respectively). After controlling for smoking history, gender and age, the most significant gene-gene interaction appears to be between rs10801575 (CFH) and rs2014307 (PLEKHA1/HTRA1) (P < 10-11). The best genotypic fit for rs10801575 and rs2014307 was an additive model based on LRT. After applying a Bonferonni correction, no other significant interactions were identified between any other SNPs.
CONCLUSION: This is the first replication study on the NEI dbGAP SNPs, demonstrating that alleles on 1q, 2q and 10q may predispose an individual to AMD. ||||| We executed a genome-wide association scan for age-related macular degeneration (AMD) in 2,157 cases and 1,150 controls. Our results validate AMD susceptibility loci near CFH (P < 10(-75)), ARMS2 (P < 10(-59)), C2/CFB (P < 10(-20)), C3 (P < 10(-9)), and CFI (P < 10(-6)). We compared our top findings with the Tufts/Massachusetts General Hospital genome-wide association study of advanced AMD (821 cases, 1,709 controls) and genotyped 30 promising markers in additional individuals (up to 7,749 cases and 4,625 controls). With these data, we identified a susceptibility locus near TIMP3 (overall P = 1.1 x 10(-11)), a metalloproteinase involved in degradation of the extracellular matrix and previously implicated in early-onset maculopathy. In addition, our data revealed strong association signals with alleles at two loci (LIPC, P = 1.3 x 10(-7); CETP, P = 7.4 x 10(-7)) that were previously associated with high-density lipoprotein cholesterol (HDL-c) levels in blood. Consistent with the hypothesis that HDL metabolism is associated with AMD pathogenesis, we also observed association with AMD of HDL-c-associated alleles near LPL (P = 3.0 x 10(-3)) and ABCA1 (P = 5.6 x 10(-4)). Multilocus analysis including all susceptibility loci showed that 329 of 331 individuals (99%) with the highest-risk genotypes were cases, and 85% of these had advanced AMD. Our studies extend the catalog of AMD associated loci, help identify individuals at high risk of disease, and provide clues about underlying cellular pathways that should eventually lead to new therapies. ||||| Age-related macular degeneration (AMD) is a late onset vision disorder. Recent studies demonstrate that alterations in complement cascade genes are associated with AMD. Of the three identified complement loci, variants in complement factor H (CFH) have the highest impact as does an independent locus at 10q26. Our matched case-control study using the Age-Related Eye Disease Study (AREDS) cohort confirms and extends the associations in these loci. Subjects were genotyped for single nucleotide polymorphisms (SNPs) from CFH, complement component 2 (C2), complement component 3 (C3), complement factor B (CFB), age-related maculopathy susceptibility (ARMS2), HtrA serine peptidase 1 (HTRA1), and apolipoprotein E (APOE). Individual SNPs, and haplotypes showed risk trends consistent with those seen in other population studies for CFH, C3, C2, and CFB. SNP rs10490924 on chromosome 10 in exon 1 of the ARMS2 gene showed a highly significant association with an odds ratio (OR) of 3.2 (95% CI 2.4-4.2) for the risk allele and rs11200638 located in the proximal promoter region of HTRA1 showed a higher significant association with an OR of 3.4 (95% CI 2.5-4.6) with our AMD cases. We found that APOE haplotypes were not significantly associated with disease status. Adjustments for other risk factors did not significantly alter the observed associations. This study validates the complement pathway's involvement in AMD and suggests that allelic variants in complement genes have a direct role in disease. These results also support previous findings that variants in the region of 10q26 exert an independent risk for AMD. ||||| BACKGROUND/AIMS: A strong association has been confirmed between age-related macular degeneration (AMD) and variants at two independent loci including Tyr402His in the complement factor H (CFH) on 1q32 and Ser69Ala at LOC387715, a hypothetical gene on chromosome 10q26. The contribution of both loci to AMD was investigated in an isolated north-west Russian population.
METHODS: Together with a PLEKHA1 variant at 10q26, the CFH Tyr402His and LOC387715 Ser69Ala polymorphisms were genotyped in 155 patients with AMD and 151 age-matched controls. chi(2) and Mantel-Haenszel (M-H) score tests were used to test for association. Sex-adjusted ORs were calculated.
RESULTS: The frequency of the Tyr402His C allele was significantly higher in patients with AMD compared with controls (p(M-H)=0.0035). The increased risk observed in patients homozygous for the C allele (OR(HOM)=2.71, 95% CI 1.25 to 5.90) in this indigenous Russian population was considerably lower than that observed in previous western Caucasian populations. A significant increase in the frequency of the LOC387715 variant was observed in patients with late-stage AMD compared with controls (p(M-H)=0.007), with a homozygous OR of 3.47 (95% CI 1.01 to 11.9), although this association was not seen with early-stage AMD.
CONCLUSION: The CFH gene contributes to AMD in this Russian population, although the risk conferred is considerably lower in this population than that found in other Western populations. A contribution of LOC387715 to disease in this population is also likely to be of weak effect. ||||| PURPOSE: To compare the genomic contribution of the ARMS2/HTRA1 region of chromosome 10q26 to typical neovascular age-related macular degeneration (nAMD) (also known as typical exudative AMD) and to polypoidal choroidal vasculopathy (PCV) METHODS: DNA samples were prepared from 84 patients with typical nAMD, 181 patients with PCV, and 276 control participants. All of the 18 haplotype-tagging single-nucleotide polymorphisms (SNPs) derived from the HapMap data and the potential functional variant, rs11200638, which extended the ARMS2/HTRA1 region by 85.2 kb, were genotyped. Associations were tested using single-SNP and haplotype analyses.
RESULTS: Statistically significant associations were found for six of the 19 SNPs with both typical nAMD and PCV (P < 1 × 10(-3)), peaking at a segment containing three of the SNPs: rs3793917, rs10490924, and rs11200638 (P < 10(-7)). Six common haplotypes were inferred from the nine SNPs spanning 33 kb, which included the six SNPs associated with both phenotypes. Among the six common haplotypes, one showed a positive association with typical nAMD, and two, including the one mentioned above, were associated with PCV. In addition, they corresponded to the risk alleles rs10490924 and rs11200638.
CONCLUSIONS: The association pattern and haplotype estimation in the ARMS2/HTRA1 region of Japanese patients with PCV were very similar to those of Japanese patients with typical nAMD. The polymorphisms responsible for nAMD and PCV may be located in this region or in the strong linkage disequilibrium of rs10490924 and rs11200638. ||||| PURPOSE: To determine the characteristics of the polymorphisms in the ARMS2 gene in Japanese patients with age-related macular degeneration (AMD) and those with polypoidal choroidal vasculopathy (PCV) and in healthy controls, and also to show possible associations of the polymorphisms with the disease.
DESIGN: Case-control association study.
METHODS: Fifty-six unrelated Japanese individuals with AMD, 55 with PCV, and 77 controls were studied. The most common polymorphism in the ARMS2 gene on chromosome 10 was resequenced. Association tests were performed for inferred haplotypes.
RESULTS: A total of 22 polymorphisms were identified, and 13 were shared with those in White persons with AMD. The sequence of the deletion-and-insertion polymorphism, de1443ins54, a functional polymorphism causing an instability of the messenger ribonucleic acid of ARMS2 in the Japanese, did not differ from that in White persons. Among the polymorphisms seen in the White population, rs10490923 (R3H) as well as 7 other polymorphisms were not observed in the Japanese. One haplotype, which contained the T allele of the rs10490924 (A69S) and the variant of de1443ins54 polymorphism, had an odds ratio of 3.14 (P = 7.8 x 10(-6)) for AMD and 2.00 (P = .0058) for PCV. Among the 9 polymorphisms that were unique to the Japanese population, 2 had a minor allelic frequency of more than 0.05, and these 2 polymorphism were included as nonrisk haplotypes.
CONCLUSIONS: The de1443ins54 polymorphism is a common variant between White and Japanese populations. It is strongly associated not only with AMD but also with PCV. ||||| Age-related macular degeneration (AMD) is a prevalent multifactorial disorder of the central retina. Genetic variants at two chromosomal loci, 1q31 and 10q26, confer major disease risks, together accounting for more than 50% of AMD pathology. Signals at 10q26 center over two nearby genes, ARMS2 (age-related maculopathy susceptibility 2, also known as LOC387715) and HTRA1 (high-temperature requirement factor A1), suggesting two equally probable candidates. Here we show that a deletion-insertion polymorphism in ARMS2 (NM_001099667.1:c.(*)372_815del443ins54) is strongly associated with AMD, directly affecting the transcript by removing the polyadenylation signal and inserting a 54-bp element known to mediate rapid mRNA turnover. As a consequence, expression of ARMS2 in homozygous carriers of the indel variant is not detectable. Confirming previous findings, we demonstrate a mitochondrial association of the normal protein and further define its retinal localization to the ellipsoid region of the photoreceptors. Our data suggest that ARMS2 has a key role in AMD, possibly through mitochondria-related pathways. ||||| Genetic variants at chromosomes 1q31-32 and 10q26 are strongly associated with susceptibility to age-related macular degeneration (AMD), a common blinding disease of the elderly. We demonstrate, by evaluating 45 tag SNPs spanning HTRA1, PLEKHA1, and predicted gene LOC387715/ARMS2, that rs10490924 SNP alone, or a variant in strong linkage disequilibrium, can explain the bulk of association between the 10q26 chromosomal region and AMD. A previously suggested causal SNP, rs11200638, and other examined SNPs in the region are only indirectly associated with the disease. Contrary to previous reports, we show that rs11200638 SNP has no significant impact on HTRA1 promoter activity in three different cell lines, and HTRA1 mRNA expression exhibits no significant change between control and AMD retinas. However, SNP rs10490924 shows the strongest association with AMD (P = 5.3 x 10(-30)), revealing an estimated relative risk of 2.66 for GT heterozygotes and 7.05 for TT homozygotes. The rs10490924 SNP results in nonsynonymous A69S alteration in the predicted protein LOC387715/ARMS2, which has a highly conserved ortholog in chimpanzee, but not in other vertebrate sequences. We demonstrate that LOC387715/ARMS2 mRNA is detected in the human retina and various cell lines and encodes a 12-kDa protein, which localizes to the mitochondrial outer membrane when expressed in mammalian cells. We propose that rs10490924 represents a major susceptibility variant for AMD at 10q26. A likely biological mechanism is that the A69S change in the LOC387715/ARMS2 protein affects its presumptive function in mitochondria. ||||| PURPOSE: There is still a debate as to whether the LOC387715 or HTRA1 genes represent the key significant association identified with age-related macular degeneration (AMD) on the long arm of chromosome 10, region 26.
METHODS: An Australian patient cohort was genotyped by using tagged single nucleotide polymorphisms (tSNPs) to identify a causal SNP within this region.
RESULTS: Multiple tSNPs across the region showed association with AMD with the tSNP rs3793917 (odds ratio [OR], 3.45; 95% confidence interval [CI], 2.36-5.05, P = 2.8 × 10(-13)) having the highest association with AMD. This tSNP occurred in the intergenic region between the LOC387715 and HTRA1 genes. A second tSNP rs2672587 (OR, 2.92; 95% CI, 2.04-4.17; P = 7.7 × 10(-11)) located in intron 1 of the HTRA1 gene had the second highest association with AMD. After logistic regression analysis, the only tSNP to survive covariate testing was rs3793917, which occurred in the same LD block as the HTRA1 promoter SNP rs11200638 (r(2) = 0.88, D' = 0.97).
CONCLUSIONS: The findings indicate that the intergenic region between the tSNP rs3793917 and the SNP rs11200638 in the HTRA1 gene is the most likely site explaining the significant association with AMD. ||||| OBJECTIVE: To examine if the genes encoding the pleckstrin homology domain-containing protein gene (PLEKHA1), hypothetical LOC387715/ARMS2 gene, and HtrA serine peptidase 1 gene (HTRA1) located on the long arm of chromosome 10 (10q26 region) confer risk for neovascular age-related macular degeneration (AMD) in an independent or interactive manner when controlling for complement factor H gene (CFH) genotype and smoking exposure.
DESIGN: Retrospective matched-pair case-control study.
PARTICIPANTS: Hospital clinic-based sample of 134 unrelated patients with neovascular AMD who have a sibling with normal maculae (268 subjects).
METHODS: Disease status was ascertained by at least 2 investigators by review of fundus photographs and/or fluorescein angiography according to the Age-Related Eye Disease Study grading scale. If necessary, a home retinal examination was performed (n = 6). A combination of direct sequencing and analysis of 8 highly polymorphic microsatellite markers was used to genotype 33 megabases of the 10q26 region on leukocyte DNA. Smoking history was obtained via a standardized questionnaire and measured in pack-years. The family-based association test, haplotype analysis, multiple conditional logistic regression, and linkage analysis were used to determine significant associations.
MAIN OUTCOME MEASURE: Neovascular AMD status.
RESULTS: Of the 23 variants we identified in the 10q26 region, 6 were significant. Four of the 6 were novel and included 2 genotypes that reduced risk of AMD. Many single-nucleotide polymorphisms (SNPs), including the previously reported variants rs10490924 (hypothetical LOC387715/ARMS2) and rs11200638 (HTRA1), defined 2 significant haplotypes associated with increased risk of neovascular AMD. The coding HTRA1 SNP rs2293870, not part of the significant haplotypes containing rs10490924 and rs11200638, showed as strong an association with increased susceptibility to neovascular AMD. Linkage analysis supported our findings of SNP association (P<10(-15)). No significant interactions were found between any of the SNPs in the 10q26 and smoking or between these SNPs and CFH genotype.
CONCLUSIONS: Independent of CFH genotype or smoking history, an individual's risk of AMD could be increased or decreased, depending on their genotype or haplotype in the 10q26 region. ||||| PURPOSE: Mapping the genes for age-related macular degeneration (AMD) had not been successful until recent genome-wide association studies revealed Tyr402His in CFH and rs11200638 in HTRA1 as AMD-related genetic variants. This study was conducted to identify other critical factors in HTRA1 that are associated with exudative AMD.
METHODS: The promoter, splice regions, and coding exons of HTRA1 were sequenced in 163 patients with exudative AMD and 183 sex- and age-matched control subjects. Also documented were the CFH genotype and smoking status.
RESULTS: Four significant SNPs were found in the promoter and the first exon of HTRA1: rs11200638 (-625G>A), rs2672598 (-487T>C), rs1049331 (102C>T, Ala34Ala), and rs2293870 (108G>T, Gly36Gly) with respective P = 1.7 x 10(-14), 3.0 x 10(-10), 3.7 x 10(-12), and 3.7 x 10(-12). Among them, rs11200638 is the most significant associated SNP with a high odds ratio (OR) of 7.6 (95% CI: 3.94-14.51). One risk haplotype block across the promoter and exon 1, ACCTT, significantly predisposes to AMD (P = 6.68 x 10(-14)). In both models, significant independent additive effects were identified with smoking and rs800292 (184G>A, Val62Ile) of CFH. Smoking and rs11200638 (HTRA1) combined caused a 15.7-fold increased risk, whereas combined rs800292 and rs11200638 caused a 23.3-fold increased risk. An extremely high population attributable risk (PAR) of 78% was also found.
CONCLUSIONS: A high impact of the additive effect of CFH and HTRA1 in the development of exudative AMD was shown. The HTRA1-smoking additive effect found in this study further suggests the importance of this environmental risk factor in AMD. ||||| Age-related macular degeneration (AMD) is a multifactorial disease and a prevalent cause of visual impairment in developed countries. Risk factors include environmental components and genetic determinants. The complement factor H (CFH) has been the first major susceptibility gene for AMD identified within 1q32. Here, we focused on a second region of interest in 10q26 where a recent meta-analysis revealed strongest evidence for linkage to AMD at a genome-wide significance level. Within an interval of 22 Mb, we have analyzed 93 single nucleotide polymorphisms for allelic association with AMD in two independent case-control cohorts of German origin (AMD(combined) n=1166; controls(combined) n=945). Significant association was found across a 60 kb region of high linkage disequilibrium harboring two genes PLEKHA1 and hypothetical LOC387715. The strongest association (P=10(-34)) centered over a frequent coding polymorphism, Ala69Ser, at LOC387715, strongly implicating this gene in the pathogenesis of AMD. Besides abundant expression in placenta, we demonstrate weak expression of LOC387715 in the human retina. At present, however, there is no functional information on this gene, which appears to have evolved recently within the primate lineage. The joint contribution of the common risk allele at LOC387715, Ala69Ser, and at CFH, Tyr402His, was assessed in our case-control population, which suggests an additive model indicating an independent contribution of the two gene loci to disease risk. Our data show a disease odds ratio of 57.6 (95% CI: 37.2, 89.0) conferred by homozygosity for risk alleles at both CFH and LOC387715 when compared with the baseline non-risk genotype. ||||| OBJECTIVES: To determine the effects of the polymorphisms CFH Tyr402His and ARMS2 del443ins54 on susceptibility to age-related macular degeneration (AMD) and to find the frequencies of these single-nucleotide polymorphisms in an Italian population that was not examined clinically.
METHODS: A total of 286 control subjects (126 men and 160 women) and 159 white patients (73 men and 86 women) harboring exudative AMD in 1 eye were recruited. A third group of 182 DNA samples from blood donors of the same geographical areas were also typed to assess the frequency of CFH Tyr402His and ARMS2 del443ins54 polymorphisms in the general population. The data were analyzed statistically by a standard 2 x 2 table, Fisher exact tests, and odds ratios.
RESULTS: The deletion-insertion at chromosome 10q26 (del443ins54) showed the strongest association with AMD in terms of both P value and odds ratio (P = 2.7 x 10(-15); odds ratio = 3.25), and a highly significant association was also confirmed for Tyr402His at the CFH locus (P = 9.9 x 10(-13); odds ratio = 2.86). We found no differences in allele and genotype association between classic and occult choroidal neovascularization. We also observed that 39% of the samples in the general Italian population were at least 5.4 times more likely than control subjects to develop AMD.
CONCLUSIONS: To our knowledge, this is the first confirmation of the association of del443ins54 in Italian patients with AMD, and we also confirmed the association of Tyr402His with CFH. Genetic analysis of the general population suggested that analysis of the ARMS2 and CFH risk alleles alone may be helpful in differentiating high-risk individuals (odds ratio > 5.00) from low-risk individuals (odds ratio < 0.45).
CLINICAL RELEVANCE: Individuals at high risk for developing AMD could be identified and selected for specific prevention programs. In this context, the development of prevention programs based on dietary antioxidants or on close monitoring of at-risk individuals should be considered or suggested. ||||| PURPOSE: differentiate the associations of exudative age-related macular degeneration (AMD) and polypoidal choroidal vasculopathy (PCV) with the ARMS2/HTRA1 locus.
METHODS: The entire ARMS2 sequence was sequenced and HTRA1 rs11200638 genotyped in 568 unrelated Chinese individuals: 156 exudative AMD patients, 164 PCV patients, and 248 controls. A meta-analysis was performed to examine the effects of rs10490924 and rs11200638 at the ARMS2/HTRA1 locus in PCV.
RESULTS: In total, 31 polymorphisms in ARMS2 were identified. Significant associations with both exudative AMD and PCV were observed in 11 of them and HTRA1 rs11200638, with different genotypic distributions between exudative AMD and PCV (P < 0.001). After adjusting for rs11200638, ARMS2 rs10490924 remained significantly associated with exudative AMD (P = 0.011), but not with PCV (P = 0.077). Meta-analysis showed consistent allelic associations of rs10490924 and rs11200638 with PCV in different study populations.
CONCLUSIONS: There is a strong and consistent association of the ARMS2/HTRA1 locus with both exudative AMD and PCV, suggesting the two disorders share, at least partially, similar molecular mechanisms. Different effect sizes indicate the existence of additional genetic and environmental factors affecting them to different extents. ||||| BACKGROUND: The wet form of age-related macular degeneration (ARMD) is a leading cause of irreversible blindness in Caucasians. Our purpose was to assess influence of gene polymorphisms A69S (rs10490924) and R38X (rs2736911) ARMS2 and Y402 (rs1061170) CFH on wet ARMD risk in a Polish population.
MATERIAL/METHODS: 130 unrelated patients (90 with wet ARMD and 40 controls) took part in the study. Dry blood was used for DNA isolation. PCR amplification and gene sequencing were performed. In subjects with R38X and A69S, SNP gene cloning was used to exclude the possible combined variant.
RESULTS: Homozygous Y402H and A69S conferred a significance risk of wet ARMD in Poland: Y402H odds ratio (OR) was 5.57 (95% confidence interval: 1.58-19.6), p=0.002; and A69S OR was 7.72 (95% confidence interval: 1.73-34.36), p=0.001. R38X is probably more common in healthy subjects: OR was 0.45 (95% confidence interval: 0.19-1.05), p=0.053.
CONCLUSIONS: The etiologic role in ARMD of A69S ARMS2 and Y402H CFH gene variants were confirmed in a Polish population for the first time. R38X variant of ARMS2 seems to be protective from wet ARMD. ||||| PURPOSE: Identification of genetic factors for age-related macular degeneration (AMD) is of crucial importance in this common cause of blindness. Exudative AMD is rapidly progressive and usually associated with severe prognosis. Our purpose was to investigate this association on locus 10q26 in a case-control study including French patients specifically affected with exudative AMD.
METHODS: Polymorphisms rs4146894:G>A of Pleckstrin Homology Domain-containing Protein Family A member 1 (PLEKHA1) gene, rs10490924:G>T at LOC387715, and rs11200638:G>A of HTRA1 (HTRA serine peptidase 1) gene were analyzed in AMD cases (n=118, age=72.3+/-3.8 years old) and healthy controls (n=116, age=72.0+/-3.8 years old).
RESULTS: PLEKHA1 polymorphism was associated with AMD. The A allele frequency was 0.67 in cases versus 0.41 in controls, (p=0.0001). After age and sex adjustment, the odds ratio for risk of AMD was 9.1 (4.0-20.9, 95% CI, p=0.0001) for the AA genotype and 2.6 (1.3-5.5, 95% CI, p=0.04) for the AG genotype, conditional on HTRA1. Association was even stronger and independent with HTRA1. The A allele frequency was 0.51 in cases versus 0.22 in controls, (p=0.0001). The odds ratio was 15.5 (5.5-43.9, 95% CI, p=0.0001) for the AA genotype and 3.4 (1.9-6.1, 95% CI, p=0.0001) for the AG genotype. No further information was obtained from LOC387715 due to virtually complete linkage disequilibrium with HTRA1 polymorphism in cases (D'=1.0) and controls (D'=0.98). Although a role for PLEKHA1 could not be totally excluded, there was a four times higher AMD risk was associated with haplotype "A-T-A" involving "PLEKHA1-LOC387715-HTRA1" risk alleles.
CONCLUSIONS: Compared to PLEKHA1, HTRA1/LOC387715 genetic variations were independently and strongly associated with exudative AMD in the French population. Chromosome-10 genetic variants appear as potentially useful risk markers for early detection of AMD. ||||| Controversy remains as to which gene at the chromosome 10q26 locus confers risk for age-related macular degeneration (AMD) and statistical genetic analysis is confounded by the strong linkage disequilibrium (LD) across the region. Functional analysis of related genetic variations could solve this puzzle. Recently, Fritsche et al. reported that AMD is associated with unstable ARMS2 transcripts possibly caused by a complex insertion/deletion (indel; consisting of a 443 bp deletion and an adjacent 54 bp insertion) in its 3'UTR (untranslated region). To validate this indel, we sequenced our samples. We found that this indel is even more complex and is composed of two side-by-side indels separated by 17 bp: (1) 9 bp deletion with 10 bp insertion; (2) 417 bp deletion with 27 bp insertion. The indel is significantly associated with the risk of AMD, but is also in strong LD with the non-synonymous single nucleotide polymorphism rs10490924 (A69S). We also found that ARMS2 is expressed not only in placenta and retina but also in multiple human tissues. Using quantitative PCR, we found no correlation between the indel and ARMS2 mRNA level in human retina and blood samples. The lack of functional effects of the 3'UTR indel, the amino acid substitution of rs10490924 (A69S), and strong LD between them suggest that A69S, not the indel, is the variant that confers risk of AMD. To our knowledge, it is the first time it has been shown that ARMS2 is widely expressed in human tissues. Conclusively, the indel at 3'UTR of ARMS2 actually contains two side-by-side indels. The indels are associated with risk of AMD, but not correlated with ARMS2 mRNA level. ||||| Age-related macular degeneration (AMD) is a common cause of blindness in the elderly. Caucasian patients are predominantly affected by the dry form of AMD, whereas Japanese patients have predominantly the wet form of AMD and/or polypoidal choroidal vasculopathy (PCV). Although genetic association in the 10q26 (ARMS2/HTRA1) region has been established in many ethnic groups for dry-type AMD, typical wet-type AMD, and PCV, the contribution of the 1q32 (CFH) region seem to differ among these groups. Here we show a single nucleotide polymorphism (SNP) in the ARMS2/HTRA1 locus is associated in the whole genome for Japanese typical wet-type AMD (rs10490924: p = 4.1 x 10(-4), OR = 4.16) and PCV (rs10490924: p = 3.7 x 10(-8), OR = 2.72) followed by CFH (rs800292: p = 7.4 x 10(-5), OR = 2.08; p = 2.6 x 10(-4), OR = 2.00), which differs from previous studies in Caucasian populations. Moreover, a SNP (rs2241394) in complement component C3 gene showed significant association with PCV (p = 2.5 x 10(-3), OR = 3.47). We conclude that dry-type AMD, typical wet-type AMD, and PCV have both common and distinct genetic risks that become apparent when comparing Japanese versus Caucasian populations. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s12177-009-9047-1) contains supplementary material, which is available to authorized users. | [
{
"source_pmid": "18436811",
"source_text": "PURPOSE: Single nucleotide polymorphisms (SNPs) in the LOC387715 (rs10490924), HTRA1 (rs11200638), and CFH (rs1061170) genes have been implicated in age-related macular degeneration (AMD). The present study was undertaken to determine the involvement of the LOC38... |
29978377 | CONCLUSIONS: The results of the present meta-analysis show a significant 18% reduced risk for fish and a 20% increased risk for alcohol consumption. In addition, an increased risk was observed for meat, but only in the subgroup of early AMD. | Little evidence exists regarding associations between age-related macular degeneration (AMD) and moderate alcohol consumption, patterns of consumption, or different types of alcoholic beverage. The authors examined associations between AMD prevalence and alcohol intake using 20,963 participants from the Melbourne Collaborative Cohort Study aged 40-69 years at baseline (1990-1994). Participants' alcohol consumption was determined from a structured interview at baseline. At follow-up from 2003 to 2007, digital macula photographs of both eyes were taken and evaluated for early and late AMD signs. Drinking more than 20 g of alcohol per day was associated with an approximate 20% increase in the odds of early AMD (odds ratio = 1.21, 95% confidence interval: 1.06, 1.38; P = 0.004) when compared with those who reported no alcohol intake at baseline, having adjusted for sex, age, smoking, country of birth, education, physical activity, and energy from food. This positive association was apparent for wine, beer, and spirits. The estimates were similar for both sexes. The odds ratio for those drinking more than 20 g of alcohol per day for late AMD was 1.44 (95% confidence interval: 0.85, 2.45; P = 0.17). These results show a modest association between alcohol consumption and increased AMD risk. ||||| OBJECTIVE: To assess the relationship between baseline dietary fatty acids and 10-year incident age-related macular degeneration (AMD).
METHODS: In an elderly Australian cohort, 3654 participants were examined at baseline and 2454 were examined 5 and/or 10 years later. We assessed AMD from retinal photographs. Participants completed a semiquantitative food frequency questionnaire.
RESULTS: After adjusting for age, sex, and smoking, 1 serving of fish per week was associated with reduced risk of incident early AMD (relative risk, 0.69 [95% confidence interval, 0.49-0.98]), primarily among participants with less than the median linoleic acid consumption (0.57 [0.36-0.89]). Findings were similar for intake of long-chain omega-3 polyunsaturated fatty acids. One to 2 servings of nuts per week was associated with reduced risk of incident early AMD (relative risk, 0.65 [95% confidence interval, 0.47-0.91]). Protective associations between the intake of nuts and reduced risk of pigmentary abnormalities were seen among nonsmokers, participants with less than the median ratio of serum total to high-density lipoprotein cholesterol, and those with beta carotene intake greater than the median level.
CONCLUSIONS: This study provides evidence of protection against early AMD from regularly eating fish, greater consumption of omega-3 polyunsaturated fatty acids, and low intakes of foods rich in linoleic acid. Regular consumption of nuts may also reduce AMD risk. Joint effects from multiple factors are suggested. ||||| PURPOSE: To evaluate the associations between intakes of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) and the intermediate and advanced stages of age-related macular degeneration (AMD).
DESIGN: Prospective cohort study.
PARTICIPANTS: We followed 75 889 women from the Nurses' Health Study and 38 961 men from the Health Professionals Follow-Up Study who were at least 50 years old, from 1984 to 2012 and 1986 to 2010, respectively. Cohort participants are mostly white (≥95%).
METHODS: We assessed dietary intake by a validated food frequency questionnaire (FFQ) at baseline and every 4 years. We calculated cumulative average intakes of EPA and DHA from FFQs and also computed predicted erythrocyte and plasma scores directly from food intake using regression models. Cox proportional hazards models were used to compute the associations with AMD outcomes.
MAIN OUTCOME MEASURES: We confirmed 1589 incident intermediate and 1356 advanced AMD cases (primarily neovascular AMD) with a visual acuity of 20/30 or worse, owing primarily to AMD, by medical record review.
RESULTS: For intermediate AMD, the pooled hazard ratio (HR) between the 2 cohorts for DHA comparing the extreme quintiles of intake was 0.78 (95% confidence interval [CI], 0.66-0.92; P trend, 0.008) and for EPA + DHA was 0.83 (95% CI, 0.71-0.98; P trend, 0.03). The pooled HR for fatty fish, comparing ≥5 servings per week to almost never, was 0.61 (95% CI, 0.46-0.81; P trend, <0.001). For advanced AMD, the pooled HR for DHA was 1.01 (95% CI, 0.84-1.21; P trend, 0.75) and for fatty fish was 0.80 (95% CI, 0.59-1.08; P trend, 0.11). Secondary analyses using predicted erythrocyte and plasma scores of EPA and DHA yielded slightly stronger inverse associations for intermediate AMD and similar results for advanced AMD.
CONCLUSIONS: Higher intakes of EPA and DHA may prevent or delay the occurrence of visually significant intermediate AMD. However, the totality of current evidence for EPA and DHA and advanced AMD is discordant, though there was no association with advanced AMD in the present study. ||||| PURPOSE: To assess the 15-year incidence and progression of age-related macular degeneration (AMD) in an older Australian population.
DESIGN: Population-based cohort study.
PARTICIPANTS: Blue Mountains Eye Study (BMES) participants (n = 3654) aged 49+ years were examined during 1992-1994. Of these, 2334 (75.8% of survivors) were reexamined after 5 years (1997-1999), 1952 (76.7% of survivors) after 10 years (2002-2004), and 1149 (56.1% of survivors) after 15 years (2007-2010).
METHODS: Color retinal photographs were taken, and comprehensive questionnaires were administered at each visit and DNA was genotyped. Retinal photographic grading was performed by the same graders following the Wisconsin AMD grading protocol. Side-by-side comparisons were used to confirm newly developed AMD lesions. Incidence was estimated using Kaplan-Meier estimates. Associations of AMD incidence with age, sex, smoking status, presence of the complement factor H (CFH)-rs1061170 and age-related maculopathy susceptibility 2 (ARMS2)-rs10490924 polymorphisms, and fish consumption were analyzed using discrete logistic regression models. Generalized estimation equation models were used to assess the risk of incident late AMD associated with baseline AMD lesion characteristics.
MAIN OUTCOME MEASURES: The 15-year incidence and progression of AMD, and associated factors.
RESULTS: The 15-year incidence was 22.7% for early AMD and 6.8% for late AMD. After adjusting for competing risks, early and late AMD incidence were 15.1% and 4.1%, respectively. Age was strongly associated with early and late AMD incidence (both P < 0.0001). After age standardization to the Beaver Dam Eye Study (BDES) population, early and late AMD incidence in the BMES were 13.1% and 3.3%, respectively. Female sex and the presence of both risk alleles of CFH-rs1061170 or ARMS2-rs10490924 were independently associated with early AMD incidence, whereas current smoking and presence of ≥1 risk allele of CFH-rs1061170 or ARMS2-rs10490924 were associated with late AMD incidence. Fish consumption was inversely associated with late but not early AMD incidence. Severity of early AMD lesion characteristics was a strong predictor of progression to late AMD.
CONCLUSIONS: We documented the 15-year incidence of early and late AMD in an older Australian population that were comparable to BDES observations. Risk of progression to late AMD was strongly associated with severity of early AMD lesions. ||||| OBJECTIVE: To investigate the possible relationship between overall or specific alcohol consumption and risk of aging macula disorder (AMD), a synonym for age-related macular degeneration, in a general population.
METHODS: Alcohol consumption and risk of early or late incident AMD (iAMD) were examined among all participants in the prospective population-based Rotterdam Study, with complete data on alcohol consumption among 4229 subjects at risk of AMD. Aging macula disorder was graded according to the International Classification and Grading System for AMD by 2 trained professionals who were masked for all other determinants. We used Cox proportional hazards regression models to estimate hazard ratios and corresponding 95% confidence intervals.
RESULTS: During a mean follow-up period of 8.0 years, 600 cases of iAMD were identified, of which 519 were early iAMD and 81 were late iAMD. After correction for age, sex, smoking, complement factor H genotype status, and other potential confounders, we did not find an association between overall or specific alcohol consumption and development of early iAMD or dry or wet late iAMD.
CONCLUSION: Our findings suggest that overall or specific alcohol consumption is not a risk factor for AMD. ||||| PURPOSE: To examine the association between potential risk factors and the 14-year incidence of age-related maculopathy (ARM).
DESIGN: Population-based cohort study.
PARTICIPANTS: At baseline, 946 volunteers participated in the study during 1986--88. These subjects were between 60 and 80 years of age and lived in the Østerbro district of Copenhagen. Excluding participants who had died since baseline, 359 subjects (97.3% of survivors) were re-examined 14 years later, during 2000--2002. A total of 31.8% (301/946) of the original material was included in the risk factor analyses.
METHODS: Participants underwent an ophthalmological examination at Rigshospitalet, the National University Hospital of Copenhagen. Similar standardized protocols for physical examination were used at the baseline and follow-up examinations. Age-related maculopathy lesions were determined by the same grader grading colour fundus photographs from both examinations using a modification of the Wisconsin Age-related Maculopathy Grading System protocol.
RESULTS: Of the 359 participants, 94 had incident early ARM and 52 had incident late ARM at follow-up in either eye. In logistic regression, the risk factors for early ARM or worse were as follows: cataract (odds ratio [OR] 2.8, 95% confidence interval [CI] 1.2-6.2); family history of ARM (OR 4.5, 95% CI 1.3--15.5), and alcohol consumption >250 g/week (OR 4.6, 95% CI 1.1-19.2). High levels of apolipoprotein B (>100 mg/l) decreased the risk of development of early ARM or worse (OR 0.4, 95% CI 0.2-0.8), while high levels of apolipoprotein A1 (>or= 150 mg/l) increased the risk of late ARM (OR 2.5, 95% CI 1.2-5.3). Advanced age at baseline was also associated with the incidence of late ARM (OR 2.0, 95% CI 1.4-2.9).
CONCLUSIONS: These findings indicate a direct correlation between age, cataract, family history, alcohol consumption, the apolipoproteins A1 and B and the 14-year incidence of ARM. ||||| PURPOSE: To establish risk factors for five-year incidence of age-related macular degeneration (AMD).
DESIGN: Population-based, prospective cohort study, and risk analysis.
METHODS: A random sample from the Reykjavik Population Census for individuals 50 years and older was selected. We took fundus stereo color photographs and used standard grading system to study the five-year incidence of drusen, pigmentary abnormalities, and AMD and to examine possible risk factors. A questionnaire including information on disease, medication, diet, and lifestyle from the Reykjavik Eye Study database provided additional information.
RESULTS: Current alcohol consumption decreased the risk for drusen. Being married rather than divorced or widowed decreased the risk for soft drusen; being single decreased the risk of hypopigmentation as compared with being divorced or married. Both consuming dietary fiber-rich vegetables and meat and meat products once a week or less frequently was a risk factor for developing soft drusen and decreased the risk of pigmentary abnormalities. Those who had smoked 20 pack-years or more as compared with nonsmokers had decreased survival rate over the five years (odds ratio (OR) 0.46, 95% confidence interval (CI) 0.27 to 0.80; P = .006).
CONCLUSIONS: Risk factors for drusen appear to differ from risk factors for pigmentary abnormalities. The effect of smoking on developing AMD is partly masked by selective mortality. ||||| BACKGROUND: Individuals with early or intermediate stages of age-related macular degeneration (AMD) make up a large, growing segment of the elderly population. Evidence is sparse regarding modifiable factors that may decrease the risk of progression to the advanced forms of AMD.
OBJECTIVE: To advise patients with a high risk for advanced forms of AMD about preventive measures through our evaluation of the relationship between dietary fat intake and the progression of early or intermediate AMD to the advanced stages of the disease associated with visual loss.
DESIGN: A prospective cohort study with an average follow-up time of 4.6 years.
SETTING: A hospital-based clinical retinal practice specializing in macular degeneration. Patients The 261 participants were aged 60 years and older and had some sign of nonexudative AMD and visual acuity of 20/200 or better in at least 1 eye. Main Outcome Measure Progression to advanced AMD, which was defined as having geographic atrophy or neovascular disease.
RESULTS: Higher total fat intake increased the risk of progression to the advanced forms of AMD, with a relative risk (RR) of 2.90 (95% confidence interval, 1.15-7.32) for the highest fat-intake quartile relative to the lowest fat-intake quartile, after controlling for other factors (P trend =.01). Animal fat intake was associated with a 2-fold increased risk of progression (RR, 2.29 for the highest quartile compared with the lowest quartile; 95% confidence interval, 0.91-5.72), although the trend for increasing risk with higher animal fat intake was not significant (P=.09). Higher vegetable fat intake had a stronger relationship with increased risk of AMD progression with an RR of 3.82 (95% confidence interval, 1.58-9.28) for the highest quartile compared with the lowest quartile (P trend =.003). Saturated, monounsaturated, polyunsaturated, and transunsaturated fats increased the likelihood of progression (RR, 2.09 and P trend =.08; RR, 2.21 and P trend =.04; RR, 2.28 and P trend =.04; RR, 2.39 and P trend =.008, respectively). Higher fish intake was associated with a lower risk of AMD progression among subjects with lower linoleic acid intake. Processed baked goods, which are higher in some of these fats, increased the rate of AMD progression approximately 2-fold, and nuts were protective.
CONCLUSIONS: Among individuals with the early or intermediate stages of AMD, total and specific types of fat intake, as well as some fat-containing food groups, modified the risk of progression to advanced AMD. Fish intake and nuts reduced risk. Since advanced AMD is associated with visual loss and reduced quality of life, these preventive measures deserve additional research and greater emphasis. ||||| OBJECTIVE: To examine whether intake of ω-3 fatty acids and fish affects incidence of age-related macular degeneration (AMD) in women.
DESIGN: A detailed food-frequency questionnaire was administered at baseline among 39 876 female health professionals (mean [SD] age: 54.6 [7.0] years). A total of 38 022 women completed the questionnaire and were free of a diagnosis of AMD. The main outcome measure was incident AMD responsible for a reduction in best-corrected visual acuity to 20/30 or worse based on self-report confirmed by medical record review.
RESULTS: A total of 235 cases of AMD, most characterized by some combination of drusen and retinal pigment epithelial changes, were confirmed during an average of 10 years of follow-up. Women in the highest tertile of intake for docosahexaenoic acid, compared with those in the lowest, had a multivariate-adjusted relative risk of AMD of 0.62 (95% confidence interval, 0.44-0.87). For eicosapentaenoic acid, women in the highest tertile of intake had a relative risk of 0.66 (95% confidence interval, 0.48-0.92). Consistent with the findings for docosahexaenoic acid and eicosapentaenoic acid, women who consumed 1 or more servings of fish per week, compared with those who consumed less than 1 serving per month, had a relative risk of AMD of 0.58 (95% confidence interval, 0.38-0.87).
CONCLUSION: These prospective data from a large cohort of female health professionals without a diagnosis of AMD at baseline indicate that regular consumption of docosahexaenoic acid and eicosapentaenoic acid and fish was associated with a significantly decreased risk of incident AMD and may be of benefit in primary prevention of AMD. ||||| We aimed to establish the collective influence of four lifestyle practices (physical activity, diet, smoking and alcohol consumption) on the prevalence and incidence of AMD. At baseline, 2428 participants aged 49+ with complete lifestyle and AMD data were examined, and of these, 1903 participants were re-examined 15 years later. AMD was assessed from retinal photographs. A health behaviour score was calculated, allocating 1 point for each poor behaviour: current smoking; fruits and vegetables consumed <4 serves daily; <3 episodes of physical activity per week; and >2 alcoholic drinks per day. Cross-sectional analysis showed that participants who engaged in all 4 poor health behaviours (n = 29) versus those who did not engage in unhealthy behaviours (reference group; n = 677) had greater odds of any and late AMD: multivariable-adjusted OR, 5.14 (95% CI, 1.04-25.45) and OR 29.53 (95% CI 2.72-321.16), respectively. A marginally non-significant association was observed between increasing number of poor health behaviours and 15-year incidence of early AMD (multivariable-adjusted P-trend = 0.08). Our data suggests that motivating patients with AMD to eat better, exercise more, limit alcohol intake and avoid smoking seems advisable to decelerate the development or worsening of existing AMD. ||||| BACKGROUND: Adherence to a Mediterranean-type diet is linked to a lower risk of mortality and chronic disease, but the association with the progression of age-related macular degeneration (AMD) and genetic susceptibility is unknown.
OBJECTIVE: We examined the association of adherence to the Mediterranean diet and genetic susceptibility with progression to advanced AMD.
DESIGN: Among 2525 subjects in the AREDS (Age-Related Eye Disease Study), 1028 eyes progressed to advanced AMD over 13 y. Baseline data for demographic and behavioral covariates were collected by using questionnaires. Dietary data were collected from food-frequency questionnaires. The alternate Mediterranean diet (aMeDi) score (range: 0-9) was constructed from individual intakes of vegetables, fruit, legumes, whole grains, nuts, fish, red and processed meats, alcohol, and the ratio of monounsaturated to saturated fats. Ten genetic loci in 7 genes [complement factor H (CFH), age-related maculopathy susceptibility 2/high-temperature requirement A serine peptidase 1 (ARMS2/HTRA1), complement component 2 (C2), complement factor B (CFB), complement component 3 (C3), collagen type VIII α 1 (COL8A1), and RAD51 paralog B (RAD51B)] were examined. Survival analysis was used to assess individual eyes for associations between incident AMD and aMeDi score, as well as interaction effects between aMeDi score and genetic variation on risk of AMD.
RESULTS: A high aMeDi score (score of 6-9) was significantly associated with a reduced risk of progression to advanced AMD after adjustment for demographic, behavioral, ocular, and genetic covariates (HR: 0.74; 95% CI: 0.61, 0.91; P-trend = 0.007). The aMeDi score was significantly associated with a lower risk of incident advanced AMD among subjects carrying the CFH Y402H nonrisk (T) allele (P-trend = 0.0004, P-interaction = 0.04). The aMeDi score was not associated with AMD among subjects who were homozygous for the risk (C) allele.
CONCLUSION: Higher adherence to a Mediterranean diet was associated with reduced risk of progression to advanced AMD, which may be modified by genetic susceptibility. This trial was registered at clinicaltrials.gov as NCT00594672. ||||| Habitual consumption of dairy products has been shown to play an important role in the prevention of several chronic diseases. We aimed to prospectively assess the relationship between the change in dairy product consumption (both regular fat and low/reduced fat) and the 15-year incidence of age-related macular degeneration (AMD). In the Blue Mountains Eye Study, 2037 participants aged 49 years or above at baseline were re-examined at follow-up in 1997-9, 2002-4 and/or 2007-9. AMD was assessed from retinal photographs. Dietary data were collected using a semi-quantitative FFQ, and servings of dairy product consumption calculated. Over the 15-year follow-up, there were 352, 268 and eighty-four incident cases of any, early and late AMD, respectively. After adjusting for age, sex, current smoking, white cell count and fish consumption, a significant linear trend (P for trend = 0·003) was observed with decreasing consumption of total dairy foods and the 15-year incidence of late AMD, comparing the lowest v. highest quintile of intake (OR 2·80, 95 % CI 1·21, 3·04). Over the 15 years, decreased consumption of reduced-fat dairy foods was associated with an increased risk of incident late AMD, comparing the lowest to highest quintile of intake (OR 3·10, 95 % CI 1·18, 8·14, P for trend = 0·04). Decreasing total dietary Ca intake over the 15 years was also associated with an increased risk of developing incident late AMD (multivariable-adjusted P for trend = 0·03). A lower consumption of dairy products (regular and low fat) and Ca was independently associated with a higher risk of developing incident late AMD in the long term. Additional cohort studies are needed to confirm these findings. ||||| Age-related macular degeneration (AMD) is the leading cause of blindness among older people, and diet has been postulated to alter risk of AMD. To evaluate associations between red meat and chicken intake and AMD, the authors conducted a cohort study of 6,734 persons aged 58-69 years in 1990-1994 in Melbourne, Australia. Meat intake was estimated from a food frequency questionnaire at baseline. At follow-up (2003-2006), bilateral digital macular photographs were taken and evaluated for AMD (1,680 cases of early AMD, 77 cases of late AMD). Logistic regression was used to estimate odds ratios, adjusted for age, smoking, and other potential confounders. Higher red meat intake was positively associated with early AMD; the odds ratio for consumption of red meat > or =10 times/week versus <5 times/week was 1.47 (95% confidence interval: 1.21, 1.79; P-trend < 0.001). Similar trends toward increasing prevalence of early AMD were seen with higher intakes of fresh and processed red meat. Conversely, consumption of chicken > or =3.5 times/week versus <1.5 times/week was inversely associated with late AMD (odds ratio = 0.43, 95% confidence interval: 0.20, 0.91; P-trend = 0.007). These results suggest that different meats may differently affect AMD risk and may be a target for lifestyle modification. ||||| OBJECTIVE: To examine the intake of antioxidant vitamins and carotenoids as well as fruits and vegetables in relation to the development of age-related maculopathy (ARM).
METHODS: We conducted a prospective follow-up study of women in the Nurses' Health Study and men in the Health Professionals Follow-up Study. We followed 77 562 women and 40 866 men who were at least 50 years of age and had no diagnosis of ARM or cancer at baseline for up to 18 years for women and up to 12 years for men. Fruit and vegetable intakes were assessed with a validated semiquantitative food-frequency questionnaire up to 5 times for women and up to 3 times for men during follow-up.
RESULTS: A total of 464 (329 women and 135 men) incident cases of early ARM and 316 (217 women and 99men) cases of neovascular ARM, all with visual loss of 20/30 or worse due primarily to ARM, were diagnosed during follow-up. Fruit intake was inversely associated with the risk of neovascular ARM. Participants who consumed 3 or more servings per day of fruits had a pooled multivariate relative risk of 0.64 (95% confidence interval, 0.44-0.93; P value for trend =.004) compared with those who consumed less than 1.5 servings per day. The results were similar in women and men. However, intakes of vegetables, antioxidant vitamins, or carotenoids were not strongly related to either early or neovascular ARM.
CONCLUSION: These data suggest a protective role for fruit intake on the risk of neovascular ARM. ||||| PURPOSE: To investigate alcohol consumption as a risk factor for the 15-year cumulative incidence and progression of age-related macular degeneration (AMD).
DESIGN: Prospective population-based study in Beaver Dam, WI with four examinations at five-year intervals initiated in 1988 (n = 3,509 contributed data for this analysis).
METHODS: History of alcohol consumption was obtained via questionnaire. Cumulative incidence of early AMD, exudative AMD, pure geographic atrophy, and progression of AMD were assessed from fundus photographs taken at each examination.
RESULTS: Heavy drinking (four or more drinks daily) at baseline was related to the 15-year cumulative incidence of pure geographic atrophy in men (odds ratio, 9.2; 95% confidence interval, 1.7 to 51.2). There were no consistent associations with the amount of beer, wine, or liquor consumption and the incidence or progression of AMD.
CONCLUSIONS: Alcohol consumption is unlikely to strongly increase (or decrease) the risk of AMD. ||||| PURPOSE: Vascular risk factors, including alcohol intake, have been hypothesized to play a role in the development of age-related macular degeneration (AMD). We examined the relationship of alcohol intake with AMD in the Physicians' Health Study (PHS).
METHODS: The PHS was a randomized trial of aspirin and beta-carotene among 22,071 U.S. male physicians age 40 to 84 years at entry. A total of 21,041 physicians with complete data on alcohol consumption and no AMD at baseline were included in this analysis. Proportional hazards models were used to estimate relative risks (RR) and 95% confidence interval (CI).
RESULTS: During an average follow-up period of 12.5 years, 278 physicians were confirmed by medical record review to have incident AMD resulting in vision loss ( acuity 20/30 or worse). After adjusting for age, randomized treatment assignment, and other potential risk factors, the RR for > or = 1 drink/week versus < 1 drink/week was 0.97 (CI: 0.78-1.21). For categories of alcohol intake, the RRs for those reporting alcohol consumption of < 1 drink/week, 1 drink/week, 2-4 drinks/week, 5-6 drinks/week, and > or = 1 drink/day were 1.00 (referent), 1.00 (0.65-1.55), 0.68 (0.44-1.04), 1.32 (0.89-1.95), and 1.27 (0.93-1.73), respectively.
CONCLUSIONS: These prospective data indicate that alcohol intake is not appreciably associated with the risk of incident AMD. However, the width of the confidence intervals are compatible with a possible small effect (reduction or increase) in risk for low to moderate levels of alcohol intake, which warrant further investigation. ||||| PURPOSE: To identify risk factors for the progression of early age-related macular degeneration (AMD) in Koreans.
METHODS: This study was conducted at a health-screening center and followed a prospective cohort study design. Of 10,890 participants older than 50 years, 318 (2.92%) presented with early AMD. Among these 318 participants, we re-examined 172 participants after a mean duration of 4.4 years. Progression was defined by the Age-Related Eye Disease Study (AREDS) simplified AMD severity scale. Multivariable logistic regression was used to examine associations between AMD progression and baseline physical, demographic, behavioral, and ocular characteristics.
RESULTS: Of the 172 participants with early AMD who were re-examined, 34 (19.8%) had progression. Multivariable analyses revealed that current smoking (odds ratio, OR, 7.0, 95% confidence interval, CI, 1.4-34.4, adjusted for age, alcohol consumption, body mass index, BMI, blood pressure, BP, total cholesterol, and high density lipoprotein, HDL, cholesterol) and hypertension (OR 10.3, 95% CI 1.9-55.7, adjusted for age, smoking status, alcohol consumption, BMI, total cholesterol, and HDL cholesterol) were independently associated with progression of early AMD. Additionally, the presence of a central drusen lesion within one-third disc diameter of the macula (age-adjusted OR 4.8, 95% CI 1.3-17.6) and 20 or more drusen (age adjusted OR 7.8, 95% CI 2.5-24.0) were independently associated with progression of early AMD.
CONCLUSION: Current smoking, hypertension, central drusen location, and increasing number of drusen were associated with an increased risk of early AMD progression in Koreans. ||||| PURPOSE: To estimate the incidence of age-related macular degeneration (AMD) and the association of smoking and alcohol in a population of older women.
DESIGN: Prospective cohort study.
METHODS: Subjects were women who attended the Study of Osteoporotic Fractures year-10 and year-15 follow-up clinic visits and had fundus photographs taken at both visits (n = 1958; 245 Black and 1713 White subjects; mean age at year 10 visit, 78.2 years). Forty-five degree stereoscopic fundus photographs were graded for AMD. Logistic regression was used to test whether risk factors were associated with incident AMD.
RESULTS: The overall 5-year AMD incidence was 24.1% (95% confidence interval [CI], 21.7 to 26.6) for early and 5.7% (95% CI, 4.6 to 6.8) for late. Early AMD incidence in White subjects ranged from 21.9% in those aged 74 to 79 years to 33.2% in those 80 to 84 years, but was observed at the slightly lower rate of 29.0% in subjects > or =85 years (trend P < .0001). After confounder adjustment, alcohol consumption was significantly associated with an elevated risk of incident early AMD (odds ratio [OR], 1.57; 95% CI, 1.18 to 2.11). There was an increased risk of early AMD among subjects aged 80 years or older who were smoking compared to those younger than 80 years who were not smoking (OR, 5.49; 95% CI, 1.57 to 19.20; P for interaction = .026).
CONCLUSIONS: The magnitude of the greater-than-additive effect of smoking on the age-adjusted risk of AMD reinforces recommendations to quit smoking even for older individuals. ||||| BACKGROUND: Dietary factors are known risk factors for age-related macular degeneration (AMD) -- the leading cause of visual loss among persons aged > or =65 y. High-glycemic-index diets have been hypothesized as a risk factor for AMD, but prospective data are unavailable.
OBJECTIVE: The objective was to examine the association between dietary glycemic index and the 10-y incidence of AMD in the Blue Mountain Eye Study population.
DESIGN: This was a population-based cohort study with 3,654 participants (> or =49 y) examined at baseline (1992-1994); 2,335 patients were reexamined after 5 y and 1952 after 10 y. The Wisconsin System was used to grade 10-y incident early and late AMD from retinal photographs. A food-frequency questionnaire was used to collect dietary information at baseline, and an Australian database was used to calculate the mean glycemic index.
RESULTS: Over 10 y, 208 of 1,810 persons (cumulative incidence: 14.1%) developed early AMD. After age, smoking, other risk factors, and dietary constituents were adjusted for, a higher mean dietary glycemic index was associated with an increased 10-y risk of early AMD in a comparison of quartiles 1 and 4 [relative risk (RR): 1.77; 95% CI: 1.13, 2.78; P for trend = 0.03]. Conversely, a greater consumption of cereal fiber (RR: 0.68; 95% CI: 0.44, 1.04; P for trend = 0.05) and breads and cereals (predominantly lower glycemic index foods such as oatmeal) (RR: 0.67; 95% CI: 0.44, 1.02; P for trend = 0.03) was associated with a reduced risk of incident early AMD. No relation was observed with late AMD.
CONCLUSIONS: A high-glycemic-index diet is a risk factor for early AMD -- the recognized precursor of sight-threatening late AMD. Low-glycemic-index foods such as oatmeal may protect against early AMD. ||||| OBJECTIVE: To describe the relationship between alcohol consumption and the incidence of age-related macular degeneration (AMD).
METHODS: We conducted a prospective study among female nurses between 1980 and 1994 and among male health professionals between 1986 and 1994. We included 32764 women and 29488 men who were 50 years or older, without a diagnosis of AMD or cancer at baseline, and added additional subjects to the analysis as they reached 50 years of age. Their alcohol intake was assessed at baseline and updated during follow-up evaluations using a validated semiquantitative food-frequency questionnaire. After separate analyses for women and men, pooled estimates of the relationship of alcohol to the risk of AMD were calculated.
RESULTS: Age-related macular degeneration associated with a visual acuity loss of 20/30 or worse, including the early and dry and wet types, was diagnosed in 298 women (from 697498 person-years of follow-up) and 153 men (229 180 person-years) by 1994, the end of follow-up. After controlling for age, smoking, and other risk factors, the pooled relative risks (RRs) and 95% confidence intervals (CIs) for AMD compared with nondrinkers were 1.0 (0.7-1.2) for drinkers who consumed 0.1 to 4.9 g/d of alcohol; 0.9 (0.6-1.4) for 5 to 14.9 g/d; 1.1 (0.7-1.7) for 15 to 29.9 g/d; and 1.3 (0.9-1.8) for 30 g/d or more. Among women, there was a suggestion of a modest increased risk of the disease in drinkers who consumed 30 g/d or more (RR, 1.5; 95% CI, 1.0-2.4); this was limited to an increased risk of the early and dry form (RR, 2.0; 95% CI, 1.2-3.4). No specific type of alcohol provided protection against AMD.
CONCLUSION: This prospective study does not support an inverse relationship between moderate alcohol consumption and risk of AMD. ||||| OBJECTIVE: To evaluate associations between past dietary fat intake and the prevalence of age-related macular degeneration (AMD).
METHODS: Six thousand seven hundred thirty-four participants aged 58 to 69 years in 1990-1994 took part in this cohort study. Participants' nutrient intakes were estimated from a food frequency questionnaire at baseline. At follow-up from 2003 to 2006, digital macula photographs of both eyes were evaluated for early and late AMD signs. Logistic regression was used to estimate odds ratios, with adjustment for age, smoking, and other potential confounders.
RESULTS: Higher trans-unsaturated fat intake was associated with an increased prevalence of late AMD; the odds ratio comparing the highest with the lowest quartile of trans fat was 1.76 (95% confidence interval, 0.92-3.37; P = .02). Higher omega-3 fatty acid intake (highest quartile vs lowest quartile) was inversely associated with early AMD (odds ratio, 0.85; 95% confidence interval, 0.71-1.02; P = .03). Olive oil intake (> or =100 mL/week vs <1 mL/week) was associated with decreased prevalence of late AMD (odds ratio, 0.48; 95% confidence interval, 0.22-1.04; P = .03). No significant associations with AMD were observed for intakes of fish, total fat, butter, or margarine.
CONCLUSION: A diet low in trans-unsaturated fat and rich in omega-3 fatty acids and olive oil may reduce the risk of AMD. ||||| OBJECTIVE: To evaluate the association between dietary patterns and age-related macular degeneration (AMD).
DESIGN: Food frequency data were collected from Melbourne Collaborative Cohort Study (MCCS) participants at the baseline study in 1990-1994. During follow-up in 2003-2007, retinal photographs were taken and evaluated for AMD.
PARTICIPANTS: At baseline, 41514 participants aged 40 to 70 years and born in Australia or New Zealand (69%), or who had migrated from the United Kingdom, Italy, Greece, or Malta (31%) were recruited. Of these, 21132 were assessed for AMD prevalence at follow-up.
METHODS: Principal component analysis was used to identify dietary patterns (Factors F1-6) among the food items. Logistic regression was used to assess associations of dietary patterns with AMD.
MAIN OUTCOME MEASURES: Odds ratios (ORs) for early stages and advanced AMD in association with dietary patterns.
RESULTS: A total of 2508 participants (12.8%) had early stages of AMD, and 108 participants (0.6%) had advanced AMD. Six factors characterized by predominant intakes of fruits (F1); vegetables (F2); grains, fish, steamed or boiled chicken, vegetables, and nuts (F3); red meat (F4); processed foods comprising cakes, sweet biscuits, and desserts (F5); and salad (F6) were identified. Higher F3 scores were associated with a lower prevalence of advanced AMD (fourth vs. first quartile) (OR, 0.49; 95% confidence interval [CI], 0.28-0.87), whereas F4 scores greater than the median were associated with a higher prevalence of advanced AMD (OR, 1.46; 95% CI, 1.0-2.17).
CONCLUSIONS: Rather than specific individual food items, these factors represent a broader picture of food consumption. A dietary pattern high in fruits, vegetables, chicken, and nuts and a pattern low in red meat seems to be associated with a lower prevalence of advanced AMD. No particular food pattern seemed to be associated with the prevalence of the earliest stages of AMD. ||||| OBJECTIVE: To examine effect modification between genetic susceptibility to age-related macular degeneration (AMD) and dietary antioxidant or fish consumption on AMD risk.
DESIGN: Pooled data analysis of population-based cohorts.
PARTICIPANTS: Participants from the Blue Mountains Eye Study (BMES) and Rotterdam Study (RS).
METHODS: Dietary intakes of antioxidants (lutein/zeaxanthin [LZ], β-carotene, and vitamin C), long-chain omega-3 polyunsaturated fatty acids, and zinc were estimated from food frequency questionnaires. The AMD genetic risk was classified according to the number of risk alleles of CFH (rs1061170) or ARMS2 (rs10490924) as low (no or 1 risk allele) or high (≥ 2 risk alleles). Interactions between dietary intake and genetic risk levels were assessed. Associations between dietary intake and AMD risk were assessed comparing the highest with the 2 lower intake tertiles by genetic risk subgroups using discrete logistic regression, conducted in each study separately and then using pooled data. Participants without AMD lesions at any visit were controls. We adjusted for age and sex in analyses of each cohort sample and for smoking status and study site in pooled-data analyses.
MAIN OUTCOME MEASURES: All 15-year incident late AMD cases were confirmed by chief investigators of the Beaver Dam Eye Study, BMES, and RS. Intergrader reproducibility was assessed in an early AMD subsample, with 86.4% agreement between BMES and RS graders, allowing for a 1-step difference on a 5-step AMD severity scale.
RESULTS: In pooled data analyses, we found significant interaction between AMD genetic risk status and LZ intake (P=0.0009) but nonsignificant interactions between genetic risk status and weekly fish consumption (P=0.05) for risk of any AMD. Among participants with high genetic risk, the highest intake tertile of LZ was associated with a >20% reduced risk of early AMD, and weekly consumption of fish was associated with a 40% reduced risk of late AMD. No similar association was evident among participants with low genetic risk. No interaction was detected between β-carotene or vitamin C and genetic risk status.
CONCLUSIONS: Protection against AMD from greater LZ and fish consumption in persons with high genetic risk based on 2 major AMD genes raises the possibility of personalized preventive interventions. ||||| BACKGROUND: The relation between intakes of total fat and specific types of fat and age-related macular degeneration (AMD) remains unclear.
OBJECTIVE: Our objective was to examine prospectively the association between fat intake and AMD.
DESIGN: We conducted a prospective follow-up study of participants in the Nurses' Health Study and the Health Professionals Follow-up Study. At baseline (1984 for women and 1986 for men), the study included 42743 women and 29746 men aged > or = 50 y with no diagnosis of AMD who were followed until 1996. Fat intake was assessed with a food-frequency questionnaire.
RESULTS: We accrued 567 patients with AMD with a visual loss of 20/30 or worse. The pooled multivariate relative risk (RR) for the highest compared with the lowest quintile of total fat intake was 1.54 (95% CI: 1.17, 2.01; P for trend = 0.008). Linolenic acid was positively associated with risk of AMD (top versus bottom quintile of RR: 1.49; 95% CI: 1.15, 1.94; P for trend = 0.0009). Docosahexaenoic acid had a modest inverse relation with AMD (top versus bottom quintile of RR: 0.70; 95% CI: 0.52, 0.93; P for trend = 0.05), and >4 servings of fish/wk was associated with a 35% lower risk of AMD compared with < or = 3 servings/mo (RR: 0.65; 95% CI: 0.46, 0.91; P for trend = 0.009).
CONCLUSIONS: Total fat intake was positively associated with risk of AMD, which may have been due to intakes of individual fatty acids, such as linolenic acid, rather than to total fat intakes per se. A high intake of fish may reduce the risk of AMD. ||||| PURPOSE: To estimate the 5-year incidence and risk factors for age-related maculopathy (ARM) in a representative older Japanese population.
METHODS: A population-based cohort study was conducted in 1998 on 1482 Hisayama residents aged 50 years or older, and 961 of these subjects attended the 5-year follow-up examinations in 2003. At both time points, the characteristics of ARM were determined by grading color fundus photographs according to the Wisconsin Age-Related Maculopathy Grading System. Using these cohort data, logistic regression analyses were performed to determine the risk factors for ARM. Nine possible risk factors were examined: age, sex, hypertension, diabetes, hyperlipidemia, smoking, alcohol intake, body mass index, and white blood cell count.
RESULTS: The 5-year incidence of early ARM was 8.5%, and that of late ARM was 0.8%. Men were found to have a significantly higher incidence of late ARM than did women. The incidence of both early and late ARM increased significantly with age. Multiple logistic regression analysis showed that age and smoking were significantly associated with early and late ARM.
CONCLUSIONS: The results suggest that the overall 5-year incidence of early ARM is 8.0% and that of late ARM is 0.8% in the general Japanese population and that higher age and smoking are relevant risk factors for early and late ARM in the Japanese. ||||| OBJECTIVE: To assess longitudinal associations between dietary fat and incident age-related maculopathy (ARM) in an older, population-based, historical cohort.
METHODS: A total of 3654 persons, 49 years or older, participated in the Blue Mountains Eye Study (1992-1994); 2335 (75.1% of survivors) were reexamined after 5 years (1997-1999). Dietary data were collected from 2895 people (79%) at baseline by means of a semiquantitative food frequency questionnaire to calculate dietary fat intakes. Presence of ARM was graded from retinal photographs (Wisconsin ARM Grading System). Logistic regression adjusted for age, sex, vitamin C intake, and smoking.
RESULTS: Participants with the highest vs lowest quintiles of n-3 polyunsaturated fat intake had lower risk of incident early ARM (odds ratio [95% confidence interval], 0.41 [0.22-0.75). A 40% reduction of incident early ARM was associated with fish consumption at least once a week (odds ratio [95% confidence interval], 0.58 [0.37-0.90]), whereas fish consumption at least 3 times per week could reduce the incidence of late ARM (odds ratio [95% confidence interval], 0.25 [0.06-1.00]). We found no association between incident ARM and butter, margarine, or nut consumption.
CONCLUSIONS: A regular diet high in n-3 polyunsaturated fat, especially from fish, suggests protection against early and late ARM in this older Australian cohort. Our study could not confirm deleterious effects of higher polyunsaturated fat intakes reported by other clinic-based studies. | [
{
"source_pmid": "22847604",
"source_text": "Little evidence exists regarding associations between age-related macular degeneration (AMD) and moderate alcohol consumption, patterns of consumption, or different types of alcoholic beverage. The authors examined associations between AMD prevalence and alcohol ... |
30880485 | Conclusions: We identified low to moderate quality evidence describing post-intervention mean ocular perfusion pressure in open angle glaucoma. Bimatoprost increases mean ocular perfusion pressure when compared to timolol. As a class, prostaglandins increase mean ocular perfusion pressure. Prostaglandins may provide beneficial ocular perfusion pressure profiles compared to alternative agents.
| OBJECTIVE: To evaluate and compare the effects of latanoprost 0.005% once daily and brimonidine tartrate 0.2% twice daily in patients with normal-tension glaucoma (NTG).
DESIGN: A randomized, open-label, crossover study.
PARTICIPANTS: Twenty-eight NTG patients with progressive visual field defects/optic disc excavation, new disc hemorrhage, or field defects that threatened fixation.
INTERVENTION: Patients were randomly allocated to one of two groups. Patients in group 1 were treated with latanoprost, lubricant, and brimonidine for 4 weeks each, whereas patients in group 2 were treated with brimonidine, lubricant, and latanoprost for 4 weeks each.
MAIN OUTCOME MEASURES: Intraocular pressure (IOP), pulse rate, and blood pressure were measured at 8 am, 12 noon, and 4 pm after each 4-week treatment. Ocular perfusion pressure (OPP) was calculated.
RESULTS: Latanoprost and brimonidine reduced the average IOP by 3.6 +/- 1.9 mmHg (P < 0.001) and 2.5 +/- 1.3 mmHg (P < 0.001), respectively, with a significant difference between the two regimens (P = 0.009). Both drugs significantly reduced IOP at each time point. Latanoprost decreased IOP significantly more than did brimonidine at 8 am (11.7 +/- 2.2 mmHg vs. 13.7 +/- 2.1 mmHg, P = 0.004) and 4 pm (11.4 +/- 2.1 mmHg vs. 13.2 +/- 2.9 mmHg, P = 0.004), but IOP was equal between the two agents at 12 noon (11.5 +/- 2.6 mmHg vs. 11.5 +/- 2.3 mmHg, P = 0.967). IOP was maintained at 12 mmHg or lower in 18 (66.7%) of 27 patients after treatment with latanoprost and in 9 (33.3%) of 27 patients after treatment with brimonidine. Latanoprost monotherapy reduced IOP by 30% in 8 patients (29.6%), but brimonidine monotherapy did not reduce IOP by that much in any of the patients. OPP increased after latanoprost treatment (P < 0.001) but did not increase after brimonidine treatment (P = 0.355). There was no significant change in pulse rate or blood pressure.
CONCLUSIONS: Both latanoprost and brimonidine reduce IOP in NTG patients. Brimonidine has a peak IOP-lowering effect equal to that of latanoprost but produces a higher mean diurnal IOP than does latanoprost because of its shorter effect. Latanoprost might favorably alter optic disc blood perfusion by increasing OPP. ||||| OBJECTIVE: To investigate the effects of topical latanoprost 0.005% and topical brimonidine tartrate 0.2% on retrobulbar blood flow in patients with primary open-angle glaucoma (POAG) and ocular hypertension (OHT).
METHODS: Forty-one consecutive patients with POAG and OHT were enrolled in this prospective, open-label, randomized, parallel study. Patients received either latanoprost 0.005% or brimonidine 0.2% for 3 months. Baseline retrobulbar blood flow measurements of the ophthalmic artery, central retinal artery and temporal short posterior ciliary artery were taken using colour Doppler imaging ultrasound, concurrently with systemic blood pressure, heart rate, ocular perfusion pressure and intraocular pressure (IOP) measurements. These measurements were repeated after 3 months.
RESULTS: Both latanoprost and brimonidine significantly reduced IOP (p < 0.05). While there was a statistically significant increase in peak systolic velocity of the ophthalmic artery, no significant change was observed in the other vessels with latanoprost treatment (p < 0.05). Topical brimonidine did not significantly alter flow velocities or resistive indices in the retrobulbar vessels after 3 months.
CONCLUSION: Topical latanoprost and brimonidine significantly reduced IOP in patients with POAG and OHT without causing significant haemodynamic alterations in the retrobulbar vessels. ||||| PURPOSE: To compare the 24-hour (24h) effects on intraocular pressure (IOP) and cardiovascular parameters of timolol 0.5% and bimatoprost 0.01% in open angle glaucoma and ocular hypertensive subjects.
METHODS: In this prospective, randomized, double masked, crossover, clinical trial, after washout from previous medications enrolled subjects underwent 24h IOP, blood pressure (BP) and heart rate (HR) measurements and were randomized to either topical bimatoprost 0.01% at night plus placebo in the morning or to timolol 0.5% bid. After 8 weeks of treatment a second 24h assessment of IOP, BP and HR was performed and then subjects switched to the opposite treatment for additional 8 weeks when a third 24h assessment was performed. The primary endpoint was the comparison of the mean 24h IOP after each treatment. Secondary endpoints included the comparisons of IOP at each timepoint of the 24h curve and the comparison of BP, HR, ocular perfusion pressure and tolerability.
RESULTS: Mean untreated 24h IOP was 20.3 mmHg (95%CI 19.0 to 21.6). Mean 24h IOP was significantly lower after 8 weeks of treatment with bimatoprost 0.01% than after 8 weeks of treatment with timolol 0.5% bid (15.7 vs 16.8 mmHg, p = 0.0003). Mean IOP during the day hours was significantly reduced from baseline by both drugs while mean IOP during the night hours was reduced by -2.3 mmHg (p = 0.0002) by bimatoprost 0.01% plus placebo and by -1.1 mmHg by timolol 0.5% bid (p = 0.06). Timolol 0.5% significantly reduced the mean 24h systolic BP from baseline, the diastolic BP during the day hours, the HR during the night hours, and the mean 24h systolic ocular perfusion pressure.
CONCLUSION: Both Bimatoprost 0.01% and Timolol 0.5% are effective in reducing the mean 24h IOP from an untreated baseline but Bimatoprost 0.01% is more effective than timolol 0.5% throughout the 24h. Timolol 0.5% effect on IOP is reduced during the night hours and is associated with reduced BP, HR and ocular perfusion pressure.
TRIAL REGISTRATION: EU Clinical Trial Register and EudraCT# 2010-024272-26. ||||| PURPOSE: To compare the 24-h changes of intraocular pressure (IOP) and mean ocular perfusion pressure (MOPP) obtained with tafluprost versus travoprost in patients with normal-tension glaucoma (NTG).
METHODS: This study is a randomized crossover study of 50 patients newly diagnosed with NTG who received either tafluprost or travoprost given once at 9 PM for 2 months, after which they were crossed over to the other medication for another 2 months. IOP and blood pressure were measured for 24 h before starting the treatment and after finishing the first and second treatment periods.
RESULTS: Forty-one patients completed the study. The mean (±standard deviation) 24-h IOP was 16.8±2.0 mmHg at baseline, 14.4±2.2 mmHg on tafluprost, and 13.6±1.8 mmHg on travoprost. Both prostaglandin monotherapies significantly reduced mean 24-h IOP as compared with baseline (P<0.001, P<0.001, respectively), and travoprost demonstrated a lower mean 24-h IOP than tafluprost (P=0.044). Both treatments significantly reduced the IOP from baseline at every point over 24 h. At 3 individual time points, travoprost provided a lower IOP than tafluprost: at 4 PM (13.8±2.7 vs. 14.8±2.6 mmHg, P=0.041), at 6 PM (13.5±2.5 vs. 14.4±2.5 mmHg, P=0.006), and at 8 PM (13.3±2.5 vs. 14.5±2.4 mmHg, P=0.029). Both tafluprost and travoprost significantly increased the 24-h MOPP (P=0.008, P=0.002, respectively), and travoprost demonstrated a greater 24-h MOPP than tafluprost (P=0.027).
CONCLUSIONS: Both tafluprost and travoprost were effective in lowering IOP and increasing MOPP throughout 24 h in NTG. However, travoprost reduced IOP greater than tafluprost in the late afternoon and evening. ||||| PURPOSE: To evaluate the circadian effects on intraocular pressure (IOP) and ocular perfusion pressure (OPP) of 0.5% timolol or 0.005% latanoprost in Caucasian patients affected by normal-tension glaucoma (NTG).
PATIENTS AND METHODS: In this crossover trial, 30 consecutive NTG subjects underwent three 24-hour assessments of IOP, blood pressure (BP), heart rate (HR), and OPP [calculated according to the formula OPP = (1/3 systolic BP + 2/3 diastolic BP) x 2/3 - IOP]: at baseline, and after 1-month treatment with timolol or latanoprost. These parameters were recorded at 4 a.m., 8 a.m., noon, 4 p.m., 8 p.m., and midnight.
RESULTS: Both timolol and latanoprost reduced IOP (p < 0.001), with a difference in favour of latanoprost of 1.3 mmHg (95% CI 0.9, 1.6; p < 0.001). After timolol, BP and HR decreased with respect to baseline (p < 0.001). Latanoprost increased mean OPP (3.6 mmHg, 95% CI 2.9, 4.3; p < 0.001), whereas timolol did not improve it.
CONCLUSIONS: Latanoprost induces an IOP reduction greater than timolol, also achieving a better circadian flattening of the IOP curve. Only latanoprost significantly increased mean 24-hour OPP. The management of Caucasian NTG patients should be critically realized, considering the 24-hour influence of each IOP-lowering drug on the ocular blood perfusion. ||||| PURPOSE: To investigate the circadian and blood pressure (BP) reduction obtained with timolol maleate 0.5% solution administered twice daily versus timolol 0.1% in gel-forming carbomer administered in the morning in patients with primary open-angle glaucoma (POAG).
METHODS: This investigator-masked, crossover study prospectively enrolled naive POAG patients not receiving systemic cardiovascular medications. Following a baseline evaluation, they were randomized to receive a timolol 0.5% solution or timolol 0.1% hydrogel for 2 months and then switched to the alternative medication for a further 2 months. Intraocular pressure (IOP) phasing (sitting Goldmann tonometry at 10 am, 2 pm, 6 pm, and 10 pm and supine Perkins tonometry at 2 am and 6 am) and ambulatory home BP monitoring were measured at baseline and after each treatment period.
RESULTS: On the basis of a prospective sample size estimate, 28 patients were analyzed. Mean 24-hour IOP decreased from 23.1 ± 0.7 mm Hg at baseline to 18.9 ± 0.6 mm Hg after timolol 0.5% and 18.9 ± 0.8 mm Hg after timolol 0.1% hydrogel (P < .001); both formulations also significantly decreased diurnal, nocturnal, and individual time point IOP in a statistically similar manner. Systolic and diastolic BP remained generally unaffected. The calculated diastolic ocular perfusion pressure was either unaffected or tended to increase with either medication.
CONCLUSION: Both timolol formulations show similar and significant circadian efficacy and have minimal effects on BP and calculated diastolic ocular perfusion pressure. ||||| BACKGROUND: To compare the effects of 2 dosing regimens of brimonidine tartrate 0.2% on diurnal intraocular pressure (IOP) and systemic hemodynamics in patients with normal-tension glaucoma (NTG).
METHODS: Twenty NTG patients were enrolled and randomized to receive either brimonidine twice daily (BID) for 4 weeks followed by brimonidine 3 times daily (TID) for another 4 weeks, or in reverse order. Diurnal variations of IOP and ocular perfusion pressure (OPP), as well as the 24-hour ambulatory blood pressure (BP) and pulse rate, were evaluated at baseline and after treatment. Baseline and post-treatment data were compared using a paired Student's t test, and treatment effects were compared between regimens using a crossover-designed analysis of variance.
RESULTS: Both regimens decreased the mean (p < 0.001) and minimum (p < 0.001) diurnal IOP, and only the TID regimen decreased the maximum IOP with a marginal significance (p = 0.049). The TID regimen decreased the maximum OPP (p = 0.009) while the BID regimen caused no changes in OPP. No significant difference in IOP or OPP was noted between regimens at each time point. Neither regimen caused changes in BP or pulse rate as assessed using the 24-hour ambulatory monitoring device.
CONCLUSIONS: The TID regimen of brimonidine produces similar reductions in diurnal IOP for NTG patients as the BID regimen, and it alone decreases the maximum OPP. Neither of the 2 regimens causes exaggerated nocturnal reduction of BP. ||||| BACKGROUND: There is evidence that perfusion abnormalities of the optic nerve head are involved in the pathogenesis of glaucoma. There is therefore considerable interest in the effects of topical antiglaucoma drugs on ocular blood flow. A study was undertaken to compare the ocular haemodynamic effects of dorzolamide and timolol in patients with primary open angle glaucoma (POAG) or ocular hypertension (OHT).
METHODS: One hundred and forty patients with POAG or OHT were included in a controlled, randomised, double blind study in two parallel groups; 70 were randomised to receive timolol and 70 to receive dorzolamide for a period of 6 months. Subjects whose intraocular pressure (IOP) did not respond to either of the two drugs were switched to the alternative treatment after 2 weeks. Scanning laser Doppler flowmetry was used to measure blood flow in the temporal neuroretinal rim and the cup of the optic nerve head. Pulsatile choroidal blood flow was assessed using laser interferometric measurement of fundus pulsation amplitude.
RESULTS: Five patients did not respond to timolol and were changed to the dorzolamide group, and 18 patients changed from dorzolamide treatment to timolol. The effects of both drugs on IOP and ocular perfusion pressure were comparable. Dorzolamide, but not timolol, increased blood flow in the temporal neuroretinal rim (8.5 (1.6)%, p<0.001 versus timolol) and the cup of the optic nerve head (13.5 (2.5)%, p<0.001 versus timolol), and fundus pulsation amplitude (8.9 (1.3)%, p<0.001 versus timolol).
CONCLUSIONS: This study indicates augmented blood flow in the optic nerve head and choroid after 6 months of treatment with dorzolamide, but not with timolol. It remains to be established whether this effect can help to reduce visual field loss in patients with glaucoma. ||||| PURPOSE: To compare the effects of latanoprost (Xalatan) and dorzolamide (Trusopt) on ocular hemodynamics in normal-tension glaucoma patients.
METHODS: A randomized, single-masked, parallel design study was conducted. After a 4-week washout period, 20 normal tension glaucoma patients, recruited from a single university-based ophthalmology clinic, received either latanoprost once daily or dorzolamide 3 times daily for 4 weeks. The subjects were examined at baseline and post-treatment. Outcome measures included heart rate (HR), blood pressure (BP), logMar visual acuity (VA), contrast sensitivity (CS), intraocular pressure (IOP), color Doppler imaging (CDI), and fluorescein angiography with the Rodenstock scanning laser ophthalmoscope (SLO). CDI measurements of the retrobulbar vessels included peak systolic velocity, end diastolic velocity, and the calculated resistance index. Arterio-venous passage time (AVP) in the superior and inferior temporal retina was calculated from the SLO angiograms.
RESULTS: Neither dorzolamide nor latanoprost had any statistically significantly effect on HR or BP. Both drugs significantly lowered IOP without altering calculated ocular perfusion pressure (p<0.05). There was no statistically significant difference in any CDI measurement. Dorzolamide significantly decreased AVP time in the superior retina (p=0.011), while latanoprost did not (p=0.62).
CONCLUSIONS: Dorzolamide, unlike latanoprost, significantly reduced AVP times in the superior temporal retina in normal tension glaucoma (NTG) patients. ||||| PURPOSE: To evaluate the effect of the timolol-dorzolamide fixed combination (TDFC) and latanoprost 0.005% on 24-hour intraocular pressure (IOP), systolic (SBP) and diastolic (DBP) blood pressure, and diastolic ocular perfusion pressure (DOPP) in patients with primary open-angle glaucoma (POAG).
METHODS: This was an institutional, randomized clinical trial. After a 24-hour assessment without treatment, 27 previously untreated patients with POAG were randomized to 6 weeks' treatment with twice-daily TDFC (8 AM and 8 PM) followed by once-daily latanoprost 0.005% (8 PM), or vice versa. One eye was analyzed per patient. The mean values of IOP, DBP, SBP, and DOPP (difference between DBP and IOP) were recorded at each time point, and the 24-hour data are the mean values of each patient's measurements over the 24-hour period. The differences between the values of the first treatment period and the baseline and the second treatment period and washout were calculated and analyzed by means of an analysis of variance model that tested the effects of sequence and treatment.
RESULTS: Both treatments significantly reduced 24-hour IOP (P < 0.0001), but TDFC led to lower 24-hour pressure (mean +/- SD: 15.4 +/- 1.9 vs. 16.7 +/- 1.7 mm Hg; P = 0.004). Latanoprost did not lead to any significant reduction in mean 24-hour SBP and DBP (SBP: P = 0.952; DBP: P = 0.831), but TDFC did (SBP and DBP: P < 0.0001). Both treatments significantly increased 24-hour DOPP (P < 0.0001), with no difference between the two medications (P = 0.09).
CONCLUSIONS: In previously untreated patients with POAG, TDFC, and latanoprost equally enhanced 24-hour DOPP: the former by counteracting the decrease in DBP with a substantial reduction in IOP and the latter by not affecting DBP and significantly reducing IOP. (isrctn.org number, ISRCTN67123277.). | [
{
"source_pmid": "12466165",
"source_text": "OBJECTIVE: To evaluate and compare the effects of latanoprost 0.005% once daily and brimonidine tartrate 0.2% twice daily in patients with normal-tension glaucoma (NTG).\nDESIGN: A randomized, open-label, crossover study.\nPARTICIPANTS: Twenty-eight NTG patients ... |
31876869 | CONCLUSIONS: Second glaucoma drainage implantation can be considered a viable approach after a failed drainage implant, but patients should be counseled on the need for continued medical therapy and the risk of corneal decompensation. | PURPOSE: To compare tube shunt revision with additional tube shunt after failed tube shunt surgery.
METHODS: We identified 281 patients who underwent a primary tube shunt procedure from 1985 to 1998 at Indiana University and reviewed 33 eyes of 33 patients that had failed and required further surgery. Shunt revision was performed in 12, whereas an additional shunt was placed in 21 eyes. Intraocular pressure, antiglaucoma medications, visual acuity, and complications were noted. Success was defined as at least a 25% reduction in intraocular pressure that was deemed clinically adequate. Qualified success was defined as a 25% intraocular pressure reduction but with additional medications or a significant reduction in medications with stable intraocular pressure for preoperative intraocular pressure less than 21 mm Hg.
RESULTS: Preoperative intraocular pressures (mean +/- 95% confidence interval) for the revision and additional tube groups were 28.8 +/- 5.8 mm Hg and 29.8 +/- 2.7 mm Hg (P =.73), with an average follow-up period of 25.2 months (range, 3 to 108 months) and 34.8 months (range, 6 to 84 months), respectively. Final mean intraocular pressure was 25.3 +/- 6.7 mm Hg for the revision group and 17.7 +/- 3.4 mm Hg for the additional tube group (P =.037). Forty-two percent in the revision group versus 62% in the additional tube group achieved at least a qualified success (P =.30, Fisher exact test). Corneal edema was a common complication, especially in the additional tube group. Limitations of this study include the small sample sizes and the uneven distribution of neovascular glaucoma between the two groups (six of 12 in the revision group vs two of 21 in the additional tube group; P =.015, Fisher exact test).
CONCLUSIONS: Our series showed that after failed tube shunt surgery, an additional tube shunt offers better intraocular pressure control than revision by excision of an encapsulated bleb. ||||| BACKGROUND AND OBJECTIVE: To evaluate the efficacy and safety of implantation of a second glaucoma drainage device for eyes that have failed a primary device.
PATIENTS AND METHODS: Medical records of patients receiving a primary glaucoma drainage device at Bascom Palmer Eye Institute from January 1987 to October 1998 were reviewed, of which 18 eyes of 18 patients were studied. Patients failing a primary glaucoma drainage procedure and receiving a second glaucoma drainage device were included in this study. The second eye in the same patient was excluded if a second drainage implant was required. All patients received a second device in a standardized fashion with the drainage tube inserted in the anterior chamber. Main outcome measures included: visual acuity, intraocular pressure (IOP), antiglaucomatous medication, length of follow up, and surface area of glaucoma drainage device. Success was defined as an IOP less than or equal to 21 mm Hg with or without medications, and at least a 20% reduction in IOP, without the need for additional glaucoma procedures.
RESULTS: The mean postoperative IOP (19.6 +/- 9.4 mm Hg; range, 8-50 mm Hg) was significantly (P = 0.006) lower than the mean preoperative IOP (29.5 +/- 8.1 mm Hg; range, 20-52 mm Hg) at last follow up (mean 19.6 +/- 13.6 months; range, 6-47 months). The mean number of postoperative antiglaucomatous medications (2.2 +/- 1.2; range 0-4) was statistically similar (P = 0.2) to mean preoperative number of antiglaucomatous medications (2.6 +/- 1.2, range 1-4). Using Kaplan-Meier estimates, successful IOP reduction was observed in 89%, 83%, 63%, and 37% of eyes at 6 months, 1, 2, and 3 years, respectively. Four patients (21%) had a decline in visual acuity.
CONCLUSIONS: Implantation of secondary glaucoma drainage devices may be useful in eyes that have failed primary devices. ||||| PURPOSE: Compare intraocular pressure (IOP) control and complication rates of a second glaucoma drainage device (GDD) to diode transscleral cyclophotocoagulation (TSCPC) following failure of an initial GDD.
PATIENTS AND METHODS: Eyes with 1 GDD that required a second GDD or TSCPC for glaucoma control were included. Exclusion criteria were a cyclodestructive procedure before initial GDD, no light perception vision, or follow-up <1 year. Failure was defined as ≥1 of (1) reoperation for lowering IOP; (2) explantation of second GDD; (3) persistent hypotony; (4) use of oral carbonic anhydrase inhibitor for lowering IOP in the study eye; or (5) loss of light perception. Reoperation for lowering IOP included additional GDD implantation or additional cyclodestruction, except if additional cyclodestruction was within 6 months of the initial session.
RESULTS: A total of 75 eyes (35 in second GDD; 40 in TSCPC) were included (mean follow-up, 25.5 mo). Both procedures lowered IOP [-11.4 mm Hg (±13.6) for second GDD and -7.8 mm Hg (±11.8) for TSCPC groups] and decreased the number of IOP-lowering medications at the last visit. The second GDD group had significantly greater mean survival time [45.0 mo (±4.2)] than the TSCPC group [26.5 mo (±2.8)] but significantly more postoperative complications (60% of eyes) and non-IOP-related procedures (40% of eyes) than the TSCPC group (20% for postoperative complications and 18% for non-IOP-related procedures).
CONCLUSIONS: Although both second procedures are efficacious in lowering IOP and number of IOP-lowering medications, TSCPC failed earlier, whereas a second GDD had significantly more complications. ||||| PURPOSE: To evaluate success rates in controlling intraocular pressure (IOP) after implantation of a second glaucoma drainage device (GDD) with a Baerveldt glaucoma implant in patients with refractory glaucoma, with a secondary aim of reducing the need for postoperative glaucoma medications.
MATERIAL AND METHODS: This retrospective, noncomparative, interventional study included patients undergoing a second GDD for uncontrolled glaucoma from a tertiary care glaucoma service. Data were obtained from the medical records for the preoperative period and after the 1st, 15th, and 30th day, 3, 6, and 12 months, and then yearly until the last postoperative visit. Visual acuity, IOP, and number of glaucoma medications (NGM) from the follow-up visits were compared to baseline. Success and failure criteria were analyzed based on IOP level or need of glaucoma medications.
RESULTS: Forty-nine patients were studied, with a mean follow-up time of 25 ± 21 months. The mean preoperative IOP was 23.7 ± 8.2 mmHg, and decreased to 14.8 ± 4.0 mmHg after 1 year, 14.4 ± 3.9 mmHg after 2 years, and 16.6 ± 8.5 mmHg after 3 years. The mean preoperative NGM was 3.4 ± 1.3, and decreased to 2.0 ± 1.8 after 1 year, 2.5 ± 1.6 after 2 years, and 2.8 ± 2.0 after 3 years. Absolute success was 9% after 1 year for a postoperative IOP between 5 and 18 mmHg, and 76% for a postoperative IOP between 5 and 21 mmHg. The qualified success was 88% at the first and second years and 83% at the third year.
CONCLUSION: With up to 3 years of follow-up, a second glaucoma drainage device was successful in reducing IOP to below 21 mmHg, but not as successful below 18 mmHg. The success rate is improved with the use of glaucoma medications with up to 3 years of follow-up. ||||| BACKGROUND/AIMS: To evaluate long-term efficacy of a second glaucoma drainage device (GDD) versus cyclophotocoagulation (CPC) after failure of primary drainage implant.
METHODS: This is a non-randomised, retrospective cohort study. A chart review was conducted of patients who underwent GDD surgery between July 1986 and November 2012 requiring further glaucoma procedures for intraocular pressure (IOP) control. An additional GDD was placed in 15 eyes, while 32 eyes underwent CPC. The main outcome measurement was IOP control and/or time to failure of secondary intervention (IOP >18 mm Hg on two sequential measurements).
RESULTS: Mean follow-up after the second procedure was 63±65.8 months (range 6-254 months) in the CPC group and 132±91.8 months (range 12-254 months) in the GDD group. Thirty-four per cent (11/32 eyes) undergoing CPC later required further treatment at a mean of 13.6±10.7 months with 10/11(91%) of additional interventions occurring within 2 years. Despite an initially high success rate for IOP control in the first 5 years, eventually 60% (9/15 eyes) that underwent a second tube required additional treatment at a mean of 73.4 months with only 2/9(22%) requiring this within the first 2 years. The risk of visual acuity worsening by 2 Snellen lines or more at 12 months was 5/14 for the GDD group (36%) and 4/23(17%) for the CPC group.
CONCLUSIONS: After failure of an initial drainage implant to control IOP, a sequential tube had a high initial rate of success but a relatively high likelihood of long-term failure, generally after 6 years. Eyes that received CPC tended to fail earlier, often within the first year, but had relatively few late failures. ||||| PURPOSE: To compare sequential glaucoma drainage device (GDD) implantation with transscleral diode cyclophotocoagulation (CPC) following failure of a primary GDD.
MATERIALS AND METHODS: A retrospective review of all patients who underwent GDD implantation at a single institution over 10 years. Patients who required an additional GDD and/or CPC were analyzed. Success was defined as absence of loss of light perception, reoperation for glaucoma, and intraocular pressure (IOP) >21 or <6 at 2 consecutive visits after an initial 3-month period.
RESULTS: Thirty-two patients received sequential GDD. Twenty-one underwent CPC. Cohorts were statistically similar in regards to age, sex, race, and number of previous surgeries. Preoperatively, the GDD cohort had a lower IOP and better visual acuity. The mean length of follow-up was 37.9 months for the GDD group and 46.3 months for CPC. Both procedures significantly reduced IOP; however, CPC led to a greater reduction (P=0.0172). Survival analysis found the 5-year probability of surgical success to be 65.3% for sequential GDD and 58.0% for CPC (P=0.8678). No cases of phthisis occurred in either group. There were 2 cases of endophthalmitis (6.3%) in the GDD group, and none in the CPC group. In eyes without preexisting corneal edema, estimated corneal decompensation probability at 3 years was 31.6% for GDD and 6.7% for CPC (P=0.0828).
CONCLUSIONS: Sequential GDD and CPC are both effective at reducing IOP following the failure of a primary GDD. CPC after GDD failure warrants further investigation as it led to a greater reduction in IOP with fewer serious adverse events. ||||| PURPOSE: To examine the results of same-eye second Ahmed glaucoma drainage device (GDD) insertion in eyes with refractory glaucoma despite previous Ahmed GDD insertion and maximal tolerated medical therapy.
METHODS: Noncomparative retrospective case series.
RESULTS: Twenty-one patients who had undergone 2 GDD surgeries in the same eye were identified. Following chart review, 19 patients had follow-up of at least 1 year and were included in the analysis. All surgeries involved Ahmed valves. The mean drop in intraocular pressure (IOP) at 12 months and at final follow-up was 8 (43%) and 7.9 mm Hg (42%), respectively. The mean number of glaucoma medications used postoperatively (2.4 at 12 mo and 2.6 at final follow-up) was significantly less than preoperatively (4.1). Although the mean visual acuity was poorer postoperatively, this did not reach statistical significance. Sixteen of the 19 patients (84.2%) were defined as complete or partial success, as they achieved IOP of >/=5 and </=21 mm Hg and >/=20% decrease on preoperative IOP with or without glaucoma drops. Three patients were considered complete failures at 12 months and final follow-up. There were no significant intraoperative complications. One patient (5.3%) required anterior chamber reformation on day 1 postoperatively. One patient (5.3%) suffered a decrease in vision from 20/70 preoperatively to counting fingers postoperatively owing to corneal decompensation.
CONCLUSIONS: Second Ahmed GDD surgery seems to be a safe and effective option when IOP remains uncontrolled despite previous GDD implantation. ||||| PURPOSE: To evaluate the efficacy of a second glaucoma implant in eyes with prior glaucoma implant surgery and inadequate intraocular pressure (IOP) control.
DESIGN: Retrospective observational cohort study.
METHODS: Patients undergoing a second glaucoma implant surgery from 1996 to 2008 were included. Outcome measures included visual acuity, IOP, glaucoma medication use, and complications. Success was defined as IOP < 21 mm Hg (criterion 1) and IOP < 17 mm Hg (criterion 2), with at least 25% reduction in IOP and no prolonged hypotony.
RESULTS: Forty-three eyes (43 patients) had a mean follow-up of 32.6 +/- 21.6 months. Life-table analysis demonstrated success rates of 93%, 89%, and 83% using criterion 1 and 83%, 75%, and 75% using criterion 2 at 1, 2, and 3 years, respectively. At last follow-up, mean IOP (13.6 +/- 4.6 vs 24.7 +/- 7.5 mm Hg; P < .001) and mean number of medications (1.4 +/- 1.2 vs 3.9 +/- 1.2; P < .001) were lower following the second implant. There was no difference in preoperative and most recent logarithm of the minimal angle of resolution (logMAR) visual acuities (0.86 +/- 0.13 vs 1.1 +/- 0.13; P = .07). The most frequently used second implants were similar in percentage IOP reduction (Baerveldt implant, 45 +/- 19%; Ahmed valve, 40 +/- 18%; P = .4).
CONCLUSIONS: A second glaucoma implant may effectively lower IOP in eyes with refractory glaucoma. ||||| OBJECTIVE: To evaluate intraocular pressure (IOP) control, change in visual acuity, and complications in eyes that have undergone a second glaucoma tube shunt procedure.
DESIGN: Retrospective, noncomparative case series.
PARTICIPANTS: Twenty-two eyes of 22 patients that have undergone sequential tube implants for management of glaucoma.
METHODS: Parameters analyzed included IOP, visual acuity, and number of hypotensive agent before each shunt procedure and at last follow-up visit. The overall IOP lowering effect attributable to each tube shunt was calculated. Any ocular complications after the second tube shunt were recorded. Success was defined as an IOP between 6 and 21 mm Hg and a 20% reduction in IOP from the second tube shunt procedure. Qualified successes met one of these two requirements at the last follow-up visit. Total failures did not meet any of the above criteria, required additional surgical intervention to lower IOP, or both.
MAIN OUTCOME MEASURES: Intraocular pressure control, visual acuity preservation, and complications.
RESULTS: At the last follow-up visit, the average percent reduction in IOP from both tube shunt procedures was 42+/-21%. The average percent IOP reduction from the second tube shunt was 33+/-17%. Eleven (50%) patients met the criteria for success, 8 (36.4%) patients were qualified successes, and 3 (13.6%) were failures. The median number of hypotensive agents decreased from two to one. Ten patients experienced new or worse pseudophakic bullous keratopathy after the second tube shunt, six of whom underwent penetrating keratoplasty. Thirteen (59%) patients maintained visual acuity within one line of their second tube shunt pre-operative Snellen visual acuity. Seven (32%) patients lost more than 2 lines, and one patient lost light perception.
CONCLUSIONS: Although corneal morbidity is a common complication, a second tube shunt does not cause higher-than-expected rates of other complications associated with tube shunt surgery. Eyes that undergo a second tube shunt procedure can achieve pressure control, require fewer hypotensive agents, and may maintain stable visual acuity. | [
{
"source_pmid": "10764852",
"source_text": "PURPOSE: To compare tube shunt revision with additional tube shunt after failed tube shunt surgery.\nMETHODS: We identified 281 patients who underwent a primary tube shunt procedure from 1985 to 1998 at Indiana University and reviewed 33 eyes of 33 patients that ... |
30328707 | Limited studies have examined DME patients' experiences and perceptions of treatment and QoL. The outcomes of these studies lack agreement on the effectiveness of treatment, treatment preferences and impact of QoL in patients with DME. Future research which enhances current knowledge will therefore serve to improve treatment outcomes and QoL in these patients. | PURPOSE: To examine patient-reported outcome (PRO) in a selected group of Swedish patients about to receive anti-vascular endothelial growth factor (VEGF) treatment for diabetic macular edema (DME).
MATERIAL AND METHODS: In this cross-sectional study, 59 patients with diabetes mellitus, who regularly visited the outpatient eye-clinics, were included. Sociodemographic and clinical data were collected and the patients completed PRO measures before starting anti-VEGF treatment. PRO measures assessed eye-specific outcomes (NEI-VFQ-25) and generic health-related quality of life (SF-36).
RESULTS: The participants consisted of 30 men and 29 women (mean age, 68.5years); 54 (92%) patients had type 2 diabetes; 5 (9%) patients had moderate or severe visual impairment; 28 (47%) were classified as having mild visual impairment. Some of the patients reported overall problems in their daily lives, such as with social relationships, as well as problems with impaired sight as a result of reduced distance vision.
CONCLUSIONS: Further studies are needed to investigate PRO factors related to low perceived general health in this patient population. It is important to increase our understanding of such underlying mechanisms to promote improvements in the quality of patient care. ||||| Purpose: To determine the patient-centered effectiveness of treatment with the slow-release dexamethasone intravitreal implant (DEX implant) and intravitreal bevacizumab using the Impact of Vision Impairment Questionnaire (IVI), a vision-related quality of life (VRQoL) measure, in patients with visual impairment secondary to center-involving diabetic macular edema (DME).
Methods: Patients with DME were enrolled in a phase 2, prospective, multicenter, randomized, single-masked clinical trial and received either DEX implant 4 monthly or bevacizumab monthly, both pro re nata. Vision-related quality of life was measured at baseline and 24 months, using the IVI's three component scales, namely reading, mobility, and emotional well-being. Rasch analysis was used to generate interval-level estimates of VRQoL, which were then analyzed using t-tests to assess changes over time.
Results: Forty-eight patients completed the main study; 43 (90%) answered the IVI at the baseline and 24-month (final efficacy) visits. Vision-related quality of life improved significantly, with average increases of 1.44, 0.99, and 1.49 logits, for the reading, mobility, and emotional well-being scales respectively, from baseline to 24 months, (P < 0.001). There was no significant between-group difference in improvement in VRQoL in the DEX implant only compared with the bevacizumab-only group, in any of the three scales listed above (with 1.41, 1.08, and 2.11 logits improvement, in reading, mobility, and emotional well-being, respectively, for DEX implant group, compared with 1.48, 1.06, and 2.11 for bevacizumab; P values > 0.1.).
Conclusions: We found that both DEX implant and bevacizumab treatment result in significant and similar improvements in VRQoL in patients with DME over a 24-month period. (Clinicaltrials.gov identifier NCT01298076). ||||| OBJECTIVES: To evaluate the translation of the IPSS (Hong Kong Chinese version 1) and to assess the applicability, validity, reliability and sensitivity of the instrument in both males and females with LUTS in Chinese population.
METHODS: The translation of the IPSS (Hong Kong Chinese version 1) was reviewed through back translation. Modifications were made, resulting in the development of The IPSS (Hong Kong Chinese version 2). The content validity was assessed by contend validity index. 233 subjects with LUTS were recruited in Hong Kong primary care settings for pilot psychometric testing. The construct validity was assessed by corrected item-total correlation and Pearson's correlation test against ICIQ-UI SF, IIQ-7 and SF-12 v2. The reliability was assessed by the internal consistency (Cronbach's Alpha coefficient) and test -retest reliability (Intraclass correlation coefficient). The Sensitivity was determined by performing known group comparisons by independent T-test.
RESULTS: The content validity index for all items could reach 1. Corrected item-total correlation scores were ≥0.4 for four symptom questions (feeling of incomplete bladder emptying, intermittency, weak stream and straining). Overall, the total symptom score moderately correlated with ICIQ-UI SF. The quality of life score moderately correlated with the IIQ-7 but weakly correlated with SF-12 v2. Overall, the reliability of the IPSS (Hong Kong Chinese version 2) was acceptable (Cronbach's Alpha coefficient = 0.71, ICC of the symptom questions =0.8, ICC of the quality of life question =0.7). The symptoms questions and quality of life questions of the IPSS (Hong Kong Chinese versions 2) were sensitive in detecting differences between groups.
CONCLUSIONS: The IPSS (Hong Kong Chinese version 2) is a valid, reliable and sensitive measure to assess Chinese females and males with lower urinary tract symptoms. The IPSS quality of life question is more sensitive than the generic quality of life measure to differentiate subgroups. ||||| BACKGROUND: Vision-related quality of life (vrQoL) is advancing more and more into the focus of interest in ophthalmological clinical research. However, to date only little information is available about vrQoL from large non-interventional studies in terms of "real-world evidence". The purpose of this investigation was to describe baseline VFQ-25 visual function scores, to evaluate whether they differ from previous phase III clinical trials, to determine which contributing factors (e.g. indication, age, gender) affect VFQ-25 scores and to identify its impact on driving.
METHODS: The non-interventional OCEAN study (Observation of treatment patterns with LuCEntis and real life ophthalmic monitoring, including optional OCT in Approved iNdications) is the largest ophthalmic study conducted in Germany, to evaluate the real world situation of patients treated with ranibizumab (NCT02194803). The NEI-VFQ-25 questionnaire was conducted at baseline, months 4, 12 and 24. Descriptive statistics was used to analyse the baseline data. ANOVA was performed to evaluate the impact of various contributing factors on composite and selected subscale scores.
RESULTS: Overall, 4844 (84.1 %) of all 5760 OCEAN patients completed the VFQ-25 questionnaire at baseline. Thereof, 3414 treatment-naïve patients were further analysed. Overall, the VFQ subscore general health was most affected by the ocular disease, followed by general vision. No major differences were detected in comparison to corresponding VFQ-25 scores of previous phase III clinical trials, except in DME patients, or with respect to possible contributing factors. A tendency towards a more decreased VFQ-25 composite score was observed for nAMD, for elderly patients ≥75 years of age, for female patients, for patients with low baseline visual acuity (VA; <50 letters) and for those with statutory health insurance. Indication, age, gender, baseline VA (all p <0.01) and the interaction of age and indication, as well as baseline VA and indication (p <0.01 each) had a significant impact on composite, general vision and distance vision scores (ANOVA). About 10 % of patients gave up driving due to eyesight issues.
CONCLUSIONS: The knowledge of a patient's subjective disease burden is crucial to understanding anxieties and mental anguish. Additionally, the understanding of the impact of various contributing factors on the VFQ-25 scores and the extent to which they can be influenced help to optimize patient care. It demonstrates the need for medical and mental support by all medical staff, to encourage patients' compliance with a comprehensive anti-VEGF therapy, to increase BCVA and, consecutively, VFQ-25 scores.
TRIAL REGISTRATION: NCT02194803. ||||| IMPORTANCE: Few data are available on relative changes in vision-related function after treatment for diabetic macular edema (DME).
OBJECTIVE: To determine the impact of intravitreal ranibizumab, 0.5 mg, compared with laser on patient-reported visual function.
DESIGN: Phase 3, randomized, double-masked, 12-month study (RESTORE).
SETTING: Outpatient retina practices in Australia, Canada, and Europe.
PARTICIPANTS: Patients 18 years or older with type 1 or 2 diabetes mellitus and visual impairment due to DME.
INTERVENTIONS: Patients were randomized to ranibizumab plus sham laser (n = 116), ranibizumab plus laser (n = 118), or sham injections plus laser (n = 111). Ranibizumab and sham injections were given for 3 consecutive months then as needed; laser or sham laser treatment was given at baseline then as needed.
MAIN OUTCOMES AND MEASURES: National Eye Institute Visual Functioning Questionnaire 25 (NEI VFQ-25) scores at 0, 3, and 12 months for patients receiving 1 or more study treatments with 1 or more postbaseline NEI VFQ-25 assessments and last observation carried forward for missing data.
RESULTS: Mean baseline NEI VFQ-25 composite scores were 72.8, 73.5, and 74.1 in the ranibizumab, laser, and ranibizumab plus laser groups, respectively. At 12 months, the mean composite scores (95% CIs) improved by 5.0 (ranibizumab vs laser, 2.6 to 7.4; P = .01 vs laser) and 5.4 (ranibizumab plus laser vs laser alone, 3.3 to 7.4; P = .004 vs laser) from baseline in the ranibizumab and ranibizumab plus laser groups, respectively, compared with 0.6 (-1.8 to 3.0) for the laser group. Near activities scores improved by 9.0 (ranibizumab vs laser, 5.0 to 13.0; P = .01) and 9.1 (ranibizumab plus laser vs laser, 5.6 to 12.6; P = .006) compared with 1.1 (-3.0 to 5.2) for the laser group, whereas distance activities scores improved by 5.3 (ranibizumab vs laser, 1.8 to 8.9; P = .04) and 5.6 (ranibizumab plus laser vs laser, 2.3 to 9.0; P = .03) compared with 0.4 (-3.1 to 3.8) for the laser group. Patients with better baseline visual acuity or lower central retinal thickness had greater improvements with ranibizumab treatment compared with laser in composite and some subscale scores compared with patients with worse visual acuity or higher central retinal thickness.
CONCLUSIONS AND RELEVANCE: These data provide vision-related, patient-reported outcome evidence that mirrors visual acuity outcomes and supports benefits from ranibizumab or ranibizumab plus laser treatment for patients with DME and characteristics similar to those enrolled in this randomized clinical trial.
TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00687804. ||||| OBJECTIVE: To examine the effects of intravitreal ranibizumab (Lucentis; Genentech, Inc., South San Francisco, CA) treatment on patient-reported vision-related function, as assessed by 25-item National Eye Institute Visual Function Questionnaire (NEI VFQ-25) scores, in patients with visual impairment secondary to center-involved diabetic macular edema (DME).
DESIGN: Within 2 randomized, double-masked, phase 3 clinical trials (RIDE [A Study of Ranibizumab Injection in Subjects With Clinically Significant Macular Edema {ME} With Center Involvement Secondary to Diabetes Mellitus; NCT00473382] and RISE [A Study of Ranibizumab Injection in Subjects With Clinically Significant Macular Edema {ME} With Center Involvement Secondary to Diabetes Mellitus; NCT00473330]), the NEI VFQ-25 was administered at baseline and at the 6-, 12-, 18-, and 24-month follow-up visits.
PARTICIPANTS: Three hundred eighty-two (100%) RIDE patients and 377 (100%) RISE patients.
INTERVENTION: Patients were randomized 1:1:1 to monthly injections of intravitreal ranibizumab 0.3 or 0.5 mg or sham. Study participants could receive macular laser for DME from month 3 onward if specific criteria were met.
MAIN OUTCOME MEASURES: Exploratory post hoc analysis of mean change from baseline in NEI VFQ-25 scores at 12 and 24 months.
RESULTS: Across all treatment arms, 13% to 28% of enrolled eyes were the better-seeing eye. For all eyes in RIDE and RISE, the mean change in NEI VFQ-25 composite score improved more in ranibizumab-treated eyes at both the 12- and 24-month visits compared with sham treatment. For the better-seeing eyes at baseline, the mean change in composite score with 0.3 mg ranibizumab at the 24-month visit was 10.9 more (95% confidence interval [CI], 2.5-19.2) than sham for RIDE patients and 1.3 more (95% CI, -10.5 to 13.0) than sham for RISE patients. For the worse-seeing eyes at baseline, the mean change in composite score with 0.3 mg ranibizumab at the 24-month visit was 1.0 more (95% CI, -4.7 to 6.7) than sham for RIDE patients and 1.8 more (95% CI, -2.7 to 6.2) than sham for RISE patients. Similar results for most of these outcomes were seen with 0.5 mg ranibizumab.
CONCLUSIONS: These phase 3 trials demonstrated that ranibizumab treatment for DME likely improves patient-reported vision-related function outcomes compared with sham, further supporting treatment of DME with ranibizumab. ||||| Objectives were to evaluate the psychometric properties and to determine optimal scoring of the retinopathy treatment satisfaction questionnaire (RetTSQ) in a cross-sectional study of 207 German patients with diabetic retinopathy and a wide range of treatment experience. Forty patients (19%) also had clinically significant macular oedema. Principal components analysis was used to identify factor structures and Cronbach's alpha to assess internal consistency reliabilities. Two highly reliable subscales represented negative versus positive aspects of treatment (both alpha = 0.85). A highly reliable total score can be calculated (alpha = 0.90). Construct validity was examined by testing expected relationships of RetTSQ scores with visual impairment, stage of diabetic retinopathy, additional impact of macular oedema, SF-12 scores and scores of the RetDQoL measure of quality of life in diabetic retinopathy. Worse impairment, worse diabetic retinopathy and macular oedema were associated with less treatment satisfaction. RetTSQ scores correlated moderately with SF-12 scores (r: 0.33-0.53, p < 0.001) and RetDQoL scores (r: 0.43-0.51, p < 0.001). Answers to an open-ended question indicated no need for additional items. Repeating the analyses in a subsample with experience of more intense treatment showed very similar results. It can be concluded that the RetTSQ is valid and reliable for people with diabetic retinopathy with or without macular oedema who have experienced different treatments. ||||| People with vision-threatening diabetic retinopathy are likely to experience enhanced social and emotional strain. Critically, those with both vision-threatening diabetic retinopathy and psychosocial problems may have significantly reduced levels of functioning compared with psychologically healthy counterparts. This can cause inadequate compliance, increased strain on family functioning, worse diabetes control, increased progression of diabetic retinopathy and, consequently, further psychosocial stress resulting in a number of concerning implications for disease management, clinical outcomes and healthcare costs. However, the emotional and social health consequences of diabetic retinopathy have not yet been systematically explored. This information is crucial as it allows for a targeted approach to treatment and prevention and avoidance of the potentially detrimental implications described above. Therefore, this paper reviews the current qualitative and quantitative evidence regarding the social and emotional impact of diabetic retinopathy and identifies directions for future research. Key search terms were applied to the electronic databases Pubmed, ISI Web of Science and Embase and the bibliographies of relevant papers were systematically reviewed for additional references. Overall, the evidence suggests that diabetic retinopathy and associated vision loss have several debilitating effects, including disruption of family functioning, relationships and roles; increased social isolation and dependence; and deterioration of work prospects resulting in increased financial strain. Adverse emotional responses include fear, anxiety, vulnerability, guilt, loss of confidence, anger, stress and self-perception issues. However, the research to date is largely qualitative in nature, with most quantitative studies being small, cross-sectional and somewhat outdated. Similarly, the outcome measures used in many studies to date are suboptimal in terms of content and validity. Therefore, this review identifies the need for improved outcome measures to provide valid, meaningful measurement of the social and emotional impact of diabetic retinopathy and discusses potential directions for future research such as item banking and computer adaptive testing. ||||| PURPOSE: To compare vision function and self-reported quality of life (QoL) in patients with diabetic macular edema (DME) treated with intravitreous pegaptanib 0.3 mg or sham injection.
METHODS: This randomized (1:1), controlled, multicenter trial included subjects with DME (center point thickness on OCT, ≥ 250 μm) and visual acuity (VA) ≤ 65 letters and ≥ 35 letters. In year 1, pegaptanib or sham was administered every 6 weeks with focal/grid photocoagulation at investigator discretion after week 18. Subjects received injections as often as every 6 weeks per pre-specified criteria in year 2. Primary efficacy endpoint: proportion gaining ≥10 letters of VA from baseline to week 54. Change in QoL from baseline to weeks 54 and 102 was assessed with the 25-item National Eye Institute-Visual Function Questionnaire (NEI-VFQ 25) and the EQ-5D.
RESULTS: One hundred thirty-three pegaptanib- and 127 sham-treated subjects were in the year 1 intent-to-treat population. From baseline to week 54, ≥ 10 letter gains seen in 49 (36.8%) pegaptanib- and 25 (19.7%) sham-treated subjects (odds ratio [95% CI]: 2.38 [1.32-4.30]; P = 0.0047). At 2 years, the VA trend favored pegaptanib. The NEI-VFQ 25 domains of Near Vision, Distance Vision, and Social Functioning (week 54) and Distance Vision, Social Functioning, Mental Health, and Composite Score (week 102) demonstrated clinically meaningful (>5-point between-group difference) and statistically significant (P < 0.05) benefits favoring pegaptanib. No significant difference in the mean change in generic EQ-5D-weighted utility scores was seen.
CONCLUSIONS: The VA improvement from pegaptanib treatment versus sham is reflected by improved vision-related QoL as reported by the DME patient (ClinicalTrials.gov number, NCT00605280). ||||| AIMS: To examine objective visual acuity measured with ETDRS, retinal thickness (OCT), patient reported outcome and describe levels of glycated hemoglobin and its association with the effects on visual acuity in patients treated with anti-VEGF for visual impairment due to diabetic macular edema (DME) during 12months in a real world setting.
METHODS: In this cross-sectional study, 58 patients (29 females and 29 males; mean age, 68years) with type 1 and type 2 diabetes diagnosed with DME were included. Medical data and two questionnaires were collected; an eye-specific (NEI VFQ-25) and a generic health-related quality of life questionnaire (SF-36) were used.
RESULTS: The total patient group had significantly improved visual acuity and reduced retinal thickness at 4months and remains at 12months follow up. Thirty patients had significantly improved visual acuity, and 27 patients had no improved visual acuity at 12months. The patients with improved visual acuity had significantly improved scores for NEI VFQ-25 subscales including general health, general vision, near activities, distance activities, and composite score, but no significant changes in scores were found in the group without improvements in visual acuity.
CONCLUSIONS: Our study revealed that anti-VEGF treatment improved visual acuity and central retinal thickness as well as patient-reported outcome in real world 12months after treatment start. ||||| PURPOSE: An important factor in the choice of therapy is the impact it has on the patient's quality of life. This survey aimed to understand treatment burden, treatment-related anxiety and worry, and practical issues such as appointment attendance and work absence in patients receiving injection therapy for diabetic macular edema (DME) or retinal vein occlusion (RVO).
PATIENTS AND METHODS: A European sample of 131 retinal patients completed a detailed questionnaire to elucidate the impact of injection therapy on individuals with DME or RVO.
RESULTS: RVO and DME greatly impact a patient's quality of life. An intensive injection regimen and the requirements for multiple hospital visits place a large practical burden on the patient. Each intravitreal injection appointment (including travel time) was reported to take an average of 4.5 hours, with a total appointment burden over 6 months of 13.5 hours and 20 hours for RVO and DME patients, respectively. This creates a significant burden on patient time and may make appointment attendance difficult. Indeed, 53% of working patients needed to take at least 1 day off work per appointment and 71% of patients required a carer's assistance at the time of the injection appointment, ~6.3 hours per injection. In addition to practical issues, three-quarters of patients reported experiencing anxiety about their most recent injection treatment, with 54% of patients reporting that they were anxious for at least 2 days prior to the injection. Patients' most desired improvement to their treatment regimen was to have fewer injections and to require fewer appointments, to achieve the same visual results.
CONCLUSION: Patients' quality of life is clearly very affected by having to manage an intensive intravitreal injection regimen, with a considerable treatment burden having a large negative effect. Reducing the appointment burden to achieve the same visual outcomes and the provision of additional support for patients to attend appointments would greatly benefit those receiving intravitreal injection therapies for DME and RVO. ||||| PURPOSE: To compare the changes in vision related quality of life (VR-QoL) in patients with diabetic macular edema (DME) undergoing intravitreal ranibizumab (IVR) injection or focal/grid laser.
MATERIAL AND METHODS: In this prospective study, 70 patients with clinically significant macular edema (CSME) were randomized to undergo IVR injection (n=35) and focal/grid laser (n=35). If necessary, the laser or ranibizumab injections were repeated. Distance and near visual acuities, central retinal thickness (CRT) and The 25-item Visual Function Questionnaire (VFQ-25) were used to measure the effectiveness of treatments and VR-QoL before and after 6 months following IVR or laser treatment.
RESULTS: The demographic and clinical findings before the treatments were similar in both main groups. The improvements in distance and near visual acuities were higher in IVR group than the laser group (p<0.01). The reduction in CRT in IVR group was higher than that in laser treatment group (p<0.01). In both groups, the VFQ-25 composite score tended to improve from baseline to 6 months. And at 6th month, the changes in composite score were significantly higher in IVR group than in laser group (p<0.05). The improvements in overall composite scores were 6.3 points for the IVR group compared with 3.0 points in the laser group. Patients treated with IVR and laser had large improvements in composite scores, general vision, near and distance visual acuities in VFQ-25 at 6 months, in comparison with baseline scores, and also mental health subscale in IVR group.
CONCLUSION: Our study revealed that IVR improved not only visual acuity or CRT, but also vision related quality of life more than laser treatment in DME. And these patient-reported outcomes may play an important role in the treatment choice in DME for clinicians. ||||| AIMS: The aim of this study was to determine the impact of diabetic macular oedema (DME) on the quality of life (QOL) in patients with type 2 diabetes mellitus.
METHODS: The study was a prospective, consecutive, non-comparative case series. An observational study evaluated the quality of vision and vision-specific QOL using the 25-item National Eye Institute Visual Function Questionnaire (NEI VFQ-25). Mean VFQ-25 subscale scores in type 2 diabetic study patients were compared with mean VFQ-25 subscale score in groups of patients with type 1 diabetic retinopathy (T1DR) and varying degrees of age-related macular degeneration (ARMD), glaucoma and cataracts and in reference populations.
RESULTS: Thirty-three patients completed the NEI VFQ-25. The mean age of the study population was 64 years. When performing a comparison of those patients with DME versus those with isolated T1DR we found that for the general health subscale, the DME versus T1DR group means were 42+/-4.4 versus 61+/-1.0 respectively. The DME versus T1DR quality of vision categorical mean scores were 69+/-4.1 versus 93+/-3.9. The DME versus T1DR VR-QOL categorical mean scores were 62+/-5.0 versus 93+/-1.0. The DME group was significantly worse in each of these three categories compared with the T1DR group (p<0.01). An additional analysis was performed to examine the differences in VR-QOL in the DME group versus varying common ocular diseases, including age-related macular degeneration (ARMD), glaucoma, cataracts and disease-free reference groups. The mean values of VFQ-25 subscale in the DME group were significantly lower then the glaucoma group in ten of 12 subscales, the cataract group in 11 of 12 subscales, and the reference group in 12 of 12 subscales. However, the mean values of VFQ-25 subscale in the DME group were only significantly different from the ARMD group in three of 12 subscales.
CONCLUSIONS: Type 2 diabetes patients with macular oedema experience a decreased VR-QOL compared with type 1 diabetic patients with diabetic retinopathy, glaucoma or cataracts. However, VR-QOL in type 2 diabetic patients with macular oedema was similar to those individuals with ARMD. ||||| AIMS: To explore the patient experience of symptoms of eye disease related to diabetes and its treatment, including increase of symptoms over time and their relation to severity of the condition and the effect of multiple treatments and symptoms on quality of life.
METHODS: A qualitative interview study was implemented at four eye clinics in the UK. This study design was intended to yield 240 interviews in patients having their first laser treatment or first follow-up and in multi-treatment patients with a clinically documented loss of visual function in at least one eye (VA </= 6/12). The intention was to have an approximately equal number of patients with proliferative diabetic retinopathy (PDR) or macular oedema (MO).
RESULTS: A total of 227 interviews were completed (54% PDR and 46% MO). The most frequently reported symptom prior to initial treatment was blurred vision (55%). First-time-treatment patients reported fewer symptoms than the multi-treatment patients. After a pronounced reduction of quality-of-life impacts after the first laser treatment, results all demonstrate an increasing impact as patients move from first treatment to multiple treatments. The main responses regarding satisfaction with laser treatment were that, although patient expectations were basically met, the treatment had less of an impact than they hoped for, and they would have the treatment again if needed.
CONCLUSIONS: The current study provides a qualitative exploration of visual symptoms, levels of self-reported visual impairment, and general description of the areas of impact or restriction that patients experienced due to their eye disease, both pre- and post-laser treatment. ||||| OBJECTIVE: Accounting for patient preferences may be especially important in diabetes mellitus, given the challenge in identifying factors associated with treatment adherence. Although preference studies have been performed in diabetes, none have examined treatments used in diabetic retinopathy (DR). The objective of this study was to elicit patient preferences for attributes associated with antivascular endothelial growth factor, focal and panretinal laser, and steroid therapy used in DR management.
METHODS: A cross-sectional conjoint survey was administered to DR patients at three Canadian eye centers. The survey involved making tradeoffs among 11 DR treatment attributes, including the chance of improving vision and risks of adverse events over a 1-year treatment period. Attribute utilities were summed for each product profile to determine the most preferred treatment.
RESULTS: Based on the results from 161 patients, attributes affecting visual functioning, including improving visual acuity and reducing adverse events (eg, chance of cataracts), were more important than those not directly affecting vision (eg, administration). Overall, 52%, 20%, 17%, and 11% preferred the product profiles matching to the antivascular endothelial growth factor, steroid, focal laser, and panretinal laser therapies. Preferences did not vary substantially by previous treatment experience, age, or type of DR (macular edema, proliferative DR, both or neither), with the exception that more macular edema only patients preferred focal laser over steroid treatment (19% versus 14%, respectively).
CONCLUSIONS: When considering the potential effects of treatment over a 1-year period, treatment preferences in DR are most influenced by those that may positively or negatively affect visual functioning. ||||| OBJECTIVE: To describe the impact of co-morbidities, visual acuity, diabetic retinopathy (DR) grade, and macular edema (ME) on the health-related quality of life (HRQOL) among patients with diabetic retinopathy.
METHODS: Analysis of data of 207 patients with diabetic retinopathy from Germany in 2003. HRQOL assessment was done using the generic (SF-12) questionnaire. It was hypothesized that exogenous variables (co-morbidities, visual acuity impairment, DR, and ME) would have an impact on HRQOL. Using a structural equation modelling procedure, the effects of exogenous variables on endogenous variables physical component summaries (PSC) and mental component summaries (MCS) reflecting HRQOL were tested.
RESULTS: The number of co-morbidities had a negative effect on visual acuity (b = -0.26, standardized) and a similar negative effect on PCS (b = -0.27). DR grade had a negative effect on visual acuity (b = -0.19) and a positive effect on the variable ME (b = 0.44). ME displayed a negative effect on visual acuity (b = -0.58) and also on MCS (b = -0.29). Visual acuity had a positive effect (b = 0.48) on PCS.
CONCLUSIONS: Presence of DR and ME, visual acuity impairment and patient co-morbidities lead to significant impairment of both the physical and mental components of HRQOL. ||||| Macular edema is the final common pathway of many intraocular and systemic insults. It may develop in a diffuse pattern where the macula appears generally thickened or it may acquire the characteristic petaloid appearance referred to as cystoid macular edema. Although macular edema may be associated with protean underlying conditions, it is most commonly seen following intraocular surgery, venous occlusive disease, diabetic retinopathy, and posterior segment inflammatory disease. As well as clinical suspicion, a wide range of investigations may lead to the diagnosis of macular edema. Fluorescein angiography and optical coherence tomography provide enhanced visualization of the geometry and distribution of macular edema. A variety of approaches to the treatment of macular edema have been attempted, with a variable degree of success. These options have included topical and systemic steroids, topical and oral non-steroidal anti-inflammatory agents and laser photocoagulation treatment. More recently other therapeutic modalities, including immunomodulators, intravitreal injection of triamcinolone, and pars plana vitrectomy have also been employed. Clinical trials are currently looking into the use of a steroid slow-release intravitreal device for the management of macular edema secondary to uveitis and diabetes. This article reviews the clinical entity of macular edema focusing on the current therapeutic strategies for its management. ||||| PURPOSE: To investigate the vision-related quality of life (VR-QOL) and visual function in patients undergoing intravitreal injection of bevacizumab (IVB) for persistent diabetic macular edema (DME) after vitrectomy.
METHODS: This institutional study enrolled 20 consecutive patients (20 eyes) who had received 1.25 mg IVB for persistent macular edema after vitrectomy for DME at least 3 months previously. Visual function and VR-QOL were measured before, and 1 and 3 months after IVB. Measurements included the logarithm of the minimum angle of resolution (logMAR), best corrected visual acuity (BCVA), letter contrast sensitivity, severity of metamorphopsia using M-CHARTS, central retinal thickness using optical coherence tomography, and VR-QOL with the 25-item National Eye Institute Visual Function Questionnaire (VFQ-25).
RESULTS: One month after IVB, statistically significant improvements were observed in central retinal thickness, letter contrast sensitivity, and the VFQ-25 "mental health" subscale score (P < 0.05, Dunnett test). LogMAR BCVA, metamorphopsia, and the VFQ-25 composite score did not improve significantly. Three months after IVB, there were no significant improvements in any parameters examined.
CONCLUSIONS: Intravitreal bevacizumab injection for persistent DME after vitrectomy temporarily improved central retinal thickness, contrast sensitivity, and the psychometric aspect of the VR-QOL, but these effects did not last for over 3 months. ||||| OBJECTIVES: Psychometric development of the Retinopathy-Dependent Quality of Life (RetDQoL) questionnaire in a cross-sectional study of 207 German patients with diabetic retinopathy. Forty patients (19%) also had clinically significant macular edema.
METHODS: Principal component analyses identified factor structure, and Cronbach's alpha assessed internal consistencies. Construct validity was examined by testing the additional impact of macular edema and expected relationships of RetDQoL scores with visual impairment, stage of diabetic retinopathy, subscales of the SF-12, and scores of the Retinopathy Treatment Satisfaction Questionnaire (RetTSQ). Analyses were conducted using the RetDQoL's AWI score (average weighted impact of diabetic retinopathy on 26 life domains) and its two overview items (present QoL in general and retinopathy-specific QoL). Content validity was investigated using an open-ended question to identify any additional items needed.
RESULTS: A forced one-factor solution of the 26 specific weighted impact ratings showed all items except working life (applicable to 27%) to load>0.55, and Cronbach's alpha was 0.96, showing very high reliability. Greater impairment, worse diabetic retinopathy, and macular edema were associated with greater negative impact on scores. AWI correlated as expected more highly with retinopathy-specific QoL (r=0.71, P<0.01) than with present QoL (r=0.28, P<0.01). RetDQoL scores correlated moderately with SF-12 subscales (r=0.22-0.51, P<0.01) and RetTSQ scores (r=0.27-0.51, P<0.01). For six domains, >60% of patients reported no impact. No additional domains were needed.
CONCLUSIONS: The RetDQoL is valid and reliable for patients with diabetic retinopathy with or without macular edema. It may be shortened if findings are confirmed cross-culturally. ||||| OBJECTIVE: To report the 12-month results of the first head-to-head comparison of a dexamethasone implant (Ozurdex; Allergan, Inc., Irvine, CA) versus bevacizumab (Avastin; Genentech, South San Francisco, CA) for center-involving diabetic macular edema (DME).
DESIGN: Phase 2, prospective, multicenter, randomized, single-masked clinical trial (clinicaltrials.gov identifier NCT01298076).
PARTICIPANTS: We enrolled 88 eyes of 61 patients with center-involving DME.
METHODS: Forty-two eyes were randomized to receive bevacizumab every 4 weeks and 46 eyes were randomized to receive a dexamethasone implant every 16 weeks, both pro re nata. Results were analyzed using linear regression with generalized estimation equation methods to account for between-eye correlation.
MAIN OUTCOME MEASURES: The primary outcome was the proportion of eyes that improved vision by 10 logarithm of minimum angle of resolution letters. Secondary outcomes included mean change in best-corrected visual acuity (BCVA), change in central macular thickness (CMT), injection frequency, and adverse events. Patient-reported outcomes were measured using the Impact of Vision Impairment (IVI) questionnaire.
RESULTS: Improvement in BCVA of 10 or more letters was found in 17 of 42 eyes (40%) treated with bevacizumab compared with 19 of 46 dexamethasone implant-treated eyes (41%; P = 0.83). None of the 42 bevacizumab eyes lost 10 letters or more, whereas 5 of 46 (11%) dexamethasone implant eyes did, mostly because of cataract. Mean CMT decreased by 122 μm for bevacizumab eyes and by 187 μm for dexamethasone implant eyes (P = 0.015). Bevacizumab-treated eyes received a mean of 8.6 injections compared with 2.7 injections for dexamethasone implant eyes. Significant improvement in IVI scores occurred for both treatment groups.
CONCLUSIONS: Dexamethasone implant achieved similar rates of visual acuity improvement compared with bevacizumab for DME, with superior anatomic outcomes and fewer injections. Both treatments were associated with improvement in visual quality-of-life scores. However, more dexamethasone implant-treated eyes lost vision, mainly because of cataract. | [
{
"source_pmid": "26318959",
"source_text": "PURPOSE: To examine patient-reported outcome (PRO) in a selected group of Swedish patients about to receive anti-vascular endothelial growth factor (VEGF) treatment for diabetic macular edema (DME).\nMATERIAL AND METHODS: In this cross-sectional study, 59 patient... |
22890029 | CONCLUSIONS: Results suggest no difference in effectiveness between bevacizumab and ranibizumab, but the wide credible intervals cannot exclude the possibility that either drug might be superior. Sufficiently powered, direct head to head trials are needed. | OBJECTIVE: Evaluate intravitreal 0.5 mg ranibizumab or 4 mg triamcinolone combined with focal/grid laser compared with focal/grid laser alone for treatment of diabetic macular edema (DME).
DESIGN: Multicenter, randomized clinical trial.
PARTICIPANTS: A total of 854 study eyes of 691 participants with visual acuity (approximate Snellen equivalent) of 20/32 to 20/320 and DME involving the fovea.
METHODS: Eyes were randomized to sham injection + prompt laser (n=293), 0.5 mg ranibizumab + prompt laser (n=187), 0.5 mg ranibizumab + deferred (> or =24 weeks) laser (n=188), or 4 mg triamcinolone + prompt laser (n=186). Retreatment followed an algorithm facilitated by a web-based, real-time data-entry system.
MAIN OUTCOME MEASURES: Best-corrected visual acuity and safety at 1 year.
RESULTS: The 1-year mean change (+/-standard deviation) in the visual acuity letter score from baseline was significantly greater in the ranibizumab + prompt laser group (+9+/-11, P<0.001) and ranibizumab + deferred laser group (+9+/-12, P<0.001) but not in the triamcinolone + prompt laser group (+4+/-13, P=0.31) compared with the sham + prompt laser group (+3+/-13). Reduction in mean central subfield thickness in the triamcinolone + prompt laser group was similar to both ranibizumab groups and greater than in the sham + prompt laser group. In the subset of pseudophakic eyes at baseline (n=273), visual acuity improvement in the triamcinolone + prompt laser group appeared comparable to that in the ranibizumab groups. No systemic events attributable to study treatment were apparent. Three eyes (0.8%) had injection-related endophthalmitis in the ranibizumab groups, whereas elevated intraocular pressure and cataract surgery were more frequent in the triamcinolone + prompt laser group. Two-year visual acuity outcomes were similar to 1-year outcomes.
CONCLUSIONS: Intravitreal ranibizumab with prompt or deferred laser is more effective through at least 1 year compared with prompt laser alone for the treatment of DME involving the central macula. Ranibizumab as applied in this study, although uncommonly associated with endophthalmitis, should be considered for patients with DME and characteristics similar to those in this clinical trial. In pseudophakic eyes, intravitreal triamcinolone + prompt laser seems more effective than laser alone but frequently increases the risk of intraocular pressure elevation. ||||| PURPOSE: To report the efficacy of a single intravitreal bevacizumab injection alone or in combination with intravitreal triamcinolone acetonide versus macular laser photocoagulation (MPC) as primary treatment of diabetic macular edema (DME).
METHODS: In this randomized, three-arm clinical trial, 103 eyes of 97 patients with clinically significant DME and no previous treatment were enrolled. The eyes were randomly assigned to one of three study arms: the intravitreal bevacizumab (IVB) group, patients who received 1.25 mg of intravitreal bevacizumab (37 eyes); the IVB/IVT group, patients who received 1.25 mg of intravitreal bevacizumab and 2 mg of intravitreal triamcinolone (33 eyes); and the MPC group, patients who underwent focal or modified grid laser (33 eyes). Primary outcome measure was change in visual acuity.
RESULTS: Visual acuity changes +/- SD at 12 weeks were -0.22 +/- 0.23, -0.13 +/- 0.31, and + 0.08 +/- 0.31 logarithm of the minimal angle of resolution in the IVB, IVB/IVT, and MPC groups, respectively. The marginal regression model based on generalized estimating equation analysis demonstrated that the visual acuity changes in the groups were statistically significant at both 6 weeks (P < 0.0001) and 12 weeks (P = 0.024). The significant treatment effect was demonstrated at both 6 weeks and 12 weeks in the IVB group and only at 6 weeks in the IVB/IVT group. Significant central macular thickness (CMT) reduction was observed in eyes in the IVB and IVB/IVT groups only up to 6 weeks; however, CMT changes were not significant in the groups.
CONCLUSION: Up to 12 weeks, intravitreal bevacizumab treatment of patients with DME yielded better visual outcome than laser photocoagulation, although it was not associated with a significant decrease in CMT. No further beneficial effect of intravitreal triamcinolone could be demonstrated. Further clinical trials with longer follow-up are required to evaluate the long-term visual outcomes and complication profiles after primary treatment with such medications. ||||| PURPOSE: To assess the effect of initial central macular thickness (CMT) on the response to treatment in diabetic macular edema.
METHODS: The data of 150 eyes of 129 patients with clinically significant diabetic macular edema and no previous treatment who had been randomly assigned in the original trial to 1 of the 3 groups, 1) intravitreal bevacizumab (IVB) group (50 eyes); 2) combined intravitreal bevacizumab and triamcinolone (IVB/IVT) group (50 eyes); and 3) macular laser photocoagulation group (50 eyes), were reevaluated. This time the data of the cases were reanalyzed based on their initial CMT. Accordingly, the original treatment groups were categorized into 3 subgroups: 1) <250 μm, 2) 250 μm to 349 μm, and 3) ≥350 μm. Visual acuity and CMT changes in response to different treatments were compared. Main outcome measures were changes in visual acuity and CMT at Weeks 6, 12, 24, and 36.
RESULTS: At 6 weeks in all subgroups, mean visual acuity improvement in the IVB group was significantly greater than the other groups (P = 0.002, P = 0.003, P < 0.001, for subgroups of <250, 250-349, and ≥350 μm, respectively). At 12, 24, and 36 weeks in the subgroup >350 μm and at 24 weeks in the subgroup 250 μm to 349 μm, the difference of mean visual acuity changes among the groups reached to a significant level (P = 0.010, P = 0.028, P < 0.001, and P < 0.001, respectively) in favor of the IVB group. The difference in mean CMT changes at 6 weeks and 12 weeks was significant among the groups in the subgroup ≥350 μm (P < 0.001 and P < 0.001) in favor of the IVB group and in the subgroup 250 μm to 349 μm at 24 weeks in favor of combined IVB/IVT group (P < 0.001).
CONCLUSION: In the primary treatment of diabetic macular edema, initial CMT may be an important factor in decision making. Regardless of initial CMT, IVB caused a better visual outcome only at 6 weeks. With longer follow-up, however, IVB was superior to IVB/IVT and macular laser photocoagulation only in the eyes with initial CMT of ≥350 μm. Concerning CMT reduction, this superiority of IVB in the eyes with initial CMT of ≥350 μm was not observed beyond 12 weeks. ||||| PURPOSE: To report the findings at 1 year of a study comparing repeated intravitreal bevacizumab (ivB) and modified Early Treatment of Diabetic Retinopathy Study (ETDRS) macular laser therapy (MLT) in patients with persistent clinically significant diabetic macular edema (CSME).
DESIGN: Prospective, randomized, masked, single-center, 2-year, 2-arm clinical trial.
PARTICIPANTS: A total of 80 eyes of 80 patients with center-involving CSME and at least 1 prior MLT.
METHODS: Subjects were randomized to either ivB (6 weekly; minimum of 3 injections and maximum of 9 injections in the first 12 months) or MLT (4 monthly; minimum of 1 treatment and maximum of 4 treatments in the first 12 months).
MAIN OUTCOME MEASURES: The primary end point was the difference in ETDRS best-corrected visual acuity (BCVA) at 12 months between the bevacizumab and laser arms.
RESULTS: The baseline mean ETDRS BCVA was 55.7+/-9.7 (range 34-69) in the bevacizumab group and 54.6+/-8.6 (range 36-68) in the laser arm. The mean ETDRS BCVA at 12 months was 61.3+/-10.4 (range 34-79) in the bevacizumab group and 50.0+/-16.6 (range 8-76) in the laser arm (P = 0.0006). Furthermore, the bevacizumab group gained a median of 8 ETDRS letters, whereas the laser group lost a median of 0.5 ETDRS letters (P = 0.0002). The odds of gaining > or =10 ETDRS letters over 12 months were 5.1 times greater in the bevacizumab group than in the laser group (adjusted odds ratio, 5.1; 95% confidence interval, 1.3-19.7; P = 0.019). At 12 months, central macular thickness decreased from 507+/-145 microm (range 281-900 microm) at baseline to 378+/-134 microm (range 167-699 microm) (P<0.001) in the ivB group, whereas it decreased to a lesser extent in the laser group, from 481+/-121 microm (range 279-844 microm) to 413+/-135 microm (range 170-708 microm) (P = 0.02). The median number of injections was 9 (interquartile range [IQR] 8-9) in the ivB group, and the median number of laser treatments was 3 (IQR 2-4) in the MLT group.
CONCLUSIONS: The study provides evidence to support the use of bevacizumab in patients with center-involving CSME without advanced macular ischemia. ||||| OBJECTIVE: To demonstrate superiority of ranibizumab 0.5 mg monotherapy or combined with laser over laser alone based on mean average change in best-corrected visual acuity (BCVA) over 12 months in diabetic macular edema (DME).
DESIGN: A 12-month, randomized, double-masked, multicenter, laser-controlled phase III study.
PARTICIPANTS: We included 345 patients aged ≥18 years, with type 1 or 2 diabetes mellitus and visual impairment due to DME.
METHODS: Patients were randomized to ranibizumab + sham laser (n = 116), ranibizumab + laser (n = 118), or sham injections + laser (n = 111). Ranibizumab/sham was given for 3 months then pro re nata (PRN); laser/sham laser was given at baseline then PRN (patients had scheduled monthly visits).
MAIN OUTCOME MEASURES: Mean average change in BCVA from baseline to month 1 through 12 and safety.
RESULTS: Ranibizumab alone and combined with laser were superior to laser monotherapy in improving mean average change in BCVA letter score from baseline to month 1 through 12 (+6.1 and +5.9 vs +0.8; both P<0.0001). At month 12, a significantly greater proportion of patients had a BCVA letter score ≥15 and BCVA letter score level >73 (20/40 Snellen equivalent) with ranibizumab (22.6% and 53%, respectively) and ranibizumab + laser (22.9% and 44.9%) versus laser (8.2% and 23.6%). The mean central retinal thickness was significantly reduced from baseline with ranibizumab (-118.7 μm) and ranibizumab + laser (-128.3 μm) versus laser (-61.3 μm; both P<0.001). Health-related quality of life, assessed through National Eye Institute Visual Function Questionnaire (NEI VFQ-25), improved significantly from baseline with ranibizumab alone and combined with laser (P<0.05 for composite score and vision-related subscales) versus laser. Patients received ∼7 (mean) ranibizumab/sham injections over 12 months. No endophthalmitis cases occurred. Increased intraocular pressure was reported for 1 patient each in the ranibizumab arms. Ranibizumab monotherapy or combined with laser was not associated with an increased risk of cardiovascular or cerebrovascular events in this study.
CONCLUSIONS: Ranibizumab monotherapy and combined with laser provided superior visual acuity gain over standard laser in patients with visual impairment due to DME. Visual acuity gains were associated with significant gains in VFQ-25 scores. At 1 year, no differences were detected between the ranibizumab and ranibizumab + laser arms. Ranibizumab monotherapy and combined with laser had a safety profile in DME similar to that in age-related macular degeneration. ||||| OBJECTIVE: To report expanded 2-year follow-up of a previously reported randomized trial evaluating intravitreal 0.5 mg ranibizumab or 4 mg triamcinolone combined with focal/grid laser compared with focal/grid laser alone for treatment of diabetic macular edema (DME).
DESIGN: Multicenter, randomized clinical trial.
PARTICIPANTS: A total of 854 study eyes of 691 participants with visual acuity of 20/32 to 20/320 (approximate Snellen equivalent) and DME involving the fovea.
METHODS: Continuation of procedures previously reported for the randomized trial.
MAIN OUTCOME MEASURES: Best-corrected visual acuity and safety at the 2-year visit.
RESULTS: At the 2-year visit, compared with the sham + prompt laser group, the mean change in the visual acuity letter score from baseline was 3.7 letters greater in the ranibizumab + prompt laser group (95% confidence interval adjusted for multiple comparisons [aCI], -0.4 to +7.7), 5.8 letters greater in the ranibizumab + deferred laser group (95% aCI, +1.9 to +9.8), and 1.5 letters worse in the triamcinolone + prompt laser group (95% aCI, -5.5 to +2.4). After the 1- to 2-year visit in the ranibizumab + prompt or deferred laser groups, the median numbers of injections were 2 and 3 (potential maximum of 13), respectively. At the 2-year visit, the percentages of eyes with central subfield thickness ≥250 μm were 59% in the sham + prompt laser group, 43% in the ranibizumab + prompt laser group, 42% in the ranibizumab + deferred laser group, and 52% in the triamcinolone + prompt laser group. No systemic events attributable to study treatment were apparent. Three eyes in 3 (0.8%) of 375 participants had injection-related endophthalmitis in the ranibizumab groups, whereas elevated intraocular pressure and cataract surgery were more frequent in the triamcinolone + prompt laser group.
CONCLUSIONS: The expanded 2-year results reported are similar to results published previously and reinforce the conclusions originally reported: Ranibizumab should be considered for patients with DME and characteristics similar to those of the cohort in this clinical trial, including vision impairment with DME involving the center of the macula. ||||| PURPOSE: To compare the results of intravitreal bevacizumab (IVB) injection alone or in combination with intravitreal triamcinolone acetonide (IVT) versus macular laser photocoagulation (MPC) as a primary treatment of diabetic macular edema (DME).
DESIGN: Randomized 3-arm clinical trial.
PARTICIPANTS: A total of 150 eyes of 129 patients with clinically significant DME and no previous treatment.
METHODS: The eyes were randomly assigned to 1 of the 3 study arms: the IVB group, patients who received 1.25 mg IVB (50 eyes); the IVB/IVT group, patients who received 1.25 mg of IVB and 2 mg of IVT (50 eyes); and the MPC group, patients who underwent focal or modified grid laser (50 eyes). Retreatment was performed at 12-week intervals whenever indicated.
MAIN OUTCOME MEASURES: Change in best-corrected visual acuity (VA) at week 24.
RESULTS: VA changes among the groups were statistically significant at 6 (P<0.001) and 24 (P = 0.012) weeks. The significant treatment effect was demonstrated in the IVB group at all follow-up visits and in the IVB/IVT group at 6 and 12 weeks. VA changes +/- standard deviation at 36 weeks were -0.28+/-0.25, -0.04+/-0.33, and +0.01+/-0.27 logarithm of minimum angle of resolution in the IVB, IVB/IVT, and MPC groups, respectively (P = 0.053). Significant central macular thickness (CMT) reduction was observed in all groups only up to 6 weeks; however, CMT changes were not significant among the groups in all visits. Overall, retreatment was required for 27 eyes up to 36 weeks (14 in the IVB group, 10 in the IVB/IVT group, and 3 in the MPC group). In the IVB group, in which a greater VA improvement was observed, only 1 injection was required in 72% of the cases. VA improvement >2 Snellen lines at 36 weeks was detected in 37%, 25%, and 14.8% of patients in the IVB, IVB/IVT, and MPC groups, respectively.
CONCLUSIONS: Intravitreal bevacizumab injection in patients with DME yielded a better visual outcome at 24 weeks compared with macular photocoagulation. A change in CMT beyond the 6-week time point that corresponded to the vision change was not detected. No adjunctive effect of IVT was demonstrated.
FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article. ||||| OBJECTIVES: To determine the long-term effects of ranibizumab (RBZ) in patients with diabetic macular edema (DME).
DESIGN: Prospective, randomized, interventional, multicenter clinical trial.
PARTICIPANTS: One hundred twenty-six patients with DME.
METHODS: Subjects were randomized 1:1:1 to receive 0.5 mg RBZ at baseline and months 1, 3, and 5 (group 1), focal or grid laser photocoagulation at baseline and month 3 if needed (group 2), or a combination of 0.5 mg RBZ and focal or grid laser at baseline and month 3 (group 3). Starting at month 6, if retreatment criteria were met, all subjects could be treated with RBZ.
MAIN OUTCOME MEASURES: The mean change from baseline in best-corrected visual acuity (BCVA) at month 24.
RESULTS: After the primary end point at month 6, most patients in all groups were treated only with RBZ, and the mean number of injections was 5.3, 4.4, and 2.9 during the 18-month follow-up period in groups 1, 2, and 3, respectively. For the 33 patients in group 1, 34 patients in group 2, and 34 patients in group 3 who remained in the study through 24 months, the mean improvement in BCVA was 7.4, 0.5, and 3.8 letters at the 6-month primary end point, compared with 7.7, 5.1, and 6.8 letters at month 24, and the percentage of patients who gained 3 lines or more of BCVA was 21, 0, and 6 at month 6, compared with 24, 18, and 26 at month 24. The percentage of patients with 20/40 or better Snellen equivalent at month 24 was 45% in group 1, 44% in group 2, and 35% in group 3. Mean foveal thickness (FTH), defined as center subfield thickness, at month 24 was 340 μm, 286 μm, and 258 μm for groups 1, 2, and 3, respectively, and the percentage of patients with center subfield thickness of 250 μm or less was 36%, 47%, and 68%, respectively.
CONCLUSIONS: Intraocular injections of RBZ provided benefit for patients with DME for at least 2 years, and when combined with focal or grid laser treatments, the amount of residual edema was reduced, as were the frequency of injections needed to control edema.
FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references. ||||| OBJECTIVES: To compare ranibizumab with focal/grid laser or a combination of both in diabetic macular edema (DME).
DESIGN: Prospective, randomized, interventional, multicenter clinical trial.
PARTICIPANTS: A total of 126 patients with DME.
METHODS: Subjects were randomized 1:1:1 to receive 0.5 mg of ranibizumab at baseline and months 1, 3, and 5 (group 1, 42 patients), focal/grid laser photocoagulation at baseline and month 3 if needed (group 2, 42 patients), or a combination of 0.5 mg of ranibizumab and focal/grid laser at baseline and month 3 (group 3, 42 patients).
MAIN OUTCOME MEASURES: The primary end point was the change from baseline in best-corrected visual acuity (BCVA) at month 6.
RESULTS: At month 6, the mean gain in BCVA was significantly greater in group 1 (+7.24 letters, P = 0.01, analysis of variance) compared with group 2 (-0.43 letters), and group 3 (+3.80 letters) was not statistically different from groups 1 or 2. For patients with data available at 6 months, improvement of 3 lines or more occurred in 8 of 37 (22%) in group 1 compared with 0 of 38 (0%) in group 2 (P = 0.002, Fisher exact test) and 3 of 40 (8%) in group 3. Excess foveal thickness was reduced by 50%, 33%, and 45% in groups 1, 2, and 3, respectively.
CONCLUSIONS: During a span of 6 months, ranibizumab injections by the current protocol had a significantly better visual outcome than focal/grid laser treatment in patients with DME. ||||| PURPOSE: The purpose of this study was to assess macular perfusion with fundus fluorescein angiography at the 4-month time point in a prospective randomized, single-center 2-year trial comparing intravitreal bevacizumab and laser therapy in patients with diabetic macular edema.
METHODS: All enrolled patients had standard Early Treatment of Diabetic Retinopathy Study 7-field fundus photographs and fundus fluorescein angiography at baseline and subsequently at 4-month intervals. Patients were excluded from the study if either the greatest linear dimension of the foveal avascular zone (FAZ) was >1,000 microm in diameter or there was severe perifoveal capillary loss (Early Treatment of Diabetic Retinopathy Study criteria) on fundus fluorescein angiography. The fundus fluorescein angiograms of the bevacizumab (n=42) and laser (n=38) groups were graded for greatest linear dimension of the FAZ, area of the FAZ, and perifoveal capillary loss by the Moorfields Reading Centre in a masked fashion.
RESULTS: At baseline, the mean greatest linear dimension of the FAZ in the laser group was 685 +/- 262 microm and in the bevacizumab group was 737 +/- 262 microm. There was no significant difference at the 4-month time point (P 0.40) with the mean greatest linear dimension of the FAZ in the laser group recorded as 678 +/- 221 microm and in the bevacizumab group was 678 +/- 231 microm. At baseline, the median area of the FAZ in the laser group was 0.36 mm(2) (interquartile range, 0.21-0.46) and in the bevacizumab group was 0.33 mm(2) (interquartile range, 0.27-0.49). There was no significant difference at the 4-month time point (P=0.30) with the median area of the FAZ in the laser group recorded as 0.35 mm(2) (interquartile range, 0.20-0.52) and in the bevacizumab group was 0.34 mm(2) (interquartile range, 0.23-0.47). Similarly, there was no difference between the two treatment groups (P=0.64) when a comparison was made of the number of grades of change in perifoveal capillary loss observed in each patient. To date, no patients have been withdrawn from the study because of worsening macular ischemia.
CONCLUSION: At 4 months, there was no evidence of worsening macular ischemia in either group. | [
{
"source_pmid": "20427088",
"source_text": "OBJECTIVE: Evaluate intravitreal 0.5 mg ranibizumab or 4 mg triamcinolone combined with focal/grid laser compared with focal/grid laser alone for treatment of diabetic macular edema (DME).\nDESIGN: Multicenter, randomized clinical trial.\nPARTICIPANTS: A total of... |
15994659 | CONCLUSIONS: Lowering intraocular pressure in patients with ocular hypertension or manifest glaucoma is beneficial in reducing the risk of visual field loss in the long term. | One hundred seven patients with intraocular pressures (IOPs) between 22 and 28 mmHg with normal visual fields on Goldmann perimetry and without evidence of optic nerve damage were randomly assigned to either a timolol treatment (TT) or a no treatment (NT) arm in a prospective clinical trial. The patients were followed for an average of 56 and 51 months, respectively. Criteria for failure were a confirmed IOP of greater than 32 mmHg, stereophotographically documented optic nerve progression, or development of glaucomatous visual field loss by Goldmann or Octopus perimetry. Nine patients failed in the TT group and 17 in the NT group (P = 0.07). Of the nine TT group failures, six had discontinued timolol before failure (4 for greater than 6 months). In a Cox proportional hazards analysis controlling for confounding variables, timolol was found to be significantly protective with an adjusted risk ratio of 0.38 (95% confidence interval = 0.16-0.89, P = 0.03). When only field and disc failure criteria were considered, timolol treatment was found to be significantly protective in an analysis considering patients who stopped timolol as being lost to follow-up (P = 0.05). A higher tonographic facility of outflow was protective in all analyses. A trend toward a substantial loss of effectiveness of timolol on IOP was not observed. Seasonal fluctuations in IOP were observed (P = 0.0007), with higher IOP occurring in the winter. The results demonstrate a favorable influence of timolol therapy on the clinical course of patients with mildly elevated IOP.(ABSTRACT TRUNCATED AT 250 WORDS) ||||| One hundred forty-three patients with intraocular pressures (IOPs) above 22 mmHg and without visual field defects or any obvious evidence of optic nerve damage were randomly assigned to either a timolol treatment group or no treatment in a 6-year prospective clinical trial. Endpoints were defined as reproducible visual field defects on automatic perimetry, disc hemorrhages, or stereophotographically documented optic nerve head changes. Endpoints developed in 42 patients: 28 visual field defects, 8 changes in disc appearance, and 6 disc hemorrhages. Of the 42 patients, 20 were treated and 22 were not. Survival analysis showed no statistically significant differences in failure time to any endpoints between the two groups. In the untreated group, the time to failure of disc change was related to the mean IOP during the study and also to the changes in the IOP from baseline. A significant correlation was found between initial cup-to-disc ratio and survival time to visual field defects in the untreated group. ||||| PURPOSE: In a companion paper, we determined that intraocular pressure is part of the pathogenesis of normal-tension glaucoma by analyzing the effect of a 30% intraocular pressure reduction on the subsequent course of the disease. We report an intent-to-treat analysis of the study data to determine the effectiveness of pressure reduction.
METHODS: One eligible eye of 145 subjects with normal-tension glaucoma was randomized either to no treatment (control) or to a 30% intraocular pressure reduction from baseline. To be eligible for randomization, the normal-tension glaucoma eyes had to show documented progression of field defects or a new disk hemorrhage or had to have field defects that threatened fixation when first presented for the study. Survival analysis compared time to progression of all randomly assigned patients during the course of follow-up from the initial baseline at randomization. In a separate analysis, data of patients developing cataracts were censored at the time that cataract produced 2 lines of Snellen visual acuity loss.
RESULTS: Visual field progression occurred at indistinguishable rates in the pressure-lowered (22/66) and the untreated control (31/79) arms of the study (P = .21). In an analysis with data censored when cataract affected visual acuity, visual field progression was significantly more common in the untreated group (21/79) compared with the treated group (8/66). An overall survival analysis showed a survival of 80% in the treated arm and of 60% in the control arm at 3 years, and 80% in the treated arm and 40% in the controls at 5 years. The Kaplan-Meier curves were significantly different (P = .0018). The analyses gave different results because of a higher incidence of cataract in the group that underwent filtration surgery.
CONCLUSIONS: The favorable effect of intraocular pressure reduction on progression of visual change in normal-tension glaucoma was only found when the impact of cataracts on visual field progression, produced largely by surgery, was removed. Lowering intraocular pressure without producing cataracts is beneficial. Because not all untreated patients progressed, the natural history of normal-tension glaucoma must be considered before embarking on intraocular pressure reduction with therapy apt to exacerbate cataract formation unless normal-tension glaucoma threatens serious visual loss. ||||| BACKGROUND: Primary open-angle glaucoma (POAG) is one of the leading causes of blindness in the United States and worldwide. Three to 6 million people in the United States are at increased risk for developing POAG because of elevated intraocular pressure (IOP), or ocular hypertension. There is no consensus on the efficacy of medical treatment in delaying or preventing the onset of POAG in individuals with elevated IOP. Therefore, we designed a randomized clinical trial, the Ocular Hypertension Treatment Study.
OBJECTIVE: To determine the safety and efficacy of topical ocular hypotensive medication in delaying or preventing the onset of POAG.
METHODS: A total of 1636 participants with no evidence of glaucomatous damage, aged 40 to 80 years, and with an IOP between 24 mm Hg and 32 mm Hg in one eye and between 21 mm Hg and 32 mm Hg in the other eye were randomized to either observation or treatment with commercially available topical ocular hypotensive medication. The goal in the medication group was to reduce the IOP by 20% or more and to reach an IOP of 24 mm Hg or less.
MAIN OUTCOME MEASURES: The primary outcome was the development of reproducible visual field abnormality or reproducible optic disc deterioration attributed to POAG. Abnormalities were determined by masked certified readers at the reading centers, and attribution to POAG was decided by the masked Endpoint Committee.
RESULTS: During the course of the study, the mean +/- SD reduction in IOP in the medication group was 22.5% +/- 9.9%. The IOP declined by 4.0% +/- 11.6% in the observation group. At 60 months, the cumulative probability of developing POAG was 4.4% in the medication group and 9.5% in the observation group (hazard ratio, 0.40; 95% confidence interval, 0.27-0.59; P<.0001). There was little evidence of increased systemic or ocular risk associated with ocular hypotensive medication.
CONCLUSIONS: Topical ocular hypotensive medication was effective in delaying or preventing the onset of POAG in individuals with elevated IOP. Although this does not imply that all patients with borderline or elevated IOP should receive medication, clinicians should consider initiating treatment for individuals with ocular hypertension who are at moderate or high risk for developing POAG. ||||| PURPOSE: To determine whether treatment with betaxolol can delay or prevent the conversion from ocular hypertension to early glaucoma on the basis of visual field criteria, by means of a prospective, randomised, placebo-controlled trial.
METHODS: Three hundred and fifty-six ocular hypertensives were randomized to treatment with either betaxolol drops or placebo drops during the period 1992-1996. Each patient was followed prospectively with 4-monthly visits. Examination at each visit included visual field testing, intra-ocular pressure (IOP) measurement and optic disc imaging. Conversion to early glaucoma was defined on the basis of visual field change by AGIS criteria. An intent-to-treat analysis compared visual field conversion after 3 years in the treatment and placebo arms. Normal visual field survival analysis was also performed. The IOP characteristics of the two treatment groups were compared.
RESULTS: Two hundred and fifty-five patients completed the study, which ended in 1998, with a range of follow-up of 2-6 years. Sixteen (13.2%) of 121 patients in the placebo group converted to glaucoma, compared with 12 (9.0%) of 134 patients in the betaxolol group. The intent-to-treat analysis demonstrated no evidence of any difference in conversion rates between the betaxolol and placebo groups after 3 years. Visual field survival analysis demonstrated no significant difference between the betaxolol and placebo groups. The betaxolol-treated group had significantly lower post-treatment IOP values. Converters had significantly higher pre- and post-treatment IOP values than non-converters.
CONCLUSIONS: Betaxolol significantly lowered the IOP level compared with placebo. Conversion to glaucoma was found to be related to both the baseline and post-treatment IOP levels. However the intent-to-treat analysis did not demonstrate a statistically significant reduction in the conversion rate in the betaxolol-treated group. ||||| BACKGROUND: Increased intraocular pressure (IOP) has been shown to be one of the most important risk factors for developing glaucoma. Yet it has not been clearly demonstrated that IOP-lowering treatment can reduce the incidence of glaucoma damage in patients with ocular hypertension. The aim of the current paper was to report the results of a long-term study addressing this very problem.
METHODS: We conducted a randomised, double-masked study comparing timolol and placebo treatment in 90 patients with ocular hypertension plus some additional risk factor. Patients were followed at 3-month intervals prospectively for 10 years or until glaucomatous field loss could be demonstrated with computerised perimetry. A post-study analysis was performed including all available data, thus extending maximum follow-up to 17 years.
RESULTS: After 5 years of follow-up eight patients in the placebo group and five patients in the timolol group had developed glaucomatous field loss (NS); the corresponding figures after 10 years were 15 patients in the placebo group and seven patients in the timolol group. Survival analysis showed a tendency but no statistically significant difference between treatment groups (P = 0.07). Study attrition was large. Eighteen patients in each group had developed glaucomatous field loss when also post-study data were included. IOP reduction was greater in eyes passing the 10-year visit without field loss (5.7 mmHg), than in those that reached an end-point (2.3 mmHg; P = 0.0002).
CONCLUSION: In this long-term study we found a tendency but failed to prove a beneficial effect of topical timolol treatment in patients with elevated IOP, normal visual fields and some additional risk factor. The intent-to-treat analysis showed no difference between treatment groups. The high attrition shows the difficulties associated with very long follow-up. | [
{
"source_pmid": "2685707",
"source_text": "One hundred seven patients with intraocular pressures (IOPs) between 22 and 28 mmHg with normal visual fields on Goldmann perimetry and without evidence of optic nerve damage were randomly assigned to either a timolol treatment (TT) or a no treatment (NT) arm in a... |
21576320 | This meta-analysis supports the association between C3 and AMD and provides a robust estimate of the genetic risk. | Genome-wide association studies (GWASs) assess correlation between traits and DNA sequence variation using large numbers of genetic variants such as single nucleotide polymorphisms (SNPs) distributed across the genome. A GWAS produces many trait-SNP associations with low p-values, but few are replicated in subsequent studies. We sought to determine if characteristics of the genomic loci associated with a trait could be used to identify initial associations with a higher chance of replication in a second cohort. Data from the age-related eye disease study (AREDS) of 100,000 SNPs on 395 subjects with and 198 without age-related macular degeneration (AMD) were employed. Loci highly associated with AMD were characterized based on the distribution of genotypes, level of significance, and clustering of adjacent SNPs also associated with AMD suggesting linkage disequilibrium or multiple effects. Forty nine loci were highly associated with AMD, including 3 loci (CFH, C2/BF, LOC387715/HTRA1) already known to contain important genetic risks for AMD. One additional locus (C3) reported during the course of this study was identified and replicated in an additional study group. Tag-SNPs and haplotypes for each locus were evaluated for association with AMD in additional cohorts to account for population differences between discovery and replication subjects, but no additional clearly significant associations were identified. Relying on a significant genotype tests using a log-additive model would have excluded 57% of the non-replicated and none of the replicated loci, while use of other SNP features and clustering might have missed true associations. ||||| Dysregulation of the alternative pathway (AP) of complement cascade has been implicated in the pathogenesis of age-related macular degeneration (AMD), the leading cause of blindness in the elderly. To further test the hypothesis that defective control of complement activation underlies AMD, parameters of complement activation in blood plasma were determined together with disease-associated genetic markers in AMD patients. Plasma concentrations of activation products C3d, Ba, C3a, C5a, SC5b-9, substrate proteins C3, C4, factor B and regulators factor H and factor D were quantified in patients (n = 112) and controls (n = 67). Subjects were analyzed for single nucleotide polymorphisms in factor H (CFH), factor B-C2 (BF-C2) and complement C3 (C3) genes which were previously found to be associated with AMD. All activation products, especially markers of chronic complement activation Ba and C3d (p<0.001), were significantly elevated in AMD patients compared to controls. Similar alterations were observed in factor D, but not in C3, C4 or factor H. Logistic regression analysis revealed better discriminative accuracy of a model that is based only on complement activation markers Ba, C3d and factor D compared to a model based on genetic markers of the complement system within our study population. In both the controls' and AMD patients' group, the protein markers of complement activation were correlated with CFH haplotypes.This study is the first to show systemic complement activation in AMD patients. This suggests that AMD is a systemic disease with local disease manifestation at the ageing macula. Furthermore, the data provide evidence for an association of systemic activation of the alternative complement pathway with genetic variants of CFH that were previously linked to AMD susceptibility. ||||| BACKGROUND: Age-related macular degeneration (AMD) is a prevalent cause of blindness in Western societies. Variants in the genes encoding complement factor H (CFH), complement component 3 (C3) and age-related maculopathy susceptibility 2 (ARMS2) have repeatedly been shown to confer significant risks for AMD; however, their role in disease progression and thus their potential relevance for interventional therapeutic approaches remains unknown.
METHODOLOGY/PRINCIPAL FINDINGS: Here, we analyzed association between variants in CFH, C3 and ARMS2 and disease progression of geographic atrophy (GA) due to AMD. A quantitative phenotype of disease progression was computed based on longitudinal observations by fundus autofluorescence imaging. In a subset of 99 cases with pure bilateral GA, variants in CFH (Y402H), C3 (R102G), and ARMS2 (A69S) are associated with disease (P = 1.6x10(-9), 3.2x10(-3), and P = 2.6x10(-12), respectively) when compared to 612 unrelated healthy control individuals. In cases, median progression rate of GA over a mean follow-up period of 3.0 years was 1.61 mm(2)/year with high concordance between fellow eyes. No association between the progression rate and any of the genetic risk variants at the three loci was observed (P>0.13).
CONCLUSIONS/SIGNIFICANCE: This study confirms that variants at CFH, C3, and ARMS2 confer significant risks for GA due to AMD. In contrast, our data indicate no association of these variants with disease progression which may have important implications for future treatment strategies. Other, as yet unknown susceptibilities may influence disease progression. ||||| PURPOSE: Nonsynonymous coding single nucleotide polymorphisms (nsSNPs) in complement component 3 (C3) alter the risk of age-related macular degeneration (AMD). This was a study of the effect of haplotypes across C3 on AMD risk.
METHODS: Nine SNPs tagging haplotypes across C3 were genotyped on 738 subjects at the Mayo Clinic. Haplotype analyses were performed with and without conditioning on individual SNPs. Replication studies were performed using 1541 subjects from the age-related eye disease study (AREDS).
RESULTS: Two nsSNPs located 5125 bp apart in the 5' end of C3 showed the highest association (rs1047286 or P314L, P = 9.2E-05; rs2230199 or R102G, P = 4.1E-05) with AMD. The minor alleles of both SNPs tagged a single risk haplotype. The effects of the two nsSNPs could not be distinguished due to high linkage disequilibrium. The risk SNPs preferentially promoted the development of advanced AMD relative to early AMD in both the Mayo and AREDS subjects. Haplotypes in the 3' end of the C3 locus were associated with AMD in both the Mayo and AREDS subjects. The effect persisted after conditioning on the nsSNPs only in the Mayo subjects. No interaction was found between rs2230199 and smoking or other AMD loci.
CONCLUSIONS: nsSNPs in C3 increased the risk of developing AMD 1.8-fold for 1 risk allele or 2.4-fold for two risk alleles and were preferentially associated with advanced AMD. Further study is needed to determine whether haplotypes in the 3' end of C3 have an independent association with AMD. ||||| PURPOSE: To investigate whether the previously reported noncoding variant of the complement factor H (CFH) gene and two coding variants of the complement component 3 (C3) gene are associated with exudative age-related macular degeneration (AMD) in Chinese patients.
METHODS: One hundred fifty Chinese patients with exudative AMD and 161 control individuals without AMD were recruited for the study. Genomic DNA was extracted from blood leukocytes. The noncoding variant of the CFH gene (rs1410996) and two coding variants of the C3 gene (rs2230199 and rs1047286) were genotyped by polymerase chain reaction (PCR) followed by allele-specific restriction enzyme digestion and direct sequencing.
RESULTS: Significant association was detected for exudative AMD with the CFH noncoding variant rs1410996. Frequencies of the risk C allele at rs1410996 were 72.0% in AMD cases versus 55.6% in controls (P < 0.001). The odds ratio for risk of AMD was 1.71 (95% confidence interval [CI], 0.82-3.54) for heterozygous TC genotype and 3.85 (95% CI, 1.84-8.05) for homozygous CC genotype compared with the wild TT genotype. In contrast, the C3 variants rs2230199 and rs1047286 were not associated with exudative AMD in the studied subjects. Frequencies of the risk G allele at rs2230199 and of the risk T allele at rs1047286 were 0.3% to 1.0% in both cases and controls.
CONCLUSIONS: The data suggest that the noncoding variant rs1410996 of the CFH gene moderately increased the risk of exudative AMD in a Chinese population. The C3 variants were rare and not associated with exudative AMD in this Chinese cohort. ||||| BACKGROUND: Age related macular degeneration (AMD) is a leading cause of blindness. AMD is a complex disorder caused by genetic and environmental factors in which single nucleotide polymorphisms (SNPs) in the genes CFH and LOC387715/HTRA1/ARMS2 have prognostic importance for progression to advanced AMD (with visual loss). CFH may also have a pharmacogenetic role by affecting treatment response to widely used nutritional supplements. This paper examines other AMD susceptibility genes to determine if these genotypes influenced disease progression and treatment response.
METHODS: Three cohorts, totalling 3137 individuals, were genotyped for SNPs in 13 genes previously published to be associated with advanced AMD (other than CFH and LOC387715/ARMS2/HTRA1). Those genes found associated were then evaluated for their involvement in disease progression. Interactions between the genes and with AREDS (Age-Related Eye Disease Study) nutritional supplements were investigated.
RESULTS: Positive independent associations were noted in SNPs in the genes C2 (p = 0.0001, odds ratio (OR) 0.35, 95% confidence interval (CI) 0.2 to 0.6), CFB (p = 0.0001, OR 0.35, 95% CI 0.2 to 0.6), C3 (p = 0.0001, OR 3.91, 95% CI 1.94 to 7.88), APOE (epsilon4, p = 0.01, OR 0.50, 95% CI 0.29 to 0.86) and VEGFA (p = 0.01, OR 2.23, 95% CI 1.06 to 4.68). C2/CFB and C3 were independently related to progression from early/intermediate to advanced AMD with OR 0.32 (95% CI 0.14 to 0.73) and 3.32 (95% CI 1.46 to 7.59), respectively. Gene-gene and pharmacogenetic interactions were not observed. No preferential associations were observed with geographic atrophy or choroidal neovascularisation.
CONCLUSION: This study provides insights into the genetic pathogenesis of AMD. Five genes have now been shown to be independently involved in progression from intermediate disease (before vision loss has occurred) to advanced disease in which blindness is frequent. ||||| PURPOSE: Genes in the complement pathway, including complement factor H (CFH), C2/BF, and C3, have been reported to be associated with age-related macular degeneration (AMD). Genetic variants, single-nucleotide polymorphisms (SNPs), in these genes were geno-typed for a case-control association study in a mainland Han Chinese population.
METHODS: One hundred and fifty-eight patients with wet AMD, 80 patients with soft drusen, and 220 matched control subjects were recruited among Han Chinese in mainland China. Seven SNPs in CFH and two SNPs in C2, CFB', and C3 were genotyped using the ABI SNaPshot method. A deletion of 84,682 base pairs covering the CFHR1 and CFHR3 genes was detected by direct polymerase chain reaction and gel electrophoresis.
RESULTS: Four SNPs, including rs3753394 (P = 0.0276), rs800292 (P = 0.0266), rs1061170 (P = 0.00514), and rs1329428 (P = 0.0089), in CFH showed a significant association with wet AMD in the cohort of this study. A haplotype containing these four SNPs (CATA) significantly increased protection of wet AMD with a P value of 0.0005 and an odds ratio of 0.29 (95% confidence interval: 0.15-0.60). Unlike in other populations, rs2274700 and rs1410996 did not show a significant association with AMD in the Chinese population of this study. None of the SNPs in CFH showed a significant association with drusen, and none of the SNPs in CFH, C2, CFB, and C3 showed a significant association with either wet AMD or drusen in the cohort of this study. The CFHR1 and CFHR3 deletion was not polymorphic in the Chinese population and was not associated with wet AMD or drusen.
CONCLUSION: This study showed that SNPs rs3753394 (P = 0.0276), rs800292 (P = 0.0266), rs1061170 (P = 0.00514), and rs1329428 (P = 0.0089), but not rs7535263, rs1410996, or rs2274700, in CFH were significantly associated with wet AMD in a mainland Han Chinese population. This study showed that CFH was more likely to be AMD susceptibility gene at Chr.1q31 based on the finding that the CFHR1 and CFHR3 deletion was not polymorphic in the cohort of this study, and none of the SNPs that were significantly associated with AMD in a white population in C2, CFB, and C3 genes showed a significant association with AMD. ||||| Age-related macular degeneration (AMD) is a late onset vision disorder. Recent studies demonstrate that alterations in complement cascade genes are associated with AMD. Of the three identified complement loci, variants in complement factor H (CFH) have the highest impact as does an independent locus at 10q26. Our matched case-control study using the Age-Related Eye Disease Study (AREDS) cohort confirms and extends the associations in these loci. Subjects were genotyped for single nucleotide polymorphisms (SNPs) from CFH, complement component 2 (C2), complement component 3 (C3), complement factor B (CFB), age-related maculopathy susceptibility (ARMS2), HtrA serine peptidase 1 (HTRA1), and apolipoprotein E (APOE). Individual SNPs, and haplotypes showed risk trends consistent with those seen in other population studies for CFH, C3, C2, and CFB. SNP rs10490924 on chromosome 10 in exon 1 of the ARMS2 gene showed a highly significant association with an odds ratio (OR) of 3.2 (95% CI 2.4-4.2) for the risk allele and rs11200638 located in the proximal promoter region of HTRA1 showed a higher significant association with an OR of 3.4 (95% CI 2.5-4.6) with our AMD cases. We found that APOE haplotypes were not significantly associated with disease status. Adjustments for other risk factors did not significantly alter the observed associations. This study validates the complement pathway's involvement in AMD and suggests that allelic variants in complement genes have a direct role in disease. These results also support previous findings that variants in the region of 10q26 exert an independent risk for AMD. ||||| OBJECTIVE: To explore the association between polymorphisms in the complement component 3 (C3) gene and age-related macular degeneration (AMD), and to investigate the modifying effect of complement factor H (CFH) Y402H, LOC387715 A69S and smoking.
DESIGN: Pooled data from the prospective, population-based Rotterdam Study (enrolment between 1990 and 1993, and 3 follow-up examinations between September 1, 1993, and December 31, 2004) and an independent case-control study from the Netherlands.
PARTICIPANTS: The Rotterdam Study comprised a total of 6418 persons aged >or=55 years who had gradable fundus photographs. The case-control study consisted of 357 unrelated AMD patients and 173 control individuals aged >or=55 years.
METHODS: The variants R102G and P314L of the C3 gene, CFH Y402H and LOC387715 A69S, were genotyped in all study participants. Information on cigarette smoking was obtained by interview at baseline.
MAIN OUTCOME MEASURES: Early and late stages of prevalent and incident AMD, graded according to the international classification and grading system for AMD.
RESULTS: We found a population frequency of 0.217 for R102G and 0.211 for P314L in the Rotterdam Study. Both alleles significantly increased the risk of early AMD and all subtypes of late AMD, and this risk seemed to be independent of CFH Y402H, LOC387715 A69S, and smoking. Detailed analysis showed that the haplotype carrying both alleles had the highest frequency difference between cases and controls (P=0.006). We estimated a total population-attributable risk of 14.6%. A meta-analysis of all currently available data yielded a pooled odds ratio (OR) of 1.61 (95% confidence interval [CI], 1.46-1.78) for the R102G allele, and an OR of 1.50 (95% CI, 1.31-1.71) for the P314L allele.
CONCLUSIONS: Our study showed a significant association between variants in the C3 gene and AMD and further highlights the crucial role of the complement pathway in the etiology of AMD. ||||| BACKGROUND: Age-related macular degeneration is the most common cause of blindness in Western populations. Susceptibility is influenced by age and by genetic and environmental factors. Complement activation is implicated in the pathogenesis.
METHODS: We tested for an association between age-related macular degeneration and 13 single-nucleotide polymorphisms (SNPs) spanning the complement genes C3 and C5 in case subjects and control subjects from the southeastern region of England. All subjects were examined by an ophthalmologist and had independent grading of fundus photographs to confirm their disease status. To test for replication of the most significant findings, we genotyped a set of Scottish cases and controls.
RESULTS: The common functional polymorphism rs2230199 (Arg80Gly) in the C3 gene, corresponding to the electrophoretic variants C3S (slow) and C3F (fast), was strongly associated with age-related macular degeneration in both the English group (603 cases and 350 controls, P=5.9x10(-5)) and the Scottish group (244 cases and 351 controls, P=5.0x10(-5)). The odds ratio for age-related macular degeneration in C3 S/F heterozygotes as compared with S/S homozygotes was 1.7 (95% confidence interval [CI], 1.3 to 2.1); for F/F homozygotes, the odds ratio was 2.6 (95% CI, 1.6 to 4.1). The estimated population attributable risk for C3F was 22%.
CONCLUSIONS: Complement C3 is important in the pathogenesis of age-related macular degeneration. This finding further underscores the influence of the complement pathway in the pathogenesis of this disease. ||||| BACKGROUND: Variants in the complement cascade genes and the LOC387715/HTRA1, have been widely reported to associate with age-related macular degeneration (AMD), the most common cause of visual impairment in industrialized countries.
METHODS/PRINCIPAL FINDINGS: We investigated the association between the LOC387715 A69S and complement component C3 R102G risk alleles in the Finnish case-control material and found a significant association with both variants (OR 2.98, p = 3.75 x 10(-9); non-AMD controls and OR 2.79, p = 2.78 x 10(-19), blood donor controls and OR 1.83, p = 0.008; non-AMD controls and OR 1.39, p = 0.039; blood donor controls), respectively. Previously, we have shown a strong association between complement factor H (CFH) Y402H and AMD in the Finnish population. A carrier of at least one risk allele in each of the three susceptibility loci (LOC387715, C3, CFH) had an 18-fold risk of AMD when compared to a non-carrier homozygote in all three loci. A tentative gene-gene interaction between the two major AMD-associated loci, LOC387715 and CFH, was found in this study using a multiplicative (logistic regression) model, a synergy index (departure-from-additivity model) and the mutual information method (MI), suggesting that a common causative pathway may exist for these genes. Smoking (ever vs. never) exerted an extra risk for AMD, but somewhat surprisingly, only in connection with other factors such as sex and the C3 genotype. Population attributable risks (PAR) for the CFH, LOC387715 and C3 variants were 58.2%, 51.4% and 5.8%, respectively, the summary PAR for the three variants being 65.4%.
CONCLUSIONS/SIGNIFICANCE: Evidence for gene-gene interaction between two major AMD associated loci CFH and LOC387715 was obtained using three methods, logistic regression, a synergy index and the mutual information (MI) index. ||||| Inflammation has long been suspected to play a role in the pathogenesis of age-related macular degeneration (AMD). Association of variants in the complement factor H (CFH) and complement factor B (CFB) genes has targeted the search for additional loci to the alternative complement cascade, of which C3 is a major component. Two non-synonymous coding polymorphisms within C3, R102G and L314P, have previously been strongly associated with increased risk. These variants are in strong linkage disequilibrium (LD), making the contribution of this locus to AMD even more difficult to ascertain. We sought to determine whether the C3 association resulted primarily from only one of these two variants or from a combined effect of both in 223 families and an independent dataset of 701 cases and 286 unrelated controls. The C3 polymorphisms were in strong LD (r(2) = 0.85), and both were associated in the family-based and case-control datasets (R102G genoPDT P = 0.02, case-control genotypic P = 0.004; L314P genoPDT P = 0.001, case-control genotypic P = 0.04). In conditional analyses in the case-control dataset, R102G remained associated with disease in the L314P risk allele carriers (P = 0.01), but there was no effect of L314P in the R102G risk allele carriers (P = 0.2). After adjusting for age, smoking, CFH Y402H, LOC387715 A69S, and CFB R32Q, the effect of R102G remained strong [P = 0.015, odds ratio = 1.55, 95% confidence interval 1.09 to 2.21, adjusted PAR(population attributable risk) = 0.17]. Therefore, while the strong LD between R102G and L314P makes it difficult to disentangle their individual effects on disease risk, the R102G polymorphism acting alone provides the best model for disease in our data. ||||| PURPOSE: A non-synonymous single nucleotide polymorphism (SNP) in complement component 3 has been shown to increase the risk of age-related macular degeneration (AMD). We assess its effect on AMD risk in a Northern Irish sample, test for gene-gene and gene-environment interaction, and review a risk prediction model.
METHODS: SNP rs2230199 was genotyped in 1,358 samples, which comprised 437 cases, 436 no-disease controls, and 485 participants randomly sampled from the Northern Ireland population. Allele frequencies were assessed in cases and controls. Logistic regression analysis was used to assess interaction and develop a risk prediction model.
RESULTS: We report a minor allele frequency of 0.248 for rs2230199 in the population (n=485), 0.296 in cases (n=437), and 0.221 in controls (n=436; odds ratio [OR]=1.48; confidence interval [CI]: 1.19-1.85; p=0.0003). The significant association is retained following multivariate analysis with adjustment for age, smoking status, Complement Factor H (CFH), Age-Related Maculopathy Susceptibility 2 (ARMS2), Complement Component 2 (CC2), and Complement Factor B (CFB; OR=1.45; CI: 1.10-1.91; p=0.009). No evidence to support an interaction between any of the covariates within the regression model was found. The area under the receiver operator characteristic curve calculated for the fully adjusted model, including all variables, was 0.86 for late AMD.
CONCLUSIONS: Our study confirmed the association between Complement Component 3 (C3) and late-stage AMD. There was no evidence for an interaction with environmental exposures, nor did we find data to support a gene-gene effect. ||||| Age-related macular degeneration (AMD) is a progressive disease and major cause of severe visual loss. Toward the discovery of tools for early identification of AMD susceptibility, we evaluated the combined predictive capability of proteomic and genomic AMD biomarkers. We quantified plasma carboxyethylpyrrole (CEP) oxidative protein modifications and CEP autoantibodies by ELISA in 916 AMD and 488 control donors. CEP adducts are uniquely generated from oxidation of docosahexaenoate-containing lipids that are abundant in the retina. Mean CEP adduct and autoantibody levels were found to be elevated in AMD plasma by approximately 60 and approximately 30%, respectively. The odds ratio for both CEP markers elevated was 3-fold greater or more in AMD than in control patients. Genotyping was performed for AMD risk polymorphisms associated with age-related maculopathy susceptibility 2 (ARMS2), high temperature requirement factor A1 (HTRA1), complement factor H, and complement C3, and the risk of AMD was predicted based on genotype alone or in combination with the CEP markers. The AMD risk predicted for those exhibiting elevated CEP markers and risk genotypes was 2-3-fold greater than the risk based on genotype alone. AMD donors carrying the ARMS2 and HTRA1 risk alleles were the most likely to exhibit elevated CEP markers. The results compellingly demonstrate higher mean CEP marker levels in AMD plasma over a broad age range. Receiver operating characteristic curves suggest that CEP markers alone can discriminate between AMD and control plasma donors with approximately 76% accuracy and in combination with genomic markers provide up to approximately 80% discrimination accuracy. Plasma CEP marker levels were altered slightly by several demographic and health factors that warrant further study. We conclude that CEP plasma biomarkers, particularly in combination with genomic markers, offer a potential early warning system for assessing susceptibility to this blinding, multifactorial disease. ||||| PURPOSE: The purpose of this study was to determine whether the genetic polymorphisms of complement factor 3 (C3) are associated with neovascular age-related macular degeneration (AMD) in the Chinese population.
METHODS: A total of 123 unrelated Chinese Han patients with neovascular AMD and 130 control subjects were recruited. Their six single-nucleotide polymorphisms (SNPs) in the C3 gene, one in the complement factor H (CFH) gene and two in the complement factor B (CFB) gene were characterized. Their genotypes, allele frequencies, and odds ratios were analyzed.
RESULTS: The G allele of the C3 IVS2 rs2250656, but not other tested C3 SNPs of rs2230205, rs10411506, rs2230199, rs339392, and rs163913, was significantly associated with a reduced risk for AMD in the Chinese population (OR 0.605, 95% CI 0.39-0.93, p = 0.023), even after adjusting for age, gender, smoking status, CFH rs1061170, CFB rs4151667, and CFB rs641153 allele status (OR 0.58, 95% CI 0.35-0.96, p = 0.033). However, the C3 haplotype of A-A-C-A-T-T was identified as a statistically significant risk factor for neovascular AMD (OR 1.41, 95% CI 1.02-1.94). Furthermore, the C allele of the CFH rs1061170, but not the CFB rs4151667 and rs641153, was significnatly associated with increased risk for AMD (OR 3.09, 95% CI 1.55-6.15, p < 0.001).
CONCLUSION: The G allele of C3 IVS2 rs2250656 may be a significantly protective factor for neovascular AMD in the Chinese population. This, together with low MAF of C3 R102G, may be partially responsible for the low prevalence of AMD in the Chinese population. ||||| PURPOSE: Several genes encoding complement system components and fragments are associated with age-related macular degeneration (AMD). This study was conducted to determine whether alterations in circulating levels of these markers of complement activation and regulation are also independently associated with advanced AMD and whether they are related to AMD genotypes.
METHODS: Plasma and DNA samples were selected from individuals in our AMD registry who had progressed to or developed the advanced stages of AMD, including 58 with geographic atrophy and 62 with neovascular disease. Subjects of similar age and sex, but without AMD, and who did not progress were included as controls (n = 60). Plasma complement components (C3, CFB, CFI, CFH, and factor D) and activation fragments (Bb, C3a, C5a, iC3b, and SC5b-9) were analyzed. DNA samples were genotyped for seven single-nucleotide polymorphisms in six genes previously shown to be associated with AMD: CFB, CFH, C2, C3, and CFI and the LOC387715/ARMS2 gene region. The association between AMD and each complement biomarker was assessed by using logistic regression, controlling for age, sex, and proinflammatory risk factors: smoking and body mass index (BMI). Functional genomic analyses were performed to assess the relationship between the complement markers and genotypes. Concordance, or C, statistics were calculated to assess the effect of complement components and activation fragments in an AMD gene-environment prediction model.
RESULTS: The highest quartiles of Bb and C5a were significantly associated with advanced AMD, when compared with the lowest quartiles. In multivariate models without genetic variants, the odds ratio (OR) for Bb was 3.3 (95% confidence interval [CI] = 1.3-8.6), and the OR for C5a was 3.6 (95% CI = 1.2-10.3). With adjustment for genetic variants, these ORs were substantially higher. The alternative pathway regulator CFH was inversely associated with AMD in the model without genotypes (OR = 0.3; P = 0.01). Positive associations were found between BMI and plasma C3, CFB, CFH, iC3b, and C3a. There were also significant associations between C5a fragment and LOC387715/ARMS2 and C3 genotypes (P for trend = 0.02, 0.04), respectively. C statistics for models with behavioral and genetic factors increased to 0.94 +/- 0.20 with the addition of C3a, Bb, and C5a.
CONCLUSIONS: Increased levels of activation fragments Bb and C5a are independently associated with AMD. Higher BMI is related to increased levels of complement components. C5a is associated with AMD genotypes. C statistics are stronger with the addition of C3a, Bb, and C5a in predictive models. Results implicate ongoing activation of the alternative complement pathway in AMD pathogenesis. | [
{
"source_pmid": "19043567",
"source_text": "Genome-wide association studies (GWASs) assess correlation between traits and DNA sequence variation using large numbers of genetic variants such as single nucleotide polymorphisms (SNPs) distributed across the genome. A GWAS produces many trait-SNP associations ... |
28887138 | IOP reduction was highly correlated across follow-up periods. For angle-closure glaucoma, results showed an IOP decrease of -6.4 mmHg (95% CI: -9.4 to -3.4) at final follow-up (12 months and longer). For the open-angle glaucoma group, there was an overall IOP change of -2.7 mmHg (95% CI -3.7 to -1.7) from baseline. For pseudoexfoliation glaucoma further research is needed to reach an adequate evidence-based conclusion. The influence of inherent sources of bias, including loss to follow-up, washout and medication use, and lack of a control group, was evaluated numerically. These sources of bias pulled the IOP estimate in opposite directions and are therefore unlikely to affect the main conclusions substantially. Future prospective clinical trials, including other outcomes such as quality of life, clinical severity information, and cost-effectiveness analysis, are needed to determine the role of phacoemulsification alone within the glaucoma treatment algorithm. | PURPOSE: To compare phacoemulsification alone and phacoemulsification with micro-bypass stent implantation in eyes with primary open-angle glaucoma.
SETTING: Instituto di Fisiopatologia Clinica, Clinica Oculistica, Universita' di Torino, Torino, Italy.
METHODS: In this prospective double-masked randomized clinical trial, patients had phacoemulsification alone (control group) or phacoemulsification with iStent implantation (combined group). Primary outcomes were intraocular pressure (IOP) and reduction in medication use over 15 months and IOP after a 1-month washout of ocular hypotensive agents (ie, 16 months postoperatively).
RESULTS: The baseline IOP was similar between groups (combined group: 17.9 mm Hg +/- 2.6 [SD]; control group: 17.3 +/- 3.0 mm Hg) (P = .512). Three patients in the control group were lost to follow-up. The mean IOP was 14.8 +/- 1.2 mm Hg in the combined group and 15.7 +/- 1.1 mm Hg in the control group at 15 months and 16.6 +/- 3.1 mm Hg and 19.2 +/- 3.5 mm Hg, respectively, after washout; the IOP was statistically significantly lower in the combined group than in the control group at both time points (P = .031 and P = .042, respectively). At 15 months, the mean number of medications was lower in the combined group than in the control group (0.4 +/- 0.7 and 1.3 +/- 1.0, respectively; P = .007), as was the proportion of patients on ocular hypotensive medication (33% and 76%, respectively).
CONCLUSIONS: Phacoemulsification with stent implantation was more effective in controlling IOP than phacoemulsification alone; the safety profiles were similar. ||||| PURPOSE: To compare the midterm efficacy and safety of phacoviscocanalostomy (viscocanalostomy, phacoemulsification, and intraocular lens [IOL] implantation) and cataract surgery (phacoemulsification and IOL implantation) in patients with normal-tension glaucoma (NTG) and cataract.
SETTING: Sensho-kai Eye Institute, Kyoto, Japan.
METHODS: Thirty-one eyes had phacoviscocanalostomy, and 35 eyes had uncomplicated cataract surgery only. The intraocular pressure (IOP), postoperative antiglaucoma medications, and visual outcomes were compared between groups.
RESULTS: The mean follow-up was 34.9 months+/-19.8 (SD) (range 7 to 78 months). At 36 months, the mean preoperative IOP and postoperative IOP were 17.2+/-1.5 mm Hg and 14.1+/-1.6 mm Hg, respectively, in the phacoviscocanalostomy group and 16.7+/-1.4 mm Hg and 15.6+/-3.4 mm Hg, respectively, in the cataract surgery only group. The differences between groups were significant at all time points (P<.05). The success probabilities of the phacoviscocanalostomy group achieving 20% and 30% IOP reductions with (or without) medications were 78.5% (67.4%) and 35.5% (37.4%) at 24 months and 58.0% (44.2%) and 28.0% (26.6%) at 48 months, which were significantly better than the probabilities in the cataract surgery only group, which were 16.0% (9.5%) and 5.7% (2.9%) at 24 months (P<.001 for each comparison, Kaplan-Meier life-table analysis with log-rank test). Based on the modified Aulhorn-Greve classification, the visual acuity and visual fields did not deteriorate in the phacoviscocanalostomy group; the visual fields deteriorated in 6 eyes in the cataract surgery only group during the follow-up (P=.024).
CONCLUSION: Phacoviscocanalostomy lowered IOP and maintained postoperative visual outcomes; it was safe and effective in elderly patients with coexisting NTG and cataract. ||||| BACKGROUND AND OBJECTIVE: To evaluate changes in intraocular pressure (IOP) following uneventful phacoemulsification cataract extraction with posterior chamber intraocular lens implantation (Phaco/PC IOL) in primary open-angle glaucoma (POAG) patients.
PATIENTS AND METHODS: The authors retrospectively reviewed preoperative and postoperative IOP in 31 consecutive medically-controlled POAG patients who underwent uneventful Phaco/PC IOL. None of the patients had prior intraocular surgery.
RESULTS: The mean preoperative IOP in the POAG group was 18.1+/-3.1 mm Hg with patients receiving a mean of 1.7 antiglaucoma medications. With a mean follow-up of 16.4 months, the average postoperative IOP in the POAG group was 15.2+/-2.9 mm Hg (P < .001, Student's t test) with patients receiving a mean of 0.7 antiglaucoma medication (P < .001).
CONCLUSION: Phaco/PC IOL may be associated with a significant decrease in IOP in POAG patients, allowing for decreased postoperative antiglaucoma medication. ||||| OBJECTIVE: To compare phacoemulsification alone versus combined phacotrabeculectomy in medically controlled chronic angle closure glaucoma (CACG) with coexisting cataract.
DESIGN: Randomized clinical trial.
PARTICIPANTS: Seventy-two medically controlled CACG eyes with coexisting cataract.
INTERVENTION: Recruited patients were randomized into group 1 (phacoemulsification alone) or group 2 (combined phacotrabeculectomy with adjunctive mitomycin C). Postoperatively, patients were reviewed every 3 months for 2 years.
MAIN OUTCOME MEASURES: Intraocular pressure (IOP) and requirement for topical glaucoma drugs.
RESULTS: Thirty-five CACG eyes were randomized into group 1, and 37 CACG eyes were randomized into group 2. There were no statistically significant differences (P>0.05) in mean IOP between the 2 treatment groups preoperatively and postoperatively, except at 1 month (P = 0.001) and 3 months (P = 0.008). Combined phacotrabeculectomy with adjunctive mitomycin C resulted in 0.80 less topical glaucoma drugs (P<0.001) in the 24-month postoperative period compared with phacoemulsification alone. The differences in IOP control were, however, not associated with differences in glaucomatous progression. Combined surgery was associated with more postoperative (P<0.001) complications compared with phacoemulsification alone.
CONCLUSIONS: Combined phacotrabeculectomy with adjunctive mitomycin C may be marginally more effective than phacoemulsification alone in controlling IOP in medically controlled CACG eyes with coexisting cataract. Combined surgery may be associated with more complications and additional surgery in the postoperative period. Further study is needed to determine whether the marginally better IOP control of combined surgery justifies the potential additional risks of complications and further surgery.
FINANCIAL DISCLOSURE(S): The authors have no proprietary or commercial interest in any materials discussed in this article. ||||| PURPOSE: We evaluated 2-year safety and efficacy of supraciliary microstenting (CyPass Micro-Stent; Transcend Medical, Inc., Menlo Park, CA) for treating mild-to-moderate primary open-angle glaucoma (POAG) in patients undergoing cataract surgery.
DESIGN: Multicenter (24 US sites), interventional randomized clinical trial (RCT) (ClinicalTrials.gov identifier, NCT01085357).
PARTICIPANTS: Subjects were enrolled beginning July 2011, with study completion in March 2015. Subjects had POAG with mean diurnal unmedicated intraocular pressure (IOP) 21-33 mmHg and were undergoing phacoemulsification cataract surgery.
METHODS: After completing cataract surgery, subjects were intraoperatively randomized to phacoemulsification only (control) or supraciliary microstenting with phacoemulsification (microstent) groups (1:3 ratio). Microstent implantation via an ab interno approach to the supraciliary space allowed concomitant cataract and glaucoma surgery.
MAIN OUTCOME MEASURES: Outcome measures included percentage of subjects achieving ≥20% unmedicated diurnal IOP lowering versus baseline, mean IOP change and glaucoma medication use, and ocular adverse event (AE) incidence through 24 months.
RESULTS: Of 505 subjects, 131 were randomized to the control group and 374 were randomized to the microstent group. Baseline mean IOPs in the control and microstent groups were similar: 24.5±3.0 and 24.4±2.8 mmHg, respectively (P > 0.05); mean medications were 1.3±1.0 and 1.4±0.9, respectively (P > 0.05). There was early and sustained IOP reduction, with 60% of controls versus 77% of microstent subjects achieving ≥20% unmedicated IOP lowering versus baseline at 24 months (P = 0.001; per-protocol analysis). Mean IOP reduction was ↓7.4 mmHg for the microstent group versus ↓5.4 mmHg in controls (P < 0.001), with 85% of microstent subjects not requiring IOP medications at 24 months. Mean 24-month medication use was 67% lower in microstent subjects (P < 0.001); 59% of control versus 85% of microstent subjects were medication free. Mean medication use in controls decreased from 1.3±1.0 drugs at baseline to 0.7±0.9 and 0.6±0.8 drugs at 12 and 24 months, respectively, and in the microstent group from 1.4±0.9 to 0.2±0.6 drugs at both 12 and 24 months (P < 0.001 for reductions in both groups at both follow-ups vs. baseline). No vision-threatening microstent-related AEs occurred. Visual acuity was high in both groups through 24 months; >98% of all subjects achieved 20/40 best-corrected visual acuity or better.
CONCLUSIONS: This RCT demonstrated safe and sustained 2-year reduction in IOP and glaucoma medication use after microinterventional surgical treatment for mild-to-moderate POAG. ||||| PURPOSE: To compare the 2-year efficacy of phacoemulsification and intraocular lens implant (phaco/IOL) with laser peripheral iridotomy (LPI) in the early management of acute primary angle closure (APAC) and coexisting cataract.
DESIGN: Randomized, controlled trial.
PARTICIPANTS: We included 37 subjects presenting with APAC who had responded to medical treatment such that intraocular pressure (IOP) was ≤30 mmHg within 24 hours, and had cataract with visual acuity of ≤6/15.
MAIN OUTCOME MEASURES: The primary outcome measure was failure of IOP control defined as IOP between 22 to 24 mmHg on 2 occasions (readings taken within 1 month of each other) or IOP ≥25 mmHg on 1 occasion, either occurring after week 3. Secondary outcome measures were complications, degree of angle opening, amount of peripheral anterior synechiae, visual acuity, and corneal endothelial cell count (CECC).
METHODS: Subjects were randomized to receive either LPI or phaco/IOL in the affected eye within 1 week of presentation and were examined at fixed intervals over 24 months. Patients underwent a standardized examination that included Goldmann applanation tonometry, gonioscopy, and CECC measurements. Logistic regression was used to estimate the effect of treatment on failure of IOP control. Time to failure was evaluated using the Kaplan-Meier technique and Cox regression was used to estimate the relative risk of failure.
RESULTS: There were 18 patients randomized to LPI and 19 to phaco/IOL. The average age of subjects was 66.0±9.0 years and mean IOP after medical treatment was 14.5±6.9 mmHg. The 2-year cumulative survival was 61.1% and 89.5% for the LPI and phaco/IOL groups, respectively (P = 0.034). There was no change in CECC for either group from baseline to month 6. There was 1 postoperative complication in the phaco/IOL group compared with 4 in the LPI group (P = 0.180).
CONCLUSIONS: Performed within 1 week in patients with APAC and coexisting cataract, phaco/IOL resulted in lower rate of IOP failure at 2 years compared with LPI. ||||| PURPOSE: To assess the safety and effectiveness of the Hydrus Microstent (Ivantis, Inc, Irvine, CA) with concurrent cataract surgery (CS) for reducing intraocular pressure (IOP) in open-angle glaucoma (OAG).
DESIGN: Prospective, multicenter, randomized, single-masked, controlled clinical trial.
PARTICIPANTS: One hundred eyes from 100 patients 21 to 80 years of age with OAG and cataract with IOP of 24 mmHg or less with 4 or fewer hypotensive medications and a washed-out diurnal IOP (DIOP) of 21 to 36 mmHg.
METHODS: On the day of surgery, patients were randomized 1:1 to undergo CS with the microstent or CS alone. Postoperative follow-up was at 1 day, 1 week, and 1, 3, 6, 12, 18, and 24 months. Washout of hypotensive medications was repeated at 12 and 24 months.
MAIN OUTCOME MEASURES: Response to treatment was defined as a 20% or more decrease in washed out DIOP at 12 and 24 months of follow-up compared with baseline. Mean DIOP at 12 and 24 months, the proportion of subjects requiring medications at follow-up, and the mean number of medications were analyzed. Safety measures included change in visual acuity, slit-lamp observations, and adverse events.
RESULTS: The proportion of patients with a 20% reduction in washed out DIOP was significantly higher in the Hydrus plus CS group at 24 months compared with the CS group (80% vs. 46%; P = 0.0008). Washed out mean DIOP in the Hydrus plus CS group was significantly lower at 24 months compared with the CS group (16.9±3.3 mmHg vs. 19.2±4.7 mmHg; P = 0.0093), and the proportion of patients using no hypotensive medications was significantly higher at 24 months in the Hydrus plus CS group (73% vs. 38%; P = 0.0008). There were no differences in follow-up visual acuity between groups. The only notable device-related adverse event was focal peripheral anterior synechiae (1-2 mm in length). Otherwise, adverse event frequency was similar in the 2 groups.
CONCLUSIONS: Intraocular pressure was clinically and statistically significantly lower at 2 years in the Hydrus plus CS group compared with the CS alone group, with no differences in safety. ||||| PURPOSE: To evaluate the influence of recently performed cataract phacoemulsification in glaucomatous eyes on postoperative intraocular pressure (IOP).
MATERIAL AND METHODS: 100 eyes of 86 glaucoma patients who underwent cataract phacoemulsification with simultaneous intraocular lens implantation, were retrospectively analyzed. The patients were divided into two groups: I--61 patients (71 eyes) with open angle glaucoma, and II--25 patients (29 eyes) with angle closure glaucoma. Both groups were subdivided into two subgroups, depending on presence of symptoms of pseudoexfoliation (PEX) syndrome (A = with, and B = without symptoms of PEX syndrome). All patients were examined in the department where the surgeries were performed; before surgery, on the first day after the procedure, and again during the last follow-up examinations, 6 to 30 months after the procedure.
RESULTS: Before surgery, the intraocular pressure (IOP) was at mean value of 19.02 +/- 4.55 mmHg in group I, and 20.01 +/- 6.43 mmHg in group II. On the first day after surgery, the IOP was 17.42 +/- 7.17 and 20.36 +/- 8.98 mmHg, respectively. lOP exceeding 20 mmHg was found in 7 eyes in group I, and in 6 eyes in group II. During the last follow-up examinations the lOP was 14.59 +/- 3.73 and 14.01 +/- 4.50 mmHg, respectively, and was lower than measured before surgery, by an average of 4.43 mmHg in group I (P < 1 x 10(-5)), and 6.00 mmHg in group II (P < 1 x 10(-4)). In both groups, the reduction of lOP in patients with PEX was even more remarkable. The number of glaucoma medication necessary to control the pressure was reduced on average by 0.28 in group I, and 0.31 in group II.
CONCLUSIONS: Phacoemulsification done on glaucomatous eyes results in lowering of lOP, and hence the dosage of glaucoma drugs over the long term can be simplified or even discontinued. ||||| BACKGROUND: Primary angle-closure glaucoma is a leading cause of irreversible blindness worldwide. In early-stage disease, intraocular pressure is raised without visual loss. Because the crystalline lens has a major mechanistic role, lens extraction might be a useful initial treatment.
METHODS: From Jan 8, 2009, to Dec 28, 2011, we enrolled patients from 30 hospital eye services in five countries. Randomisation was done by a web-based application. Patients were assigned to undergo clear-lens extraction or receive standard care with laser peripheral iridotomy and topical medical treatment. Eligible patients were aged 50 years or older, did not have cataracts, and had newly diagnosed primary angle closure with intraocular pressure 30 mm Hg or greater or primary angle-closure glaucoma. The co-primary endpoints were patient-reported health status, intraocular pressure, and incremental cost-effectiveness ratio per quality-adjusted life-year gained 36 months after treatment. Analysis was by intention to treat. This study is registered, number ISRCTN44464607.
FINDINGS: Of 419 participants enrolled, 155 had primary angle closure and 263 primary angle-closure glaucoma. 208 were assigned to clear-lens extraction and 211 to standard care, of whom 351 (84%) had complete data on health status and 366 (87%) on intraocular pressure. The mean health status score (0·87 [SD 0·12]), assessed with the European Quality of Life-5 Dimensions questionnaire, was 0·052 higher (95% CI 0·015-0·088, p=0·005) and mean intraocular pressure (16·6 [SD 3·5] mm Hg) 1·18 mm Hg lower (95% CI -1·99 to -0·38, p=0·004) after clear-lens extraction than after standard care. The incremental cost-effectiveness ratio was £14 284 for initial lens extraction versus standard care. Irreversible loss of vision occurred in one participant who underwent clear-lens extraction and three who received standard care. No patients had serious adverse events.
INTERPRETATION: Clear-lens extraction showed greater efficacy and was more cost-effective than laser peripheral iridotomy, and should be considered as an option for first-line treatment.
FUNDING: Medical Research Council. ||||| OBJECTIVE: To assess the safety and efficacy of the iStent trabecular micro-bypass stent (Glaukos Corporation, Laguna Hills, CA) in combination with cataract surgery in subjects with mild to moderate open-angle glaucoma.
DESIGN: Prospective, randomized, open-label, controlled, multicenter clinical trial.
PARTICIPANTS: A total of 240 eyes with mild to moderate open-angle glaucoma with intraocular pressure (IOP) ≤24 mmHg controlled on 1 to 3 medications were randomized to undergo cataract surgery with iStent implantation (treatment group) or cataract surgery only (control). Fifty additional subjects were enrolled to undergo cataract surgery with iStent implantation under protocol expansion. Data in this report are based on the first 240 eyes enrolled.
INTERVENTION: Implantation of the iStent trabecular micro-bypass stent in conjunction with cataract surgery or cataract surgery only.
MAIN OUTCOME MEASURES: The primary efficacy measure was unmedicated IOP ≤21 mmHg at 1 year. A secondary measure was unmedicated IOP reduction ≥20% at 1 year. Safety measures included best-corrected visual acuity (BCVA), slit-lamp observations, complications, and adverse events.
RESULTS: The study met the primary outcome, with 72% of treatment eyes versus 50% of control eyes achieving the criterion (P<0.001). At 1 year, IOP in both treatment groups was statistically significantly lower from baseline values. Sixty-six percent of treatment eyes versus 48% of control eyes achieved ≥20% IOP reduction without medication (P = 0.003). The overall incidence of adverse events was similar between groups with no unanticipated adverse device effects.
CONCLUSIONS: Pressure reduction on fewer medications was clinically and statistically significantly better 1 year after stent plus cataract surgery versus cataract surgery alone, with an overall safety profile similar to that of cataract surgery alone. ||||| BACKGROUND: Acute primary angle closure (PAC) can be refractory to conventional treatment and intraocular pressure (IOP) is beyond control. Surgical intervention should be considered at the moment. The aim of the study was to compare small-incision phacotrabeculectomy (phacotrab, small-incision trabeculectomy combined with phacoemulsification) with phacoemulsification (phaco) in patients with refractory acute PAC and coexisting cataract.
METHODS: Analyzed 49 eyes (49 patients) with acute PAC and cataract received small-incision phacotrab (24 eyes) or phaco (25 eyes) randomly. All these cases were refractory to conventional treatment involved the use of preoperative topical IOP-lowering agents, corticosteroids, mannitol, methazolamide and paracentesis to reduce IOP. The effects on best corrected visual acuity (BCVA), IOP, anterior chamber depth (ACD), glaucoma medications, and complications were observed for twelve months.
RESULTS: After operation BCVA of 18 patients (75 %) in phacotrab group and 20 patients (80 %) in phaco group improved compared to preoperative vision. No statistically significant differences in mean BCVA were found between the two groups. The mean postoperative IOP levels at all follow up time points were lower than the mean preoperative IOP in each group (P < 0.001). There was statistically significant difference in mean IOP between the two groups only at 12 months postoperatively (P = 0.006). The surgical success rate (without medications, IOP ≤ 21 mmHg) was 83.33 % (20 eyes) and 72 % (18 eyes) in phacotrab group and phaco group respectively at 12 months. No statistically significant differences in the mean ACD were found between the two groups. There were no serious intra- or post-operative complications in the two treatment groups.
CONCLUSIONS: Besides phaco, small incision phacotrab may be another effective and safe choice in the treatment of patients with refractory acute PAC and coexisting cataract. Whether phacotrab is more effective in IOP control in the long term needs to be verified in the further. ||||| OBJECTIVES: To establish the relative safety and effectiveness of trabecular aspiration in combination with phacoemulsification and intraocular lens (IOL) implantation (asp+IOL) for decreasing intraocular pressure (IOP), and to compare the outcome of this method of treatment with that of phacoemulsification and IOL implantation alone (IOL-alone) or standard filtering glaucoma triple procedure (triple procedure).
DESIGN: Prospective, controlled study randomized with respect to assignment to trabecular aspiration, with a case-control design between the asp+IOL and triple procedure groups.
PARTICIPANTS: Seventy-four eyes of 74 patients with uncontrolled pseudoexfoliation glaucoma without a history of previous intraocular or extraocular surgery and in need of cataract surgery. Forty-eight patients were randomized to those receiving adjunctive trabecular aspiration (asp+IOL group of 26 eyes) and those given no trabecular aspiration (IOL-alone group of 22 eyes). The triple procedure group consisted of 26 cases, closely matched to the asp+IOL cases in terms of age, sex, cup-disc ratio, glaucoma medication requirements, and systemic diseases.
INTERVENTIONS: Temporal clear corneal phacoemulsification and foldable IOL implantation was performed in all eyes. In the asp+IOL group, trabecular aspiration was performed with a suction force of 100 to 200 mm Hg under light tissue-instrument contact using a modified intraocular aspiration probe. A modified Cairns-type trabeculectomy without adjunctive antimetabolites was performed superiorly in the triple procedure eyes after IOL implantation.
MAIN OUTCOME MEASURES: Surgical outcome was assessed in terms of IOP change, need of adjunctive glaucoma medication, visual acuity outcome, and complications. Surgical failure was defined as an outcome requiring additional surgical intervention or more than 1 medication to achieve IOP control to the target pressure.
RESULTS: Two years after surgery, success rates were 36%, 64%, and 78% in the IOL-alone, asp+IOL, and triple procedure groups, respectively (P<.001). Hyphema (46%) and ocular hypotony (11%) were observed in the triple procedure group only, whereas blood reflux (61%) and descemetolysis (19%) were seen exclusively in the asp+IOL group.
CONCLUSIONS: In pseudoexfoliative eyes, asp+IOL is significantly more effective than cataract surgery alone in reducing postoperative IOP and the necessity for glaucoma medication. Although trabecular aspiration in the triple procedure did not achieve pressure control in all patients, especially in the low target pressure range, the risk profile appears to be more favorable in the trabecular aspiration-treated eyes than in the filtering glaucoma triple procedure group. Trabecular aspiration in the glaucoma triple procedure could serve as a possible first-line treatment for pseudoexfoliative eyes with coexisting cataract and glaucoma. ||||| UNLABELLED: RATIONALE (HYPOTHESIS): Although cataract and glaucoma represent an increasingly common situation encountered concomitantly, the management of this association is still debatable. OBJECTIVE (AIM): We aimed to assess intraocular pressure dynamics after phacoemulsification in patients with uncontrolled primary open angle glaucoma (POAG).
METHODS AND RESULTS: The present study was designed as a prospective, non-randomized, cohort study. The study population comprised of 38 patients with medically uncontrolled POAG who underwent cataract surgery by phacoemulsification between 2011 and 2012. Most of the patients (32/38, 84.2%) needed glaucoma surgery after a variable time (mean time between surgeries was 11.6 +/- 4.18 months). Mean preoperative IOP decreased with 2,1 +/- 3,7 mmHg at 6 months (CI 95% 1.96 to 3.56) and with 1,9 +/- 3,9 mmHg at 12 months compared with the baseline IOP. Postoperative IOP was statistically significant lower compared with its preoperative value at 6 months (p=9.11 x 10⁻⁸) and at one year (p=9.2 x 10⁻⁵). The difference between mean IOP at 6 months and 1 year after cataract surgery was not statistically significant (p>0.05). Preoperatively, all the patients received topical antiglaucoma therapy. After phacoemulsification, their number did not change statistically significant, but it showed a slight increase. Average number of topical glaucoma medications used preoperatively was 2.66 + / -0.66, while at 6 months after surgery it was 2.71 + / - 0,75 and at 12 months postoperatively, 2.9 +/- 0.53.
DISCUSSION: IOP decreased statistically significant after phacoemulsification in patients with uncontrolled POAG, but the decrease was not sufficient for optimal glaucoma management; therefore, many patients needed subsequent glaucoma surgery. ||||| Primary angle closure occurs as a result of crowded anterior segment anatomy, causing appositional contact between the peripheral iris and trabecular meshwork, thereby obstructing aqueous outflow. Several studies highlight the role of the crystalline lens in its pathogenesis. The objective of this work is to compare the long-term efficacy of phacoemulsification versus laser peripheral iridotomy (LPI) in the management of chronic primary angle closure (CPAC). Prospective case-control study with 30 eyes of 30 patients randomly divided in two groups: 15 eyes in the LPI group and 15 eyes in the IOL group. Patients in the LPI group underwent LPI using argon and Nd:YAG laser. Patients in the IOL group underwent phacoemulsification with posterior chamber intraocular lens (IOL) implantation. Examinations before and after the procedure included gonioscopy, Goldmann applanation tonometry, and anterior chamber evaluation using the Pentacam rotating Scheimpflug camera. The mean follow-up time was 31.13 ± 4.97 months. There was a statistically significant reduction in the intraocular pressure (IOP) and number of anti-glaucoma medications (p < 0.01) only in the IOL group. Anterior chamber depth, angle, and volume were all higher in the IOL group (p < 0.01) at the end of the follow-up period. Phacoemulsification with posterior chamber IOL implantation results in a higher anterior chamber depth, angle, and volume, when compared to LPI. Consequently, phacoemulsification has greater efficacy in lowering IOP and preventing its long-term increase in patients with CPAC and cataract. ||||| PURPOSE: To compare the angle and intraocular pressure (IOP) changes after phacoemulsification between eyes with closed-angle or open-angle glaucoma.
METHODS: Angle measurements using Visante AS-OCT imaging was performed for a prospective cohort of 24 subjects with closed-angle and 30 subjects with open-angle glaucoma before and 3 months after phacoemulsification. IOP measurement was measured at 6 and 12 months after surgery using Goldmann applanation tonometry as secondary outcome measures.
RESULTS: Eyes with closed angles were smaller than those with open angles (mean axial length 22.88 vs. 24.11 mm, P<0.001). Mean anterior chamber depth, area, volume, AOD500, AOD750, ARA, TISA500, and TISA750 increased after phacoemulsification in all eyes regardless of preexisting angle status (all P<0.001). Increase in AOD500, AOD750, TISA500, and TISA750 were greater in eyes with open angles compared with closed angles (P=0.03, 0.04. 0.04, 0.04, respectively). Mean IOP decreased by 1.8 and 2.1 mm Hg at 6 and 12 months, respectively, after phacoemulsification for all eyes (P<0.001 for both timepoints compared with preoperative baseline). However, postoperative reduction in the mean IOP was not significantly different between eyes with closed and open angles (Mann-Whitney test P=0.32 at 6 mo and P=0.75 at 12 mo postsurgery compared with preoperative).
CONCLUSIONS: Angle opening postphacoemulsification was considerable in all eyes. A similar IOP reduction after phacoemulsification was observed in all eyes regardless of angle status. ||||| PURPOSE: To evaluate long-term IOP control after sutureless clear corneal phacoemulsification in eyes with preoperatively controlled glaucoma.
SETTING: Institutional study.
METHODS: The charts of 345 patients who had uneventful sutureless clear corneal phacoemulsification with acrylic foldable lens (IOL) implantation were retrospectively reviewed. Included were 58 patients with medically controlled open-angle glaucoma and 287 normal controls. Follow-up was 1 to 2 years. Outcome measures were postoperative IOP and number of glaucoma medications.
RESULTS: Postoperatively, there was an insignificant decrease in IOP in the glaucoma group; the mean decrease was 1.5 mm Hg +/- 4.4 (SD) at 12 months and 1.9 +/- 4.9 mm Hg at 24 months. The mean number of medications decreased significantly at 12 months (0.53 +/- 0.86) and at 24 months (0.38 +/- 0.9) (P=.04). The control group also had a significant decrease in IOP, with a mean decrease of 0.72 +/- 3.7 mm Hg at 12 months (P=.01) and 1.33 +/- 3.2 mm Hg at 24 months (P<.0001). The decrease in IOP was more pronounced in eyes with a higher preoperative IOP in both the glaucoma and control groups.
CONCLUSIONS: These findings suggest that sutureless clear corneal phacoemulsification with foldable acrylic IOL implantation is a relatively simple and efficient surgical option in patients with cataract and well-controlled glaucoma. The approach combines long-term IOP control with fewer medications and leads to rapid visual rehabilitation. ||||| OBJECTIVE: To compare phacoemulsification alone versus combined phacotrabeculectomy in medically uncontrolled chronic angle closure glaucoma (CACG) with coexisting cataract.
DESIGN: Prospective randomized clinical trial.
PARTICIPANTS: Fifty-one medically uncontrolled CACG eyes with coexisting cataract of 51 patients.
INTERVENTION: Recruited patients were randomized into group 1 (phacoemulsification alone) or group 2 (combined phacotrabeculectomy with adjunctive mitomycin C). Postoperatively, patients were reviewed every 3 months for 2 years.
MAIN OUTCOME MEASURES: Intraocular pressure (IOP) and requirement for topical glaucoma drugs.
RESULTS: Twenty-seven CACG eyes were randomized into group 1, and 24 CACG eyes were randomized into group 2. Combined phacotrabeculectomy resulted in lower mean postoperative IOP than phacoemulsification alone at 3 months (14.0 vs. 17.0 mmHg, P = 0.01), 15 months (13.2 vs. 15.4 mmHg, P = 0.02), and 18 months (13.6 vs. 15.9 mmHg, P = 0.01). Combined phacotrabeculectomy resulted in 1.25 fewer topical glaucoma drugs (P<0.001) in the 24-month postoperative period, compared with phacoemulsification alone. Combined surgery was associated with more postoperative complications (P<0.001) and more progression of optic neuropathy (P = 0.03), compared with phacoemulsification alone.
CONCLUSIONS: Combined phacotrabeculectomy with adjunctive mitomycin C is more effective than phacoemulsification alone in controlling IOP in medically uncontrolled CACG eyes with coexisting cataract. Combined phacotrabeculectomy is associated with more postoperative complications. ||||| AIM: To determine the long term intraocular pressure (IOP) response to phacoemulsification in patients with and without exfoliation syndrome (XFS).
METHODS: Prospective, multicentre, cohort study with the following inclusion criteria: age over 50 years, open iridocorneal angle, and cataract. Two groups were enrolled: those with XFS and those without. The main outcome was mean IOP reduction 2 years after phacoemulsification cataract extraction (PCE). Univariate and multivariate analyses were performed.
RESULTS: 183 patients were enrolled, 71 with and 112 without XFS. There were 29 patients with glaucoma in both groups. Mean baseline IOP was higher in XFS compared to control eyes (17.60 (SD 3.23) mm Hg v 16.08 (3.18) mm Hg, p = 0.002). Overall IOP reduction was significantly greater in the XFS group at the 2 year time point (-1.85 mm Hg v -0.62 mm Hg in the controls (p = 0.0037)). Multivariate analysis demonstrated that the IOP lowering effect in the XFS group may be related to irrigation volume at the time of surgery. In the subgroup analyses IOP lowering was significantly greater in the XFS and XFG patients than in controls without glaucoma, and POAG controls, respectively. The percentage of patients with a postoperative IOP spike was similar and relatively high in both XFS and control groups (34% v 25%; p = 0.54).
CONCLUSION: IOP decreases more in patients with XFS following PCE compared to control eyes without XFS. This effect is more pronounced in glaucoma patients and persists for at least 2 years. ||||| PURPOSE: To assess the effect of phacoemulsification with posterior chamber intraocular lens (IOL) implantation performed by a single surgeon on intraocular pressure (IOP) and glaucoma medication requirements in pseudoexfoliation (PFX) eyes with or without glaucoma.
SETTING: Private practice, Boston, Massachusetts, USA.
METHODS: This retrospective analysis comprised 1122 eyes with PFX having uneventful phacoemulsification with IOL implantation. Of the eyes, 882 did not have glaucoma (PFX group) and 240 had glaucoma (PXG group). A comparative outcomes analysis was performed; the analysis focused on IOP and change in glaucoma medication requirements between the 2 groups.
RESULTS: The mean IOP was statistically significantly reduced through 7 years postoperatively compared with preoperatively in the PFX group. The PXG group had reduced mean IOP for 1 year and reduced glaucoma medication requirements at almost all postoperative time intervals. Higher mean preoperative IOP was associated with a greater reduction in mean IOP postoperatively in both groups. Intraocular pressure spikes (> 30 mm Hg) 1 day postoperatively occurred in 4% in the PFX group and 17% in the PXG group. Postoperatively, 2.7% of PFX eyes progressed to a need for glaucoma medication and 3.7% of PXG eyes progressed to a need for laser and/or glaucoma surgery.
CONCLUSIONS: A long-term reduction in mean IOP occurred in PFX eyes with and without glaucoma. The IOP reduction was proportional to the preoperative IOP; higher preoperative IOP was associated with a greater reduction in IOP. Glaucoma progression in both groups was low, suggesting a protective effect of phacoemulsification on IOP in these eyes. ||||| PURPOSE: To examine the effect of cataract surgery on intraocular pressure (IOP) control in eyes with angle-closure glaucoma (ACG) and open-angle glaucoma (OAG).
SETTING: Hayashi Eye Hospital, Fukuoka, Japan.
METHODS: This study included 74 eyes with ACG and 68 eyes with OAG having cataract surgery. The IOP was measured and the number of glaucoma medications recorded preoperatively, 1 month postoperatively, and then every 3 months. The IOP control in the 2 groups was compared using survival analysis, with failure criteria being an IOP greater than 21 mm Hg, addition of medications, or the need for additional glaucoma surgery.
RESULTS: The mean IOP and number of medications decreased significantly after surgery in both groups (P <.0001). However, the mean decrease in IOP and percentage of IOP reduction in the ACG group were greater than in the OAG group, and fewer medications were required in the ACG group. The cumulative survival probability of IOP control at 24 months was 91.9% in the ACG group and 72.1% in the OAG group. The survival curve in the ACG group was significantly better than in the OAG group (P =.0012). The IOP was controlled without medication in 30 eyes (40.5%) in the ACG group and 13 (19.1%) in the OAG group; the difference between groups was significant (P =.0055).
CONCLUSIONS: Cataract surgery substantially reduced IOP and the number of medications required for IOP control in glaucomatous eyes. Specifically, cataract extraction normalized the IOP in most eyes with ACG. ||||| PURPOSE: To evaluate clinical risk factors of disease progression after cataract surgery using phacoemulsification with posterior chamber intraocular lens implantation, in eyes with chronic angle-closure glaucoma (CACG) and coexisting cataract.
DESIGN: Retrospective study.
METHODS: The data of 56 eyes of 45 CACG patients who had undergone uncomplicated phacoemulsification with posterior chamber intraocular lens implantation were retrospectively analyzed. Disease progression was defined as glaucomatous optic nerve change or visual field (VF) deterioration according to the European Glaucoma Society guideline. Correlations between VF progression and various preoperative and postoperative factors were determined by χ and independent t tests. Linear regression analysis [(odds ratio (OR)] was used to determine predictive risk factors for disease progression using univariate and multivariate analyses.
RESULTS: The mean postoperative follow-up period was 45.13 ± 17.54 (24 to 84) months. Fourteen eyes (25%) with cataracts diagnosed with CACG progressed after phacoemulsification, but the remaining 42 eyes (75%) did not. According to univariate analysis, disease progression was significantly associated with older age, more number of preoperative/postoperative antiglaucoma drugs, higher scores of preoperative pattern standard deviation, and lower scores of preoperative and postoperative visual field index (VFI) (P<0.05). Using multivariate analysis, a lower score of preoperative VFI (OR: 0.86, P=0.044) and lower postoperative intraocular pressure (IOP) reduction, which was not sustained below 20% less than the preoperative mean IOP, were significantly correlated with disease progression after cataract surgery (OR: 8.44, P=0.048).
CONCLUSIONS: CACG patients with low preoperative VFI and high postoperative IOP are at risk for disease progression even after uncomplicated cataract surgery. ||||| PURPOSE: To evaluate efficacy and survival rates of intraocular pressure (IOP)-lowering effect obtained with phacoemulsification (phaco) alone or in combination with canaloplasty (PCP) in patients with open-angle glaucoma (OAG).
METHODS: Retrospective chart review of consecutive cases at the Department of Ophthalmology, Indiana University. Visual acuity (VA), IOP, number of medications (Meds), failures, and survival rates of IOP-lowering effect were analyzed. Inclusion criteria were: patients older than 18 years with OAG and cataract. Exclusion criteria were: no light perception vision, prior glaucoma surgery, chronic uveitis, angle-closure glaucoma, and advanced-stage or end-stage OAG. Failure criteria were: IOP>21 mm Hg or <20% reduction, IOP<6 mm Hg, further glaucoma surgeries, and loss of light perception vision.
RESULTS: Thirty-seven patients underwent phaco and 32 patients had PCP. Follow-up was 21.8±10.1 versus 18.8±9.6 months for phaco and PCP, respectively (P=0.21). Age (y) (74.7±9.8 vs. 76.1±8.3, P=0.54), sex (P=81), and laser status (P=0.75) were similar between the groups. Preoperatively, mean±SD logMAR VA (0.5±0.7 vs. 0.5±0.5, P=0.77), IOP (16.2±4.6 vs. 18.2±5.1, P=0.13), and Meds (1.4±1.1 vs. 1.3±0.7, P=0.75) were similar for phaco and PCP, respectively. At 24-month phaco (n=17) and PCP (n=11), respectively, mean±SD were: logMAR VA 0.2±0.2 versus 0.4±0.7, P=0.29; IOP 14.1±4.0 versus 12.9±3.8, P=0.43; and Meds 1.5±1.2 versus 0.3±0.5, P=0.005. Rates of successful IOP lowering without medications for phaco versus PCP at 12 months were 34% versus 75%, respectively (P=0.003).
CONCLUSIONS: A combination of canaloplasty with phaco results in a decreased number of glaucoma medications and increased survival rate of IOP-lowering effect compared with phaco alone. ||||| BACKGROUND: To evaluate the long-term effects of combined endoscopic cyclophotocoagulation and phacoemulsification (phaco) versus phacoemulsification alone on intraocular pressure control and medication reliance in the treatment of mild to moderate glaucoma.
DESIGN: Retrospective chart review in private practice setting by glaucoma fellowship trained surgeons.
PARTICIPANTS: A total of 261 eyes in the combined phaco-endoscopic cyclophotocoagulation group with 52 eyes in the phaco-alone group.
METHODS: Comparison of phaco-endoscopic cyclophotocoagulation with phaco alone over 36 months.
MAIN OUTCOME MEASURES: Full and qualified success cumulative survival, intraocular pressure and medication reliance 6-36 months compared with baseline. Full success was defined as minimum 20% intraocular pressure reduction with a decrease of at least one ocular hypertensive medication. Qualified success was defined as intraocular pressure no higher than baseline with a decrease of at least one ocular hypertensive medication.
RESULTS: At 36 months, mean intraocular pressure in the combined phaco-endoscopic cyclophotocoagulation group was 14.6 mmHg, whereas the phaco-alone group was 15.5 mmHg (P = 0.34). Mean medication reliance in the combined phaco-endoscopic cyclophotocoagulation group was 0.2 medications, whereas the phaco-alone group was 1.2 (P < 0.001). Full success in the phaco-endoscopic cyclophotocoagulation group was 61.4%; the phaco-alone group was 23.3% (P < 0.001). Qualified success survival was 72.6% in the phaco-endoscopic cyclophotocoagulation group and 23.3% in the phaco-alone group (P < 0.001).
CONCLUSIONS: Combined phaco-endoscopic cyclophotocoagulation effectively lowers or maintains intraocular pressure and results in ocular hypertensive medication reduction up to 36 months when compared with phaco alone. Therefore, phaco-endoscopic cyclophotocoagulation may help to increase medication compliance and reduce glaucoma progression in mild to moderate glaucoma. ||||| PURPOSE: This study evaluates the change in intraocular pressure (IOP) and glaucoma medication requirements after clear corneal phacoemulsification in open angle glaucoma patients, glaucoma suspects, and normal patients at 3 years and last follow-up (mean 5 y).
PATIENTS AND METHODS: This study represents a retrospective analysis of patients who had clear corneal phacoemulsification and at least 3 years of follow-up. The patients were classified into 3 groups: glaucoma (G), glaucoma suspects (GS), and no glaucoma (NG). No patient had a history of previous intraocular surgery. Single factor analysis of variance, Fisher exact tests, 2-tailed paired Student t tests and Kaplan-Meier analysis were applied.
RESULTS: Forty-eight patients (55 eyes) in the glaucoma group, 41 patients (44 eyes) in the GS group, and 59 patients (59 eyes) in the NG group met the above criteria. At 3 years follow-up IOP was significantly decreased in all groups; (G) group decreased 1.4+/-3.3 mm Hg (P = 0.0025), GS 1.4+/-4.2 mm Hg (P = 0.004), and NG 1.7+/-3.1 mm Hg (P = 0.0005). At the final follow-up visit (mean near 5 y for all groups) the IOP was significantly decreased in all groups, (G) group 1.8+/-3.5 mm Hg (P = 0.005), GS 1.3+/-3.7 mm Hg (P = 0.025), and NG 1.5+/-2.5 mm Hg (P < 0.0001). The number of preoperative and postoperative glaucoma medications in the (G) group did not show any significant change at 3 and 5 years (P = 0.36, P = 0.87). Kaplan-Meier analysis shows that at 3 years, 85% of the (G) group, 81% of GS, and 90% of the NG had IOPs less than or equal to their preoperative IOP, with the same number of glaucoma medications or less. At 5 years the percentages were 76%, 79%, and 85%, respectively.
CONCLUSIONS: This study demonstrates that cataract removal by clear cornea phacoemulsification in glaucoma patients, glaucoma suspects, and normal patients results in a small but significant decrease in IOP that is sustained at 3 years and a mean of 5 years in all groups. This study does not imply that cataract removal by phacoemulsification is a substitute for a combined procedure but may be an appropriate procedure for certain patients based on medication requirements and extent of optic nerve damage. ||||| PURPOSE: To evaluate the long-term therapeutic efficacy of phacoemulsification with intraocular lens (IOL) implantation in treating phacomorphic glaucoma.
SETTING: Ophthalmology Department, Maryknoll Hospital, Busan, Korea.
METHODS: This study evaluated eyes that had phacoemulsification with IOL implantation to treat phacomorphic glaucoma. Intraocular pressure (IOP), corrected distance visual acuity (CDVA), and anterior chamber depth (ACD) were measured preoperatively and postoperatively. The minimum follow-up was 48 months.
RESULTS: The mean IOP in the 26 eyes was 49.0 mm Hg +/- 10.4 (SD) (range 31 to 70 mm Hg) preoperatively and 13.2 +/- 2.8 mm Hg (range 8 to 20 mm Hg) 48 months postoperatively (P<.0001, paired t test). No eye had increased IOP over the follow-up. The postoperative IOP was significantly lower 1 day postoperatively (P<.000, paired t test). The improvement in CDVA was statistically significant from 1 week postoperatively (P<.0001, paired t test). The CDVA improved postoperatively except in 1 eye with a preoperative acuity of no light perception. The CDVA was 20/50 or better in 16 eyes (61.5%). Preoperatively, the ACD was shallow (mean 1.5 +/- 0.3 mm) because of the swollen lens; the mean postoperative ACD was 2.6 +/- 0.1 mm; the increase was statistically significant. The mean preoperative ratio of lens thickness to axial length was 0.25 +/- 0.01, indicating a shallow ACD. In 1 eye, peripheral anterior synechias were seen on gonioscopy immediately after surgery; the eye required continuous postoperative medication for IOP control.
CONCLUSION: Phacoemulsification with IOL implantation was effective in treating phacomorphic glaucoma. | [
{
"source_pmid": "20202537",
"source_text": "PURPOSE: To compare phacoemulsification alone and phacoemulsification with micro-bypass stent implantation in eyes with primary open-angle glaucoma.\nSETTING: Instituto di Fisiopatologia Clinica, Clinica Oculistica, Universita' di Torino, Torino, Italy.\nMETHODS:... |
19354339 | Cost-of-illness studies determine the total financial burden of a disease by considering direct and indirect costs, including medication, diagnostics and surgery. Studies of resource use and costs associated with primary open-angle glaucoma have used varying methodologies. Most have focused on consumption of healthcare resources at various stages of disease to anticipate costs. The direct costs associated with the disease often continue to increase as glaucoma progresses from the earliest to most advanced stages. Determinations of the costs associated with glaucoma progression and prevention should also incorporate the chance of patient non-compliance with treatment. Since glaucoma severity most often correlates with increased costs, minimizing or halting visual field loss and increasing patient treatment compliance may all contribute to a reduction in the overall economic burden of glaucoma. | PURPOSE: Glaucoma is a prevalent ophthalmologic disease and leading cause of blindness. A retrospective analysis was conducted to evaluate resources and costs for end-stage glaucoma patients receiving visual rehabilitation care (VRC).
MATERIALS AND METHODS: A chart review was conducted in 3 United States VRC centers. Charts of patients with primary open-angle glaucoma as the primary cause of vision loss (1998 to 2003) were selected, yielding 81 records. Data were collected from patient-level billing and reimbursement records (ophthalmologist/optometrist visits, glaucoma medications, procedures, and specialized low-vision and glaucoma-related services). Visual rehabilitation services included utilization of low-vision devices, assessment of daily functioning, orientation and mobility training, and patient counseling.
RESULTS: Mean age at baseline was 72.7 years [standard deviation (SD)=17.2, range: 29 to 95]. Of those with known sex (n=77), 55.8% were women. Medicare was the payer type for most patients (59.3%), whereas 20% had Medicaid. Mean number of visits was 7.1 (SD=6.1) in year 1 and 3.7 (SD=4.2) in year 2, for an annual mean of 5.4 (SD=5.0) visits overall. Total mean cost per patient in year 1 was greater than year 2 [$2170 (SD=$2252) vs. $1202 (SD=$1080), respectively]; of the total 2-year costs, 15% were VRC, 37% ophthalmology care, and 48% pharmacy. Analysis of nonpharmacy costs revealed that VRC accounted for 28% and ophthalmology for 72%.
CONCLUSIONS: End-stage glaucoma is associated with appreciable resource utilization and costs, because of both vision rehabilitation and ophthalmology care. Advanced primary open-angle glaucoma has a substantial cost-of-illness, warranting improved management in early stages of disease. ||||| PURPOSE: A longitudinal, retrospective study investigated the cost of primary open angle glaucoma (POAG).
METHODS: Patient files from two tertiary care glaucoma practices were reviewed. Patients diagnosed with POAG and >/=2.5 years of follow-up data were included. Data collected included visual field mean deviation, physician's assessment, and resource utilization (physician visits, procedures, and medications). Costs, reported in 2001 Canadian dollars, were compared between groups, based on initial visual field mean deviation, including mild (<5 dB), moderate (5 to <12 dB), and severe (>/=12 dB), and based on physician's assessment, including controlled, uncontrolled, or patients initially uncontrolled for 12 months who become controlled.
RESULTS: Of 411 patient charts extracted, 265 were included; 35 were excluded for ocular comorbidities and 111 patients with insufficient follow-up. Mean (standard deviation) yearly costs overall (N = 265) and for mild (n = 90), moderate (n = 91), and severe (n = 84) groups were $508 ($278), $408 ($266), $512 ($288), and $609 ($243), respectively. Differences between mean yearly costs were statistically significant for all three groups (P < 0.05). Costs for controlled (n = 110), uncontrolled (n = 76), and uncontrolled then controlled group (n = 79) were $423 ($243), $594 ($314), and $542 ($256), respectively. The controlled group cost was significantly lower than both of the other groups (P < 0.05).
DISCUSSION AND CONCLUSIONS: The cost of treating POAG increases with visual field mean deviation severity and uncontrolled disease. Many patients diagnosed with glaucoma had already progressed to later stages in the disease process. Early disease detection may provide a substantial cost savings to the health care system. ||||| PURPOSE: A retrospective analysis determined the association between intraocular pressure (IOP) control levels (mean and last IOP) and disease stability, and the association between IOP and yearly treatment cost in primary open angle glaucoma (POAG).
METHODS: Data were collected from POAG patients, referred to a tertiary glaucoma clinic. All IOP measurements, visual field mean deviation (VF) scores, physicians' impressions, and resources used (physician visits, procedures, and medications) were recorded and costed using standard resource unit cost lists from the Ministry of Health's perspective. Patients were categorized by the average VF score of their first three visits [mild (< 5 dB), moderate (> or = 5 dB to < 12 dB) and severe (> or = 12 dB)]. Pearson's r quantified the association between IOP control levels and stability, where stability was defined by the physician's subjective impression of the patient's disease. Spearman's rho was determined to quantify association between mean IOP and yearly treatment cost within VF categories.
RESULTS: Four hundred and eleven charts were reviewed of which 265 were acceptable for analysis. A negative relationship was determined between the probability of reaching stability and mean IOP in all three VF severity groups. Pearson's r was -0.68 (p < 0.001), -0.72 (p < 0.001), and -0.52 (p < 0.001) for the mild, moderate, and severe groups, respectively. A similar correlation was determined between the last measured IOP and stability. Pearson's r was -0.49 (p < 0.001), -0.80 (p < 0.001), and -0.65 (p < 0.001) for the mild, moderate and severe groups, respectively. A positive relationship was reported between mean yearly costs and IOP. Spearman's rho between mean yearly costs and mean IOP was 0.11 (p = 0.28), 0.23 (p < 0.05), and 0.26 (p < 0.05) for each respective VF level.
DISCUSSION AND CONCLUSION: Lower IOP control levels are associated with higher probabilities of stability. In addition, lower IOP control levels are associated with lower costs of managing POAG in patients either with moderate VF loss or with severe VF loss. Economic burden increased with increasing disease severity. ||||| PURPOSE: To describe the patterns and the economics of glaucoma treatment.
PATIENT AND METHODS: Ophthalmologists selected at random were asked to include 4 consecutive patients over 18 years of age seen in consultation during a week. Socio-demographics, general and eye comorbidities, glaucoma risk factors, clinical data, and medical item consumption data for the preceding 5 years were collected for each patient. The economic perspective was societal, and predictive medical factors of costs were identified using a stepwise regression.
RESULTS: Eighty-eight ophthalmologists included 337 patients, with a gender ratio of 4 males to 6 females, and a mean age of 62. Thirty-four percent had OHT. Glaucoma patients were older and no difference was found on the known confounding factors. Patients with glaucoma visited practitioners more often than those with OHT, had more exams, more often used expensive drug combination therapies, and had more hospitalizations. Drugs represented 37.1% to 63.1% of the expenses followed by exams (17.7% to 34.3%) and visits (13.8% to 28.0%). Two clinical factors contributed to costs: abnormalities of the optic nerve head the day of the study visit and the number of treatment changes. These were followed by intraocular pressure (IOP) and visual acuity.
CONCLUSION: Two major independent factors explained the bulk of total cost variance: drug treatment changes and the presence of glaucoma instead of OHT. They contributed independently in an additive way to total cost. ||||| To determine the health care resource use and costs of patients with glaucoma or ocular hypertension in the Netherlands during the first 2 years after primary diagnosis, we performed a study based on retrospective chart review. Data of 200 patients and their health care resource use were collected in five hospitals. Unit-prices were calculated using micro costing in two hospitals. The mean 2-year costs per patient were estimated to be US$ 877. Outpatient visits to the ophthalmologist and medications were the cost-driving factors, and were responsible for 40 and 30% of total costs, respectively. Total costs were considered to be low, when compared to the estimated costs per patient in Sweden and the USA. In multiple least-squares regression only baseline IOP-value, the change in IOP-value between baseline and the next visit and the hospital of treatment were significantly related with total costs. The variation in costs between patients largely depended on whether or not a patient had undergone surgery. ||||| AIM: This study analyzes the resource utilization and costs of ocular hypertension and glaucoma (staged by severity) in Italian ophthalmology departments.
METHODS: The project was a multi-centre observational study conducted in 17 Italian ophthalmology departments throughout the country. A total of 659 patients were recruited and followed prospectively for 1 year. For the purpose of analysis, the patients were divided into 3 groups according to the severity at onset: ocular hypertension, glaucoma and advanced glaucoma.
RESULTS: The subgroups differed significantly in the main demographic and clinical variables. As expected, greater severity was associated with older mean age and worse visual acuity, and with higher resource consumption and costs. The annual average cost per patient was EUR 788.7 and rose significantly with disease severity (EUR 572.0 for ocular hypertension, EUR 734.3 for glaucoma and EUR 1,054.9 for advanced glaucoma). Drugs and specialist consultations were by far the largest cost components.
CONCLUSIONS: This study offers some information on the medical costs of glaucoma in Italy potentially useful for decision-making in the health care services. Health care resources and costs increased with disease severity. ||||| OBJECTIVE: To estimate the societal economic burden and the governmental budgetary impact of the following visual disorders among US adults aged 40 years and older: visual impairment, blindness, refractive error, age-related macular degeneration, cataracts, diabetic retinopathy, and primary open-angle glaucoma.
DESIGN: We estimated 3 components of economic burden: direct medical costs, other direct costs, and productivity losses. We used private insurance and Medicare claims data to estimate direct medical costs; epidemiologic evidence from multiple published sources to estimate other direct costs, such as nursing home costs; and data from the Survey of Income and Program Participation to estimate productivity losses. We used budgetary documents and our direct medical and other direct cost estimates to approximate the governmental budgetary impact.
RESULTS: We estimated that the annual total financial burden of major adult visual disorders is $35.4 billion ($16.2 billion in direct medical costs, $11.1 billion in other direct costs, and $8 billion in productivity losses) and that the annual governmental budgetary impact is $13.7 billion.
CONCLUSIONS: Major visual disorders among Americans older than 40 years result in substantial economic costs for the US economy. Well-designed public health programs may have the ability to reduce this burden in the future. ||||| PURPOSE: To estimate resource use and costs associated with the diagnosis and treatment of glaucoma and ocular hypertension in the Netherlands in 1996 and to determine how costs differed between patients, diagnoses, and hospitals.
PATIENTS AND METHODS: Patient characteristics and glaucoma-related resource use were collected for 500 patients with glaucoma or ocular hypertension from the medical records of 10 hospitals. Costs were calculated by multiplying the health care resource use of each patient with actual unit costs. Multiple least-squares regression was used to analyze the relationship between costs and patient characteristics, diagnosis, and type of hospital (general or academic).
RESULTS: The mean annual frequency of visits to the ophthalmologist for patients with ocular hypertension and glaucoma was 2.43 and 3.74, respectively, and the mean cost per patient was $280 and $559, respectively. The mean cost of patients with glaucoma who had no changes in medication therapy was $347 and increased to $1,765 in patients with more than three adjustments in medication therapy. Outpatient visits to the ophthalmologist and medication contributed most to total costs. Regression analysis showed that costs were significantly related to intraocular pressure, diagnosis, severe excavation of the optic nerve head, and type of hospital.
CONCLUSIONS: The costs of patients with glaucoma were twice as high as the costs of patients with ocular hypertension. Aside from diagnosis, differences in costs between patients could partly be explained by baseline patient characteristics. Patients in academic hospitals had more severe glaucoma and treatment was considerably more expensive than for patients in nonacademic hospitals. ||||| OBJECTIVE: To examine resource consumption and the direct costs of treating glaucoma at different disease severity levels.
DESIGN: Observational, retrospective cohort study based on medical record review.
PARTICIPANTS: One hundred fifty-one records of patients with primary open-angle or normal-tension glaucoma, glaucoma suspect, or ocular hypertension (age > or =18 years) were randomly selected from 12 sites in the United States and stratified according to severity based on International Classification of Diseases, Ninth Revision, Clinical Modification codes. Patients had to have been followed up for a minimum of 5 years. Patients with concomitant ocular disease likely to affect glaucoma treatment-related resource consumption were excluded.
METHODS: Glaucoma severity was assessed and assigned using a 6-stage glaucoma staging system, modified from the Bascom Palmer (Hodapp-Anderson-Parrish) system. Clinical and resource use data were collected from the medical record review. Resource consumption for low-vision care and vision rehabilitation was estimated for patients with end-stage disease based on specialist surveys. For each stage of disease, publicly available economic data were then applied to assign resource valuation and estimate patient-level direct costs from the payer perspective.
MAIN OUTCOME MEASURES: Average annual resource use and estimated total annual direct cost of treatment were calculated at the patient level and stratified by stage of disease. Direct costs by specific resource types, including ophthalmology visits, glaucoma surgeries, medications, visual field examinations, and other glaucoma services, were also assessed.
RESULTS: Direct ophthalmology-related resource use, including ophthalmology visits, glaucoma surgeries, and medication use, increased as disease severity worsened. Average direct cost of treatment ranged from $623 per patient per year for glaucoma suspects or patients with early-stage disease to $2511 per patient per year for patients with end-stage disease. Medication costs composed the largest proportion of total direct cost for all stages of disease (range, 24%-61%).
CONCLUSIONS: The study results suggest that resource use and direct cost of glaucoma management increase with worsening disease severity. Based on these findings, a glaucoma treatment that delays the progression of disease could have the potential to significantly reduce the health economic burden of this chronic disease over many years. ||||| PURPOSE: Primary open-angle glaucoma is a significant health-economic burden in both the United States and Europe that is likely to increase. This study compared treatment patterns and cost among patients with primary open-angle glaucoma in these locations.
METHODS: Retrospective medical chart reviews were conducted in the United States (1990 to 2002) and Europe (1995 to 2003). A total sample of 151 US charts and 194 European charts was studied, and patients were assigned a baseline intraocular pressure (IOP) and baseline stage, using a 6-stage visual functional glaucoma staging algorithm. Resource utilization and direct costs were assessed by stage of disease using publicly available United States and European costs. Cox Proportional Hazards modeling were used to examine covariates predicting glaucoma surgery. Total cost was predicted, adjusting for covariates using Generalized Linear Models, with baseline stage as the independent variable.
RESULTS: Glaucoma surgery requirement was highly associated with baseline disease stage and IOP increase before surgery in the United States and somewhat associated with these factors in Europe. Within both locations, baseline IOP was highly associated with glaucoma surgery requirement. Controlling for covariates, patients at higher baseline stages incurred greater costs in the United States (P=0.0017) and Europe (P=0.0715). Surgery and medication were also highly predictive of increased cost (P<0.0001). Cost of care differed greatly between the European countries, with costs lowest in Italy.
CONCLUSIONS: Increases in annual cost were related to higher baseline IOP, higher baseline stage, medication, and surgery. Thus, significant potential savings and reductions in annual healthcare burden are possible if patients are diagnosed and treated at earlier stages of glaucoma. ||||| PURPOSE: This study describes the treatment in ordinary clinical practice in Spain of patients with glaucoma with a two-drug combination therapy. The authors present the treatment outcome as endof-period intraocular pressure (IOP) and the calculated direct medical costs over a 2-year period.
METHODS: Data were extracted retrospectively from patient charts recording the use of all medical resources related to glaucoma. Costs were estimated using unit costs from public sources (2005). Descriptive cost analysis according to combination treatment at baseline was performed.
RESULTS: The study included 216 patients from 21 centers. Around half of the patients were started on a beta-blocker/prostaglandin analogue combination, while the rest received various other combinations containing either an alpha2-agonist or a carbonic anhydrase inhibitor. Across the seven groups considered, there was a statistically significant difference in the costs of the least and the two most costly groups, while the confidence intervals were overlapping in all other pairwise comparisons. The least costly drug combination was brimonidine/timolol. Assessing IOP at the end of follow-up, all the groups were equally effective (overlapping confidence intervals). In a multivariate regression analysis, the drug combination did not have an independent, significant impact on total direct medical costs, drug costs, or end-of-period IOP. Significant determinants of these variables were surgical interventions and one or more changes of drug combination during the follow-up.
CONCLUSIONS: Costs are determined by the response to treatment. Inadequate response triggers treatment changes and sometimes eventually surgical interventions, thereby increasing costs significantly. ||||| Glaucoma is a common ophthalmic condition, often associated with elevated intraocular pressure (IOP). It affects >2 million people in the US, and the incidence is expected to exceed 3 million by 2020. However, relatively little is known about the cost of glaucoma compared with costs for other eye conditions. This comprehensive report reviews published literature on costs and cost effectiveness of treatments for glaucoma. Cost-of-illness studies in glaucoma focus on direct medical costs and generally exclude indirect costs. In general, increased costs are associated with increased severity or lack of control over IOP and the distribution of costs (e.g. medication vs procedures) varies with severity. A large number of studies have evaluated the cost of glaucoma medications, assessing the number of drops per bottle and associated cost per drop or per treatment dose. These studies have limited usefulness as they generally evaluate unit medication costs without including differential effectiveness or adverse effects associated with various therapies, and thus provide only one component of real-world costs for glaucoma. Broader comparative cost studies, mainly adopting a cost-minimisation approach, have evaluated the impact of differing treatments and management strategies on all types of medical care resource utilisation and associated costs, but a variety of metrics for success makes interpretation challenging. Studies have generally found beta2-adrenoceptor antagonists to be associated with greater healthcare costs than newer therapies. Among newer treatments such as prostaglandin analogues, no specific treatment has demonstrated a clear cost advantage over other treatments. A number of studies have modelled hypothetical cohorts of glaucoma patients through courses of therapy, projecting costs, outcomes and cost effectiveness. A majority of these cost-effectiveness models compare one of the newer prostaglandin analogues with older medications or with one another. Existing studies suggest that bimatoprost may be more cost effective than other agents. However, the effectiveness outcomes used in these studies vary, including achieving IOP thresholds, IOP-controlled days, percent reduction in IOP and QALYs. Methods used to determine costs also vary substantially between studies. Future evaluations of the burden of glaucoma need to consider the issues of comparability between, and generalisability of, study results. Differences in methods have created barriers to understanding the cost of glaucoma and comparing costs or cost effectiveness between studies. Furthermore, future studies should also consider direct costs of glaucoma generally not covered by health insurance as well as indirect costs of glaucoma. As new screening technologies for early detection of individuals at elevated risk of glaucoma are now in use, more complete estimates of the cost of glaucoma are critical for issues of resource allocation and health policy. ||||| This paper reviews the burden and economic consequences of glaucoma upon healthcare systems and patients, especially elderly patients. An extensive review of the literature was conducted, primarily using MEDLINE, but also by examining selected article reference lists, relevant websites and the proceedings of specialised conferences. All relevant articles and documents were analysed. Glaucoma is characterised by destruction of the optic nerve. It is most often a continuous, chronic eye disease and the most frequent diagnosis is primary open angle glaucoma (POAG). POAG is mostly associated with intraocular hypertension which can be delayed by medication, surgery or laser therapy. The prevalence rate of glaucoma is about 1% in the population >50 years of age. The rate increases with age and is higher in Black and Hispanic populations. Glaucoma affects more than 67 million people worldwide. Cost-of-illness studies have shown the importance of this disease, on which more than pound300 million was spent in the UK in 2002. Most of the costs (45%) were associated with direct medical costs, but direct nonmedical costs (20%) and indirect costs (35%) were also not negligible. Recent economic studies have shown a dramatic increase in the number of patients with glaucoma receiving treatment but a reduction in use of surgical procedures to treat the condition, especially as first-line therapy. The greater part of medical expenditure is now on medication, with new, more potent, better tolerated, but more costly drugs replacing older and less expensive medications. Treatment costs are directly related to the severity of disease and the number of different treatments used; they are also negatively correlated with treatment efficacy in reducing intraocular pressure. However, long-term economic benefits that may be associated with use of more potent new drugs (by delaying institutionalisation) have never been documented. Glaucoma screening has also been found not to be cost effective, although these results should be reconsidered in the light of new data. ||||| PURPOSE: The objective of this study was to investigate what treatment strategies prevail in different countries for patients newly diagnosed with primary open-angle glaucoma (POAG) or ocular hypertension (OH) only and initiated on treatment with beta-blockers, and to estimate the total direct cost of treatment for two years. In addition, differences in costs between and within the countries and the determinants of variations in costs across patients were examined.
MATERIALS AND METHODS: The authors performed a retrospective medical record analysis in several academic and office-based study centers in Sweden and the United States. Standard costs for each resource item were determined and applied to all centers within the country. Differences in treatment costs within the countries are thus the effect of differences in treatment strategies, not of differences in prices.
RESULTS: There was considerable variation between the centers of each country. Sweden had a higher number of surgical interventions, which may be explained by the fact that the Swedish cohort had a higher mean intraocular pressure (IOP) at baseline and a higher proportion of patients with definite POAG and exfoliation glaucoma. However, in both countries the mean IOP at study end was approximately 18 mm Hg. Total direct costs for two years were 15,119 SEK (US$2,160; $1US = 7 SEK) and $2,109, respectively. In a multiple regression analysis, the estimated effects of baseline IOP and of IOP change after treatment initiation on treatment costs were positively and negatively significant, respectively, in both countries.
CONCLUSION: Despite differences in baseline diagnosis and in treatment strategies, mean IOP was decreased to 18 mm Hg in both countries. Baseline IOP was positively correlated with treatment costs, while the initial IOP-lowering effect of treatment was negatively correlated with two-year costs. ||||| PURPOSE: To assess resource utilization and costs associated with glaucoma management in France and Sweden.
METHODS: A total of 267 patient records (121 in France, 146 in Sweden) with diagnoses of primary open-angle glaucoma (POAG) and ocular hypertension (OH), treated medically, were reviewed for a 2-year period (beginning during 1997-99) for relevant clinical and resource utilization data. Economic data were applied to estimate treatment costs.
RESULTS: The annual cost of treating glaucoma was estimated at SEK5305 (531 euro )/patient in Sweden and 390 euro/patient in France. In both countries, medication costs comprised about half of the total costs. Surgical procedures and hospitalizations represented greater proportions of total cost in France (7.0% and 9.6%, respectively) than in Sweden (3.7% and 0.6%, respectively).
CONCLUSION: Medication costs represent a high proportion of total treatment costs. These findings highlight the relative importance of medical therapy and of assessing the cost-effectiveness of medications in glaucoma. ||||| OBJECTIVE: To examine trends in the utilization and cost of eye care in the Medicare population.
METHODS: Data were obtained from fee-for-service physician claims (Part B) from a 5% sample of Medicare beneficiaries 65 years and older. Use of eye care services and procedures, frequency of ocular diagnoses, and allowed charges were compared for each year from 1991 through 1998.
RESULTS: The proportion of beneficiaries receiving eye care increased from 41.4% to 48.1% during the 8-year period. Part B charges attributable to eye care decreased from 12.5% to 10.4%, with annual inflation-adjusted charges per beneficiary decreasing from 235 dollars to 176 dollars (1998 dollars). The proportion of beneficiaries with cataract-related claims increased from 23.4% to 27.3%, accounting for approximately 60% of eye care charges each year; beneficiaries with retinal disease claims increased from 7.8% to 11.4%, capturing 15.4% of eye care charges in 1998, up from 10.7% in 1991; and beneficiaries with glaucoma claims increased from 6.8% to 9.5%, accounting for nearly 10% of eye care charges each year.
CONCLUSIONS: The proportion of the Medicare population receiving eye care increased between 1991 and 1998. Nevertheless, eye care costs did not increase, primarily because of constraints in charges associated with the management of cataract. ||||| PURPOSE: Primary open-angle glaucoma (POAG) poses a large burden on eye care resources in the United States. We evaluated the total health care and POAG-specific charges (both pharmacy and nonpharmacy) incurred by patients with POAG using a longitudinal U.S. commercial insurance claims database to determine the relative magnitude of glaucoma care charges to overall health care charges for those patients with glaucoma.
DESIGN: Retrospective cohort design.
PARTICIPANTS: Sixty-four thousand three hundred eighty patients with POAG were identified.
METHODS: Patients with POAG were selected (International Classification of Diseases, 9th Revision code 365.11 on at least 2 encounters) from a managed care claims database. Total health care and POAG-specific charges were calculated. Component charges (pharmacy and nonpharmacy) also were evaluated and the charge per treated person was calculated.
MAIN OUTCOME MEASURE: Health care charges.
RESULTS: The mean total health care charges per person in the first year after initial entry into the database with POAG were $13,404 (standard deviation [SD], $33,987), with a median charge of $5403. The mean POAG-specific charge per person was $1570 (SD, $3428), with a median charge of $840. Pharmacy charges were 25% of the POAG-specific charges. The POAG-specific charges in subsequent years after the initial year decreased by 7% per year, whereas the total health care mean charge increased by 39% per year. Patients aged 65 years and older had significantly higher mean charges for both total health care charges ($16,759 vs. $11,651; P<0.0001) and POAG-specific charges ($1624 vs. $1542; P = 0.0049), for an age-related increase of 44% for total charges and 5% for POAG-specific charges. Overall, POAG-specific mean charges represented 12% of total mean charges in the first year and 8% of total overall mean charges in subsequent years.
CONCLUSIONS: There is a substantial cost burden associated with POAG in a population with commercial insurance, and most of these charges are not pharmacy related. ||||| BACKGROUND: Resource utilisation and direct costs associated with glaucoma progression in Europe are unknown. As population progressively ages, the economic impact of the disease will increase.
METHODS: From a total of 1655 consecutive cases, the records of 194 patients were selected and stratified by disease severity. Record selection was based on diagnoses of primary open angle glaucoma, glaucoma suspect, ocular hypertension, or normal tension glaucoma; 5 years minimum follow up were required. Glaucoma severity was assessed using a six stage glaucoma staging system based on static threshold visual field parameters. Resource utilisation data were abstracted from the charts and unit costs were applied to estimate direct costs to the payer. Resource utilisation and estimated direct cost of treatment, per person year, were calculated.
RESULTS: A statistically significant increasing linear trend (p = 0.018) in direct cost as disease severity worsened was demonstrated. The direct cost of treatment increased by an estimated 86 for each incremental step ranging from 455 euro per person year for stage 0 to 969 euro per person year for stage 4 disease. Medication costs ranged from 42% to 56% of total direct cost for all stages of disease.
CONCLUSIONS: These results demonstrate for the first time in Europe that resource utilisation and direct medical costs of glaucoma management increase with worsening disease severity. Based on these findings, managing glaucoma and effectively delaying disease progression would be expected to significantly reduce the economic burden of this disease. These data are relevant to general practitioners and healthcare administrators who have a direct influence on the distribution of resources. | [
{
"source_pmid": "16988605",
"source_text": "PURPOSE: Glaucoma is a prevalent ophthalmologic disease and leading cause of blindness. A retrospective analysis was conducted to evaluate resources and costs for end-stage glaucoma patients receiving visual rehabilitation care (VRC).\nMATERIALS AND METHODS: A ch... |
26493180 | AUTHORS' CONCLUSIONS: The trials included in this review confirm the clinical observation that laser photocoagulation of drusen leads to their disappearance. However, treatment does not result in a reduction in the risk of developing CNV, and was not shown to limit the occurrence of geographic atrophy or visual acuity loss.Ongoing studies are being conducted to assess whether the use of extremely short laser pulses (i.e. nanosecond laser treatment) cannot only lead to drusen regression but also prevent neovascular AMD. | PURPOSE: The Drusen Laser Study (DLS) of high-risk age-related maculopathy (ARM) is a randomised, controlled clinical trial designed to answer two questions: (1). Do drusen resolve after macular laser photocoagulation (2). Does macular laser photocoagulation prevent choroidal neovascularisation (CNV) in high-risk eyes? In this report, we present the results of the interim, pooled analysis of CNV prophylaxis for patients in the Unilateral Group of the DLS.
METHODS: The DLS is a randomised controlled clinical trial of prophylactic macular photocoagulation for high-risk ARM. Patients in the Unilateral Group had a neovascular complication in the first eye; their fellow eye (Study Eye) had visual acuity of 6/12 or better and drusen. Following informed consent, patients were randomised to the Treatment Group or the No Treatment Group. Patients randomised to treatment received 12 light spots of argon laser photocoagulation to their Study Eye: four burns were placed 750 microm from the centre of the fovea at 12, 3, 6, and 9 o'clock, and the eight remaining burns were placed 1500 microm from the centre of the fovea at 12, 1:30, 3, 4:30, 6, 7:30, 9, and 10:30 o'clock. Drusen were treated directly only if they were present at the protocol treatment locations. All patients were followed in an identical fashion at regular intervals. Best-corrected visual acuity was measured and recorded by a masked observer. Fluorescein angiography was performed at baseline and yearly review, as well as nonprotocol visits if symptoms suggested CNV. Five clinical centres utilised and conformed to a common DLS protocol. Patient care and data collection methodologies were deemed sufficiently similar to permit a pooled data analysis.
RESULTS: There were 156 patients included in the interim analysis, and timed information was available on 153. CNV occurred in 21 of 81 (26%) patients in the Treatment Group and in 13 of 75 (17%) patients in the No Treatment Group (P=0.19). Kaplan-Meier survival analysis showed earlier onset of CNV in the Treatment Group compared to patients in the No Treatment Group (statistical significance not calculated). Visual acuity loss at 2 years occurred in nine of 54 (17%) patients in the Treatment Group compared to the two of 48 (4%) patients in the No Treatment Group (P=0.056).
CONCLUSIONS: We are only the second group to identify possible laser-induced CNV despite other similar studies in progress. Equipoise of the DLS investigators was lost, and recruitment was halted. We feel ethically bound to notify the ophthalmic community of this finding. ||||| PURPOSE: The Drusen Laser Study evaluated macular laser to prevent choroidal neovascularization (CNV) and vision loss in high-risk age-related maculopathy (ARM).
DESIGN: Prospective, interventional, randomized, controlled clinical trial in five hospital centers.
METHODS: Patients in the unilateral group had neovascular ARM and drusen in the study eye. Study eyes were randomized to laser-treated or no-laser groups. For patients in the bilateral drusen group, eyes were randomized to right eye, laser or no laser; and left eye, alternative. Laser treatment comprised 12 argon spots. Outcome was best-corrected visual acuity and CNV signs, which were monitored for 3 years.
RESULTS: In the unilateral group, vision loss occurred in 21 (28.8%) of 73 patients in laser vs 13 (19.7%) of 66 no-laser patients (P=.214). Incidence of CNV was 27 (29.7%) of 91 in laser vs 15 (17.65%) of 85 no-laser patients (P=.061). CNV onset was approximately 6 months earlier in laser-treated compared with no-laser patients (P=.05). In the bilateral group, vision loss occurred in six (8.3%) of 72 laser-treated vs 10 (13.9%) of 72 fellow eyes (P=.3877). CNV incidence was 12 (11.6%) of 103 in laser-treated vs seven (6.8%) of 103 fellow eyes (P=.225). There was no difference in onset of CNV.
CONCLUSIONS: Results do not support prophylactic laser of the fellow eye of patients with neovascular ARM. Its role in patients with bilateral drusen remains unclear. ||||| PURPOSE: This study aimed to investigate whether mild laser treatment of soft drusen maculopathy might reduce the incidence of choroidal neovascularization (CNV) and/or significantly reduce loss of visual acuity compared with outcomes in a control group.
METHODS: A total of 135 patients (mean age 70.4 years) were randomized into a treatment group of 67 subjects and a control group of 68 subjects. The treatment group was subdivided into a group of 54 subjects with bilateral soft drusen and a group of 13 subjects with unilateral soft drusen in the study eye and advanced AMD in the fellow eye. The control group was subdivided into a bilateral group of 54 subjects and a unilateral group of 14 subjects. Sub-threshold or barely visible laser spots were scattered on and between drusen in the posterior pole. Inclusion of patients was stopped prematurely as other studies did not show any benefit from the treatment. Mean follow-up time was 3.7 years.
RESULTS: More CNVs developed in the treated group (4/54 eyes in the bilateral group, 3/13 eyes in the unilateral group; 7/67 eyes in total) than in the control group (3/54 eyes in the bilateral group, 2/14 eyes in the unilateral group; 5/68 eyes in total) but these differences were not statistically significant for either the bilateral or unilateral groups (p = 0.20-0.32). No CNV developed in the bilateral treated group before 4 years of follow-up. Visual acuity was significantly reduced from baseline to the last follow-up in all groups (p < 0.0001-0.02) except the unilateral control group (p = 0.08), but there were no significant differences between the treated and control groups for either the bilateral or unilateral groups (p = 0.17-0.97).
CONCLUSIONS: Mild prophylactic laser treatment of soft drusen maculopathy was neither beneficial nor harmful and cannot be recommended. ||||| OBJECTIVE: To describe characteristics of participants in the Complications of Age-Related Macular Degeneration Prevention Trial (CAPT) at baseline and to investigate associations among visual function, fundus features, and vision-related quality of life.
DESIGN: Cross-sectional study.
PARTICIPANTS: The 1052 participants in CAPT, a multicenter, randomized clinical trial. Eligibility criteria for CAPT included > or =10 large drusen and visual acuity > or =20/40 in each eye.
METHODS: At baseline, the visual acuity, contrast sensitivity, and critical print size for each eye were measured, color stereo photographs of the disc and macula of each eye were taken, and the 25-item National Eye Institute Visual Functioning Questionnaire (NEI-VFQ-25) was self-administered. Graders from a central photograph reading center evaluated the photographs for drusen characteristics and focal hyperpigmentation. All procedures were performed using standardized protocols. Associations among characteristics were assessed by Spearman correlation coefficients and multiple linear regression.
RESULTS: Among CAPT participants at baseline, the mean age was 71.0 years, 60.6% were women, and 99.3% were white. The median visual acuity of the better eye was 20/20 and of the worse eye 20/25. In approximately one third of eyes, drusen covered > or =10% of the retina within 3000 microm of the foveal center, and 67.7% of eyes had focal hyperpigmentation. Drusen area and focal hyperpigmentation were weakly correlated (r = -0.08 to -0.18) with the measures of visual function. The measures of visual function were weakly associated with the NEI-VFQ-25 scores. An association of fundus features with NEI-VFQ-25 scores was not found.
CONCLUSION: At baseline, CAPT participants had good visual function and several risk factors for progression to neovascular age-related macular degeneration. Scores on the NEI-VFQ-25 indicated that participants perceived some problems with their vision. Within this relatively homogeneous group of participants, measures of visual function were only weakly associated with the measures of vision-related quality of life. ||||| AIM: To investigate the effect of prophylactic laser treatment on drusen area and incidence of exudative lesions in patients with soft drusen maculopathy.
METHODS: In a prospective study, patients with early age related maculopathy (ARM) and good visual acuity were randomized to laser treatment or to a control group. Each group consisted of two subgroups: a fellow eye group and a bilateral drusen group. At 3 years, 36 of 38 enrolled patients remained in the study. Photocoagulation was performed with an argon green laser, approximately 100 mild laser burns being placed on and between the drusen in a perifoveal temporal horseshoe-shaped area. Both cases and controls were subjected to fundus colour photographs and fluorescein angiograms at regular intervals, and the drusen area was calculated in both photographs and angiograms. At baseline, there were no significant differences (p > 0.3-0.8) in drusen area between the groups.
RESULTS: In the treatment group, mean drusen area decreased significantly in the fundus photographs as well as in the angiograms (p < 0.001). Visual acuity and colour contrast sensitivity (CCS) did not change significantly. All these results are valid also for the subgroups. In the control group, however, mean drusen area increased significantly (p < 0.001). Mean visual acuity decreased significantly (p < 0.01) as did the colour contrast sensitivity along the tritan axis (p = 0.02). For the fellow eye control group (n = 7), the increase in drusen area in fundus photographs and the decrease in CCS along the tritan axis were not statistically significant (p = 0.57 and p = 0.37, respectively). Furthermore, at 3 years, five patients in the control group showed exudative lesions (1/7 in the fellow eye group and 4/12 in the bilateral drusen group), whereas no such complications occurred in the treatment group. One patient developed a small atrophy, however. Thus, there is now a significant difference (p = 0.047), however with a large 95% confidence interval, 0.06-0.46, regarding exudative complications between the treated group and the control group in our small patient material.
CONCLUSION: Perifoveal mild laser treatment causes a reduction in drusen area in patients with soft drusen maculopathy and may lower the incidence of exudative lesions. ||||| PURPOSE: To evaluate the effect on subfoveal and nasal drusen when laser treatment is applied only to the soft drusen located in the temporal macula.
METHODS: A prospective pilot study of 20 patients with confluent soft drusen involving the fovea was conducted. One spot of argon green laser (100-microns spot at 100 mW for 0.1 sec) was applied to each soft druse in the temporal macula.
RESULTS: Treated and untreated drusen disappeared in all patients after mean times of 2 months and 10 months, respectively. The treated temporal drusen disappeared first, followed by the subfoveal and then the nasal drusen. Superonasal drusen persisted longer. Visual acuity improved by one line or more in 6 (30%) patients, remained unchanged in 13 (65%), and worsened in 1 (5%) patient. No treatment-related complications were observed after an 18-month follow-up period.
CONCLUSION: Treatment with laser photocoagulation caused resolution not only of treated soft drusen but also of untreated soft drusen located far from the laser scars in the nasal macula. ||||| PURPOSE: To identify risk factors for the development of choroidal neovascularization (CNV) and vision loss in the Fellow Eye Study of the Choroidal Neovascularization Prevention Trial.
METHODS: Retrospective review of 121 patients enrolled in a multicentered, randomized, controlled trial. Patients had neovascular age-related macular degeneration in one eye and more than 10 large drusen in the other eye. Records of patients randomly assigned to laser treatment or observation were reviewed through 4 years of follow-up. Three candidate risk factors for the development of CNV and vision loss were evaluated.
RESULTS: Eyes with hyperfluorescent drusen on fluorescein angiography at 3 minutes appeared to have a decreased risk of CNV. Patchy choroidal filling was seen in 14% of patients. Eyes with patchy choroidal perfusion showed a higher risk of developing CNV that was not statistically significant, and the increased risk was present only in treated eyes. Reticular pseudodrusen were present in only three eyes.
CONCLUSIONS: Reticular pseudodrusen were rare. Late drusen fluorescence may protect against the development of CNV. ||||| PURPOSE: To study the effect of mild laser treatment on the incidence of exudative complications in patients with soft drusen maculopathy in a longterm perspective.
METHODS: In a prospective study, 38 patients with early age-related maculopathy and good visual acuity (VA) were randomized either to laser treatment using an argon green laser or to observation. At 8 years, 29 patients remained in the study, 16 in the control group and 13 in the treatment group.
RESULTS: During follow-up, mean VA decreased significantly in both groups, to 0.53 in the treatment group (p < 0.05) and to 0.25 in the control group (p < 0.001). At 8 years, 9/16 in the control group showed exudative complications, whereas only 2/13 in the treatment group developed such changes (p < 0.03).
CONCLUSION: In this randomized pilot study, mild laser treatment of soft drusen maculopathy significantly reduced the rate of exudative complications in a longterm perspective. As the study is small, the results should be viewed with caution. ||||| OBJECTIVE: To evaluate the efficacy and safety of low-intensity laser treatment in the prevention of visual acuity (VA) loss among participants with bilateral large drusen.
DESIGN: Multicenter randomized clinical trial. One eye of each participant was assigned to treatment, and the contralateral eye was assigned to observation.
PARTICIPANTS: A total of 1052 participants who had > or =10 large (>125 microm) drusen and VA> or =20/40 in each eye enrolled through 22 clinical centers.
INTERVENTION: The initial laser treatment protocol specified 60 barely visible burns applied in a grid pattern within an annulus between 1500 and 2500 mum from the foveal center. At 12 months, eyes assigned to treatment that had sufficient drusen remaining were retreated with 30 burns by targeting drusen within an annulus between 1000 and 2000 mum from the foveal center.
MAIN OUTCOME MEASURE: Proportion of eyes at 5 years with loss of > or =3 lines of VA from baseline. Secondary outcome measures included the development of choroidal neovascularization or geographic atrophy (GA), change in contrast threshold, change in critical print size, and incidence of ocular adverse events.
RESULTS: At 5 years, 188 (20.5%) treated eyes and 188 (20.5%) observed eyes had VA scores > or = 3 lines worse than at the initial visit (P = 1.00). Cumulative 5-year incidence rates for treated and observed eyes were 13.3% and 13.3% (P = 0.95) for choroidal neovascularization and 7.4% and 7.8% (P = 0.64) for GA, respectively. The contrast threshold doubled in 23.9% of treated eyes and in 20.5% of observed eyes (P = 0.40). The critical print size doubled in 29.6% of treated eyes and in 28.4% of observed eyes (P = 0.70). Seven treated eyes and 14 observed eyes had an adverse event of a > or =6-line loss in VA in the absence of late age-related macular degeneration or cataract.
CONCLUSION: As applied in the Complications of Age-Related Macular Degeneration Prevention Trial, low-intensity laser treatment did not demonstrate a clinically significant benefit for vision in eyes of people with bilateral large drusen. ||||| In this prospective, randomised trial, 19 patients (mean age 72.2 +/- 6.6 years) with soft drusen maculopathy and good visual acuity (0.93 +/- 0.1) were treated with argon green laser photocoagulation. Fundus colour photography and fluorescein angiography were performed at study entry and after 3, 6 and 12 months. Nineteen patients (mean age 68.5 +/- 6.2 years) with visual acuity 0.95 +/- 0.1 and similar fundus changes served as a control group. The area occupied by drusen within a circular zone was calculated in the fundus colour photographs (radius 2500 microns) and in the angiograms (radius 1250 microns). Mean drusen area of the treatment group did not differ from that of the control group at study entry (p > 0.5-0.7). In the treatment group, mean drusen area had decreased significantly from 7.87% to 2.93% (p = 0.00013) and from 19.22% to 7.15% (p < 0.0001) at 12 months respectively in the colour photographs and in the angiograms. Visual acuity and colour contrast sensitivity did not change. No complications were seen in the treated group. In the control group, mean drusen area increased from 8.33% to 10.69% and from 17.41% to 22.05%, respectively. These differences did not reach statistical significance. When comparing the 12-month change in drusen area in the two groups, significant differences were found both in fundus colour photographs and angiograms (p < 0.001). In the control group, mean visual acuity decreased to 0.89 +/- 0.1 (p = 0.008) and mean colour contrast threshold for the tritan axis increased significantly (p = 0.044), indicating impairments of retinal function. Three patients in the control group advanced to an exudative stage of the disease. ||||| AIM: To evaluate whether perifoveal laser photocoagulation of soft drusen reduces the total area occupied by drusen.
METHOD: In a prospective, randomised study, 20 patients (mean age 71.3 (SD 7.7) years) with early age-related maculopathy (ARM) in the form of soft drusen and pigmentary changes and with good visual acuity (0.94 (0.09)) were treated with argon green laser photocoagulation. Mild laser burns (200 microns) were placed within a temporal horseshoe-shaped area, extending from a distance of no less than 500 microns from the centre of the fovea to the vascular arcades. They were placed on the drusen and scattered over areas where no drusen were present. Fundus colour photography and fluorescein angiography were performed at study entry as well as after 3 and 6 months. Nineteen age-matched patients (68.5 (6.2) years) with soft drusen maculopathy (visual acuity 0.95 (0.10)) were followed as a control group. Using a computer system, the area occupied by drusen was determined as a portion of the total area of a circle with a radius corresponding to 1250 microns in the fundus for the angiograms and 2500 microns for the colour photographs, respectively. At study entry, the mean area occupied by drusen in the treatment group was not significantly (p > 0.5-0.7) different from that of the control group.
RESULTS: The mean drusen area of the angiograms and fundus colour photographs in the treated group decreased significantly from 19.3% to 13.8% (p = 0.002) and from 7.84% to 5.02% (p = 0.005), respectively. In the untreated group, the mean area occupied by drusen increased significantly from 17.4% to 20.4% (p = 0.030) and from 8.33% to 9.23% (p = 0.002), respectively. No significant changes in visual acuity (p > 0.05-0.5) or in visual fields (p > 0.05-0.3) occurred in either of the two groups during 6 months.
CONCLUSION: The study suggests that the area occupied by soft drusen in patients with early ARM decreases after perifoveal laser photocoagulation but increases in an untreated control group. ||||| OBJECTIVE: To describe the relationship of laser-induced drusen reduction to change in visual function at 1 year among patients enrolled in the Choroidal Neovascularization Prevention Trial (CNVPT).
DESIGN: Comparison of groups with and without drusen reduction; follow-up of a randomized controlled trial.
PARTICIPANTS: Evaluations of drusen and visual acuity at baseline and at 1 year were performed for 351 eyes of the 432 eyes enrolled in the CNVPT Bilateral Drusen Study and Fellow Eye Study (81%). One hundred eighty-four eyes were assigned to observation, and 167 eyes were assigned to laser treatment. Eyes with conditions that precluded an analysis of drusen reduction, such as those that developed choroidal neovascularization (CNV) within the first year, are excluded from this analysis.
METHODS: Change in macular drusen between initial visit and after 1 year was assessed by side-by-side grading by evaluators masked to information on visual function. Visual acuity, contrast threshold, and critical print size were measured by certified visual function examiners.
MAIN OUTCOME MEASURES: Change in visual acuity is the primary outcome. Change in contrast threshold and change in critical print size are secondary outcome measures.
RESULTS: Laser-treated eyes with 50% or more drusen reduction at 1 year had more 1- and 2-line increases in visual acuity and less losses in visual acuity compared with laser-treated eyes with less drusen reduction or with observed eyes (P = 0.001). Similar improvements were noted for contrast threshold but not critical print size at 1 year.
CONCLUSIONS: Laser-induced drusen reduction is associated with improved visual acuity and contrast sensitivity in eyes at 1 year. Longer term effects of laser-induced drusen reduction on visual function require additional observation. The overall potential value of laser treatment in eyes with high-risk drusen requires consideration of not only short-term effects on vision but also the effects of CNV and atrophy on vision. ||||| AIM: Previous studies have suggested that laser photocoagulation therapy is associated with the resolution of drusen in some age related macular degeneration (AMD) patients. The main aim of the study was to determine whether low intensity laser treatment applied according to the Complications of AMD Prevention Trial (CAPT) protocol produces changes in the choroidal circulation that may help explain the mechanism leading to the resolution of drusen material.
METHODS: This ancillary study included 30 CAPT patients with bilateral drusen that were treated and followed at the University of Pennsylvania. Laser Doppler flowmetry was used to measure relative choroidal blood velocity (Ch(vel)), volume (Ch(vol)), and flow (Ch(flow)) in the centre of the fovea. Measurements were obtained through a dilated pupil in both eyes of each patient at the initial CAPT visit before laser treatment was applied in one eye. Measurements were repeated in both eyes of each subject three months later. Analysis of laser Doppler measurements was performed in a masked fashion.
RESULTS: In comparison to baseline, no significant differences in Ch(vel), Ch(vol), or Ch(flow) were observed three months following the application of low intensity laser according to the CAPT protocol in the untreated and treated eyes. In comparison to the untreated eyes, no significant differences were detected in the treated eyes. Based on the variability of flow measurements in the untreated eyes, the authors estimated an 85% power to detect a 15% change in relative blood flow.
CONCLUSIONS: The results suggest that large alterations in choroidal blood flow do not occur at three months after low intensity laser therapy following the CAPT protocol. ||||| PURPOSE: To update the findings from the Choroidal Neovascularization Prevention Trial (CNVPT) with respect to resolution of drusen, incidence of choroidal neovascularization, and visual function.
DESIGN: A multicenter, randomized, controlled, pilot clinical trial.
PARTICIPANTS: The 120 patients enrolled in the CNVPT. Patients had signs of choroidal neovascularization or retinal pigment epithelial detachment in 1 eye and had >/=10 large (>63- micro m) drusen in the contralateral, or fellow, eye.
INTERVENTION: The fellow eye of 59 patients was assigned randomly to argon green laser treatment consisting of multiple 100- micro m spots at least 750 micro m from the center of the fovea. The fellow eye of the remaining 61 patients was assigned randomly to observation.
MAIN OUTCOME MEASURES: Change in visual acuity was the primary outcome measure. Incidence of choroidal neovascularization, resolution of drusen, change in contrast threshold, change in critical print size for reading, and incidence of geographic atrophy were secondary outcome measures.
RESULTS: Throughout 4 years of follow-up, there were no statistically significant differences in change in visual acuity, contrast threshold, critical print size, or incidence of geographic atrophy. With additional follow-up, the large increase in the incidence of choroidal neovascularization observed within 18 months of treatment was maintained; however, by 30 months, the incidence in the two treatment groups was the same. Most drusen resolution in treated eyes occurred within 24 months of the initial treatment. Treated eyes that received higher-intensity laser burns had an increased risk of choroidal neovascularization. Among eyes developing choroidal neovascularization in each treatment group, most lesions (two thirds or more) were composed of occult neovascularization only.
CONCLUSIONS: Laser treatment as applied in the CNVPT caused an excess risk of choroidal neovascularization in the first year or so after treatment. The increased early incidence of choroidal neovascularization was not associated with either a harmful or beneficial effect in this pilot study. ||||| OBJECTIVE: To explore the relationship between laser burn intensity and the subsequent risk for development of choroidal neovascularization (CNV) in eyes assigned to the treatment group of the Fellow Eye Study (FES) of the Choroidal Neovascularization Prevention Trial (CNVPT), using computerized methods for laser burn quantitation, and to examine the association between laser burn intensity and (1) drusen reduction and (2) visual acuity.
METHODS: Color fundus images before and immediately after laser treatment in the CNVPT FES were available for 53 of 59 eyes. Prelaser and postlaser treatment images were analyzed using custom-developed computer software, allowing for laser burn identification and quantitation. As measures of laser burn intensity, we derived integrated burn rating (IBR) (the integral of the normalized intensity difference divided by the burn pixels), and the maximum burn intensity (MAX). We identified CNV using fluorescein angiography. A Cox proportional hazards model was fit to the time to development of CNV. Baseline and 6-month color photographs were used to determine reduction in drusen. Visual acuity was measured using a standardized protocol.
RESULTS: The IBR and MAX spanned 4.5 logarithm units. After adjusting for smoking history and predominant drusen size, the risk ratio for CNV per logarithm unit of increasing laser burn intensity for each measure was 2.0 (P =.05) for MAX and 1.7 (P =.07) for IBR. When patients were divided into high- and low-intensity treatment groups of equal size, the high-intensity group had more drusen reduction (57% vs 32%; P =.14). There was no effect of laser intensity on change in visual acuity at 6 months.
CONCLUSION: Higher-intensity prophylactic laser applications appear to be associated with a greater risk for development of CNV and with more extensive drusen reduction. ||||| PURPOSE: To determine whether laser treatment applied according to the complications of age-related macular degeneration prevention trial (CAPT) has an effect on the choroidal circulation.
DESIGN: Randomized controlled trial.
METHODS: This study included 30 CAPT patients with bilateral drusen. Laser Doppler flowmetry was used to measure relative choroidal blood flow (Ch(flow)) in the fovea. Measurements were obtained through dilated pupils in both eyes of each patient before photocoagulation was applied in one eye. Measurements were repeated at three months (30 patients) and 28 months (23 patients).
RESULTS: Average Ch(flow) at baseline, three months, and 28 months was 7.2 +/- 2.1 (+/-1 SD), 7.3 +/- 2.5, and 6.8 +/- 2.7 arbitrary units (AU) in the control eyes and 6.6 +/- 1.6, 7.0 +/- 2.3, and 7.8 +/- 3.0 AU in the treated eyes. In comparison to control eyes, there was no significant change in Ch(flow) in the treated eyes at three months after treatment. At 28 months, however, there was a 5.6% drop in Ch(flow) in control eyes and an 18.2% increase in Ch(flow) in treated eyes from baseline. The average difference of 23.8% between the percentage changes in Ch(flow) observed in the control and treated eyes was statistically significant (paired two-tailed Student t test; P = .05).
CONCLUSIONS: Our results suggest an increase in choroidal blood flow 28 months after laser treatment according to the CAPT protocol. This increase may play a role in the mechanism leading to the disappearance of drusen after photocoagulation. Whether removal of drusen after photocoagulation is beneficial to the patients is not known at this time. ||||| PURPOSE: Initial studies suggest that drusen associated with age-related maculopathy resolve in response to laser photocoagulation; there are conflicting reports regarding whether this treatment might prevent neovascular complications and blindness. The goal of the Drusen Laser Study is to maintain good visual acuity in eyes at the highest risk for neovascular complications of age-related maculopathy. In this report, we alert the ophthalmic community to possible laser-induced complications in patients treated within the context of this clinical trial.
METHODS: A double-masked, randomized, controlled clinical trial of prophylactic macular photocoagulation for high-risk age-related maculopathy is in progress. Patients randomly assigned to treatment received a ring-type distribution of 12 light spots of argon laser photocoagulation. Drusen were treated directly only if they were present at the protocol treatment locations. Fluorescein angiography was performed in all patients at yearly review, and at nonprotocol visits if symptoms or clinical examination were suggestive of choroidal neovascularization.
RESULTS: Fluorescein angiographic abnormalities suggestive of choroidal neovascularization have been seen in treated eyes only: one patient in the pilot study and six patients in the Drusen Laser Study. No fluorescein angiographic abnormalities were seen in eyes of control subjects.
CONCLUSIONS: Laser photocoagulation in high-risk age-related maculopathy may induce choroidal neovascularization and, therefore, is not recommended outside the context of a randomized, controlled clinical trial. ||||| BACKGROUND: The Complications of Age-Related Macular Degeneration Prevention Trial (CAPT) is a randomized clinical trial to evaluate whether prophylactic laser treatment to the retina can prevent the complications of the advanced stage of Age-Related Macular Degeneration (AMD), the leading cause of irreversible blindness.
METHODS: CAPT is conducted in 23 clinical centers and in three central resource centers. The primary outcome measure is change in visual acuity; secondary outcomes include the incidence of complications of AMD, changes in other measures of visual functioning and vision-related quality of life. In total, 1052 patients with two high-risk eyes were enrolled. One eye was randomized to receive laser treatment and the other eye to observation. All patients were treated immediately after randomization and again at 12 months, dependent on clinical status. All patients are followed via study visits and telephone calls for a minimum of five years. Study visit procedures include established tests of visual function conducted by examiners masked to the treatment assignment of each eye, a biomicroscopic examination by CAPTophthalmologists, and photographs of each eye taken according to protocol and assessed by masked graders in a centralized Photograph Reading Center.
RESULTS: This paper describes the CAPT study, including study rationale, operational structure, and measures implemented to ensure standardization of assessments, adherence to protocol, quality assurance, and maintaining follow-up. Several features related to study design and procedures that are specific to CAPT are highlighted, including clinic selection and judgements regarding patient eligibility.
CONCLUSIONS: An intervention that can reduce the risk of advanced AMD by 30% in the eyes of people with two high-risk eyes may halve the rate of bilateral blindness from AMD. It would also yield substantial savings in expenditures devoted to treating advanced AMD and the disability it causes, and enhance the quality of life for people at risk. ||||| PURPOSE: To update the results of a study on the disappearance of macular soft drusen after laser treatment in the natural evolution of age-related macular degeneration.
METHODS: A total of 46 patients with confluent soft drusen and pigmentary changes were studied prospectively. Group 1 was composed of 30 patients with bilateral drusen; the authors randomly assigned one eye of each patient for treatment and the fellow eye for the control. In 16 patients a choroidal neovascular membrane was present in one eye, and treatment was applied to the fellow eye (group 2). Argon green laser treatment was applied directly to the soft drusen in the temporal macula.
RESULTS: All treated drusen disappeared in a mean of 3.5 months after treatment, and untreated drusen disappeared in all but three patients in an average of 8.5 months. After an average period of 3 years, only one control eye and none of the treated eyes in group 1 developed a choroidal neovascular membrane (P = 0.500). In group 2, neovascularization occurred in 18% of the patients. The initial improvement in Snellen acuity after subfoveal drusen disappearance diminished as a consequence of cataract progression.
CONCLUSIONS: Although no definitive conclusions should be made because of the small number of patients studied, results seem to show that this treatment does not reduce the risk of choroidal neovascularization in the treated eye of patients with a history of exudative disease in the fellow eye. It may be effective in patients with high-risk bilateral soft drusen, that is, in less advanced stages of the disease. ||||| PURPOSE: To determine the predictors of drusen reduction in eyes with nonexudative age-related macular degeneration (ARMD) treated with subthreshold infrared (810 nm) diode laser macular grid photocoagulation. Additionally, to determine the relationship of laser-induced drusen reduction and best-corrected visual acuity (BCVA) 18 months after laser treatment.
DESIGN: Randomized controlled clinical trial.
METHODS: Fifty patients (100 eyes) with bilateral nonexudative ARMD were enrolled at two centers. One eye of each patient was randomized to the observation; the other eye was treated with 48 subthreshold (invisible end point) applications of infrared (810 nm) diode laser in a macular grid pattern. The eyes that received subthreshold laser treatment were compared with the eyes that received no treatment. The baseline fundus characteristics (number, size, and distribution of drusen, as well as focal hyperpigmentation) from two macula areas (central 1500 micro diameter, pericentral 1500 micro ring area) on stereo color photographs, the number of laser-induced lesions, and the area of laser induced retinal pigment epithelial (RPE) lesions on fluorescein angiography 3 months after treatment were studied as predictors of major drusen reduction (> or = 50% drusen reduction from baseline) 18 months after laser treatment. BCVA at baseline and 18 months later was compared in observation eyes and in laser-treated eyes.
RESULTS: Eighteen months after randomization, 24 (48%) of 50 eyes treated with subthreshold laser had major drusen reduction compared with three (6%) of 50 observation eyes (P =.00001). At 3 months post-treatment in laser-treated eyes with major drusen reduction, the mean number of laser-induced lesions on fluorescein angiography was 30.7 and the mean area of RPE change was 0.81 mm(2) compared with 14.8 laser-induced lesions and 0.35 mm(2) area of RPE change in eyes without major drusen reduction (P =.0001 and P =.0003, respectively). At baseline, fundus characteristics were not significantly different between observation eyes and laser-treated eyes or between the major drusen reduction group and the nonmajor drusen reduction group. At 18 months after treatment, BCVA was not significantly different in laser-treated eyes and in observation eyes.
CONCLUSIONS: Subthreshold infrared (810 nm) diode laser macular grid photocoagulation in eyes with nonexudative ARMD significantly reduced drusen 18 months after laser treatment. Both the number of subthreshold laser lesions and the area of RPE changes visible on fluorescein angiography 3 months after treatment appeared to be predictors for major drusen reduction 18 months after treatment. However, it remains to be determined whether laser-induced drusen reduction is beneficial for visual acuity or reduces the incidence of choroidal neovascularization (CNV) in eyes with nonexudative ARMD. ||||| OBJECTIVE: This study aimed to describe characteristics of choroidal neovascularization (CNV) that developed in high-risk eyes of patients with age-related macular degeneration (AMD) enrolled in the Choroidal Neovascularization Prevention Trial (CNVPT).
DESIGN: Consecutive case series among patients enrolled in a multicenter, randomized controlled trial.
PARTICIPANTS: Eighteen eyes of 18 patients who developed exudative AMD were studied from among 156 patients with large drusen enrolled in the Bilateral Drusen Study and 120 patients having one eye with exudative AMD and the other eye with large drusen enrolled in the Fellow Eye Study. The CNVPT Fellow Eye Study provided 12 eyes (10, treatment group; 2, control group), and the CNVPT Bilateral Drusen Study contributed 6 eyes (4, treatment group; 2, control group).
METHODS: The CNVPT Reading Center assessment and grading of patients with CNV and other exudative complications was reviewed.
MAIN OUTCOME MEASURES: Onset of CNV, laser intensity for treated eyes, classification of lesion components, size of lesion, location of lesion, foveal involvement, and change in visual acuity were measured.
RESULTS: Eighteen eyes showed onset of CNV between 2 and 21 months after enrollment. In comparison with the CNVPT Laser Standard Intensity, variations in laser treatment intensity (6 eyes graded less than standard intensity and 8 eyes graded standard intensity) were not associated with CNV events. Seventeen of 18 eyes showed occult CNV in whole or in part, and only 1 eye manifested purely classic CNV. The median size range was 2 to 3.5 disc areas. Among the 14 treated eyes that developed exudative lesions, 7 showed subfoveal involvement and 13 had CNV associated with the region of treatment. At the time of the CNV event, 9 of 18 eyes showed greater than a 2-line loss of vision from baseline while the remaining eyes were stable.
CONCLUSIONS: Preliminary data show that visually significant exudative manifestations of AMD may develop in patients with high-risk drusen who undergo macular laser photocoagulation. The CNV lesions typically are occult, often subfoveal, and associated with the region of treatment. Longer follow-up is warranted. ||||| OBJECTIVE: This pilot study collected preliminary information on the effectiveness and safety of infrared (810-nm) diode laser macular grid photocoagulation in patients with nonexudative age-related macular degeneration (AMD). Results from this pilot study were used in designing a larger, multicenter, randomized clinical trial.
DESIGN: A multicenter, randomized, controlled, clinical trial.
PARTICIPANTS: A total of 229 eyes of 152 patients with AMD were enrolled in the pilot study. Seventy-five patients with 1 eye eligible (75 eyes) were enrolled in the unilateral arm of the study; 77 patients with both eyes eligible (154 eyes) were enrolled in the bilateral arm of the study. In the unilateral study arm, 32 eyes were randomized to the observation group, 27 eyes were treated with visible endpoint burns, and 16 eyes were treated with invisible endpoint (subthreshold) lesions. In the bilateral study arm, 77 eyes were in the observation group, 36 eyes were treated with visible burns, and 41 eyes were treated with subthreshold (invisible) lesions.
INTERVENTION: Eyes were treated with infrared (810-nm) diode laser macular grid photocoagulation using either visible burns or subthreshold (invisible) lesions and compared to eyes receiving no treatment.
MAIN OUTCOME MEASURES: Reduction of drusen, change in visual acuity, and rate of choroidal neovascularization (CNV) membrane formation.
RESULTS: At 12 months after treatment, 62% of eyes treated with visible burns had a clinically significant reduction in drusen, whereas this proportion (65%) was reached in 18 months for eyes treated with subthreshold lesions. At 24 months' follow-up, treated eyes had a significant reduction in drusen compared to observation eyes (P < 0.0001). Visual acuity was significantly improved in treated eyes at 12, 18, and 24 months compared to observation eyes (P < 0.001). Choroidal neovascularization formation was similar in treated and observation eyes through 24 months' follow-up. Complications included CNV associated with six eyes treated with visible burns and a juxtafoveal laser scar in one eye treated with visible burns.
CONCLUSIONS: Infrared (810-nm) diode laser macular grid photocoagulation in patients with nonexudative AMD significantly reduces drusen levels (P < 0.0001) and significantly improves visual acuity (P < 0.001) when either visible endpoint burns or subthreshold endpoint lesions are used. Complications were fewer using subthreshold endpoint lesions. A larger, multicenter, prospective clinical trial with longer follow-up is needed to determine the efficacy of treatment in reducing the rate of CNV formation. Data from this clinical pilot study have been used to design the Prophylactic Treatment of AMD Trial (PTAMD), a multicenter, randomized, prospective clinical trial currently in progress comparing subthreshold (invisible) treatment to observation in eyes with nonexudative AMD. ||||| PURPOSE: The authors determined the effect of photocoagulation of drusen on visual acuity and progression to subretinal neovascular membranes (SRNV).
METHODS: One of paired eyes was randomized to photocoagulation with other eye to control in 27 patients having symmetrical maculopathy and visual acuities, aged 46 to 81 years (mean, 69.7 years); follow-up 1 to 6 years (mean, 3.2 years).
RESULTS: Final visual acuity was improved in treated eye or decreased in control eye in 12 patients, equal in 13 patients, and decreased in treated eye in 2 patients (P < 0.006). Progression to SRNV was less with treatment.
CONCLUSION: Laser photocoagulation of confluent soft macular drusen may improve long-term visual prognosis. ||||| OBJECTIVE: This study aimed to describe the short-term effects of low-intensity laser treatment in eyes with drusen at risk of having choroidal neovascularization (CNV) develop secondary to age-related macular degeneration.
DESIGN: The study design was a multicentered, randomized clinical trial of laser treatment versus observation.
PARTICIPANTS: One hundred fifty-six patients without exudative age-related macular degeneration and with more than 10 large (> 63 microns) drusen in each eye were enrolled in the Bilateral Drusen Study. One hundred twenty patients with exudative age-related macular degeneration in 1 eye and more than 10 large drusen in the other eye were enrolled in the Fellow Eye Study.
INTERVENTION: The treatment protocol for most (85%) of the eyes consisted of 20 laser burns, 100 microns in diameter, in a pattern of 3 rows placed between the 12- and 6-o'clock positions beyond the temporal perimeter of the foveal avascular zone. The desired intensity of the burns was a gray-white lesion. Whenever the area of drusen had not been reduced by 50% or more at 6 months, a second treatment was applied nasal to the fovea in a mirror image of the first treatment. During the last 6 months of enrollment, a second laser treatment protocol was adopted that specified 24 laser burns, 100 microns in diameter, in a circular pattern of 2 rows surrounding the macular drusen.
MAIN OUTCOME MEASURES: Change in visual acuity is the primary outcome measure. Incidence of CNV, change in contrast threshold, and change in critical print size are secondary outcome measures.
RESULTS: In the Bilateral Drusen Study, CNV developed in 4 of 156 treated eyes and in 2 of 156 observed eyes (P = 0.62); in the Fellow Eye Study, the proportions are 10/59 treated eyes and 2/61 observed eyes (P = 0.02). Changes in visual acuity are similar in treated and observed eyes in the Bilateral Drusen Study through 18 months. However, by 18 months, observed eyes in the Fellow Eye Study have lost more visual acuity than treated eyes (P = 0.02). Changes in contrast threshold are similar in treated and observed eyes in each study.
CONCLUSIONS: Laser treatment to high-risk fellow eyes may increase the short-term incidence of CNV. Long-term effects in fellow eyes and effects in patients with bilateral drusen require additional observation. | [
{
"source_pmid": "12855972",
"source_text": "PURPOSE: The Drusen Laser Study (DLS) of high-risk age-related maculopathy (ARM) is a randomised, controlled clinical trial designed to answer two questions: (1). Do drusen resolve after macular laser photocoagulation (2). Does macular laser photocoagulation prev... |
25767134 | CONCLUSIONS: Nocturnal blood pressure fall is a risk factor for progressive visual field loss in glaucoma. However, prospective studies are needed to define a tolerable degree of dipping. Antihypertensive therapy in glaucomatous patients should be controlled with ambulatory blood pressure monitoring. | PURPOSE: This study was designed to uncover a new sensitive and specific factor for predicting the progression of glaucoma.
METHODS: The 24-hour ambulatory blood pressure and diurnal curve of intra-ocular pressure were recorded in seventy patients: 51 primary open angle glaucoma (POAG) and 19 normal tension glaucoma (NTG). The mean systolic, diastolic and average arterial blood pressure were calculated, along with the nocturnal dip of systolic pressure and diastolic blood pressure. Two-year disease progression was assessed for all patients by means of retrospective analysis of visual fields defects on repeated perimetries.
RESULTS: Abnormal (absence or increased) nocturnal dip of systolic blood pressure was found to be correlated with disease progression in POAG and NTG patients with a sensitivity of 86% and a specificity of 85%, whereas no significant correlation was found for the other risks factors envisaged. Furthermore, a significant relationship between stable visual field defects and the use of diuretics/laser procedure was evidenced.
CONCLUSION: The nocturnal dip of systolic blood pressure should be considered as a predictive factor of disease progression in NTG and POAG. Further prospective studies are needed to ascertain whether dip normalization could help slow down the visual field loss in these patients. ||||| The role of systemic blood pressure in glaucomatous damage remains undefined, with systemic hypertension and hypotension being implicated in different studies. We have previously reported that the physiologic nocturnal blood pressure "dip" may be exaggerated in some glaucoma patients with progressive field loss. A 24-hour ambulatory blood pressure recording was originally performed on 84 patients with glaucoma. The mean result across all our glaucoma patients were within the ranges reported in the literature for normal subjects. The normal-tension glaucoma and primary open-angle glaucoma groups did not differ significantly in blood pressure variables. Nocturnal blood pressure variables were lower in the patients with progressive field defects compared to those with stable visual fields. To determine long-term outcomes in these patients, we reevaluated the visual fields of the original 84 patients studied. In 70 patients with long-term visual field data (mean, 5.1 years), those who had shown greater nocturnal blood pressure dips were more likely to have shown field progression at some stage, despite good intraocular pressure control. Patients who had field progression showed significantly lower nocturnal blood pressure variables, with the dips of the systolic, diastolic, and mean arterial pressure significantly larger (systolic dip, P = 0.01). They also had a greater history of disk hemorrhages. A review of other 24-hour blood pressure studies in the literature shows that most are in agreement with these findings. The nocturnal reduction in blood pressure may, therefore, be an additional risk factor in glaucoma patients. ||||| PURPOSE: To compare circadian changes of systemic circulation in patients with normal tension glaucoma (NTG) and normal subjects.
METHODS: Forty-three patients with NTG and 226 normal subjects were enrolled in this study. Circulatory parameters, including blood pressure (BP) and pulse rate (PR), were measured in all subjects for 49 hours using an ambulatory monitoring system. In addition to a comparison between NTG patients and normal controls, the same parameters were compared between NTG patients who had progressive field defects and NTG patients who had stable field defects.
RESULTS: The BP in NTG patients was significantly higher than in normal subjects. The nocturnal dip of BP in NTG patients was similar to the dip in normal subjects. However, the BP dip in NTG patients showing progressive visual field defects was significantly smaller than in patients with NTG showing stable visual field defects. Blood pressure fluctuation in sleep in the 'progressive' patients was significantly greater than in the 'stable' patients. Patients with NTG whose random BP was in a normal range showed a higher BP than normal subjects. The dip in PR in NTG patients was significantly lower than in normal subjects.
CONCLUSIONS: An insufficient physiological nocturnal BP dip or a greater nocturnal fluctuation in BP may disturb the microcirculation of, and/or may directly damage, the optic nerve, resulting in increasing field loss in NTG. ||||| We measured and compared diurnal and nocturnal blood pressure (BP) with the Space Labs Holter in progressive and non-progressive glaucomatous patients with a satisfactory diurnal control of IOP in order to identify any link between a progressive worsening of their visual field (VF) defects and the characteristics of their nocturnal BP "dip". Ambulatory 24-hour BP monitoring and inpatient IOP curves were done on two consecutive days on 36 patients (17 women, 19 men, mean age 67.44 +/- 8.06 years) with moderate to severe POAG and good diurnal therapeutic control of IOP (daytime IOP < or = 21 mm Hg). Depending on the stability or progression of their VF defects during the last two years, the patients were classified in two groups: the progressive group comprised 24 patients (14 women, 10 men) and the stable group 12 patients (9 men, 3 women). We compared local and systemic risk factors for POAG, mean and maximum daytime and nighttime IOP in each group. The mean systolic and diastolic daytime BP, mean systolic and diastolic nighttime BP and the nocturnal systolic and diastolic BP dip were calculated for each patient. The distribution of these parameters was then statistically compared with normal reference values and for the two groups. The groups were closely comparable as regards their IOP 24-hour profile. The overall mean daytime, nighttime, and nocturnal dips fell within the normal range of the reference population. We found a significanty smaller systolic and diastolic BP dip in the progressive group and a broader distribution of the lower values both for systolic and diastolyc BP in the progressive group. A broader distribution of the lower values for systolic and diastolic BP dip was also noticed when progressive patients were compared with the reference population. The relative absence of a nocturnal BP dip may be interpreted as another disturbing factor in the self-regulatory mechanisms of the optic nerve head in glaucoma. ||||| PURPOSE: In a significant number of glaucoma patients, progression of visual field loss occurs despite adequate intraocular pressure (IOP) control. Other factors, mainly vascular, seem to play a role in the pathogenesis of these glaucomas. The purpose of this study was to investigate the role of blood pressure (BP) as one of the vascular risk factors for progression of glaucomatous damage.
METHODS: Eighty-three glaucoma patients were categorizated as to whether their visual field defect were stable or progressive in the face of clinically stable IOP; all patients were followed for at least two years. The mean systolic and diastolic BP were determined, using a 24-hour ambulatory recording device, during diurnal (6 am-10 pm) and nocturnal (10 pm-6 am) periods. For each patient, the nocturnal systolic and diastolic dips, and the BP variability (i.e. standart deviation, and percentage decrease from maximal to minimal readings) were determined.
RESULTS: Forty-three patients had stable visual fields (25 females, 58.9 years old +/- 6.88; 18 males, 58.6 years old +/- 11), while 40 patients showed progressive visual field loss (23 females, 67.4 years old +/- 9.98; 17 males, 64.5 years old +/- 9.44). In the progressive group, women were older (p = 0.017), systolic (p = 0.0375) and diastolic (p = 0.0083) dips were greater, as also BP variability: systolic standard deviation was greater (p = 0.027) as percentage decrease from maximal systolic readings (p = 0.034). There were no difference for systolic, diastolic, diurnal or nocturnal mean BP in these two groups.
CONCLUSIONS: The finding in this study suggests that age, decreased nocturnal BP and high BP variability may be additional risk factors for progression of glaucomatous field loss. | [
{
"source_pmid": "10090444",
"source_text": "PURPOSE: This study was designed to uncover a new sensitive and specific factor for predicting the progression of glaucoma.\nMETHODS: The 24-hour ambulatory blood pressure and diurnal curve of intra-ocular pressure were recorded in seventy patients: 51 primary op... |
27428613 | CONCLUSIONS: Meta-analysis of existing data showed that rs1799750 may affect individual susceptibility to glaucoma. Nevertheless, more studies with large sample size and various ethnicities are warranted in light of the limited studies. | BACKGROUND: Primary open angle glaucoma (POAG) is considered to be a leading cause of irreversible blindness worldwide. Matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) have been extensively studied as POAG risk factors. Recently, several single-nucleotide polymorphisms (SNPs) for MMPs and TIMPs encoding genes have been reported in POAG patients. The aim of this study was to investigate association of the -1607 1G/2G MMP1 and 372 T/C TIMP1 gene polymorphisms with risk of POAG in a Polish population.
MATERIAL/METHODS: In the present case-control study we examined a group of 449 unrelated Caucasian subjects consisting of 196 POAG patients (66 males and 130 females; mean age 70 ± 14) and 253 controls (72 males and 181 females; mean age 67 ± 16). The MMP1-1607 1G/2G and TIMP1 372 T/C gene polymorphisms were determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). The odds ratios (ORs) and 95% confidence intervals (CIs) for each genotype and allele were calculated.
RESULTS: We found a statistically significant increase of the 2G/2G genotype (OR 1.73; 95% CI 1.05-2.86; p=0.019) as well as the 2G allele frequency (OR 1.34; 95% CI 1.03-1.75; p=0.017) of MMP1 in POAG patients in comparison to healthy controls. There were no differences in the genotype and allele distributions and odds ratios of the TIMP1 polymorphism between patients and controls group. We also did not find any association of TIMP1 with MMP1 gene-gene interaction and risk of POAG occurrence.
CONCLUSIONS: In conclusion, we suggest that the -1607 1G/2G polymorphism of MMP1 gene may be considered as an important risk factor associated with primary open angle glaucoma in a Polish population. However, further in vivo study is needed to evaluate biological importance of MMPs polymorphisms as a risk factor of POAG.<br /> ||||| BACKGROUND: Primary open-angle glaucoma (POAG) is the main cause of irreversible blindness worldwide. Matrix metalloproteinases (MMPs) and their regulators (TIMPs and ILs) have been extensively studied as POAG risk factors. Recent reports have showed several single-nucleotide polymorphisms (SNPs) for MMPs, TIMPs and ILs encoding genes in patients with POAG. The aim of this study was to investigate association of the -1607 1G/2G MMP1, -the 1562 C/T MMP9, the -82 A/G MMP12, the -511 C/T IL-1β and the 372 T/C TIMP1 gene polymorphisms with POAG occurrence and to investigate their impact on main clinical features.
MATERIAL AND METHODS: In the present case-control study, we examined group of 511 unrelated Caucasian subjects consist of 255 patients with POAG (mean age 70 ± 15) and 256 controls (mean age 67 ± 16). Determination of genes polymorphic variants was made using polymerase chain reaction-restriction fragment length polymorphism technique (PCR-RFLP). The odds ratios (ORs) and 95% confidence intervals (CIs) for each genotype and allele were calculated.
RESULTS: Presented study showed statistically significant increase in the POAG development risk of the -1607 2G/2G MMP1 genotype (OR 1.75; 95% CI, 1.11-2.75; p = 0.014) and for the -1607 2G MMP1 allele (OR 1.35; 95% CI, 1.05-1.73; p = 0.017), as well as for the -1562 C/T MMP9 genotype (OR 1.74; 95% CI, 1.17-2.59; p = 0.006) and the -1562 T MMP9 allele (OR 1.55; 95% CI, 1.10-2.17; p = 0.012) in patients with POAG in comparison with healthy control group. We also observed positive association of the -511 T/T IL-1β genotype (OR 2.60; 95% CI, 1.41-4.80; p = 0.002) as well as the -511 T IL-1β allele occurrence with an increased POAG development risk (OR 1.47; 95% CI, 1.13-1.90; p = 0.003). Furthermore, we found an association of the -1607 1G/2G MMP1, -1562 C/T MMP9 (anova, p < 0.001) and the -511 C/T IL-1β gene polymorphism (anova, p < 0.05) with decreased retinal nerve fibre layer (RNFL) thickness in patients with POAG group. Results displayed also an association of the 372 T/C TIMP1 gene polymorphism with normal range RNFL (anova, p < 0.001). We observed an association of decreased RA value (rim area) with the -82 A/G MMP12 (anova, p < 0.001). Normal RA value was observed in patients with POAG group connected with the 372 T/C TIMP1 (anova, p < 0.05) and the -511 C/T IL-1β (anova, p < 0.05) genes polymorphisms occurrence. Finally, results showed an association of the -1562 C/T MMP9 (anova, p < 0.001) gene polymorphism with decreased cup/disc index in patients with POAG group.
CONCLUSION: In conclusion, we suggest that the -1607 1G/2G MMP1, -1562 C/T MMP9, -511 C/T IL-1β gene polymorphisms can be considered as an important risk factors associated with POAG. ||||| PURPOSE: Matrix metalloproteinases (MMPs) play an important role in remodeling of the extracellular matrix during development and growth of various tissues including the eye. Various functional polymorphisms in MMPs have been implicated in the pathogenesis of different types of glaucoma. The aim of the present study was to investigate the role of various polymorphisms in Pakistani patients with glaucoma.
METHODS: The present case-control study included 112 patients with primary open-angle glaucoma (POAG), 82 patients with primary angle closure glaucoma (PACG), and 118 control subjects. Genotyping of polymorphisms was done using PCR followed by restriction fragment length polymorphism analysis.
RESULTS: A significant difference in the genotype frequencies of MMP1 rs1799750 (-1607 1G/2G) was observed between the patients with POAG and the control subjects (p = 0.001). This was attributed to the female subjects (p < 0.001), while the association was not significant in male subjects (p > 0.47). In addition, a significant difference was observed in genotype frequencies of MMP9 rs17576 (c.836A>G) in patients with PACG compared to the control subjects (p < 0.001), which after gender stratification remained significant in men (p = 0.009) but not in women (p = 0.14). No significant associations were found for MMP7 (c.-181T>C) and MMP9 (c.-1562C>T) polymorphisms.
CONCLUSIONS: Our data suggest that the MMP1 rs1799750 (-1607 1G/2G) and MMP9 rs17576 polymorphisms might be of value for further study as potential gender-dependent risk factors for developing POAG and PACG, respectively, in Pakistan. ||||| PURPOSE: Matrix metalloproteinases (MMPs) play an essential role in the turnover of the extracellular matrix and cellular behavior. MMP1, MMP2, and MMP9 have previously been implicated in the pathogenesis of primary open angle glaucoma (POAG) and open angle glaucoma secondary to exfoliation syndrome (XFG), respectively. Functional gene polymorphisms of these MMPs such as MMP1 -1607 1G/2G (rs1799750), MMP2 -1306 C/T (rs243865), MMP2 -1575 G/A (rs243866), and MMP9 Q279R (rs17576) are thus plausible candidates as risk factors for open angle glaucomas. The purpose of the present study was to investigate hypothesized associations between these polymorphisms and the presence of POAG and XFG in a Caucasian population.
METHODS: The present case-control study included 322 patients with POAG, 202 patients with XFG, and 248 control subjects. Genotyping of polymorphisms was done using polymerase chain reaction.
RESULTS: No significant differences in either genotype distributions or allelic frequencies of MMP1 -1607 1G/2G, MMP2 -1306 C/T, MMP2 -1575 G/A, and MMP9 Q279R were found between patients with POAG and control subjects and patients with XFG and control subjects, respectively (p>0.05). The presence of POAG or XFG was not predicted by any of the investigated polymorphisms.
CONCLUSIONS: Our data suggest that the MMP1 -1607 1G/2G, MMP2 -1306 C/T, MMP2 -1575 G/A, and MMP9 Q279R polymorphisms themselves are unlikely major risk factors among Caucasian patients with either POAG or XFG. ||||| PURPOSE: To investigate possible genetic associations of matrix metalloproteinase-1 (MMP1) and MMP3 gene polymorphisms with exfoliation syndrome (XFS) with (XFS/+G) and without (XFS/-G) glaucoma in a cohort of Greek patients.
METHODS: A total of 182 unrelated Greek patients with XFS, including 92 patients with XFS/+G, and 214 unrelated age- and gender-matched controls were enrolled in the study. MMP1 -1607 1G/2G (rs1799750) and MMP3 -1171 5A/6A (rs3025058) polymorphisms were determined using standard PCR/restriction fragment length polymorphism methods. Differences in allele and genotype distributions were analyzed using logistic regression.
RESULTS: The distribution of genotypes and alleles in MMP1 and MMP3 polymorphisms was not significantly different between cases with exfoliation syndrome, with or without glaucoma, and controls. However, the allele contrast for the MMP1 variant showed a trend for a significant association with XFS/-G (Odds Ratio=1.47 [1.03-2.10]), since after correction for multiple comparisons, this association was no longer statistically significant.
CONCLUSIONS: Our study provided some evidence of a possible role of the MMP1 variant in the development of exfoliation syndrome in Greek patients. | [
{
"source_pmid": "21709637",
"source_text": "BACKGROUND: Primary open angle glaucoma (POAG) is considered to be a leading cause of irreversible blindness worldwide. Matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) have been extensively studied as POAG risk factors. Recently, several single-nucl... |
25052803 | CONCLUSIONS: As primary therapy of OAG or OHT, SLT is no more effective than PGA in success rate. IOP reduction affected by SLT is not effective than PGA. Compared with PGA, SLT can reduce the use of anti-glaucoma medications. | PURPOSE: To study the effectiveness and safety of selective laser trabeculoplasty (SLT) on primary open-angle glaucoma and ocular hypertension in Chinese eyes.
METHODS: This was a prospective randomized controlled clinical study in which 58 eyes of 29 patients with primary open-angle glaucoma or ocular hypertension were included. One eye of each patient was randomized to receive SLT (Group 1) and the fellow eyes received medical treatment (Group 2). Patients were evaluated after laser treatment at 2 h, 1 day, 1 week, 2 weeks, 1 month, 3 months, 6 months, and then yearly.
RESULTS: All patients (13 male, 16 female) were Chinese. The mean age was 51.9 +/- 14.7 years. The mean baseline intraocular pressure was 26.8 +/- 5.6 mmHg in group 1 and 26.2 +/- 4.2 mmHg in group 2 (P = 0.62). The failure rate, defined as intraocular pressure >21 mmHg with maximal medications, was 17.2% in group 1 and 27.6% in group 2 at 5-year follow-up (P = 0.53). Eight eyes (27.6%) in group 1 required medications to control the intraocular pressure to below 21 mmHg. There was no statistically significant difference in the intraocular pressure reductions between the two groups at all time intervals (P > 0.05). The mean number of antiglaucoma medications was significantly lower in the SLT than the medical treatment group up to 5 years of follow up (P < 0.001). Transient post-SLT intraocular pressure spike >5 mmHg was observed in three eyes (10.3%).
CONCLUSION: With fewer medications, SLT gives similar intraocular pressure reduction to medical therapy alone in Chinese patients with primary open-angle glaucoma or ocular hypertension. ||||| AIM: To compare 90 degrees , 180 degrees , and 360 degrees selective laser trabeculoplasty (SLT, 532 nm Nd:YAG laser) with latanoprost 0.005% for the control of intraocular pressure (IOP) in ocular hypertension (OHT) and open angle glaucoma (OAG).
METHODS: A prospective, randomised clinical trial in the Department of Ophthalmology, St Thomas's Hospital, London, and Clayton Eye Centre, Wakefield, West Yorkshire. 167 patients (167 eyes) with either OHT or OAG were randomised to receive 90 degrees , 180 degrees , and 360 degrees SLT or latanoprost 0.005% at night and were evaluated at 1 hour, 1 day, 1 week and 1, 3, 6, and 12 months.
RESULTS: The mean follow up was 10.3 months (range 1--12 months). Early, transient, complications such as postoperative ocular pain, uveitis, and 1 hour IOP spike occurred in a number of eyes after SLT, with pain being reported more frequently after 360 degrees than 90 degrees treatments (p>0.001). Success rates defined in terms of both a 20% or more and a 30% or more IOP reduction from baseline measurements with no additional antiglaucomatous interventions were better with latanoprost than 90 degrees (p<0.001) and 180 degrees SLT (p<0.02) treatments. Differences in success rates between latanoprost and 360 degrees SLT did not reach statistical significance (p<0.5). Success rates were greater with 180 degrees and 360 degrees compared to 90 degrees SLT (p<0.05). With 360 degrees SLT, 82% of eyes achieved a >20% IOP reduction and 59% a >30% reduction from baseline. Although success rates were better with 360 degrees than 180 degrees SLT treatments, differences did not reach statistical significance. There were no differences with regard to age, sex, race, pretreatment IOP, OHT versus OAG, laser power settings, and total laser energy delivered between eyes which responded, in terms of a >20% and a >30% IOP reduction, and those that did not respond with 180 degrees and 360 degrees SLT treatments.
CONCLUSIONS: Success rates were higher with latanoprost 0.005% at night than with 90 degrees and 180 degrees SLT treatments. 90 degrees SLT is generally not effective. 360 degrees SLT appears to be an effective treatment with approximately 60% of eyes achieving an IOP reduction of 30% or more. Transient anterior uveitis with associated ocular discomfort is not unusual in the first few days after SLT. Late complications causing ocular morbidity after SLT were not encountered. ||||| PURPOSE: To compare outcomes of selective laser trabeculoplasty (SLT) with drug therapy for glaucoma patients in a prospective randomized clinical trial.
PATIENTS AND METHODS: Sixty-nine patients (127 eyes) with open-angle glaucoma or ocular hypertension were randomized to SLT or medical therapy. Target intraocular pressure (IOP) was determined using the Collaborative Initial Glaucoma Treatment Study formula. Patients were treated with SLT (100 applications 360 degrees) or medical therapy (prostaglandin analog). Six visits over 1 year followed initial treatment. If target IOP range was not attained with SLT, additional SLT was the next step, or in the medical arm additional medications were added.
PRIMARY OUTCOME: IOP; secondary: number of steps.
RESULTS: Sixty-nine patients were treated. Data collection terminated with 54 patients reaching 9 to 12-months follow-up. Twenty-nine patients were in the SLT group, 25 patients in the medical group. Baseline mean IOP for all eyes was 24.5 mm Hg in the SLT group, 24.7 mm Hg in the medical group. Mean IOP (both eyes) at last follow-up was 18.2 mm Hg (6.3 mm Hg reduction) in the SLT arm, 17.7 mm Hg (7.0 mm Hg reduction) in the medical arm. By last follow-up, 11% of eyes received additional SLT, 27% required additional medication. There was not a statistically significant difference between the SLT and medication groups.
CONCLUSIONS: IOP reduction was similar in both arms after 9 to 12-months follow-up. More treatment steps were necessary to maintain target IOP in the medication group, although there was not a statistically significant difference between groups. These results support the option of SLT as a safe and effective initial therapy in open-angle glaucoma or ocular hypertension. | [
{
"source_pmid": "15281969",
"source_text": "PURPOSE: To study the effectiveness and safety of selective laser trabeculoplasty (SLT) on primary open-angle glaucoma and ocular hypertension in Chinese eyes.\nMETHODS: This was a prospective randomized controlled clinical study in which 58 eyes of 29 patients w... |
24532137 | AUTHORS' CONCLUSIONS: This review provides some limited evidence that control of IOP is better with trabeculectomy than viscocanalostomy. For deep sclerectomy, we cannot draw any useful conclusions. This may reflect surgical difficulties in performing non-penetrating procedures and the need for surgical experience. This review has highlighted the lack of use of quality of life outcomes and the need for higher methodological quality RCTs to address these issues. Since it is unlikely that better IOP control will be offered by NPFS, but that these techniques offer potential gains for patients in terms of quality of life, we feel that such a trial is likely to be of a non-inferiority design with quality of life measures. | PURPOSE: To compare the intraocular pressure (IOP)-lowering effect and complication rate of nonpenetrating deep sclerectomy (NPDS) with reticulated hyaluronic acid (SK-GEL) scleral implant versus traditional punch trabeculectomy (PT) in the management of primary open angle glaucoma (POAG).
METHODS: Prospective, randomized comparative study including 93 patients with uncontrolled POAG. Group 1 (43 eyes) underwent NPDS with SK-GEL scleral implant; Group 2 (50 eyes) underwent PT. Mitomycin C (0.2 mg/mL) was applied intraoperatively in both techniques. Study follow-up evaluations were conducted at 36 and 48 months. Complete success indicated the achievement of the target IOP without antiglaucoma medications, while qualified success indicated the same goal with medications. These categories were assessed at two target IOP levels, <21 mmHg and <18 mmHg.
RESULTS: At 36 months for complete and qualified success with a <21 and <18 mmHg target IOP, no significant differences were noted between the two groups. At 48 months postprocedure when a <21 mmHg IOP target was considered, the rate of eyes that achieved complete success was 51.1% in the NPDS group versus 72% in the PT group (p<0.05). As for the <18 mmHg IOP target, the rate of eyes that achieved complete success was 32.5% in the NPDS group versus 44% in the PT group (p<0.05). Complications occurred significantly more frequently after PT than after NPDS.
CONCLUSIONS: The IOP-lowering effects of the two procedures were comparable at 36 months. At 48 months PT showed a significantly higher rate of complete success compared with NPDS. Complications were more frequent after PT than after NPDS. ||||| OBJECTIVE: To establish the efficacy and safety of nonpenetrating deep sclerectomy versus trabeculectomy in primary open-angle glaucoma.
DESIGN: Prospective randomized trial.
PARTICIPANTS: Thirty-nine patients (78 eyes) with bilateral primary open angle glaucoma were included in the study.
INTERVENTION: Eyes were randomly assigned to receive deep sclerectomy in one eye and trabeculectomy in the other eye.
MAIN OUTCOME MEASURES: Mean intraocular pressure (IOP), postoperative medications, visual acuity, success rate, and complications.
RESULTS: At 12 months, mean IOP reduction was 12.3 +/- 4.2 (sclerectomy) versus 14.1 +/- 6.4 mmHg (trabeculectomy) (P = 0.15), and an IOP </= 21 mmHg was achieved in 36 (92.3%) and 37 eyes (94.9%) (P = 0.9), respectively. Complications included three (7.7%) flat/shallow anterior chambers and one (2.6%) hypotony (trabeculectomy), whereas internal iris incarceration was encountered in two eyes (5.1%) (sclerectomy).
CONCLUSIONS: Deep sclerectomy may provide comparable IOP reduction with fewer complications in management of primary open angle glaucoma. ||||| PURPOSE: To compare IOP behavior after deep sclerectomy (DS) and trabeculectomy with the Crozafon-De Laage Punch (TP), using low-dosage intraoperative mitomycin C (MMC) in both techniques.
METHODS: The study was a prospective randomized clinical trial. All patients met inclusion and exclusion criteria, and were scheduled for glaucoma surgery. Forty patients were randomized to undergo either a nonpenetrating DS with MMC (DSMMC) (19 eyes) or a TP with MMC (TPMMC) (21 eyes). Postoperative examinations were performed at the 1st day, the 1st, 2nd and 3rd weeks and the 1st, 3rd, 6th, 9th and 12th months. Postoperative complications, number of antiglaucoma medications and the IOP level were checked at each control. Complete success (without antiglaucoma medications) and qualified success (with or without medications) were assessed at two target IOP levels, namely < or = 21 and < or = 17 mm Hg in both groups. Moreover, the success rates at < or = 21 mm Hg target IOP level were compared with those from previous series of patients who had undergone DS without MMC (historical control group).
RESULTS: Data from all eyes were available until the 12th month. The mean preoperative IOP +/- SD was 29.6 +/- 5.8 mm Hg in DSMMC eyes, 28.0 +/- 6.0 in TPMMC eyes; the mean IOP at the 1st postoperative day was 12.5 +/- 4.2 and 13.9 +/- 6.5 mm Hg, while at the endpoint the mean IOP was 14.5 +/- 4.0 and 16.1 +/- 3.8, respectively, with significant reduction (p < 0.0005) of the preoperative IOP in both groups. Complete success (< or = 21 mm Hg target IOP) in 15 eyes (78.9%) of the DSMMC group and in 15 eyes (71.4%) of the TPMMC group was respectively found, while qualified success was achieved in all the eyes. When a < or = 17 mm Hg target IOP was considered, complete success in 12 eyes (63.1%) and 13 eyes (61.9%), and qualified success in 13 eyes (68.4%) and 15 eyes (71.4%) were found in the DSMMC and TPMMC groups, respectively. No significant intergroup differences were found in terms of success rate. There is no statistical significance in the Kaplan-Meier cumulative survival curves as for complete and qualified success rate in both surgical groups for a < or = 17 mm Hg target IOP (log rank, p = 0.918 and p = 0.429, respectively). As for the frequency of postoperative complications, hypotony and shallow anterior chamber were significantly more frequent in TPMMC when compared with the DSMMC group. The historical comparison between the DSMMC group and simple DS cases shows no significant difference between the groups, with a mild positive trend in DSMMC when compared with DS eyes.
CONCLUSIONS: Both techniques, DSMMC and TPMMC, control IOP efficaciously at our endpoint. Our results indicate that low-dosage MMC can be considered a mild enhancement of DS IOP lowering effect without any negative effect on the well-known intra- and postoperative safety of the technique. ||||| PURPOSE: To compare the intraocular pressure-lowering effect and safety of viscocanalostomy and trabeculectomy with mitomycin C.
METHODS: Twenty-five patients with bilateral primary open-angle glaucoma were enrolled in a prospective clinical study. The eyes of each patient were randomly assigned to receive viscocanalostomy in one eye and trabeculectomy with mitomycin C in the other eye. The patients were followed up for 12 months. At each visit, best-corrected visual acuity, intraocular pressure, and the appearance of the surgical wound, anterior chamber, and indirect ophthalmoscopy were recorded.
RESULTS: The mean baseline intraocular pressure was 25.0+/-2.2 mmHg in viscocanalostomy-treated eyes and 24.8+/-2.6 mmHg in trabeculectomy-treated eyes. The mean postoperative intraocular pressure was 15.3+/-1.7 mmHg, 17.1+/-1.5 mmHg, and 17.1+/-1.5 mmHg in viscocanalostomy-treated eyes and 11.7+/-4.4 mmHg, 11.8+/-4.6 mmHg, and 12.6+/-4.3 mmHg in trabeculectomy-treated eyes at 3-, 6- and 12-month intervals, respectively. The mean intraocular pressure in viscocanalostomy-treated eyes was significantly higher than that in trabeculectomy-treated eyes at every visit (P<0.0001). At 12 months, 16 viscocanalostomy-treated eyes (64%) and 22 trabeculectomy-treated eyes (88%) achieved an intraocular pressure of less than or equal to 20 mmHg without medication; there was a significant difference between the two groups (P=0.0240). There were fewer complications in viscocanalostomy-treated eyes. Complications included four cases of shallow anterior chamber (16%) and five of hypotony (20%) in trabeculectomy-treated eyes, against intraoperative microperforation of Descemet's membrane in one of viscocanalostomy-treated eye (4%).
CONCLUSION: Trabeculectomy with mitomycin C may be more effective than viscocanalostomy in lowering intraocular pressure in patients with primary open-angle glaucoma, while eyes undergoing viscocanalostomy experience a lower incidence of complications. Further investigation of more cases is needed. ||||| PURPOSE: To compare the efficacy and safety of viscocanalostomy and trabeculectomy in patients with primary open-angle glaucoma (POAG).
SETTING: Department of Ophthalmology, Ankara Education and Research Hospital, Ankara, Turkey.
METHODS: In this prospective randomized trial, 50 eyes of 50 patients with medically uncontrolled POAG were randomized to have a trabeculectomy (25 eyes) or a viscocanalostomy (25 eyes). Visual acuity, intraocular pressure (IOP), and slitlamp examinations were performed before surgery and 1 day, 1 week, 1, 3, and 6 months, and 1, 2, and 3 years postoperatively.
RESULTS: At 3 years, the mean IOP was 16.0 mmHg +/- 7.07 (SD) in the trabeculectomy group and 17.8 +/- 4.6 mmHg in the viscocanalostomy group (P=.694). Complete success (IOP 6 to 21 mm Hg without medication) was achieved in 66.2% of eyes at 6 months and 55.1% at 3 years in the trabeculectomy group and in 52.9% and 35.3%, respectively, in the viscocanalostomy group (P>.05). Qualified success (IOP 6 to 21 mmHg with medication) was achieved in 95.8% of eyes at 6 months and 79.2% at 3 years in the trabeculectomy group and in 90.7% and 73.9%, respectively, in the viscocanalostomy group (P>.05). Postoperative hypotony and cataract formation occurred more frequently in the trabeculectomy group than in the viscocanalostomy group (P=.002).
CONCLUSIONS: Primary trabeculectomy lowered IOP more than viscocanalostomy in POAG patients. However, the complication rate was lower in the viscocanalostomy group. | [
{
"source_pmid": "18850554",
"source_text": "PURPOSE: To compare the intraocular pressure (IOP)-lowering effect and complication rate of nonpenetrating deep sclerectomy (NPDS) with reticulated hyaluronic acid (SK-GEL) scleral implant versus traditional punch trabeculectomy (PT) in the management of primary ... |
28231380 | AUTHORS' CONCLUSIONS: Perioperative medications are superior to no medication or placebo to prevent IOP spikes during the first two hours and up to 24 hours after LTP, but some medications can cause temporary conjunctival blanching, a short-term cosmetic effect. Overall, perioperative treatment was well tolerated and safe. Alpha-2 agonists are useful in helping to prevent IOP increases after LTP, but it is unclear whether one medication in this class of drugs is better than another. There was no notable difference between apraclonidine and pilocarpine in the outcomes we were able to assess. Future research should include participants who have been using these antiglaucoma medications for daily treatment of glaucoma before LTP was performed. | OBJECTIVE: The authors compared the efficacy of apraclonidine 1% versus pilocarpine 4% prophylaxis of post-argon laser trabeculoplasty (ALT) intraocular pressure (IOP) spike.
DESIGN: Prospective randomized clinical trial.
PARTICIPANTS: Two hundred twenty-eight eyes of 228 patients with primary open-angle glaucoma undergoing ALT were studied.
INTERVENTION: Patients were given 1 drop of either apraclonidine 1% (n = 114) or pilocarpine 4% (n = 114) 15 minutes before ALT.
MAIN OUTCOME MEASURES: Peri-ALT IOPs and incidences of post-ALT IOP spikes at 5 minutes, 1 hour, and 24 hours were compared between the two groups.
RESULTS: The two groups were similar in age, race, and medical dependency. Post-ALT mean IOPs at 5 minutes, 1 hour, and 24 hours were significantly lower than pre-ALT mean IOPs in both apraclonidine (P < 0.001) and pilocarpine (P < 0.001) groups. Incidences of IOP spikes greater than 1, 3, and 5 mmHg at 1 hour post-ALT were 21.1%, 14.9%, and 8.8% for the apraclonidine group and 12.3%, 5.3%, and 4.4% for the pilocarpine group (P = 0.076, 0.015, and 0.18 chi-square test). In the apraclonidine prophylaxis group, patients on long-term apraclonidine showed significantly higher incidence of post-ALT IOP spike than the patients without such long-term apraclonidine use (35.7%, 15 of 42 eyes, vs. 12.5%, 9 of 72 eyes; P = 0.003). In addition, peri-ALT pilocarpine prophylaxis tended to be less effective in patients undergoing long-term pilocarpine therapy but without statistical significance (17.4%, 8 of 46 eyes, vs. 9.4%, 6 of 64 eyes; P = 0.17).
CONCLUSION: Peri-ALT pilocarpine 4% was at least as effective as, if not more effective than, apraclonidine 1% in post-ALT IOP spike prophylaxis. Peri-ALT apraclonidine prophylaxis was not effective in patients on long-term apraclonidine, and peri-ALT pilocarpine prophylaxis tended to be less effective in patients undergoing long-term pilocarpine therapy. Pilocarpine 4% can be considered as a first-choice drug for post-ALT IOP spike prophylaxis, especially in patients under treatment with apraclonidine. ||||| A prospective, randomized, investigator-masked, parallel study compared the capability of five different intraocular pressure (IOP) lowering agents to prevent acute IOP elevations following argon laser trabeculoplasty. Two hundred sixty eyes (patients) received either apraclonidine 1% (125 eyes), pilocarpine hydrochloride 4% (37 eyes), timolol maleate 0.5% (35 eyes), dipivefrin 0.1% (32 eyes), or acetazolamide 250 mg (31 eyes) both 1 hour before and immediately following 360-degree argon laser trabeculoplasty. Apraclonidine was the only medication that significantly decreased mean IOP from baseline. Only 4 (3%) of the apraclonidine-treated eyes had IOP rises greater than 5 mm Hg. This frequency was significantly lower than that found in eyes treated with acetazolamide (39%), dipivefrin (38%), pilocarpine (33%), or timolol (32%). ||||| ALO 2145 (Apraclonidine Chlorhydrate)*, is a new hypotensive agent; it acts as a selective alpha-2-adrenergic agonist to produce a marked reduction in intraocular pressure with minimal effect on the cardiovascular system. 38 patients undergoing ocular laser surgery were allocated to treatment with either ALO 2145 1% (n = 20), or to placebo (n = 18), in a double-masked fashion. One drop of study medication was instilled into the operative eye one hour before laser surgery, and one drop immediately after the laser surgery. ALO 2145 treated eyes exhibited a significantly lower mean intraocular pressure increase in the immediate postoperative phase, compared with placebo treated eyes. ALO 2145 also significantly reduced the postoperative incidence of intraocular pressure spikes, defined as intraocular pressure increases of more than 10 mmHg over baseline (17% of cases for active treatment vs 60% of cases for placebo). ALO 2145 1% was shown to be effective and well tolerated in the dosage regimen employed in this study. ||||| Sixty patients with medically uncontrolled open-angle glaucoma (intraocular pressure greater than 21 mm Hg) were randomly assigned to one of two treatment regimens with apraclonidine before undergoing 360-degree argon laser trabeculoplasty. One drop of apraclonidine 1% was instilled one hour before and immediately after laser treatment in 30 eyes or apraclonidine was delivered only after trabeculoplasty in 30 eyes. Intraocular pressure before laser treatment, number of antiglaucoma medications, and the laser treatment settings were comparable between the two groups. The mean and percent change in intraocular pressures were similar in both treatment groups one and two hours after trabeculoplasty. One drop of apraclonidine 1% instilled immediately after argon laser trabeculoplasty prevented intraocular pressure increase one hour and two hours postoperatively as effectively as its instillation both one hour before and immediately after laser treatment. ||||| OBJECTIVE: To evaluate the efficacy of 0.5% brimonidine tartrate, an alpha 2-adrenergic agonist, in preventing intraocular pressure (IOP) elevation following argon laser trabeculoplasty.
DESIGN: In a multicenter, double-masked, randomized study, 248 patients (248 eyes) who underwent argon laser trabeculoplasty were allocated to four treatment groups: (1) brimonidine administered before and after the procedure; (2) brimonidine administered before the procedure; (3) brimonidine administered after the procedure; and (4) a vehicle administered before and after the procedure.
RESULTS: In the first 3 hours after argon laser trabeculoplasty, only one (0.54%) of the 183 brimonidine-treated patients had a postlaser IOP increase of 10 mm Hg or more, while increases of this magnitude occurred in 13 (23%) of the 56 patients who received only the vehicle (P < .001). The three brimonidine-treatment groups demonstrated significant mean reductions in IOP from the pretrabeculoplasty level (-4 to -8 mm Hg), whereas the vehicle-treated group showed an increase in mean IOP (4 mm Hg). Side effects associated with brimonidine treatment included conjunctival blanching (40.9%), lid retraction (7.6%), and a slight lowering of the systolic blood pressure.
CONCLUSIONS: One drop of 0.5% brimonidine administered either before or after surgery was found to be efficacious and safe in preventing posttrabeculoplasty elevations in IOP. ||||| A prospective, randomised double-masked study was undertaken to compare the effect of pretreatment with acetazolamide or placebo on the immediate intraocular pressure (IOP) rise following argon laser trabeculoplasty. One hundred eyes (100 patients) underwent 180 degree of laser treatment with a mean of 59 spots of 50 microns size and 800 to 1000 mW power. The IOP was measured during the first three hours after laser treatment, at 24 hours, and at two months. Forty-six patients (92%) in the placebo group had an immediate rise of IOP. The mean rise (SD) for these patients was 8.6 (7.1) mmHg. Fifteen patients (30%) in this group had an IOP rise of greater than 10 mmHg. Nine patients (18%) receiving acetazolamide had an immediate rise of IOP. The mean rise for these patients was 4.3 (3.1) mmHg, and no patient had an increase in IOP of greater than 8 mmHg. Acetazolamide appears to be effective in preventing a critical IOP rise after argon laser trabeculoplasty (p less than 0.0001). ||||| BACKGROUND AND OBJECTIVE: Brimonidine tartrate 0.5%, a topical alpha 2-adrenergic agonist, was administered before and after argon laser trabeculoplasty (ALT) to evaluate its efficacy against postoperative intraocular pressure (IOP) spikes.
PATIENTS AND METHODS: Two randomized, double-masked, vehicle-controlled investigations evaluated four treatment regimens in 471 patients undergoing ALT for glaucoma or ocular hypertension. The combined results are presented.
RESULTS: IOP elevations > or = 10 mm Hg occurred in 1% (1/122) of the patients who received brimonidine before and after ALT; in 2% (2/119) of those receiving brimonidine before and vehicle after; in 1% (1/114) of those receiving vehicle before and brimonidine after; and in 23% (27/116) of those receiving vehicle before and after (P < .001).
CONCLUSION: The brimonidine regimens were generally effective and well-tolerated ocularly and systemically. ||||| A prospective, randomized, double-masked study compared topical 1% ALO 2145, an alpha 2-agonist, with placebo in therapy for immediate postoperative intraocular pressure (IOP) rise after argon laser trabeculoplasty. Seventy-three eyes (73 patients) underwent 360 degrees of treatment utilizing 80 spots of 800 to 1000 mW of power. Intraocular pressure rise was measured hourly for the first three hours after operation, at one week, and at one month. Eyes treated with ALO 2145 had both significantly lower mean IOPs and greater IOP decreases from baseline than placebo-treated eyes during the first three hours after operation. No eyes treated with ALO 2145 and six eyes (18%) treated with placebo experienced an IOP rise of 10 mm Hg or greater. Twenty eyes (59%) in the placebo group and eight eyes (21%) treated with ALO 2145 had an IOP elevation. No change was detected in the mean heart rate. ALO 2145 appears to be effective in eliminating large, acute IOP elevations after argon laser trabeculoplasty. ||||| PURPOSE: The authors explored the empirical dosing requirement for administration of an alpha 2-adrenoceptor agonist, brimonidine, and determined its efficacy in decreasing elevations in intraocular pressure (IOP) after 360 degrees argon laser trabeculoplasty (ALT).
METHODS: This vehicle-controlled, double-masked, multicenter trial evaluated three dosing regimens of brimonidine. Two hundred thirty-two patients for whom 360 degrees ALT was indicated were randomized into one of four treatment groups: 0.5% brimonidine both before and after ALT; brimonidine before but vehicle after ALT; vehicle before but brimonidine after ALT; or vehicle at both times.
RESULTS: During the first 3 hours after 360 degrees ALT, the overall incidence of IOP elevations of 5 mmHg or greater was 38% (23 of 60 eyes) in the group receiving vehicle only, and it ranged from 3% to 9% (2 of 62 to 5 of 53 eyes) in the groups receiving any brimonidine treatment. There was little difference in efficacy between the three dosing regimens of brimonidine. Brimonidine was well tolerated by the patients.
CONCLUSION: Based on this large, controlled, multicenter study, 0.5% brimonidine was an effective agent for reducing elevations in IOP after 360 degrees ALT. Only one dose, administered either before or after 360 degrees ALT, was required. ||||| BACKGROUND AND OBJECTIVE: Both apraclonidine hydrochloride 0.5% and brimonidine tartrate 0.5% are potent alpha-2 agonists, effective in controlling the intraocular pressure (IOP) rise following argon laser trabeculoplasty (ALT). Brimonidine has recently become available commercially as a 0.2% solution. Our goal in this study was to compare the efficacy and side effect profile of 0.2% brimonidine to that of 0.5% apraclonidine in the prevention of IOP spikes following anterior segment laser procedures.
PATIENTS AND METHODS: Patients undergoing argon laser trabeculoplasty, Nd:Yag peripheral iridectomy or posterior capsulotomy were prospectively randomized to receive either apraclonidine 0.5% or brimonidine 0.2%, approximately 10 minutes prior to laser surgery. Intraocular pressure was measured by a masked observer, using Goldmann applanation tonometry, before and 1 hour after the treatment.
RESULTS: 51 ALTs, 21 peripheral iridectomies, and 13 posterior capsulotomies were performed. The incidence of an IOP rise greater than 5 mmHg was 3/43 (7.0%) in the brimonidine group and 0/42 (0%) in the apraclonidine group (P = 0.08, chi-squared). There were no IOP elevations greater than 8 mmHg. All IOP rises of greater than 5 mmHg occurred in the ALT sub-group, and within this sub-group, the mean change in IOP from pre- to post-op was -4.00 +/- 5.87 in the brimonidine group versus -4.29 +/- 3.86 in the apraclonidine group (P = 0.84). There was a statistically significant decrease in IOP from baseline in both drug groups (P < .0001).
CONCLUSIONS: Both drugs are highly effective in controlling IOP spikes following anterior segment laser procedures. There is a tendency toward higher risk of IOP rise following argon laser trabeculoplasty with 0.2% brimonidine as compared to 0.5% apraclonidine, however, this was not statistically significant. ||||| Apraclonidine and pilocarpine have been shown to be effective in reducing the incidence of intraocular pressure (IOP) spikes following argon laser trabeculoplasty. An additional reduction in the incidence of acute pressure rise might theoretically be expected by combining these two effective agents. In a prospective randomised study we compared the ability of apraclonidine and pilocarpine alone and in combination to prevent post laser pressure spikes. Patients receiving regular pilocarpine to either eye were excluded. Seventy five eyes received either apraclonidine (26 eyes), pilocarpine (23 eyes), or both drugs (26 eyes). Apraclonidine 1% was instilled 1 hour before and immediately after, and pilocarpine 4% immediately after trabeculoplasty. IOP was measured before and at 1, 2, and 3 hours following trabeculoplasty. In only two (8%) eyes receiving combined treatment was a pressure rise observed. This frequency was significantly lower than that seen in eyes treated with apraclonidine alone (38%), or pilocarpine alone (39%). The mean fall in IOP at 1, 2, and 3 hours was significantly greater in those eyes receiving combined treatment than in the other two groups. ||||| PURPOSE: To evaluate the efficacy of 2% dorzolamide hydrochloride opthalmic solution in preventing spikes in intraocular pressure (IOP) after anterior segment laser surgery.
METHODS: This 24-hour, placebo-controlled, randomized, double-masked, multicenter evaluation was conducted to determine the efficacy of dorzolamide hydrochloride 2% in controlling IOP after neodimium:yttrium-aluminum-garnet (Nd:YAG) laser capsulotomy, argon laser trabeculoplasty, or laser iridotomy. The 122 patients enrolled were assigned in randomized fashion to receive dorzolamide or placebo 1 hour before and immediately after the procedure; IOP was measured 1, 2, 3, 4, and 24 hours after the procedure.
RESULTS: Of 61 patients receiving dorzolamide, only one (1.7%) had a spike in IOP of 10 mmHg or more, compared with 9 (14.8%) of the 61 patients receiving placebo. Mean IOP among patients receiving dorzolamide was significantly reduced both from baseline and compared with that among patients receiving placebo from 1 to 4 hours after administration. Only 5 (8%) of the 61 patients receiving dorzolamide experienced at least one adverse event, compared with 15 (25%) of the 61 patients receiving placebo.
CONCLUSION: Dorzolamide was effective in preventing spikes in IOP after anterior segment laser surgery. Dorzolamide was generally well tolerated after short-term use. ||||| Brimonidine tartrate of 0.5% was identified as the most effective and safe dose for acute intraocular pressure (IOP) lowering. The efficacy of brimonidine tartrate 0.2% in preventing IOP elevation after an argon laser trabeculoplasty (ALT) was evaluated. Eighty patients were selected for a randomized, prospective study. Each patient was assigned to one of four treatment regimens: (1) brimonidine before and after ALT(B/B), (2) brimonidine before and placebo after ALT(B/P), (3) placebo before and brimonidine after ALT(P/B), (4) placebo before and after ALT(P/P). IOP elevation of 5 mmHg or greater occurred in 3.3% (2/60) of brimonidine-treated patients and in 30% (6/20) of placebo-treated patients. There was a mean decrease of IOP from baseline during the first 3 hours after ALT in all brimonidine-treated groups (7.1 +/- 3.4, 6.2 +/- 4.4, 3.5 +/- 2.9 mmHg for the B/B, B/P, P/B groups), but no change of mean IOP in the Placebo-treated group. Only one drop of brimonidine tartrate of 0.2% installed either before or after ALT was sufficient to prevent post-ALT IOP spike and minimize the undesired systemic adverse effects that two drop installation can produce. ||||| The aim of this meta-analysis was to evaluate the association between cyclin-dependent kinase Inhibitor-2B (CDKN2B) gene rs1063192 polymorphism and glaucoma risk. We searched the databases of PubMed, and Embase. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by using fixed-effect or random-effect models. A total of 14 case-control studies involving 11,316 cases and 24,055 controls were included. Meta-analysis showed that CDKN2B gene rs1063192 polymorphism was associated with a decreased risk of glaucoma. Stratification analysis of ethnicity indicated that rs1063192 polymorphism decreased the risk of glaucoma among Caucasians and Asians. Stratification analysis by type of glaucoma revealed that rs1063192 polymorphism conferred a protective factor of primary open-angle glaucoma (POAG) and non-POAG. Stratification by source of controls uncovered an association between rs1063192 polymorphism and glaucoma in groups of population-based controls. In conclusion, this meta-analysis indicates that CDKN2B gene rs1063192 polymorphism is significantly associated with a decreased risk of glaucoma. ||||| The effect of pilocarpine pretreatment on the transient pressure elevations immediately following primary laser trabeculoplasty was investigated in a prospective, randomised study. Fifty eyes of 50 patients, 33 with exfoliative and 17 with simple glaucoma, were treated in 360 degrees of the trabecular meshwork. The mean maximum pressure increase was 2.4 (SD = 4.4)mm Hg with pilocarpine pretreatment and 12.8 (SD = 11.2)mm Hg without pretreatment (p less than 0.05). Except in two cases, all peak pressures appeared during the first two hours after treatment. The degree of chamber angle pigmentation was predictive of the magnitude of the post laser hypertensive pressure response in eyes without pretreatment (p less than 0.05). ||||| OBJECTIVE: To determine whether brimonidine 0.2% can control intraocular pressure (IOP) spikes as well as apraclonidine 1.0% can in those patients undergoing argon laser trabeculoplasty (ALT).
DESIGN: Prospective, randomized, double-masked, clinical trial.
PARTICIPANTS: A total of 56 eyes of 41 patients with open-angle glaucoma or ocular hypertension were entered in the study; 46 eyes of 41 patients were eventually used for the final analysis.
INTERVENTION: Patients were randomized to receive either brimonidine 0.2% or apraclonidine 1.0% before and after 360 degrees ALT. Both patient and physician were masked as to which agent each patient received.
MAIN OUTCOME MEASURES: Intraocular pressure measurements were recorded before surgery and at 1, 2, and 4 hours after surgery. The difference between the preoperative IOP (baseline) and the highest recorded postoperative IOP was recorded as the maximum IOP change. The mean of the maximum IOP change for each group was analyzed using a two-sample, one-tailed t test.
RESULTS: The mean of the maximum IOP change in the brimonidine 0.2% group was -2.6+/-3.6 mmHg, and the mean for the apraclonidine 1.0% group was -2.3+/-3.7 mmHg (P = 0.8). No patient had a pressure spike greater than 10 mmHg.
CONCLUSIONS: Brimonidine 0.2% appears to be as effective as apraclonidine 1.0% in preventing IOP spikes after argon laser trabeculoplasty. ||||| The effect of an alpha adrenergic agonist, ALO 2145 (para-amino-clonidine [PAC]), was examined in a double-masked, multicenter study on the postoperative intraocular pressure (IOP) elevation after laser surgery in 165 patients (83 trabeculoplasty, 36 iridotomy, and 46 capsulotomy). One drop of 1.0% ALO 2145 or vehicle was instilled 1 hour before and immediately after laser surgery. The mean IOP increase in the ALO 2145-treated group was lower (P less than 0.05) than in the placebo group at each of the first three postoperative hours. Overall, 18% of placebo-treated eyes experienced IOP increases greater than or equal to 10 mmHg as compared with 4% of ALO 2145-treated eyes (P less than 0.003). Ocular and systemic side effects were minimal and did not differ between the treatment groups. ALO 2145 safely and effectively reduced the incidence and magnitude of potentially harmful IOP elevations after anterior segment laser surgery. | [
{
"source_pmid": "10366082",
"source_text": "OBJECTIVE: The authors compared the efficacy of apraclonidine 1% versus pilocarpine 4% prophylaxis of post-argon laser trabeculoplasty (ALT) intraocular pressure (IOP) spike.\nDESIGN: Prospective randomized clinical trial.\nPARTICIPANTS: Two hundred twenty-eight ... |
26147908 | CONCLUSION: Both iStent implantation with concurrent phacoemulsification and phacoemulsification alone result in a significant decrease in IOP and topical glaucoma medications. In terms of both reductions, iStent with phacoemulsification significantly outperforms phacoemulsification alone. | AIM: To evaluate the influence of clear cornea phacoemulsification on filtering bleb morphology, function, and intraocular pressure (IOP) in glaucomatous eyes with previously successful filtering surgery.
METHODS: The clinical course of 30 patients (30 eyes) who underwent clear cornea phacoemulsification after successful filtering glaucoma surgery was prospectively evaluated. Mean IOP and filtering bleb morphology (standardised assessment criteria and score 0-12, 12 = optimum) were determined before surgery, and 3 days, 6 months, and 12 months after surgery. The control group consisted of 36 patients with glaucoma after clear cornea phacoemulsification without previous filtering surgery.
RESULTS: Mean IOP increased after phacoemulsification by about 2 mm Hg (preoperatively 14.28 (SD 3.71) mm Hg, 12 months postoperatively 16.33 (3.31) mm Hg, p = 0.006). 15 patients (50%) showed an IOP increase of >2 mm Hg, 11 patients (36.7%) had no IOP difference (within 2 mm Hg), and in four patients (13.3%) IOP decreased >2 mm Hg. Mean score of filtering bleb morphology 1 year after surgery decreased from 9.5 to 9.0 (p = 0.154). In three of 30 preoperatively IOP regulated eyes the postoperative IOP was 21 mm Hg. The control group showed an average IOP decrease of 2.01 mm Hg (p = 0.014) 12 months after cataract surgery.
CONCLUSION: An increase in IOP was found 1 year after phacoemulsification in half of the filtered glaucomatous eyes. IOP in glaucomatous eyes without previous filtering surgery decreased in the same period. Cataract extraction using clear cornea phacoemulsification may be associated with a partial loss of the previously functioning filter and with an impairment of filtering bleb morphology. ||||| PURPOSE: To compare phacoemulsification alone and phacoemulsification with micro-bypass stent implantation in eyes with primary open-angle glaucoma.
SETTING: Instituto di Fisiopatologia Clinica, Clinica Oculistica, Universita' di Torino, Torino, Italy.
METHODS: In this prospective double-masked randomized clinical trial, patients had phacoemulsification alone (control group) or phacoemulsification with iStent implantation (combined group). Primary outcomes were intraocular pressure (IOP) and reduction in medication use over 15 months and IOP after a 1-month washout of ocular hypotensive agents (ie, 16 months postoperatively).
RESULTS: The baseline IOP was similar between groups (combined group: 17.9 mm Hg +/- 2.6 [SD]; control group: 17.3 +/- 3.0 mm Hg) (P = .512). Three patients in the control group were lost to follow-up. The mean IOP was 14.8 +/- 1.2 mm Hg in the combined group and 15.7 +/- 1.1 mm Hg in the control group at 15 months and 16.6 +/- 3.1 mm Hg and 19.2 +/- 3.5 mm Hg, respectively, after washout; the IOP was statistically significantly lower in the combined group than in the control group at both time points (P = .031 and P = .042, respectively). At 15 months, the mean number of medications was lower in the combined group than in the control group (0.4 +/- 0.7 and 1.3 +/- 1.0, respectively; P = .007), as was the proportion of patients on ocular hypotensive medication (33% and 76%, respectively).
CONCLUSIONS: Phacoemulsification with stent implantation was more effective in controlling IOP than phacoemulsification alone; the safety profiles were similar. ||||| PURPOSE: To determine the change in intraocular pressure (IOP) after cataract extraction in the observation group of the Ocular Hypertension Treatment Study.
DESIGN: Comparative case series.
PARTICIPANTS: Forty-two participants (63 eyes) who underwent cataract surgery in at least 1 eye during the study and a control group of 743 participants (743 eyes) who did not undergo cataract surgery.
METHODS: We defined the "split date" as the study visit date at which cataract surgery was reported in the cataract surgery group and a corresponding date in the control group. Preoperative IOP was defined as the mean IOP of up to 3 visits before the split date. Postoperative IOP was the mean IOP of up to 3 visits including the split date (0, 6, and 12 months' with "0 months" equaling the split date). In both groups, we censored data after initiation of ocular hypotensive medication or glaucoma surgery of any kind.
MAIN OUTCOME MEASURES: Difference in preoperative and postoperative IOP.
RESULTS: In the cataract group, postoperative IOP was significantly lower than the preoperative IOP (19.8 ± 3.2 mmHg vs. 23.9 ± 3.2 mmHg; P<0.001). The postoperative IOP remained lower than the preoperative IOP for at least 36 months. The average decrease in postoperative IOP from preoperative IOP was 16.5%, and 39.7% of eyes had postoperative IOP ≥ 20% below preoperative IOP. A greater reduction in postoperative IOP occurred in the eyes with the highest preoperative IOP. In the control group, the corresponding mean IOPs were 23.8 ± 3.6 before the split date and 23.4 ± 3.9 after the split date.
CONCLUSIONS: Cataract surgery decreases IOP in patients with ocular hypertension over a long period of time. ||||| AIMS: To evaluate the mid-term efficacy and safety of the GTS-400-iStent combined with phacoemulsification in patients with cataract and open-angle glaucoma (OAG) or ocular hypertension (OHT).
METHODS: Prospective, non-comparative, uncontrolled, interventional case series study. Subjects underwent phacoemulsification and two GTS-400 implantation. Efficacy outcomes: intraocular pressure (IOP) and antiglaucoma medications. Safety outcomes: complications, best-corrected visual acuity and endothelial cell count (ECC). Follow-up was 1 year.
RESULTS: 20 patients were enrolled (mean age: 75.1 ± 8.6 years). Mean medicated baseline IOP was 19.95 ± 3.71 mm Hg and 26 ± 3.11 mm Hg without medication. Mean final IOP was 16.75 ± 2.24, determining a final IOP decrease of 35.68% (9.42 ± 3 mm Hg; p<0.001), from baseline washout IOP. Mean number of medications fell from 1.3 ± 0.66 to 0.3 ± 0.57 (P<0.001). 75% of patients were off medications at one year. Mean ECC decreased from 2289.64 ± 393.5 cells/mm(2) to 1986.95 ± 520.58 cells/mm(2).
CONCLUSIONS: Combined cataract surgery with implantation of GTS-400-iStent seems to be an effective and safe procedure. ||||| OBJECTIVE: To investigate the effect of cataract extraction on the visual fields of patients with open-angle glaucoma.
METHODS: Patients in a prospective cohort study in a tertiary center underwent standard automated perimetry every 6 months. We compared the mean results of the 2 examinations immediately before and 2 examinations immediately after phacoemulsification cataract extraction and intraocular lens implant (effect analysis) and the mean results of the first 2 and last 2 examinations from 4 consecutive examinations obtained more than 1 year after the cataract surgery (control analysis).
RESULTS: Our sample contained 34 eyes of 26 patients (mean +/- SD age, 69.2 +/- 10.8 years). While the mean logMAR best-corrected visual acuity improved significantly by approximately 2 Snellen lines after surgery (P < .001), the average change in mean deviation in both the effect and control analyses was less than 0.1 dB and not statistically significant (P = .85). There was a strong correlation between change in foveal sensitivity and change in mean deviation in the effect analysis but not in the control analysis (r = 0.76 [P < .001] and r = 0.30 [P = .08], respectively). There was no relationship between change in visual acuity or initial mean deviation and change in mean deviation in either analysis. Change in pointwise total deviation was not systematically related to the respective baseline value in either analysis; however, the variance of the distribution of change in total deviation was significantly higher in the effect analysis (P < .001).
CONCLUSION: While there was an improvement in best-corrected visual acuity after cataract surgery, the changes in the visual field as a group were negligible. ||||| PURPOSE: To study the mode of intraocular pressure (IOP) reduction based on correlation with the preoperative IOP after filtering and nonfiltering surgeries.
METHODS: Pre- and postsurgical IOPs at 6 months were compared in one eye of each of 789 subjects with primary open-angle glaucoma, pseudoexfoliation glaucoma, or ocular hypertension who underwent trabeculectomy with adjunctive mitomycin C alone (Lectomy-MMC) (n = 145), phaco-viscocanalostomy (Phaco-VCS) (n = 320), phaco-trabeculotomy ab externo (Phaco-lotomy) (n = 116), or phacoemulsification aspiration and intraocular lens implantation alone (PEA+IOL) (n = 208).
RESULTS: The correlation between the preoperative and 6-month postoperative IOP was not significant in eyes that underwent Lectomy MMC (r = -0.026, P = 0.7552, IOP reduction 51.9%), but was significant in eyes treated by Phaco-VCS (r = 0.409; IOP reduction, 24.8%) or PEA+IOL alone (r = 0.294; IOP reduction, 9.9%), and was marginal in eyes treated by Phaco-lotomy (P = 0.062; r = 0.174; IOP reduction, 24.1%). Among the four cohorts studied, the variation in the 6-month postoperative IOP was the largest after Lectomy-MMC.
CONCLUSION: After glaucoma surgery, there are two modes of IOP reduction. The postoperative IOP after Lectomy MMC did not correlate with the preoperative IOP, whereas the postoperative IOP levels after Phaco-VCS, Phaco-Lotomy, and PEA+IOL correlated with preoperative IOP levels. We may be able to predict postsurgical IOP after nonfiltering surgery. ||||| AIM: To evaluate daily tonometric curves after cataract surgery in patients with cataract only and in patients with cataract and glaucoma.
METHODS: 108 patients scheduled for cataract surgery were randomly allocated to two groups: 57 patients with cataract only (normal) and 51 with cataract and primary open angle glaucoma (POAG). All patients underwent extracapsular cataract extraction (ECCE) (manual technique with long wound), phacoemulsification (automated technique with short wound), or nucleus capture (manual technique with short wound). Intraocular pressure (IOP) was measured by Goldmann tonometry in all patients every 2 hours for 12 hours before the operation and at 1 and 6 months postoperatively.
RESULTS: 79 patients completed the 6 month examination. ECCE resulted in greater reductions in IOP than the other procedures (ECCE: 27% and 36% in normal patients and those with POAG, respectively; nucleus capture: 20% and 31%, respectively; phacoemulsification: 19% and 22%, respectively). The fluctuations in IOP before and after surgery were not statistically significant.
CONCLUSION: Cataract surgery in normal patients reduces IOP but does not eliminate fluctuations which are directly proportional to the IOP value and result partly from circadian rhythms. This important finding might influence our approach to treatment of patients with glaucoma. ||||| BACKGROUND: To evaluate the 6-month efficacy and safety of the iStent microtrabecular bypass stent in patients with open-angle glaucoma.
DESIGN: A prospective, uncontrolled, interventional case series.
PARTICIPANTS: Forty-four eyes with open-angle glaucoma were reported.
METHODS: All subjects underwent ab interno implantation of a single iStent together with (n = 40) or without (n = 4) cataract surgery.
MAIN OUTCOME MEASURES: Patients were assessed at postoperative week 1, months 1 and 3, and quarterly, thereafter. Data collected included visual acuity, intraocular pressure measurement using Goldmann tonometry, number of glaucoma medications, and number and type of complications.
RESULTS: The mean age of the sample was 76.8 years. The mean duration since glaucoma diagnosis was 5.3 years (standard deviation 2.9 years). The mean visual acuity was 0.53 logMAR at baseline that improved to 0.23 at 6 months postoperatively. The mean baseline intraocular pressure was 21.1 mmHg, and this decreased significantly to 16.7 mmHg at 6 months (P < 0.01). The mean number of drops prescribed preoperatively was 2.3, which decreased to 0.6 at 6 months (P < 0.01). Sixty-six per cent of patients were drop-free at 6 months. One patient developed an hyphaema following surgery; no other adverse events were recorded.
CONCLUSIONS: The iStent proved to be a safe and effective treatment for patients with open-angle glaucoma over our 6-month follow up period. Insertion resulted in a significant decrease in intraocular pressure as well as the number of topical antiglaucoma medications required for adequate intraocular pressure control. ||||| INTRODUCTION: Reducing intraocular pressure (IOP) is the only proven treatment modality for reducing the risk of glaucomatous progression. In this study, we evaluated the safety and efficacy of a new tool in IOP reduction, implanted with cataract surgery: the Glaukos iStent trabecular micro-bypass stent.
METHODS: This was a prospective, 24-month, uncontrolled, non-randomised, multicentre study. Subjects with uncontrolled primary open-angle glaucoma (including pseudoexfoliation and pigmentary) and a cataract underwent clear cornea phacoemulsification cataract extraction with ab-interno gonioscopically guided implantation of the study stent. Subjects who had completed at least 6 months of follow-up were included in this interim analysis (n=47).
RESULTS: At baseline, mean (+/-standard deviation) IOP was 21.5+/-3.7 mmHg, and subjects were taking a mean of 1.5+/-0.7 ocular hypotensive medications. Six months after implantation of the study stent the mean IOP was 15.8+/- 3.0 mmHg, a mean IOP reduction of 5.7+/-3.8 mmHg (25.4%, P<0.001). The mean number of patient medications after 6 months was 0.5+/-0.8 medications, a mean decrease of 1.0+/-0.8 medications (66.7%, P<0.001). Most subjects (70%) were able to discontinue all glaucoma medications. There were no complications traditionally associated with filtering surgery, and no serious adverse events were reported.
CONCLUSION: In this interim analysis of subjects with glaucoma and cataracts, this novel stent implantation in subjects undergoing cataract surgery represents a new surgical approach to provide clinically significant decreases in IOP and drug burden. ||||| PURPOSE: To study the effect of phacoemulsification and intraocular lens implantation (PHACO IOL) on intraocular pressure (IOP) and glaucoma medication in open-angle glaucoma (OAG) eyes.
METHODS: 38 open-angle glaucoma (OAG) eyes with cataract underwent phacoemulsification and intraocular lens implantation (PHACO IOL) performed by one surgeon (RJU). None of the patients had prior intraocular surgery. Surgery was performed by scleral incision on 37% and by clear corneal incision on 63%. Patients were re-examined on the first postoperative day, after one week, 4 months, and in 29 cases 1-3.7 (mean 2.8) years after the operation.
RESULTS: The mean preoperative IOP was 18.4+/-3.3 mmHg with a mean of 1.7 glaucoma medications. On the first postoperative day, the mean IOP rose to 28.2 +/- 12.5 mmHg. IOP > or = 30 mmHg occurred in 39.5% of the eyes. After one week, IOP had returned to the preoperative level. After 4 months, IOP had further decreased to 16.1 +/- 3.8 mmHg (p = 0.0027). After a mean follow-up of 1-3.7 (mean 2.8) years, the average postoperative IOP was 15.1 +/- 2.9 mmHg, being significantly (p = 0.001) lower than the preoperative IOP with 86% of the patients having a mean of 1.6 drugs on average. The type of incision (scleral vs. corneal) did not affect the postoperative IOP level. Using the criteria of Bigger and Becker (1971) the long-term IOP control after PHACO-IOL surgery was improved or unchanged in 86% and worse in 14% of the preoperatively well-controlled OAG eyes.
CONCLUSIONS: In OAG eyes PHACO IOL is associated with a significant decrease in IOP with less medication up to 1-3.7 (mean 2.8) years. ||||| PURPOSE: To assess the long-term effect of vitreous loss during phacoemulsification on intraocular pressure (IOP) control in glaucoma patients.
SETTING: Birmingham and Midland Eye Centre, City Hospital, Birmingham, United Kingdom.
METHODS: In this study, 26 glaucoma cases with vitreous loss during phacoemulsification were identified from operative room records. The cases were performed from January 1999 to December 2001. Minimum follow-up was 12 months. Postoperative IOP control in eyes with vitreous loss (Group 1) was assessed and compared with that in stable fellow eyes (Group 2), which served as controls. Another control group (Group 3) comprised patients with primary open-angle glaucoma who had successful phacoemulsification. Case notes of 22 patients from the same period fulfilled these criteria.
RESULTS: The 3 groups were comparable in age, sex, laterality, ethnicity, mean IOP, and mean number of medications preoperatively. Twelve months after surgery, 43.2% in Group 1, 23.1% in Group 2 (P<.05) and 4.5% in Group 3 had significantly worse IOP; the differences between Group 1 and Groups 2 and 3 were statistically significant (P<.05). Intraocular pressure control was significantly better in Group 3 than in Group 2 (P<.05).
CONCLUSIONS: Vitreous loss during cataract surgery in glaucoma patients adversely affected IOP control in the long term. Results suggest that uneventful cataract surgery in glaucoma patients improves IOP control. ||||| OBJECTIVE: To assess the safety and efficacy of the iStent trabecular micro-bypass stent (Glaukos Corporation, Laguna Hills, CA) in combination with cataract surgery in subjects with mild to moderate open-angle glaucoma.
DESIGN: Prospective, randomized, open-label, controlled, multicenter clinical trial.
PARTICIPANTS: A total of 240 eyes with mild to moderate open-angle glaucoma with intraocular pressure (IOP) ≤24 mmHg controlled on 1 to 3 medications were randomized to undergo cataract surgery with iStent implantation (treatment group) or cataract surgery only (control). Fifty additional subjects were enrolled to undergo cataract surgery with iStent implantation under protocol expansion. Data in this report are based on the first 240 eyes enrolled.
INTERVENTION: Implantation of the iStent trabecular micro-bypass stent in conjunction with cataract surgery or cataract surgery only.
MAIN OUTCOME MEASURES: The primary efficacy measure was unmedicated IOP ≤21 mmHg at 1 year. A secondary measure was unmedicated IOP reduction ≥20% at 1 year. Safety measures included best-corrected visual acuity (BCVA), slit-lamp observations, complications, and adverse events.
RESULTS: The study met the primary outcome, with 72% of treatment eyes versus 50% of control eyes achieving the criterion (P<0.001). At 1 year, IOP in both treatment groups was statistically significantly lower from baseline values. Sixty-six percent of treatment eyes versus 48% of control eyes achieved ≥20% IOP reduction without medication (P = 0.003). The overall incidence of adverse events was similar between groups with no unanticipated adverse device effects.
CONCLUSIONS: Pressure reduction on fewer medications was clinically and statistically significantly better 1 year after stent plus cataract surgery versus cataract surgery alone, with an overall safety profile similar to that of cataract surgery alone. ||||| PURPOSE: To evaluate the safety and efficacy of the iStent Trabecular Micro-bypass Stent in patients undergoing concurrent cataract and glaucoma surgery.
METHODS: Prospective, 24-month, uncontrolled, multicenter, multicountry evaluation of 58 patients with uncontrolled primary open-angle glaucoma (including pseudoexfoliation and pigmentary) and cataract. Patients underwent clear cornea phacoemulsification followed by ab interno gonioscopically guided implantation of the iStent. Of the 48 per protocol population, 42 patients completed 12 months of the 24-month study, and their data are included in this interim analysis.
RESULTS: At baseline, mean (+/-SD) intraocular pressure (IOP) was 21.7+/-3.98 mmHg. At 12 months, mean IOP was reduced to 17.4+/-2.99 mmHg, a mean IOP reduction of 4.4+/-4.54 mmHg (p<0.001, 18.3%). At baseline, patients were taking a mean 1.6+/-0.8 medications. By 12 months, the mean number of medications was reduced to 0.4+/-0.62 (p<0.001). Half the patients achieved an IOP < or =18 mmHg and were able to discontinue hypotensive medication by the 12-month visit. The most commonly reported device-related adverse events were the appearance of stent lumen obstruction (7 eyes) and stent malposition (6 eyes). None of the adverse events were deemed serious.
CONCLUSIONS: In patients undergoing concurrent cataract and glaucoma surgery, the iStent was safe and efficacious for the reduction of IOP and medication therapy. ||||| PURPOSE: To determine the intraocular pressure (IOP) response to phacoemulsification cataract extraction with posterior chamber intraocular lens (PC IOL) implantation in patients with pseudoexfoliation syndrome.
SETTING: Eye clinics at the University of Ottawa Eye Institute, Ottawa, Ontario, Canada.
METHODS: A retrospective cohort study design assigned patients to 1 of 3 subgroups: pseudoexfoliation syndrome (PEX) (n = 21), primary open-angle glaucoma (POAG) control (n = 23), and cataract control (n = 23). Inclusion criteria consisted of age older than 50 years, open angle by gonioscopy, and a cataract requiring phacoemulsification. The IOP response was determined at intervals up to 18 months.
RESULTS: Postoperative IOP changes from baseline in the PEX group were -1.81, -4.52, and -2.31 mm Hg at 3, 6, and 12 months, respectively. The changes in the POAG control group were -2.22, -2.32, and -1.88 mm Hg, respectively, and in the cataract control group, -2.49, +0.45, and +0.28 mm Hg. Patients in the PEX group had a reduction in IOP from baseline at all postoperative measurements. That reduction was significantly greater than in the POAG and cataract control groups at 6 months (P =.012 and P =.002, respectively) and 12 months (P =.001 and P =.050, respectively).
CONCLUSIONS: Patients with pseudoexfoliation syndrome had a postoperative IOP reduction from baseline at all measurements and a significantly greater reduction than patients in the POAG and cataract control groups at 6 and 12 months. Phacoemulsification cataract surgery with PC IOL implantation may be effective in managing patients with pseudoexfoliation syndrome who have elevated IOP and visually significant cataract but no advanced optic nerve damage. ||||| PURPOSE: To evaluate intraocular pressure (IOP) after phacoemulsification in patients with medically controlled open-angle glaucoma (OAG), and examine the association of biometric variables to IOP changes.
DESIGN: Retrospective case series.
METHODS: Open-angle glaucoma patients without prior incisional glaucoma surgery undergoing phacoemulsification by a single surgeon between January 1997 and October 2011 were evaluated. Patient charts were reviewed to obtain demographic information, preoperative glaucoma medications, severity and treatment measures, and preoperative and postoperative IOP.
RESULTS: A total of 157 eyes (157 patients) were included in the study. The average preoperative IOP of 16.3 ± 3.6 mm Hg decreased to 14.5 ± 3.4 mm Hg at 1 year (P < .001). Sixty eyes (38%) required additional medications or laser for IOP control within the first year postoperatively, or had a higher IOP at postoperative year 1 without medication change. Among eyes without postoperative medication changes (n = 102), higher preoperative IOP (P < .001), older age (P = .006), and deeper anterior chamber depth (P = .015) were associated with lower postoperative IOP.
CONCLUSIONS: Phacoemulsification resulted in a small average decrease in IOP in patients with OAG. A sizeable proportion of medically controlled glaucoma patients with open angles undergoing phacoemulsification experienced an increase in IOP or required more aggressive treatment to control IOP postoperatively. ||||| PURPOSE: To evaluate long-term IOP control after sutureless clear corneal phacoemulsification in eyes with preoperatively controlled glaucoma.
SETTING: Institutional study.
METHODS: The charts of 345 patients who had uneventful sutureless clear corneal phacoemulsification with acrylic foldable lens (IOL) implantation were retrospectively reviewed. Included were 58 patients with medically controlled open-angle glaucoma and 287 normal controls. Follow-up was 1 to 2 years. Outcome measures were postoperative IOP and number of glaucoma medications.
RESULTS: Postoperatively, there was an insignificant decrease in IOP in the glaucoma group; the mean decrease was 1.5 mm Hg +/- 4.4 (SD) at 12 months and 1.9 +/- 4.9 mm Hg at 24 months. The mean number of medications decreased significantly at 12 months (0.53 +/- 0.86) and at 24 months (0.38 +/- 0.9) (P=.04). The control group also had a significant decrease in IOP, with a mean decrease of 0.72 +/- 3.7 mm Hg at 12 months (P=.01) and 1.33 +/- 3.2 mm Hg at 24 months (P<.0001). The decrease in IOP was more pronounced in eyes with a higher preoperative IOP in both the glaucoma and control groups.
CONCLUSIONS: These findings suggest that sutureless clear corneal phacoemulsification with foldable acrylic IOL implantation is a relatively simple and efficient surgical option in patients with cataract and well-controlled glaucoma. The approach combines long-term IOP control with fewer medications and leads to rapid visual rehabilitation. ||||| AIM: To determine the long term intraocular pressure (IOP) response to phacoemulsification in patients with and without exfoliation syndrome (XFS).
METHODS: Prospective, multicentre, cohort study with the following inclusion criteria: age over 50 years, open iridocorneal angle, and cataract. Two groups were enrolled: those with XFS and those without. The main outcome was mean IOP reduction 2 years after phacoemulsification cataract extraction (PCE). Univariate and multivariate analyses were performed.
RESULTS: 183 patients were enrolled, 71 with and 112 without XFS. There were 29 patients with glaucoma in both groups. Mean baseline IOP was higher in XFS compared to control eyes (17.60 (SD 3.23) mm Hg v 16.08 (3.18) mm Hg, p = 0.002). Overall IOP reduction was significantly greater in the XFS group at the 2 year time point (-1.85 mm Hg v -0.62 mm Hg in the controls (p = 0.0037)). Multivariate analysis demonstrated that the IOP lowering effect in the XFS group may be related to irrigation volume at the time of surgery. In the subgroup analyses IOP lowering was significantly greater in the XFS and XFG patients than in controls without glaucoma, and POAG controls, respectively. The percentage of patients with a postoperative IOP spike was similar and relatively high in both XFS and control groups (34% v 25%; p = 0.54).
CONCLUSION: IOP decreases more in patients with XFS following PCE compared to control eyes without XFS. This effect is more pronounced in glaucoma patients and persists for at least 2 years. ||||| PURPOSE. To evaluate the changes in aqueous humor dynamics and the efficacy and safety of the iStent (Glaukos Corp., Laguna Hills, CA), in combination with cataract surgery. METHODS. This investigation was a prospective, randomized, clinical study in patients with open-angle glaucoma or ocular hypertension who were undergoing cataract surgery. Aqueous flow (F) and trabecular outflow facility (C(T)) were measured by fluorophotometry before surgery and at months 1, 6, and 12 in both groups. RESULTS. Thirty-three eyes of 33 patients were randomized to either two stents and cataract surgery (n = 17, group 1) or cataract surgery alone (n = 16, group 2). Before surgery, F and C(T) were similar in groups 1 and 2 (1.78 +/- 0.44 and 1.74 +/- 0.82 microL/min, P = 0.18; 0.12 +/- 0.03 and 0.13 +/- 0.06 microL/min/mm Hg, P = 0.71, respectively). After surgery, there were no changes of note in F, however, C(T) increased in both groups. At 1 year, C(T) was 0.45 +/- 0.27 microL/min/mm Hg in group 1 and 0.19 +/- 0.05 microL/min/mm Hg in group 2 (P = 0.02), which represented increases of 275% and 46%, respectively. Mean IOP reduction was also greater in group 1 than in group 2 (6.6 +/- 3.0 mm Hg vs. 3.9 +/- 2.7 mm Hg; P = 0.002). The mean number of medications was significantly lower in group 1 than in group 2 (0.0 vs. 0.7 +/- 1.0, respectively; P = 0.007). CONCLUSIONS. Compared with cataract surgery alone, implantation of the iStent concomitant with cataract extraction significantly increased trabecular outflow facility, reduced IOP, and reduced the number of medications at 1 year. Longer follow-up is needed to assess the long-term effect on outflow facility. (ClinicalTrials.gov number, NCT00326066.). ||||| PURPOSE: To assess the effect of phacoemulsification with posterior chamber intraocular lens (IOL) implantation performed by a single surgeon on intraocular pressure (IOP) and glaucoma medication requirements in pseudoexfoliation (PFX) eyes with or without glaucoma.
SETTING: Private practice, Boston, Massachusetts, USA.
METHODS: This retrospective analysis comprised 1122 eyes with PFX having uneventful phacoemulsification with IOL implantation. Of the eyes, 882 did not have glaucoma (PFX group) and 240 had glaucoma (PXG group). A comparative outcomes analysis was performed; the analysis focused on IOP and change in glaucoma medication requirements between the 2 groups.
RESULTS: The mean IOP was statistically significantly reduced through 7 years postoperatively compared with preoperatively in the PFX group. The PXG group had reduced mean IOP for 1 year and reduced glaucoma medication requirements at almost all postoperative time intervals. Higher mean preoperative IOP was associated with a greater reduction in mean IOP postoperatively in both groups. Intraocular pressure spikes (> 30 mm Hg) 1 day postoperatively occurred in 4% in the PFX group and 17% in the PXG group. Postoperatively, 2.7% of PFX eyes progressed to a need for glaucoma medication and 3.7% of PXG eyes progressed to a need for laser and/or glaucoma surgery.
CONCLUSIONS: A long-term reduction in mean IOP occurred in PFX eyes with and without glaucoma. The IOP reduction was proportional to the preoperative IOP; higher preoperative IOP was associated with a greater reduction in IOP. Glaucoma progression in both groups was low, suggesting a protective effect of phacoemulsification on IOP in these eyes. ||||| PURPOSE: To evaluate the efficacy of multiple trabecular micro-bypass stents combined with cataract surgery in patients with open-angle glaucoma (OAG) and cataract.
SETTING: Private practice, Mississauga, Ontario, Canada.
DESIGN: Comparative case series.
METHODS: Eyes with OAG had implantation of 2 or 3 micro-bypass stents with concurrent cataract surgery and follow-up through 1 year. Efficacy measures were intraocular pressure (IOP) and topical ocular hypotensive medication use. Safety assessment included complications and corrected distance visual acuity (CDVA).
RESULTS: The study comprised 53 eyes (47 patients); 28 had implantation of 2 stents and 25 had implantation of 3 stents. The overall mean 1-year postoperative IOP was 14.3 mm Hg, which was significantly lower than preoperative IOP overall and in each group (P<.001). The target IOP was achieved in a significantly higher proportion of eyes at 1 year versus preoperatively (77% versus 43%; P<.001). Overall, 83% of eyes had a decrease in topical ocular hypotensive medication at 1 year from preoperatively, with a 74% decrease in the mean number of medications (from 2.7 to 0.7) at 1 year (P<.001). The 3-stent group was on significantly fewer medications than the 2-stent group at 1 year (0.4 versus 1.0; P=.04).
CONCLUSIONS: Using multiple micro-bypass stents with concurrent cataract surgery led to a mean postoperative IOP of less than 15 mm Hg and allowed patients to achieve target pressure control with significantly fewer medications through 1 year.
FINANCIAL DISCLOSURE: Dr. Ahmed is a consultant to Glaukos Corp. No other author has a financial or proprietary interest in any material or method mentioned. ||||| PURPOSE: To compare intraocular pressure (IOP) and the incidence of complications after combined viscocanalostomy and cataract surgery with cataract surgery alone in 206 Japanese eyes with POAG or OH.
PATIENTS AND METHODS: In a nonrandomized comparative, clinical study, 103 eyes underwent viscocanalostomy and cataract surgery (VCS group), and 103 eyes underwent cataract surgery alone (CSA group) (follow-up, 6-24 months). Reductions in IOP and medications, the probability of successful IOP reduction visual acuity changes, and complications were compared between the 2 groups.
RESULTS: The reductions in IOP and number of medications in the VCS group were significantly greater than in the CSA group (P < or = 0.0038 and P < or = 0.0259, respectively). The probabilities of achieving IOPs less than 21, 18, and 15 mm Hg at 24 months in the VCS groups were 85.0%, 53.6%, and 17.2% with medications, and 61.1%, 43.9%, and 16.2% without medications, and significantly better than in the CSA group (P < 0.0002). The visual outcomes were similar in both groups. Postoperative complications such as hyphema and fibrin formation, although more frequent in the VCS group, were not vision threatening.
CONCLUSION: Combined viscocanalostomy and cataract surgery provides good postoperative visual acuity with minimal complications and significantly greater IOP reduction than cataract surgery alone for Japanese patients with glaucoma. ||||| OBJECTIVE: To examine the changes in anterior chamber angle width and depth induced by intraocular lens (IOL) implantation in eyes with angle-closure glaucoma (ACG), in eyes with open-angle glaucoma (OAG), and in eyes with no evidence of glaucoma or ocular hypertension.
DESIGN: A comparative, nonrandomized, interventional study.
PARTICIPANTS: Seventy-seven eyes with ACG, 73 eyes with OAG, and 74 control eyes undergoing cataract extraction and IOL implantation.
INTERVENTION: All eyes underwent phacoemulsification and soft acrylic IOL implantation.
MAIN OUTCOME MEASURES: The angle width and depth of the anterior chamber were measured using a Scheimpflug videophotography system before surgery, and at 1 week and at 1, 3, 6, 9, and 12 months after surgery.
RESULTS: Before surgery, the mean anterior chamber angle width and depth in the ACG group was less than that in either the OAG or control groups by approximately 10 degrees in angle width and 1.0 mm in depth (P < 0.0001). After cataract extraction and IOL implantation, the angle width and depth increased significantly in all three groups (P < 0.0001). Although the width and depth in the ACG group were still smaller than that in the other groups, the differences decreased to 2 degrees for angle width and 0.3 mm for depth. In addition, no significant differences were found in these values between the OAG and control groups before or after surgery. Furthermore, no significant changes were observed in the angle width or depth in any of the three groups throughout the postoperative observation period. As expected, the mean preoperative intraocular pressure (IOP) in the ACG and OAG groups was higher than that in the control group. After cataract surgery, however, the mean IOP decreased significantly and was almost the same in all three groups at 1, 6, and 12 months after surgery.
CONCLUSIONS: The width and depth of the anterior chamber angle in eyes with ACG increased significantly after cataract extraction and IOL implantation and became similar to that in eyes with OAG and that in normal eyes, which may lead to the decrease in IOP seen in the postoperative period. No significant changes were observed in angle width and depth in any of the three groups after surgery. ||||| PURPOSE: To investigate the long-term effect of phacoemulsification on intraocular pressure (IOP) in patients with ocular hypertension and open-angle glaucoma.
SETTING: Three multispecialty ophthalmology practices and one glaucoma specialty group.
DESIGN: Retrospective comparative case series.
METHODS: Review of medical records of patients with open-angle glaucoma or ocular hypertension who had had unilateral phacoemulsification (without other prior or concurrent ophthalmic procedure) with the fellow eye remaining phakic at least 3 years postoperatively.
RESULTS: Preoperatively, the IOP in the surgical and fellow eyes in the 29 patients was 15.66 mm Hg ± 3.33 (SD) and 15.64 ± 4.23 mm Hg (P=.98), respectively. Postoperatively, it was 13.56 ± 2.04 mm Hg and 14.92 ± 2.85 mm Hg, respectively, at 4.5 months (P=.06); 14.88 ± 3.20 mm Hg and 15.27 ± 3.19 mm Hg, respectively, at 1 year (P=.67); 14.16 ± 2.61 mm Hg and 14.95 ± 2.79 mm Hg, respectively, at 2 years (P=.37); and 14.68 ± 3.44 mm Hg and 14.68 ± 2.68 mm Hg at 3 years (P=1.00), respectively. There was no significant difference in the mean number of IOP-lowering medications used in the surgical eyes (1.96 ± 1.40) and fellow eyes (2.08 ± 1.44) postoperatively (P=.77).
CONCLUSIONS: In a cohort of ocular hypertensive and glaucoma patients, uncomplicated phacoemulsification had no significant IOP-lowering effect compared with the phakic fellow eye for up to 3 years postoperatively. There was also no difference between the mean number of postoperative IOP-lowering medications used in the surgical and fellow eyes.
FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. ||||| PURPOSE: To identify preoperative factors associated with postoperative intraocular pressure (IOP) reduction after phacoemulsification cataract extraction in patients with primary open-angle glaucoma (POAG) treated at a Veterans Affairs Medical Center.
METHODS: Examination records of 103 eyes of 75 patients with POAG who underwent uncomplicated phacoemulsification cataract extraction were reviewed. Preoperative data collected for analysis included IOP, number of glaucoma medications, spherical equivalent refractive errors, central corneal thickness, anterior chamber depth, and axial length. The IOPs measured 3 to 6 months after surgery were used to calculate the change in IOP after cataract extraction. Statistical analysis was performed to identify preoperative factors associated with postoperative IOP reduction.
RESULTS: The mean postoperative IOP reduction was 1.8 ± 3.5 mm Hg (p < 0.001). Seventy-four percent of eyes (76 of 103) had decreased IOP after cataract surgery. Eight percent of eyes (8 of 103) had no change in IOP. Eighteen percent of eyes (19 of 103) had increased IOP after cataract surgery. The mean preoperative IOPs for eyes with increased, same, and decreased postoperative IOPs were 12 ± 2.2 mm Hg, 14.0 ± 2.3 mm Hg, and 16.4 ± 3.1 mm Hg, respectively. The mean postoperative IOPs change for eyes with increased and decreased postoperative IOPs were +2.7 ± 2.1 mm Hg and -3.7 ± 2.5 mm Hg, respectively. Preoperative IOP was the only preoperative factor significantly associated with postoperative IOP reduction (p < 0.001).
CONCLUSIONS: Preoperative IOP was the only factor significantly associated with postoperative IOP reduction after cataract surgery in POAG patients. A higher preoperative IOP was strongly associated with a greater postoperative IOP reduction. Patients with low preoperative IOPs tended to have minimal reduction or even a mild increase in postoperative IOPs. These findings have important implications when considering combined cataract extraction and filtration surgery for POAG patients. ||||| PURPOSE: To evaluate the safety and efficacy of circumferential viscodilation and tensioning of the inner wall of Schlemm canal, a new nonpenetrating surgical procedure (canaloplasty) to treat open-angle glaucoma (OAG), combined with clear corneal phacoemulsification and posterior chamber intraocular lens (IOL) implantation.
SETTING: Multicenter surgical sites.
METHODS: This international multicenter prospective study comprised adult patients with OAG having combined glaucoma and cataract surgery. Patients with qualifying treated preoperative intraocular pressure (IOP) of at least 21 mm Hg or higher and open angles were eligible. Evaluation was performed at baseline and 1 day, 1 week, and 1, 3, 6, and 12 months postoperatively. Intraoperative and postoperative high-resolution ultrasound imaging was used to assess Schlemm canal and anterior segment angle morphology, including distension of the trabecular meshwork due to the tensioning suture.
RESULTS: Data from 54 eyes that had combined glaucoma and cataract surgery performed by 11 surgeons at 9 study sites were analyzed for this interim analysis. The mean baseline IOP was 24.4 mm Hg+/-6.1 (SD) with a mean of 1.5+/-1.0 medications per eye. In all eyes, the mean postoperative IOP was 13.6+/-3.8 mm Hg at 1 month, 14.2+/-3.6 mm Hg at 3 months, 13.0+/-2.9 mm Hg at 6 months, and 13.7+/-4.4 mm Hg at 12 months. Medication use dropped to a mean of 0.2+/-0.4 per patient at 12 months. Surgical complications were reported in 5 eyes (9.3%) and included hyphema (n=3, 5.6%), Descemet tear (n=1, 1.9%), and iris prolapse (n=1, 1.9%). Transient IOP elevation of more than 30 mm Hg was observed in 4 eyes (7.3%) 1 day postoperatively.
CONCLUSION: Circumferential viscodilation and tensioning of Schlemm canal combined with clear corneal phacoemulsification and posterior chamber IOL implantation was a safe and effective procedure to reduce IOP in adult patients with OAG. ||||| PURPOSE: This study evaluates the change in intraocular pressure (IOP) and glaucoma medication requirements after clear corneal phacoemulsification in open angle glaucoma patients, glaucoma suspects, and normal patients at 3 years and last follow-up (mean 5 y).
PATIENTS AND METHODS: This study represents a retrospective analysis of patients who had clear corneal phacoemulsification and at least 3 years of follow-up. The patients were classified into 3 groups: glaucoma (G), glaucoma suspects (GS), and no glaucoma (NG). No patient had a history of previous intraocular surgery. Single factor analysis of variance, Fisher exact tests, 2-tailed paired Student t tests and Kaplan-Meier analysis were applied.
RESULTS: Forty-eight patients (55 eyes) in the glaucoma group, 41 patients (44 eyes) in the GS group, and 59 patients (59 eyes) in the NG group met the above criteria. At 3 years follow-up IOP was significantly decreased in all groups; (G) group decreased 1.4+/-3.3 mm Hg (P = 0.0025), GS 1.4+/-4.2 mm Hg (P = 0.004), and NG 1.7+/-3.1 mm Hg (P = 0.0005). At the final follow-up visit (mean near 5 y for all groups) the IOP was significantly decreased in all groups, (G) group 1.8+/-3.5 mm Hg (P = 0.005), GS 1.3+/-3.7 mm Hg (P = 0.025), and NG 1.5+/-2.5 mm Hg (P < 0.0001). The number of preoperative and postoperative glaucoma medications in the (G) group did not show any significant change at 3 and 5 years (P = 0.36, P = 0.87). Kaplan-Meier analysis shows that at 3 years, 85% of the (G) group, 81% of GS, and 90% of the NG had IOPs less than or equal to their preoperative IOP, with the same number of glaucoma medications or less. At 5 years the percentages were 76%, 79%, and 85%, respectively.
CONCLUSIONS: This study demonstrates that cataract removal by clear cornea phacoemulsification in glaucoma patients, glaucoma suspects, and normal patients results in a small but significant decrease in IOP that is sustained at 3 years and a mean of 5 years in all groups. This study does not imply that cataract removal by phacoemulsification is a substitute for a combined procedure but may be an appropriate procedure for certain patients based on medication requirements and extent of optic nerve damage. | [
{
"source_pmid": "15834092",
"source_text": "AIM: To evaluate the influence of clear cornea phacoemulsification on filtering bleb morphology, function, and intraocular pressure (IOP) in glaucomatous eyes with previously successful filtering surgery.\nMETHODS: The clinical course of 30 patients (30 eyes) who... |
26404116 | Rs3825942 (G) was an at risk allele for PEX/PEXG in Caucasians, Japanese, Koreans, Chinese, South Asians, and Middle Easterners, but protective in Black South Africans (OR = 0.10, 95%CI:0.06-0.16). Rs1048661 (G) was an at risk allele for PEX/PEXG in Caucasians, South Asians, Middle Easterners and Black South Africans, but was protective in Japanese (OR = 0.03, 95%CI:0.02-0.06) and Koreans (OR = 0.10, 95%CI:0.05-0.22). These associations we-re confirmed for the genotypic recessive models. Rs2165241 (C) was a protective allele for PEX/PEXG in Caucasians, but was an at risk allele in Japanese (OR = 7.49, 95%CI:3.22-17.41) and Koreans (OR = 6.63, 95%CI:2.60-16.90). This was confirmed for the genotypic dominant model. Other genetic and/or environmental factors may modify the effect of LOXL1 polymorphisms in certain ethnic groups. | PURPOSE: We performed genetic association studies using a native Japanese population to examine the reproducibility of results of lysyl oxidase-like 1 (LOXL1) genetic association studies for exfoliation glaucoma (XFG) beyond the differences of ethnicity. We also quantified LOXL1 mRNA expression in the human lens capsule to examine the possible correlation between LOXL1 expression and XFG pathogenesis.
METHODS: We performed a case-control study using 95 Japanese XFG patients and 190 controls. Real-time polymerase chain reaction (PCR) analysis was performed using lens capsules obtained during surgery.
RESULTS: The TT genotype in the single nucleotide polymorphism (SNP) rs1048661 and the GG genotype in the SNP rs3825942 in exon 1 of LOXL1 were significantly associated with an increased risk of XFG under recessive models (chi(2) test, p=5.34 x 10(-34) and p=2.1 x 10(-8), respectively). Quantification of LOXL1 mRNA expression demonstrated no significant difference between XFG and senile cataract samples.
CONCLUSIONS: Although the functional effects of the LOXL1 SNP appear to be qualitative rather than quantitative, the amino acid substitution (R141L) caused by SNP rs1048661 is not a simple decisive factor for XFG due to the inverted allele frequency between Japanese XFG and Caucasian XFG patients. Further genetic and functional studies are essential for clarifying XFG pathogenesis. ||||| PURPOSE: Three common sequence variants in the lysyl oxidase-like 1 (LOXL1) gene were recently associated with both pseudoexfoliation (PEX) and pseudoexfoliation glaucoma (PEXG) in populations from Iceland and Sweden. In this study, the genetic association of these variants was investigated in patients with PEX or PEXG of German and Italian descent.
METHODS: The three LOXL1 single-nucleotide polymorphisms (SNPs), one intronic (rs2165241) and two nonsynonymous coding SNPs (rs1048661: R141L and rs3825942: G153D) were genotyped in a total of 726 unrelated patients with PEX or PEXG (517 Germans and 209 Italians) and 418 healthy subjects who had normal findings in repeated ophthalmic examinations, and a genetic association study was performed.
RESULTS: Strong association with the three LOXL1 common sequence variants was seen in both the PEX and PEXG patient groups independent of their geographic origin (rs2165241, combined OR = 3.42, P = 1.28 x 10(-40); rs1048661, OR = 2.43, P = 2.90 x 10(-19); and rs3825942, OR = 4.87, P = 8.22 x 10(-23)). Similarly, the common frequent haplotype (G-G) composed of the two coding SNPs (rs1048661 and rs3825942) was strongly associated in PEX and PEXG cohorts of both populations with the disease (combined OR = 3.58, P = 5.21x 10(-43)).
CONCLUSIONS: Genetic variants in LOXL1 confer risk to PEX in German and Italian populations, independent of the presence of secondary glaucoma, confirming findings in patients from Northern Europe. ||||| PURPOSE: In Uygur populations, exfoliation syndrome (XFS) and exfoliation glaucoma (XFG) occurred at a high frequency. In this study, we evaluate the association profiles of the lysyl oxidase-like 1 (LOXL1) gene polymorphisms with XFS in the Uygur population.
METHODS: Sixty-four unrelated Uygur patients with XFS and 127 Uygur control subjects were included in this study. Genotypes of the three single nucleotide polymorphisms (SNPs) of LOXL1 (rs1048661, rs2165241, and rs3825942) were analyzed by direct sequencing, and a case-control association study was performed.
RESULTS: The three SNPs were significantly associated with XFS and XFG individually. The G allele of rs1048661 (OR [95%CI]: 1.92 [1.14-3.22]), G of rs3825942 (OR [95%CI]: 4.86 [2.02-11.68]), and T of rs2165241 (OR [95%CI]: 3.98 [2.54-6.25]) were risk alleles for the disorder. The genotypes GG for rs1048661 (OR [95%CI]: 2.13 [1.14-3.97]), GG for rs3825942 (OR [95%CI]: 5.68 [2.28-14.17]), and TT for rs2165241 (OR [95%CI]: 6.13 [2.68-14.01]) were risk genotypes for the disease. The haplotypes G-G for the SNPs rs1048661and rs3825942, G-T for the SNPs rs1048661 and rs2165241, and SNPs rs3825942 and rs2165241 were found to be significantly associated with XFS/G. The haplotypes G-G-T for the three SNPs were determined to be significantly associated with XFS/G. There were significant differences of the allelic and genotypic proportion in different gender/age patients and controls for all three SNPs. T allele of rs2165241 and G of rs3825942 were risk alleles for the disorder in both the male and female groups. G allele of rs1048661 was a risk allele for the disorder in the below 65-year-old group. T of rs2165241 was a risk allele for the disorder in both age groups. G of rs3825942 was a risk allele for the disorder in the over 65-year-old group. The genotypes also showed significant differences in the below 65-year-old group of rs1048661, both groups of rs2165241, and over 65-year-old group of rs3825942.
CONCLUSIONS: LOXL1 is a susceptibility gene of XFS/XFG in Uygur populations. The risk alleles of rs1048661, rs3825942 and rs2165241 in Uygur subjects were found to be similar to those of populations in Iceland and the United States and different from Han populations in China. The genotypic and allelic distributions of these SNPs are similar between XFS and XFG. ||||| PURPOSE: To investigate the association of the two single-nucleotide polymorphisms (SNPs) in the lysyl oxidase-like 1 (LOXL1) gene with pseudoexfoliation syndrome (PEX), pseudoexfoliative glaucoma (PEXG), and primary open-angle glaucoma (POAG) in a Greek population-based setting, from the Thessaloniki Eye study.
METHODS: A total of 233 subjects with successful DNA extraction, PCR amplification, and genotyping were included in the genetic analysis of G153D and R141L SNPs of LOXL1 gene and classified into four groups: controls (n = 93); subjects with PEX (n = 40); POAG (n = 66); and PEXG (n = 34). Multinomial logistic regression was used to test their association with LOXL1 SNPs with adjustment for covariates. The association of LOXL1 with IOP (in untreated subjects) and with systemic diseases was explored.
RESULTS: Both LOXL1 SNPs were present in high frequencies in controls and cases. The G153D was strongly associated with both PEX (odds ratio [OR] = 23.2, P = 0.003 for allele G) and PEXG (OR = 24.75, P = 0.003 for allele G) and was not associated with POAG (P = 0.451). In contrast, the R141L was not associated with PEX (P = 0.81), PEXG (P = 0.063), or POAG (P = 0.113). No association of the G153D with either intraocular pressure (IOP) or systemic diseases was found.
CONCLUSIONS: In the Thessaloniki Eye Study, the G153D SNP of LOXL1 gene was strongly associated with both PEX and PEXG, whereas the R141L was not associated. No association of the LOXL1 with IOP or with systemic diseases was found. These findings further support the hypothesis that the LOXL1 gene contributes to onset of PEXG through PEX. Gene variants of LOXL1 do not help to identify those with PEX at increased risk for glaucoma development. ||||| PURPOSE: To evaluate the association of the lysyl oxidase-like 1 (LOXL1) single nucleotide polymorphisms (SNPs) in a Spanish population with pseudoexfoliation syndrome (XFS) and pseudoexfoliation glaucoma (XFG).
MATERIALS AND METHODS: The present case-control study included 100 Spanish patients (60 patients with XFS and 40 patients with XFG) and 90 control subjects. Genotypes of the three single nucleotide polymorphisms of LOXL1 (rs1048661, rs3825942, and rs2165241) were analyzed with direct sequencing.
RESULTS: The G allele and the GG genotype of SNP rs3825942 were detected at a statistically higher frequency in pseudoexfoliation patients than in control subjects (p = 3.36 × 10(-5), OR = 5.71, 95% CI: 2.30-14.18; p = 3.38 × 10(-5), OR = 6.91, 95% CI: 2.51-19.03 respectively). The T allele and the TT genotype of SNP rs2165241 presented at significantly higher frequencies in pseudoexfoliation patients than in controls (p = 2.50 × 10(-4), OR = 2.18, 95% CI: 1.43-3.33; p = 1.21 × 10(-2), OR = 2.13, 95% CI: 1.75-3.85 respectively). No significant association between XFS/XFG and the rs1048661 was observed. The GGT haplotype composed of all three risk alleles was determined to be significantly associated with pseudoexfoliation. The genotypic and allelic distributions of the three SNPs were similar between XFS and XFG.
CONCLUSIONS: This is the first study associating two SNPs of LOXL1 (rs3825942 and rs2165241) and XFS/XFG in a Spanish population, confirming findings in patients from Europe. However rs1048661 SNP did not show an association with XFS. ||||| IMPORTANCE: This study was necessary to establish the association between common genetic variants in the lysyl oxidase-like 1 (LOXL1) gene with pseudoexfoliation (PEX) syndrome and emphasize the reversal of promoter risk allele in a South Indian population.
OBJECTIVE: To investigate the potential association of genetic variants across the LOXL1 gene in South Indian patients with PEX syndrome and glaucoma.
DESIGN, SETTING, AND PARTICIPANTS: A case-control study of individuals from Madurai, India, with PEX syndrome and glaucoma as well as healthy people serving as controls. Three hundred unrelated people with PEX syndrome and 225 age- and ethnically matched controls were recruited for genetic analysis.
MAIN OUTCOMES AND MEASURES: Four single-nucleotide polymorphisms in LOXL1 (rs16958477, rs1048661, rs3825942, and rs2165241) were genotyped by direct sequencing in all participants. Regulatory regions and 7 coding exons of LOXL1 were directly sequenced in 50 patients and 50 controls. A case-control association analysis was performed using the Golden Helix SVS suite.
RESULTS: An association between 4 LOXL1 single-nucleotide polymorphisms with PEX syndrome and glaucoma was observed (rs16958477, P = 4.77 × 10-6 [odds ratio, 0.50]; rs1048661, P = 4.28 × 10-5 [1.79]; rs3825942, P = 4.68 × 10-30 [9.19]; and rs2165241, P = 1.98 × 10-15 [2.88]). Sequencing of 7 exons and regulatory regions of LOXL1 identified 11 additional sequence variants; only rs41435250 showed an association (P = 3.80 × 10-5 [0.49]) with PEX syndrome and glaucoma.
CONCLUSIONS AND RELEVANCE: Genetic variants in LOXL1 are associated with PEX syndrome and glaucoma in the South Indian population. To our knowledge, this is the first study to demonstrate the association of rs41435250 with PEX as well as reversal of the promoter risk allele. Understanding the role of the LOXL1 gene in PEX pathogenesis will facilitate early detection in individuals at risk for this condition. ||||| PURPOSE: To assess whether lysyl oxidase-like 1 (LOXL1) polymorphisms are associated with primary open-angle glaucoma (POAG) and exfoliation syndrome (XFS).
METHODS: Japanese patients with POAG (n=213) or XFS (n=89) and 191 control subjects were analyzed for LOXL1 polymorphisms (rs1048661: 758G/T, Arg141Leu and rs3825942: 794G/A, Gly153Asp). Demographic and clinical features of POAG patients and control subjects were compared in terms of the TT/GG compound genotype of rs1048661 and rs3825942.
RESULTS: There was a significant difference in the genotype frequencies between XFS patients and control subjects (p<0.0001). Frequencies of the T allele of rs1048661 and the G allele of rs3825942 were significantly higher in XFS patients than in control subjects (rs1048661: 99.4% versus 55.0%; rs3825942: 99.4% versus 85.3%; p<0.0001). Except for one who had the TG/AG compound genotype, all XFS patients had the TT/GG compound genotype. An almost 250 fold increase in the risk of XFS (p<0.0001; odds ratio: 252.2; 95% confidence interval: 32.7 to more than 1000) was found in patients with the TT/GG compound genotype compared to those without the genotype. There were no significant differences in the genotype and allele frequencies between POAG patients and control subjects. Furthermore, no significant differences were noted in the demographic and clinical features of POAG patients as well as control subjects with and without the TT/GG high-risk compound genotype.
CONCLUSIONS: LOXL1 polymorphisms were associated with XFS. However, the frequencies of the polymorphisms differed between Japanese and Caucasian XFS patients. These polymorphisms had no influence on the phenotypic features of POAG patients. ||||| BACKGROUND: Pseudoexfoliation syndrome is a major risk factor for glaucoma in many populations throughout the world. Using a U.S. clinic-based case control sample with broad ethnic diversity, we show that three common SNPs in LOXL1 previously associated with pseudoexfoliation in Nordic populations are significantly associated with pseudoexfoliation syndrome and pseudoexfoliation glaucoma.
METHODS: Three LOXL1 SNPs were genotyped in a patient sample (206 pseudoexfoliation, 331 primary open angle glaucoma, and 88 controls) from the Glaucoma Consultation Service at the Massachusetts Eye and Ear Infirmary. The SNPs were evaluation for association with pseudeoexfoliation syndrome, pseudoexfoliation glaucoma, and primary open angle glaucoma.
RESULTS: The strongest association was found for the G allele of marker rs3825942 (G153D) with a frequency of 99% in pseudoexfoliation patients (with and without glaucoma) compared with 79% in controls (p = 1.6 x 10-15; OR = 20.93, 95%CI: 8.06, 54.39). The homozygous GG genotype is also associated with pseudoexfoliation when compared to controls (p = 1.2 x 10-12; OR = 23.57, 95%CI: 7.95, 69.85). None of the SNPs were significantly associated with primary open angle glaucoma.
CONCLUSION: The pseudoexfoliation syndrome is a common cause of glaucoma. These results indicate that the G153D LOXL1 variant is significantly associated with an increased risk of pseudoexfoliation and pseudoexfoliation glaucoma in an ethnically diverse patient population from the Northeastern United States. Given the high prevalence of pseudooexfoliation in this geographic region, these results also indicate that the G153D LOXL1 variant is a significant risk factor for adult-onset glaucoma in this clinic based population. ||||| PURPOSE: The single nucleotide polymorphisms (SNPs) rs1048661, rs3825942, and rs2165241 within the LOXL1 gene were recently found to confer risk of pseudoexfoliation glaucoma (XFG) through pseudoexfoliation syndrome (XFS) in Caucasians. The purpose of this study was to test this association in Japanese subjects with XFS/XFG.
METHODS: Japanese subjects with clinically diagnosed XFS/XFG and normal control subjects were recruited. Genomic DNA was extracted and the three SNPs of the LOXL1 gene were genotyped by bidirectional sequencing. The association of individual SNPs with XFG/XFS was evaluated by using chi(2) and the Fisher exact test.
RESULTS: Two hundred nine Japanese patients (106 XFG and 103 XFS) and 172 control subjects were studied. Strong associations were observed for all three SNPs of LOXL1 for XFS (odds ratio [OR] = 13.56, P = 3.39 x 10(-28) for allele T of rs1048661; OR = 10.71, P = 1.49 x 10(-7) for allele G of rs3825942; and OR = 4.55, P = 5.33 x 10(-4) for allele C of rs2165241) and XFG (OR = 25.21, P = 1.44 x 10(-34) for allele T of rs1048661; OR = 11.02, P = 1.40 x 10(-7) for allele G of rs3825942; and OR = 11.89, P = 4.76 x 10(-6) for allele C of rs2165241). The risk-associated alleles of rs1048661 and rs2165241 differed between the Japanese and Caucasians, whereas allele G of rs3825942 was associated with disease in both populations. Conditional analysis indicated that rs3825942 was not independent but correlated highly with rs1048661. The at-risk haplotype T-G-C was present at an approximately two times higher rate (94.7% vs. 50.6%, P = 4.22 x 10(-43)) in cases than in control subjects and conferred a 2.9-fold (95% confidence interval [CI], 2.357-3.464) increased likelihood of XFS.
CONCLUSIONS: Polymorphisms in the LOXL1 gene confer risk to XFS/XFG in the Japanese, but there are different risk-associated alleles and haplotypes in the Japanese. ||||| Pseudoexfoliation (PEX) syndrome is a generalized disease of the extracellular matrix and the most common identifiable cause of open-angle glaucoma. Two single nucleotide polymorphisms in the lysyl oxidase-like 1 (LOXL1) gene (rs1048661 and rs3825942) have been recently identified as strong genetic risk factors for both PEX syndrome and PEX glaucoma. Here we investigated the expression and localization of LOXL1, LOXL2, and lysyl oxidase (LOX) in tissues of PEX syndrome/glaucoma patients and controls in correlation with their individual single nucleotide polymorphism genotypes and stages of disease. LOXL1 ocular expression was reduced by approximately 20% per risk allele of rs1048661, whereas risk alleles of rs3825942, which were highly overrepresented in PEX cases, did not affect LOXL1 expression levels. Irrespective of the individual genotype, LOXL1 expression was significantly increased in early PEX stages but was decreased in advanced stages both with and without glaucoma compared with controls, whereas LOX and LOXL2 showed no differences between groups. LOXL1 was also found to be a major component of fibrillar PEX aggregates in both intra- and extraocular locations and to co-localize with various elastic fiber components. These findings provide evidence for LOXL1 involvement in the initial stages of abnormal fibrogenesis in PEX tissues. Alterations of LOXL1 activation, processing, and/or substrate specificity may contribute to the abnormal aggregation of elastic fiber components into characteristic PEX fibrils. ||||| In this study, three single-nucleotide polymorphisms (SNPs) on the lysyl oxidase-like 1 (LOXL1) gene associated with exfoliation syndrome (XFS) and exfoliation glaucoma (XFG) were investigated in the Finnish population. A case-control study of 59 sporadic patients with XFS, 82 with XFG, 71 with primary open-angle glaucoma (POAG) and 26 individuals without these disorders from the southern Finnish population, and a family study of an extended family with 28 patients with XFS or XFG and 92 unaffected relatives from Kökar islands, Southwestern Finnish archipelago, were conducted. Anonymous blood donors (n=404) were studied as population-based controls. Three SNPs, rs1048661 (R141L), rs3825942 (G153D) and rs2165241, of the LOXL1 gene were genotyped by PCR sequencing. Association and linkage analyses were carried out. In both case-control and family materials, significant association for allele G of rs1048661 (P=2.65 x 10(-5); P=0.0007), allele G of rs3825942 (P=2.24 x 10(-8); P=0.49) and allele T of rs2165241 (P=2.62 x 10(-13); P<0.0001) was found in XFS/XFG. However, linkage was not observed for LOXL1 risk alleles. The corresponding three-locus haplotype GGT increased the risk of XFS/ XFG nearly 15-fold relative to low-risk haplotype GAC (odds ratio (OR): 14.9, P=1.6 x 10(-16)). In conclusion, the earlier reported polymorphisms of the LOXL1 gene showed significant association also in the Finnish population. ||||| PURPOSE: The purpose of this study was to evaluate association profiles of lysyl oxidase-like 1 (LOXL1) gene polymorphisms with pseudoexfoliation syndrome (XFS) in a Korean population.
METHODS: A total of 110 Korean patients with XFS and 127 control subjects were included in this study. Genotypes of three single nucleotide polymorphisms (SNPs) of LOXL1 (rs1048661, rs3825942, and rs2165241) were analyzed with direct sequencing, and a case-control association study was performed. Genotype frequencies of each SNP were compared according to the XFS phenotypes.
RESULTS: All three SNPs were significantly associated with XFS. The T allele at rs1048661 (odds ratio [OR] = 14.29, 95% confidence interval [CI] = 6.25-33.3) and the C allele at rs2165241 (OR = 7.14, 95% CI = 1.59-33.3) were risk alleles in Korean subjects, which was consistent with findings in other Asian populations. However, our findings were opposite to results from Caucasian populations in which the risk alleles at rs1048661 and rs2165241 were G and T, respectively. At the rs3825942, the G allele (OR = 12.50, 95% CI = 2.94-50.0) was a risk allele for XFS, which was similar to results from most other ethnic groups except black South Africans in whom the A allele increased the risk. In the haplotype analysis, the T-G-C haplotype composed of all three risk alleles was significantly overrepresented in XFS and conferred an 11.36 fold (95% CI = 5.97-23.49) increased likelihood of XFS. There was no significant association between the genotype frequencies of the three SNPs and the XFS phenotypes.
CONCLUSIONS: Three SNPs of LOXL1 (rs1048661, rs3825942, and 2,165,241) are highly associated with XFS in a Korean population. The risk alleles of these SNPs were similar to those of other Asian populations, such as Japanese or Chinese, but differed from non-Asian populations, suggesting that still unidentified genetic or environmental factors may contribute to disease expression. ||||| PURPOSE: To investigate the association of lysyl oxidase like 1 (LOXL1) variants with exfoliation syndrome (XFS), exfoliation glaucoma (XFG), and primary open angle glaucoma (POAG) in a Turkish population.
METHODS: Two LOXL1 single nucleotide polymorphisms (SNPs), rs1048661 (R141L) and rs3825942 (G153D), were analyzed in 300 Turkish patients (100 patients with XFS, 100 patients with XFG, 100 patients with POAG) and 100 control subjects.
RESULTS: The T allele of rs1048661 was underrepresented in patients with XFS (odds ratio [OR]=0.334, 95% confidence interval [CI]: 0.198-0.564, p=2.54 × 10(-5)) and XFG (OR=0.366, 95% CI: 0.219-0.611, p=8.56 × 10(-5)) compared to the control subjects. None of the patients with XFS or XFG had the A allele of rs3825942, whereas 16% of the control subjects had that variant (OR=0.025, 95% CI: 0.003-0.188, p=3.69×10(-9)). No association was observed between the SNPs studied and POAG. By using logistic regression analysis, the effect of rs1048661 remained significant (p=8.45 × 10(-8)) after controlling for the effect of rs3825942, whereas rs3825942 was not significant with conditioning on rs1048661. Female gender was protective against the disease controlling with the effect of the two SNPs (OR=0.527, 95% CI: 0.358-0.776, p=0.001).
CONCLUSIONS: The findings of the current study indicate that in a logistic regression analysis model the T allele of rs1048661 is the most important risk-modifying factor for the development of XFS and XFG. Our results also confirm in a Turkish population the findings of previous reports describing the association between LOXL1 polymorphisms and XFS/XFG but not with POAG. The allele and genotype distribution in this cohort appear to be similar to those of Caucasians. ||||| PURPOSE: Three common sequence variants in the lysyl oxidase-like 1 (LOXL1) gene were recently associated with pseudoexfoliation (PEX) and pseudoexfoliation glaucoma (PEXG) in populations from various parts of the world. In this study, the genetic association of these variants was investigated in Greek patients with PEX and PEXG.
METHODS: The three LOXL1 single nucleotide polymorphisms (SNPs), one intronic (rs2165241) and two nonsynonymous coding SNPs (rs1048661: R141L and rs3825942: G153D), were genotyped in a total of 48 unrelated patients with PEX, 35 patients with PEXG, and 52 healthy subjects who had normal findings in repeated ophthalmic examinations. A genetic association study was performed.
RESULTS: Between the two coding SNPs, R141L did not show an association with PEX (p=0.297 for allele G, p=0.339 for genotype GG), whereas allele G of G153D showed a significant association (odds ratio [OR]=3.52, 95% confidence interval [CI]=1.735-7.166, p=3.24×10(-4) for allele G, p=0.004 for genotype GG). Likewise, for the intronic SNP of rs2165241, genotype TT (p=0.005) and its corresponding allele T (OR=2.99, 95% CI=1.625-5.527, p=3.53×10(-4)) showed a significant association with PEX. The allele G of G153D showed a significant association with PEXG (OR=3.74, 95% CI=1.670-8.387, p=0.001). The combined haplotype GGT, consisting of all three risk alleles, was associated with PEX (p=0.037), conferring a 1.8-fold of increased risk to the disease (OR=1.799, 95% CI=1.04-3.13). Furthermore, the haplotype GGT presented in 39.8% of the patients with PEX and 26.9% of the controls.
CONCLUSIONS: Certain genetic variants in LOXL1 confer risk for PEX in Greek populations, confirming in part findings in patients from Northern Europe. ||||| PURPOSE: To identify if recently described LOXL1 (lysyl oxidase-like 1) polymorphisms are associated with pseudoexfoliation glaucoma (XFG) in a United States (U.S.) Caucasian patient population.
METHODS: Individuals with XFG were identified using standard clinical examination techniques. TaqMan allelic discrimination assays were used to genotype 13 single nucleotide polymorphisms (SNPs) that tag LOXL1 in Caucasian individuals. The coding region of exon 1 that includes the previously associated SNP, rs1048661, was sequenced. Allele and genotype frequencies were compared between cases and unrelated controls.
RESULTS: Fifty affected individuals and 235 control individuals were recruited into this study. We replicated the previously reported association of three SNPs (rs1048661, rs2165241, and rs3825942) in our independent XFG population (single SNP p-values were 0.001-0.02). The risk alleles at these three and several other intragenic SNPs are part of an extended XFG-associated LOXL1 haplotype with a frequency of 32.0% in XFG patients and 21.6% in controls.
CONCLUSIONS: We have performed an analysis of LOXL1 and XFG in a United States patient population and have confirmed the strong association previously reported for Icelandic and Swedish samples. However, due to the high frequency of risk alleles in non-XFG individuals, this association should not form the basis of a diagnostic test for XFG. It is likely that additional genetic or environmental factors modulate the penetrance of LOXL1 susceptibility alleles. ||||| PURPOSE: Exfoliation syndrome (XFS) is characterized by an accumulation of abnormal extracellular material in the anterior part of the eye that frequently leads to increased intraocular pressure and glaucomatous optic neuropathy. Recently, two non-synonymous polymorphisms (rs1048661 G>T and rs3825942 G>A) of lysyl oxidase-like protein 1 (LOXL1), a monoamine oxidase that catalyzes the polymerization of tropoelastin to elastin, were found to be associated with increased risk for XFS and exfoliation glaucoma (XFG). The aim of the present study was to investigate the role of these LOXL1 variants in a Central European cohort of Caucasian patients with XFG.
METHODS: The present case-control study comprised of 167 unrelated patients with XFG and 170 control subjects. Genotyping of the LOXL1 rs1048661 and rs3825942 polymorphisms was done using polymerase chain reaction.
RESULTS: The frequency of allele G of rs1048661 as well as rs3825942 was significantly higher in patients than in controls (rs1048661: 0.841 in patients versus 0.669; p<0.001; rs3825942: 0.994 in patients versus 0.817; p<0.001). Odds ratios of 52.1 (95% confidence interval [CI]: 13.85-195.6) and 14.67 (95% CI: 3.81-56.2), respectively, were calculated for the two high-risk haplotypes GG and TG compared to the haplotype GA.
CONCLUSIONS: Our data confirm the previously reported association between LOXL1 polymorphisms and XFG and extend our knowledge to a Central European population. ||||| PURPOSE: To evaluate the association of lysyl oxidase like 1 (LOXL1) gene variants in Japanese patients with open-angle glaucoma.
METHODS: We evaluated the association of three LOXL1 variants (rs1048661, rs3825942, and rs2165241) in 142 Japanese patients with exfoliation syndrome (EX; n=59) and exfoliation glaucoma (EG; n=83) as well as in 251 control patients aged 70 years or older with primary open-angle glaucoma (PG; n=40), normal tension glaucoma (NG; n=54), and cataract (CT; n=157).
RESULTS: In comparison with the CT group, the single nucleotide polymorphisms (SNPs) showed significant association with EX, EG, and EX+EG. The odds ratio (OR)=19.71-28.23 and p=1.69 x 10(-23) - 3.00 x 10(-45) for allele T of rs1048661; OR=28.21-39.78 and p=1.77 x 10(-8) - 2.42 x 10(-22) for allele G of rs3825942; and OR=16.59-23.40 and p=4.79 x 10(-5) - 1.08 x 10(-9) for allele C of rs2165241. In comparison with the controls (CT+PG+NG), the haplotype rs1048661/rs3825942 (T/G) was significantly associated with EX+EG (p=8.27 x 10(-44)), and haplotype G/A had a significant protective effect (p=2.25 x 10(-14)). None of the three SNPs showed significant differences between the EX and EG groups or between the PG and NG groups.
CONCLUSIONS: These SNPs are associated with exfoliation syndrome/glaucoma in the Japanese population. The risk alleles in rs1048661 and rs2165241 are different from other populations. Additional genetic or environmental risk factors other than these LOXL1 SNPs could be associated with the development of exfoliation syndrome as well as exfoliation glaucoma among exfoliation syndrome patients. ||||| Pseudoexfoliation syndrome is a generalized disorder of the extracellular matrix, characterized by the pathological accumulation of abnormal fibrillar material in the anterior segment of the eye predisposing to glaucomatous optic neuropathy. We investigated the role of lysyl oxidase-like 1(LOXL1) sequence variation in a Caucasian Australian population-based cohort of 2508 individuals, 86 (3.4%) of whom were diagnosed with pseudoexfoliation syndrome. Two non-synonymous variants in exon 1 of LOXL1 (Arg141Leu;Gly153Asp) were found to be strongly associated with pseudoexfoliation. Two copies of the high risk haplotype at these single-nucleotide polymorphisms conferred a risk of 7.20 (95%CI: 3.04-20.75) compared with no copies of the high risk haplotype. Each of the disease-associated alleles is by far commoner in the normal population, and examination of cross-species homology reveals that the two disease-associated coding variants belong to the ancestral version of the gene. LOXL1 was found to be expressed by reverse transcription-polymerase chain reaction in all ocular tissues examined except retina. The presence of LOXL1 protein in ocular tissues of interest was demonstrated by western blotting. Specific bands of approximately 130 and 80 kDa, representing polymerized protein forms, were detected in the cornea, iris, ciliary body, lens capsule and optic nerve. The 42 kDa mature form of LOXL1 was detected in the iris and ciliary body. Our Caucasian population has a 9-fold lower lifetime incidence of pseudoexfoliation syndrome compared with Nordic populations despite having similar allelic architecture at the LOXL1 locus. This strongly suggests that as yet unidentified genetic or environmental factors independent of LOXL1 strongly influence the phenotypic expression of the syndrome. ||||| PURPOSE: To evaluate genetic susceptibility of lysyl oxidase-like 1 (LOXL1) gene polymorphisms to exfoliation syndrome (XFS) and exfoliation glaucoma (XFG) in a case-control cohort of American and European patients.
METHODS: DNA from a total of 620 individuals including 287 exfoliation patients and 333 healthy control subjects were extracted by standard methods. Three single nucleotide polymorphisms (SNPs) of rs1048661 (R141L), rs3825942 (G153D), and rs2165241 were genotyped in these individuals by SNaPshot Assay. The seven coding exons of the LOXL1 gene and their immediate flanking regions were directly sequenced in 95 affected patients. Data management and case-control association studies were performed with SNP-STAT and PLINK programs. The obtained DNA sequences were evaluated with the STADEN package.
RESULTS: The 287 unrelated exfoliation cases comprised of 171 American patients (mostly of European background) and 116 patients from 12 European countries. This phenotype was further divided into patients with exfoliation only and no glaucoma (XFO; n=95), exfoliation with glaucoma (XFG; n=133), and exfoliation unclassified (XFU; n=59). Genotypic data were analyzed separately for XFO, XFG, XFU, and XFS (all exfoliations; n=287) and for Americans and Europeans. The observed genotypic frequencies for each exfoliation phenotype or population were tabulated separately and tested for deviation from the Hardy-Weinberg equilibrium (HWE) using a standard Chi(2) test. There were no HWE deviations and no significant genotypic differences between these subcategories for the three studied SNPs. For the combined exfoliation cohort, homozygote genotypes of G/G (rs1048661), G/G (rs3825942), and T/T (rs2165241) were significantly overrepresented. Likewise, case-control allelic association for rs1048661 (p=7.74x10(-9)), rs3825942 (p=3.10x10(-17)), and rs2165241 (p=4.85x10(-24)) were highly significant. The corresponding two-locus haplotype frequencies of GG for rs1048661-rs3825942 (p=1.47x10(-27)), GT for rs1048661-rs2165241 (p=1.29x10(-24)), and GT for rs3825942-rs2165241 (p=2.02x10(-24)) were highly associated with exfoliation phenotypes. The combined effect of these three SNPs revealed that the GGT haplotype is overrepresented by 66% in exfoliation cases, and this deviation from controls is highly significant (p=1.93x10(-24)). This haplotype constituted a major risk factor for development of exfoliation in both XFS and XFG. By contrast, the GAC haplotype was significantly underrepresented (p=4.99x10(-18)) in exfoliation cases by 83% and may potentially have a protective effect for this condition with an estimated attributable risk percent reduction of 457%. The only other haplotype that was significantly different between cases and controls was TGC (p=5.82x10(-9)). No observation was made for the GAT haplotype. The combined three haplotypes of GGT, GAC, and TGC were associated with 91% of the exfoliation syndrome cases in the studied populations. Seven coding exons of LOXL1 were also sequenced in 95 affected cases. In addition to the three above-mentioned SNPs, 12 other variations were also observed in these patients (G240G, D292D, A320A, V385V, rs2304719, IVS3+23C>T, IVS3-155G>A, IVS3-101G>A, IVS4+49G>A, rs2304721, IVS5-121C>T, and rs2304722). None were considered a disease-causing mutation.
CONCLUSIONS: We confirmed a strong association with LOXL1 variants in our patients. For the LOXL1 gene, individual alleles of rs1048661 (G), rs3825942 (G), and rs2165241 (T) are highly associated with XFS and XFG in American and European populations. The GGT haplotype constitutes a major risk haplotype for exfoliation, and GAC may have a protective role. DNA sequencing of 95 affected patients did not show any mutations in this gene. The LOXL1 SNPs are located in the 15q24.1 band and within a genetic locus (GLC1N) that is associated with primary open-angle glaucoma (POAG). However, the LOXL1 genetic predisposition is only limited to exfoliation with or without glaucoma and does not include the POAG phenotype. ||||| PURPOSE: To investigate the lysyl oxidase-like 1 (LOXL1) gene for single nucleotide polymorphism (SNP) variations in Japanese patients with exfoliation syndrome (XFS) and exfoliation glaucoma (XFG) and to examine the phenotypes of the patients with these variations.
METHODS: Fifty-six unrelated Japanese patients with XFS, including 36 patients with XFG, were studied. Genomic DNA was extracted from the leukocytes of peripheral blood, and three SNPs (rs1048661; p.Arg141Leu, rs3825942; p.Gly153Asp, and rs2165241) were identified. These SNPs were amplified by polymerase chain reaction (PCR), directly sequenced, and genotyped.
RESULTS: Two nonsynonymous variants in exon 1 of LOXL1,rs1048661 and rs3825942, were found to be strongly associated with XFS including XFG. The frequency of the T allele (0.964) in rs1048661 in eyes with XFS was much higher in controls (0.507) with a p value of 7.7x10(-18). The odds ratio for the T allele in rs1048661 was 26.0 (95% confidence interval, 18.3-37.1). In the haplotype analysis, T-G was overrepresented in XFS subjects (p=7.7x10(-18)), showing a highly significant difference in frequency between primary open-angle glaucoma (POAG) and the control group (p=0.07), but the G-G and G-A haplotypes were less represented in XFS subjects (p=1.1x10(-11) and p=1.0x10(-4), respectively). However, an earlier study reported the strongest associated SNP with XFS and XFG, rs2165241, showed no association.
CONCLUSIONS: SNPs of LOXL1 (rs1048661; Arg141Leu and rs3825942; Gly153Asp) are highly associated with XFS in the Japanese population. However, unidentified genetic or environmental factors independent of LOXL1 will most likely influence the phenotypic expression of the syndrome. ||||| PURPOSE: To evaluate total antioxidant status (TAS) in the plasma of pseudoexfoliation glaucoma (PEG) patients and to compare this level with a matching control group. Additionally, we aim to investigate the effect of the combined action of the lysyl oxidase-like 1 (LOXL1) mutation status with TAS level on the development of PEG.
METHODS: Plasma samples were obtained from 54 PEG patients and 54 controls of matching age, sex, and ethnicity. TAS in all samples was determined by spectrophotometric and enzyme-linked immunosorbent assay methods. The coding region of LOXL1, where it encompasses both single nucleotide polymorphisms (SNPs; rs1048661 and rs3825942), was sequenced.
RESULTS: The mean (±SD) total antioxidant (TAS) value was lower among patients: 0.87 (0.24), range 0.9-1.41 than controls: 1.07 (0.23), range 0.72-1.94, and this difference was statistically significant (p<0.0001: 95%CI: -0.295-0.114). Evaluating the impact of age, sex, and the mutation in addition to the mean TAS value in patients with PEG, a logistic regression analysis was conducted using diseased/not diseased as the outcome of interest (the dependent variable). Results show that, controlling for all other variables, mean TAS value (p<0.0001) and the mutation G/G in rs3825942 (p=0.041) are significant risk factors for PEG.
CONCLUSIONS: Our findings provide evidence that TAS decreases in the plasma of PEG patients, suggesting that TAS may have an important role in the pathogenesis of PEG. The combined effect of the "G" allele and the decreased TAS may contribute to the overall pathogenesis of PEG. ||||| PURPOSE: In the Icelandic and Swedish populations, pseudoexfoliation syndrome (XFS) and pseudoexfoliation glaucoma (XFG) has been significantly associated with LOXL1 exon 1 polymorphisms - allele G of rs1048661 (R141L) and allele G of rs3825942 (G135D). In this study, we looked at the association of rs1048661 and rs3825942 in a southern Indian population.
METHODS: Fifty-two cases with XFS (including XFG) and 97 matched controls that had thorough glaucoma evaluations were included in the study. Exon 1 of the LOXL1 gene with the single nucleotide polymorphisms (SNPs) were amplified and sequenced. For statistical significance, Pearson's Chi(2) test was performed. The HAPLOVIEW program v4.0 was used to determine the Hardy-Weinberg equilibrium and haplotype association.
RESULTS: In our study population, there was a significant association of allele G of rs3825942 with XFS (p=0.0001) and genotype GG (p=0.000305) with XFS.
CONCLUSIONS: Out of the two non-synonymous SNPs in exon 1 of the LOXL1 gene, rs3825942 has a significant association with XFS cases in the patients of the southern Indian population. To the best of our knowledge, this is the first Asian study replicating the European studies. ||||| PURPOSE: To evaluate the association between lysyl-oxidase-like 1 (LOXL1) gene polymorphisms and exfoliation glaucoma, pigmentary glaucoma and normal tension glaucoma in a case-control cohort of German patients.
METHODS: Six single nucleotide polymorphisms in a 22 kb genomic region encompassing the LOXL1 gene plus an additional "outlier" single nucleotide polymorphism located approximately 1.1 Mb upstream of LOXL1 were genotyped in 128 exfoliation glaucoma patients, 88 pigmentary glaucoma patients, 273 normal tension glaucoma patients, and 280 healthy control subjects either with TaqMan allelic discrimination assays or by direct sequencing, and a genetic association study was performed.
RESULTS: For the exfoliation glaucoma cases, case-control allelic association for 6 single nucleotide polymorphisms were highly significant. In contrast, there were no genotypic differences between pigmentary glaucoma cases, normal tension glaucoma cases and controls. However, an association between rs1048661 genotype and age at disease onset was suggested for pigmentary glaucoma patients.
CONCLUSIONS: Our study reveals that in the German population the LOXL1 genetic predisposition is limited to exfoliation glaucoma and does not include normal tension glaucoma. In addition, our study implicates that LOXL1 polymorphisms are not likely to have a major influence on the pathophysiology of pigmentary glaucoma. However, 1 nonsynonymous polymorphism may serve as a predictor of age at disease onset in pigmentary glaucoma. ||||| PURPOSE: In the Greek population of Epirus, exfoliation syndrome (XFS) and exfoliation glaucoma (XFG) occur at a high prevalence. In this study, we validate a novel lysyl oxidase-like 1 (LOXL1) genotyping method, investigate the previously reported association of LOXL1 with XFS/XFG, and evaluate apolipoprotein E (APOE) and methylenetetrahydrofolate reductase (MTHFR) polymorphisms as genetic risk factors for both conditions in our population.
METHODS: Blood samples were collected from 82 patients with XFG, 69 patients with XFS, 52 patients with primary open-angle glaucoma (POAG), and 107 controls. APOE and MTHFR 677C>T genotyping was performed from extracted genomic DNA with established methods. A novel methodology of real-time PCR and melting curve analysis was developed and validated to accurately genotype the LOXL1 G153D and R141L polymorphisms by using two different fluorescent channels of the LightCycler instrument (Roche) examining each SNP separately.
RESULTS: No significant differences were observed for the APOE and MTHFR polymorphisms between the patients with XFS, the patients with XFG, and the control subjects. The APOE ε2 allele appears to be associated with elevated risk of POAG in our population. Our novel LOXL1 genotyping method was easy to perform, fast, and accurate. A statistically significant association was found for the LOXL1 gene with XFS/XFG in this Greek population. The association of XFS and XFG with G153D appeared to be less powerful in this population (XFS: odds ratio [OR]=2.162, p=0.039, XFG: OR=2.794, p=0.002) compared to other populations, and for R141L, the association was proven only with XFG (OR=3.592, p<0.001). Neither of the two LOXL1 SNPs was significantly associated with POAG.
CONCLUSIONS: We confirmed the association between LOXL1 and XFS/XFG, but the APOE and MTHFR polymorphisms are not significant risk factors for the development of XFS/XFG in our population of patients from Epirus (Greece). ||||| PURPOSE: To investigate whether variants in the lysyl oxidase-like 1 (LOXL1) gene are associated with exfoliation glaucoma (XFG) and primary open-angle glaucoma (POAG) in an ancestral population from South Africa.
METHODS: Black South African subjects with XFG, POAG, and age matched unaffected controls were recruited from the St. John Eye Hospital in Soweto, Johannesburg, South Africa, using standard clinical examination techniques. Fifty individuals were collected for each of the three groups: XFG, POAG, and normal controls. The complete coding region of LOXL1 was sequenced using the PCR-based Sanger method. The allele frequencies of the identified sequence variants were compared between XFG or POAG and controls using Fisher's exact test.
RESULTS: A large number of coding variants were identified, including rs1048661 (R141L), rs3825942 (G153D), S159A, S161L, rs41435250 (A320A), rs13329473 (F489F), and T567A. The allele frequencies of both rs3825942 and rs1048661 differed significantly between the XFG and control subjects from South Africa (p=5.2 x 10(-13) and 1.7 x 10(-5), respectively). The G allele for rs1048661 (encoding arginine) was the risk allele which is similar to other populations. The A allele of rs3825942 (encoding aspartic acid) was the risk allele, in sharp contrast to the G allele (encoding glycine) reported in multiple other populations. There was no significant difference in the allele frequencies of coding variants in LOXL1 between POAG and control subjects.
CONCLUSIONS: This represents the first genetic association study of LOXL1 in an ancestral African population with XFG. We have confirmed the association between variants of LOXL1 and XFG. To date, the G allele of the major susceptibility variant rs3825942 has consistently been shown in multiple populations to increase the risk of XFG. Surprisingly, we have found a strong association with the opposite allele in the South African population. This suggests that other as yet unknown causal variants of LOXL1 contribute to the genetic risk of XFG. ||||| Exfoliation glaucoma (XFG) is the commonest identifiable cause of secondary open-angle glaucoma worldwide, characterized by the deposition of fibrillar proteins in the anterior segment of the eye. We investigated LOXL1 gene variants previously identified to confer susceptibility to XFG in a Utah Caucasian cohort. After a standard eye examination protocol we genotyped SNPs rs2165241and rs3825942 in 62 XFG or exfoliation syndrome (XFS) patients and 170 normal controls. Genotype frequency distribution, odds ratios (ORs) and population attributable risks were calculated for the risk alleles. The SNP rs2165241 was significantly associated with XFG and XFS (p = 4.13 x 10(-9)) for an additive model, OR(het) = 4.42 (2.30-8.50), OR(hom) = 34.19 (4.48-261.00); T allele: 83.1% in cases versus 52.4% in controls). Significant association was also found for rs3825942: (p = 1.89 x 10(-6)). Our findings confirm genetic association of LOXL1 with XFG and XFS and implicate a potential role of cross linking of elastin in the pathogenesis of XFG. This information will potentially guide glaucoma monitoring efforts by targeting individuals whose genetic profiles put them at higher risk for XFG. ||||| PURPOSE: To investigate the contribution of two single-nucleotide polymorphisms (SNPs) of the lysyl oxidase-like 1 (LOXL1) gene, recently shown to be associated with exfoliation syndrome (XFS) and exfoliation glaucoma (XFG) in the Nordic population, to the occurrence of XFS and XFG in the Japanese population.
DESIGN: Case-control association study.
METHODS: A total of 59 unrelated Japanese individuals with XFS, 27 XFG patients, and 190 population-based controls were recruited. The SNPs rs1048661 (R141L) and rs3825942 (G153D) in the LOXL1 gene were genotyped directly. Association tests were performed for the two SNPs and inferred haplotypes.
RESULTS: The frequency of the G allele in rs1048661, reportedly a functional risk allele in White persons, existed in only 0.8% of Japanese XFS cases, but occurred with much higher frequency in controls (46.0%) and yielded a P value of 3.0x10(-19), and the odds ratio for the T allele in rs1048661 was 99.8 (95% confidence interval, 13.8 to 722). For rs3825942, the frequency of the G allele, which is another possible risk allele in White persons with XFS, was 1.000 vs 0.857 in the controls (P=1.4x10(-5)). The most frequent haplotype in Japanese XFS patients was haplotype (T,G) (99.2%). The (G,G) haplotype, which generates the highest risk in White persons, was present in only a small percentage of Japanese XFS cases (0.8%).
CONCLUSIONS: The SNPs rs1048661 and rs3825942 of the LOXL1 gene seem to be highly associated with XFS in the Japanese population, but a different polymorphism of LOXL1 may cause the development of XFS in the Japanese population. ||||| PURPOSE: To evaluate the association of the lysyl oxidase-like 1 (LOXL1) single nucleotide polymorphisms (SNPs) in the Korean population with exfoliation syndrome (XFS) and to investigate the association between the SNPs and phenotypes of XFS.
METHODS: Eighty-nine unrelated patients with XFS and 146 unrelated control subjects were recruited. LOXL1 SNPs, rs1048661, rs3825942, and rs2165241, were genotyped by direct DNA sequencing. Association between cases and controls was analyzed and phenotypic features of XFS were compared in terms of the SNPs.
RESULTS: The three SNPs were found to be significantly associated with XFS. After adjusting for rs3825942, rs2165241, and other factors influencing the prevalence of XFS, only rs1048661 among three SNPs remained significant (95% confidence interval=4.11-35.78, p=6.11×10(-6)). T allele and TT genotype of rs1048661 and C allele and CC genotype of rs2165241 were associated with XFS, showing risk alleles and genotypes opposite to those reported in Caucasians. In the haplotype analysis, T-G-C was the only risk haplotype (p=3.35×10(-12)), which was not associated with XFS in Caucasians. No significant differences were noted in the allele and genotype frequencies depending on phenotypic features of XFS.
CONCLUSIONS: Three LOXL1 SNPs are associated with XFS in the Korean population. Risk alleles and genotypes of rs1048661 and rs2165241 in Korean have a similar pattern with those of East Asians, including Japanese and Northern Chinese, while they have a different pattern from those of Caucasians. ||||| OBJECTIVE: To investigate the association between 2 lysyl oxidase-like 1 (LOXL1) polymorphisms, rs1048661 (R141L) and rs3825942 (G153D), and exfoliation syndrome (XFS) in black South African individuals.
METHODS: A total of 43 black patients with XFS and 47 ethnically matched controls were recruited for genetic analysis. Samples were analyzed for presence of the LOXL1-R141L and G153D variants using restriction fragment length polymorphism analysis. A case-control association study was performed.
RESULTS: The R141L and G153D single-nucleotide polymorphisms (SNPs) were both significantly associated with XFS (P = .00582 and P < .00001, respectively). Consistent with findings in white populations but not in Asian cohorts, the GG genotype of the R141L SNP was present in significantly more XFS cases than controls (P = .00582). However, in this black South African study population, the AA genotype of G153D was present in an overwhelming majority of cases with XFS (P < .00001; odds ratio, 17.10; 95% confidence interval, 4.91-59.56), contrary to all previous articles in which the GG genotype was strongly associated with the disease phenotype.
CONCLUSION: The LOXL1 SNPs R141L and G153D are significantly associated with XFS in this black South African population. The AA genotype of G153D confers XFS risk in this population, as opposed to the GG genotype described in all other populations, suggesting that unidentified genetic or environmental factors independent of these LOXL1 SNPs may influence phenotypic expression of the syndrome.
CLINICAL RELEVANCE: Elucidation of the role of genetic factors, including the LOXL1 gene, in XFS will facilitate identification of individuals predisposed to developing this condition. ||||| PURPOSE: Single nucleotide polymorphisms (SNPs) rs1048661 (p.R141L) and rs3825942 (p.G153D) in the lysyl oxidase-like 1 (LOXL1) gene have been previously reported to be associated with pseudoexfoliation glaucoma (PEXG) in various Asian and European populations, but these SNPs have not yet been studied in the Pakistani population. Therefore the aim of the present study was to investigate the association of these two coding LOXL1 SNPs in Pakistani PEXG patients.
METHODS: One hundred twenty-eight Pakistani patients diagnosed with PEXG and 180 healthy controls were recruited for the study. Genomic DNA was extracted and both SNPs were genotyped by direct sequencing. Association of genotype and allele frequencies with PEXG were analyzed using the Chi-square (χ(2)) test.
RESULTS: Genotype and allele frequencies of both rs1048661 and rs3825942 were found to be significantly associated with PEXG. The GG genotypes of both LOXL1 SNPs were associated with an increased risk of developing PEXG. In addition the G alleles of rs1048661 and rs3825942 confer an increased risk for PEXG with an odds ratio (OR) of 2.98 (95% CI 1.94-4.57) and OR 6.83 (95% CI 2.94-16.67), respectively.
CONCLUSIONS: A significant association was found for the G allele of rs1048661 and rs3825942 in PEXG patients of Pakistani origin. ||||| Glaucoma is a leading cause of irreversible blindness. A genome-wide search yielded multiple single-nucleotide polymorphisms (SNPs) in the 15q24.1 region associated with glaucoma. Further investigation revealed that the association is confined to exfoliation glaucoma (XFG). Two nonsynonymous SNPs in exon 1 of the gene LOXL1 explain the association, and the data suggest that they confer risk of XFG mainly through exfoliation syndrome (XFS). About 25% of the general population is homozygous for the highest-risk haplotype, and their risk of suffering from XFG is more than 100 times that of individuals carrying only low-risk haplotypes. The population-attributable risk is more than 99%. The product of LOXL1 catalyzes the formation of elastin fibers found to be a major component of the lesions in XFG. ||||| PURPOSE: To evaluate the association profiles of the lysyl oxidase-like 1 (LOXL1) gene polymorphisms with exfoliation syndrome in a Chinese population.
METHODS: Fifty unrelated patients with exfoliation syndrome and 125 control subjects were included. Genotypes of the three single nucleotide polymorphisms (SNPs) of LOXL1 (rs1048661, rs3825942, and rs2165241) were analyzed by direct sequencing, and a case-control association study was performed.
RESULTS: The three SNPs were significantly associated with exfoliation syndrome (XFS) and exfoliation glaucoma (XFG) individually. After controlling for rs3825942 and rs2165241, the association between rs1048661 and XFS/XFG remained significant (p=3.6 x 10(-7)). At this SNP, the T allele and TT genotype conferred a 7.59-(95% confidence interval [CI]: 3.87-14.89, p=6.95 x 10(-11)) and 8.69-(95% CI: 4.15-18.20, p<1.00 x 10(-7)) fold increased risk to the disease. The alleles of T at rs1048661 and C at rs2165241 were found to be risk alleles in Chinese subjects, which were opposite to Caucasian individuals. The haplotypes T-G, defined by SNPs rs1048661 and rs3825942, and T-C by SNPs rs1048661 and rs2165241, were also significantly associated with the disorder. However when the genotypic or allelic frequencies of the three SNPs were compared between XFS and XFG, no significant difference was detected.
CONCLUSIONS: LOXL1 is a susceptibility gene of XFS/XFG in the Chinese population, and the association is mainly attributed to SNP rs1048661. The risk alleles of rs1048661 and rs2165241 in Chinese subjects were found to be opposite to that of Caucasians. The genotypic and allelic distributions of these SNPs are similar between XFS and XFG. ||||| PURPOSE: Single nucleotide polymorphisms (SNPs) within the lysyl oxidase like-1 gene (LOXL1; rs1048661 and rs3825942) were found to confer risk to pseudoexfoliation glaucoma (XFG) through the pseudoexfoliation syndrome (XFS) in Nordic, Caucasian, and two Asiatic populations (Indian and Japanese). The prevalence (0.2%-0.7%) of XFS in the Chinese is considerably lower compared to Nordic populations. The aim of this study was to determine the association of LOXL1 in Chinese subjects with XFS/XFG.
METHODS: Chinese subjects with clinically diagnosed XFS/XFG and normal controls were recruited. Genomic DNA was extracted, and the two LOXL1 SNPs (rs1048661 and rs3825942) were genotyped by bidirectional sequencing. Allele and genotype frequencies were compared between cases and unrelated controls using PLINK. Linkage disequilibrium (LD) calculations and haplotype association analysis were done using the Haploview package and WHAP package, respectively.
RESULTS: Sixty-two Chinese patients (17 XFG and 45 XFS) and 171 Chinese controls were studied. The G allele of LOXL1 SNP rs3825942 was moderately associated (OR=10.97, p=0.0018) with pseudoxfoliation in the Chinese. The frequency of the G allele of rs1048661 was not significantly different in cases compared to controls (p=0.142) in the allelic association test. However, the genotype test showed marginal association for rs1048661 (p=0.030). Only three haplotypes were observed (T-G, G-G, and G-A) with G-G as a risk haplotype (p=0.0034) and G-A as a protective haplotype (p=0.00039). T-G, which was a risk haplotype in the Japanese, was not associated with XFG in the Chinese (p=0.124).
CONCLUSIONS: Polymorphisms in LOXL1 confer risk to XFS/XFG in the Chinese. The lower incidence of XFS compared to other populations suggests additional genetic or environmental factors to have a major influence on the phenotypic expression of XFS in the Chinese. The G allele of rs3825942 has been shown to be associated with XFS/XFG in all populations studied to date. ||||| PURPOSE: Pseudoexfoliation syndrome (XFS) is a major risk factor for exfoliation glaucoma (XFG). A significant association exists between XFG and several SNPs in the lysyl oxidase-like 1 (LOXL1) gene. The purpose of this study was to report the results of the first association study between LOXL1 polymorphisms and XFS and/or XFG in a Latin American population.
METHODS: Genotypes of three high-risk SNPs of LOXL1 (rs1048661, rs3825942, and rs2165241) were analyzed by direct sequencing. A case-control study was conducted with 102 unrelated XFS/XFG Mexican patients (42 XFS/60 XFG) as well as 97 control subjects. Allele frequencies, Hardy-Weinberg equilibrium, and haplotype association analysis were assessed with the Haplo View software.
RESULTS: The T allele of the intronic SNP rs2165241 was more frequent in XFS/XFG patients than in controls (OR [95% CI] = 2.41 [1.59-3.64]; p = 0.00001). The G allele of rs3825942 was found in a higher frequency in XFS/XFG than in controls (100% vs 95% respectively, p = 0.0019). No significant association between XFS and the rs1048661 (R141L) SNP was observed. The TGT haplotype was observed in a higher frequency in patients than in controls (p = 0.025), and produced the highest risk in our study (OR [95% CI] = 3.20 [1.09-9.39]; p = 0.025).
CONCLUSIONS: This is the first study associating LOXL1 gene polymorphism and XFS/XFG in Latin America. LOXL1 variants are associated with an elevated risk for XFS/XFG in the Mexican population. A higher risk was conferred by the T allele of the intronic rs2165241 SNP rather than by the worldwide "high-risk" G allele of rs3825942. ||||| PURPOSE: To investigate whether single nucleotide polymorphisms (SNPs) in the lysyl oxidase-like 1 (LOXL1) gene are associated with pseudoexfoliation glaucoma (PEG) in the Saudi Arabian population.
METHODS: The coding regions of LOXL1 were fully sequenced in 93 clinically diagnosed PEG patients and 101 healthy controls. Both groups were Saudi Arabs. Previously reported and newly identified SNPs were evaluated for possible association with PEG and their pathological consequences on the gene were assessed.
RESULTS: The "G" allele frequencies of both rs1048661 and rs3825942 SNPs differed between PEG patients and control subjects from Saudi Arabia (p=0.0056 and p=0.000005, respectively). This significance remained after applying the Bonferroni correction. Two non-synonymous novel SNPs in LOXL1 were detected in the PEG patients and not in the controls. One of these SNPs was in exon 4 (g.25722 C>G; codon change D484E) of LOXL1 and was predicted to be non-pathological; the other was in exon 6 of LOXL1 (g.28084 T>G; codon change Y559D) and was predicted to be probably damaging. All alleles of SNPs (rs28706550, rs35203737, rs41429348, rs12906373, rs41435250, and rs13329473) were monoallelic in this population. No allele frequency difference for rs8818 and rs3522 SNP between patients and controls (p values were 0.126 and 0.994 respectively).
CONCLUSIONS: Similar to almost all non-African populations tested thus far, the "G" allele of both rs1048661 and rs3825942 SNPs were associated with the risk of PEG in the Saudi Arab population. ||||| PURPOSE: To assess the possible association of lysyl oxidase-like 1 (LOXL1) gene variants with pseudoexfoliation syndrome (PEX) in Polish population.
METHODS: The group studied comprised of 36 patients with PEX (men and women) who presented to Department of Ophthalmology Collegium Medicum UMK in Bydgoszcz, Poland, and 30 control subjects. Blood samples were obtained from each patient via peripheral venipuncture, and genomic DNA was isolated according to the standard procedures. Three LOXL1 single nucleotide polymorphisms (SNPs) rs1048661 (R141L), rs3825942 (G153D) and rs216524 were genotyped in patient sample.
RESULTS: The significant association with PEX was found for the G allele of rs3825942 (p = 0.0047) and for the T allele of rs216541 (p = 0.021). The haplotype (GGT) consisting of all three risk alleles was significantly overrepresented (87.5%) in patients with PEX.
CONCLUSION: Single nucleotide polymorphisms in LOXL1 are associated with PEX in Polish population which confirms the association previously reported for Icelandic, Swedish, Indian and other populations. | [
{
"source_pmid": "18552979",
"source_text": "PURPOSE: We performed genetic association studies using a native Japanese population to examine the reproducibility of results of lysyl oxidase-like 1 (LOXL1) genetic association studies for exfoliation glaucoma (XFG) beyond the differences of ethnicity. We also ... |
11466259 | CONCLUSION: This meta-analysis suggests that latanoprost is more effective than timolol in lowering IOP. However, it often causes iris pigmentation. While current evidence suggests that this pigmentation is benign, careful lifetime evaluation of patients is still justified. | PURPOSE: Latanoprost, a new prostaglandin analogue, was compared with timolol for ocular hypotensive efficacy and side effects.
METHODS: In a multicenter, randomized, double-masked, parallel group study, 268 patients with ocular hypertension or early primary open-angle glaucoma received either 0.005% latanoprost once daily or 0.5% timolol twice daily for 6 months. All except ten patients from each group successfully completed the study.
RESULTS: Intraocular pressure (IOP) was significantly (P<0.001) reduced and maintained by both medications without evidence of a long-term drift over 6 months. Comparing 6-month with baseline diurnal IOP values, the IOP reduction (mean +/- standard deviation) achieved with latanoprost (-6.7 +/- 3.4 mmHg) was significantly (P<0.001) greater than that produced with timolol (4.9 +/- 2.9 mmHg). Four patients treated with timolol and none treated with latanoprost were withdrawn from the study because of inadequate IOP control. Pulse rate was significantly reduced with timolol, but not with latanoprost. Slightly more conjunctival hyperemia appeared in latanoprost-treated compared with timolol-treated eyes. Fewer subjective side effects occurred in latanoprost-treated eyes. Both eyes of a patient with a characteristic, concentric iris heterochromia (darker centrally) at baseline showed a definite, photographically documented increase in pigmentation during latanoprost treatment, making the irides uniformly darker. Three additional patients treated with latanoprost were suspects for this color change. Otherwise, no significant difference between treatment groups occurred visual acuity, slit-lamp examination, blood pressure, and laboratory values.
CONCLUSION: Latanoprost has the potential for becoming a new first-line treatment for glaucoma. ||||| OBJECTIVE: To evaluate the intraocular pressure (IOP)-reducing effect and the side effects of latanoprost (PhXA41), a new phenyl-substituted prostaglandin F2 alpha-isopropyl ester analogue, in patients with elevated IOP, using timolol maleate as the reference drug.
METHODS: A total of 184 patients with primary open-angle glaucoma or ocular hypertension at 35 medical centers participated in this randomized double-masked study. The patients were randomized to receive either 0.005% latanoprost once daily or 0.5% timolol maleate twice daily, for a period of 12 weeks. Intraocular pressure was measured 24 hours after the administration of timolol, at 2, 4, 8, and 12 weeks of treatment.
RESULTS: Latanoprost reduced IOP at the end of 12 weeks by 6.2 +/- 2.7 mm Hg (mean +/- SD) (26.8%), while timolol reduced IOP by 4.4 +/- 2.3 mm Hg (19.9%). At all visits latanoprost reduced IOP significantly more than timolol did. The main ocular side effects observed in both groups were conjunctival hyperemia and smarting. The main systemic side effect was a reduced pulse rate, which occurred in patients treated with timolol.
CONCLUSIONS: The results of this study demonstrated that 0.005% latanoprost taken once daily is well tolerated and more effective in reducing IOP than 0.5% timolol taken twice daily. Thus, latanoprost may become an important choice for the medical treatment of glaucoma. ||||| BACKGROUND: Latanoprost is a PGF2 alpha analogue which reduces the intraocular pressure (IOP) by increasing the uveoscleral outflow. The objective of this study was to investigate the effect of two different regimens of latanoprost on the diurnal IOP and also the effect of latanoprost on the blood-aqueous barrier measured with a laser flare cell meter (Kowa FM-500). Moreover, the safety aspects of the two regimens regarding hyperemia were studied.
METHODS: A double-masked, randomized study was performed in 30 patients (9 males, 21 females; mean age 61.9 years) with primary open-angle glaucoma or pseudoexfoliation glaucoma. Twenty patients were treated with latanoprost 0.0015% twice daily or 0.005% once daily for 3 weeks in a cross-over design. Ten patients received timolol 0.5% twice daily as control.
RESULTS: Latanoprost 0.005% once daily reduced IOP (+/- SEM) more effectively than latanoprost 0.0015% twice daily (9.8 +/- 0.9 mm Hg and 6.7 +/- 0.9 mm Hg, respectively). There was a statistically significant increase in the aqueous humour protein concentration within the timolol group (P = 0.004), but not within the latanoprost group (P = 0.97). There was no statistically significant difference in the change in aqueous humour protein concentration from baseline between latanoprost and timolol groups (P = 0.08). No statistically significant difference in conjunctival hyperemia between the two latanoprost regimens was found (P = 0.37).
CONCLUSION: Latanoprost 0.005% once daily reduced IOP more effectively than latanoprost 0.0015% twice daily (P < 0.001). Latanoprost had no statistically or clinically significant effect on the blood-aqueous barrier. There was no difference in hyperemia between the two regimens. Both concentrations of latanoprost reduced IOP at least as well as timolol 0.5% eye drops. ||||| PURPOSE: To compare the intraocular pressure (IOP)-reducing effect and side effects of 0.005% latanoprost administered once daily with 0.5% timolol administered twice daily in patients with open-angle glaucoma or ocular hypertension.
METHODS: This was a randomized, double-masked study with two parallel groups and a treatment period of 6 months. The primary objective of the study is to compare the IOP-reducing effect of lantanoprost with that of timolol at the end of the 6-month treatment period. A total of 294 patients were included: 149 were in the latanoprost group and 145 were in timolol group. Latanoprost was administered in the evening.
RESULTS: Diurnal IOP (9:00 am, 1:00 pm, 5:00 pm) was reduced from 25.2 to 16.7 mmHg (33.7%) with lantanoprost and from 25.4 to 17.1 mmHg (32.7%) with timolol as determined at the end of the 6-month treatment period. No upward drift in IOP occurred with either drug during the treatment period. Latanoprost caused a somewhat more conjunctival hyperemia than timolol and more corneal punctuate epithelial erosions. However, both drugs were generally well tolerated. The most significant side effect of latanoprost was increased pigmentation of the iris which was observed in 15 patients (10.1%). Timolol caused more systemic side effects than latanoprost.
CONCLUSIONS: Latanoprost 0.005% administered once daily in the evening reduced IOP at least as well as timolol 0.5% administered twice daily. Latanoprost was generally well tolerated systemically and in the eye. However, the drug has an unusual side effect of increasing the pigmentation of the iris, particularly in individuals with green-brown or blue-brown eyes. ||||| A randomised observer masked clinical study was conducted to assess the additive effect of latanoprost (13,14-dihydro-17-phenyl-18,19,20-trinorprostaglandin F2 alpha-isopropylester) to timolol maleate in patients with elevated intraocular pressure (IOP). Patients were randomly assigned to two treatment groups. One group (n = 10) received timolol, the other group (n = 9) received latanoprost twice daily for 1 week. After 1 week all patients received both timolol and latanoprost. Eyes treated with timolol (mean diurnal IOP (SD) day 0, 24.2 (2.8) mm Hg) and latanoprost (mean diurnal IOP day 0, 28.5 (5.6) mm Hg) showed an IOP reduction of 5.9 (2.3) mm Hg (24%) and 8.9 (2.5) mm Hg (31%), respectively after the first week. Adding latanoprost to the eyes treated with timolol as well as timolol to the eyes receiving latanoprost gave a further reduction of 2.6 (1.1) mm Hg (13%) and 2.6 (2.2) mm Hg (14%), respectively. Only mild transient hyperaemia was observed in patients receiving latanoprost. The results indicate that latanoprost and timolol can be combined successfully and that complete or almost complete additivity is reached even at pressure levels below 20 mm Hg. ||||| PURPOSE: To examine the effects of topical timolol and latanoprost on retrobulbar vessel blood velocity in patients with glaucoma or ocular hypertension.
METHODS: Nine patients with primary open-angle glaucoma and six patients with ocular hypertension were enrolled for this study. All patients were treated topically with 0.5% timolol or 0.005% latanoprost, using a double-masked crossover design with a 3-week washout before administration of each drug. Each patient had a baseline color Doppler imaging ultrasound of the central retinal artery, short posterior ciliary arteries, and ophthalmic artery and two other ultrasound examinations during the 1-week treatment with each drug, performed 12 hours after the first dose of the drug and 12 hours after the last dose, 7 days later.
RESULTS: Both topical timolol and topical latanoprost significantly reduced the intraocular pressure. The only significant change observed in the retrobulbar blood velocity with timolol was a reduction of end diastolic velocity in the ophthalmic artery 12 hours after the first dose, accompanied by a trend toward a decrease in the peak systolic velocity and an increase in the resistance index in the same vessel. No change in blood velocity was observed with latanoprost.
CONCLUSION: Topical timolol and latanoprost significantly reduced the intraocular pressure in ocular hypertensive and glaucoma patients without creating substantial hemodynamic changes in the retrobulbar vessels. ||||| OBJECTIVE: To compare the efficacy and side effects and the effect on aqueous humor dynamics of 0.005% latanoprost applied topically once daily with 0.5% timolol given twice daily for 12 months to patients with pigmentary glaucoma.
DESIGN: Prospective, randomized, double-masked, clinical study.
PARTICIPANTS: Thirty-six patients affected with bilateral pigmentary glaucoma controlled with no more than a single hypotensive medication were enrolled in the study.
INTERVENTION: The sample population was randomly divided into 2 age- and gender-matched groups each of 18 patients. Group 1 received 0.005% latanoprost eyedrops once daily and the vehicle (placebo) once daily; group 2 was assigned to timolol 0.5% eyedrops twice daily.
MAIN OUTCOME MEASURES: Diurnal curves of intraocular pressure (IOP) were performed on the baseline day and after 0.5, 3, 6, and 12 months of treatment. The IOP measurements were performed at 8:00 AM, 12:00 noon, 4:00 PM, and 8:00 PM. Outflow facility ("C") was measured on the baseline day and on the last day of the study with a Schiotz electronic tonometer. A two-tailed Student's t test for paired or unpaired data was used for statistical evaluation of differences between treatment and baseline values or between the latanoprost and timolol group. Diurnal IOP measurements were compared hour by hour. Mean values of the two eyes IOP and "C" were used for analysis.
RESULTS: Compared with baseline measurements, both latanoprost and timolol caused a significant (P < 0.001) reduction of IOP at each hour of diurnal curve throughout the duration of therapy. Reduction of IOP was 6.0 +/- 4.5 and 5.9 +/- 4.6 with latanoprost and 4.8 +/- 3.0 and 4.6 +/- 3.1 with timolol after 6 and 12 months, respectively. Comparison of mean diurnal measurements with latanoprost and timolol showed a statistical significant (P < 0.001) difference at 3, 6, and 12 months. Mean "C" was found to be significantly enhanced (+30%) only in the latanoprost-treated group compared with the baseline (P = 0.017). Mean conjunctival hyperemia was graded at 0.3 in latanoprost-treated eyes and 0.2 in timolol-treated eyes. A remarkable change in iris color was observed in both eyes of 1 of the 18 patients treated with latanoprost and none of the 18 patients who received timolol. Darkening of the peripheral iris stroma was suspected in two patients treated with latanoprost. In the timolol group, heart rate was significantly reduced from 72 +/- 9 at baseline to 67 +/- 10 beats per minute at 12 months.
CONCLUSIONS: Although further studies may need to confirm these data on a larger sample and to evaluate the side effect of increased iris pigmentation on long-term follow-up, in patients with pigmentary glaucoma, 0.005% latanoprost taken once daily was well tolerated and more effective in reducing IOP than 0.5% timolol taken twice daily. ||||| PURPOSE: To compare the effect on intraocular pressure (IOP) and side effects of 0.005% latanoprost applied once daily, morning or evening, with 0.5% timolol applied twice daily.
METHODS: A 6-month randomized, double-masked, multicenter study with three parallel groups was undertaken. Two hundred sixty-seven patients were randomized, 84 to timolol, 89 to latanoprost in the morning for 3 months and then in the evening for another 3 months, and 94 to latanoprost with the treatment schedule reversed.
RESULTS: After 6 months, timolol reduced diurnal IOP from 24.6 to 17.9 mmHg (27%); latanoprost applied in the morning, from 25.5 to 17.7 mmHg (31%); and latanoprost applied in the evening, from 24.8 to 16.2 mmHg (35%). The efficacy of latanoprost applied in the evening was statistically superior to latanoprost applied in the morning and to timolol (P < 0.001). Latanoprost induced a slight increase in conjunctival hyperemia in 31.4% of treated patients, compared with 15.9% for timolol. Sporadic episodes of mild punctate corneal epithelial erosions were three times as frequent in latanoprost-treated eyes as in timolol-treated eyes. The most significant ocular side effect was increased pigmentation of the iris observed in five and suspected in seven more latanoprost-treated eyes. All these eyes had a mixed green-brown or blue/gray-brown iris color. Timolol reduced heart rate by 3 beats/minute (P < 0.005).
CONCLUSIONS: The effect on diurnal IOP of latanoprost applied once daily in the evening is superior to that of timolol. The main difference in side effects is increased pigmentation of the iris induced by latanoprost, most likely due to stimulation of melanogenesis in iris stromal melanocytes. ||||| PURPOSE: To compare the calculated mean ocular perfusion pressure at the end of 3 weeks' treatment with latanoprost 0.005% once daily or timolol 0.5% twice daily in normal-tension glaucoma patients.
METHODS: In a three-center, double-masked, randomized, crossover study, 36 patients were allocated to two treatment groups; one received 3 weeks each of placebo, latanoprost, placebo, and timolol, whereas the other group had placebo, timolol, placebo, and latanoprost. Intraocular pressure and resting systemic blood pressure were measured at 9 AM, 12 noon, and 4 PM. Ocular perfusion pressure was calculated for each time period as well as the mean of three values (daytime average). Systemic blood pressure and heart rate were also recorded at 30-minute intervals during the last 24 hours of each treatment period.
RESULTS: The average daytime mean ocular perfusion pressure (mean +/- SEM) following latanoprost treatment was 53.2 +/- 1.4 mm Hg, an increase of 8% from the latanoprost run-in period, compared with 50.9 +/- 1.1 mm Hg following timolol treatment, an increase of 2% from the timolol run-in period (P < .05, ANOVA). Timolol reduced the blood pressure. The difference in mean daytime and nighttime systolic blood pressure measurements as well as nighttime diastolic blood pressure was about 5 mm Hg between the latanoprost and timolol treatments. The daytime and nighttime heart rates were also slower during the timolol treatment.
CONCLUSION: Because ocular perfusion pressure may be important in some glaucomatous patients, latanoprost appears to affect ocular perfusion pressure more favorably than timolol does in patients with normal-tension glaucoma. ||||| OBJECTIVE: To compare the intraocular pressure (IOP)-reducing effect of the fixed combinations of timolol 0.5% and latanoprost 0.001% or 0.005% after 4 weeks' treatment.
DESIGN: Following a 1-week run-in period on timolol 0.5% once daily, 139 patients were randomized to once-daily treatment with a fixed combination of timolol 0.5% and latanoprost 0.001% (comb. 10) or latanoprost 0.005% (comp. 50) or to the individual monotherapies. The IOP was measured at inclusion and at 8 a.m., noon and 4 p.m. on days 1, 7 and 28.
RESULTS: Comb. 10, comb. 50, latanoprost and timolol reduced IOP by 3.7, 6.1, 4.9 and 2.1 mmHg, respectively, from a baseline mean diurnal IOP (+/- SEM) of 24.8 +/- 0.5, 24.1 +/- 0.4, 25.2 +/- 1.2 and 24.8 +/- 0.9 mmHg, respectively. The difference in IOP reduction was significant between comb. 50 and comb. 10 (P < 0.001), latanoprost (P = 0.046) and timolol (P < 0.001) in favor of comb. 50. There was also a significant difference between latanoprost and timolol (P = 0.007), in favor of latanoprost. All treatments were generally well tolerated.
CONCLUSION: This study indicates that a fixed combination of latanoprost 0.005% and timolol 0.5% could be useful in the treatment of glaucoma. | [
{
"source_pmid": "8628544",
"source_text": "PURPOSE: Latanoprost, a new prostaglandin analogue, was compared with timolol for ocular hypotensive efficacy and side effects.\nMETHODS: In a multicenter, randomized, double-masked, parallel group study, 268 patients with ocular hypertension or early primary open... |
29090356 | CONCLUSIONS: The visual acuity outcomes in patients affected by nontractional diabetic macular edema using pars plana vitrectomy with ILM peeling versus no ILM peeling were not significantly different. A larger prospective and randomized study would be necessary. | PURPOSE: A prospective, comparative, nonrandomized study to evaluate the efficacy of pars plana vitrectomy (PPV) with and without inner limiting membrane (ILM) peeling for persistent diffuse clinically significant macular edema.
METHODS: Eighteen patients with persistent diffuse clinically significant macular edema despite laser photocoagulation were recruited for the study. Clinical assessment included determination of best-corrected visual acuity, fundus fluorescein angiography, optical coherence tomography, and perifoveal cone function testing. Eight patients underwent PPV with elevation and removal of the posterior hyaloid alone, and 10 patients underwent vitrectomy and ILM peeling. The follow-up was 12 months.
RESULTS: Patients with ILM peeling had improvement in foveal thickness (P = 0.07) and significant improvement in the macular volume (P = 0.039) 12 months after surgery but did not have significant improvement in Early Treatment Diabetic Retinopathy Study vision or perifoveal cone function. There was no significant difference in outcome parameters between the no peeling group and the ILM peeling group.
CONCLUSIONS: In this prospective, comparative study of PPV with and without ILM peeling for diffuse clinically significant macular edema, structural improvement was seen but with limited visual improvement after ILM peeling. ||||| PURPOSE: To evaluate the effect of internal limiting membrane (ILM) peeling on the long-term visual outcomes in eyes with diffuse, nontractional diabetic macular edema.
METHODS: One hundred and sixteen eyes of 58 patients with the same degree of diabetic macular edema in both eyes underwent pars plana vitrectomy with the creation of a posterior vitreous detachment in both eyes. Internal limiting membrane peeling was performed in one randomly selected eye (ILM-off group), and ILM peeling was not performed (ILM-on group) in the fellow eye. The postoperative follow-up period ranged from 12 months to 161 months (average, 80.4 months).
RESULTS: In the ILM-off group, the mean best-corrected visual acuity in logMAR units (Snellen equivalent) increased from 0.55 ± 0.31 (20/71) before surgery to 0.35 ± 0.35 (20/45) at 1 year (P < 0.0001) and 0.46 ± 0.43 (20/59) at the final visit (P = 0.058). In the ILM-on group, the mean best-corrected visual acuity increased from 0.55 ± 0.41 (20/71) before surgery to 0.43 ± 0.38 (20/54) at 1 year (P = 0.010) and 0.44 ± 0.45 (20/56) at the final visit (P = 0.043). The differences in the best-corrected visual acuity between the two groups were not significant at any time point.
CONCLUSION: Pars plana vitrectomy with or without ILM peeling improves the long-term visual acuity of nontractional diabetic macular edema. Internal limiting membrane peeling does not affect the postoperative best-corrected visual acuity significantly. ||||| PURPOSE: To report the long-term results of pars plana vitrectomy for diffuse nontractional diabetic macular edema.
DESIGN: Interventional, retrospective, consecutive case series.
METHODS: Clinical records of 332 consecutive patients (496 eyes) with diabetic macular edema without a thickened and taut posterior hyaloid on contact lens examination were reviewed. Four hundred eighty-six eyes of 326 consecutive patients were included in this study. All patients underwent pars plana vitrectomy with the creation of a posterior vitreous detachment by one surgeon. Simultaneous phacoemulsification with intraocular lens implantation was performed on 456 phakic eyes. Internal limiting membrane peeling was performed on 178 (36.6%) of 486 eyes. The main outcome measured was best-corrected visual acuity results during follow-up periods.
RESULTS: Postoperative follow-up ranged from 12 to 170 months (mean, 74.0 months). Five year follow-up data were available for 356 (71.8%) of 496 eyes. Mean preoperative best-corrected visual acuity significantly increased from 0.19 (20/105) to 0.32 (20/63) at 1 year after surgery (P < 0.0001), and 0.30 (20/67) at the final visit (P < 0.0001). The final best-corrected visual acuity improved in 256 (52.7%) of the 486 eyes, remained unchanged in 152 eyes (31.3%), and worsened in 78 eyes (16.0%). Postoperative major complications included neovascular glaucoma in 19 eyes (3.9%), recurrent vitreous hemorrhage in 10 eyes (2.1%), hard exudate deposits in the center of the macula in 21 eyes (4.2%), and glaucoma in 22 eyes (4.5%).
CONCLUSIONS: Pars plana vitrectomy with and without internal limiting membrane peeling appears to be beneficial in eyes with diffuse nontractional diabetic macular edema, and its effectiveness is maintained long term. ||||| PURPOSE: To prospectively determine the efficacy of vitrectomy combined with intravitreal triamcinolone acetonide (IVTA) injection, internal limiting membrane (ILM) peeling, or both in treating diffuse nontractional diabetic macular edema (ME).
METHODS: Patients with diffuse ME of <6 months who had no evidence of macular traction or macular ischemia were included in the study. Patients previously diagnosed with glaucoma underwent vitrectomy with ILM peeling. All other patients were randomly assigned to vitrectomy or vitrectomy with ILM peeling followed by IVTA injection.
RESULTS: Forty-two eyes of 38 patients were included in the study. Mean follow-up was 12 months. A statistically significant reduction in macular thickness was found at 1 month to 6 months, disappearing at 12 months. No differences in visual acuity between treatment groups were found during follow-up. Visual acuity improved in 5 (12%) of 42 eyes, remained unchanged in 32 (76%) of 42 eyes, and worsened in 5 (12%) of 42 eyes. Complications included increase in intraocular pressure in 8 (26%) of 31 eyes, mild vitreous hemorrhage in 6 (14%) of 42 eyes, central retinal pigment epithelium changes in 5 (12%) of 42 eyes, and cataract progression in 11 (38%) of 29 phakic eyes.
CONCLUSION: In diffuse diabetic ME with no retinal traction, vitrectomy with either ILM peeling or IVTA injection at the end of surgery produces a short-term improvement in retinal thickness but no long-term anatomical or functional improvements. | [
{
"source_pmid": "16395132",
"source_text": "PURPOSE: A prospective, comparative, nonrandomized study to evaluate the efficacy of pars plana vitrectomy (PPV) with and without inner limiting membrane (ILM) peeling for persistent diffuse clinically significant macular edema.\nMETHODS: Eighteen patients with p... |
31334388 | Conclusions: The present meta-analysis revealed that MTHFR A1298C polymorphism is significantly associated with the increased risk of glaucoma, but not MTHFR C677T polymorphism.
| PURPOSE: Increased plasma homocysteine levels have been found in patients with primary open angle glaucoma (POAG) and glaucoma secondary to pseudoexfoliation syndrome (PEXG). A common polymorphism of the methylenetetrahydrofolatereductase (MTHFR 677C>T) leads to moderately elevated plasma homocysteine levels particularly under conditions of impaired folate status. It was the aim of this study to investigate a hypothesized association between this polymorphism and the presence of either POAG or PEXG.
METHODS: The present retrospective case-control study included a total of 553 participants comprising 204 patients with POAG, 138 patients with PEXG, and 211 control subjects. Genotyping for the MTHFR 677C>T polymorphism was performed by polymerase chain reaction (PCR).
RESULTS: No significant difference in the genotype distribution of the MTHFR 677C>T polymorphism was found between control subjects and patients with POAG or PEXG. The prevalence of the MTHFR 677TT genotype was 6.9% in patients with POAG, 11.6% in patients with PEXG, and 9.5% in control subjects.
CONCLUSIONS: The present data suggest that the MTHFR 677C>T polymorphism itself is not a major genetic risk factor for POAG and PEXG in a central European population. ||||| Glaucoma is a major cause of blindness worldwide. A single nucleotide polymorphism of the MTHFR gene (C677T) has been associated with susceptibility to this disease, although this is controversial in the last decade. In this study, the possible association between the MTHFR C677T polymorphism and the risk of developing primary open angle (POAG) and pseudoexfoliation glaucoma (PEXG) was investigated. For this, a prospective study consisting of 73 POAG, 85 PEXG and 90 matched controls was undertaken in an Iranian population. Genomic DNA was extracted from whole blood. Genotyping of all individuals for the MTHFR C677T polymorphism was conducted using the PCR-RFLP technique. Our findings revealed no significant association between the MTHFR C677T polymorphism in POAG and PEXG compared with controls. Consistent with several other studies, our analysis suggests that the MTHFR C677T polymorphism is unlikely to be a factor contributing to the risk of developing specific forms of glaucoma. ||||| PURPOSE: Primary angle closure (PAC) is the early stage of primary angle closure glaucoma (PACG). It is believed that the formation of PAC is regulated by a tissue remodeling pathway. This study investigated the association between gene variants in extracellular matrix metalloprotease-9 (MMP-9), methylenetetrahydrofolate reductase (MTHFR), frizzled-related protein (MFRP), heat shock protein 70 (HSP70), and PAC.
METHODS: The study was part of the Jiangsu Eye Study. The sample consisted of 232 subjects with PAC and 306 controls obtained from a population-based prevalence survey conducted in Funing County in Jiangsu Province, China. The single nucleotide polymorphisms (SNPs) included rs17576 and rs3918249 in MMP-9, rs1801133 in MTHFR, rs3814762 in MFRP, and rs1043618 in HSP70. SNP genotyping was performed with a TaqMan MGB probe using the real-time PCR system.
RESULTS: Among the five SNPs tested, only MFRP rs3814762 and HSP70 rs1043618 showed a nominal association with PAC. The frequency of the minor T allele of MFRP rs3814762 was higher in the control group than in the PAC group (uncorrected p=0.016 and p=0.027, for alleles and genotypes, respectively) and conferred an odds ratio (OR) of 0.67 in the allelic analysis, indicating a protective role of the SNP in developing PAC. In contrast, the frequency of the CC genotype of HSP70 rs1043618 was higher in the PAC group than in the control group (uncorrected p=0.048 and p=0.022 for the genotypes general model and recessive model, respectively) and conferred an OR of 1.79 in the recessive model, indicating a harmful role in developing PAC. However, the differences did not remain statistically significant after Bonferroni correction. The remaining three SNPs showed no differences in the distribution of the genotypes and allele frequencies between the two groups.
CONCLUSIONS: Our study reveals a suggestive association of MFRP and HSP70 with PAC in a Han Chinese population. The results from this population-based survey will serve as the baseline for prospective observation of the role of tissue remodeling pathway in the development of PACG. ||||| PURPOSE: Homozygous polymorphism of the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene and resultant hyperhomocysteinaemia have been established as an independent risk factor for vascular diseases. There are evidences that vascular abnormalities are involved in the pathogenesis and progression of normal-tension glaucoma (NTG). In the present study, we were to find out the associations between 677C>T and 1298A>C polymorphisms of the MTHFR gene and NTG.
METHODS: This was a retrospective, case-controlled study enrolling 78 NTG patients and 100 controls. DNA from peripheral blood lymphocytes was extracted and the genotypes of polymorphisms (677C>T and 1298A>C) in the MTHFR gene were determined using PCR followed by restriction enzyme digestion. The frequencies of the polymorphic genotypes in the patients with NTG and controls were compared.
RESULTS: The frequencies of the polymorphisms of the MTHFR gene (677C>T and 1298A>C) in the NTG patients were not significantly different from those of controls. But the younger NTG patients (age at diagnosis < or = 45 years) showed significantly higher prevalence of 677C>T polymorphism than the older NTG patients (age at diagnosis > 45 years) (TT genotype, 38.9 vs 11.9%, P=0.006, OR=4.71, 95% CI=1.49-14.9) and than the younger control subgroup (TT genotype, 38.9 vs 6.1%, P=0.001, OR=9.86, 95% CI=2.23-42.4).
CONCLUSIONS: The 677C>T polymorphism was significantly associated with NTG in the younger patients, while 1298A>C polymorphism was not. This suggests that 677C>T polymorphism of the MTHFR gene can be a genetic risk factor of NTG in Korean population. ||||| Hyperhomocysteinemia induced by the C677T genetic variant in MTHFR (methylenetetrahydrofolate reductase) has been implicated in neuronal cell death of retinal ganglion cells (RGC), which is a characteristic feature of glaucoma. However, association of MTHFR C677T with glaucoma has been controversial because of inconsistent results across association studies. Association between MTHFR C677T and glaucoma has not been reported in Indian population. Therefore, with a focus on neurodegenerative death of RGC in glaucoma, the current study aimed to investigate association of MTHFR C677T with Primary Open Angle Glaucoma (POAG) and Primary Angle Closure Glaucoma (PACG) in a North Indian population. A total of 404 participants (231 patients and 173 controls) were included in this study. Genotyping was performed by Polymerase Chain Reaction-Restriction Fragment Length Polymorphism. A few random samples were also tested by direct sequencing. Genotypic and allelic distributions of the POAG and PACG cohorts were compared to that of controls by chi-square test and odds ratios were reported with 95% confidence intervals. Genotypic and allelic distributions between POAG cases and controls were significantly different (p = 0.03 and p = 0.01 respectively). Unlike POAG, we did not find significant difference in the genotypic and allelic distributions of C677T between PACG cases and controls (p>0.05). We also observed a higher proportion of TT associated POAG in females than that in males. However, this is a preliminary indication of gender specific risk of C677T that needs to be replicated in a larger cohort of males and females. The present investigation on MTHFR C677T and glaucoma reveals that the TT genotype and T allele of this polymorphism are significant risk factors for POAG but not for PACG in North Indian population. Ours is the first report demonstrating association of MTHFR C677T with POAG but not PACG in individuals from North India. ||||| PURPOSE: To assess whether or not the c.677C/T and c.1298A/C genetic polymorphisms of the methylenetetrahydrofolate reductase (MTHFR) gene are associated with open angle glaucoma (OAG).
METHODS: Genomic DNA was examined in a cohort of 131 Japanese patients with normal tension glaucoma (NTG), 133 patients with primary open angle glaucoma (POAG), and 106 control subjects. The mean age at the time of blood sampling was 62.8+/-13.3 years (mean+/-SD) in the patients with NTG, 61.8+/-15.4 years in the patients with POAG, and 65.0+/-10.5 years in the control subjects. MTHFR c.677C/T and c.1298A/C genotype and allele frequencies were determined using pyrosequencing analysis, and the findings were compared between the OAG patients and control subjects. The frequencies of compound MTHFR c.677C/T and c.1298A/C genotypes were also compared between OAG patients and control subjects.
RESULTS: No significant differences were observed (p>0.05, chi2 test or Fisher's exact test) regarding the MTHFR c.677C/T genotype (TT: 14.5%, CT: 44.3%, CC: 41.2% for patients with NTG; TT: 20.3%, CT: 41.4%, CC: 38.3% for patients with POAG; TT: 17.9%, CT: 36.8%, CC: 45.3% for control subjects) and c.1298A/C (CC: 0%, AC: 38.9%, AA: 61.1% for patients with NTG; CC: 2.3%, AC: 32.3%, AA: 65.4% for patients with POAG; CC: 0.9%, AC: 41.5%, AA: 57.6% for control subjects). There were no allele frequencies between the NTG or POAG patients and the control subjects. In addition, no significant differences (p>0.05, chi2 test) were found in the frequencies of the compound MTHFR c.677C/T and c.1298A/C genotypes between the NTG or POAG patients and the control subjects.
CONCLUSIONS: The MTHFR c.677C/T and c.1298A/C polymorphisms were not found to be associated with NTG and POAG. Further studies in the different ethnic populations should be performed to elucidate the relationship between MTHFR and OAG. ||||| Homocysteine levels and the frequency of heterozygous methylenetetrahydrofolate reductase (MTHFR) C677T mutation are increased in open-angle glaucoma. Since homocysteine can induce vascular injury, alterations in extracellular matrix remodelling, and neuronal cell death, these findings may have important implications for understanding glaucomatous optic neuropathy. ||||| The aim of this study was to investigate the association of multiple primary open-angle glaucoma (POAG)-risk alleles in a Mexican population for the first time. Genotyping was performed for a total of 26 previously associated alleles located in 11 different genes, including MYOC, CYP1B1, OPTN, IL1A, TNF, OPA1, EDNRA, AGTR2, MTHFR, GSTM1, and GSTT1. The frequencies of these variants were compared in a group of 218 individuals (118 with POAG and 100 adult controls without the disease). Genomic DNA was extracted from blood leukocytes, and genotyping was performed using PCR followed by direct sequencing. GSTM1 and GSTT1 deletion variants were screened by agarose gel analysis. Individual SNP analysis showed that no specific variants conferred an elevated risk for developing POAG. However, the CG genotype for rs5335 polymorphism in EDNRA showed a protective effect against the development of POAG, as it provides an estimated odds ratio of 0.5 (95% CI, 0.3-0.9; p = 0.03). Moreover, one haplotype consisting of rs1056827 and rs100012 in CYP1B1 gene was significantly associated with a protective effect against POAG (p = 0.0045; OR = 0.3; 95% CI, 0.1-0.7). This is the first case-control investigation of POAG-risk alleles in multiple genes in a Latino population. Although our results support that the analyzed variants are not major risk factors for POAG in this ethnic group, they also point toward a protective effect conferred by EDNRA rs5335, as well as by a CYP1B1 haplotype consisting of rs1056827 and rs100012. Our study emphasizes the importance of genotyping ethnic groups with a complex admixture of ancestral populations for contributing to dissecting the genetics of POAG. ||||| PURPOSE: To determine whether or not there is an association of the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism with disease in cohorts of primary open-angle glaucoma (POAG) and primary closed-angle glaucoma (PCAG) from Pakistan.
METHODS: This was a prospective study consisting of 150 patients (90 POAG and 60 PCAG) and 70 control subjects. Genomic DNA was extracted from leukocytes of the peripheral blood. MTHFR C677T polymorphism analysis was performed by the polymerase chain reaction-restriction fragment length polymorphism (RFLP) technique.
RESULTS: The prevalence of the MTHFR C/T genotype was 22.2% in POAG, 13.3% in PACG, and 18.6% in controls whereas the MTHFR T/T genotype was present solely in the PACG group (6.9%). The difference regarding the T/T genotype between PACG and controls was statistically significant (p<0.01).
CONCLUSIONS: The MTHFR C677T polymorphism was found to be associated with PCAG but not POAG in patients of Pakistani origin. ||||| PURPOSE: Hyperhomocysteinemia has been found in patients with primary open-angle glaucoma. The purpose of the present study was to determine if hyperhomocysteinemia-associated polymorphisms of the methylenetetrahydrofolate reductase gene (MTHFR) are overrepresented in primary open-angle glaucoma.
METHODS: Patients with primary open-angle glaucoma (n = 243) and controls (n = 187) were analyzed for the MTHFR 677 C > T and 1298 A > C polymorphisms using minisequencing technique.
RESULTS: No significant differences were observed in allele and genotype frequencies of the MTHFR 677C > T and 1298A > C polymorphisms between controls and the primary open-angle glaucoma group.
CONCLUSIONS: If hyperhomocysteinemia is important in the pathogenesis of glaucoma, this study does not support a role for MTHFR polymorphisms in this context. ||||| PURPOSE: To evaluate the variants of 10 genes for association with primary open-angle glaucoma (POAG) in a Chinese population.
METHODS: A total of 405 unrelated patients with POAG (255 high-tension glaucoma [HTG], 100 normal-tension glaucoma [NTG], and 50 juvenile-onset open-angle glaucoma [JOAG]) and 201 control subjects were recruited. Seventeen variants in 10 genes with reported association with POAG were genotyped for analysis of allele and haplotype frequencies between cases and control subjects. These genes included CDH1 (cadherin 1, type 1, E-cadherin), CDKN1A (cyclin-dependent kinase inhibitor 1A), CYP1B1 (cytochrome P450, family 1, subfamily B, polypeptide 1), GSTM1 (glutathione S-transferase mu 1), GSTT1 (glutathione S-transferase theta 1), MTHFR (5,10-methylenetetrahydrofolate reductase), NOS3 (nitric oxide synthase 3), OPA1 (optic atrophy 1), TNF (tumor necrosis factor), and TP53 (tumor protein p53).
RESULTS: One SNP (-308G>A; rs1800629) in TNF demonstrated a significant association with HTG (P = 0.012). The allele G frequency was higher in HTG patients than in control subjects (94.6% vs. 90.3%; OR = 1.89). One haplotype consisting of rs1799724 and rs1800629 was significantly associated with HTG (P = 0.015, corrected P = 0.045). One SNP (R72P; rs1042522) in TP53 was significantly associated with NTG (P = 0.018). The allele G frequency was higher in NTG patients than in control subjects (56.1% vs. 45.8%; OR = 1.52). The significance of these associations survived the Bonferroni correction (corrected P < 0.024). Other gene variants were not significantly associated with HTG (P > 0.063) or NTG (P > 0.13). None of the studied variants was significantly associated with JOAG (P > 0.17).
CONCLUSIONS: The findings suggest that variants in TNF and TP53 are risk factors for POAG, whereas variants in other studied genes are not major risk factors for POAG, at least in the Chinese population. ||||| PURPOSE: To evaluate genes involved in homocysteine metabolism as secondary risk factors for pseudoexfoliation syndrome (PXFS) and the associated glaucoma (PXFG).
METHODS: One hundred eighty-six unrelated patients with PXFS, including 140 patients with PXFG and 127 unrelated control subjects were recruited from the Massachusetts Eye and Ear Infirmary. All the patients and controls were Caucasian of European ancestry. Seventeen tag SNPs from 5 genes (methylenetetrahydrofolate reductase [MTHFR], methionine synthase [MTR], methionine synthase reductase [MTRR], methylenetetrahydrofolate dehydrogenase [MTHFD1], and cystathionine beta-synthase [CBS]) were genotyped. Single-SNP association was analyzed using Fisher's exact test (unconditional) or logistic regression after conditioning on the effects of age and three LOXL1 SNPs (rs1048661, rs3825942, and rs2165241). Interaction analysis was performed between the homocysteine and LOXL1 SNPs using logistic regression. Haplotype analysis and the set-based test were used to test for association of individual genes. Multiple comparisons were corrected using the Bonferroni method.
RESULTS: One SNP (rs8006686) in MTHFD1 showed a nominally significant association with PXFG (p=0.015, OR=2.23). None of the seventeen SNPs tested were significantly associated with PXFS or PXFG after correcting for multiple comparisons (Bonferroni corrected p>0.25). After controlling for the effects of age and three associated LOXL1 SNPs, none of the seventeen tested SNPs were associated with PXFS (p>0.12). No significant interaction effects on PXFS were identified between the homocysteine and LOXL1 SNPs (p>0.06). Haplotype analysis and the set-based test did not find significant association of individual genes with PXFS (p>0.23 and 0.20, respectively).
CONCLUSIONS: Five genes that are critical components of the homocysteine metabolism pathway were evaluated as secondary factors for PXFS and PXFG. Our results suggest that these genes are not significant risk factors for the development of these conditions. ||||| BACKGROUND: The purpose of this study was to investigate plasma homocysteine levels and polymorphisms in genes encoding enzymes in the metabolic pathway of homocysteine in association with primary open-angle glaucoma (POAG) and pseudoexfoliation glaucoma (PXFG).
METHODS: A total of 156 glaucoma patients (76 with POAG and 80 with PXFG) and 135 controls matched for age and sex were enrolled in this study. Plasma homocysteine levels were measured using a commercially available enzyme-linked immunosorbent assay kit. DNA was extracted from peripheral blood leukocytes and real-time polymerase chain reaction was performed for genotyping of the samples. Patients were genotyped using predesigned TaqMan(®) single nucleotide polymorphism genotyping assays for two exon variations (rs1801131, rs1801133) in the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene and one intron variation (rs8006686) in the methylenetetrahydrofolate dehydrogenase (MTHFD1) gene.
RESULTS: Homocysteine levels were slightly higher in the patient group (POAG and PXFG) compared with controls, but the difference did not reach statistical significance. The minor alleles of the MTHFR single nucleotide polymorphisms showed a protective effect for POAG and showed an increased risk for PXFG, but none of these associations reached statistical significance (P>0.05). The minor allele of MTHFD1 rs8006686 showed a trend for increased risk of both POAG and PXFG (P>0.05). No statistically significant interaction was seen between the genetic variants and homocysteine levels (P>0.05).
CONCLUSION: Our results show that neither the examined single nucleotide polymorphisms from genes involved in the pathway of homocysteine metabolism nor the measured homocysteine levels were associated with POAG or PXFG in our study cohort. ||||| PURPOSE: To estimate the prevalence of C677T single nucleotide polymorphism in the 5,10-methylentetrahydrofolate reductase (MTHFR) gene in primary open-angle glaucoma (POAG) and pseudoexfoliation open-angle glaucoma (PEXG).
DESIGN: Case-control study
METHODS: MTHFR was assessed in 147 patients (76 POAG, 71 PEXG) and 71 control subjects with cataract. Associations of genotypes were assessed by Armitage's trend test and the corresponding odds ratio (OR) for allele positivity with 95% confidence interval (CI).
RESULTS: We observed significant evidence of a higher prevalence of C677T in POAG (9% homozygote, 49% heterozygote, 42% wildtype, P = .01, OR = 2.38, 95% CI 1.23-4.62), but not in PEXG (9% homozygote, 41% heterozygote, 50% wildtype, P = .09, OR = 1.78, 95% CI 0.91-3.50) compared with the controls (3% homozygote, 34% heterozygote, 63% wildtype).
CONCLUSIONS: The MTHFR C677T variant leading to moderate hyperhomocysteinemia may play a role in the pathogenesis of POAG acting as a genetic risk factor. ||||| BACKGROUND: Methylenetetrahydrofolate reductase (MTHFR), a critical enzyme in folate metabolism is involved in DNA synthesis, DNA repair and DNA methylation. The functional polymorphism of MTHFR gene, C677T has been shown to impact various diseases and implicated as a risk factor for the development of various neurodegenerative disorders including glaucoma.
METHODS: We investigated MTHFR C677T genotypes and alleles frequencies in primary glaucoma [primary open angle glaucoma (POAG) and primary angle closure glaucoma (PACG)] patients and matched healthy controls in a case-control study. Two hundred ten primary glaucoma cases were studied for MTHFR C677T polymorphism and compared with 280 controls taken from the healthy population, employing the polymerase chain reaction-restriction fragment length polymorphism technique (PCR-RFLP). The MTHFR gene was amplified using specific primers. The PCR products (294 bp) was subsequently digested with HinfI (New England Biolabs) at 37 °C for 12 h, separated by electrophoresis on 2 % agarose gels, and visualized with ethidium bromide staining. The restriction digestion yielded 168 and 126 bp fragments for TT, 294, 168 and 126 bp fragments for CT and undigested PCR product 294 bp indicating CC genotype.
RESULTS: We found the frequency of the genotypes and alleles of MTHFR C677T differ significantly between cases and controls. The frequencies of allele T and genotype CT were significantly higher while the frequencies of allele C and genotype CC were lower in primary glaucoma patients as compared to controls (p <0.05). Upon stratification of our results into POAG and PACG, significantly higher frequencies of allele T (19.44 %) and genotype CT (38.89 %) were found in POAG patients compared to controls (12.5 % and 25 % respectively). The frequencies of alleles and genotypes were almost similar in PACG and controls (p = 0.8).
CONCLUSION: This study indicates that the allele T and genotype CT of MTHFR C677T polymorphism are significantly associated with POAG while allele C and CC genotype may be protective for it. We conclude that the MTHFR C677T polymorphism increases the risk for POAG development in Saudi population and can be a genetic marker however, further studies are needed with multiple-ethnic populations affected with POAG to strengthen these findings. ||||| OBJECTIVE: Elevated plasma homocysteine has been associated with an increased risk of cardiovascular disease. The association between open-angle glaucoma and cardiovascular disease has recently stimulated interest in the role of homocysteine in the pathogenesis of glaucoma. Some studies report elevated plasma homocysteine in patients with pseudoexfoliation syndrome and pseudoexfoliation glaucoma (PXFG), but have not found this association consistently in other types of open-angle glaucoma. In this study, we have measured plasma homocysteine and C677T methylenetetrahydrofolate reductase (MTHFR) mutation, the commonest genetic cause of elevated plasma homocysteine, in patients with PXFG, primary open-angle glaucoma (POAG), and normal tension glaucoma (NTG).
DESIGN: Prospective cross-sectional cohort study.
PARTICIPANTS: Forty-eight patients with PXFG, 36 patients with POAG, 34 patients with NTG, and 42 controls without glaucoma.
METHODS: Fasting venous blood samples from each participant were analyzed for plasma homocysteine and the C677T MTHFR gene mutation. MAIN OUTCOME OF INTEREST: Mean plasma homocysteine levels, number of individuals with homocysteine above the reference range, and percentage of individuals with heterozygous or homozygous C677T MTHFR gene mutations.
RESULTS: Mean plasma homocysteine was significantly higher in PXFG (11.77+/-4.18 micromol/L), POAG (11.21+/-2.84 micromol/L), and NTG (11.74+/-3.79 micromol/L) compared with control (9.82+/-1.75 micromol/L). Hyperhomocysteinemia was found in 27.1% of PXFG patients, 30.6% of POAG patients, and 29.4% of NTG patients. There was no significant difference in frequency of MTHFR C677T gene mutation between groups.
CONCLUSIONS: Plasma homocysteine was elevated in PXFG, POAG, and NTG. Elevated plasma homocysteine seems to be associated with glaucoma in these patients. | [
{
"source_pmid": "16636653",
"source_text": "PURPOSE: Increased plasma homocysteine levels have been found in patients with primary open angle glaucoma (POAG) and glaucoma secondary to pseudoexfoliation syndrome (PEXG). A common polymorphism of the methylenetetrahydrofolatereductase (MTHFR 677C>T) leads to ... |
24685235 | CONCLUSION: Although the two surgical procedures resulted in equivalent efficacy in IOP control, the trabeculectomies performed with releasable sutures were better tolerated than those without releasable sutures. | PURPOSE: To compare the efficacy and complications of releasable suture trabeculectomy and standard trabeculectomy.
PATIENTS AND METHODS: Sixty-four patients with uncontrolled glaucoma despite maximally tolerated medical therapy were included in a prospective, comparative, randomized clinical study. Standard trabeculectomy was performed on the 32 patients (Group 1) by one ophthalmologist and releasable suture trabeculectomy was also performed on the 32 patients (Group 2) by another ophthalmologist. Intraocular pressure, hypotony, shallow anterior chamber, iridocorneal touch and other complications were evaluated postoperatively. Examinations were performed daily for 1 week, for the 1st month and thereafter for every 3 months.
RESULTS: The mean follow-up period was 11.0 +/- 2.4 months in Group 1 and 11.5 +/- 3.8 months in Group 2. On the first postoperative day mean intraocular pressure was determined 9 +/- 2.7 mmHg in Group 1, and 21.6 +/- 1.1 mmHg in Group 2 (p = 0.007). The mean intraocular pressure was 10.1 +/- 1.4 mmHg in Group 2 after suture removal. Shallow anterior chamber was observed in 11 (34.3%) patients of Group 1 and 2 (6.2%) patients of the Group 2 in the early postoperative period (p = 0.005). Iridocorneal touch was observed in 5 (15.6%) patients of Group 1 and 1 (3.1%) patient of Group 2 (p = 0.196). There was no statistically significant difference in the mean intraocular pressure between the two groups at 3, 6 and 12 months (p = 0.663, p = 0.362, p = 0.182, respectively).
DISCUSSION: Releasable scleral flap sutures reduce the incidence of shallow anterior chamber and iridocorneal touch after trabeculectomy. Releasable scleral flap suture technique and standard trabeculectomy are similar in terms of lowering intraocular pressure at 1-year-follow up. ||||| PURPOSE: To compare the efficacy and complication rates of laser suture lysis (LSL) or releasable sutures techniques after trabeculectomy.
MATERIALS AND METHODS: Forty-eight eyes of 43 consecutive patients with uncomplicated glaucoma who were recruited for primary trabeculectomy with mitomycin-C were divided into 2 groups. Group 1 and group 2 comprised 27 and 21 eyes that were randomly assigned to a standard surgery and releasable suture groups, respectively. A target intraocular pressure (IOP) had been determined on the basis of the severity of the glaucoma and was called a complete success, qualified success, or failure.
RESULTS: In group 1, the mean change in IOP after LSL was 7.31+/-1.98 mm Hg, 6.1+/-1.1 mm Hg, and 3.9+/-1.5 mm Hg when sutures were lysed on the first, second, and third months. In group 2, the mean change in IOP after releasable suture removed was 8.20+/-2.74 mm Hg, 5.12+/-1.65 mm Hg, and 4.4+/-1.0 mm Hg when sutures were released at the first, second, and third months. At the end of 6 months, the success (complete and qualified success) rates were 92% and 90% for LSL and releasable suture groups, respectively. There was no statistically significant differences in success (P>0.05) and complication (P>0.05) rates between groups.
CONCLUSIONS: We observed an effective IOP reduction in eyes that had suture release both in the early and late postoperative periods after LSL and suture release. We believe that both the laserable and releasable suture techniques can be preferred to permanent sutures for closing scleral flaps in primary trabeculectomy with mitomycin-C in uncomplicated glaucoma. ||||| OBJECTIVE: To compare the short-term and long-term efficacy of using releasable sutures vs conventional interrupted sutures for scleral flap suturing in trabeculectomy.
DESIGN: A prospective randomized study.
SETTING: A university-affiliated referral eye hospital.
PATIENTS: Thirty consecutive patients requiring trabeculectomy for uncontrolled primary glaucoma.
INTERVENTION: Fifteen patients underwent trabeculectomy with permanent interrupted sutures; the same number underwent trabeculectomy with releasable sutures.
MAIN OUTCOME MEASURES: Incidence of short-term shallowing of anterior chamber or hypotony and related complications, and long-term intraocular pressure control and bleb score.
RESULTS: The mean percentage reduction in intraocular pressure on day 1 in the group with releasable sutures was 55.2%, while only a 0.8% reduction in anterior chamber depth was noted. This compared with figures of 59.3% and 10.1%, respectively, in the group without releasable sutures. Hypotony (intraocular pressure < or =6 mm Hg) was noted in 8 (53%) of cases without releasable sutures and 3 (20%) of cases with releasable sutures. Shallow anterior chamber (central anterior chamber depth, < or =1 mm) was noted in 5 (33%) of cases without releasable sutures and 1 (7%) of cases with releasable sutures. The mean +/- SD final bleb score was 5.4 +/- 0.3 in the group with releasable sutures compared with 4.2 +/- 0.6 in the group without releasable sutures (P<.001). The mean +/- SD final intraocular pressure at the end of 12 months was 16.9 +/- 1.2 mm Hg in the group without releasable sutures and 15.0 +/- 0.9 mm Hg in the group with releasable sutures (P<.001). Final intraocular pressure was controlled (intraocular pressure < or =21 mm Hg) in all patients in the group with releasable sutures, giving a success rate of 100%, and in 12 patients in the group without releasable sutures, giving a success rate of 80%.
CONCLUSIONS: Use of releasable sutures is an effective way at no extra cost or instrumentation to maximize the long-term bleb score and lower intraocular pressure, and to minimize the short-term complications of trabeculectomy. ||||| PURPOSE: To compare the intraocular pressure lowering effect of adjustable sutures and laser suture lysis for trabeculectomy in eyes with primary open angle glaucoma.
METHODS: Fifty patients with primary open angle glaucoma were studied. Eyes were assigned randomly to either trabeculectomy augmented with mitomycin C with adjustable sutures or with laser suture lysis. Patients were followed up for 12 months and success rate based on intraocular pressure was compared. Adjustable sutures were carried out as reported by Wells et al.
RESULTS: Mean baseline intraocular pressure was 27.8±2.8 mm Hg in the adjustable suture group and 27.3±2.9 mm Hg in the laser suture lysis group (P=0.7). Mean postoperative intraocular pressure was 12.1±2.0 mm Hg at 3 months, 12.7±3.2 mm Hg at 6 months, and 12.9±3.4 mm Hg at 12 months in the adjustable suture group and 12.1±2.6 mm Hg at 3 months, 13.1±4.7 mm Hg at 6 months, and 13.4±3.5 mm Hg at 12 months in the laser suture lysis group. There was no significant difference in the mean intraocular pressure between the groups at any time point. At 12 months, 24 patients (96%) in the adjustable suture group and 23 patients (92%) in the laser suture lysis group achieved an intraocular pressure of ≥20 mm Hg without medication and a minimum of 30 percent reduction (P=0.7). Significant anterior chamber reduction was found in no patient (0%) in the adjustable suture group and 6 patients (24%) in the laser suture lysis group after loosening of the adjustable sutures or laser suture lysis.
CONCLUSIONS: There was no significant difference in hypotensive efficacy between adjustable suture group and laser suture lysis group. The use of adjustable sutures may reduce the incidence of shallow anterior chamber and hypotony after postoperative intraocular pressure lowering procedures. ||||| PURPOSE: To evaluate the effects of mitomycin C and a releasable suture technique on outcomes of primary trabeculectomy in primary glaucoma patients.
METHODS: A prospective analysis of patients who underwent primary trabeculectomy with a mitomycin C concentration of 0.2 mg/mL for 2 minutes. For closing the scleral flap, releasable sutures were used in 18 patients (17 eyes), Group 1, or permanent sutures in 18 patients (20 eyes), Group 2. Clinical outcome factors including postoperative intraocular pressure (IOP), visual acuity, and incidence of complications were determined.
RESULTS: The mean follow-up periods were 8.1 +/- 1.3 months in Group 1 and 8.3 +/- 1.3 months in Group 2. The postoperative reduction in IOP was highly significant (P <.0001) at all time intervals in both groups. In all measurement of IOP before the second week, mean IOP in Group 2 was found significantly lower than the mean IOP in Group 1 (P =.01). No statistically significant differences were found between the groups at later mean IOP measurements. At the last visit, the complete success rate was 88.8% in Group 1 and 85.0% in Group 2. No serious complications such as hypotonous maculopathy were observed in any patient.
CONCLUSION: Primary trabeculectomy with mitomycin C in eyes with primary glaucoma showed effective IOP pressure reduction. There were no cases of serious complications. In the early postoperative period IOP was controlled better in the releasable suture group. ||||| INTRODUCTION: The aim of this prospective study is to verify, in terms of both early postoperative complications and intraocular pressure (IOP) outcomes, the performance of a scleral flap removable suture.
MATERIALS AND METHODS: Sixty-six patients that underwent trabeculectomy were randomly divided into two groups: in the first group (group A, 33 eyes) a standard fornix-based trabeculectomy was performed by using a conjunctival chain suture. In the second group (group B, 33 eyes) the same technique was performed with the additional employment of a new removable suture to the scleral flap. The patients were followed-up for 12 months.
RESULTS: After 1 year the mean IOP was 16.58 mmHg (+/-3.73 mmHg) in group A, and 16.12 mmHg (+/-4.21 mmHg) in group B; statistical analysis did not show significant differences between the two groups (P = 0.19). Early postoperative hypotony and shallowing of the anterior chamber were significantly more frequent after standard trabeculectomy than after trabeculectomy using the removable suture (P < 0.02).
CONCLUSIONS: The employment of a fornix-based conjunctival chain suture for the flap allows the use of the removable scleral flap suture, which has proved very effective in preventing insufficient flap resistance with aqueous overdrainage and hypotony, and which is also easy to apply and to remove. Compared with standard trabeculectomy, this device has proved to have similar IOP-lowering efficacy, together with a lower rate of early postoperative complications. | [
{
"source_pmid": "16779569",
"source_text": "PURPOSE: To compare the efficacy and complications of releasable suture trabeculectomy and standard trabeculectomy.\nPATIENTS AND METHODS: Sixty-four patients with uncontrolled glaucoma despite maximally tolerated medical therapy were included in a prospective, c... |
26796995 | This meta-analysis has thus revealed suggestive evidence for TLR3 rs3775291 as an associated marker for AMD in Caucasians but not in Asians. This SNP may have only a small effect on AMD susceptibility. Further studies in larger samples are warranted to confirm its role. | Despite significant progress in the identification of genetic loci for age-related macular degeneration (AMD), not all of the heritability has been explained. To identify variants which contribute to the remaining genetic susceptibility, we performed the largest meta-analysis of genome-wide association studies to date for advanced AMD. We imputed 6 036 699 single-nucleotide polymorphisms with the 1000 Genomes Project reference genotypes on 2594 cases and 4134 controls with follow-up replication of top signals in 5640 cases and 52 174 controls. We identified two new common susceptibility alleles, rs1999930 on 6q21-q22.3 near FRK/COL10A1 [odds ratio (OR) 0.87; P = 1.1 × 10(-8)] and rs4711751 on 6p12 near VEGFA (OR 1.15; P = 8.7 × 10(-9)). In addition to the two novel loci, 10 previously reported loci in ARMS2/HTRA1 (rs10490924), CFH (rs1061170, and rs1410996), CFB (rs641153), C3 (rs2230199), C2 (rs9332739), CFI (rs10033900), LIPC (rs10468017), TIMP3 (rs9621532) and CETP (rs3764261) were confirmed with genome-wide significant signals in this large study. Loci in the recently reported genes ABCA1 and COL8A1 were also detected with suggestive evidence of association with advanced AMD. The novel variants identified in this study suggest that angiogenesis (VEGFA) and extracellular collagen matrix (FRK/COL10A1) pathways contribute to the development of advanced AMD. ||||| Age-related macular degeneration (AMD) is a devastating disease that results in irreversible central vision loss. TLRs signaling pathway has been found to play an important role in AMD pathogenesis as evidenced by several studies. The objective of the study was to determine the single nucleotide polymorphism (SNP) changes in TLR3 in North Indian AMD patients. We recruited 176 patients comprising 115 AMD patients and 61 controls. Real time PCR was used to evaluate the SNP changes at rs3775291 locus. Pearson's χ(2) test was used evaluate association between various groups. No significant association in genotype and allele frequency was found in AMD patients as compared to control. The results suggest that AMD pathology in North Indian AMD patients is not affected by TLR3 signaling but it could be influenced by other genetic or environmental factors unique to North India. ||||| Toll-like receptor 3 (TLR3) variants in mainland northern Chinese patients with polypoidal choroidal vasculopathy (PCV) and neovascular age-related macular degeneration (nAMD) were investigated. The complete genes of TLR3, including all exons and the promoter region, were assessed using direct sequencing technology of 284 unrelated mainland northern Chinese individuals: 96 nAMD patients, 92 PCV patients, and 96 controls. Six single nucleotide polymorphisms were identified: rs5743303, rs5743305, rs5743312, rs3775291, rs3775290, and rs6830345. The distribution of TLR3 genotypes for nAMD and PCV was not significantly different compared with normal controls. This study indicates that the TLR3 gene polymorphism is not associated with nAMD and PCV in northern Chinese patients. ||||| BACKGROUND: Age-related macular degeneration is the most common cause of irreversible visual impairment in the developed world. Advanced age-related macular degeneration consists of geographic atrophy and choroidal neovascularization. The specific genetic variants that predispose patients to geographic atrophy are largely unknown.
METHODS: We tested for an association between the functional toll-like receptor 3 gene (TLR3) variant rs3775291 (involving the substitution of phenylalanine for leucine at amino acid 412) and age-related macular degeneration in Americans of European descent. We also tested for the effect of TLR3 Leu and Phe variants on the viability of human retinal pigment epithelial cells in vitro and on apoptosis of retinal pigment epithelial cells from wild-type mice and Tlr3-knockout (Tlr3(-/-)) mice.
RESULTS: The Phe variant (encoded by the T allele at rs3775291) was associated with protection against geographic atrophy (P=0.005). This association was replicated in two independent case-control series of geographic atrophy (P=5.43x10(-4) and P=0.002). No association was found between TLR3 variants and choroidal neovascularization. A prototypic TLR3 ligand induced apoptosis in a greater fraction of human retinal pigment epithelial cells with the Leu-Leu genotype than those with the Leu-Phe genotype and in a greater fraction of wild-type mice than Tlr3(-/-) mice.
CONCLUSIONS: The TLR3 412Phe variant confers protection against geographic atrophy, probably by suppressing the death of retinal pigment epithelial cells. Since double-stranded RNA (dsRNA) can activate TLR3-mediated apoptosis, our results suggest a role of viral dsRNA in the development of geographic atrophy and point to the potential toxic effects of short-interfering-RNA therapies in the eye. ||||| Age-related macular degeneration (AMD) is a leading cause of visual loss in Western populations. Susceptibility is influenced by age, environmental and genetic factors. Known genetic risk loci do not account for all the heritability. We therefore carried out a genome-wide association study of AMD in the UK population with 893 cases of advanced AMD and 2199 controls. This showed an association with the well-established AMD risk loci ARMS2 (age-related maculopathy susceptibility 2)-HTRA1 (HtrA serine peptidase 1) (P =2.7 × 10(-72)), CFH (complement factor H) (P =2.3 × 10(-47)), C2 (complement component 2)-CFB (complement factor B) (P =5.2 × 10(-9)), C3 (complement component 3) (P =2.2 × 10(-3)) and CFI (P =3.6 × 10(-3)) and with more recently reported risk loci at VEGFA (P =1.2 × 10(-3)) and LIPC (hepatic lipase) (P =0.04). Using a replication sample of 1411 advanced AMD cases and 1431 examined controls, we confirmed a novel association between AMD and single-nucleotide polymorphisms on chromosome 6p21.3 at TNXB (tenascin XB)-FKBPL (FK506 binding protein like) [rs12153855/rs9391734; discovery P =4.3 × 10(-7), replication P =3.0 × 10(-4), combined P =1.3 × 10(-9), odds ratio (OR) = 1.4, 95% confidence interval (CI) = 1.3-1.6] and the neighbouring gene NOTCH4 (Notch 4) (rs2071277; discovery P =3.2 × 10(-8), replication P =3.8 × 10(-5), combined P =2.0 × 10(-11), OR = 1.3, 95% CI = 1.2-1.4). These associations remained significant in conditional analyses which included the adjacent C2-CFB locus. TNXB, FKBPL and NOTCH4 are all plausible AMD susceptibility genes, but further research will be needed to identify the causal variants and determine whether any of these genes are involved in the pathogenesis of AMD. ||||| PURPOSE: Innate immunity appears to play a key role in age-related macular degeneration (AMD). Although two previous studies reported that gene variations in Toll-like receptor (TLR)-3 and -4 are associated with AMD, other studies have not confirmed these associations. In this study, three independent samples (two U.S. clinic-based case-control study samples and one Australian population-based study sample) were used to further assess the association of the polymorphisms rs3775291 in TLR3 and rs4986790 in TLR4 with AMD.
METHODS: AMD cases and unrelated controls were collected from the National Eye Institute Clinical Center (NEI, n = 320), the Age-Related Eye Disease Study (AREDS, n = 483), and the Blue Mountains Eye Study (BMES, n = 852). DNA extracted from subjects was genotyped for rs3775291 and rs4986790, and the associations with AMD were investigated.
RESULTS: Neither of the two polymorphisms rs3775291 and rs4986790 had a statistically significant association with AMD in any of the three sample sets or in combinations of the sets. Analysis of the combined geographic atrophy or neovascular AMD cases in the NEI, AREDS, and BMES sample sets also failed to demonstrate statistically significant associations of those two single nucleotide polymorphisms with advanced AMD.
CONCLUSIONS: Even with previously verified samples sets and adequate study powers, the results did not confirm the reported associations of TLR3 rs3775291 and TLR4 rs4986790 with AMD in the three independent samples, individually or combined. ||||| BACKGROUND/AIMS: Age-related macular degeneration (AMD) is a leading cause of visual impairment. A single-nucleotide polymorphism (SNP; rs3775291) in the Toll-like receptor 3 (TLR3) gene has recently been implicated in the pathogenesis of AMD in Caucasian populations. The aim of this study was to examine this association in Chinese persons with choroidal neovascularization (CNV) secondary to AMD and polypoidal choroidal vasculopathy (PCV).
METHODS: This was an observational cross-sectional study in Singapore. Study subjects were of Chinese ethnicity and included patients with exudative maculopathy and normal control subjects. The diagnoses of CNV and PCV were made based on fundus examination, fluorescein angiography and indocyanine green angiography findings. Genomic DNA was extracted, and genotypes were determined by bidirectional DNA sequencing. We compared the allele and genotype frequencies between subjects with CNV and PCV with controls using the software PLINK.
RESULTS: A total of 246 subjects with exudative maculopathy (consisting of 126 with CNV and 120 with PCV) and 274 normal control subjects were recruited. The distribution of rs3775291 SNP genotypes for CNV and PCV was not significantly different from that for normal controls.
CONCLUSION: This study indicates that the TLR3 rs3775291 gene polymorphism is not associated with CNV and PCV in Singaporean Chinese patients. | [
{
"source_pmid": "21665990",
"source_text": "Despite significant progress in the identification of genetic loci for age-related macular degeneration (AMD), not all of the heritability has been explained. To identify variants which contribute to the remaining genetic susceptibility, we performed the largest ... |
31284308 | Conclusions: This meta-analysis confirmed the association of rs10483727 and rs33912345 in SIX1-SIX6 with POAG. The associations of both SNPs were specifically detected in East Asian and Caucasian cohorts, rather than in South Asian and African cohorts, suggesting an ethnic difference. SNP rs12436579 is a candidate variant for the disease that awaits validation in other populations. | PURPOSE: Despite the different etiology of primary open angle glaucoma (POAG), primary angle closure glaucoma (PACG), and pseudoexfoliative glaucoma (PEXG), several studies have suggested that these forms of glaucoma have overlapping genetic risk factors. Therefore, the aim of this study was to evaluate the role of genetic variants recently associated with POAG in different types of glaucoma in Pakistani POAG, PACG, and PEXG patient cohorts.
METHODS: Six variants in CDKN2B-AS1 (rs4977756), CDKN2B (rs1063192), ATOH7 (rs1900004), CAV1 (rs4236601), TMCO1 (rs4656461), and SIX1 (rs10483727) were genotyped using TaqMan assays. A total of 513 unrelated patients with glaucoma (268 with POAG, 125 with PACG, and 120 with PEXG) and 233 healthy controls were included in the study. Genotypic and allelic associations were analyzed with a chi-square test.
RESULTS: The frequency of the G allele of TMCO1 rs4656461 was significantly lower in the patients with POAG (p=0.003; OR [odds ratio]=0.57), PACG (p=0.009; OR=0.52), and PEXG (p=0.01; OR=0.54) compared to the control individuals. The T allele of ATOH7 rs1900004 was observed less frequently in the patients with PACG (p=0.03; OR=0.69) compared to the control individuals. The A allele of CAV1 rs4236601 was found more frequently in the patients with POAG (p=0.008; OR=1.49) compared to the control individuals. This study demonstrates that the TMCO1 rs4656461 variant is associated with POAG, PACG and PEXG in the Pakistani population. Our study was unable to confirm previous associations reported for variants in CDKN2B-AS1, CDKN2B, and SIX1 with any type of glaucoma.
CONCLUSIONS: In conclusion, we found consistent evidence of the significant association of three common variants in TMCO1, ATOH7, and CAV1. ||||| BACKGROUND: Primary open-angle glaucoma (POAG) is a complex disease of multigenic inheritance and the most common subtype of glaucoma.
METHODS: To address this question, the
RESULTS: We identified two known rare and two common variants in the
CONCLUSION: Altogether, our data further support the implication of ||||| The purpose of this study was to confirm previously reported associations of common variants in or near CDC7/TGFBR3, ZP4, SRBD1, ELOVL5, CAV1/CAV2, TLR4, CDKN2B, CDKN2B-AS1, ATOH7, PLXDC2, TMTC2, SIX1, and CARD10, with primary open angle glaucoma (POAG) in the Afro-Caribbean population of Barbados, West Indies. A total of 437 unrelated subjects from the Barbados Family Study of Open Angle Glaucoma (BFSG), including 272 with POAG and 165 unaffected individuals were included in this study. Eighteen SNPs were genotyped by using the multiplex SNaPshot method. Allelic, genotypic and model-based (dominant, recessive, and additive) associations of the SNPs with POAG were analyzed using Chi-squared tests and logistic regression. SNP rs1063192 (near CDKN2B) was found to be significantly associated with POAG (allelic P = 0.0008, genotypic P = 0.0029), and the minor allele C of rs1063192 was protective against POAG (OR = 0.39; 95%CI = 0.22-0.69). Suggestive association was also noted for rs7916697 (near ATHO7, allelic P = 0.0096, genotypic P = 0.01) with the minor allele being protective (OR = 0.67; 95% CI = 0.50-0.91), although this finding did not withstand correction for multiple testing. However, a significant interactive effect on POAG risk was identified between rs1063192 and rs7916697 (P-interaction = 2.80 × 10(-5)). Individuals with the rs1063192 protective genotype CC or CT and also rs7916697 genotypes GG or GA show a significantly decreased risk of POAG (OR = 0.17, 95%CI: 0.07-0.41). Our study confirms the significant association between SNP rs1063192 (CDKN2B, previously shown to influence vertical cup-to-disc ratio and POAG at 9p21) and POAG in the Afro-Caribbean population of Barbados. The minor allele of rs1063192 interacts with that of rs7916697 (ATOH7)) to reduce POAG risk. Our results also suggest that rs1063912 is a common protective variant for POAG in populations of African as well as European descent. ||||| Multiple loci have been associated with either primary open angle glaucoma (POAG) or heritable ocular quantitative traits associated with this condition. This study examined the association of these loci with POAG, with central corneal thickness (CCT), vertical cup-to-disc ratio (VCDR) and with diabetes mellitus in a group of black South Africans (215 POAG cases and 214 controls). The population was homogeneous and distinct from other African and European populations. Single SNPs in the MYOC, COL8A2, COL1A1 and ZNF469 gene regions showed marginal associations with POAG. No association with POAG was identified with tagging SNPs in TMCO1, CAV1/CAV2, CYP1B1, COL1A2, COL5A1, CDKN2B/CDKN2BAS-1, SIX1/SIX6 or the chromosome 2p16 regions and there were no associations with CCT or VCDR. However, SNP rs12522383 in WDR36 was associated with diabetes mellitus (p = 0.00008). This first POAG genetic association study in black South Africans has therefore identified associations that require additional investigation in this and other populations to determine their significance. This highlights the need for larger studies in this population if we are to achieve the goal of facilitating early POAG detection and ultimately preventing irreversible blindness from this condition. ||||| Glaucoma, a blinding neurodegenerative disease, whose risk factors include elevated intraocular pressure (IOP), age, and genetics, is characterized by accelerated and progressive retinal ganglion cell (RGC) death. Despite decades of research, the mechanism of RGC death in glaucoma is still unknown. Here, we demonstrate that the genetic effect of the SIX6 risk variant (rs33912345, His141Asn) is enhanced by another major POAG risk gene, p16INK4a (cyclin-dependent kinase inhibitor 2A, isoform INK4a). We further show that the upregulation of homozygous SIX6 risk alleles (CC) leads to an increase in p16INK4a expression, with subsequent cellular senescence, as evidenced in a mouse model of elevated IOP and in human POAG eyes. Our data indicate that SIX6 and/or IOP promotes POAG by directly increasing p16INK4a expression, leading to RGC senescence in adult human retinas. Our study provides important insights linking genetic susceptibility to the underlying mechanism of RGC death and provides a unified theory of glaucoma pathogenesis. ||||| PURPOSE: To ascertain if single nucleotide polymorphisms (SNPs) involved in the determination of central corneal thickness, optic disc area, and vertical cup-to-disc ratio (VCDR) also are associated with open-angle glaucoma (OAG).
DESIGN: Retrospective case-control genetic association study.
METHODS: A total of 16 SNPs associated with central corneal thickness, optic disc area, and VCDR were genotyped in 876 OAG cases and 883 normal controls. To determine if the SNPs were also correlated with OAG severity, the cohort was stratified into advanced OAG (n = 326) and nonadvanced OAG (n = 550). Both the cases and controls were of European descent and were recruited from within Australia.
RESULTS: Two VCDR SNPs were found to be significantly associated with OAG after correction for multiple testing. The 2 SNPs were rs10483727, found adjacent to the SIX1 gene (P = 6.2 × 10(-06); odds ratio, 1.38; 95% confidence interval, 1.20 to 1.59), and rs1063192, found within the CDKN2B gene (P = 2.2 × 10(-05); odds ratio, 0.74; 95% confidence interval, 0.64 to 0.85). The CDKN2B variant rs1063192 also was found to be associated more strongly with advanced OAG.
CONCLUSIONS: The findings from this study indicate that variants influencing VCDR are also risk alleles for OAG in our Australian cohort of European descent. The identification of SIX1 and CDKN2B as susceptibility loci will assist in understanding the pathologic mechanisms involved in the development of OAG. ||||| This study investigated the genetic association of three single nucleotide polymorphisms (SNPs; rs10483727, rs33912345, and rs146737847) at the SIX1-SIX6 locus with primary open angle glaucoma (POAG) in the Chinese population. A total of 866 subjects with POAG (685 high-tension glaucoma (HTG) and 181 normal-tension glaucoma (NTG)) and 266 control individuals were included. Significant genetic association was identified for rs10483727 in HTG (P=0.02; odds ratio (OR)=1.31), NTG (P=7.41×10(-6); OR=2.71), and POAG (i.e., HTG and NTG combined; P=0.001; OR=1.44). rs33912345 was also significantly associated with HTG (P=0.008; OR=1.36), NTG(P=2.72×10(-6); OR=2.27), and POAG (P=3.84×10(-4); OR=1.49). The rare SIX6 mutation, rs146737847, was not found in the subjects enrolled in this study. Stratification by patient age identified that both rs10483727 and rs33912345 were significantly associated with NTG in patients aged above 40 years (P=2.08×10(-5); OR=2.28), whereas in patients aged between 20-40 years, rs33912345 was significantly associated with NTG (P=0.017; OR=2.06). In HTG, the genetic associations for both rs10483727 and rs33912345 were significant in patients aged between 20-40 years (P=0.006; OR=1.56) but not in those aged above 40 years (P=0.118, OR=1.21 and P=0.042, OR=1.29, respectively). This study replicated the association of POAG with two SNPs at the SIX1-SIX6 locus and demonstrated that SNPs, rs10483727 and rs33912345, are significantly associated with POAG, especially with NTG in patients aged above 40 years. ||||| PURPOSE: To investigate the associations between the non-intraocular pressure (IOP)-related genetic variants (genetic variants associated with vulnerability of the optic nerve independent of IOP) and primary open-angle glaucoma (POAG), including normal-tension glaucoma (NTG) and high-tension glaucoma (HTG), and between the non-IOP-related genetic variants and a family history of glaucoma.
DESIGN: Case-control study.
METHODS: Japanese patients with NTG (n = 213) and HTG (n = 212) and 191 control subjects were genotyped for 5 non-IOP-related genetic variants predisposing to POAG near the SRBD1, ELOVL5, CDKN2B/CDKN2B-AS1, SIX1/SIX6, and ATOH7 genes. The load of these genetic variants was compared between the control subjects and patients with NTG or HTG and between the POAG patients with and without a family history of glaucoma.
RESULTS: The total number of POAG risk alleles and the product of the odds ratios (POAG risk) of these genetic variants were significantly larger (P < .0025) in patients with both NTG and HTG than in the control subjects, and were significantly larger (P = .0042 and P = .023, respectively) in POAG patients with a family history of glaucoma than in those without. As the number of relatives with glaucoma increased, the total number of risk alleles and the product of the odds ratios increased (P = .012 and P = .047, respectively).
CONCLUSIONS: Non-IOP-related genetic variants contribute to the pathogenesis of HTG as well as NTG. A positive family history of glaucoma in cases of POAG is thought to reflect the influence of genetic variants predisposing to POAG. ||||| BACKGROUND: Recently SIX1 and SIX6 genes have been associated with primary open angle glaucoma (POAG). This study was planned to do mutation screening in SIX1 and SIX6 genes in North Indian POAG patients and correlate with clinical phenotypes.
MATERIALS AND METHODS: SIX1 and SIX6 genes were amplified by PCR and sequenced in 115 POAG cases and 105 controls. Four pathogenecity prediction tools (MutationTaster, PolyPhen-2 HumDiv, PolyPhen-2 HumVar and SIFT) were used to predict the pathogenicity of the missense mutations. Protein modeling studies were done to predict the effect of the missense mutations on the protein structure and function.
RESULTS: Two novel mutations p.R116G and p.R116E were observed in the SIX6 gene of patients with POAG. The mutations p.R116G and p.R116E were predicted to be pathogenic and replacement of R116 by G or E might lead to loss of interaction between DNA and R116 of wild type SIX6 protein. The patients with the mutation p.R116E had significantly more visual field damage (MD) and early age of onset of the disease. No sequence variations were observed in the SIX1 gene.
CONCLUSION: These results expand the mutation spectrum of SIX6 gene and suggest that SIX6 gene plays an important role in POAG pathogenesis. ||||| PURPOSE: To test the genetic association between Japanese patients with primary open-angle glaucoma (POAG) and the previously reported POAG susceptibility loci and to perform genotype-phenotype analysis.
METHODS: Genetic associations for 27 SNPs from 16 loci previously linked to POAG were assessed using genome-wide SNP data of the primary cohort (565 Japanese POAG patients and 1,104 controls). Reproducibility of the assessment was tested in 607 POAG cases and 455 controls (second cohort) with a targeted genotyping approach. For POAG-associated variants, a genotype-phenotype correlation study (additive, dominant, recessive model) was performed using the objective clinical data derived from 598 eyes of 598 POAG patients.
RESULTS: Among 27 SNPs from 16 loci previously linked to POAG, genotypes for total of 20 SNPs in 13 loci were available for targeted association study. Among 8 SNPs in 3 loci that showed at least nominal association (P < 5.00E-02) in the primary cohort, a representative SNP for each loci (rs2157719 for CDKN2B-AS1, rs33912345 for SIX6, and rs9913911 for GAS7) were selected. For these SNPs the association was found significant in both the second cohort analysis and meta-analysis. The genotype-phenotype analysis revealed significant correlations between CDKN2B-AS1 (rs2157719) and decreased intraocular pressure (β = -6.89 mmHg, P = 1.70E-04; dominant model) after multiple corrections. In addition, nominal correlation was observed between CDKN2B-AS1 (rs2157719) and optic nerve head blood flow (β = -0.54 and -0.67 arbitrary units (AU), P = 2.00E-02 and 1.39E-02), between SIX6 (rs33912345) and decreased total peripapillary retinal nerve fiber layer thickness (β = -2.16 and -2.82 μm, P = 4.68E-02 and 2.40E-02, additive and recessive model, respectively) and increased optic nerve head blood flow (β = 0.44 AU, P = 2.20E-02; additive model) and between GAS7 (rs9913911) and increased cup volume (β = 0.03 mm3, P = 4.60E-02) and mean cup depth (β = 0.03 mm3, P = 4.11E-02; additive model) and decreased pattern standard deviation (β = -0.87 dB, P = 2.44E-02; dominant model).
CONCLUSION: The association between SNPs near GAS7 and POAG was found in Japanese patients for the first time. Clinical characterization of the risk variants is an important step toward understanding the pathology of the disease and optimizing treatment of patients with POAG. ||||| PURPOSE: Multiple genes have been associated with primary open angle glaucoma (POAG) in Caucasian populations. We now examine the association of these loci in populations of African ancestry, populations at particularly high risk for POAG.
METHODS: We genotyped DNA samples from two populations: African American (1150 cases and 999 controls) and those from Ghana, West Africa (483 cases and 593 controls). Our analysis included 57 single nucleotide polymorphisms (SNPs) in five loci previously associated with POAG at the genome-wide level, including CDKN2B-AS1, TMCO1, CAV1/CAV2, chromosome 8q22 intergenic region, and SIX1/SIX6. We evaluated association in the full datasets, as well as subgroups with normal pressure glaucoma (NPG, maximum IOP ≤21 mm Hg) and high pressure glaucoma (HPG, IOP >21 mm Hg).
RESULTS: In African Americans, we identified an association of rs10120688 in the CDNK2B-AS1 region with POAG (P = 0.0020). Several other SNPs were nominally associated, but did not survive correction for multiple testing. In the subgroup analyses, significant associations were identified for rs10965245 (P = 0.0005) in the CDKN2B-AS1 region with HPG and rs11849906 in the SIX1/SIX6 region with NPG (P = 0.006). No significant association was identified with any loci in the Ghanaian samples.
CONCLUSIONS: POAG genetic susceptibility alleles associated in Caucasians appear to play a greatly reduced role in populations of African ancestry. Thus, the major genetic components of POAG of African origin remain to be identified. This finding underscores the critical need to pursue large-scale genome-wide association studies in this understudied, yet disproportionately affected population. ||||| Purpose: To examine the associations of the earlier reported glaucoma-related genes to the regional circumpapillary retinal nerve fiber layer thicknesses (cpRNFLTs) and corresponding visual field defects.
Methods: We studied 756 patients with primary open-angle glaucoma (POAG) and 3094 normal controls. Each participant was genotyped for nine single nucleotide polymorphisms (SNPs) of four glaucoma-susceptible genes: the CDKN2B(AS1), TMCO1, CAV1/CAV2, and SIX1/SIX6 genes. For the SNPs that were significantly associated with the POAG case-control analyses, the associations of SNP genotypes with the cpRNFLTs of 12 sectors were also analyzed, and then finer assessments were performed using 768 points of the cpRNFLT and corresponding visual field defect sensitivities using case-only subjects.
Results: We confirmed that there was a significant association of the CDKN2B(AS1) gene to POAG. For the suggested region-specific associations of these genes with the 12-sectored cpRNFLT, a 768-point cpRNFLT examination showed that rs4977756 near CDKN2B had significant signal peaks in the temporal region at 330° to 360° and 0° to 30° (maximum β = 2.92, P = 2.9 × 10-5 at 351.1° and maximum β = 3.97, P = 2.2 × 10-4 at 23.4°, respectively). These region-specific signals were validated by the corresponding visual field defect patterns of the paracentral/lower hemifield (P < 0.05).
Conclusions: Genetic association analyses using the cpRNFLT with 768 points suggest that the CDKN2B gene was associated with paracentral/lower hemifield scotomas. Our regional association analyses on cpRNFLT allow detailed characterization of glaucoma-related genes and should be a new target for genomic studies for glaucoma endophenotypes. ||||| We performed a genome-wide association study for primary open-angle glaucoma (POAG) in 1,007 cases with high-pressure glaucoma (HPG) and 1,009 controls from southern China. We observed genome-wide significant association at multiple SNPs near ABCA1 at 9q31.1 (rs2487032; P = 1.66 × 10(-8)) and suggestive evidence of association in PMM2 at 16p13.2 (rs3785176; P = 3.18 × 10(-6)). We replicated these findings in a set of 525 HPG cases and 912 controls from Singapore and a further set of 1,374 POAG cases and 4,053 controls from China. We observed genome-wide significant association with more than one SNP at the two loci (P = 2.79 × 10(-19) for rs2487032 representing ABCA1 and P = 5.77 × 10(-10) for rs3785176 representing PMM2). Both ABCA1 and PMM2 are expressed in the trabecular meshwork, optic nerve and other ocular tissues. In addition, ABCA1 is highly expressed in the ganglion cell layer of the retina, a finding consistent with it having a role in the development of glaucoma. ||||| PURPOSE: Recently the common SIX6 missense variant rs33912345 was found to be highly associated with glaucoma. The aim of this study was to investigate the association between this SIX6 variant and peripapillary retinal nerve fiber layer (RNFL) thickness measured by spectral-domain optical coherence tomography (SD-OCT) in a population setting.
METHODS: Study subjects were enrolled from the Singapore Chinese Eye Study (SCES), a population-based survey of Singaporean Chinese aged 40 years or older. Subjects underwent a comprehensive ocular examination. Spectral-domain OCT was used to measure RNFL thicknesses. Genotyping of SIX6 rs33912345 (Asn141His) was performed using HumanExome BeadChip.
RESULTS: A total of 2129 eyes from 1243 SCES subjects (mean age: 55.0 ± 7.4 years) with rs33912345 genotype data and SD-OCT images were included for the analysis. Of these, 26 eyes of 21 subjects had glaucoma. The frequency of rs33912345 risk variant C (His141) was 80% in the study subjects. Each rs33912345 C allele was associated with a decrease of 1.44 μm in RNFL thickness after adjusting for age, sex, genetic principal components, and axial length (P = 0.001). These associations remained similar in 2096 nonglaucoma eyes in which each C allele was associated with a decrease of 1.39 μm in RNFL thickness (P = 0.001). The strongest association was observed in the superior RNFL sector (a decrease of 2.83 μm per risk allele, P < 0.001) followed by the inferior RNFL sector (a decrease of 2.24 μm per risk allele, P = 0.003), while the association did not reach significance in the nasal and temporal sectors.
CONCLUSIONS: Nonglaucomatous individuals with the SIX6 missense variant have reduced RNFL thickness in regions known to be particularly affected in those with glaucoma. This may be the primary mechanism for increased risk of POAG in individuals who carry the SIX6 His141 risk variant. ||||| Glaucoma is a leading cause of blindness worldwide. Primary open-angle glaucoma (POAG) is the most common subtype and is a complex trait with multigenic inheritance. Genome-wide association studies have previously identified a significant association between POAG and the SIX6 locus (rs10483727, odds ratio (OR) = 1.32, p = 3.87×10(-11)). SIX6 plays a role in ocular development and has been associated with the morphology of the optic nerve. We sequenced the SIX6 coding and regulatory regions in 262 POAG cases and 256 controls and identified six nonsynonymous coding variants, including five rare and one common variant, Asn141His (rs33912345), which was associated significantly with POAG (OR = 1.27, p = 4.2×10(-10)) in the NEIGHBOR/GLAUGEN datasets. These variants were tested in an in vivo Danio rerio (zebrafish) complementation assay to evaluate ocular metrics such as eye size and optic nerve structure. Five variants, found primarily in POAG cases, were hypomorphic or null, while the sixth variant, found only in controls, was benign. One variant in the SIX6 enhancer increased expression of SIX6 and disrupted its regulation. Finally, to our knowledge for the first time, we have identified a clinical feature in POAG patients that appears to be dependent upon SIX6 genotype: patients who are homozygous for the SIX6 risk allele (His141) have a statistically thinner retinal nerve fiber layer than patients homozygous for the SIX6 non-risk allele (Asn141). Our results, in combination with previous SIX6 work, lead us to hypothesize that SIX6 risk variants disrupt the development of the neural retina, leading to a reduced number of retinal ganglion cells, thereby increasing the risk of glaucoma-associated vision loss. ||||| Primary open-angle glaucoma (POAG) is a leading cause of blindness worldwide. To identify new susceptibility loci, we performed meta-analysis on genome-wide association study (GWAS) results from eight independent studies from the United States (3,853 cases and 33,480 controls) and investigated the most significantly associated SNPs in two Australian studies (1,252 cases and 2,592 controls), three European studies (875 cases and 4,107 controls) and a Singaporean Chinese study (1,037 cases and 2,543 controls). A meta-analysis of the top SNPs identified three new associated loci: rs35934224[T] in TXNRD2 (odds ratio (OR) = 0.78, P = 4.05 × 10(-11)) encoding a mitochondrial protein required for redox homeostasis; rs7137828[T] in ATXN2 (OR = 1.17, P = 8.73 × 10(-10)); and rs2745572[A] upstream of FOXC1 (OR = 1.17, P = 1.76 × 10(-10)). Using RT-PCR and immunohistochemistry, we show TXNRD2 and ATXN2 expression in retinal ganglion cells and the optic nerve head. These results identify new pathways underlying POAG susceptibility and suggest new targets for preventative therapies. ||||| AIMS: Variant rs10483727 in the SIX1/SIX6 locus has been significantly associated with primary open angle glaucoma (POAG) in multiple ethnic groups. We conducted a case-control study to investigate the association between this variant and POAG in a Saudi cohort.
MATERIALS AND METHODS: Polymorphism rs10483727 was genotyped by using a TaqMan
RESULTS: The "C" allele frequency was 0.33 and 0.45 among POAG cases and controls, respectively (odds ratio [OR] = 0.58, 95% confidence interval [CI] = 0.38-0.89; p = 0.013), suggesting a protective effect; and the "T" allele was associated with increased susceptibility to POAG (OR = 1.7, 95% CI = 1.11-2.58; p = 0.013). Genotype distribution was also significantly associated with POAG (χ
CONCLUSION: The "T" allele of the rs10483727 polymorphism is an independent significant risk factor for POAG in the Saudi population. ||||| PURPOSE: We investigated the association of genetic factors with primary open angle glaucoma (POAG), including high tension glaucoma (HTG) and normal tension glaucoma (NTG), in a Han Chinese population.
METHODS: We recruited 1157 POAG cases, including 860 HTG and 297 NTG, and 934 normal controls. A total of 13 previously reported single nucleotide polymorphisms (SNPs) located at four gene regions (TMCO1, CDKN2B-AS1, ATOH7, and SIX1/SIX6) was genotyped. Distributions of allele frequencies were compared between cases and controls as well as in the HTG and NTG subgroups. The IOP, vertical cup-to-disc ratio (VCDR), central corneal thickness (CCT), axial length (AL), and age at diagnosis also were investigated as quantitative phenotypes with genotypes of these SNPs.
RESULTS: The SNPs rs4656461 and rs7555523 at TMCO1, rs523096 and rs2157719 at CDKN2B-AS1, as well as rs33912345 and rs10483727 at SIX1/SIX6 showed statistically significant association with POAG. The SNPs at ATOH7 did not show statistically significant association with POAG in our dataset. In the subgroup analysis of HTG and NTG, multiple variants at CDKN2B-AS1 and SIX1/SIX6 showed stronger association with NTG than HTG. The SNPs rs523096 and rs2157719 at CDKN2B-AS1 as well as rs33912345 and rs10483727 at SIX1/SIX6 were found to be associated with IOP where the minor alleles were associated with an increase in IOP. In contrast, SNPs at TMCO1 showed significant association with HTG only.
CONCLUSIONS: Genetic variants in CDKN2B-AS1, SIX1/SIX6, and TMCO1 were associated with POAG in a Han Chinese population. Genes CDKN2B-AS1 and SIX1/SIX6 seem to harbor a tendency toward POAG with lower IOP, while carriers of risk alleles at TMCO1 seem to be predisposed to developing POAG with higher IOP. ||||| PURPOSE: To determine if open-angle glaucoma (OAG)-associated single nucleotide polymorphisms (SNPs) are associated with incident glaucoma and if such genetic information is useful in OAG risk prediction.
DESIGN: Case-control from within a population-based longitudinal study.
METHODS: study population: Individuals aged over 49 years of age living in the Blue Mountains region west of Sydney and enrolled in the Blue Mountains Eye Study. observation: Cases for this sub-study (n = 67) developed incident OAG between baseline and 10-year visits, in either eye, while controls (n = 1919) had no evidence for OAG at any visit. All participants had an ocular examination and DNA genotyped for reported OAG risk SNPs. main outcome measure: Incident OAG.
RESULTS: Two loci also known to be associated with cup-to-disc ratio as well as OAG (9p21 near CDKN2B-AS1 and SIX1/SIX6) were both significantly associated with incident OAG in the Blue Mountains Eye Study cohort (P = .006 and P = .004, respectively). The TMCO1 locus was nominally associated (P = .012), while the CAV1/CAV2 and 8q22 loci were not associated. Multivariate logistic regression and neural network analysis both indicated that the genetic risk factors contributed positively to the predictive models incorporating traditional risk factors.
CONCLUSIONS: This study shows that previously reported genetic variations related to OAG and cup-to-disc ratio are associated with the onset of OAG and thus may become useful in risk prediction algorithms designed to target early treatment to those most at risk of developing glaucoma. ||||| The purpose of the study was to evaluate the association profiles of the SIX6 locus with primary open-angle glaucoma (POAG) in southern Chinese and Japanese. In this study, we tested single marker and haplotype-based associations of 11 tagging single nucleotide polymorphisms (SNPs) covering the SIX6 locus with POAG in a Hong Kong Chinese cohort (N = 1402). A novel SNP (i.e., rs12436579) and two SNPs (i.e., rs33912345 and rs10483727) from previous genome-wide association studies were further tested in a Chinese cohort from Shantou (N = 888) and a Japanese cohort from Osaka (N = 463). Results from the three cohorts were meta-analysed using a random-effect model. We found rs12436579, which has not been previously reported, was associated with POAG in Hong Kong and Shantou Chinese (P ||||| Primary open angle glaucoma (POAG) is one of leading causes of adult blindness worldwide. To identify genetic variants associated with susceptibility to POAG, we conducted a genome-wide association study (GWAS) using 1394 cases and 6599 controls. Subsequently, we analyzed 33 single nucleotide polymorphisms (SNPs) which showed suggestive association (P < 1 × 10(-4)) by GWAS, using an additional set of 1802 cases and 7212 controls. In addition to confirmation of the association of the chromosome 9p21 locus [rs1063192, P= 5.2 × 10(-11), odds ratio (OR) = 0.75], and 14q23 (rs10483727, P = 9.49 × 10(-8), OR = 0.79) with POAG in Caucasians reported recently, we identified a suggestive-associated locus on 2q21 (rs7588567, P = 3.89 × 10(-7), OR = 0.85). For these described SNPs, minor alleles are suspected to have a protective effect from the disease. An linkage disequilibrium block containing rs10483727 includes the SIX6 gene that was implicated to have a critical role in eye development, and genes in both represented loci (SIX6 on chromosome 14q23, and CDKN2A-CDKN2B on chromosome 9p21) are known to be expressed in human ocular tissues, including the retina. Our GWAS results should contribute to better insight into the genetic basis of POAG. ||||| PURPOSE: Genetically complex disorders, such as primary open angle glaucoma (POAG), may include highly heritable quantitative traits as part of the overall phenotype, and mapping genes influencing the related quantitative traits may effectively identify genetic risk factors predisposing to the complex disease. Recent studies have identified SNPs associated with optic nerve area and vertical cup-to-disc ratio (VCDR). The purpose of this study was to evaluate the association between these SNPs and POAG in a US Caucasian case-control sample.
METHODS: Five SNPs previously associated with optic disc area, or VCDR, were genotyped in 539 POAG cases and 336 controls. Genotype data were analyzed for single SNP associations and SNP interactions with VCDR and POAG.
RESULTS: SNPs associated with VCDR rs1063192 (CDKN2B) and rs10483727 (SIX1/SIX6) were also associated with POAG (P = 0.0006 and P = 0.0043 for rs1063192 and rs10483727, respectively). rs1063192, associated with smaller VCDR, had a protective effect (odds ratio [OR] = 0.73; 95% confidence interval [CI], 0.58-0.90), whereas rs10483727, associated with larger VCDR, increased POAG risk (OR = 1.33; 95% CI, 1.08-1.65). POAG risk associated with increased VCDR was significantly influenced by the C allele of rs1900004 (ATOH7), associated with increased optic nerve area (P-interaction = 0.025; OR = 1.89; 95% CI, 1.22-2.94).
CONCLUSIONS: Genetic variants influencing VCDR are associated with POAG in a US Caucasian population. Variants associated with optic nerve area are not independently associated with disease but can influence the effects of VCDR variants suggesting that increased optic disc area can significantly contribute to POAG risk when coupled with risk factors controlling VCDR. | [
{
"source_pmid": "25489222",
"source_text": "PURPOSE: Despite the different etiology of primary open angle glaucoma (POAG), primary angle closure glaucoma (PACG), and pseudoexfoliative glaucoma (PEXG), several studies have suggested that these forms of glaucoma have overlapping genetic risk factors. Therefo... |
21505997 | It is concluded that, compared with the non-penetrating trabeculectomy, the traditional trabeculectomy could reduce IOP more and had higher success rate while the non-penetrating trabecular surgery is associated with lower postoperative complications. | AIMS: To compare trabeculectomy with viscocanalostomy augmented with adjunctive antimetabolite use for the control of intraocular pressure (IOP) in open angle glaucoma (OAG).
METHODS: 45 patients (50 eyes) with uncontrolled OAG were randomised to either trabeculectomy (25 eyes) or a viscocanalostomy technique (25 eyes). Preoperatively, all eyes were graded in terms of risk factors for drainage failure and were given intraoperative antimetabolites (5-fluorouracil 25 mg/ml (5-FU), mitomycin C (MMC) 0.2 mg/ml and 0.4 mg/ml) according to a standard protocol.
RESULTS: There were no significant differences between the groups in age, sex, type of OAG, preoperative medications, risk factors for drainage failure, and preoperative IOP. Mean follow up was 20 months (range 3-24 months). It was 12 months or longer in all eyes, except two lost to follow up at 3 months. At 12 months, complete success (IOP<21 mm Hg without antiglaucoma medications) was seen in 91% of eyes undergoing trabeculectomy, but in only 60% of eyes undergoing viscocanalostomy (p<0.02). Similarly, at the last follow up visit (mean 20 months) complete success was seen in 68% of eyes undergoing trabeculectomy and 34% with viscocanalostomy (p<0.05). In terms of qualified success (IOP<21 mm Hg with or without glaucoma medications) and mean IOP measurements postoperatively there were no difference between the groups, although the mean number of antiglaucomatous medications required postoperatively was less with trabeculectomy (0.39) than viscocanalostomy (1.04) (p<0.05). Needling procedures were more commonly required after trabeculectomy (p<0.02). YAG goniotomy was required in three eyes (13%) after viscocanalostomy. Early transient complications such as anterior chamber shallowing and encysted blebs were more common in the trabeculectomy group (p<0.05). Late postoperative cataract formation was similar between the two groups.
CONCLUSION: In terms of complete success and number of antiglaucomatous medications required postoperatively, IOP control appears to be better with trabeculectomy. Viscocanalostomy is associated with fewer early transient postoperative complications. ||||| PURPOSE: To study the intraocular pressure (IOP)-reducing effect of deep sclerectomy on normal-tension glaucoma (NTG) patients.
METHODS: We retrospectively analysed 21 eyes of 18 consecutive NTG patients who had undergone deep sclerectomy with mitomycin-C and a collagen implant.
RESULTS: Median (range) preoperative IOP was 15.1 mmHg (9.3-20.8) and median follow-up time 13 months (12-18). At the 1-year follow-up visit, median IOP was significantly (P < 0.001) reduced to 10.5 mmHg (4-15) with median IOP reduction from preoperative values of 37% (12-78). Laser goniopuncture was performed in 10 eyes (48%) 1-16 months postoperatively. After 13 months' follow-up, a complete success at 20%, 25% and 30% IOP reduction levels was achieved in 67%, 62% and 52% of eyes, respectively. Few complications were encountered, but these included reduced visual acuity, problems with conjunctiva, microperforation, hyphaema, Dellen formation and encapsulated bleb. We encountered no complications related to postoperative hypotony.
CONCLUSION: Deep sclerectomy with a collagen implant and mitomycin-C was a safe and effective method for reducing IOP in NTG patients during 1-year follow-up. ||||| PURPOSE: To compare the intraocular pressure lowering effect and the frequency of post-operative complications in two of the most used filtration surgery techniques: trabeculectomy and non-penetrating deep sclerectomy (NPDS) without collagen implants.
METHODS: Thirty-four eyes of 17 patients with medically uncontrolled symmetrical primary open-angle glaucoma were included in the study. One randomly selected eye per patient had either trabeculectomy or NPDS without collagen implants as the first surgical procedure. The other eye underwent the second filtration surgery technique less than 6 weeks later. Post-operatively, the intraocular pressure (IOP) diurnal curves were determined at 1, 2, 3, 6, 12 and 18 months. The intergroup differences in IOP lowering effect were determined in an analysis of covariance (ANCOVA), with pre-operative IOP as a changing covariate. Kaplan-Meier survival curves were drawn for IOP, and intercurve analysis was performed. Comparisons of the number of post-operative antiglaucomatous medications, as well as of the complication rate, were done by 2 x 2 frequency tables. A p value of less than 0.05 was considered statistically significant.
RESULTS: There were statistically significant differences in post-operative IOP level between the two groups at 1, 2, 3, 6, 12 and 18 months, with a lower level in the trabeculectomy group. Using the Kaplan Meier cumulative survival curve, the trabeculectomy patients had a better complete success rate than the NPDS patients at 18 months post-operatively. There were statistically significantly fewer complications in the NPDS group.
CONCLUSION: Trabeculectomy lowers the IOP more than the NPDS technique. However, the complication rate seems to be lower in NPDS. ||||| OBJECTIVE: To establish the efficacy and safety of nonpenetrating deep sclerectomy versus trabeculectomy in primary open-angle glaucoma.
DESIGN: Prospective randomized trial.
PARTICIPANTS: Thirty-nine patients (78 eyes) with bilateral primary open angle glaucoma were included in the study.
INTERVENTION: Eyes were randomly assigned to receive deep sclerectomy in one eye and trabeculectomy in the other eye.
MAIN OUTCOME MEASURES: Mean intraocular pressure (IOP), postoperative medications, visual acuity, success rate, and complications.
RESULTS: At 12 months, mean IOP reduction was 12.3 +/- 4.2 (sclerectomy) versus 14.1 +/- 6.4 mmHg (trabeculectomy) (P = 0.15), and an IOP </= 21 mmHg was achieved in 36 (92.3%) and 37 eyes (94.9%) (P = 0.9), respectively. Complications included three (7.7%) flat/shallow anterior chambers and one (2.6%) hypotony (trabeculectomy), whereas internal iris incarceration was encountered in two eyes (5.1%) (sclerectomy).
CONCLUSIONS: Deep sclerectomy may provide comparable IOP reduction with fewer complications in management of primary open angle glaucoma. ||||| Results of trabeculectomy (TE) and viscocanalostomy (VCO) were compared in a prospective randomised study in two fellow eyes of 22 consecutive patients with bilateral symmetrical high-tension glaucoma. Rates of overall surgical success with intraocular pressures (IOP) < or = 18 mm Hg with or without medications were 91 for the TE, and 95 for the VCO group after a mean follow-up of 18 months. Complete success rates without medications were 64 and 59 for TE and VCO groups, respectively (p = 0.750). Both procedures significantly reduced IOP, however, IOP course following trabeculectomy was significantly lower (p = 0.026). Rates of complications were not found to be different between the two groups of eyes, except for an apparent--though not significant (p = 0.066)--increase in cataract progression with TE. Various types of conjunctival blebs were detected in all eyes with surgical success in both groups, however, diffuse, elevated or multi-cystic functional blebs appeared to be more predominant in eyes with TE, compared to the VCO group in which low-lying, localised blebs had a higher incidence (p = 0.015). Viscocanalostomy was found to be a safe and effective filtration technique in patients with uncomplicated high-tension glaucoma, though IOP decrease was more pronounced with trabeculectomy. ||||| BACKGROUND: An investigation was carried out to compare post-operative inflammation following deep sclerectomy with collagen implant (DSCI) versus standard trabeculectomy.
METHODS: In this prospective randomized study, 46 eyes of 46 Caucasian patients with medically uncontrolled chronic open-angle glaucoma and without previous glaucoma surgery underwent filtering surgery. Twenty-four eyes underwent DSCI. Twenty-two eyes underwent standard trabeculectomy. Pre- and post-operative flare, measured using laser flare photometry, were compared between the two groups.
RESULTS: In both groups, the mean anterior chamber flare increased on the first post-operative day, then decreased progressively. DSCI was associated with lower flare measurements post-operatively. The difference was statistically significant up to 1 month post-operatively: 16.3 +/- 7.8 vs 72.5 +/- 38.9 (P < 0.001) at 1 day, 7.8 +/- 4.6 vs 44.7 +/- 29.2 (P < 0.001) at 1 week, 5.9 +/- 1.6 vs 7.0 +/- 2.8 (P = 0.012) at 1 month, 6.4 +/- 1.8 vs 6.5 +/- 1.9 (P = 0.77) at 2 months, 5.9 +/- 1.8 vs 6.1 +/- 1.6 (P = 0.65) at 3 months.
CONCLUSION: Surgically induced inflammation can be reduced with DSCI. This may be due to the lack of iridectomy, irrigation, and penetration of the anterior chamber. Eyes at increased risk of post-operative inflammation, such as those with uveitic or traumatic glaucoma, may benefit from this procedure. Further studies are needed to evaluate the long-term functional and anatomical outcomes of DSCI. ||||| BACKGROUND: Non-penetrating trabecular surgery is a new filtrating surgery without opening in ternal trabecular structures. This study was to estimate the overall efficacy of non-penetrating trabecular surgery for open angle glaucoma.
METHODS: The published articles selected for this study were obtained by a computerised Medline and China Biological Medicine Disk search of the literature and a manual search of the bibliographies of relevant articles. Articles meeting the inclusion criteria were reviewed systematically, and the reported data were aggregated using the statistical techniques of meta-analysis.
RESULTS: A total of 37 articles were included in the meta-analysis. The pooled complete success rates of non-penetrating trabecular surgery with different techniques were: deep sclerectomy single, 69.7% (95% CI: 58.5% - 81.0%); deep sclerectomy with collagen implant, 59.4% (95% CI: 47.0% - 71.8%); deep sclerectomy with reticulated hyaluronic acid implant, 71.1% (95% CI: 56.8% - 85.3%); and viscocanalostomy, 72.0% (95% CI: 57.6% - 86.4%). The overall weighted complete success rate of non-penetrating trabecular surgery was 67.8% (95% CI: 61.4% - 74.3%).
CONCLUSIONS: Non-penetrating trabecular surgery is the best available therapy method for medically uncontrolled open angle glaucoma with a complete success rate of over 60%. But the different techniques cannot belie the complete success rate of non-penetrating trabecular surgery. ||||| PURPOSE: To assess the intraocular pressure-lowering efficacy and the postoperative complication profile of viscocanalostomy versus trabeculectomy.
PATIENTS AND METHODS: Sixty eyes of 60 patients with medically uncontrolled open-angle glaucoma were randomized either to the viscocanalostomy or to the trabeculectomy group of the trial. Viscocanalostomy was performed according to Stegmann's technique using high-molecular-weight sodium hyaluronate to fill the ostia of the Schlemm canal. For trabeculectomy, a modified Cairns-trabeculectomy was performed. Examinations were performed before surgery and postoperatively daily for 1 week. Follow-up visits were scheduled 1, 6, and 12 months after surgery.
RESULTS: The mean (SD) preoperative intraocular pressure was 27.1 (7.1) mm Hg for all patients enrolled. One day after surgery, mean (SD) intraocular pressure was 15.9 (5.2) for the trabeculectomy group (P <0.001) and 15.7 (3.6) for the viscocanalostomy group (P <0.001), respectively. The success rate, defined as an intraocular pressure lower than 22 mm Hg without medication, was 56.7% in the trabeculectomy group and 30% in the viscocanalostomy group at 12 months postoperatively (P = 0.041). The number of postoperative complications was lower in the viscocanalostomy group than in the trabeculectomy group.
CONCLUSIONS: In eyes with open-angle glaucoma, viscocanalostomy is less effective in reducing intraocular pressure than standard filtering surgery. However, postoperative complications are more frequent after filtering surgery. ||||| PURPOSE: To compare viscocanalostomy, a nonpenetrating procedure for glaucoma treatment, with trabeculectomy.
DESIGN: Randomized controlled trial.
PARTICIPANTS: Twenty white subjects (20 eyes) with open-angle glaucoma with no history of surgery were enrolled.
METHODS: Ten subjects were randomly assigned to viscocanalostomy according to Stegmann's technique and 10 subjects to a modified Cairns trabeculectomy. A complete ophthalmologic examination was performed the day before surgery and postoperatively. Further visits were scheduled monthly for 6 to 8 months after surgery.
MAIN OUTCOME MEASURES: Success was defined as intraocular pressure (IOP) between 7 and 20 mmHg, with no medication.
RESULTS: After a mean follow-up of 6 months (range, 6-8 months), success was obtained in 5 of 10 cases in the trabeculectomy group and in no case in the viscocanalostomy group. With Kaplan-Meier's method, subjects with viscocanalostomy showed shorter postoperative IOP-reduction periods than subjects undergoing trabeculectomy.
CONCLUSIONS: According to the results of this short-term study, trabeculectomy was more effective than viscocanalostomy in lowering IOP in glaucomatous eyes of white patients. | [
{
"source_pmid": "15258016",
"source_text": "AIMS: To compare trabeculectomy with viscocanalostomy augmented with adjunctive antimetabolite use for the control of intraocular pressure (IOP) in open angle glaucoma (OAG).\nMETHODS: 45 patients (50 eyes) with uncontrolled OAG were randomised to either trabecul... |
22696359 | AUTHORS' CONCLUSIONS: At this time, it is not possible to draw reliable conclusions from the available data to determine whether cataract surgery is beneficial or harmful in people with AMD. Physicians will have to make practice decisions based on best clinical judgment until controlled trials are conducted and their findings published.It would be valuable for future research to investigate prospective RCTs comparing cataract surgery to no surgery in patients with AMD to better evaluate whether cataract surgery is beneficial or harmful in this group. However ethical considerations need to be addressed when delaying a potentially beneficial treatment and it may not be feasible to conduct a long-term study where surgery is withheld from the control group. Utilization of pre-existing, standardized systems for grading cataract and AMD and measuring outcomes (visual acuity, change in visual acuity, worsening of AMD and quality of life measures) should be encouraged. | [] | |
21031019 | CONCLUSIONS: HTRA1 rs11200638 G→A polymorphism and LOC387715/ARMS2 rs10490924 G→T polymorphism play important roles in AMD. Gene-gene and gene-environmental interactions, as well as precise mechanisms underlying common variants in the HTRA1 gene and LOC387715/ ARMS2 gene, potentially increase the risk of AMD and need further exploration. | PURPOSE: Single nucleotide polymorphisms (SNPs) in the LOC387715 (rs10490924), HTRA1 (rs11200638), and CFH (rs1061170) genes have been implicated in age-related macular degeneration (AMD). The present study was undertaken to determine the involvement of the LOC387715 and HTRA1 in an AMD cohort from India.
METHODS: The coding region of LOC387715 (exon 1) and the promoter of HTRA1 were screened by resequencing in AMD cases and normal controls. Odds ratios were calculated to assess the risk of individual genotypes. Linkage disequilibrium (LD) and haplotype frequencies were estimated with Haploview software. Population attributable risk (PAR %) for the associated SNPs and their combined effects were calculated.
RESULTS: Resequencing revealed seven different SNPs in these genes, of which significant associations were noted with the risk alleles of rs10490924 (T allele; P = 5.34 x 10(-12)) in LOC387715, and rs11200638 (A allele; P = 4.32 x 10(-12)) and rs2672598 (C allele; P = 3.39 x 10(-11)) in HTRA1 among the cases. Correspondingly, the homozygous risk genotypes TT, AA, and CC in these SNPs exhibited higher disease odds and PAR %. rs10490924 and rs11200638 were in tight LD (D', 0.90; 95% CI, 0.84-0.93). G-C-T-A-C was the risk haplotype (P = 8.04 x 10(-15)), whereas the G-C-G-G-T haplotype was protective (P = 2.01 x 10(-4)). The combined effect of the CFH (CC) and LOC387715 (TT) risk genotypes exhibited a PAR of 93.7% (OR, 73.89; 95% CI, 8.69-628.13).
CONCLUSIONS: The present data provided an independent validation of the association of LOC387715 and HTRA1 SNPs, along with their risk estimates among Indian patients with AMD. These associations underscore their significant involvement in AMD susceptibility, which may be useful for predictive testing. ||||| BACKGROUND: Age-related macular degeneration (AMD) is the major cause of blindness in the elderly. Those with the neovascular end-stage of disease have irreversible loss of central vision. AMD is a complex disorder in which genetic and environmental factors play a role. Polymorphisms in the complement factor H (CFH) gene, LOC387715, and the HTRA1 promoter are strongly associated with AMD. Smoking also contributes to the etiology. We aimed to provide a model of disease risk based on these factors.
METHODS AND FINDINGS: We genotyped polymorphisms in CFH and LOC387715/HTRA1 in a case-control study of 401 patients with neovascular AMD and 266 controls without signs of disease, and used the data to produce genetic risk scores for the European-descent population based on haplotypes at these loci and smoking history. CFH and LOC387715/HTRA1 haplotypes and smoking status exerted large effects on AMD susceptibility, enabling risk scores to be generated with appropriate weighting of these three factors. Five common haplotypes of CFH conferred a range of odds ratios (ORs) per copy from 1 to 4.17. Most of the effect of LOC387715/HTRA1 was mediated through one detrimental haplotype (carriage of one copy: OR 2.83; 95% confidence interval [CI] 1.91-4.20), with homozygotes being at particularly high risk (OR 32.83; 95% CI 12.53-86.07). Patients with neovascular macular degeneration had considerably higher scores than those without disease, and risk of blinding AMD rose to 15.5% in the tenth of the population with highest predicted risk.
CONCLUSIONS: An individual's risk of developing AMD in old age can be predicted by combining haplotype data with smoking status. Until there is effective treatment for AMD, encouragement to avoid smoking in those at high genetic risk may be the best option. We estimate that total absence of smoking would have reduced the prevalence of severe AMD by 33%. Unless smoking habits change or preventative treatment becomes available, the prevalence of AMD will rise as a consequence of the increasing longevity of the population. ||||| PURPOSE: Exudative age-related macular degeneration (AMD) is one of the most common causes of severe visual loss. Both environmental and genetic factors, such as the complement factor H (CFH) 402H allele, have been associated with AMD. Recently, the HTRA1 -625A allele was identified as a novel risk marker in both a North American and a Chinese population. The present study was performed to evaluate the association of the HTRA1 -625A allele with exudative AMD in a Central European population.
METHODS: The present case-control study included 242 patients with exudative AMD and 157 control subjects. Genotypes of the HTRA1 -625G>A polymorphism were determined by a 5'-exonuclease assay (TaqMan). Determination of CFH Y402H genotypes was done by allele specific digestion of polymerase chain products.
RESULTS: Carriers of the HTRA1 -625AA genotype were found significantly more often in AMD patients than among control subjects (27.7% versus 5.1%; p<0.001). Binary logistic regression analysis binary logistic regression analysis revealed an odds ratio (OR) of 2.7 (95% confidence interval (CI): 1.1-6.8) for AMD among subjects heterozygous for the HTRA1 -625A allele compared to those with the wildtype genotype, when adjusted for CFH Y402H genotypes (p=0.034). The OR increased to 10.2 (95% CI: 3.0-34.5) among subjects homozygous for the HTRA1 -625A allele (p<0.001). The OR for AMD among heterozygous carriers of the CFH 402H variant was 3.6 (95% CI: 1.6-7.8) compared to those with the wildtype genotype, when adjusted for HTRA1 -625G>A genotypes (p=0.001). The OR increased to 9.8 (95% CI: 3.7-25.9) among subjects homozygous for the CFH 402HH genotype (p<0.001). Interaction terms between CFH and HTRA1 genotypes were not significantly associated with AMD.
CONCLUSIONS: Our data suggest that both the HTRA1 -625A allele and the CFH 402H allele are independently associated with exudative AMD in a Central European population. ||||| Age-related macular degeneration (AMD), the most common cause of irreversible vision loss in individuals aged older than 50 years, is classified as either wet (neovascular) or dry (nonneovascular). Inherited variation in the complement factor H gene is a major risk factor for drusen in dry AMD. Here we report that a single-nucleotide polymorphism in the promoter region of HTRA1, a serine protease gene on chromosome 10q26, is a major genetic risk factor for wet AMD. A whole-genome association mapping strategy was applied to a Chinese population, yielding a P value of <10(-11). Individuals with the risk-associated genotype were estimated to have a likelihood of developing wet AMD 10 times that of individuals with the wild-type genotype. ||||| Genetic variants at chromosomes 1q31-32 and 10q26 are strongly associated with susceptibility to age-related macular degeneration (AMD), a common blinding disease of the elderly. We demonstrate, by evaluating 45 tag SNPs spanning HTRA1, PLEKHA1, and predicted gene LOC387715/ARMS2, that rs10490924 SNP alone, or a variant in strong linkage disequilibrium, can explain the bulk of association between the 10q26 chromosomal region and AMD. A previously suggested causal SNP, rs11200638, and other examined SNPs in the region are only indirectly associated with the disease. Contrary to previous reports, we show that rs11200638 SNP has no significant impact on HTRA1 promoter activity in three different cell lines, and HTRA1 mRNA expression exhibits no significant change between control and AMD retinas. However, SNP rs10490924 shows the strongest association with AMD (P = 5.3 x 10(-30)), revealing an estimated relative risk of 2.66 for GT heterozygotes and 7.05 for TT homozygotes. The rs10490924 SNP results in nonsynonymous A69S alteration in the predicted protein LOC387715/ARMS2, which has a highly conserved ortholog in chimpanzee, but not in other vertebrate sequences. We demonstrate that LOC387715/ARMS2 mRNA is detected in the human retina and various cell lines and encodes a 12-kDa protein, which localizes to the mitochondrial outer membrane when expressed in mammalian cells. We propose that rs10490924 represents a major susceptibility variant for AMD at 10q26. A likely biological mechanism is that the A69S change in the LOC387715/ARMS2 protein affects its presumptive function in mitochondria. ||||| The purpose of this investigation was to determine whether the high-temperature requirement A-1 (HTRA1) gene polymorphism is associated with age-related macular degeneration (AMD) in native, unrelated Japanese patients. A total of 123 patients with AMD and 133 control subjects without AMD were recruited for this study. The single-nucleotide polymorphism (SNP) rs11200638 in the HTRA1 gene was assessed using a TaqMan assay. The risk A allele frequencies in the AMD cases and control patients were 0.577 and 0.380, respectively, and were associated with a significant risk of developing AMD (p=7.75x10(-6)). The results were more significant in subtype analyses with wet AMD (p=5.96x10(-7)). We conclude that the rs11200638 variant in the HTRA1 gene is strongly associated with AMD in the Japanese population. This result supports the hypothesis that the HTRA1 gene may increase susceptibility to AMD development and can participate in a potential new molecular pathway for AMD pathogenesis by extending this association across diverse ethnicities. ||||| Age-related macular degeneration (AMD) is a leading cause of irreversible visual impairment in the world. Advanced AMD can be divided into wet AMD (choroidal neovascularization) and dry AMD (geographic atrophy, GA). Drusen is characterized by deposits in the macula without visual loss and is an early AMD sign in the Caucasian population. rs11200638 in the promoter of HTRA1 has recently been shown to increases the risk for wet AMD in both Caucasian and Hong Kong Chinese populations. In order to replicate these results in a different cohort, we genotyped rs11200638 for 164 Chinese patients (90 wet AMD and 74 drusen) and 106 normal controls in a Han Mainland Chinese cohort. The genotypes were compared using chi square analysis for an additive allelic model. rs11200638 was significantly associated with wet AMD (p=5.00x10(-12)). Unlike in the Caucasian population, the risk allele of rs11200638 was not associated with drusen in our Chinese population. These findings confirm the association of HTRA1 with wet AMD. ||||| OBJECTIVE: To examine if the genes encoding the pleckstrin homology domain-containing protein gene (PLEKHA1), hypothetical LOC387715/ARMS2 gene, and HtrA serine peptidase 1 gene (HTRA1) located on the long arm of chromosome 10 (10q26 region) confer risk for neovascular age-related macular degeneration (AMD) in an independent or interactive manner when controlling for complement factor H gene (CFH) genotype and smoking exposure.
DESIGN: Retrospective matched-pair case-control study.
PARTICIPANTS: Hospital clinic-based sample of 134 unrelated patients with neovascular AMD who have a sibling with normal maculae (268 subjects).
METHODS: Disease status was ascertained by at least 2 investigators by review of fundus photographs and/or fluorescein angiography according to the Age-Related Eye Disease Study grading scale. If necessary, a home retinal examination was performed (n = 6). A combination of direct sequencing and analysis of 8 highly polymorphic microsatellite markers was used to genotype 33 megabases of the 10q26 region on leukocyte DNA. Smoking history was obtained via a standardized questionnaire and measured in pack-years. The family-based association test, haplotype analysis, multiple conditional logistic regression, and linkage analysis were used to determine significant associations.
MAIN OUTCOME MEASURE: Neovascular AMD status.
RESULTS: Of the 23 variants we identified in the 10q26 region, 6 were significant. Four of the 6 were novel and included 2 genotypes that reduced risk of AMD. Many single-nucleotide polymorphisms (SNPs), including the previously reported variants rs10490924 (hypothetical LOC387715/ARMS2) and rs11200638 (HTRA1), defined 2 significant haplotypes associated with increased risk of neovascular AMD. The coding HTRA1 SNP rs2293870, not part of the significant haplotypes containing rs10490924 and rs11200638, showed as strong an association with increased susceptibility to neovascular AMD. Linkage analysis supported our findings of SNP association (P<10(-15)). No significant interactions were found between any of the SNPs in the 10q26 and smoking or between these SNPs and CFH genotype.
CONCLUSIONS: Independent of CFH genotype or smoking history, an individual's risk of AMD could be increased or decreased, depending on their genotype or haplotype in the 10q26 region. ||||| PURPOSE: To investigate whether variants in the LOC387715 locus and the HtrA serine peptidase 1 (HTRA1) gene within the 10q26 locus are associated with polypoidal choroidal vasculopathy (PCV) and wet age-related macular degeneration (AMD) in a Japanese population, and whether genetic diversity exists between PCV and wet AMD in this locus.
DESIGN: Cross-sectional study.
METHODS: We genotyped 243 Japanese individuals, including 76 PCV cases, 73 wet AMD cases, and 94 controls using two single nucleotide polymorphisms (SNPs) that are located in the LOC387715 locus (rs10490924) or the HTRA1 gene (rs11200638). Genotyping was performed using TaqMan assays (Applied Biosystems, Foster City, California, USA).
RESULTS: Two SNPs generated highly significant allelic associations with PCV (rs10490924, P = 5.7 x 10(-6); rs11200638, P = 5.2 x 10(-6)) and AMD (rs10490924, P = 1.4 x 10(-6); rs11200638, P = 3.4 x 10(-7)). The odds ratios and population attributable risks were higher for the AMD cases than for the PCV cases. Homozygotes for the risk allele at rs11200638 had a 6.33-fold increased risk of PCV and a 13.77-fold increased risk of wet AMD when compared with homozygotes for the wild-type allele. There were no significant differences in either allelic or genotypic frequencies between PCV and AMD cases.
CONCLUSIONS: The LOC387715/HTRA1 variants are associated with PCV and wet AMD in the Japanese population. The associations are stronger in AMD than in PCV. PCV and AMD share common genetic factors, which suggests that PCV and wet AMD are similar in some pathophysiologic aspects. ||||| PURPOSE: Mapping the genes for age-related macular degeneration (AMD) had not been successful until recent genome-wide association studies revealed Tyr402His in CFH and rs11200638 in HTRA1 as AMD-related genetic variants. This study was conducted to identify other critical factors in HTRA1 that are associated with exudative AMD.
METHODS: The promoter, splice regions, and coding exons of HTRA1 were sequenced in 163 patients with exudative AMD and 183 sex- and age-matched control subjects. Also documented were the CFH genotype and smoking status.
RESULTS: Four significant SNPs were found in the promoter and the first exon of HTRA1: rs11200638 (-625G>A), rs2672598 (-487T>C), rs1049331 (102C>T, Ala34Ala), and rs2293870 (108G>T, Gly36Gly) with respective P = 1.7 x 10(-14), 3.0 x 10(-10), 3.7 x 10(-12), and 3.7 x 10(-12). Among them, rs11200638 is the most significant associated SNP with a high odds ratio (OR) of 7.6 (95% CI: 3.94-14.51). One risk haplotype block across the promoter and exon 1, ACCTT, significantly predisposes to AMD (P = 6.68 x 10(-14)). In both models, significant independent additive effects were identified with smoking and rs800292 (184G>A, Val62Ile) of CFH. Smoking and rs11200638 (HTRA1) combined caused a 15.7-fold increased risk, whereas combined rs800292 and rs11200638 caused a 23.3-fold increased risk. An extremely high population attributable risk (PAR) of 78% was also found.
CONCLUSIONS: A high impact of the additive effect of CFH and HTRA1 in the development of exudative AMD was shown. The HTRA1-smoking additive effect found in this study further suggests the importance of this environmental risk factor in AMD. ||||| PURPOSE: Identification of genetic factors for age-related macular degeneration (AMD) is of crucial importance in this common cause of blindness. Exudative AMD is rapidly progressive and usually associated with severe prognosis. Our purpose was to investigate this association on locus 10q26 in a case-control study including French patients specifically affected with exudative AMD.
METHODS: Polymorphisms rs4146894:G>A of Pleckstrin Homology Domain-containing Protein Family A member 1 (PLEKHA1) gene, rs10490924:G>T at LOC387715, and rs11200638:G>A of HTRA1 (HTRA serine peptidase 1) gene were analyzed in AMD cases (n=118, age=72.3+/-3.8 years old) and healthy controls (n=116, age=72.0+/-3.8 years old).
RESULTS: PLEKHA1 polymorphism was associated with AMD. The A allele frequency was 0.67 in cases versus 0.41 in controls, (p=0.0001). After age and sex adjustment, the odds ratio for risk of AMD was 9.1 (4.0-20.9, 95% CI, p=0.0001) for the AA genotype and 2.6 (1.3-5.5, 95% CI, p=0.04) for the AG genotype, conditional on HTRA1. Association was even stronger and independent with HTRA1. The A allele frequency was 0.51 in cases versus 0.22 in controls, (p=0.0001). The odds ratio was 15.5 (5.5-43.9, 95% CI, p=0.0001) for the AA genotype and 3.4 (1.9-6.1, 95% CI, p=0.0001) for the AG genotype. No further information was obtained from LOC387715 due to virtually complete linkage disequilibrium with HTRA1 polymorphism in cases (D'=1.0) and controls (D'=0.98). Although a role for PLEKHA1 could not be totally excluded, there was a four times higher AMD risk was associated with haplotype "A-T-A" involving "PLEKHA1-LOC387715-HTRA1" risk alleles.
CONCLUSIONS: Compared to PLEKHA1, HTRA1/LOC387715 genetic variations were independently and strongly associated with exudative AMD in the French population. Chromosome-10 genetic variants appear as potentially useful risk markers for early detection of AMD. ||||| PURPOSE: To investigate HTRA1 polymorphisms in unrelated Taiwan Chinese patients with age-related macular degeneration (AMD) and control subjects without AMD.
METHODS: A total of 95 unrelated Taiwan Chinese patients with AMD and 90 age- and sex-matched control subjects were enrolled in the study. Genomic DNA was prepared from peripheral blood obtained from all patients with AMD and control subjects. Polymerase chain reactions were used to analyze two HTRA1 single-nucleotide polymorphisms (rs11200638 [G/A] and rs10490924 [G/T]).
RESULTS: Of the 95 participants with AMD, dry AMD was diagnosed in 52 patients and wet AMD in 43 patients. Both rs11200638 (G/A) and rs10490924 (G/T) were significantly associated with all AMD (rs11200638: P = 6.7 x 10(-7) for an additive allele-dosage model, OR(het) = 1.97 [0.81, 4.81], OR(hom) = 8.59 [3.28, 22.49], A allele: 73% in all AMD versus 47% in controls; rs10490924: P = 9.2 x 10(-6), OR(het) = 1.86 [0.79, 4.35], OR(hom) = 5.08 [2.21, 11.70], T allele: 73% in all AMD versus 50% in controls). In terms of significance of association, rs11200638 was the most significantly associated variant. Subtype analysis including dry and wet AMD also revealed similar results. Haplotype analysis demonstrated that AT was significantly associated with wet and all AMD (P = 0.011 and 0.004, respectively), whereas GG was significantly associated with the control group when compared with all AMD (P = 0.035).
CONCLUSIONS: The study demonstrated that both single-nucleotide polymorphisms were significantly associated with dry and wet AMD and rs11200638 was the most significantly associated variant in a Taiwan Chinese population. ||||| Single nucleotide polymorphism (SNP), rs11200638, in the promoter of HTRA1 has recently been shown to increase the risk for AMD. In order to investigate the association of this HTRA1 polymorphism and the bilaterality of AMD, we genotyped rs11200638 in control, unilateral, and bilateral advanced AMD patients. The A allele for SNP rs11200638 in HTRA1, was significantly more prevalent in bilateral wet AMD and GA patients than in unilateral groups (p=.02 and p=.03, respectively). The homozygote odds ratios of bilateral wet AMD and GA are significantly greater than those seen in unilateral groups (twofold and threefold increase, respectively). This finding is consistent with the role of HTRA1 in AMD pathogenesis and will help aid in the clinical management and prognosis of AMD patients. | [
{
"source_pmid": "18436811",
"source_text": "PURPOSE: Single nucleotide polymorphisms (SNPs) in the LOC387715 (rs10490924), HTRA1 (rs11200638), and CFH (rs1061170) genes have been implicated in age-related macular degeneration (AMD). The present study was undertaken to determine the involvement of the LOC38... |
23559847 | CONCLUSIONS: This meta-analysis suggests that patients with OAG may have higher TNF-α levels compared with the control subjects, and the TNF-α -308G/A polymorphism is significantly associated with the risks of high-tension glaucoma. Since potential confounders could not be ruled out completely, further studies are needed to confirm these results. | PURPOSE: Tumor necrosis factor-α (TNF-α), an important proinflammatory cytokine, exerts a variety of physiologic and pathogenic effects that lead to tissue destruction. Recent laboratory evidence indicates that TNF-α have either protective or adverse effects on primary open angle glaucoma (POAG). Inheritance of the TNF-α (-863) C allele has been associated with an elevated risk of Alzheimer disease. The neuronal injuries associated with Alzheimer disease have several similarities with the optic nerve changes often seen with POAG. In this study we investigated the possible association between the TNF-α (-863) polymorphism and the development of POAG.
METHODS: A total of 234 patients with POAG were recruited and compared with 230 healthy controls in a Chinese population. Sequence-specific primers with 3' end mismatches were used to identify the presence of specific allelic variants by polymerase chain reaction (PCR) amplification. Patients and controls were genotyped for the A/C polymorphism at position -863 of the TNF-α gene promoter region.
RESULTS: The frequency of the TNF-α (-863)A allele (22% versus 30%, respectively; p=0.007) and the carriers of the TNF-α (-863)A allele (37% versus 48%; p=0.017, OR 0.63, 95% CI 0.44-0.92) were lower in POAG patients compared with those in controls. There is a reduced risk of POAG associated with homozygosity for the TNF-α (-863)A allele (AA genotype) compared with that in the control population (AA genotype; 7% versus 11%, respectively, p=0.037; OR 0.5, 95% CI 0.26-0.98).
CONCLUSIONS: The TNF-α (-863)A allele polymorphism may be a protective factor in the development of POAG. ||||| PURPOSE: The purpose of the present study was to determine the role of the tumor necrosis factor alpha (TNF-alpha) gene polymorphism G-308A and total serum immunoglobulin E (TsIgE) levels in the onset of pseudoexfoliation glaucoma (PEXG) in Pakistani patients.
METHODS: The TNF-alpha polymorphism G-308A was analyzed in 122 patients with PEXG and 126 healthy unrelated controls by using polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP). TsIgE levels were determined by solid-phase enzyme-linked immunosorbent assay (ELISA).
RESULTS: The AA and GA genotypes were strongly associated with PEXG (p<0.001), with an odds ratio (OR) of 0.07 (95% confidence interval [CI]=0.02-0.27) and 0.24 (95% CI=0.12-0.51), respectively, while the GG genotype was found at a higher frequency in controls as compared to patients (p<0.001) OR=8.95 (95% CI=4.55-17.81). No significant difference was found in TsIgE levels of both patients and controls (p=0.86).
CONCLUSION: The present study concludes that the TNF-alpha polymorphism G-308A is strongly associated with PEXG. To our knowledge this is the first study in southeast Asia which demonstrates a strong association of a TNF-alpha polymorphism with PEXG. ||||| PURPOSE: To investigate the possible association between tumor necrosis factor alpha (TNF-alpha)-308 G/A polymorphism and pseudoexfoliation (PEX) glaucoma.
METHODS: One hundred and ten Turkish PEX glaucoma patients and 110 healthy control subjects were enrolled in the study. All participants underwent a complete ophthalmic examination. TNF-alpha-308 was genotyped by polymerase chain reaction and restriction endonuclease analysis.
RESULTS: We found a high prevalence of the G/G genotype in PEX glaucoma patients (OR=2.88, 95% CI 1.15-7.20). The A polymorphic allele frequency was 3.2% in patients with PEX compared with 8.2% in controls (p=0.023).
CONCLUSIONS: Our results suggest that TNF-alpha-308 G/A genotype is not associated with PEX glaucoma. The -308G/A variant may be a possible protective factor against PEX. ||||| OBJECTIVE: TNF-alpha is one of the most important factors recognized in the pathogenesis of open-angle glaucoma. Therefore, the association of single nucleotide polymorphisms in the TNFRI gene and the promoter region of the TNFA gene with glaucoma susceptibility was investigated in the present study.
METHOD: In total, 223 patients with glaucoma and 202 unrelated controls were genotyped by allele-specific oligonucleotide PCR and PCR- restriction fragment length polymorphism to determine TNFA -308 G/A and TNFRI +36 A/G polymorphisms, respectively.
RESULTS: In contrast to TNFRI polymorphisms, the genotypes of TNFA -308 G/A polymorphisms showed a significant difference between patients and controls (p = 0.0025). Of interest, the distribution of TNFA genotypes was significantly different between patients with primary open-angle glaucoma (p = 0.001) or pseudoexfoliative glaucoma (p = 0.001) and controls, while no difference was found when chronic angle-closure glaucoma patients were compared to controls (p = 0.72).
CONCLUSION: In line with studies showing the role of TNF-alpha in open-angle glaucoma, the results of the present study showed that inheritance of the high producer TNFA -308 A allele might be a susceptibility factor for the development of open-angle glaucoma. ||||| PURPOSE: To investigate sequence variations in the optineurin (OPTN) gene and their association with TNF-alpha polymorphisms in Japanese patients with glaucoma.
METHODS: The OPTN gene was analyzed in blood samples from 629 Japanese subjects. There were 194 patients with primary open-angle glaucoma (POAG), 217 with normal-tension glaucoma (NTG), and 218 with no eye disease (control subjects). The gene was screened for mutations by denaturing high-performance liquid chromatography. Genotyping of three polymorphisms of -308G-->A, -857C-->T, and -863C-->A in the TNF-alpha promoter region was performed. The associations between the genotypes and age, intraocular pressure (IOP), and visual field defects at the time of diagnosis were examined.
RESULTS: A possible glaucoma-causing mutation, His26Asp, was identified in 1 of the 411 Japanese patients with glaucoma. A c.412G-->A (Thr34Thr) polymorphism in the OPTN gene was significantly associated with POAG (genotype frequency, P = 0.011; allele frequency, P = 0.003). The frequency of TNF-alpha/-857T and optineurin/412A carriers was significantly higher (P = 0.006) in patients with POAG than in control subjects. Among the patients with POAG who were carriers of TNF-alpha/-857T, the optineurin/412A carriers had significantly worse (P = 0.020) visual field scores than the non-optineurin/412A ones. The frequency of TNF-alpha/-863A and optineurin/603A (or Lys98) carriers was significantly higher in patients with POAG (P = 0.008) or NTG (P = 0.027) than in control subjects. Among the patients with POAG who were carriers of TNF-alpha/-863A, the ones with optineurin/603A (or Lys98) had significantly worse (P = 0.026) visual field scores than did those with non-optineurin/603A (or Lys98).
CONCLUSIONS: These findings demonstrated that the OPTN gene is associated with POAG rather than NTG in the Japanese. Statistical analysis showed a possible interaction between polymorphisms in the OPTN and the TNF-alpha genes that would increase the risk for glaucoma. ||||| BACKGROUND: Tumour necrosis factor-alpha (TNF-α) is an important proinflammatory cytokine driving axonal degeneration and retinal ganglion cell apoptosis in glaucoma. The aim of the study was to evaluate the association of TNF-α -308 G/A and -238 G/A polymorphisms with primary open-angle glaucoma (POAG).
DESIGN: A prospective, case-control study, university hospital setting.
PARTICIPANTS: Eighty-six POAG patients and 193 healthy unrelated controls.
METHODS: TNF-α polymorphisms were screened by using direct gene sequencing.
MAIN OUTCOME MEASURES: Frequency of TNF-α -308 G/A and TNF-α -238 G/A promoter polymorphisms in glaucoma and healthy subjects.
RESULTS: The frequencies of TNF-α -308 GA genotype and 'A' allele were higher in patients with POAG (22.1% and 12.2%, respectively) in comparison with the control group (10.9% and 6%, respectively) (P = 0.046 and 0.02, respectively), with odds ratios of 2.45 (P = 0.01, 95% CI = 1.23-4.87) and 2.19 (P = 0.013, 95% CI = 1.18-4.08), respectively. Genotype distribution of the TNF-α -238 variants did not yield a statistically significant difference between the two groups (P = 0.87).
CONCLUSION: TNF-α -308 G/A polymorphism seems to be associated with POAG in Turkish population. However, population-based studies with large number of subjects and long-term follow-up are needed to verify the association of TNF-α -308 G/A polymorphism with glaucoma susceptibility. ||||| PURPOSE: To evaluate the variants of 10 genes for association with primary open-angle glaucoma (POAG) in a Chinese population.
METHODS: A total of 405 unrelated patients with POAG (255 high-tension glaucoma [HTG], 100 normal-tension glaucoma [NTG], and 50 juvenile-onset open-angle glaucoma [JOAG]) and 201 control subjects were recruited. Seventeen variants in 10 genes with reported association with POAG were genotyped for analysis of allele and haplotype frequencies between cases and control subjects. These genes included CDH1 (cadherin 1, type 1, E-cadherin), CDKN1A (cyclin-dependent kinase inhibitor 1A), CYP1B1 (cytochrome P450, family 1, subfamily B, polypeptide 1), GSTM1 (glutathione S-transferase mu 1), GSTT1 (glutathione S-transferase theta 1), MTHFR (5,10-methylenetetrahydrofolate reductase), NOS3 (nitric oxide synthase 3), OPA1 (optic atrophy 1), TNF (tumor necrosis factor), and TP53 (tumor protein p53).
RESULTS: One SNP (-308G>A; rs1800629) in TNF demonstrated a significant association with HTG (P = 0.012). The allele G frequency was higher in HTG patients than in control subjects (94.6% vs. 90.3%; OR = 1.89). One haplotype consisting of rs1799724 and rs1800629 was significantly associated with HTG (P = 0.015, corrected P = 0.045). One SNP (R72P; rs1042522) in TP53 was significantly associated with NTG (P = 0.018). The allele G frequency was higher in NTG patients than in control subjects (56.1% vs. 45.8%; OR = 1.52). The significance of these associations survived the Bonferroni correction (corrected P < 0.024). Other gene variants were not significantly associated with HTG (P > 0.063) or NTG (P > 0.13). None of the studied variants was significantly associated with JOAG (P > 0.17).
CONCLUSIONS: The findings suggest that variants in TNF and TP53 are risk factors for POAG, whereas variants in other studied genes are not major risk factors for POAG, at least in the Chinese population. ||||| PURPOSE: Primary open-angle glaucoma (POAG) is a multifactorial optic neuropathy with a strong hereditary component. Recent studies suggested a role for tumour necrosis factor-alpha(TNF-alpha) in the pathogenesis of POAG. The purpose of the present study was to investigate a hypothesized association between the TNF-alpha-308G>A and -238G>A gene polymorphisms and the presence of POAG in a Caucasian population.
METHODS: The present case-control study comprised 114 unrelated patients with POAG and 228 healthy control subjects, matched for age and gender. Genotyping of the TNF-alpha-308G>A and -238G>A polymorphisms was performed using polymerase chain reaction.
RESULTS: Allelic frequencies and genotype distributions of both the TNF-alpha-308G>A and -238G>A gene polymorphisms did not significantly differ between patients with POAG and control subjects. Presence of the TNF-alpha-308A-allele was associated with an odds ratio (OR) of 0.96 for POAG, whereas an OR of 0.52 was found among carriers of the TNF-alpha-238A-allele.
CONCLUSION: Our data suggest that none of the investigated TNF-alphagene polymorphisms is a major risk factor among Caucasian patients with POAG. ||||| PURPOSE: Genetic factors are known to play a role in the aetiology of glaucoma, and in particular the role of the immune system is highly suspected. In this study, we evaluated the association between tumour necrosis factor alpha -308 (TNF alpha -308) and primary open-angle glaucoma (POAG).
METHODS: A total of sixty POAG patients and 103 healthy volunteers as control group were enrolled in this case-controlled study. Furthermore, we used polymerase chain reaction based analysis to resolve the TNF alpha -308 polymorphism. Statistical analysis for the relative risk of TNF alpha -308 polymorphism was compared by the chi(2) test.
RESULTS: There were significant differences in the distribution of the polymorphism between the POAG patients and the control subjects (P = 0.00016; P < 0.05) and it was found that the A(-308) allele occurred more frequently in POAG patients (odds ratio: 2.72; 95% confidence interval: 1.66-4.45).
CONCLUSION: The results of our study concluded that the distribution of TNF alpha -308 was significantly higher in the POAG patients than in the control group. Therefore, the A(-308) allele appears to be associated with POAG and, therefore, could be used as a genetic marker for disease mapping. POAG is a complex disease, and a single gene could not be responsible. Understanding the role of genetic polymorphisms, like TNF alpha, could be a prediction of the disease and useful for developing new treatments for POAG. ||||| PURPOSE: TNF-alpha has been suggested to participate in the pathogenesis of exfoliation glaucoma (XFG). The purpose of the present study was to investigate a hypothesized association between two common functional polymorphisms in the promoter region of the TNF-alpha gene (TNF-alpha -308 G>A, rs1800629, and TNF-alpha -238 G>A, rs361525) and the presence of XFG in a Caucasian population.
METHODS: The present case-control study comprised 408 participants (204 patients with XFG and 204 control subjects). Control subjects were matched for age and sex. Genotypes of the TNF-alpha -308 G>A and TNF-alpha -238 G>A polymorphisms were determined by polymerase chain reaction (restriction fragment length polymorphism).
RESULTS: No significant differences regarding genotype distribution or allelic frequencies were found between patients and control subjects (p>0.025). The presence of the TNF-alpha -308 G-allele was associated with an insignificant odds ratio of 0.98 (95% confidence interval [CI]: 0.66-1.46; p=0.99) while the presence of the TNF-alpha -238 G-allele was associated with an insignificant odds ratio of 0.64 (95% CI: 0.33-1.23; p=0.25).
CONCLUSIONS: Our data suggest that both the TNF-alpha -308 G>A and the TNF-alpha -238 G>A polymorphisms are unlikely to be major risk factors for XFG in an European population of Caucasian descent. | [
{
"source_pmid": "22509108",
"source_text": "PURPOSE: Tumor necrosis factor-α (TNF-α), an important proinflammatory cytokine, exerts a variety of physiologic and pathogenic effects that lead to tissue destruction. Recent laboratory evidence indicates that TNF-α have either protective or adverse effects on p... |
17712074 | CONCLUSIONS: Tight glycemic and blood pressure control remains the cornerstone in the primary prevention of DR. Pan-retinal and focal retinal laser photocoagulation reduces the risk of visual loss in patients with severe DR and macular edema, respectively. There is currently insufficient evidence to recommend routine use of other treatments. | PURPOSE: To evaluate the effectiveness of pars plana vitrectomy (PPV) with removal of the internal limiting membrane (ILM) in diabetic patients with macular edema unresponsive to grid laser photocoagulation.
METHODS: In this randomized controlled study, 20 eyes of 10 patients with diabetic macular edema unresponsive to grid laser photocoagulation were evaluated. PPV with ILM removal was performed randomly in one eye each of 10 patients and taken as the study group; the untreated fellow eyes were taken as the control group. Main outcome measures were foveal thickness changes measured with optical coherence tomography and preoperative and post-operative visual acuity. Mann-Whitney U, Wilcoxon, and chi-square tests were used in statistical analysis.
RESULTS: The mean age of the patients was 61.5+/-6 years (range 51 to 71). All patients were followed up for 12 months. In the study group, mean foveal thickness was 391.3+/-91.6 microm preoperatively and 225.5+/-49.4 microm postoperatively (p=0.009). In the control group, mean foveal thickness was 356.2+/-140 microm at baseline and 318.4+/-111.1 microm at 12-month follow-up (p=0.138). Mean decrease in foveal thickness was 165.8+/-114.8 microm in the study group and 37.8+/-71.2 microm in the control group (p=0.016). In the study group, best-corrected log-MAR visual acuity was 0.71+/-0.43 preoperatively and 0.54+/-0.45 postoperatively (p=0.125). In the control group, best-corrected logMAR visual acuity was 0.43+/-0.44 at baseline and 0.59+/-0.55 at 12-month follow-up (p=0.235). In the study group, visual acuity improved by two or more lines in 4 eyes (40%) and remained stable in 6 eyes (60%). In the control group, visual acuity improved by two or more lines in 1 eye (10%) and decreased by two or more lines in 3 eyes (30%).
CONCLUSIONS: PPV with ILM removal appears to be an effective procedure for reducing diabetic macular edema unresponsive to grid laser photocoagulation. A further study with a large number of patients is required to assess the effectiveness and safety of this procedure. ||||| BACKGROUND: Retinopathy commonly occurs in people with type 1 diabetes. Strict glycaemic control can decrease development and progression of retinopathy only partially. Blood pressure is also a risk factor for microvascular complications. Antihypertensive therapy, especially with inhibitors of angiotensin-converting enzyme (ACE), can slow progression of nephropathy, but the effects on retinopathy have not been established. We investigated the effect of lisinopril on retinopathy in type 1 diabetes.
METHODS: As part of a 2-year randomised double-blind placebo-controlled trial, we took retinal photographs at baseline and follow-up (24 months) in patients aged 20-59 in 15 European centres. Patients were not hypertensive, and were normoalbuminuric (85%) or microalbuminuric. Retinopathy was classified from photographs on a five-level scale (none to proliferative).
FINDINGS: The proportion of patients with retinopathy at baseline was 65% (117) in the placebo group and 59% (103) in the lisinopril group (p = 0.2). Patients on lisinopril had significantly lower HbA1c at baseline than those on placebo (6.9% vs 7.3 p = 0.05). Retinopathy progressed by at least one level in 21 (13.2%) of 159 patients on lisinopril and 39 (23.4%) of 166 patients on placebo (odds ratio 0.50 [95% CI 0.28-0.89], p = 0.02). This 50% reduction was the same when adjusted for centre and glycaemic control (0.55 [0.30-1.03], p = 0.06). Lisinopril also decreased progression by two or more grades (0.27 [0.07-1.00], p = 0.05), and progression to proliferative retinopathy (0.18 [0.04-0.82], p = 0.03). Progression was not associated with albuminuric status at baseline. Treatment reduced retinopathy incidence (0.69 [0.30-1.59], p = 0.4).
INTERPRETATION: Lisinopril may decrease retinopathy progression in non-hypertensive patients who have type 1 diabetes with little or no nephropathy. These findings need to be confirmed before changes to clinical practice can be advocated. ||||| The Early Treatment Diabetic Retinopathy Study (ETDRS) enrolled 3711 patients with mild-to-severe nonproliferative or early proliferative diabetic retinopathy in both eyes. One eye of each patient was assigned randomly to early photocoagulation and the other to deferral of photocoagulation. Follow-up examinations were scheduled at least every 4 months and photocoagulation was initiated in eyes assigned to deferral as soon as high-risk proliferative retinopathy was detected. Eyes selected for early photocoagulation received one of four different combinations of scatter (panretinal) and focal treatment. This early treatment, compared with deferral of photocoagulation, was associated with a small reduction in the incidence of severe visual loss (visual acuity less than 5/200 at two consecutive visits), but 5-year rates were low in both the early treatment and deferral groups (2.6% and 3.7%, respectively). Adverse effects of scatter photocoagulation on visual acuity and visual field also were observed. These adverse effects were most evident in the months immediately following treatment and were less in eyes assigned to less extensive scatter photocoagulation. Provided careful follow-up can be maintained, scatter photocoagulation is not recommended for eyes with mild or moderate nonproliferative diabetic retinopathy. When retinopathy is more severe, scatter photocoagulation should be considered and usually should not be delayed if the eye has reached the high-risk proliferative stage. The ETDRS results demonstrate that, for eyes with macular edema, focal photocoagulation is effective in reducing the risk of moderate visual loss but that scatter photocoagulation is not. Focal treatment also increases the chance of visual improvement, decreases the frequency of persistent macular edema, and causes only minor visual field losses. Focal treatment should be considered for eyes with macular edema that involves or threatens the center of the macula. ||||| One hundred sixty eyes of 92 patients with diffuse diabetic maculopathy with or without cystoid macular edema were enrolled in a prospective randomized clinical trial to determine the efficacy of "modified grid" argon (blue-green) laser photocoagulation. At the 12- and 24-month follow-ups, visual acuity significantly improved in treated eyes (P = 0.00007 and P = 0.00031, respectively) compared to the observation group. In addition, at the 12- and 24-month follow-ups, visual acuity significantly worsened in observation eyes (P = 0.00007 and P = 0.0007, respectively) compared to the treatment group. The following factors did not statistically alter the visual prognosis: a history of systemic hypertension (P = 0.2921); systemic vascular disease (P = 0.5324); cystoid macular edema (P = 0.1010); and initial poor visual acuity (P = 0.3032). ||||| OBJECTIVE: To examine whether intensive glycemic control could decrease the frequency or severity of diabetic microvascular complications, an 8-year prospective study of Japanese patients with type 2 diabetes was performed.
RESEARCH DESIGN AND METHODS: A total of 110 patients with type 2 diabetes (55 with no retinopathy [the primary prevention cohort] and 55 with simple retinopathy [the secondary intervention cohort]) were randomly assigned to multiple insulin injection therapy (MIT) groups and administered three or more daily insulin injections or assigned to conventional insulin injection therapy (CIT) groups and administered one or two daily intermediate-acting insulin injections. Worsening of microvascular complications was regularly assessed during 8 years. Two or more steps up in the 19 stages of the modified Early Treatment of Diabetic Retinopathy Study classification in retinopathy and one or more stages up among three stages in nephropathy (normoalbuminuria, microalbuminuria, and albuminuria) were defined as worsening of complications.
RESULTS: In both primary prevention and secondary intervention cohorts, the cumulative percentages of worsening in retinopathy and nephropathy were significantly lower (P < 0.05) in the MIT group than in the CIT group. In neurological tests after 8 years, the MIT group showed significant improvement (P < 0.05) in the median nerve conduction velocities (motor and sensory nerves), whereas the CIT group showed significant deterioration (P < 0.05) in the nerve conduction velocities and vibration threshold. From this study, the glycemic threshold to prevent the onset and progression of diabetic microvascular complications was as follows: HbA1c < 6.5%, fasting blood glucose concentration < 110 mg/dl, and 2-h postprandial blood glucose concentration < 180 mg/dl.
CONCLUSIONS: Intensive glycemic control can delay the onset and progression of the early stages of diabetic microvascular complications in Japanese patients with type 2 diabetes. ||||| OBJECTIVE: To report 2-year safety and efficacy outcomes from a trial of intravitreal triamcinolone acetonide (TA) injections (4 mg) in eyes with diabetic macular edema and impaired vision that persisted or recurred after laser treatment.
DESIGN: Prospective, double-masked, placebo-controlled, randomized clinical trial.
PARTICIPANTS AND CONTROLS: Sixty-nine eyes of 43 patients were entered into the study, with 34 eyes randomized to receive active treatment and 35 placebo. Two-year data were available for 60 of 69 (87%) eyes of 35 of 41 (85%) patients; 9 eyes of 6 patients were lost to follow-up, of which 6 received a placebo and 3 received intravitreal TA.
INTERVENTION: Triamcinolone acetonide (0.1 ml) was injected through the pars plana using a 27-gauge needle. Eyes randomized to placebo received a subconjunctival injection of saline.
MAIN OUTCOME MEASURES: Improvement of best-corrected logarithm of the minimum angle of resolution visual acuity (VA) by > or =5 letters after 2 years and incidence of moderate or severe adverse events.
RESULTS: Improvement of > or =5 letters' best-corrected VA was found in 19 of 34 (56%) eyes treated with intravitreal TA, compared with 9 of 35 (26%) eyes treated with the placebo (z(generalized estimating equation) = 2.73, P = 0.006). The mean improvement in VA was 5.7 letters (95% confidence interval, 1.4-9.9) more in the intravitreal TA-treated eyes than in those treated with the placebo. An increase of intraocular pressure (IOP) of > or =5 mmHg was observed in 23 of 34 (68%) treated versus 3 of 30 (10%) untreated eyes (P<0.0001). Glaucoma medication was required in 15 of 34 (44%) treated versus 1 of 30 (3%) untreated eyes (P = 0.0002). Cataract surgery was performed in 15 of 28 (54%) treated versus 0 of 21 (0%) untreated eyes (P<0.0001). Two eyes in the intravitreal TA-treated group required trabeculectomy. There was one case of infectious endophthalmitis in the treatment group.
CONCLUSION: Intravitreal TA improves vision and reduces macular thickness in eyes with refractory diabetic macular edema. This beneficial effect persists for up to 2 years with repeated treatment. Progression of cataract and elevation of IOP commonly occur but appear manageable. Spontaneous improvement over years can still occur in eyes that are apparently severely affected by diabetic macular edema. ||||| BACKGROUND: Although several important studies have been performed in hypertensive type 2 diabetic patients, it is not known whether lowering blood pressure in normotensive (BP <140/90 mm Hg) patients offers any beneficial results on vascular complications. The current study evaluated the effect of intensive versus moderate diastolic blood pressure (DBP) control on diabetic vascular complications in 480 normotensive type 2 diabetic patients.
METHODS: The current study was a prospective, randomized controlled trial in normotensive type 2 diabetic subjects. The subjects were randomized to intensive (10 mm Hg below the baseline DBP) versus moderate (80 to 89 mm Hg) DBP control. Patients in the moderate therapy group were given placebo, while the patients randomized to intensive therapy received either nisoldipine or enalapril in a blinded manner as the initial antihypertensive medication. The primary end point evaluated was the change in creatinine clearance with the secondary endpoints consisting of change in urinary albumin excretion, progression of retinopathy and neuropathy and the incidence of cardiovascular disease.
RESULTS: The mean follow-up was 5.3 years. Mean BP in the intensive group was 128 +/- 0.8/75 +/- 0.3 mm Hg versus 137 +/- 0.7/81 +/- 0.3 mm Hg in the moderate group, P < 0.0001. Although no difference was demonstrated in creatinine clearance (P = 0.43), a lower percentage of patients in the intensive group progressed from normoalbuminuria to microalbuminuria (P = 0.012) and microalbuminuria to overt albuminuria (P = 0.028). The intensive BP control group also demonstrated less progression of diabetic retinopathy (P = 0.019) and a lower incidence of strokes (P = 0.03). The results were the same whether enalapril or nisoldipine was used as the initial antihypertensive agent.
CONCLUSION: Over a five-year follow-up period, intensive (approximately 128/75 mm Hg) BP control in normotensive type 2 diabetic patients: (1) slowed the progression to incipient and overt diabetic nephropathy; (2) decreased the progression of diabetic retinopathy; and (3) diminished the incidence of stroke. ||||| AIM: (1) To evaluate whether vitrectomy is preferable to further macular laser in improving visual acuity and resolving retinal thickening in patients with diabetic macular oedema (DMO) despite previous laser and no macular traction. (2) To determine the feasibility of further trials in this population in terms of magnitude of comparative clinical effect, rate of recruitment, and loss to follow up.
METHODS: A randomised controlled feasibility study. Patients with DMO and a visual acuity of 0.3 logMAR (6/12) or worse after one or more macular laser treatments were randomised on a 1:1 basis to either pars plana vitrectomy (PPV) with internal limiting membrane (ILM) peeling or further macular laser. Patients with a posterior vitreous detachment, biomicroscopic evidence of retinal traction, or a taut thickened posterior hyaloid (TTPH) were excluded. Primary outcome measures were (1) best corrected logMAR visual acuity, (2) mean central macular thickness on optical coherence tomography, and (3) rate of recruitment and loss to follow up. Analysis was on an intention to treat basis.
RESULTS: 19 patients were randomised to PPV and 21 to further macular laser. The mean baseline logMAR visual acuity was 0.65 (SD 0.28) for the group randomised to PPV and 0.60 (0.23) for the group randomised to laser. The mean change in best corrected visual acuity of the vitrectomy group was deterioration by 0.05 logMAR, while in the control group the mean change was an improvement of 0.03 logMAR. The median (interquartile range) baseline central macular thickness was 403 (337, 492) for the group randomised to PPV and 387 (298, 491) for the controls randomised to laser. The median change in central macular thickness from baseline to review in the vitrectomy group was a thinning by 73 mum (20%) and by 29 mum (10.7%) in the control laser group. This single centre was able to recruit 40 patients in 18 months with follow up of 82% at 1 year.
CONCLUSION: A randomised controlled trial was found to be potentially feasible in this population, the rate of recruitment was however slow and one in five patients were lost to follow up because of death and ill health. These data provide little evidence in terms of visual acuity and macular thickness of any benefit of vitrectomy over further macular laser in patients with an attached hyaloid, DMO despite previous laser, and no clinically evident macular traction or TTPH. ||||| AIM: to establish the degree to which the severity of retinopathy determines the risk for the need for subsequent photocoagulation in those with newly diagnosed Type 2 diabetes mellitus.
METHODS: Of 5102 patients entered into the UK Prospective Diabetes Study (UKPDS), 3709 had good quality retinal photographs that could be graded at entry. They were followed until the end of the study or until lost to follow-up, or until they received photocoagulation. Retinopathy severity was categorized as no retinopathy, microaneurysms (MA) only in one eye, MA in both eyes or more severe retinopathy features. The risk of photocoagulation was assessed in relation to severity of retinopathy at baseline, 3 and 6 years.
RESULTS: Of the 3709 patients assessed at entry to the UKPDS, 2316 had no retinopathy. Of these 0.2% needed photocoagulation at 3 years, 1.1% at 6 years and 2.6% at 9 years. Those with MA in one eye only (n = 708) were similar, with 0%, 1.9% and 4.7% needing photocoagulation by 3, 6 and 9 years, respectively. Amongst those who had more retinopathy features at entry (n = 509), 15.3% required photocoagulation by 3 years, and 31.9% by 9 years. When those without retinopathy at 6 years (n = 1579) were examined 3 and 6 years later (9 and 12 years after diagnosis), 0.1% and 1.8% required photocoagulation. Those with more severe retinopathy (n = 775) needed earlier treatment, 6.6% after 3 years and 13.3% after 9 years. The commonest indication for laser therapy was maculopathy, but those with more severe retinopathy were more likely to be treated for proliferative retinopathy and to need both eyes treated.
CONCLUSION: Few type 2 diabetic patients without retinopathy progress to photocoagulation in the following 3-6 years, while patients with more severe retinopathy lesions need to be monitored closely. ||||| PURPOSE: To answer the following questions regarding the effect of intensive diabetes management on retinopathy in insulin-dependent diabetes mellitus (IDDM): (1) Does intensive therapy completely prevent the development of retinopathy? (2) Are some states of retinopathy too advanced to benefit from intensive therapy? (3) Are the retinopathy endpoints in the Diabetes Control and Complications Trial (DCCT) clinically important? and (4) What other factors influence the effectiveness of therapy?
METHODS: A total of 1441 patients, ranging in age from 13 and 39 years and with IDDM of 1 to 5 years' duration and no retinopathy at baseline (primary prevention cohort) or with 1 to 15 years' duration and minimal to moderate nonproliferative retinopathy (secondary intervention cohort), were assigned randomly to either intensive or conventional diabetes therapy. Intensive therapy, aimed at achieving glycemic levels as close to the normal range as possible, included three or more daily insulin injections or a continuous subcutaneous insulin infusion, guided by four or more glucose tests daily. Conventional therapy included one or two daily injections. Seven-field stereo-scopic fundus photography was performed every 6 months, for a mean follow-up of 6.5 years (range, 4-9 years).
RESULTS: Intensive therapy reduced the risk of any retinopathy (> or = 1 microaneurysm) developing in the primary prevention cohort (70% of intensive versus 90% of conventional treatment group; P = 0.002) by 27%. It reduced the risk of retinopathy developing or progressing to clinically significant degrees by 34% to 76%. Intensive therapy was most effective when initiated early in the course of IDDM. It had a substantial beneficial effect over the entire spectrum of retinopathy studied in the DCCT and, with rare exceptions, in all patient subgroups.
CONCLUSION: Although intensive therapy does not prevent retinopathy completely, it has a beneficial effect that begins after 3 years of therapy on all levels of retinopathy studied in the DCCT. The reduction in risk observed in the study is translatable directly into reduced need for laser treatment and saved sight. Intensive therapy should form the backbone of any healthcare strategy aimed at reducing the risk of visual loss from diabetic retinopathy. ||||| Ninety-six patients with insulin-dependent diabetes mellitus (IDDM) and non-proliferative retinopathy were randomized to intensified conventional treatment (ICT) (n = 44) or regular treatment (RT) (n = 52), and followed up for 5 years. HbA1c decreased from 9.5 +/- 0.2% (mean value +/- SEM) to 7.2 +/- 0.1% in the ICT group, and from 9.4 +/- 0.2% to 8.7 +/- 0.1% in the RT group (difference between the groups, P less than 0.001). Retinopathy increased in both groups (P less than 0.001), but after 5 years it was worse in the RT group (P less than 0.05). The urinary albumin excretion rate was higher in the RT group than in the ICT group after 5 years (239.9 +/- 129.7 micrograms min-1 vs. 46.0 +/- 26.1 micrograms min-1, P less than 0.05). Eight RT patients developed manifest nephropathy, compared with none in the ICT group (P less than 0.01). After 5 years the conduction velocities of the sural (P less than 0.05), peroneal (P less than 0.01) and tibial (P less than 0.001) nerves were lower in the RT group. The respiratory sinus arrhythmia was 12.1 +/- 1.2 beats min-1 in the RT group and 16.7 +/- 1.4 beats min-1 in the ICT group at the end of the study (P less than 0.01). The increases in retinopathy (P less than 0.01), nephropathy (P less than 0.01) and neuropathy (P less than 0.001) were all related to the mean HbA1c value during the study. Smoking habits only influenced the progression of retinopathy (P less than 0.05). Serious hypoglycaemia occurred in 34 ICT patients and 29 RT patients (242 and 98 episodes, respectively) (P less than 0.05). Whereas weight was stable in the RT group, the body mass index increased by 5.8% in the ICT group (P less than 0.01). In conclusion, microvascular complications of diabetes were retarded by intensified conventional insulin treatment. However, such treatment increased the frequency of serious hypoglycaemia, and led to an increase in body weight. ||||| PURPOSE: To compare the effects of astemizole, an antihistamine, versus placebo on the 1-year course of diabetic macular edema (DME) and to illustrate use of a modified ETDRS system for grading areas of retinal thickening and hard exudates that may be useful in clinical trials of treatments for this disorder.
METHODS: Between June 1994 and September 1997, at 2 clinics, 63 patients who had, in at least one eye (the study eye), DME that had not previously been treated with macular photocoagulation, and for which photocoagulation was not currently recommended by the investigator, were enrolled and randomly assigned to astemizole or placebo. Fifty-four of the 63 patients (86%, 26 in Clinic 1 and 28 in Clinic 2) completed 1 year of followup and had adequate 7-field stereoscopic film-based color fundus photographs of the study eye at the baseline and 1-year visits. DME was > 0.33 disc diameters (DD) from the center of the macula in 48% of study eyes and involved the center in 13%. Photographs were graded using the ETDRS protocol modified to allow estimates of areas of retinal thickening (RT) and hard exudate (HE) to be made on continuous scales in disc area (DA) units. Principal outcome measures were mean change in the square root of RT area (the average diameter of the area in DD), mean change in area of HE, and change in the degree to which RT involved or threatened the center of the macula.
RESULTS: At baseline, RT area in the 54 study eyes ranged from 0.09 to 4.0 DA (median 1.1). At the 1-year visit the square root of RT area (RTdd) had decreased by > or= 0.3 DD in 10 eyes, increased by >or = 0.3 DD in 19 and was about the same in 25. Mean change at 1 year was +0.09 DD (SD 0.57) for astemizole versus +0.19 DD (SD 0.48) for placebo, for a difference of -0.10 DD (95% CI -0.38, +0.19; p = 0.51). Adjustments for baseline and time-dependent risk factors did not change this result appreciably, although there was a trend towards a difference in favor of astemizole in the subgroup of patients with more severe retinopathy. Other morphologic outcomes paralleled change in RTdd. Change in RTdd did vary by clinic: -0.03 DD in Clinic 2, versus + 0.32 DD in Clinic 1, for a difference of -0.35 DD (95% CI -0.62, -0.07; p = 0.014). Clinic 1 is a tertiary retinal referral center in Pennsylvania and Clinic 2 a retinal clinic closely affiliated with a large diabetes clinic in Copenhagen. The unexpected clinic difference in outcome provided an opportunity for further analyses using the modified ETDRS system. In comparison to Clinic 1, Clinic 2 patients were more often male, were younger at diagnosis of diabetes, and had less severe retinopathy and better visual acuity, but these differences did not appear to explain the trend for lesser increase in RTdd.
CONCLUSION: No effect of astemizole was found, but the confidence interval for the principal outcome, mean change in RTdd, included both a modest beneficial effect and a small harmful effect. This outcome measure did demonstrate a small difference in outcome by clinic, which could not be explained by baseline characteristics but may reflect differences in access to and/or continuity of care or other unmeasured differences associated with different referral patterns. Although optical coherence tomography may supplant photography as a measure of central RT, photographic assessments of change in RT and HE areas analyzed with the methods described herein may be useful outcomes in trials assessing treatment of early stages of DME. Application of these methods to other data sets is needed to confirm this conclusion. ||||| We conducted a prospective multicenter randomized trial to determine both the feasibility of maintaining blood glucose control at differing levels and the effect of improved control on diabetic microangiopathy and albuminuria. Seventy patients with diabetes (low C-peptide level) with nonproliferative retinopathy were randomly assigned to continuous subcutaneous insulin infusion or unchanged conventional injection treatment. At entry, both groups had similar demographic, clinical, and glycemic characteristics. Over the succeeding eight months, mean 24-hour glucose concentrations (175 +/- 9 mg per deciliter) and glycosylated hemoglobin levels (10.0 +/- 0.3 per cent) remained elevated during conventional treatment but fell to nearly normal levels (117 +/- 6 mg per deciliter and 8.1 +/- 0.2 per cent, respectively) with continuous insulin infusion. The frequency of biochemical hypoglycemia (less than 40 mg of blood glucose per deciliter) was similar in both groups, but ketoacidosis occurred only during continuous infusion. The level of retinopathy, assessed from photographs, progressed in both groups. Continuous infusion was associated with slightly more deterioration, mainly because of the appearance of soft exudates and intraretinal microvascular abnormalities. In contrast, elevated albumin-excretion rates fell during continuous infusion but not during conventional treatment. We conclude that maintenance of differing levels of blood glucose is feasible in a multicenter trial and that a nearly normal blood glucose level for eight months does not retard progression of, and may initially worsen, established retinopathy. These preliminary observations indicate the need for longer trials (particularly of primary prevention). | [
{
"source_pmid": "16952097",
"source_text": "PURPOSE: To evaluate the effectiveness of pars plana vitrectomy (PPV) with removal of the internal limiting membrane (ILM) in diabetic patients with macular edema unresponsive to grid laser photocoagulation.\nMETHODS: In this randomized controlled study, 20 eyes ... |
28064423 | CONCLUSION: Management of glaucoma associated with SWS is multi-dimensional and needs both medical and surgical interventions for better control. The treatment should be devised on case to case basis depending upon the intraocular pressure, stage of the disease, and type of glaucoma. | PURPOSE: To report the effect of oral propranolol on intraocular pressure (IOP) in infants newly diagnosed with unilateral Sturge-Weber syndrome (SWS) glaucoma receiving no other treatment.
METHODS: This was a prospective, nonrandomized interventional case series. Four infants presenting with unilateral SWS glaucoma with no prior treatment were treated with oral propranolol at a dose of 2 mg/kg and followed thereafter.
RESULTS: Propranolol had a temporary IOP-lowering effect in 3 of 4 children after 1 week of treatment. This effect diminished thereafter and 3 of 4 children required additional medical or surgical treatment.
CONCLUSIONS: Oral propranolol has a temporary effect on IOP in SWS glaucoma and is not effective as a single treatment in this syndrome, yet can serve to delay surgical treatment for a short period of time. In one case, the glaucoma was well-controlled on this medication. ||||| OBJECTIVE: To review the clinical manifestations and neuroimaging features of patients with Sturge-Weber syndrome (SWS) treated at Srinagarind Hospital over a 12-year period.
MATERIAL AND METHOD: A retrospective study of sixteen patients with SWS (9 males and 7 females) was conducted. The medical records, photographs, and neuroimaging studies were reviewed
RESULTS: All patients had port-wine stain (PWS) involving the eyelid. Bilateral cutaneous lesions were revealed in four patients (25%). Glaucoma was the main ocular disease being diagnosed in 11 eyes of nine patients (56.25%); four eyes were finally blind. The cyclodestructive procedure and/or surgical treatment was required in four eyes. Other ocular abnormalities were refractive error dilated episcleral vessels, corneal abnormalities, tortuous retinal vessels, choroidal hemangioma, amblyopia, and strabismus. Twelve patients (75%) had neurological impairment including seizure, hemiparesis, headache, and delayed development. However the most common neurological manifestation was epilepsy (75%), which could be controlled with antiepileptic drugs. Neurological imaging was performed in the majority of cases (14 patients). Intracranial abnormalities were demonstrated in 11 patients (78.57%). These included cerebral atrophy (81.82%), cerebral calcification (54.55%), leptomeningeal angioma (27.27%), and enlarged choroidal plexus (27.27%). The ocular complication and intracranial abnormalities were usually ipsilateral to the PWS. One patient with unilateral PWS, however had bilateral intracranial lesion.
CONCLUSION: Port-wine stains, glaucoma, and seizure were the most common clinical features of Sturge-Weber syndrome detected in the present study. Complete ophthalmic and neurological evaluation should be performed at the time ofdiagnosis. Multidisciplinary team management as well as lifelong follow-up is needed. ||||| Topiramate is used in the management of epilepsy and migraine. In the present paper we present a case of bilateral acute angle closure glaucoma associated with myopia following the use of topiramate. The patient was admitted to our ward. Complete ophthalmological examination was carried out along with ultrabiomicroscopy of the anterior segment and confocal microscopic study of the corneal endothelium. Patients on treatment with topiramate should be monitored during the first two weeks of therapy and the drug should be discontinued in case of visual disturbances or other ocular symptoms. ||||| PURPOSE: To evaluate the role of episcleral venous pressure (EVP) in the pathogenesis of glaucoma associated with Sturge-Weber syndrome (SWS).
METHODS: EVPs were determined prospectively using an episcleral venomanometer in 22 eyes of 11 patients aged 8-18 years with SWS with or without glaucoma. Pressure measurements in the glaucomatous eyes of patients with SWS were compared to those of patients with facial port wine marks but no glaucoma and to the contralateral uninvolved eye in both groups.
RESULTS: EVP in eyes with glaucoma (mean, 20.9 mm Hg) was significantly higher (P < 0.01) than EVP in contralateral uninvolved eyes (mean, 9.6 mm Hg). In patients with unilateral port wine mark and no glaucoma, EVP was normal for ipsilateral and contralateral eyes (mean, 8.6 mm Hg and 9.6 mm Hg, respectively).
CONCLUSIONS: Our data support the hypothesis that elevated EVP plays an important role in eyes with SWS glaucoma. ||||| Trabeculectomy for treatment of glaucoma associated with Sturge-Weber syndrome has a poor success rate. We report the presence of anomalous vessels over the trabeculectomy bleb in a patient with Sturge-Weber syndrome after trabeculectomy combined with mitomycin. ||||| Glaucoma, a progressive degenerative condition that results in the death of retinal ganglion cells, is one of the leading causes of blindness, affecting millions worldwide. The mechanisms underlying glaucoma are not well understood, although years of studies have shown that the largest risk factors are elevated intraocular pressure, age, and genetics. Eleven genes and multiple loci have been identified as contributing factors. These genes act by a number of mechanisms, including mechanical stress, ischemic/oxidative stress, and neurodegeneration. We summarize the recent advances in the understanding of glaucoma and propose a unified hypothesis for glaucoma pathogenesis. Glaucoma does not result from a single pathological mechanism, but rather a combination of pathways that are influenced by genes, age, and environment. In particular, we hypothesize that, in the presence of genetic risk factors, exposure to environment stresses results in an earlier age of onset for glaucoma. This hypothesis is based upon the overlap of the molecular pathways in which glaucoma genes are involved. Because of the interactions between these processes, it is likely that there are common therapies that may be effective for different subtypes of glaucoma. ||||| PURPOSE: To evaluate the safety and efficacy of primary single-plate Molteno tube implantation in the management of childhood glaucoma associated with Sturge-Weber syndrome.
PATIENTS AND METHODS: Nine eyes of seven patients were included in this prospective case series. Success was defined as intraocular pressure (IOP) < or =22 mmHg with (relative success) or without (absolute success) glaucoma medications. Intra- and postoperative complications were also evaluated.
RESULTS: Mean age at the time of the surgery was 9.6 +/- 3.7 years (range: 5-17 years) and mean follow-up duration was 32 +/- 4.7 months (range: 20-36 months). Mean IOP was reduced from 34.2 +/- 8.3 mmHg preoperatively to 21.2 +/- 7.3 mmHg at the final follow-up (P = 0.012). The number of anti-glaucoma medications was reduced from 3.4 +/- 0.5 preoperatively to 2.2 +/- 1.3 at the final follow-up (P = 0.058). The cumulative probability of relative success was 97.2% [95% confidence interval (CI): 91.85-100%] at 12 months, 78.02% (95% CI: 60.36-95.67%) at 24 months and 43.34% (95% CI: 16.18-70.5%) at the final follow-up. During the first 6 months after surgery, two patients had controlled IOP without the use of medications (absolute success); however, 6 months and later no eye had achieved absolute success. There were no intraoperative complications. Postoperative complications included choroidal effusion necessitating drainage in three eyes (33.3%), cataract formation in one eye (11%) and retinal detachment in one eye (11%). At the final follow-up, visual acuity was unchanged from preoperative values in five eyes (55.5%); no eye demonstrated visual improvement.
CONCLUSION: Outcomes of this small case study reveal that primary single-plate Molteno tube implantation appears to be associated with a limited success rate and a relatively high complication rate in eyes of children with glaucoma resulting from Sturge-Weber syndrome. ||||| OBJECTIVE: To evaluate the safety and efficacy of primary combined trabeculotomy-trabeculectomy in the management of early-onset glaucoma associated with Sturge-Weber syndrome (SWS).
DESIGN: Retrospective noncomparative case series.
PARTICIPANTS: Ten eyes of nine patients were included in this study. All patients with SWS who underwent primary combined trabeculotomy-trabeculectomy from January 1993 through December 1996 were included. One patient had bilateral surgery.
INTERVENTION: Primary combined trabeculotomy-trabeculectomy.
MAIN OUTCOME MEASURES: Pre- and postoperative intraocular pressures (IOPs), corneal clarity and diameters, visual acuities, success rate, bleb characteristics, time of surgical failure (if any), and complications.
RESULTS: The mean preoperative IOP was 28.2 mmHg +/- 7.35 mmHg with medication (mean, 1.2 +/- 0.6; range, 0-2). The mean postoperative IOP was 11.8 mmHg +/- 1.8 mmHg, with a mean percent reduction of 55.8 +/- 12.6 in IOP (P < 0.0001). All eyes maintained a postoperative IOP < 16 mmHg without medication over a mean follow-up of 27.6 +/- 16.4 months (range, 12-64 months). Normal corneal clarity was achieved in all eight eyes that had corneal edema. There were no significant intraoperative complications. Postoperatively, one patient developed a shallow anterior chamber with choroidal detachment, which was successfully managed conservatively.
CONCLUSION: Primary combined trabeculotomy-trabeculectomy is safe, effective, and sufficiently predictable to be considered the first choice of surgical treatment in early-onset glaucoma associated with SWS. ||||| The phakomatoses have been traditionally defined as a group of hereditary diseases with variable expressivity characterized by multisystem tumors with possible malignant transformation. The Sturge-Weber syndrome, Klippel-Trenaunay syndrome, and the phakomatosis pigmentovascularis have the facial port-wine stain in common. Numerous pathophysiogenetic mechanisms have been suggested such as venous dysplasia of the emissary veins in the intracranial circulation, neural crest alterations leading to alterations of autonomic perivascular nerves, mutation of the GNAO gene in the Sturge-Weber syndrome, PIK3CA mutation in malformative/overgrowth syndromes such as the Klippel-Trenaunay syndrome, and the twin-spotting phenomenon in phakomatosis pigmentovascularis. Other features linked to the port-wine stain and typical to all of the three conditions are glaucoma and choroidal alterations. Glaucoma can be due to malformations of the anterior chamber or high episcleral venous pressure and in phakomatosis pigmentovascularis it can also be associated with angle hyperpigmentation. The choroid can be thickened in all diseases. Furthermore, choroidal melanocytosis in the phakomatosis pigmentovascularis can lead to malignant transformation. Although the multiple pathophysiological mechanisms still require clarification, similarities in ophthalmic manifestations make it reasonable to classify these diseases in an independent group. ||||| Noteworthy heterogeneity exists in the rare diseases associated with childhood glaucoma. Primary congenital glaucoma is mostly sporadic; however, 10% to 40% of cases are familial. CYP1B1 gene mutations seem to account for 87% of familial cases and 27% of sporadic cases. Childhood glaucoma is classified in primary and secondary congenital glaucoma, further divided as glaucoma arising in dysgenesis associated with neural crest anomalies, phakomatoses, metabolic disorders, mitotic diseases, congenital disorders, and acquired conditions. Neural crest alterations lead to the wide spectrum of iridocorneal trabeculodysgenesis. Systemic diseases associated with childhood glaucoma include the heterogenous group of phakomatoses where glaucoma is frequently encountered in the Sturge-Weber syndrome and its variants, in phakomatosis pigmentovascularis associated with oculodermal melanocytosis, and more rarely in neurofibromatosis type 1. Childhood glaucoma is also described in systemic disorders of mitotic and metabolic activity. Acquired secondary glaucoma has been associated with uveitis, trauma, drugs, and neoplastic diseases. A database research revealed reports of childhood glaucoma in rare diseases, which do not include glaucoma in their manifestation. These are otopalatodigital syndrome, complete androgen insensitivity, pseudotrisomy 13, Brachmann-de Lange syndrome, acrofrontofacionasal dysostosis, caudal regression syndrome, and Wolf-Hirschhorn syndrome. ||||| Glaucoma is a progressive optic neuropathy. Hence, most glaucomatous eyes demonstrate signs of deterioration over time despite what may appear to be adequate treatment. The main goal of glaucoma treatment is to slow the rate of disease so that patients can prolong their functional vision. Therefore, it is important for clinicians caring for patients with glaucoma to be able to estimate rates of change with structural and functional outcomes in their patients. Various trend analysis models have been previously used to estimate rates of decay in glaucoma. The authors discuss the relevant issues and the inherent caveats related to estimating structural and functional rates of change in glaucoma. Patterns of deterioration, testing frequency, and combing structural and functional rates of change are also addressed. ||||| Facial port-wine stain (PWS) may be associated with cerebrovascular abnormalities such as Sturge-Weber syndrome (SWS). In a large series, we aimed to assess which topography of facial PWS can predict SWS. This was a cross-sectional study of consecutive patients with facial PWS seen in pediatric dermatologic or angiodysplasia consultations from 1993 to 2005 at the University Hospital Center of Tours. A standardized form was used to collect data on clinical and imaging findings. Patients with and without SWS were compared in terms of topography of the cutaneous angioma and related ophthalmologic and neurologic features. Two hundred fifty-nine patients were included, 15 with a diagnosis of SWS. All patients with SWS showed involvement of the V1 trigeminal cutaneous area. SWS was significantly associated with bilateral topography of the PWS, its extension to another territory, and involvement of the upper eyelid. Knowledge of the topography of facial PWS with risk of associated neurological or ocular anomalies allows for early diagnosis of SWS and avoids unnecessary and costly radiography for patients with uncomplicated facial PWS. ||||| The purpose of this article is to analyze and understand the mechanism of action, effectiveness, cost and time benefits, advantages and disadvantages of the femtosecond laser (FSL) assisted cataract surgery. A PubMed search was done using the topic and the keywords. Research shows considerable improvements in corneal incisions, anterior capsulotomy, and phacofragmentation using FSL. We will also discuss and compare FSL with conventional cataract extraction techniques in terms of both short-term and long-term advantages and disadvantages. Limitations of the studies reviewed include small sample size and short-term follow-up. The major dilemma is still considered to be its heavy financial feasibility to date. ||||| INTRODUCTION: Prostaglandins are increasingly used as first choice treatment for glaucoma because they are highly effective, lack relevant systemic side effects and require just once-daily administration. Latanoprost is an ester prodrug analog of prostaglandin F2α, which reduces intraocular pressure (IOP) by increasing uveoscleral outflow. Latanoprost 0.005% has received European and US approval as the first-line drug for reducing IOP in patients with open-angle glaucoma or ocular hypertension. Following the recent patent expiry for Xalatan®, a number of latanoprost generics have entered the glaucoma market.
AREAS COVERED: This review, achieved through PubMed and Medline research methods, describes the composition, pharmacokinetics, mode of action, efficacy, side effects and safety profile of latanoprost.
EXPERT OPINION: Latanoprost was the first prostaglandin analog introduced in glaucoma management and it dramatically changed the market of the disease thanks to its efficacy and safety. Conjunctival hyperemia, which is commonly found after latanoprost use, is associated with a minor efficacy and duration of trabeculectomy; yet, from the ophthalmologist's perspective, this side effect seems largely counterbalanced by the high efficacy and safety of this compound. It is always advisable to consider the pro-inflammatory mode of action of latanoprost because this may have negative effects in particular patients (i.e., those with uveitis and cystoid macular edema) for whom caution and close follow-up is necessary. ||||| PURPOSE: To evaluate peripapillary retinal nerve fiber layer, macular retinal nerve fiber layer, and ganglion cell layer-inner plexiform layer thickness and analyze their correlations in adult patients with neurofibromatosis Type 1 (NF1) and disease-free controls.
METHODS: This cross-sectional study was performed at the Azienda Policlinico Umberto I, University of Rome "La Sapienza." All participants underwent complete ophthalmologic examination. Spectral domain optical coherence tomography was used to evaluate peripapillary retinal nerve fiber layer and obtain retinal segmentation measurements to assess macular retinal nerve fiber layer and ganglion cell layer-inner plexiform layer at 1,000 μm nasal, temporal, superior, and inferior to the fovea.
RESULTS: Thirty-four eyes of 17 patients with NF1 (mean age, 42.2 ± 14.3 years) and 34 eyes of 17 disease-free control subjects (mean age, 41.4 ± 12.2 years) were included. All participants had best-corrected visual acuity of 20/20. The mean thickness of peripapillary retinal nerve fiber layer, macular retinal nerve fiber layer, and ganglion cell layer-inner plexiform layer was lower in patients with NF1 with respect to controls (P = 0.003, P = 0.022, P < 0.001, respectively). Regression analysis showed a significant correlation (P < 0.001) between mean ganglion cell layer-inner plexiform layer thickness and mean peripapillary retinal nerve fiber layer thickness in patients with NF1.
CONCLUSION: Retinal nerve fiber layer and ganglion cell loss correlate well with each other in adult patients with NF1 in comparison with a healthy control population. ||||| PURPOSE: To provide an in-depth re-examination of assumed causes of tissue hypertrophy, port-wine stains, and the Sturge-Weber, Cobb, Klippel-Trénaunay, and related syndromes to support an alternative unifying pathophysiologic mechanism of venous dysplasia producing focal venous hypertension with attendant tissue responses; to provide proof of concept with new patient data; to propose a novel etiological hypothesis for the venous dysplasia in these syndromes and find supportive evidence.
METHODS: Data from 20 patients with port-wine stains and corneal pachymetry readings was collected prospectively by the author in an institutional referral-based practice. The literature was searched using MEDLINE, and articles and textbooks were obtained from the bibliographies of these publications.
RESULTS: Newly obtained dermatologic, corneal pachymetry, fundus ophthalmoscopic, ocular and orbital venous Doppler ultrasonography, and magnetic resonance imaging findings in patients with the Sturge-Weber syndrome or isolated port-wine stains, along with published data, reveal diffusely thickened tissues and neural atrophy in all areas associated with venous congestion.
CONCLUSIONS: Contrary to traditional understanding, signs and symptoms in the Sturge-Weber and related syndromes, including both congenital and acquired port-wine stains, are shown to arise from effects of localized primary venous dysplasia or acquired venous obstruction rather than neural dysfunction, differentiating these syndromes from actual phacomatoses. Effects of focal venous hypertension are transmitted to nearby areas via compensatory collateral venous channels in the above conditions, as in the Parkes Weber syndrome. A novel underlying etiology-prenatal venous thrombo-occlusion-is proposed to be responsible for the absence of veins with persistence and enlargement of collateral circulatory pathways with data in the literature backing this offshoot hypothesis. The mechanism for isolated pathologic tissue hypertrophy in these syndromes clarifies physiologic mechanisms for exercise-induced muscle hypertrophy to occur via venous compression and increased capillary transudation. ||||| Vascular malformations may arise in any of the vascular beds present in the human body. These lesions vary in location, type, and clinical severity of the phenotype. In recent years, the genetic basis of several vascular malformations has been elucidated. This review will consider how the identification of the genetic factors contributing to different vascular malformations, with subsequent functional studies in animal models, has provided a better understanding of these factors that maintain vascular integrity in vascular beds, as well as their role in the pathogenesis of vascular malformations. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. ||||| Visual functions in Sturge-Weber syndrome (SWS) may be impaired by glaucoma, diffuse choroidal haemangioma (DCH) or leptomeningeal angioma. The aim of this study was to gain better insight in the visual deficits of SWS patients. A systematic literature search using PubMed and Embase medical databases was performed to identify articles describing visual acuity (VA) and/or visual field (VF) findings in SWS patients. In addition, a Dutch multicentre cohort with 33 SWS patients was collected and the combined results of VA and VF findings are presented. Visual acuity results of 25 studies and VF results of 12 studies were suitable for data extraction. Description of the combination of both VA and VF findings was scarce. Homonymous hemianopia (HH) was present in 42% of SWS patients. Seventy per cent of eyes had a (near) normal vision, while VA of eyes with glaucoma or DCH was severely impaired in 28% and 67%, respectively. In the Dutch cohort, only 18% (6/33) of patients had (near) normal findings of both visual parameters. In addition, half of the patients with glaucoma suffered from a combination of a HH and VA impairment. In conclusion, although SWS patients are exposed to severe functional visual impairment due to the possible cumulative consequences of glaucoma, DCH and cerebral injury, description of the combination of both VA and VF results is scarce in the literature. Particularly, the combination of visual impairment due to glaucoma or DCH, and HH might be invalidating. ||||| PURPOSE: Treatment of the capillary vascular malformation (port-wine stain) in Sturge-Weber syndrome with the use of a laser is helpful cosmetically. However, concerns have been raised that laser obliteration of port-wine stains may result in ocular hypertension. The aim of this study was to review clinical features and management of ocular complications of SWS and assess the effects of dermatological laser treatment on the incidence of glaucoma or ocular hypertension.
METHODS: This retrospective cohort study was conducted in an institutional setting. All patients had involvement of the face. Patients who underwent skin laser to the port-wine vascular malformation were analyzed further. Ocular involvement, glaucoma, and skin laser treatment and the relationship to ocular hypertension/glaucoma were observed.
RESULTS: Forty-one Sturge-Weber syndrome patients with port-wine vascular malformation were analyzed. Glaucoma was observed in 24 patients (58.5%) at mean age of 2.9 years (range, 0.0-16.5). Of these, 18 (75.0%) were treated with medical therapy, and 10 (41.7%) required trabeculectomy, with 2 of these requiring Seton implant. Of the 41 patients, 28 (68.3%) underwent laser to face/forehead. Mean age of laser commencement was 5 years (range, 0.4-16.5). Thirteen did not undergo laser treatment. Fourteen of the 28 and 10 of the 13 developed ocular hypertension/glaucoma.
CONCLUSIONS: This retrospective review did not find evidence to suggest that laser treatment of port-wine vascular malformations causes glaucoma or that it can worsen a preexisting ocular hypertension or glaucoma. Statistical analysis was inconclusive. ||||| A two-stage antiglaucoma operation was planned for the left eye of an 11-year-old boy with bilateral Sturge-Weber syndrome to avoid intraoperative and postoperative choroidal and retinal effusion as with previous trabeculectomy. The Ex-Press miniature glaucoma implant was placed 10 days before trabeculectomy with mitomycin C. There were no complications with either procedure. ||||| PURPOSE: To report the results of non-penetrating deep sclerectomy (NPDS) in the treatment of glaucoma associated with Sturge-Weber syndrome (SWS).
METHODS: We carried out a retrospective case series analysis of patients who underwent NPDS for glaucoma associated with SWS between 1998 and 2003. The control of glaucoma after NPDS, the results of surgery on intraocular pressure, the need for additional medical treatment and surgical complications were studied.
RESULTS: Twelve eyes of nine patients, aged 11 days to 24 years, underwent filtering surgery: nine NPDS procedures were performed and three surgical procedures had to be converted to trabeculectomy because NPDS was not technically achievable. The mean follow-up after surgery was 26.3 months (range 6-48 months). Two trabeculectomies were complicated by choroidal effusion, which resolved in both cases. Good control of glaucoma was obtained during follow-up.
CONCLUSIONS: Non-penetrating deep sclerectomy is transiently efficient in the treatment of SWS-associated glaucoma. Further studies of NPDS for the treatment of glaucoma associated with SWS are warranted. ||||| Sturge-Weber syndrome (SWS) is an uncommon neurocutaneous syndrome usually presenting with a triad of cutaneous, neurological, and ophthalmological symptoms. The cutaneous lesion can be observed at birth in most cases while the symptoms of the nervous and ocular systems involvement usually appear later in life. The most common ocular manifestation in SWS is glaucoma, which can occur in the early-life period. The authors reported a case of SWS in which the symptoms of glaucoma rapidly developed within two weeks following an ophthalmologic evaluation that was initially negative at the age of one week. ||||| AIM: To evaluate the efficacy of latanoprost (Xalatan) as adjunctive therapy in port wine stain related paediatric glaucoma.
METHODS: A retrospective non-randomised study. Patients with previous surgical intervention and medical treatment were included. Measurements were recorded from clinic and/or examination under anaesthetic (EUA) visits. A successful outcome was considered to be patients who required no further intervention following initiation of latanoprost, with stable glaucoma factors as well as drop in intraocular pressure.
RESULTS: 14 patients and 17 eyes were reviewed in total. The mean age of glaucoma diagnosis was 2.59 years (0.1-5.25 years) and of commencing latanoprost was 6.8 years (1.40-12.90 years). Percentage success at 1 month, 3 months, 6 months, and 1 year was 70.6%, 64.7%, 58.9%, and 47.1%, respectively, of eyes treated which translated to 71.4%, 64.2%, 57.1%, and 50% respectively of patients treated.
CONCLUSIONS: A trial of latanoprost as adjunctive therapy in patients with port wine stain related glaucoma may temporise the need for surgery; with 50% of patients being controlled at 1 year follow up. Lack of efficacy was detected as early as 1 month following commencement of treatment. ||||| PURPOSE: To compare the optical coherence tomography (OCT) findings of neurofibromatosis-1 (NF-1) patients with/without optic pathway glioma (OPG) with those of healthy controls.
METHODS: Ten patients with NF-1, 17 patients with NF-1-associated OPGs, and 17 control subjects were included in the study. Retinal nerve fiber layer (RNFL) and macular thickness findings measured with Stratus OCT were compared between the groups.
RESULTS: The average RNFL thickness was significantly lower in the OPG group (76.72 ± 22.16 μm) than in the controls (108.89 ± 9.92 μm) and NF-1 patients without OPGs (111.17 ± 12.13 μm) (p < 0.001). The macular volume was also found to be lower in NF-1 patients with OPG (6.41 ± 0.66 mm(3)) than in the healthy controls (7.19 ± 0.36 mm(3); p = 0.001) and NF-1 patients without OPGs (7.25 ± 0.26 mm(3); p = 0.005). Following this analysis the OPG group was further subdivided into two categories: OPG patients with normal visual acuity (VA) and OPG patients with decreased VA. The statistical analysis was repeated for these four subgroups, revealing that while the decrement in the average RNFL thickness was significant for both OPG groups that in the macular volume was only significant for OPG patients with decreased VA.
CONCLUSION: The results of our study suggest that RNFL thinning can be a helpful marker for the detection of OPGs in NF-1 patients. Larger studies with longitudinal data are required to confirm the role of OCT in the diagnosis and follow-up of these patients. ||||| BACKGROUND: There is limited information regarding early development of soft-tissue and/or bone hypertrophy with facial port-wine stains (PWS).
OBJECTIVE: We sought to characterize patients with hypertrophic PWS presenting during childhood.
METHODS: Patients with a facial PWS and underlying hypertrophy that developed before the age of 18 years were included in a multicenter retrospective study. Age at onset of the hypertrophy, its location, association with odontologic problems, presence of other associated complications, and response to laser treatment were recorded.
RESULTS: A total of 98 patients were included. The mean age at onset of hypertrophy, retrieved for 77 of 98 patients, was 5.6 years. The hypertrophy was congenital in 26%. Odontologic problems were noted in 39.8% of cases. Other complications, including cataract, asymmetric development of the maxillary bone, and speech delay/disorders, were reported in 18.4%. In all, 67 patients received laser treatment. Only 3% achieved complete or nearly complete clearance of the PWS.
LIMITATIONS: As only cases of PWS with early-onset hypertrophy were included, we were unable to calculate the prevalence of this manifestation.
CONCLUSION: PWS with early-onset hypertrophy are associated with a high rate of complications and a poor response to laser treatment. Periodic monitoring is recommended for early detection and treatment of complications. ||||| BACKGROUND: Sturge-Weber syndrome has been known to be frequently associated with facial cutaneous angioma and ipsilateral glaucoma. However, as far as we know, no cases accompanied by acute angle-closure glaucoma have been reported in patients with Sturge-Weber syndrome.
CASE: A 14-year-old boy with unilateral acute angle-closure glaucoma secondary to posterior scleritis associated with Sturge-Weber syndrome is described.
OBSERVATIONS: Slit-lamp examination revealed diffuse episcleral venous hemangioma in the right eye. With ultrasound biomicroscopy, a forward shift of the lens-iris diaphragm, a swelling of the ciliary body, and an anterior rotation of the ciliary processes with annular choroidal effusion were detected. The patient responded well to treatment with systemic corticosteroids and cycloplegics.
CONCLUSIONS: In our patient, inflammatory changes of the sclera, including swelling of the ciliary body, choroidal effusion, an anterior rotation of the ciliary processes at the scleral spur, and swelling of the lens, leading to closure of the anterior chamber angle, were suggested to be the major mechanisms of intraocular pressure elevation. ||||| PURPOSE: To quantify the long-term outcomes of congenital glaucoma and surgical success rates following pseudo 360-degree trabeculotomy surgery at Children's Medical Center in Dallas.
PATIENTS AND METHODS: An International Classification of Diseases (ICD-9) database was utilized for a retrospective chart review. Thirty-eight eyes of 24 who underwent primary trabeculotomy with a pseudo 360-degree technique between June 1, 1992 and December 31, 2005 were studied.
RESULTS: Mean age at the time of trabeculotomy was 11.1 ± 3.0 months, with seven eyes operated on after 1 year of age. Mean follow-up was 85.1 ± 9.0 months. Mean intraocular pressure (IOP) at the time of glaucoma diagnosis was 32.7 ± 1.1 mmHg, and final mean IOP for all eyes (after trabeculotomy and any additional surgery and/or glaucoma medications) was 17.9 ± 0.8 mmHg. With trabeculotomy and medication alone, mean final IOP was 19.9 ± 1.1 mmHg, with a mean drop in IOP of 12.5 ± 1.4 mmHg. Surgical success, defined by adequate IOP control, was achieved in 30 eyes (78.96%) at most recent follow-up. Kaplan-Meier analysis demonstrated 5- and 10-year survival probabilities of 93.1% and 66.8%, respectively. Seventeen eyes (44.7% of all eyes) achieved complete success, meaning IOP control <21 mmHg without additional medical therapy. All seventeen had primary congenital glaucoma (PCG); no eyes with aphakic glaucoma (AG) or Sturge-Weber syndrome (SWS) achieved complete success. Seven eyes (18.4%) failed primary trabeculotomy. Mean time to failure was 46.9 ± 8.6 months. Eyes with SWS had a significantly higher failure rate (P = 0.009) and a 5.81 relative risk of failure (P = 0.026).
CONCLUSIONS: Our long-term trabeculotomy success rates for congenital glaucoma compare favorably with existing reports in the literature. Eyes with AG and SWS may warrant consideration of alternative primary surgical methods, or closer postoperative surveillance. ||||| Sturge-Weber syndrome has been included in the group of phakomatoses that is characterized by hamartomas involving the brain, skin, and eyes. The characteristic facial port-wine stain, involving the first branch of the trigeminal nerve and the embryonic vasculature distribution in this area, leads to several ocular complications of the anterior segment and can involve the eyelids and conjunctiva. The posterior segment of the eyes is also affected with diffuse choroidal hemangiomas. However, the most frequent ocular comorbidity is glaucoma with a prevalence rate ranging from 30%-70%. Glaucoma is related to anterior chamber malformations, high episcleral venous pressure (EVP), and changes in ocular hemodynamics. Glaucoma can be diagnosed at birth, but the disease can also develop during childhood and in adults. The management of glaucoma in Sturge-Weber syndrome patients is particularly challenging because of early onset, frequently associated severe visual field impairment at the time of diagnosis, and unresponsiveness to standard treatment. Several surgical approaches have been proposed, but long-term prognosis for both intraocular pressure control and visual function remains unsatisfactory in these patients. Choroidal hemangiomas may also lead to visual impairment thorough exudative retinal detachment and macular edema. Treatment of exudative hemangioma complications is aimed at destructing the tumor or decreasing tumor leakage. ||||| BACKGROUND: Upper facial port-wine stain (PWS) is a feature of Sturge-Weber syndrome (SWS). Recent studies suggest that the distribution of the PWS corresponds to genetic mosaicism rather than to trigeminal nerve impairment.
OBJECTIVES: We sought to refine the cutaneous distribution of upper facial PWS at risk for SWS.
METHODS: This was a prospective multicenter study of consecutive cases of upper facial PWS larger than 1 cm² located in the ophthalmic division of trigeminal nerve distribution in infants aged less than 1 year, seen in 8 French pediatric dermatology departments between 2006 and 2012. Clinical data, magnetic resonance imaging, and photographs were systematically collected and studied. PWS were classified into 6 distinct patterns.
RESULTS: In all, 66 patients were included. Eleven presented with SWS (magnetic resonance imaging signs and seizure). Four additional infants had suspected SWS without neurologic manifestations. Hemifacial (odds ratio 7.7, P = .003) and median (odds ratio 17.08, P = .008) PWS patterns were found to be at high risk for SWS. A nonmedian linear pattern was not associated with SWS.
LIMITATIONS: Small number of patients translated to limited power of the study.
CONCLUSIONS: Specific PWS distribution patterns are associated with an increased risk of SWS. These PWS patterns conform to areas of somatic mosaicism. Terminology stipulating ophthalmic division of trigeminal nerve territory involvement in SWS should be abandoned. | [
{
"source_pmid": "25044138",
"source_text": "PURPOSE: To report the effect of oral propranolol on intraocular pressure (IOP) in infants newly diagnosed with unilateral Sturge-Weber syndrome (SWS) glaucoma receiving no other treatment.\nMETHODS: This was a prospective, nonrandomized interventional case serie... |
29753123 | CONCLUSIONS: Combination therapy decreased the number of injections of ranibizumab, although its BCVA improvement was inferior to that of monotherapy over 12 months of follow-up. Given the inherent limitations of the included trials, more studies are needed to further validate and update the findings in this area. | PURPOSE: To demonstrate noninferiority of ranibizumab in combination with verteporfin photodynamic therapy (PDT) versus ranibizumab monotherapy in patients with subfoveal choroidal neovascularization secondary to age-related macular degeneration (AMD).
DESIGN: Prospective, multicenter, double-masked, randomized, phase IIIb clinical trial.
PARTICIPANTS: Three hundred twenty-one patients randomized to receive either ranibizumab 0.5 mg monotherapy (n = 112), standard fluence (SF) verteporfin PDT combination therapy (n = 104), or reduced fluence (RF) verteporfin PDT combination therapy (n = 105).
METHODS: Ranibizumab was administered monthly in the monotherapy group. In both combination therapy groups, ranibizumab was initiated with 3 consecutive monthly injections, followed by retreatment as needed (pro re nata) with monthly monitoring. All patients were evaluated monthly for 12 months.
MAIN OUTCOME MEASURES: Mean change in best-corrected visual acuity (BCVA) from baseline at month 12 and proportion of patients randomized to either combination therapy with a ranibizumab treatment-free interval of 3 months or longer.
RESULTS: Two hundred eighty-six patients (89.1%) completed the 12-month study. Mean BCVA change at month 12 was +5.3 and +4.4 letters with verteporfin SF (n = 103) or verteporfin RF (n = 105) plus ranibizumab, respectively, compared with +8.1 letters with ranibizumab monotherapy (n = 110; adjusted 97.5% confidence interval [CI], (-7.90 to infinity); P = 0.0666; and 97.5% CI, (-8.51 to infinity); P = 0.1178; for combination regimens vs. monotherapy, respectively). Noninferiority of either combination regimen to monthly ranibizumab monotherapy was not demonstrated (primary end point). A ranibizumab treatment-free interval of 3 months or longer was achieved in 92.6% and 83.5% of the patients randomized to verteporfin SF or verteporfin RF groups, respectively, with a mean of 5.1 and 5.7 ranibizumab injections, respectively, and patients in the ranibizumab monotherapy arm received 10.5 injections. At month 12, mean central retinal thickness decreased by 151.7 μm and 140.9 μm for the verteporfin SF and RF groups, respectively, and by 172.2 μm with ranibizumab monotherapy. Safety and tolerability of all 3 regimens were similar to and consistent with previous studies in neovascular AMD. The number of ocular serious adverse events was low and occurred largely as single cases.
CONCLUSIONS: Ranibizumab monotherapy or combined with verteporfin PDT improved BCVA at month 12; however, noninferiority (7-letter margin) of combination regimens to ranibizumab monotherapy was not demonstrated. Verteporfin RF did not confer clinical benefits over verteporfin SF. All treatments were well tolerated. ||||| AIM: The aim of this study was to find predictive factors of 1-year visual outcome, analyzing novel optical coherence tomography (OCT) biomarkers in exsudative age-related macular degeneration (choroidal neovascularization (CNV)) in two groups of different treatment modalities.
METHODS: In all, 34 consecutive patients with new-onset CNV were randomized 1:1 to receive either ranibizumab monotherapy or ranibizumab combined with photodynamic therapy (PDT) with verteporfin. After three initial injections with ranibizumab, re-treatment was performed according to an as-needed scheme; PDT was performed once at baseline. Best-corrected visual acuity (BCVA) and OCT parameters like central macular volume (CMV), central macular thickness (or central retinal thickness (CRT)), subretinal and intraretinal fluid, fibrovascular lesion thickness, or inner segment/outer segment (IS/OS) junction were analyzed.
RESULTS: After 12 months, a visual gain of 6.1 letters was found in the monotherapy group, whereas patients in the combination therapy group lost - 4.8 letters from baseline to the 12-month visit. CMV and CRT decreased considerably between baseline and month 2-3 in both groups, with a following slight increase until month 12. Additional application of PDT had negative effect to 12-month BCVA, whereas higher baseline BCVA and integrity of the IS/OS junction at month 12 had positive effect to 12-month BCVA.
CONCLUSIONS: Better baseline BCVA and the integrity of IS/OS junction at 12-month visit were the most important predictive factors for final BCVA. Combination therapy caused worse final BCVA and a higher degree of IS/OS disruption. ||||| PURPOSE: To compare the efficacy and safety of same-day verteporfin photodynamic therapy (PDT) and intravitreal ranibizumab combination treatment versus ranibizumab monotherapy in neovascular age-related macular degeneration.
DESIGN: Prospective, multicenter, double-masked, randomized, active-controlled trial.
PARTICIPANTS: We included 255 patients with all types of active subfoveal choroidal neovascularization.
METHODS: Patients were randomized 1:1 to as-needed (pro re nata; PRN) combination (standard-fluence verteporfin 6 mg/m(2) PDT and ranibizumab 0.5 mg) or PRN ranibizumab monotherapy (sham infusion [5% dextrose] PDT and ranibizumab 0.5 mg). Patients received 3 consecutive monthly injections followed by PRN retreatments based on protocol-specific retreatment criteria.
MAIN OUTCOME MEASURES: Mean change in best-corrected visual acuity (BCVA) from baseline to month 12, and the proportion of patients with treatment-free interval ≥3 months at any timepoint after month 2.
RESULTS: The mean change in BCVA at month 12 was +2.5 and +4.4 letters in the combination and monotherapy groups, respectively (P = 0.0048; difference: -1.9 letters [95% confidence interval, -5.76 to 1.86], for having achieved noninferiority with a margin of 7 letters). The proportion of patients with a treatment-free interval of ≥3 months at any timepoint after month 2 was high, but did not show a clinically relevant difference between the treatment groups. Secondary efficacy endpoints included the mean number of ranibizumab retreatments after month 2 (1.9 and 2.2 with combination and monotherapy, respectively [P = 0.1373]). The time to first ranibizumab retreatment after month 2 was delayed by 34 days (about 1 monthly visit) with combination (month 6) versus monotherapy (month 5). At month 12, mean ± standard error central retinal thickness decreased by 115.3±9.04 μm in the combination group and 107.7±11.02 μm in the monotherapy group. The mean number of verteporfin/sham PDT treatments was comparable in the 2 groups (combination, 1.7; monotherapy, 1.9). The safety profiles of the 2 groups were comparable, with a low incidence of ocular serious adverse events.
CONCLUSIONS: The combination PRN treatment regimen with verteporfin PDT and ranibizumab was effective in achieving BCVA gain comparable with ranibizumab monotherapy; however, the study did not show benefits with respect to reducing the number of ranibizumab retreatment over 12 months. The combination therapy was well tolerated. ||||| PURPOSE: To investigate the injection frequency and visual acuity (VA) outcomes with combination therapy (ranibizumab plus verteporfin photodynamic therapy, PDT) versus monotherapy (ranibizumab).
METHODS: A total of 40 patients with exudative age-related macular degeneration were randomized 1:1 to ranibizumab 0.3 mg plus single standard verteporfin PDT or ranibizumab 0.3 mg plus sham PDT. Ranibizumab was administered 3 times monthly followed by 'as needed' to month 12 based on predetermined vision/anatomical criteria. Retreatment rates, VA outcomes and safety were assessed.
RESULTS: During months 3-12, combination therapy patients required fewer ranibizumab injections (mean 1.3) compared with monotherapy patients (2.8). Mean VA improved by 9.0 letters with combination therapy versus 7.5 letters in the monotherapy group at month 12. Both treatment regimens were well tolerated.
CONCLUSION: The need for ranibizumab retreatment might be reduced by administering a single verteporfin PDT on the same day as the first ranibizumab injection, without compromising VA outcomes or safety. ||||| PURPOSE: To evaluate whether ketorolac eyedrops plus intravitreal ranibizumab (IVR) or verteporfin photodynamic therapy plus IVR provides additional benefit over IVR monotherapy for treatment of choroidal neovascularization in age-related macular degeneration.
METHODS: This was a prospective, randomized, pilot study in 75 patients with naive choroidal neovascularization. Patients were randomized 1:1:1 into 3 groups: ranibizumab monotherapy (RM), ranibizumab plus ketorolac, or ranibizumab plus loading-phase reduced-fluence verteporfin photodynamic therapy (RV) groups.
RESULTS: At 12 months, all groups showed significant improvement in both best-corrected visual acuity and central retinal thickness. The mean best-corrected visual acuity change from baseline to 12 months was -0.14 ± 0.52 logMAR (20/73 ± 20/29), -0.25 ± 0.60 logMAR (20/46 ± 20/27), and -0.10 ± 0.30 (20/97 ± 20/40) logMAR in RM, ranibizumab plus ketorolac, and RV groups, respectively. The mean central retinal thickness change from baseline to 12 months was -125 ± 15 μm, -141 ± 21 μm, and -130 ± 15 μm in RM, ranibizumab plus ketorolac, and RV groups, respectively. Both ranibizumab plus ketorolac and RV groups required fewer IVR treatments than RM.
CONCLUSION: Compared with RM and ranibizumab plus verteporfin photodynamic therapy, the combination of 0.45% ketorolac eyedrops 3 times a day and ranibizumab in patients with choroidal neovascularization provided superior best-corrected visual acuity and central retinal thickness outcomes. Both combination regimens required fewer IVR injections than RM during the 12-month follow-up period. ||||| AIMS: The aim of this study is to evaluate the effect of standard-fluence verteporfin photodynamic therapy (PDT) delivered on the first day of a ranibizumab regimen for choroidal neovascularisation secondary to age-related macular degeneration compared with ranibizumab monotherapy.
METHODS: Patients were randomised to sham or standard-fluence verteporfin PDT at baseline. The first of three monthly loading doses of ranibizumab was given on the same day, and thereafter patients received monthly treatment with ranibizumab as required. All patients underwent monthly visual acuity and OCT assessment and 3-monthly fluorescein angiography with follow-up to 1 year.
RESULTS: In all, 18 patients were recruited. The PDT group gained a mean of 2.2 ETDRS letters at 1 year and the sham group gained a mean of 4.4 letters (P=0.47). Both groups required a mean of 1.3 injections of ranibizumab following the 3-month loading phase. Fluorescein angiography at 1 month demonstrated marked choroidal hypoperfusion in all patients treated with PDT with reduced choroidal perfusion persisting to month 12. This did not occur in the sham group.
CONCLUSION: The addition of standard-fluence verteporfin PDT at baseline to a ranibizumab regimen conferred no benefit in terms of visual acuity or number of ranibizumab injections required at 1 year. The combination of these treatments resulted in persistent reduced choroidal perfusion, which raises potential safety concerns. ||||| PURPOSE: Modern therapy of neovascular age-related macular degeneration consists in intravitreal injections of inhibitors of the vascular endothelial growth factor. An increasing number of these injections is required not only in monthly but also in as-needed treatment regimen. In this study, it should be examined whether an additional administered photodynamic therapy (PDT) can considerably reduce the number of injection.
METHODS: In this prospective, randomized study carried out in three large hospitals of Vienna eyes with neovascular age-related macula degeneration were included. Patients were randomized to either Ranibizumab monotherapy or combined standard fluence PDT and Ranibizumab therapy. All patients received a loading dose of three intravitreal Ranibizumab injections and were thereafter treated in an as-needed regimen based on distance acuity and retinal thickness values. In the combined treatment group, PDT was administered 1 day after the first Ranibizumab injection.
RESULTS: Fifty-one patients were randomized, 44 were finally included (four screening failures and three withdrawals). Twenty-four patients were assigned to the monotherapy and 20 patients to the combined treatment group. Fewer injections were required in the combined treatment group (4.7 versus 6.3). Overall the patients lost 0.5 letters; in the combined treatment group, the patients lost mean 7.1 letters; in the monotherapy group, they gained mean 5.1 letters. Retinal thickness decreased significantly in both groups.
CONCLUSION: A significant reduction of the number of required intravitreal injections could be achieved by the additional PDT treatment, but was accompanied by a worse functional outcome in this group. ||||| PURPOSE: To compare verteporfin photodynamic therapy combined with intravitreal ranibizumab (combination therapy) versus ranibizumab monotherapy for management of neovascular age-related macular degeneration.
METHODS: Thirty patients (40 eyes) with neovascular age-related macular degeneration were prospectively allocated to combination therapy or monotherapy. In monotherapy, the induction phase consisted of 3 consecutive monthly ranibizumab injections (0.5 mg), while the combination therapy had a single session of photodynamic therapy with intravitreal ranibizumab. Follow-up treatment for either group consisted only of additional as-needed ranibizumab injections. The main outcome measure was that a proportion of eyes losing <15 letters of visual acuity after 12 months.
RESULTS: Except for 1 eye in combination therapy, all eyes in both groups lost <15 letters of visual acuity. At 12 months, there was a mean gain of +12 letters and +3.2 letters for monotherapy and combination therapy, respectively (relative percent change of 32% vs. 7%, P = 0.03). Anatomical improvement was similar in both groups. After induction, the time until ranibizumab retreatment was longer for combination therapy (P = 0.002) while ranibizumab injections were required more frequently with monotherapy (P = 0.015).
CONCLUSION: Ranibizumab monotherapy showed greater improvement in visual acuity versus combination therapy. However, combination therapy required fewer ranibizumab injections. Larger trials need to confirm the findings of this pilot study. | [
{
"source_pmid": "22444829",
"source_text": "PURPOSE: To demonstrate noninferiority of ranibizumab in combination with verteporfin photodynamic therapy (PDT) versus ranibizumab monotherapy in patients with subfoveal choroidal neovascularization secondary to age-related macular degeneration (AMD).\nDESIGN: P... |
29343949 | Conclusion: In AMD patients, conbercept exerts considerably more positive effects on the long-term BCVA and CRT improvement than triamcinolone and TTT. The serum VEGF level in the conbercept group was lower than that in the ranibizumab group. | OBJECTIVE: To investigate the serum levels of vascular endothelial growth factor (VEGF) before and after intravitreal injection of conbercept or ranibizumab for neovascular age-related macular degeneration and polypoidal choroidal vasculopathy patients.
METHODS: This study is a prospective, interventional case series and involved 28 patients, 18 treated with 0.5 mg of conbercept and 10 treated with 0.5 mg of ranibizumab. Serum concentrations of VEGF were determined by enzyme-linked immunosorbent assay before the injection and at 1 day, 1 week, and 1 month after anti-VEGF treatments.
RESULTS: The baseline serum VEGF level of the ranibizumab group was 367.11 ± 311.87 pg/mL, whereas that of the conbercept group was 315.06 ± 170.88 pg/mL (P = 0.653). In the conbercept group, VEGF level significantly decreased to 36.32 ± 72.11 pg/mL at 1 day (P = 0.03) and returned to 136.55 ± 144.62 pg/mL at 1 week (P = 0.03). At 1 month, the concentration increased to 334.48 ± 197.41 pg/mL and showed no significant difference compared with the baseline. In the ranibizumab group, the serum VEGF levels were 292.42 ± 239.80 pg/mL, 282.60 ± 201.36 pg/mL, and 308.83 ± 266.89 pg/mL at 1 day, 1 week, and 1 month after intravitreal injection, respectively. There was no significant difference in the ranibizumab group at each detection time point (P = 0.45).
CONCLUSION: Conbercept significantly decreased serum VEGF level 1 day and 1 week after injection, but this effect was not sustained for 1 month. In contrast, ranibizumab had no significant effect on serum VEGF concentration changes. The reduction in serum VEGF by conbercept may affect its systemic safety profile. | [
{
"source_pmid": "27617537",
"source_text": "OBJECTIVE: To investigate the serum levels of vascular endothelial growth factor (VEGF) before and after intravitreal injection of conbercept or ranibizumab for neovascular age-related macular degeneration and polypoidal choroidal vasculopathy patients.\nMETHODS:... |
27743157 | CONCLUSIONS: Certain lifestyle habits could influence glaucoma progression, yet no specific interventions are currently supported by robust evidence. Awareness of the possible influences of certain habits should help guide clinical advice and is important to help patients avoid adverse outcomes and take an active role in the management of their disease. | The existing literature is controversial regarding the relationship between physical fitness and intraocular pressure (IOP). Therefore, the effects of acute submaximal exercise on IOP were compared in athletes and sedentary subjects. Acute exercise increased IOP in male athletes, but had no effect in sedentary men. Also, it decreased IOP in sedentary women, but had no effect in female athletes. Sex and physical fitness both were significant factors influencing the changes in IOP due to exercise. These results suggest that acute dynamic exercise is useful to decrease IOP in sedentary women, but not in male athletes. These results may help glaucoma screeners. ||||| The present study was planned to investigate the relationship between the magnitude of intraocular pressure (IOP) reduction after short-duration exercise and the intensity, duration and quantity of exercise in healthy subjects. Twenty-five healthy, sedentary male of the same age group, performed exercises at the levels of 80%, 60%, and 40% maximum heart rate (HRmax) for 15 minutes, 80% HRmax for 7.5 minutes, 60% HRmax for 10 minutes, and 40% HRmax for 30 minutes. IOP was measured with the Goldmann applanation tonometer. The IOP reduction at 5 minutes after 15 minutes of exercising at 80% HRmax, 60% HRmax, and 40% HRmax were 4.7 +/- 0.9, 3.5 +/- 0.7, and 0.9 +/- 0.4 mmHg, respectively. At five minutes, after exercising 7.5 minutes at 80% HRmax, 10 minutes at 60% HRmax, and 30 minutes at 40% HRmax, IOP reduced by 4.5 +/- 0.7, 3.3 +/- 0.9, and 2.9 +/- 1.1 mmHg, respectively. This study concludes that intensity of exercise seems responsible for the magnitude of the initial IOP decrease after short-term exercise. Furthermore, it seems that other factors such as duration of exercise or quantity of exercise, blood pressures, body mass index are not related to the amount of the initial fall in IOP. ||||| A number of physiological factors can influence the intra-ocular pressure of patients with normal, healthy eyes leading to the misinterpretation of tonometric findings. The influence and duration of four commonly encountered factors--drinking water, coffee, alcohol, and exercise--were investigated employing a non-contact tonometer. Drinking 1 litre of water increased the IOP for up to 140 min with a mean maximum increase of 4.4 mmHg. A similar change was induced by coffee, the increase lasting up to 95 min and displaying a mean maximum increase of 4.0 mmHg. The intra-ocular pressure fell with alcohol consumption by a maximum of 3.7 mmHg, regaining pre-test values in all subjects after 65 min. Vigorous exercise produced an immediate fall in mean intra-ocular pressure of 4.3 mmHg, initial pressure being restored in all subjects after 65 min. The impact of such factors upon normal physiology are discussed together with the implications for routine tonometry. ||||| PURPOSE: To understand those factors that determine the decrease in intraocular pressure (IOP) that occurs during acute dynamic exercise.
METHODS: Three aspects of the exercise-IOP relationship were studied. These included graded exercise, with and without CO2 addition for isocapnia; comparison of the IOP response of trained and sedentary subjects to a fixed external work load; and exercise after ocular beta-adrenoceptor blockade. Graded exercise consisted of 7 minutes each at 30 and 90 watts on a cycle ergometer, then progressive work to exhaustion. Trained and sedentary subjects were defined on the basis of the blood lactate response to fixed external work (10 minutes at 90 watts). Selective beta 1-adrenoceptor blockade (betaxolol) and nonselective beta-adrenoceptor blockade (levobunolol) were superimposed on graded exercise. Intraocular pressure was measured using applanation tonometry.
RESULTS: Graded exercise: Intraocular pressure decreased in proportion to exercise intensity. Hypocapnia developed in the last minutes of exhausting work, but preventing hypocapnia with CO2 addition failed to lessen the decrease in IOP. Response to fixed external work load: Intraocular pressure decreased significantly more in sedentary than in trained subjects; this decline was correlated with elevations in blood lactate but not with changes in metabolic rate or plasma osmolarity. Selective and nonselective beta-adrenoceptor blockade: Both drugs lowered IOP at baseline and throughout graded exercise; the drugs and exercise had apparently additive ocular hypotensive effects.
CONCLUSIONS: Acute dynamic exercise lowers IOP in a graded fashion proportional to relative, not absolute, work load. The IOP decline is correlated with blood lactate but not with PCO2 or plasma osmolarity changes, and exercise potentiates the ocular hypotensive effects of beta-adrenoceptor blockade. ||||| We studied the intraocular pressure response to short-term maximal aerobic exertion before and after exercise conditioning in ten healthy sedentary volunteers. Before exercise conditioning, mean intraocular pressure +/- S.E.M. decreased by 5.9 +/- 0.6 mm Hg after short-term maximal aerobic exercise, returning to baseline in a mean of 37 +/- 4 minutes. After four months of exercise conditioning, this ocular hypotensive response was significantly dampened, with a mean intraocular pressure reduction of only 1.6 +/- 0.4 mm Hg after short-term maximal aerobic exercise (P less than .01). Additionally, a significant reduction in baseline intraocular pressure occurred, with a mean intraocular pressure of 14.3 +/- 0.7 mm Hg before exercise conditioning, declining to a mean intraocular pressure of 13 +/- 0.9 mm Hg (P less than .02) after four months of physical training. Exercise conditioning may significantly reduce baseline intraocular pressure and attenuate the hypotensive response to short-term maximal aerobic exercise. ||||| PURPOSE: To examine the effects of jogging on intraocular pressure (IOP), blood pressure (BP), and heart rate (HR).
METHODS: Twenty-nine healthy individuals-25 athletes and 4 untrained-were studied. IOP, systolic and diastolic BP, and HR were measured before and just after 20 minutes of jogging (submaximal--70%--aerobic exercise).
RESULTS: IOP decreased after jogging. Only three individuals had unchanged IOP in one eye and one individual in both eyes. The IOP decrease (1 to 8 mmHg) was statistically significant (p<0.001). BP increased after jogging (systolic: 0 to 60 mmHg, statistically significant changes, p<0.001; diastolic: 0 to 15 mmHg, statistically significant changes, p<0.001). HR increased as well (15 to 80 pulses/min, statistically significant changes, p<0.001). However, there were individuals who presented a significant decrease of IOP and a mild BP rise and vice versa, and also individuals with mild IOP decrease and significant HR change and vice versa. The statistical analysis clearly showed that there are no linear quantitative correlations between BP or HR changes and IOP changes.
CONCLUSIONS: IOP decreases after jogging. Changes in BP and HR values have no linear quantitative correlation with IOP decrease. ||||| PURPOSE: The aim of this study is to investigate the short-term influence of a period of dynamic exercise on axial length (AXL) and intraocular pressure (IOP) in young adult subjects.
PATIENTS AND METHODS: In all, 20 young adult subjects (10 myopes and 10 emmetropes) participated. Baseline measures of ocular biometrics, IOP and ocular pulse amplitude (OPA) were taken following a 20-min rest period. Subjects then performed 10 min of moderate intensity, low impact dynamic exercise (bicycle ergometry). Measures of ocular biometrics, IOP and OPA were repeated immediately after, and then 5 and 10 min after this exercise task. Systemic blood pressure and pulse rate were also monitored. A repeated measures analysis of variance was used to investigate the changes in the measured parameters.
RESULTS: Exercise resulted in significant changes in a range of ocular parameters. A small but significant decrease in AXL was observed following exercise (P<0.0001). The largest change in AXL was noted immediately following exercise (mean decrease -17±10 μm). IOP and OPA also decreased significantly following exercise (P<0.0001). A moderate but significant positive association was found between the changes in AXL and the changes in IOP (r(2)=0.36, P<0.0001). There were no significant differences found between the myopic and emmetropic subjects in the magnitude of changes observed in ocular parameters following exercise.
CONCLUSION: The physiological effects of dynamic exercise lead to changes in a range of ocular parameters, including significant reductions in IOP, OPA and decreases in AXL. ||||| PURPOSE: To determine if walking for a short distance in a natural outdoor setting will have a clinically significant effect on intraocular pressure (IOP).
METHODS: Twenty-five healthy participants (25 eyes) aged 20.8±1.3 years had their IOP measured using noncontact tonometry at baseline, after completing a 1046 m outdoor walking course at a brisk pace and after a 20-minute resting period in a seated position. Repeated-measures analysis of variance was used to compare the average IOP at each time point and Pearson correlation was used to assess relationships between the difference in IOP, baseline IOP, and walking pace.
RESULTS: IOP decreased from 16.0±2.6 mm Hg at baseline to 14.6±3.2 mm Hg (-1.4±1.1 mm Hg, P<0.001, 95% confidence interval: +0.7--3.3 mm Hg) after the walk. The IOP remained -0.7 mm Hg below the baseline level (P=0.028, paired t test with Bonferroni correction) after the 20-minute resting period. The decrease in IOP was larger in eyes with a lower baseline IOP (partial Pearson r=0.433, P=0.035, controlled for pace). The average walking pace was 4.7±0.5 km/h and was negatively correlated to the decrease in IOP (partial Pearson r=-0.432, P=0.035, controlled for baseline IOP). The postrest recovery of IOP was greater for participants who demonstrated a greater decrease in IOP during the walking period (Pearson r=-0.427, P=0.033).
CONCLUSIONS: A short brisk walk caused a clinically significant reduction in IOP by an amount that was related to the relative intensity of the exertion, and it did not recover within a 20-minute period. Clinicians are advised to seek information regarding recent physical activity (including walking) and the subsequent resting period, when highly accurate measurements of IOP are required. ||||| 1. Several studies have shown that exercise reduces intraocular pressure (IOP) in sedentary subjects, but the effects of exercise in physically fit subjects are not fully known. Accordingly, the present study was planned to investigate the effects of exercise on intraocular pressure in physically fit subjects after elimination of those factors that can affect intraocular pressure and have been neglected by previous studies. 2. Thirty-two sedentary males of the same age group were categorized equally into control and experimental groups. Intraocular pressures were measured during and after exercise with the Goldmann applanation tonometer. The experimental group took a supervised exercise programme of 3 months duration. Physical fitness was evaluated by the measurements of maximum oxygen uptake. Each subject was tested twice by the same exercise protocol at an interval of 3 months. 3. After 3 months, resting IOP values decreased by 0.31 +/- 0.11 (P < 0.05) and 1.37 +/- 0.15 mmHg (P < 0.001) in control and experimental groups, respectively. The acute decreases following the first exercise test were 4.18 +/- 0.41 and 4.38 +/- 0.47 mmHg, while after 3 months these values were 4.12 +/- 0.45 and 2.69 +/- 0.28 mmHg in control and experimental groups, respectively. After exercise conditioning, the mean recovery time was reduced by 43.03%. 4. The results are relevant to planning trials in glaucoma. Physical fitness reduces IOP and causes significant attenuation in the IOP response to physical exercise. It would seem reasonable at present not to discourage patients who have glaucoma from light exercise; perhaps, on the contrary, it should be encouraged. ||||| The effects of the intensity, duration and quantity (intensity x duration) of exercise on the reduction of intraocular pressure (IOP) in healthy and physically fit individuals were studied. Five minutes after 15 minutes of exercise at 70%, 55% and 40% of maximum exercise load (%HRmax) the IOP decreased 4.3 +/- 0.7 mmHg, 2.2 +/- 0.7 mmHg and 0.6 +/- 0.5 mmHg, respectively. The magnitude of IOP reduction increased with exercise load. Running for 7.5 minutes at 70%HRmax decreased IOP comparable to 15 minutes of running at the same exercise load (4.4 +/- 0.6 mmHg). Twenty-five minutes of running at 40%HRmax is almost the same quantity of exercise as 15 minutes of running at 70%HRmax. However, the former did not result in IOP reductions to equal the latter (2.3 +/- 0.5 vs 4.4 +/- 0.6 mmHg). The amount of IOP reduction after short-term exercise seems to depend on the intensity of exercise, not on the duration of exercise or the quantity of exercise. | [
{
"source_pmid": "16923690",
"source_text": "The existing literature is controversial regarding the relationship between physical fitness and intraocular pressure (IOP). Therefore, the effects of acute submaximal exercise on IOP were compared in athletes and sedentary subjects. Acute exercise increased IOP ... |
26951234 | CONCLUSION: Published data on IVTB in AMRD provide only a low level of evidence on its cardiovascular safety and do not support any finite conclusions. | OBJECTIVE: To examine associations between therapies for age-related macular degeneration and risks of all-cause mortality, incident myocardial infarction, bleeding, and incident stroke.
METHODS: We conducted a retrospective cohort study of 146,942 Medicare beneficiaries 65 years or older with a claim for age-related macular degeneration between January 1, 2005, and December 31, 2006. On the basis of claims for the initial treatment, we assigned beneficiaries to 1 of 4 groups. The active control group included patients who received photodynamic therapy. The other groups included patients who received intravitreous pegaptanib octasodium, bevacizumab, or ranibizumab. We censored data from patients when they received a therapy different from the initial therapy. The main outcome measures were associations between photodynamic, pegaptanib, bevacizumab, and ranibizumab therapies and the risks of all-cause mortality, incident myocardial infarction, bleeding, and incident stroke.
RESULTS: After adjustment for baseline characteristics and comorbid conditions, we found significant differences in the rates of mortality and myocardial infarction by treatment group. Specifically, the hazard of mortality was significantly lower with ranibizumab therapy than with photodynamic therapy (hazard ratio, 0.85; 99% confidence interval, 0.75-0.95) or pegaptanib use (0.84; 0.74-0.95), and the hazard of myocardial infarction was significantly lower with ranibizumab use than with photodynamic therapy (0.73; 0.58-0.92). There were no significant differences in the hazard of mortality or myocardial infarction between bevacizumab use and the other therapies. We found no statistically significant relationship between treatment group and bleeding events or stroke.
CONCLUSION: Bevacizumab and ranibizumab use was not associated with increased risks of mortality, myocardial infarction, bleeding, or stroke compared with photodynamic therapy or pegaptanib use. ||||| PURPOSE: To compare the efficacy and safety of ranibizumab and bevacizumab intravitreal injections to treat neovascular age-related macular degeneration (nAMD).
DESIGN: Multicenter, noninferiority factorial trial with equal allocation to groups. The noninferiority limit was 3.5 letters. This trial is registered (ISRCTN92166560).
PARTICIPANTS: People >50 years of age with untreated nAMD in the study eye who read ≥ 25 letters on the Early Treatment Diabetic Retinopathy Study chart.
METHODS: We randomized participants to 4 groups: ranibizumab or bevacizumab, given either every month (continuous) or as needed (discontinuous), with monthly review.
MAIN OUTCOME MEASURES: The primary outcome is at 2 years; this paper reports a prespecified interim analysis at 1 year. The primary efficacy and safety outcome measures are distance visual acuity and arteriothrombotic events or heart failure. Other outcome measures are health-related quality of life, contrast sensitivity, near visual acuity, reading index, lesion morphology, serum vascular endothelial growth factor (VEGF) levels, and costs.
RESULTS: Between March 27, 2008 and October 15, 2010, we randomized and treated 610 participants. One year after randomization, the comparison between bevacizumab and ranibizumab was inconclusive (bevacizumab minus ranibizumab -1.99 letters, 95% confidence interval [CI], -4.04 to 0.06). Discontinuous treatment was equivalent to continuous treatment (discontinuous minus continuous -0.35 letters; 95% CI, -2.40 to 1.70). Foveal total thickness did not differ by drug, but was 9% less with continuous treatment (geometric mean ratio [GMR], 0.91; 95% CI, 0.86 to 0.97; P = 0.005). Fewer participants receiving bevacizumab had an arteriothrombotic event or heart failure (odds ratio [OR], 0.23; 95% CI, 0.05 to 1.07; P = 0.03). There was no difference between drugs in the proportion experiencing a serious systemic adverse event (OR, 1.35; 95% CI, 0.80 to 2.27; P = 0.25). Serum VEGF was lower with bevacizumab (GMR, 0.47; 95% CI, 0.41 to 0.54; P<0.0001) and higher with discontinuous treatment (GMR, 1.23; 95% CI, 1.07 to 1.42; P = 0.004). Continuous and discontinuous treatment costs were £9656 and £6398 per patient per year for ranibizumab and £1654 and £1509 for bevacizumab; bevacizumab was less costly for both treatment regimens (P<0.0001).
CONCLUSIONS: The comparison of visual acuity at 1 year between bevacizumab and ranibizumab was inconclusive. Visual acuities with continuous and discontinuous treatment were equivalent. Other outcomes are consistent with the drugs and treatment regimens having similar efficacy and safety.
FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosures may be found after the references. ||||| PURPOSE: To determine the risk of thromboembolic and gastrointestinal bleeding events in the 12 months after injections of bevacizumab or ranibizumab compared with photodynamic therapy and a nontreated community sample.
METHODS: Hospital and death records were examined for 1,267 patients treated with vascular endothelial growth factor inhibitor and 399 patients treated with photodynamic therapy attending Western Australian eye clinics from 2002 to 2008, and 1,763 community controls, aged ≥50 years. Hospital records from 1995 to 2009 were analyzed for history of myocardial infarction (MI), stroke, and gastrointestinal bleeding before treatment. Records were searched for evidence of these events in the 12 months after treatment.
RESULTS: The 12-month MI rate was higher for vascular endothelial growth factor inhibitor patients than photodynamic therapy patients and the community group (1.9/100 vs. 0.8 and 0.7, respectively). No differences were observed between patients treated with bevacizumab and ranibizumab. The adjusted MI rate was 2.3 times greater than the community group (95% confidence interval, 1.2-4.5) and photodynamic therapy rate (95% confidence interval, 0.7-7.7). The 12-month MI risk did not increase with the number of injections administered (hazard ratio, 0.9; 95% confidence interval, 0.5-1.5). Stroke and gastrointestinal bleeding did not differ between any exposure groups.
CONCLUSION: Although all the adverse events examined were rare, patients treated with vascular endothelial growth factor inhibitors were significantly more likely to experience fatal or nonfatal MI than the community group. This increased risk may be related to the underlying age-related macular degeneration or vascular endothelial growth factor inhibitor use itself. ||||| OBJECTIVE: To evaluate 2 different dosing regimens of intravitreal bevacizumab for the treatment of neovascular age-related macular degeneration (AMD) patients in China.
DESIGN: Multicenter, randomized, prospective, open-label clinical trial.
PARTICIPANTS: One hundred eighty-five patients with active neovascular AMD, exclusion of a macular scar, choroidal neovascularization not resulting from AMD, and polypoidal choroidal vasculopathy.
INTERVENTION: Patients were assigned randomly to receive intravitreal injections of bevacizumab every 6 weeks for the first 3 injections followed by injections every 6 weeks (regimen A, n = 91) or every 12 weeks (regimen B, n = 94).
MAIN OUTCOME MEASURES: The primary outcome measure was a comparison of the mean change in visual acuity from baseline. The secondary outcome measure was a comparison of the proportion of patients with a change in visual acuity of 15 letters or more. Adverse events were monitored.
RESULTS: One-hundred eighty five patients were enrolled. At 48 weeks, the increase in the mean visual acuity measurements from baseline were 12.58 letters in regimen A and 10.06 letters in regimen B (P = 0.288). At 48 weeks, the percentage of eyes losing fewer than 15 letters was 96.2% in regimen A and 93.9% in regimen B (P = 0.720). At 48 weeks, the median decrease in central retinal thickness measurements from baseline was 119 μm in regimen A and 60 μm in regimen B (P = 0.221). Adverse events during the 48 weeks included anterior chamber inflammation in 17 patients (18.7%) from regimen A and 9 patients (9.6%) from regimen B (P = 0.075). There were no other notable ocular adverse events in either group.
CONCLUSIONS: Intravitreal bevacizumab improved visual acuity and decreased macular thickness in patients with neovascular AMD when dosed either every 6 weeks or every 12 weeks after 3 doses given at 6-week intervals. Although there were no statistically significant differences between the 2 regimens, the results tended to favor the group dosed every 6 weeks (regimen A). ||||| OBJECTIVE: To describe effects of ranibizumab and bevacizumab when administered monthly or as needed for 2 years and to describe the impact of switching to as-needed treatment after 1 year of monthly treatment.
DESIGN: Multicenter, randomized clinical trial.
PARTICIPANTS: Patients (n = 1107) who were followed up during year 2 among 1185 patients with neovascular age-related macular degeneration who were enrolled in the clinical trial.
INTERVENTIONS: At enrollment, patients were assigned to 4 treatment groups defined by drug (ranibizumab or bevacizumab) and dosing regimen (monthly or as needed). At 1 year, patients initially assigned to monthly treatment were reassigned randomly to monthly or as-needed treatment, without changing the drug assignment.
MAIN OUTCOME MEASURES: Mean change in visual acuity.
RESULTS: Among patients following the same regimen for 2 years, mean gain in visual acuity was similar for both drugs (bevacizumab-ranibizumab difference, -1.4 letters; 95% confidence interval [CI], -3.7 to 0.8; P = 0.21). Mean gain was greater for monthly than for as-needed treatment (difference, -2.4 letters; 95% CI, -4.8 to -0.1; P = 0.046). The proportion without fluid ranged from 13.9% in the bevacizumab-as-needed group to 45.5% in the ranibizumab monthly group (drug, P = 0.0003; regimen, P < 0.0001). Switching from monthly to as-needed treatment resulted in greater mean decrease in vision during year 2 (-2.2 letters; P = 0.03) and a lower proportion without fluid (-19%; P < 0.0001). Rates of death and arteriothrombotic events were similar for both drugs (P > 0.60). The proportion of patients with 1 or more systemic serious adverse events was higher with bevacizumab than ranibizumab (39.9% vs. 31.7%; adjusted risk ratio, 1.30; 95% CI, 1.07-1.57; P = 0.009). Most of the excess events have not been associated previously with systemic therapy targeting vascular endothelial growth factor (VEGF).
CONCLUSIONS: Ranibizumab and bevacizumab had similar effects on visual acuity over a 2-year period. Treatment as needed resulted in less gain in visual acuity, whether instituted at enrollment or after 1 year of monthly treatment. There were no differences between drugs in rates of death or arteriothrombotic events. The interpretation of the persistence of higher rates of serious adverse events with bevacizumab is uncertain because of the lack of specificity to conditions associated with inhibition of VEGF. ||||| BACKGROUND: Bevacizumab has been suggested to have similar effectiveness to ranibizumab for treatment of neovascular age-related macular degeneration. The Inhibition of VEGF in Age-related choroidal Neovascularisation (IVAN) trial was designed to compare these drugs and different regimens. Here, we report the findings at the prespecified 2-year timepoint.
METHODS: In a multicentre, 2×2 factorial, non-inferiority randomised trial, we enrolled adults aged at least 50 years with active, previously untreated neovascular age-related macular degeneration and a best corrected distance visual acuity (BCVA) of at least 25 letters from 23 hospitals in the UK. Participants were randomly assigned (1:1:1:1) to intravitreal injections of ranibizumab (0·5 mg) or bevacizumab (1·25 mg) in continuous (every month) or discontinuous (as needed) regimens, with monthly review. Study participants and clinical assessors were masked to drug allocation. Allocation to continuous or discontinuous treatment was masked up to 3 months, at which point investigators and participants were unmasked. The primary outcome was BCVA at 2 years, with a prespecified non-inferiority limit of 3·5 letters. The primary safety outcome was arterial thrombotic event or hospital admission for heart failure. Analyses were by modified intention to treat. This trial is registered, number ISRCTN92166560.
FINDINGS: Between March 27, 2008, and Oct 15, 2010, 628 patients underwent randomisation. 18 were withdrawn; 610 received study drugs (314 ranibizumab; 296 bevacizumab) and were included in analyses. 525 participants reached the visit at 2 years: 134 ranibizumab in continuous regimen, 137 ranibizumab in discontinuous regimen, 127 bevacizumab in continuous regimen, and 127 bevacizumab in discontinuous regimen. For BCVA, bevacizumab was neither non-inferior nor inferior to ranibizumab (mean difference -1·37 letters, 95% CI -3·75 to 1·01; p=0·26). Discontinuous treatment was neither non-inferior nor inferior to continuous treatment (-1·63 letters, -4·01 to 0·75; p=0·18). Frequency of arterial thrombotic events or hospital admission for heart failure did not differ between groups given ranibizumab (20 [6%] of 314 participants) and bevacizumab (12 [4%] of 296; odds ratio [OR] 1·69, 95% CI 0·80-3·57; p=0·16), or those given continuous (12 [4%] of 308) and discontinuous treatment (20 [7%] of 302; 0·56, 0·27-1·19; p=0·13). Mortality was lower with continuous than discontinuous treatment (OR 0·47, 95% CI 0·22-1·03; p=0·05), but did not differ by drug group (0·96, 0·46-2·02; p=0·91).
INTERPRETATION: Ranibizumab and bevacizumab have similar efficacy. Reduction in the frequency of retreatment resulted in a small loss of efficacy irrespective of drug. Safety was worse when treatment was administered discontinuously. These findings highlight that the choice of anti-VEGF treatment strategy is less straightforward than previously thought.
FUNDING: UK National Institute for Health Research Health Technology Assessment programme. ||||| BACKGROUND: Vascular endothelial growth factor (VEGF) plays an important role in many diseases of the posterior pole that are characterized by macular edema and/or intraocular neovascularization. Recently anti-VEGF agents such as ranibizumab and pegaptanib sodium have been shown to be beneficial in the treatment of choroidal neovascularization (CNV) secondary to age-related macular degeneration (ARMD). However in most parts of the world, both pegaptanib sodium and ranibizumab are not readily available. Bevacizumab, a humanized recombinant monoclonal IgG antibody that binds and inhibits all VEGF isoforms, has been proposed as an alternative treatment option.
METHODS: A total of 1,265 consecutive patients were injected with bevacizumab for diseases such as proliferative diabetic retinopathy, diabetic macular edema, retinal vein occlusions, and CNV of several etiologies including ARMD at eight Latin American institutions from 1 September 2005 to 31 January 2006. Of these 1,265, 92 were excluded because they were injected once and lost to follow-up. The remaining 1,173 patients constitute the subjects of this retrospective, multicenter, open label, uncontrolled interventional case series that reports the cumulative systemic and ocular adverse events following intravitreal bevacizumab during 12 months of follow-up. Patients were examined at baseline and then monthly. If the patients were unable to attend the 12-month visit, a telephone interview was conducted to assess for possible systemic complications.
RESULTS: A total of 4,303 intravitreal injections of bevacizumab on 1,310 eyes was reported. All 1,173 patients were accounted for at the 12-month visit. Systemic adverse events were reported in 18 (1.5%) patients. These included seven (0.59%) cases of an acute elevation of systemic blood pressure, six (0.5%) cerebrovascular accidents, five (0.4%) myocardial infarctions, two (0.17%) iliac artery aneurysms, two (0.17%) toe amputations and five (0.4%) deaths. Ocular complications included seven (0.16%) bacterial endophthalmitis, seven (0.16%) tractional retinal detachments, four (0.09%) uveitis, and a case (0.02%) each of rhegmatogenous retinal detachment and vitreous hemorrhage.
CONCLUSION: Despite the limited follow-up, repeated intravitreal injections of either 1.25 mg or 2.5 mg of bevacizumab appears to be safe and well tolerated during the 1st year. ||||| OBJECTIVES: To evaluate the efficacy and safety of intravitreous bevacizumab injections for the treatment of neovascular age related macular degeneration.
DESIGN: Prospective, double masked, multicentre, randomised controlled trial.
SETTING: Three ophthalmology centres in the United Kingdom.
PARTICIPANTS: 131 patients (mean age 81) with wet age related macular degeneration randomised 1:1 to intervention or control.
INTERVENTIONS: Intravitreous bevacizumab (1.25 mg, three loading injections at six week intervals followed by further treatment if required at six week intervals) or standard treatment available at the start of the trial (photodynamic treatment with verteporfin for predominantly classic type neovascular age related macular degeneration, or intravitreal pegaptanib or sham treatment for occult or minimally classic type neovascular age related macular degeneration).
MAIN OUTCOME MEASURES: None
PRIMARY OUTCOME: proportion of patients gaining >or=15 letters of visual acuity at one year (54 weeks).
SECONDARY OUTCOMES: proportion of patients with stable vision and mean change in visual acuity.
RESULTS: Of the 131 patients enrolled in the trial, five patients did not complete the study because of adverse events, loss to follow-up, or death. In the bevacizumab group, 21 (32%) patients gained 15 or more letters from baseline visual acuity compared with two (3%) in the standard care group (P<0.001); the estimated adjusted odds ratio was 18.1 (95% confidence interval 3.6 to 91.2) and the number needed to treat was 4 (3 to 6). In addition, the proportion of patients who lost fewer than 15 letters of visual acuity from baseline was significantly greater among those receiving bevacizumab treatment (91% (59) v 67% (44) in standard care group; P<0.001). Mean visual acuity increased by 7.0 letters in the bevacizumab group with a median of seven injections compared with a decrease of 9.4 letters in the standard care group (P<0.001), and the initial improvement at week 18 (plus 6.6 letters) was sustained to week 54. Among 65 patients treated with bevacizumab, there were no cases of endophthalmitis or serious uveitis related to the intervention. All end points with respect to visual acuity in the study eye at 54 weeks favoured bevacizumab treatment over standard care.
CONCLUSIONS: Bevacizumab 1.25 mg intavitreous injections given as part of a six weekly variable retreatment regimen is superior to standard care (pegaptanib sodium, verteporfin, sham), with low rates of serious ocular adverse events. Treatment improved visual acuity on average at 54 weeks. Trial registration number Current controlled trials ISRCTN83325075. ||||| OBJECTIVE: To evaluate the relative efficacy and safety profile of bevacizumab versus ranibizumab intravitreal injections for the treatment of neovascular age-related macular degeneration (AMD).
DESIGN: Multicenter, prospective, noninferiority, double-masked, randomized clinical trial performed in 38 French ophthalmology centers. The noninferiority limit was 5 letters.
PARTICIPANTS: Patients aged ≥50 years were eligible if they presented with subfoveal neovascular AMD, with best-corrected visual acuity (BVCA) in the study eye of between 20/32 and 20/320 measured on the Early Treatment of Diabetic Retinopathy Study chart and a lesion area of less than 12 optic disc areas (DA).
METHODS: Patients were randomly assigned to intravitreal administration of bevacizumab (1.25 mg) or ranibizumab (0.50 mg). Hospital pharmacies were responsible for preparing, blinding, and dispensing treatments. Patients were followed for 1 year, with a loading dose of 3 monthly intravitreal injections, followed by an as-needed regimen (1 injection in case of active disease) for the remaining 9 months with monthly follow-up.
MAIN OUTCOME MEASURES: Mean change in visual acuity at 1 year.
RESULTS: Between June 2009 and November 2011, 501 patients were randomized. In the per protocol analysis, bevacizumab was noninferior to ranibizumab (bevacizumab minus ranibizumab +1.89 letters; 95% confidence interval [CI], -1.16 to +4.93, P < 0.0001). The intention-to-treat analysis was concordant. The mean number of injections was 6.8 in the bevacizumab group and 6.5 in the ranibizumab group (P = 0.39). Both drugs reduced the central subfield macular thickness, with a mean decrease of 95 μm for bevacizumab and 107 μm for ranibizumab (P = 0.27). There were no significant differences in the presence of subretinal or intraretinal fluid at final evaluation, dye leakage on angiogram, or change in choroidal neovascular area. The proportion of patients with serious adverse events was 12.6% in the bevacizumab group and 12.1% in the ranibizumab group (P = 0.88). The proportion of patients with serious systemic or ocular adverse events was similar in both groups.
CONCLUSIONS: Bevacizumab was noninferior to ranibizumab for visual acuity at 1 year with similar safety profiles. Ranibizumab tended to have a better anatomic outcome. The results are similar to those of previous head-to-head studies. ||||| PURPOSE: Several clinical trials have established the efficacy of ranibizumab therapy administered every 4 weeks to treat exudative age-related macular degeneration (ARMD). Bevacizumab appears to be a cost-effective alternative to ranibizumab, although an optimal injection schedule has not yet been determined. In this study, we set out to determine whether bevacizumab treatment in exudative ARMD every 6 or 8 weeks is non-inferior to bevacizumab treatment every 4 weeks.
METHODS: A total of 191 patients with exudative ARMD were randomly assigned to a 1-year continuous regimen of intravitreal bevacizumab every 4 (n = 64), 6 (n = 63) or 8 weeks (n = 64). The primary outcome was visual acuity change after 1 year of treatment.
RESULTS: In all three treatment groups, visual acuity improved between baseline and 1 year. There was no statistically significant difference in the mean change of visual acuity score at 1 year for bevacizumab administered every 4 (1.96 ± 13.70), 6 (1.60 ± 10.98) or 8 weeks (5.98 ± 8.88). Reduction in central retinal thickness was observed in all three study groups. At 1 year, the mean decrease in central foveal thickness ranged from 86 ± 97 μm in the every 6 weeks group to 109 ± 90 μm in the group every 8 weeks group (p = 0.30).
CONCLUSION: At 1 year, bevacizumab administered every 6 or 8 weeks was not inferior to therapy administered every 4 weeks. ||||| PURPOSE: To determine whether a Pro Re Nata (PRN) regimen with three initial mandatory loading doses results in better functional and anatomical outcome compared with a PRN regimen without initial loading when using intravitreal bevacizumab in patients with minimal classic or occult choroidal neovascularisation secondary to age-related macular degeneration.
METHODS: Patients were randomised (1 : 1) to Loading (LD group) or No Loading (NLD group) and treated with open label intravitreal bevacizumab. In the LD group, patients received two mandatory doses after the baseline dose before entering the PRN phase and in the NLD group, patients did not receive mandatory doses after the baseline dose. Six-weekly evaluations were performed up to week 54 and retreatment was done based on OCT criteria. Visual stability and reduction in central retinal thickness were compared between groups.
RESULTS: 49 patients were in the NLD group and 50 patients were in the LD group. At the 12-month end point, 84% of the patients in the LD group achieved visual stability (<15 letter loss) compared with 67% of the patients in the NLD group (P<0.05). The mean reduction in central macular thickness was 105.35 μm in the LD group and 81.45 μm in the NLD group (P>0.05). There was no significant difference in scores of VFQ-25 questionnaire testing between the two groups and no serious ocular or systemic side effects were observed.
CONCLUSION: The results supported our hypothesis that a loading dose leads to slightly better visual stability in terms of proportions of patients experiencing moderate visual loss, but did not support the hypothesised difference in anatomical outcome. ||||| PURPOSE: To systematically study potential adverse events associated with the use of intraocular bevacizumab at a single medical center.
METHODS: Retrospective study of all consecutive patients receiving intraocular bevacizumab injections at the Stanford University Department of Ophthalmology between November 15, 2005 and July 14, 2006. Bevacizumab was given for exudative age-related macular degeneration, retinal vascular occlusion, diabetic macular edema, neovascular glaucoma, and five other indications.
RESULTS: We analyzed medical records of 186 subjects (203 eyes) who received a total of 578 injections of 1.25 mg of bevacizumab. The average follow-up was approximately 6 months. Five eyes with exudative age-related macular degeneration developed retinal pigment epithelial (RPE) tears, all with preexisting RPE detachments. These five eyes represented 2.9% of all age-related macular degeneration eyes treated and 7% of the age-related macular degeneration eyes with preexisting RPE detachments at initiation of treatment. Other adverse events were rare and included retinal ischemia, subretinal hemorrhage, vitreous hemorrhage, ocular irritation or pain, worsened hypertension, and headache. No death or thromboembolic events were observed.
CONCLUSION: Intraocular bevacizumab appears to be well tolerated for the treatment of a variety of retinal and choroidal vascular diseases. RPE tears may occur when treating choroidal neovascularization, particularly in patients with preexisting RPE detachment. ||||| PURPOSE: To compare the efficacy and safety of bevacizumab versus ranibizumab when administered according to a treat-and-extend protocol for the treatment of neovascular age-related macular degeneration (AMD).
DESIGN: Multicenter, randomized, noninferiority trial with a noninferiority limit of 5 letters.
PARTICIPANTS: Patients aged ≥ 50 years with previously untreated neovascular AMD in 1 eye and best-corrected visual acuity (BCVA) between 20/25 and 20/320.
METHODS: Patients were randomly assigned to receive ranibizumab 0.5 mg or bevacizumab 1.25 mg intravitreal injections. Monthly injections were given until inactive disease was achieved. The patients were then followed with a gradual extension of treatment interval by 2 weeks at a time up to a maximum of 12 weeks. If signs of recurrent disease appeared, the treatment interval was shortened by 2 weeks at a time.
MAIN OUTCOME MEASURES: Change in visual acuity at 1 year.
RESULTS: Between March 2009 and July 2012, 441 patients were randomized at 10 ophthalmological centers in Norway. The 1-year visit was completed by 371 patients. In the per protocol analysis at 1 year, bevacizumab was equivalent to ranibizumab, with 7.9 and 8.2 mean letters gained, respectively (95% confidence interval [CI] of mean difference, -2.4 to 2.9; P = 0.845). The intention-to-treat analysis was concordant. There was no significant difference in measured central retinal thickness (CRT), with a mean decrease of -112 μm for bevacizumab and -120 μm for ranibizumab (95% CI of mean difference, -13 to 28; P = 0.460). There was a statistically significant difference (P = 0.001) between the drugs regarding the number of treatments: 8.9 for bevacizumab and 8.0 for ranibizumab. There were fewer arteriothrombotic events in the bevacizumab group (1.4%) than in the ranibizumab group (4.5%) (P = 0.050) and significantly more cardiac events in the ranibizumab group (P = 0.036). However, patients treated with ranibizumab more often had a history of myocardial infarction (P = 0.021).
CONCLUSIONS: Bevacizumab and ranibizumab had equivalent effects on visual acuity at 1 year when administered according to a treat-and-extend protocol. The visual acuity results at 1 year were comparable to those of other clinical trials with monthly treatment. The numbers of serious adverse events were small. ||||| BACKGROUND/AIMS: To compare retrospectively the incidence of arterial thromboembolic events (ATEs) in patients treated with bevacizumab or ranibizumab for exudative age-related macular degeneration.
METHODS: Charts of 378 patients treated with at least 1 intravitreal injection of ranibizumab or bevacizumab were reviewed to calculate the incidence of ATEs. Only patients under monotherapy were analyzed.
RESULTS: ATEs occurred in 15 patients: 12 (12/97) with bevacizumab (12.4%) and 3 (3/219) with ranibizumab (1.4%) - odds ratio 10.16; 95% confidence interval 2.80-36.93; p < 0.0001. ATEs in the bevacizumab and ranibizumab cohorts included stroke, myocardial infarction, angina pectoris, peripheral thromboembolic disease, transient ischemic attack, sudden death and lethal stroke.
CONCLUSION: In this series, bevacizumab raised the risk of ATEs when compared to ranibizumab. In an elderly population with multiple cardiovascular risk factors, the new ATEs may not be attributed exclusively to the intravitreal bevacizumab administration. These findings raise an issue that must be confirmed in randomized clinical trials. ||||| BACKGROUND: Clinical trials have established the efficacy of ranibizumab for the treatment of neovascular age-related macular degeneration (AMD). In addition, bevacizumab is used off-label to treat AMD, despite the absence of similar supporting data.
METHODS: In a multicenter, single-blind, noninferiority trial, we randomly assigned 1208 patients with neovascular AMD to receive intravitreal injections of ranibizumab or bevacizumab on either a monthly schedule or as needed with monthly evaluation. The primary outcome was the mean change in visual acuity at 1 year, with a noninferiority limit of 5 letters on the eye chart.
RESULTS: Bevacizumab administered monthly was equivalent to ranibizumab administered monthly, with 8.0 and 8.5 letters gained, respectively. Bevacizumab administered as needed was equivalent to ranibizumab as needed, with 5.9 and 6.8 letters gained, respectively. Ranibizumab as needed was equivalent to monthly ranibizumab, although the comparison between bevacizumab as needed and monthly bevacizumab was inconclusive. The mean decrease in central retinal thickness was greater in the ranibizumab-monthly group (196 μm) than in the other groups (152 to 168 μm, P=0.03 by analysis of variance). Rates of death, myocardial infarction, and stroke were similar for patients receiving either bevacizumab or ranibizumab (P>0.20). The proportion of patients with serious systemic adverse events (primarily hospitalizations) was higher with bevacizumab than with ranibizumab (24.1% vs. 19.0%; risk ratio, 1.29; 95% confidence interval, 1.01 to 1.66), with excess events broadly distributed in disease categories not identified in previous studies as areas of concern.
CONCLUSIONS: At 1 year, bevacizumab and ranibizumab had equivalent effects on visual acuity when administered according to the same schedule. Ranibizumab given as needed with monthly evaluation had effects on vision that were equivalent to those of ranibizumab administered monthly. Differences in rates of serious adverse events require further study. (Funded by the National Eye Institute; ClinicalTrials.gov number, NCT00593450.). ||||| AIM: The current accepted standard treatment for neovascular age-related macular degeneration (AMD) consists of antivascular endothelial growth factor agents including ranibizumab and bevacizumab. The aim of the study was to examine whether bevacizumab is inferior to ranibizumab with respect to maintaining/improving visual acuity.
METHODS: In this prospective randomised parallel group multicentre trial patients aged more than 50 years with treatment naive nAMD were included at 10 Austrian centres. Patients were randomised to treatment either with 0.5 mg ranibizumab or 1.25 mg bevacizumab. Both groups received three initial monthly injections and thereafter monthly evaluation of visual acuity and the activity of the lesion. Re-treatment was scheduled as needed. Outcome measures were early treatment of diabetic retinopathy visual acuity, retinal thickness, lesion size and safety evaluation.
RESULTS: A total of 321 patients were recruited of which four had to be excluded due to different reasons. Of the 317 remaining patients 154 were randomised into the bevacizumab group and 163 into the ranibizumab group. At month 12, there was a mean increase of early treatment of diabetic retinopathy visual acuity of 4.9 letters in the bevacizumab and 4.1 letters in the ranibizumab group (p=0.78). Furthermore, there were no significant differences in the decrease of retinal thickness, change of lesion size and number of adverse events between the groups.
CONCLUSIONS: Bevacizumab was equivalent to ranibizumab for visual acuity at all time points over 1 year. There was no significant difference of decrease of retinal thickness or number of adverse events. | [
{
"source_pmid": "20937996",
"source_text": "OBJECTIVE: To examine associations between therapies for age-related macular degeneration and risks of all-cause mortality, incident myocardial infarction, bleeding, and incident stroke.\nMETHODS: We conducted a retrospective cohort study of 146,942 Medicare bene... |
24921712 | CONCLUSIONS AND RELEVANCE: Although confounding factors such as size of the eye and surgeon experience are not accounted for in this meta-analysis, the risk for postoperative glaucoma after infantile cataract surgery appears to be influenced by the timing of surgery, primary implantation, and additional intraocular surgery. | PURPOSE: To evaluate the long-term visual function outcomes of intraocular lens (IOL) implantation after congenital cataract surgery in children.
METHODS: Forty children who had congenital cataract surgery with IOL implantation and at least 5 years follow-up and were 5 years or younger at the time of surgery were included. There were 18 children in the bilateral cataract group (36 pseudophakic eyes) and 22 children in the unilateral cataract group (22 pseudophakic eyes). The examination for the prospective part of this study included the recording of visual acuity, refraction, stereopsis, and intraocular pressures; preoperative, intraoperative, and postoperative details were obtained from the notes.
RESULTS: Mean final best-corrected visual acuity for the bilateral group was 0.57 logMAR (range 0.18 -1.06) and for the unilateral group 0.91 logMAR (range 0.18 -1.40). Nystagmus was recorded in 10 children (56%) of the bilateral group and 5 children (23%) of the unilateral group. Strabismus was recorded in 14 children (78%) of the bilateral group and 19 children (86%) of the unilateral group. Glaucoma was diagnosed in one child. There was a significant myopic shift in the unilateral group.
CONCLUSIONS: Reasonably good postoperative visual acuity was achieved in the bilateral cataracts group, but relatively poor acuity in the unilateral cataract group. Poor stereopsis was recorded in both groups. One child developed glaucoma. None of the children developed retinal detachment. The expected myopic shift in the unilateral group compared with the bilateral group was demonstrated. Elective primary capsulotomy and elective anterior vitrectomy are mandatory to keep a clear visual axis. ||||| PURPOSE: To evaluate long-term functional outcome after treatment of congenital unilateral cataract.
METHODS: The records of 30 consecutive children operated on before the age of 12 months at St. Erik's Eye Hospital over a 5-year period (1991-96) were reviewed retrospectively. The patients were followed until 4-9.5 years of age. Linear Snellen visual acuity (VA), occlusion therapy compliance, and the presence of nystagmus, strabismus and other complications are reported.
RESULTS: Six children achieved VA of 0.1 or better. They were all operated on before 3 months of age. Of the 12 infants operated on before 6 weeks of age, four have VA between 0.3 and 0.4 and eight have VA of finger counting or less. Four developed severe secondary glaucoma within 6 months of cataract extraction. Two of these had persistent fetal vasculature. Three eyes developing glaucoma became amaurotic. Occlusion therapy was abandoned before the age of 2.5 years in 21 children.
CONCLUSION: Good levels of VA were achieved only in children who underwent cataract surgery before 3 months of age and who adhered to the occlusion therapy schedule. Severe secondary glaucoma developed in four out of 12 children operated on within 6 weeks. Full compliance with the occlusion therapy programme was uncommon. ||||| PURPOSE: We sought to report the incidence of visual axis opacification and to evaluate the complication and reoperation rates after intraocular lens implantation in infants.
METHODS: Twenty-one infants (31 eyes) who had cataract extraction with primary hydrophobic acrylic IOL implantation between October 1996 and May 2002 were reviewed. Posterior capsule was left intact in 14 eyes (group A); posterior capsulorrhexis or capsulotomy with anterior vitrectomy was performed in 17 eyes (group B). Complication and reoperation rates were compared with an age-matched control group of 17 patients (33 eyes) who were left aphakic after pars plicata lensectomy. Mean follow-up period was 41 months (range, 22-75 months) in group A, 37 months (range, 10-75 months) in group B, and 52 months (range, 7-97 months) in the control group.
RESULTS: Mean age of the patients was 6.8 months (range, 3-10 months) in group A, 8.9 months (range, 3-18 months) in group B, and 4.9 months (range, 1-15 months) in the control group. Visual axis opacification was significantly higher in group A (86%) when compared with group B (17.6%; P < 0.0001). No significant difference was found in terms of pupillary irregularities and peripheral anterior synechiae formation between pseudophakic and aphakic group ( P = 0.43 and P = 0.306, respectively), whereas pigment dispersion and fibrinous reaction were significantly more common in the pseudophakic group ( P = 0.002). Serious complications, such as retinal detachment, pseudophakic bullous keratopathy, and secondary glaucoma, did not develop in any eye. Reoperation rate was significantly higher in group A (78%) when compared with group B (17%) and the control group (12%; P = 0.0011 and P < 0.0001, respectively).
CONCLUSIONS: Visual axis opacification requiring a reoperation was significantly more common in patients with an intact posterior capsule. To decrease the reoperation rate and maintain a clear visual axis, posterior capsulorrhexis with anterior vitrectomy should be performed. Even although early complications were quite frequent, serious late complications were not encountered in any eye. Therefore, under appropriate conditions, IOL implantation is a suitable alternative in infants. ||||| PURPOSE: To report the relative risk for aphakic glaucoma as a function of age at surgery in infants who underwent cataract surgery before 10 months of age for nontraumatic infantile cataract without microcornea.
METHODS: This was an institutional retrospective case series (January 1985 to February 2003) of children who underwent cataract surgery without intraocular lens implantation for nontraumatic infantile cataract before 10 months of age. Patients with less than 5 years' postsurgical follow-up, microcornea, persistent fetal vasculature, and/or other significant anterior segment abnormality were excluded.
RESULTS: The surgical procedure in all cases was lens aspiration, posterior capsulotomy, and anterior vitrectomy with anterior small-incision techniques. Of 210 eyes (121 patients), 55 eyes (26.2%; 31 patients [25.6%]) developed aphakic glaucoma. Relative risk for later aphakic glaucoma as a function of age at the time of surgery decreased from 1.85 (95% CI, 0.88-3.86) at 0-1 months of age to a nadir at 3-4 months of age (0.22 [95% CI, 0.05-0.96]) and then increased again to peak at 3.17 (95% CI, 1.1-9.11) at 5-6 months of age.
CONCLUSIONS: The lowest relative risk for later aphakic glaucoma in our cohort was for surgery performed at 3-4 months of age, for which the 95% CI remained less than 1.0. Further conclusions are limited by overlapping confidence intervals. However, because of amblyopia issues, we do not recommend delaying congenital cataract surgery beyond 4 weeks of life. ||||| BACKGROUND: To present the visual results and the complications of primary intraocular lens (IOL) implantation in infants aged 6 to 12 months between January 2002 and July 2007.
METHODS: A total of 26 consecutive eyes, of 16 infants with cataract aged 6 to 12 months, were reviewed in the study. All patients had cataract extraction with anterior and posterior capsulorrhexis combined with anterior vitrectomy and primary hydrophobic acrylic IOL implantation. Six infants (six eyes) had unilateral congenital cataract and ten (20 eyes), bilateral cataract. Visual acuity and complications were recorded throughout the 46.4-month mean follow-up (range 22 to 79 months).
RESULTS: All eyes had primary IOL implantation. The mean best-corrected visual acuity (logMAR) was 0.98 +/- 0.18,0.50 +/- 0.14 and 0.61 +/- 0.25 for unilateral, bilateral and all eyes respectively at the last follow-up. IOLs were implanted in the capsular bag of 25 eyes (96.2%) and in the sulcus of the remaining one eye (3.8%). Seven eyes (26.9%) developed visual axis opacification (VAO), and four eyes required secondary pars plana vitrectomy (PPV). IOL opacification occurred in one eye 54 months after implantation. Late onset open-angle glaucoma developed in one eye, and required trabeculectomy surgery. The predictors of good best-corrected visual acuity (BCVA) included partial cataract, bilateral cataract, absence of strabismus or nystagmus, and good amblyopic treatment. The greatest annual myopic change (5.15 +/- 2.08 D) was observed during the first 12 months after surgery. In unilateral cases, there was no significant difference in the axial length between the cataractous eye and the fellow normal eye both at the time of surgery (P = 0.891) and final follow-up (P = 0.693).
CONCLUSIONS: Primary IOL implantation was safe and effective for infantile cataract surgery. Total or unilateral cataract, nystagmus or strabismus, and inadequate amblyopic therapy were predictors of poor BCVA. Significant myopic shifts occurred especially in infants in the first year of surgery. The pseudophakic eye had a similar growth rate, as measured by axial length, to that of the fellow normal eye, in unilateral cases. ||||| INTRODUCTION: We sought to define the prevalence and natural history of ocular hypertension and glaucoma for at least a 10-year period after pediatric cataract surgery.
METHODS: We conducted a prospective observational study of patients who received pediatric cataract surgery. Inclusion criteria included 2 directed ophthalmologic examinations performed at a minimum of 5 and 10 years after surgery.
RESULTS: A total of 63 patients (22 with bilateral cataracts and 41 with unilateral cataracts) were examined at a median of 15.1 year (range, 10.3-21.3 years) after surgery. A majority of the subjects had glaucoma or ocular hypertension (ie, 59%; 37/63). Nineteen percent (12/63) had glaucoma (5/22 with bilateral cataracts and 7/41 with unilateral cataracts). Approximately half (7/12) had developed glaucoma during the first 5-year observational period and the remainder (5/12) developed it during the following observational period. Forty percent (25/63) of the patients had ocular hypertension in at least one aphakic eye (9/23 with bilateral cataracts and 16/40 with unilateral cataracts). The rate of progression from ocular hypertension to glaucoma over a mean observational period of 7.2 years (range, 6.2-8.1 years) was 23% (5/22).
DISCUSSION: Patients who receive surgery for pediatric cataracts are at very high risk of developing ocular hypertension and glaucoma. Patients can develop late-onset glaucoma and ocular hypertension more than 10 years after surgery. Years of ocular hypertension may precede the diagnosis of late-onset glaucoma. ||||| PURPOSE: To evaluate the complications and visual results in a consecutive series of patients having cataract extraction with intraocular lens (IOL) implantation in the first year of life.
SETTING: St. Erik's Eye Hospital, Stockholm, Sweden.
METHODS: This retrospective study comprised 28 children (31 eyes) who had cataract surgery with primary IOL implantation.
RESULTS: The median age at surgery was 2.5 months (range 8 days to 10 months). The median follow-up was 36 months. Two newborns with persistent fetal vasculature (PFV) who had surgery at 8 days and 17 days, respectively, developed intraoperative vitreous hemorrhage; a retinal detachment developed in 1 of the eyes. Intraocular lens luxation occurred in 2 infants with PFV. Seventy percent of eyes developed opacification of the visual axis that required additional surgery. Chronic glaucoma developed in 2 eyes and transitory glaucoma in 1 eye. Two of the glaucoma cases occurred in eyes with PFV. In 7 eyes of 4 infants with bilateral cataract, the median visual acuity was 20/63 (range 20/25 to 20/100). In 12 infants with unilateral cataract without PFV, 7 achieved a visual acuity between 20/32 and 20/200 (median 20/63), 4 achieved counting fingers (CF), and 1 achieved light perception. In 12 eyes with PFV, 2 achieved a visual acuity of 20/200 and the rest achieved CF or worse.
CONCLUSIONS: After-cataract with membrane formation was the main complication in infants with primary IOL implantation. The glaucoma incidence was low at the last follow-up. ||||| AIM: To determine the prevalence and risk factors associated with secondary glaucoma postcongenital cataract surgery.
METHODS: All children diagnosed as having congenital cataracts in a major children's hospital between 1985 and 2005 were included in a retrospective case series. Medical records of 423 eyes among 283 patients who underwent cataract surgery with or without intraocular lens implantation at age </=16 for congenital cataract were reviewed. The main outcome measure was presence or absence of secondary glaucoma and time to glaucoma postsurgery. The following risk factors were evaluated: age at cataract surgery, presence of systemic anomalies, microcornea, persistent hyperplastic primary vitreous (PHPV), primary capsulotomy/anterior vitrectomy, primary intraocular lens implantation, secondary membrane surgery and duration of postoperative observation.
RESULTS: The statistical methods were the use of Kaplan-Meier survival analysis and Multivariate Cox hazards regression analysis. The mean follow-up was 6.3 (SD 5.0) years (median 4.6 years; range 0.5 to 20.3 years). Glaucoma developed in 36 of 234 patients (15.4%). Multivariate Cox proportional hazards regression analysis identified age less than 9 months at time of surgery (RR 2.9, 95% CI 1.3 to 7.7; p = 0.03), microcornea (RR 3.7, 95% CI 2.0 to 7.0; p<0.001), and follow-up time as important predictors of glaucoma. PHPV (RR 1.4, 95% CI 0.7 to 2.7; p = 0.41) and primary posterior capsulotomy/anterior vitrectomy (RR 2.2, 95% CI 0.9 to 5.5; p = 0.17) were not significantly associated with secondary glaucoma in the multivariate model. The mean time to glaucoma after congenital cataract surgery was 4.9 years (range 2 weeks to 16.8 years).
CONCLUSION: Secondary glaucoma is an important sequela in patients who undergo surgery for congenital cataracts. It is imperative that these patients get lifelong surveillance, as glaucoma can occur years after the initial operation. ||||| PURPOSE: To evaluate visual and stereoscopic performance after pediatric cataract extraction with intraocular lens (IOL) implantation performed by the same surgeon over 24 years and to review the complications.
SETTING: The Alberta Children's Hospital, Calgary, Alberta, Canada.
METHODS: This retrospective review comprised children aged 1 month to 18 years who had small-incision cataract extraction with foldable posterior chamber IOL implantation from 1995 to 2008.
RESULTS: The postoperative follow-up was 6 months to 12 years. Posterior capsule opacification (PCO) requiring secondary surgical membranectomy developed in 22.7% of the children. Younger children developed PCO more often than older children. The PCO rate was 70.8% in children younger than 1 year and decreased steadily to 6.1% in children older than 7 years. The mean onset of PCO was 6.1 months postoperatively. Other complications were vitreous tags (12.0%), IOL dislocation (4.7%), and loose corneal sclera sutures (2.7%). Of the eyes in which vision could be recorded, 89.5% had improved corrected visual acuity, with no eye losing acuity. Stereopsis was present in 35% of testable children preoperatively and 91% postoperatively.
CONCLUSIONS: Cataract surgery in children younger than 2 years should be considered a 2-stage procedure in view of the higher incidence of PCO. Secondary glaucoma decreased significantly when surgery was performed after 30 days of age and the eye was left pseudophakic after surgery. Further improvements in IOL design, surgical instrumentation, and implantation techniques will continue to improve the ability to visually rehabilitate children. ||||| BACKGROUND: To determine the rate of glaucoma following congenital cataract surgery at Moorfields Eye Hospital (MEH), and to investigate potential risk factors for glaucoma in our case series.
METHODS: A retrospective case notes review was undertaken of all congenital cataract lensectomies performed at MEH between 1994 and 2000. The following parameters were ascertained: age at surgery, unilateral or bilateral cataract, whether a posterior capsulotomy (PC) was performed at the time of surgery, whether an intraocular lens (IOL) was inserted, duration of follow-up, and if aphakic glaucoma (AG) developed. All lensectomies were performed through a limbal incision by a single consultant surgeon.
RESULTS: A total of 47 subjects were identified - 40 patients with bilateral cataracts and 7 with unilateral. Of the 40 bilateral cataract patients, 76 eyes had lensectomies; with 37 of these patients (71 lensectomies) having at least 5 year follow-up. Based on patient count, the 5 year risk of AG in at least one eye following surgery was 21.6%. Based on eye count, the 5 year risk of AG after lensectomy was 15.5%. The average age at surgery of patients who did not develop AG, and had at least 5 years follow-up, was 28.7 months (range 2 weeks to 6 years), with 20% having surgery within the first month of life. In comparison, the average age at surgery of patients with at least 5 years follow-up, who developed AG was 1.6 months (range 2 weeks to 7 months), with 60% having surgery within the first month of life. In subjects with at least 5 years follow-up, a PC rate of 100% was identified in the eyes that developed AG, compared to 61% in eyes that did not develop AG. An IOL was inserted in O% of eyes with AG, compared to 57% in eyes that did not develop AG. Onset of AG ranged from one month post surgery to 7 years, with an average yearly incidence of 5.3%.
CONCLUSION: Early surgery in patients with bilateral cataracts is associated with a marked increase in risk of AG. Our data suggest that an intact posterior capsule may be associated with a lower rate of AG. ||||| PURPOSE: To determine the frequency of and identify predictors of chronic glaucoma after pediatric cataract surgery.
DESIGN: Interventional case series.
METHODS: Retrospective review at an eye hospital identified 570 eyes among 322 patients who underwent limbal-approach surgery without intraocular lens implantation at age <or=16 years for cataract unassociated with other ocular anomalies aside from microcornea. Patients had a minimum of 5 years' postoperative follow-up, which included intraocular pressure measurement. The outcome measure was the presence or absence of postcataract surgery glaucoma, defined as intraocular pressure >or=26 mm Hg, as measured on at least two occasions.
RESULTS: Mean follow-up was 9.0 +/- 3.1 years (median, 8.1 years; range, 5.0-18.3 years). Glaucoma developed in 118 of 570 patients' eyes (21%), including 101 of 272 (37%) undergoing surgery at <or=9 months of age and 17 of 298 (6%) undergoing surgery thereafter. Multivariable Cox proportional hazards regression analysis with adjustment for potential intrasubject correlation identified surgery at <or=9 months of age (hazard ratio [HR], 3.8; 95% confidence interval [CI], 1.8-7.7; P <.001), secondary membrane surgery (HR, 2.6; 95% CI, 1.3-5.3; P =.006), microcornea (HR, 1.9; 95% CI, 1.2-3.1; P =.008), and primary posterior capsulotomy/anterior vitrectomy (HR, 10.7; 95% CI, 1.4-80.6; P =.02) as predictors of glaucoma.
CONCLUSIONS: Chronic glaucoma is common after cataract surgery performed at or before, but not after, a certain age in childhood. The data suggest that this age threshold is 9 months, but a true threshold occurring at a somewhat later age cannot be fully excluded. ||||| AIMS: To estimate the risk of aphakic glaucoma after lensectomy for congenital cataract and its association with surgery within the first month of life.
METHOD: A retrospective case notes review was conducted of all patients who had lensectomy for congenital cataract during their first year of life at Great Ormond Street Hospital between 1994 and 1997. Patients with pre-existing glaucoma, anterior segment dysgenesis, and Lowe syndrome were excluded. The risk of aphakic glaucoma after surgery was estimated using Kaplan-Meier survival analysis.
RESULTS: 80 patients, undergoing 128 lensectomies were eligible. Of these, six patients (nine eyes) were lost to follow up. Based on eye count, the risk of glaucoma by 5 years after lensectomy was 15.6% (95% CI 10.2 to 23.4). Based on patient count, the 5 year risk of glaucoma in at least one eye following bilateral surgery was 25.1% (95% CI 15.1 to 40.0). The incidence of glaucoma remained at a constant level for the first 5 years after surgery. After early bilateral lensectomy, within the first month of life, the 5 year risk of glaucoma in at least one eye was 50% (95% CI 27.8 to 77.1) compared to 14.9% (95% CI 6.5 to 32.1) with surgery performed later (log rank test, p = 0.012). There was no significant difference (Kolmogorov-Smirnov test: unilateral lensectomy p = 0.587, bilateral lensectomy p = 0.369) in 5 year visual outcomes between eyes operated before and after 1 month of age.
CONCLUSION: Bilateral lensectomy during the first month of life is associated with a higher risk of subsequent glaucoma than with surgery performed later. The reason for this is unclear but it may be prudent, in bilateral cases, to consider delaying surgery until the infant is 4 weeks old. As the incidence of glaucoma is similar for each year after surgery, long term glaucoma surveillance is mandatory. ||||| PURPOSE: The method of correcting aphakia after unilateral cataract extraction during infancy is controversial. Some authorities advocate correction with an intraocular lens (IOL) whereas others advocate correction with a contact lens (CL). We compared grating visual acuity, alignment, and reoperative outcomes in age-matched children treated with these 2 modalities at 5 clinical centers.
METHODS: Twenty-five infants born in 1997 or 1998 with a dense unilateral congenital cataract who had cataract surgery coupled with (IOL group, n = 12) or without (CL group, n = 13) primary IOL implantation were enrolled in this study. All patients were prescribed half-time occlusion therapy. In July 1999, their grating visual acuities, ocular alignments, and reoperation rates were assessed.
RESULTS: The mean grating visual acuity (LogMAR) for the affected eye was 0.70 +/- 0.32 for the IOL group and 0.87 +/- 0.31 for the CL group (P =.19). The mean interocular difference in grating visual acuity was 0.26 +/- 0.30 for the IOL group and 0.50 +/- 0.28 for the CL group (P =.048). The incidence of strabismus (>10 PD) was 75% in the IOL group compared with 92% in the CL group (P =.24). The incidence of reoperations was 83% in the IOL group compared with 23% in the CL group (P =.003).
CONCLUSIONS: Our preliminary data suggest that correcting aphakia after unilateral congenital cataract surgery with primary IOL implantation results in an improved visual outcome but a higher rate of complications requiring reoperation. A randomized clinical trial, the Infant Aphakia Treatment Study, is planned to further study the optimal treatment for aphakia following unilateral cataract extraction during infancy. ||||| PURPOSE: The optimal role of intraocular lenses (IOLs) in infants remains a controversial topic for many reasons, including concerns about significant complications occurring in young rapidly developing eyes.
METHODS: To assess the number and type of significant complications requiring further intervention occurring in the first postoperative year, we reviewed the records of 15 eyes of 13 infants undergoing lensectomy with posterior chamber IOL and pars plana vitrectomy (PPV)/capsulectomy under 6 months (group A) of age as part of an ongoing prospective study of IOL use in infants. This group was compared with a group of 16 children age 10 months to 5 years undergoing an identical procedure (group B) and a group of 33 infants less than 6 months of age undergoing lensectomy/vitrectomy without IOL (group C).
RESULTS: Thirteen of 15 eyes in group A required additional surgery in the first postoperative year. Twelve of the 15 eyes (80%) developed secondary opacification across the visual axis posterior to the IOL requiring a second PPV and one eye developed pseudophakic glaucoma. Two patients required a third PPV to keep the visual axis clear. In group B, 0 of 16 (P <.0001) developed secondary opacification of the visual axis. In group C, 4 of 33 (12%; P <.0001) developed pupillary opacification in the first postoperative year.
CONCLUSIONS: Intraocular lens implants in infants may be associated with a higher complication rate requiring further surgery during the first postoperative year than is lensectomy/vitrectomy surgery without IOL implant in infants or lensectomy/IOL/vitrectomy surgery in children older than 6 months of age. ||||| INTRODUCTION: We examined the critical period for deprivation amblyopia in a cohort of patients with dense bilateral congenital cataracts to investigate the optimum timing for surgical treatment.
METHODS: Thirty-seven infants with dense bilateral congenital cataracts that were extracted by 31 weeks of age were enrolled prospectively. Visual acuity outcome was assessed at >/=5 years of age. We statistically evaluated which of 4 models provided the best fit to the data: (1) no change in visual acuity outcome with delay in surgery, (2) linear decline of outcome with delay, (3) a bilinear model in which a critical age exists after which outcome depends on delay, and (4) a bilinear model in which a critical age exists before which outcome depends on delay. In addition, we reviewed medical records for associated adverse outcomes, including strabismus, nystagmus, secondary membrane formation, and glaucoma.
RESULTS: A bilinear model with a critical age of 14 weeks fit the data better than a linear model (chi(2) = 14.7; p < 0.0006). During weeks 0-14, mean visual acuity decreased by 1 line with each 3 weeks' delay in surgery. From 14 to 31 weeks, visual acuity was independent the subject's age at surgery, averaging 20/80. Surgery after 4 weeks was associated with a greater prevalence of strabismus and nystagmus than surgery before 4 weeks, whereas surgery during the first 4 weeks was associated with a greater prevalence of secondary membrane formation and glaucoma.
CONCLUSIONS: We did not find a latent period for the treatment of children with dense bilateral congenital cataracts. Deprivation amblyopia may be minimized with early surgery for bilateral cataracts. ||||| PURPOSE: To determine the incidence and risk factors for glaucoma in pseudophakic and aphakic eyes following surgery for congenital cataract within the first year of life.
METHODS: We conducted a review of all cataract surgery performed at our unit over a 23-year period. Age at surgery, corneal diameter, intraocular lens implantation, presence of persistent foetal vasculature and visual axis opacification (VAO) were documented. Time to development of glaucoma, management and outcome were determined. One eye was selected randomly for analysis in cases of bilateral cataract.
RESULTS: Duration of follow-up was significantly longer (p < 0.001) in the aphakic (113 +/- 69 months) compared to the pseudophakic group (56 +/- 44 months). Age at surgery was significantly less (p = 0.01) in the aphakic group. The incidence of glaucoma was significantly greater (p = 0.02) in the aphakic (15 eyes, 33%) compared to the pseudophakic (seven eyes, 13%) group. Each eye that developed glaucoma underwent cataract extraction aged < or = 2.5 months. Analysis of all eyes that underwent surgery aged < or = 2.5 months revealed no statistical difference (p = 0.08) in the incidence of glaucoma. Smaller corneal diameter and VAO were not associated with increased risk of glaucoma development. Ahmed valves proved effective in controlling intraocular pressure but visual outcome was poor in the majority of cases.
CONCLUSION: Surgery for congenital cataract at an early age increases the risk of glaucoma development, regardless of whether the eye is aphakic or pseudophakic. Intraocular pressure control with Ahmed valves is frequently required. Glaucomatous damage and dense amblyopia contribute to poor visual outcome in these eyes. ||||| AIMS: To analyse the incidence of glaucoma in children undergoing cataract surgery and determine whether early surgery is associated with increased risk of glaucoma.
METHODS: A retrospective chart review of all children aged 14 years or less who had surgery for congenital or developmental cataract at one unit over the last 20 years. The children were divided into three groups; group 1 consisting of children aged < or =50 days at surgery, group 2 those aged 51 days to 1 year, and group 3 aged 1-14 years.
RESULTS: We identified a total of 104 eyes of 74 children. The medical records for 100 eyes (71 children) were available for review. In all, 17 eyes (12 children) were aged < or =50 days at surgery, none of which have developed glaucoma. Group 2 consisted of 28 eyes (17 children) with one patient developing glaucoma in both eyes 11 years after surgery. Group 3 consisted of 55 eyes (42 children), none of which have developed glaucoma. After a median follow-up period of 4.9 years (range 0.6-19.6 years, mean 6.4 +/- 5.2 years) 2% of eyes had developed glaucoma. There was no significant difference in the length of follow-up between groups (H=2.979, P=0.22, Kruskal-Wallis Test).
CONCLUSIONS: There was a low incidence of glaucoma in our series and this was not increased in those having surgery in the first 6 weeks of life. Our findings contribute further evidence for the variability in prevalence of glaucoma after paediatric cataract extraction in the literature and suggest that factors other than age at surgery are important risk factors for this condition. ||||| AIMS: To determine the incidence of glaucoma, with onset within 1 year after the date of cataract surgery (early onset) performed in the first year of life, with or without intraocular lens (IOL) implantation.
METHODS: A retrospective review of a single surgeon's cohort from 1999 to 2006. Glaucoma onset risk, comparison of aphakic/pseudophakic eyes and IOL type were analysed together with microcornea, persistent fetal vasculature (PFV) and age < or =4 weeks at surgery.
RESULTS: Ninety-eight eyes (62 patients; mean age 2.88 months) were included with 61 eyes (36 patients) aphakic (57 planned and four failed implantations), and 37 eyes (26 patients) pseudophakic. At a mean follow-up of 2.51 years,15.3% (12.2% within 1 year) of all eyes, 9.8% of eyes (6.6% within 1 year) in the planned aphakic group, all four eyes with failed implantation and 13.5% of the pseudophakic eyes (10.8% within 1 year) developed glaucoma. Glaucoma incidence stratified by absence or presence of IOL showed no statistically significant difference, but eyes in the rigid polymethylmethacrylate group had an increased glaucoma risk compared with the Acrysof group (p = 0.002). Microcornea, PFV and age < or =4 weeks at surgery were not significant predictors of early-onset glaucoma.
CONCLUSIONS: In this single surgeon study of infant cataract surgery only, age < or =4 weeks at surgery was not a predictor of early-onset glaucoma. The rate of aphakic and pseudophakic early-onset glaucoma was not found to be statistically different, but we found a statistically different rate of glaucoma between the two IOL types which needs further evaluation, given that this is a retrospective review. Excessive surgical trauma influences incidence of glaucoma. ||||| PURPOSE: To evaluate long-term functional outcome after treatment of dense congenital bilateral cataract.
METHODS: The records of 22 consecutive children operated on before the age of 12 months at St. Erik's Eye Hospital over a 5-year period (1991-96) were reviewed retrospectively. Linear Snellen visual acuity (VA) at last check, presence of stereoacuity, nystagmus, strabismus and other complications are accounted for. Subject age at last check ranged from 4 to 9 years.
RESULTS: Visual acuity could be estimated in 19 children: the median VA of the better eye was 0.4 (range: counting fingers - 0.8) and of the fellow eye 0.15 (range: amaurosis - 0.8). In nine otherwise healthy children who were operated on early (by 1 month of age), VA varied from 0.4 to 0.8 in the better eye. Four of these children achieved stereopsis. Pupillary block glaucoma developed in five eyes (in three children). Chronic glaucoma developed in eight eyes (in five children). Glaucoma occurred predominantly in children who underwent cataract extraction during the first week of life. Two of the latter had marked microphthalmos.
CONCLUSION: Good postoperative VA was achieved in most healthy children with dense bilateral congenital cataract when surgery was performed early (before 6-8 weeks of age). Chronic glaucoma developed predominantly when cataract extraction was performed during the first week of life. | [
{
"source_pmid": "19787594",
"source_text": "PURPOSE: To evaluate the long-term visual function outcomes of intraocular lens (IOL) implantation after congenital cataract surgery in children.\nMETHODS: Forty children who had congenital cataract surgery with IOL implantation and at least 5 years follow-up and... |
19032617 | CONCLUSIONS: Self-management programs appear effective for older adults with AMD. Small sample size, use of non-traditional statistics and methodological quality meant only a narrative analysis was possible. Future studies with more robust methodology including intent-to-treat analysis are still required. | PURPOSE: The psychosocial needs of patients suffering from severe visual loss associated with advanced age-related macular degeneration (ARMD) are generally ignored in the clinical routine. The aim of this study was to develop and evaluate a psychosocial intervention program for ARMD patients. This intervention program was based on six modules carried out in five weekly group sessions. These modules included (a) progressive muscle relaxation; (b) exchange of disease-related experiences; (c) understanding the connections among thought, emotion, and behavior; (d) description of and emphasis on the use of available resources; (e) improvement of general problem-solving skills, and (f) information exchange on ARMD-related treatment and rehabilitation options.
DESIGN AND METHODS: A preliminary evaluation of this intervention program was performed with the aid of a preintervention-postintervention comparison-group research design, which included 14 individuals (mean age of 73.1 years) in the interventional group and 8 participants (mean age of 72.6 years) in the comparison group. The preintervention-postintervention assessment addressed a set of emotional (e.g., positive and negative affect) as well as behavioral (e.g., limitations to activities and instrumental activities of daily living) outcome measures.
RESULTS: Although the sample size of the pilot evaluation test was small, our results demonstrate the usefulness of this pilot program. A statistical analysis comparing the interventional group with the comparison group revealed that the intervention group benefited from the program in five out of six outcome measures.
IMPLICATIONS: Psychosocial group intervention is a promising approach to improve the quality of life in patients suffering from ARMD. ||||| OBJECTIVE: To assess the effectiveness at the 6-month follow-up of an age-related macular degeneration (AMD) self-management program consisting of health education and enhancement of problem-solving skills in improving quality of life as shown by measures of mood and function.
METHODS: Six-month follow-up data were analyzed from 214 of 252 older adult volunteers (mean age, 80.8 years) with advanced AMD who had been randomly assigned to a 12-hour self-management program (n = 82), a series of 12 hours of tape-recorded health lectures (n = 66), or a waiting list (n = 66). The primary outcome measure was emotional distress (Profile of Mood States). Secondary outcome measures included function (National Eye Institute Visual Function Questionnaire), self-confidence to handle AMD-specific challenges in daily life (AMD Self-efficacy Questionnaire), and depression status on the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition.
RESULTS: At the 6-month follow-up, participants in the self-management program reported significantly less emotional distress (P=.008), better function (P=.05), and increased self-efficacy (P=.006) compared with control subjects. The latter effects were more pronounced in the depressed than in the nondepressed subjects. Finally, the incidence of clinical depression at the 6-month follow-up was significantly lower in the self-management group (P=.05) than in the control group.
CONCLUSION: The sustained positive effects at the 6-month follow-up provide support for the effectiveness of the AMD self-management program in reducing distress and disability, improving self-efficacy, and preventing depression in poorly sighted elderly patients with AMD. ||||| OBJECTIVE: The purpose of this randomized, longitudinal study was to investigate the impact of a health education program on perceived security in the performance of daily occupations 4 months after the intervention period.
METHOD: Two groups of persons with age-related macular degeneration were compared: Those who had followed a newly developed health education program that was based on occupation and those who took part in a standard individual intervention program.
RESULTS: Significant differences in the level of perceived security between the groups were found for 13 of 28 occupations. Participants in the health education group maintained or improved their level of perceived security in 22 daily occupations, whereas those in the individual intervention group declined to a lower level in 17 daily occupations.
CONCLUSION: This study provides support for the effectiveness of the health education program to enhance security and hinder a progressive decline in perceived security in daily occupations. ||||| PURPOSE: To analyse the cost-effectiveness of the activity-based Health Education Programme 'Discovering New Ways' versus a standard Individual Programme.
METHOD: Two-hundred and twenty-nine persons were randomized to either the Health Education Programme or an Individual Programme. The present study is based on 131 persons who participated in the 28-month follow-up. Costs for the low vision clinic were documented prospectively along with external costs. A cost-effectiveness analysis was done using cases with an improved level of perceived security in daily activities as the effectiveness measure.
RESULTS: The Health Education Programme led to significantly more cases with an improved level of perceived security (45 vs. 10%, CI 95%: 21-49, p value < 0.001) and the total social cost per treatment was lower (28,004 vs. 36,341 SEK). Taken separately the low vision clinic costs were slightly higher due to a higher prescription of assistive devices, but external costs were lower for the Health Education Programme compared to the Individual Programme, though neither of these differences was statistically significant.
CONCLUSION: The results suggest that replacing the standard Individual Programme with the Health Education Programme 'Discovering New Ways' is cost-effective as more persons experience increased security to a lesser total cost. ||||| OBJECTIVE: To assess the effectiveness of an age-related macular degeneration (AMD) self-management program, consisting of health education and enhancement of problem-solving skills, to improve quality of life as shown by measures of mood and function.
METHODS: Two hundred thirty-one community-dwelling cognitively intact volunteers (mean age, 80.6 years) with advanced macular degeneration were randomly assigned to a 12-hour self-management program (n = 86), a series of 12 hours of tape-recorded health lectures (n = 74), or to a waiting list (n = 72).
MAIN OUTCOME MEASURES: The primary outcome measure was emotional distress (Profile of Mood States). Secondary outcome measures included function (National Eye Institute Visual Function Questionnaire), social support (Duke Social Support Index), outlook on life (Life Optimism Test-Revised), and self-confidence to handle AMD-specific challenges in daily life (AMD Self-Efficacy Questionnaire). Clinical depression was determined in accord with the Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders, Axis I, Fourth Edition, Research Version.
RESULTS: The self-management group showed significant improvement in measures of mood and function compared with controls. These changes were significantly greater for the depressed than for the nondepressed subjects. Decreased emotional distress was associated with increased self-efficacy, while improvements in function were associated with increases in self-efficacy and perceived social support.
CONCLUSIONS: These findings suggest that the AMD self-management program was an effective intervention to enhance well-being in older persons with poor eyesight due to AMD, particularly in those who were initially depressed. ||||| UNLABELLED: In order to implement evidence-based practice, a randomized study was set up to evaluate the ADL- based Health Education Programme 'Discovering new ways' for elderly persons with age-related macular degeneration.
PURPOSE: To investigate the impact of this program on perceived security in the performance of daily activities 28 months after the intervention.
METHOD: Two-hundred and twenty-nine persons randomized to either the Health Education programme or an Individual Intervention Programme participated in the study. At the 28-month follow-up there was a dropout of 98 persons and the results are based on 62 persons participating in the Health Education Programme and 69 persons in the Individual Intervention Programme.
RESULTS: There were statistically significant differences in perceived security between the groups in 15 out of 28 daily activities. Furthermore, the Health Education Group showed a significant tendency towards an improved level of security while the Individual Intervention Group tended to deteriorate.
CONCLUSIONS: The findings provide strong support for the long-term effect of the programme and for the implementation of evidence-based practice. The study corroborates the effectiveness of the Health Education Programme in enhancing security and hindering a progressive decline in perceived security in daily activities. ||||| The purpose of this study was to conduct a randomized clinical trial to assess whether a self-management group intervention can improve mood, self-efficacy, and activity in people with central vision loss due to age-related macular degeneration (AMD). Ninety-two elderly patients with AMD (average age = 79) from a university ophthalmology clinic were randomly assigned to the self-management intervention (n = 44) or to a wait-list (n = 48). All patients were legally blind in at least one eye. The intervention consisted of 6 weekly 2-hour group sessions providing education about the disease, group discussion, and behavioral and cognitive skills training to address barriers to independence. All participants eventually completed the intervention allowing pre-post comparisons for all patients. The battery of measures included the Profile of Mood States (POMS); Quality of Well-Being Scale; and assessments of self-efficacy, participation in activities, and use of vision aids. Participants' initial psychological distress was high (mean total POMS = 59.72) and similar to distress experienced by other serious chronic illness populations (e.g. cancer, bone marrow transplant). Analysis of covariance testing the primary hypothesis revealed that intervention participants experienced significantly (p = .04) reduced psychological distress (pre mean = 61.45; post mean = 51.14) in comparison with wait-list controls (pre mean = 57.72; post mean = 62.32). Intervention participants also experienced improved (p = .02) self-efficacy (pre mean = 70.16; post mean = 77.27) in comparison with controls (pre mean = 67.71; post mean = 69.07). Further, intervention participants increased their use of vision aids (p < .001; pre mean = 3.37, post mean = 6.69). This study demonstrates that a relatively brief behavioral intervention can substantially reduce psychological distress and increase self-efficacy in elderly adults experiencing vision loss due to macular degeneration. Self-management intervention appears to improve mood, self-efficacy, and use of vision aids, further enhancing the lives of poorly sighted individuals with AMD. | [
{
"source_pmid": "15611220",
"source_text": "PURPOSE: The psychosocial needs of patients suffering from severe visual loss associated with advanced age-related macular degeneration (ARMD) are generally ignored in the clinical routine. The aim of this study was to develop and evaluate a psychosocial interven... |
18156371 | CONCLUSION: Latanoprost was found to be significantly superior to dorzolamide but not brimonidine. However, ocular adverse events were significantly fewer in latanoprost users than in brimonide users. Neither travoprost nor bimatoprost was compared to dorzolamide or brimonidine in the present literature. | AIMS: To compare the effects on intraocular pressure (IOP) and side effects of monotherapy with either latanoprost or dorzolamide in patients with glaucoma or ocular hypertension.
METHODS: 224 patients with open angle glaucoma or ocular hypertension were recruited to a 3 month open labelled study. Previous glaucoma medications were washed out and the patients were randomised to receive either latanoprost 0.005% once daily or dorzolamide 2% three times daily.
RESULTS: Of 224 patients 213 were included in the analysis of efficacy. After 3 months, latanoprost reduced mean baseline diurnal IOP from 27.2 (SD 3.0) mm Hg by 8.5 (3.3) mm Hg. The corresponding figures for dorzolamide were 27.2 (3.4) and 5.6 (2.6) mm Hg. The difference of 2.9 mm Hg (95% CI: 2.3-3.6) was highly significant (p<0.001, ANCOVA). Latanoprost reduced IOP at peak by 8.6 mm Hg (32%) compared with 6.2 mm Hg (23%) for dorzolamide, and the difference of 2.4 mm Hg was significant (p<0.001, ANCOVA). The corresponding figures at trough were 8.1 mm Hg (31%) for latanoprost and 4.7 mm Hg (17%) for dorzolamide, a significant difference of 3.4 mm Hg (p<0.001, ANCOVA). Both drugs were well tolerated systemically and locally.
CONCLUSION: Latanoprost was superior to dorzolamide in reducing the IOP, judged both from the effect on IOP at peak and trough and by the effect on diurnal IOP. ||||| PURPOSE: To compare the efficacy and tolerability of latanoprost or brimonidine in patients with elevated intraocular pressure (IOP).
MATERIALS AND METHODS: This prospective, randomized, masked-evaluator, parallel-group, multicenter study in the United States included patients with primary open angle glaucoma or ocular hypertension. Patients received latanoprost 0.005% once daily (8:00 AM; n = 152) or brimonidine tartrate 0.2% twice daily (8:00 AM and 8:00 PM; n = 151). Patients underwent evaluation at screening, baseline (randomization), and after 0.5, 3, and 6 months of treatment. IOP was measured at 8:00 AM, 10:00 AM, noon, and 4:00 PM at baseline and the months 3 and 6 visits, and at 8:00 AM only at week 2. The main outcome measure was the difference in diurnal IOP change from baseline to month 6 between treatment groups. Adverse events were recorded at each visit.
RESULTS: Baseline mean diurnal IOP levels were similar between groups. At month 6, the adjusted mean (+/- SEM) diurnal IOP reduction was 5.7 +/- 0.3 mm Hg in the latanoprost group and 3.1 +/- 0.3 mm Hg in patients receiving brimonidine (P < 0.001). The mean difference in diurnal IOP reduction was 2.5 +/- 0.3 mm Hg (95% CI: 1.9, 3.2; P < 0.001). Five times more patients receiving brimonidine than latanoprost were withdrawn from the study due to adverse events.
CONCLUSION: Latanoprost instilled once daily is more effective and better tolerated than brimonidine administered twice daily for the treatment of patients with glaucoma or ocular hypertension. During therapy, the range of daily fluctuation of IOP is less for latanoprost compared with brimonidine. ||||| BACKGROUND: Many physicians recommend either brimonidine or latanoprost as firstline therapy for chronic open-angle glaucoma or ocular hypertension. However, a search of MEDLINE indicates that there have been few head-to-head comparisons of the 2 monotherapies in a clinical setting.
OBJECTIVE: This study compared the clinical efficacy and tolerability of brimonidine 0.2% twice daily with those of latanoprost 0.005% once daily as monotherapy in patients with open-angle glaucoma or ocular hypertension.
METHODS: In this 3-month, multicenter, double-masked, parallel-group, 4-visit study, treatment-naive and previously treated patients with open-angle glaucoma or ocular hypertension and bilateral intraocular pressure (IOP) after washout of between 22 and 34 mm Hg were randomized to receive either brimonidine or latanoprost. Patients who had received previous treatment with either study drug were excluded from the study. The primary outcome measure was response rate, defined as the percentage of patients achieving > or = 20% reduction in IOP from baseline to month 3. Secondary outcome measures were mean IOP reduction from baseline to month 3 and clinical success, defined as the investigator's recommendation that the patient continue using the assigned study medication.
RESULTS: A total of 127 patients (55 treatment naive) were enrolled, 66 in the brimonidine group and 61 in the latanoprost group. After 3 months of treatment, 80% of patients in the brimonidine group and 74% of patients in the latanoprost group had achieved > or = 20% reduction in IOP from baseline. The mean reduction in IOP from baseline at month 3 was 6.8 mm Hg with brimonidine and 6.5 mm Hg with latanoprost (27.8% vs 27.0%, respectively). Among treatment-naive patients, a significantly higher percentage of brimonidine-treated patients achieved > or = 20% decrease in IOP compared with latanoprost-treated patients (88% vs 59%, respectively; P = 0.01). In previously treated patients, a higher percentage of the latanoprost group achieved > or = 20% reduction in IOP compared with the brimonidine group (88% vs 74%, respectively); however, the difference was not statistically significant. Significantly more patients in the brimonidine group achieved clinical success at month 3 compared with patients in the latanoprost group (91% vs 74%; P = 0.01).
CONCLUSIONS: At peak effect, brimonidine twice daily was as effective as latanoprost once daily in lowering IOP. In treatment-naive patients, latanoprost was associated with a significantly higher rate of nonresponse after 3 months of treatment compared with brimonidine. This suggests that brimonidine may be the more reliable choice for first-line therapy of newly diagnosed open-angle glaucoma or ocular hypertension. In previously treated patients, however, latanoprost provided greater mean IOP reduction than did brimonidine. Significantly more patients achieved clinical success with brimonidine monotherapy than with latanoprost monotherapy. ||||| PURPOSE: To compare the effect of treatment with latanoprost or brimonidine on intraocular pressure in patients with glaucoma or ocular hypertension and intraocular pressure inadequately controlled by monotherapy or dual therapy.
PATIENTS AND METHODS: Three hundred seventy-nine patients with primary open-angle glaucoma or ocular hypertension were recruited for this 6-month prospective, randomized, observer-masked multicenter study involving 30 eye clinics. All patients were receiving monotherapy or dual therapy that did not adequately control intraocular pressure. After appropriate washout periods, patients were randomized to treatment with latanoprost once daily or brimonidine twice daily. The main outcome measure was change in mean diurnal intraocular pressure after 6 months of treatment compared with baseline.
RESULTS: Of the 379 randomized patients, 375 were included in the intent-to-treat analysis. From an overall baseline mean intraocular pressure of 25.0 mm Hg, latanoprost monotherapy reduced mean diurnal intraocular pressure by 7.1 +/- 3.3 mm Hg (mean +/- SD, P < 0.001), whereas brimonidine monotherapy yielded an intraocular-pressure reduction of 5.2 +/- 3.5 mm Hg (P < 0.001). This 1.9 mm Hg difference in intraocular-pressure reduction was significantly in favor of latanoprost (P < 0.001). Ocular allergy (P < 0.001) and systemic side effects (P = 0.005) were reported significantly less frequently by latanoprost-treated patients compared with brimonidine-treated patients.
CONCLUSIONS: Both latanoprost and brimonidine reduced intraocular pressure in patients with glaucoma or ocular hypertension after 6 months of treatment. However, latanoprost once daily was significantly more effective than brimonidine twice daily in reducing mean diurnal intraocular pressure. Latanoprost was better tolerated with less frequently occurring ocular allergy and systemic side effects. | [
{
"source_pmid": "10837379",
"source_text": "AIMS: To compare the effects on intraocular pressure (IOP) and side effects of monotherapy with either latanoprost or dorzolamide in patients with glaucoma or ocular hypertension.\nMETHODS: 224 patients with open angle glaucoma or ocular hypertension were recruit... |
31626152 | CONCLUSIONS: Phaco-GSL might be an optimal procedure to treat ACG with concomitant cataract due to its bleb-less nature, and its capacity for lowering IOP seems superior to Phaco alone and comparable to Phaco-trabeculectomy/trabeculectomy. | OBJECTIVE: This study is to compare the efficacy of three different cataract surgeries in eyes with angle closure glaucoma (ACG) with concomitant cataract.
METHODS: A retrospective comparative analysis of 106 ACG patients (112 eyes) with concomitant cataract was conducted between February, 2012 and February, 2014. Clinical outcomes of ACG patients with concomitant cataract underwent phacoemulsification and intraocular lens implantation (group A, n = 34, 36 eyes, angle closure < 180°); combined phacoemulsification, intraocular lens implantation, and goniosynechialysis (group B, n = 43, 45 eyes, angle closure, 180°~270°); and combined phacoemulsification, intraocular lens implantation, and trabeculectomy (group C, n = 29, 31 eyes, angle closure > 270°) were compared during a 6-month follow-up.
RESULTS: There were no statistical differences among the 3 groups in pre-operative or post-operative average visual acuity (VA), intraocular pressure (IOP), anterior chamber depth (ACD), and angle opening distance (AOD) (all P > 0.05). Post-operative VA, IOP, ACD, AOD and the degree of angle opening in the 3 groups were all improved as compared with pre-operative levels (all P < 0.05). No statistical difference was detected among the 3 groups in the incidence of complications (χ(2) = 0.376, P = 0.829).
CONCLUSION: Phacoemulsification alone, combined phacoemulsification/goniosynechialysis, and combined phacoemulsification/trabeculectomy provide safe, effective, predictable, and stable options of cataract surgery for treatment of ACG with concomitant cataract. ||||| BACKGROUND: Goniosynechialysis (GSL) to remove peripheral anterior synechiae (PAS) alongside standard cataract surgery has potential theoretical advantages, Published randomised trials, however, have not shown conclusive functional benefits and aqueous outflow changes following GSL are unknown. This study aimed to compare electronic Shiøtz tonographic aqueous outflow facility (TOF) following phacoemulsification with or without GSL in patients with primary angle closure (PAC) and PAC glaucoma. Secondary outcomes were changes in intraocular pressure (IOP) and use of glaucoma medications.
METHODS: Prospective randomised pilot study of 26 patients on glaucoma medication, with ≥90° PAS and significant lens opacity. Patients were randomised 1:1 to receive phacoemulsification with intraocular lens (IOL) implantation only (phaco) or phacoemulsification with IOL plus GSL (phaco-GSL).
RESULTS: Fourteen patients were randomised to phaco-GSL and 12 to phaco alone. TOF increased with phaco-GSL from 0.099±0.07 μL/min/mm Hg to 0.194±0.07, μL/min/mm Hg, p=0.0006, while the phaco group showed no significant change. IOP reduced in both groups, but reduced significantly more following phaco-GSL (46.0%) compared with phaco alone (27.6%, p=0.04). Medication use and extent of PAS only reduced with phaco-GSL, from 0.923±0.86 to 0.384±0.18 medications, p=0.0279, and from 249.2±83.4 to 110.8±53.9° PAS, 6 months postoperatively. No serious adverse events occurred in either group.
CONCLUSIONS: Eyes randomised to both surgical groups had similar and good outcomes at 6 months in this pilot study. However, only eyes undergoing GSL combined with standard phacoemulsification had significantly increased TOF, reduced glaucoma medication dependence and PAS postoperatively. GSL should therefore be considered in such patients.
TRIAL REGISTRATION NUMBER: NCT00719290, Results. ||||| PURPOSE: This study aimed to compare the efficacy and safety of combined phacoemulsification, intraocular lens implantation, and goniosynechialysis with phacotrabeculectomy in the treatment of primary angle-closure glaucoma (PACG) and cataract.
DESIGN: A comparative case series.
METHODS: Sixty-five patients (65 eyes) with PACG and cataract from the Fifth Affiliated Hospital of Sun Yat-Sen University were enrolled for this study between October 2009 and July 2011. Of these, 33 underwent combined phacoemulsification, intraocular lens implantation, and goniosynechialysis (treatment group), and 32 underwent phacotrabeculectomy (control group). The effects on intraocular pressure, best-corrected visual acuity, anterior chamber angle, number of antiglaucoma medications, and complications were evaluated.
RESULTS: Both the treatment group and the control group had lowered intraocular pressure, reduced the use of antiglaucoma medications, and improved vision in patients with PACG and cataract. Complications were 8 (24.2%) of 33 in the treatment group and 12 (37.5%) of 32 in the control group.
CONCLUSIONS: Combined phacoemulsification, intraocular lens implantation, and goniosynechialysis appears to be a preferred method for the treatment of PACG and cataract because it seems to have the same efficacy as phacotrabeculectomy and has much less surgical complications. ||||| OBJECTIVE: We sought to find predictive factors for favourable postoperative intraocular pressure (IOP) after cataract surgery in patients with primary open-angle glaucoma (POAG) and primary angle-closure glaucoma (PACG).
STUDY DESIGN: Retrospective evaluation of patients who had undergone cataract surgery.
PARTICIPANTS: Forty-eight patients with POAG and 48 patients with PACG.
METHODS: Various clinical factors were evaluated retrospectively in 96 patients. All patients had undergone standard 2.75-3.5 mm limbal incision cataract surgery. Clinical parameters in patients with successful postoperative IOP courses were compared with those in unsuccessful patients. Success was defined as an IOP between 6 and 21 mm Hg, with fewer antiglaucoma medications needed compared with before surgery, and no need of additional glaucoma surgery.
RESULTS: In POAG, eyes with a highest preoperative IOP of <31 mm Hg or those being treated with <3 antiglaucoma medications before surgery had a significantly higher probability of success. In PACG, the probability of success was significantly higher if the highest preoperative IOP was <42 mm Hg, the number of antiglaucoma medications before surgery was <3, or the areas of peripheral anterior synechiae were <4 clock hours.
CONCLUSIONS: Primary small-incision cataract surgery using phacoemulsification and foldable intraocular lens implantation may be the procedure of choice in patients with medically controlled glaucoma and coexisting visually significant cataracts, considering the highest preoperative IOP and number of antiglaucoma medications in POAG and PACG, and the area of peripheral anterior synechiae in PACG. ||||| PURPOSE: To evaluate changes of anterior chamber angle (ACA) by anterior-segment optical coherence tomography (AS-OCT) in patients with primary angle closure glaucoma (PACG) following phacoemulsification (phaco) with or without goniosynechialysis (GSL).
METHODS: Patients with PACG recruited into 2 randomized controlled trials comparing phaco-GSL versus phaco were pooled for analysis. Images of ACA were obtained by AS-OCT before surgery, and at 1 and 2 weeks, and 1, 3, and 6 months after surgery. The following parameters were analyzed: angle opening distance (AOD) at 500 and 750 μm from the scleral spur, trabecular-iris space area (TISA) at 500 and 750 μm, angle recess area (ARA) at 500 and 750 μm, and scleral spur angle (SSA).
RESULTS: All parameters of ACA increased significantly after phaco-GSL (P<0.001), whereas no increase occurred in the phaco group. Negatively significant correlations were found in ΔAOD500 (P<0.05), ΔARA750 (P<0.05), ΔTISA500 (P<0.05), and ΔTISA750 (P<0.05) at 1, 3, and 6 months, and ΔSSA (P<0.05) at 3 and 6 months after phaco-GSL against Δ intraocular pressure (IOP). In the phaco-GSL group, 23 of 23 eyes had IOP<21 mm Hg without any antiglaucoma medication postoperatively. In the phaco group, 12 of 20 eyes (60%) had IOP<21 mm Hg without medication, 8 of 20 eyes required medication with IOP<21 mm Hg (15%) and uncontrollable IOP (25%) after surgery.
CONCLUSIONS: On AS-OCT evaluation, ACA in eyes with PACG opened and widened significantly after phaco-GSL in our study. It is suggested that ΔAOD500, ΔARA750, ΔTISA500, ΔTISA750, and ΔSSA would provide valuable information to estimate the effectiveness of phaco-GSL. ||||| PURPOSE: To assess the effects of phacoemulsification, intraocular lens implantation, and goniosynechialysis on patients with primary angle-closure glaucoma and cataract.
METHODS: A total of 145 eyes of 133 consecutively recruited patients were randomly divided into Phaco group and Trab group. Ocular parameters were measured before and after surgery.
RESULTS: The mean follow-up period was 13.2±5.6 months. The visual acuity in the Phaco group was significantly improved, whereas no alternation was found in the Trab group after surgery. The intraocular pressure (IOP) had no notable difference in 2 groups before surgery. Compared with preoperative IOP, there was significant decrease after surgery. No remarkable change in the IOP was measured in the 2 groups after surgery for 12 months. The anterior chamber depth was markedly augmented in the Phaco group compared with the Trab group after surgery for 3 months. Compared with the the Trab group, no obvious change in coefficient of outflow facility was found in the Phaco group before and after surgery, whereas there was a significant increase relative to its preoperation. The angle closure decreased from (290±25) to (60±35) degrees after surgery for 12 months in the Phaco group and no significant alteration was observed in the Trab group. The reduction extent of peripheral anterior synechiae was in direct proportion to the decreasing level of angle closure in the 2 groups. The change in the corneal endothelial cell density had no significant difference between 2 groups before and after surgery.
CONCLUSIONS: The treatment of phacoemulsification, intraocular lens implantation, and goniosynechialysis is safe and effective for patients with primary angle-closure glaucoma and cataract. ||||| AIMS: To compare the change in iris-trabecular contact (ITC) area using swept-source optical coherence tomography (SS-OCT) in eyes with primary angle closure glaucoma (PACG) and cataract that underwent phacoemulsification (PE) with intraocular lens implantation alone compared with PE with goniosynechialysis (GSL).
METHODS: One eye of 22 patients with PACG with peripheral anterior synechiae (PAS) detected by indentation gonioscopy was randomised into two groups (PE alone (n=11) and PE+GSL (n=11)). The anterior chamber angles were evaluated by SS-OCT under dark conditions before and 12 months after surgery using the three-dimensional angle analysis scan protocol that simultaneously obtains 128 cross-sectional radial scans across the anterior chamber at equal intervals (every 1.4°). The ITC area, defined as the area of extent of the circumferential contact of peripheral iris to the angle wall, was computed automatically by SS-OCT after an observer marked the scleral spurs of all 128 scans of each eye.
RESULTS: The majority of the 22 subjects were women (77.3%) and the mean±SD age was 67.3±5.8 years. The ITC area was significantly reduced in the PE+GSL group compared with the PE alone group (10.2 mm2 vs. 4.6 mm2, β=0.54, p=0.03) after adjusting for age, gender, intraocular pressure, extent of PAS and pupil diameter before surgery. Smaller iris volume at baseline was associated with greater ITC area reduction by PE+GSL (β=-0.728, p=0.03).
CONCLUSIONS: Eyes that undergo PE+GSL surgery have a greater reduction in circumferential ITC area than eyes that undergo PE alone. | [
{
"source_pmid": "26629184",
"source_text": "OBJECTIVE: This study is to compare the efficacy of three different cataract surgeries in eyes with angle closure glaucoma (ACG) with concomitant cataract.\nMETHODS: A retrospective comparative analysis of 106 ACG patients (112 eyes) with concomitant cataract was... |
25541937 | CONCLUSION: RBZ and RBZ + Laser had better visual and anatomic outcomes than laser monotherapy in the treatment of DME. RBZ + Laser seemed to be equivalent to RBZ. | OBJECTIVE: To assess the benefit of increased follow-up and treatment with ranibizumab between months 24 and 36 in the Ranibizumab for Edema of the Macula in Diabetes (READ-2) Study.
DESIGN: Prospective, interventional, multicenter follow-up of a randomized clinical trial.
METHODS: Patients who agreed to participate between months 24 and 36 (ranibizumab, 28 patients; laser, 22; and ranibizumab + laser, 24) returned monthly and received ranibizumab, 0.5 mg, if foveal thickness (FTH, center subfield thickness) was 250 μm or greater. Main outcome measures were improvement in best-corrected visual acuity (BCVA) and reduction in FTH between months 24 and 36.
RESULTS: Mean improvement from the baseline BCVA in the ranibizumab group was 10.3 letters at month 36 vs 7.2 letters at month 24 (ΔBCVA letters = 3.1, P = .009), and FTH at month 36 was 282 μm vs 352 μm at month 24 (ΔFTH = 70 μm, P = .006). Changes in BCVA and FTH in the laser group (-1.6 letters and -36 μm, respectively) and the ranibizumab + laser group (+2.0 letters and -24 μm) were not statistically significant. The mean number of ranibizumab injections was significantly greater in the ranibizumab group compared with the laser group (5.4 vs 2.3 injections, P = .008) but not compared with the ranibizumab + laser group (3.3, P = .11).
CONCLUSIONS: More aggressive treatment with ranibizumab during year 3 resulted in a reduction in mean FTH and improvement in BCVA in the ranibizumab group. More extensive focal/grid laser therapy in the other 2 groups may have reduced the need for more frequent ranibizumab injections to control edema.
APPLICATION TO CLINICAL PRACTICE: Long-term visual outcomes for treatment of diabetic macular edema with ranibizumab are excellent, but many patients require frequent injections to optimally control edema and maximize vision.
TRIAL REGISTRATION: clinicaltrials.gov Identifier:NCT00407381 ||||| OBJECTIVE: To demonstrate superiority of ranibizumab 0.5 mg monotherapy or combined with laser over laser alone based on mean average change in best-corrected visual acuity (BCVA) over 12 months in diabetic macular edema (DME).
DESIGN: A 12-month, randomized, double-masked, multicenter, laser-controlled phase III study.
PARTICIPANTS: We included 345 patients aged ≥18 years, with type 1 or 2 diabetes mellitus and visual impairment due to DME.
METHODS: Patients were randomized to ranibizumab + sham laser (n = 116), ranibizumab + laser (n = 118), or sham injections + laser (n = 111). Ranibizumab/sham was given for 3 months then pro re nata (PRN); laser/sham laser was given at baseline then PRN (patients had scheduled monthly visits).
MAIN OUTCOME MEASURES: Mean average change in BCVA from baseline to month 1 through 12 and safety.
RESULTS: Ranibizumab alone and combined with laser were superior to laser monotherapy in improving mean average change in BCVA letter score from baseline to month 1 through 12 (+6.1 and +5.9 vs +0.8; both P<0.0001). At month 12, a significantly greater proportion of patients had a BCVA letter score ≥15 and BCVA letter score level >73 (20/40 Snellen equivalent) with ranibizumab (22.6% and 53%, respectively) and ranibizumab + laser (22.9% and 44.9%) versus laser (8.2% and 23.6%). The mean central retinal thickness was significantly reduced from baseline with ranibizumab (-118.7 μm) and ranibizumab + laser (-128.3 μm) versus laser (-61.3 μm; both P<0.001). Health-related quality of life, assessed through National Eye Institute Visual Function Questionnaire (NEI VFQ-25), improved significantly from baseline with ranibizumab alone and combined with laser (P<0.05 for composite score and vision-related subscales) versus laser. Patients received ∼7 (mean) ranibizumab/sham injections over 12 months. No endophthalmitis cases occurred. Increased intraocular pressure was reported for 1 patient each in the ranibizumab arms. Ranibizumab monotherapy or combined with laser was not associated with an increased risk of cardiovascular or cerebrovascular events in this study.
CONCLUSIONS: Ranibizumab monotherapy and combined with laser provided superior visual acuity gain over standard laser in patients with visual impairment due to DME. Visual acuity gains were associated with significant gains in VFQ-25 scores. At 1 year, no differences were detected between the ranibizumab and ranibizumab + laser arms. Ranibizumab monotherapy and combined with laser had a safety profile in DME similar to that in age-related macular degeneration. ||||| OBJECTIVE: To report expanded 2-year follow-up of a previously reported randomized trial evaluating intravitreal 0.5 mg ranibizumab or 4 mg triamcinolone combined with focal/grid laser compared with focal/grid laser alone for treatment of diabetic macular edema (DME).
DESIGN: Multicenter, randomized clinical trial.
PARTICIPANTS: A total of 854 study eyes of 691 participants with visual acuity of 20/32 to 20/320 (approximate Snellen equivalent) and DME involving the fovea.
METHODS: Continuation of procedures previously reported for the randomized trial.
MAIN OUTCOME MEASURES: Best-corrected visual acuity and safety at the 2-year visit.
RESULTS: At the 2-year visit, compared with the sham + prompt laser group, the mean change in the visual acuity letter score from baseline was 3.7 letters greater in the ranibizumab + prompt laser group (95% confidence interval adjusted for multiple comparisons [aCI], -0.4 to +7.7), 5.8 letters greater in the ranibizumab + deferred laser group (95% aCI, +1.9 to +9.8), and 1.5 letters worse in the triamcinolone + prompt laser group (95% aCI, -5.5 to +2.4). After the 1- to 2-year visit in the ranibizumab + prompt or deferred laser groups, the median numbers of injections were 2 and 3 (potential maximum of 13), respectively. At the 2-year visit, the percentages of eyes with central subfield thickness ≥250 μm were 59% in the sham + prompt laser group, 43% in the ranibizumab + prompt laser group, 42% in the ranibizumab + deferred laser group, and 52% in the triamcinolone + prompt laser group. No systemic events attributable to study treatment were apparent. Three eyes in 3 (0.8%) of 375 participants had injection-related endophthalmitis in the ranibizumab groups, whereas elevated intraocular pressure and cataract surgery were more frequent in the triamcinolone + prompt laser group.
CONCLUSIONS: The expanded 2-year results reported are similar to results published previously and reinforce the conclusions originally reported: Ranibizumab should be considered for patients with DME and characteristics similar to those of the cohort in this clinical trial, including vision impairment with DME involving the center of the macula. | [
{
"source_pmid": "23544200",
"source_text": "OBJECTIVE: To assess the benefit of increased follow-up and treatment with ranibizumab between months 24 and 36 in the Ranibizumab for Edema of the Macula in Diabetes (READ-2) Study.\nDESIGN: Prospective, interventional, multicenter follow-up of a randomized clin... |
26513684 | CONCLUSIONS AND RELEVANCE: In this meta-analysis of anti-VEGF agents for patients with DME, assessment of the highest-level exposure group (those high-risk patients with DME who received 2 years of monthly treatment) revealed a possible increased risk for death and potentially for cerebrovascular accidents. Consideration of total exposure to anti-VEGF agents when treating those at high risk for vascular disease may be important. | PURPOSE: To report 36-month outcomes of RIDE (NCT00473382) and RISE (NCT00473330), trials of ranibizumab in diabetic macular edema (DME).
DESIGN: Phase III, randomized, multicenter, double-masked, 3-year trials, sham injection-controlled for 2 years.
PARTICIPANTS: Adults with DME (n=759), baseline best-corrected visual acuity (BCVA) 20/40 to 20/320 Snellen equivalent, and central foveal thickness (CFT) ≥ 275 μm on optical coherence tomography.
METHODS: Patients were randomized equally (1 eye per patient) to monthly 0.5 mg or 0.3 mg ranibizumab or sham injection. In the third year, sham patients, while still masked, were eligible to cross over to monthly 0.5 mg ranibizumab. Macular laser was available to all patients starting at month 3; panretinal laser was available as necessary.
MAIN OUTCOME MEASURES: The proportion of patients gaining ≥15 Early Treatment Diabetic Retinopathy Study letters in BCVA from baseline at month 24.
RESULTS: Visual acuity (VA) outcomes seen at month 24 in ranibizumab groups were consistent through month 36; the proportions of patients who gained ≥15 letters from baseline at month 36 in the sham/0.5 mg, 0.3 mg, and 0.5 mg ranibizumab groups were 19.2%, 36.8%, and 40.2%, respectively, in RIDE and 22.0%, 51.2%, and 41.6%, respectively, in RISE. In the ranibizumab arms, reductions in CFT seen at 24 months were, on average, sustained through month 36. After crossover to 1 year of treatment with ranibizumab, average VA gains in the sham/0.5 mg group were lower compared with gains seen in the ranibizumab patients after 1 year of treatment (2.8 vs. 10.6 and 11.1 letters). Per-injection rates of endophthalmitis remained low over time (∼0.06% per injection). The incidence of serious adverse events potentially related to systemic vascular endothelial growth factor inhibition was 19.7% in patients who received 0.5 mg ranibizumab compared with 16.8% in the 0.3 mg group.
CONCLUSIONS: The strong VA gains and improvement in retinal anatomy achieved with ranibizumab at month 24 were sustained through month 36. Delayed treatment in patients receiving sham treatment did not seem to result in the same extent of VA improvement observed in patients originally randomized to ranibizumab. Ocular and systemic safety was generally consistent with the results seen at month 24.
FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references. ||||| PURPOSE: A head-to-head comparison was performed between vascular endothelial growth factor blockade and laser for treatment of diabetic macular edema (DME).
DESIGN: Two similarly designed, double-masked, randomized, phase 3 trials, VISTA(DME) and VIVID(DME).
PARTICIPANTS: We included 872 patients (eyes) with type 1 or 2 diabetes mellitus who presented with DME with central involvement.
METHODS: Eyes received either intravitreal aflibercept injection (IAI) 2 mg every 4 weeks (2q4), IAI 2 mg every 8 weeks after 5 initial monthly doses (2q8), or macular laser photocoagulation.
MAIN OUTCOME MEASURES: The primary efficacy endpoint was the change from baseline in best-corrected visual acuity (BCVA) in Early Treatment Diabetic Retinopathy Study (ETDRS) letters at week 52. Secondary efficacy endpoints at week 52 included the proportion of eyes that gained ≥ 15 letters from baseline and the mean change from baseline in central retinal thickness as determined by optical coherence tomography.
RESULTS: Mean BCVA gains from baseline to week 52 in the IAI 2q4 and 2q8 groups versus the laser group were 12.5 and 10.7 versus 0.2 letters (P < 0.0001) in VISTA, and 10.5 and 10.7 versus 1.2 letters (P < 0.0001) in VIVID. The corresponding proportions of eyes gaining ≥ 15 letters were 41.6% and 31.1% versus 7.8% (P < 0.0001) in VISTA, and 32.4% and 33.3% versus 9.1% (P < 0.0001) in VIVID. Similarly, mean reductions in central retinal thickness were 185.9 and 183.1 versus 73.3 μm (P < 0.0001) in VISTA, and 195.0 and 192.4 versus 66.2 μm (P < 0.0001) in VIVID. Overall incidences of ocular and nonocular adverse events and serious adverse events, including the Anti-Platelet Trialists' Collaboration-defined arterial thromboembolic events and vascular deaths, were similar across treatment groups.
CONCLUSIONS: At week 52, IAI demonstrated significant superiority in functional and anatomic endpoints over laser, with similar efficacy in the 2q4 and 2q8 groups despite the extended dosing interval in the 2q8 group. In general, IAI was well-tolerated. ||||| PURPOSE: To evaluate the efficacy and safety of intravitreal ranibizumab in diabetic macular edema (DME) patients.
DESIGN: Two parallel, methodologically identical, phase III, multicenter, double-masked, sham injection-controlled, randomized studies.
PARTICIPANTS: Adults with vision loss from DME (best-corrected visual acuity [BCVA], 20/40-20/320 Snellen equivalent) and central subfield thickness ≥275 μm on time-domain optical coherence tomography (OCT).
INTERVENTION: Monthly intravitreal ranibizumab (0.5 or 0.3 mg) or sham injections. Macular laser was available per-protocol-specified criteria.
MAIN OUTCOME MEASURES: Proportion of patients gaining ≥15 letters in BCVA from baseline at 24 months.
RESULTS: In RISE (NCT00473330), 377 patients were randomized (127 to sham, 125 to 0.3 mg, 125 to 0.5 mg). At 24 months, 18.1% of sham patients gained ≥15 letters versus 44.8% of 0.3-mg (P<0.0001; difference vs sham adjusted for randomization stratification factors, 24.3%; 95% confidence interval [CI], 13.8-34.8) and 39.2% of 0.5-mg ranibizumab patients (P<0.001; adjusted difference, 20.9%; 95% CI, 10.7-31.1). In RIDE (NCT00473382), 382 patients were randomized (130 to sham, 125 to 0.3 mg, 127 to 0.5 mg). Significantly more ranibizumab-treated patients gained ≥15 letters: 12.3% of sham patients versus 33.6% of 0.3-mg patients (P<0.0001; adjusted difference, 20.8%; 95% CI, 11.4-30.2) and 45.7% of 0.5-mg ranibizumab patients (P<0.0001; adjusted difference, 33.3%; 95% CI, 23.8-42.8). Significant improvements in macular edema were noted on OCT, and retinopathy was less likely to worsen and more likely to improve in ranibizumab-treated patients. Ranibizumab-treated patients underwent significantly fewer macular laser procedures (mean of 1.8 and 1.6 laser procedures over 24 months in the sham groups vs 0.3-0.8 in ranibizumab groups). Ocular safety was consistent with prior ranibizumab studies; endophthalmitis occurred in 4 ranibizumab patients. The total incidence of deaths from vascular or unknown causes, nonfatal myocardial infarctions, and nonfatal cerebrovascular accidents, which are possible effects from systemic vascular endothelial growth factor inhibition, was 4.9% to 5.5% of sham patients and 2.4% to 8.8% of ranibizumab patients.
CONCLUSIONS: Ranibizumab rapidly and sustainably improved vision, reduced the risk of further vision loss, and improved macular edema in patients with DME, with low rates of ocular and nonocular harm. | [
{
"source_pmid": "23706949",
"source_text": "PURPOSE: To report 36-month outcomes of RIDE (NCT00473382) and RISE (NCT00473330), trials of ranibizumab in diabetic macular edema (DME).\nDESIGN: Phase III, randomized, multicenter, double-masked, 3-year trials, sham injection-controlled for 2 years.\nPARTICIPAN... |
29091878 | CONCLUSION: There was no apparent difference on improving vision between SDMLP monotherapy and CLP monotherapy. The most effective treatment in the network was ranibizumab therapy combined with CLP followed by SDMLP monotherapy, Bevacizumab therapy combined with CLP, and CLP monotherapy in rank order. | OBJECTIVE: To compare the efficacy and safety of ranibizumab 0.5 mg intravitreal injection, as monotherapy or in combination with laser, with laser monotherapy in patients with visual impairment caused by diabetic macular edema.
DESIGN: Twelve-month, multicentre, open-label, parallel-group, randomized, active-control study.
PARTICIPANTS: A total of 220 (ranibizumab monotherapy: n = 75, ranibizumab + laser: n = 73, laser monotherapy: n = 72) patients with a diagnosis of type I or II diabetes and visual impairment caused by macular edema were included in the efficacy analysis.
METHODS: Ranibizumab was initiated with a fixed loading phase of 3 monthly injections followed by as needed therapy until stable vision achievement. Efficacy end points were the change in best corrected visual acuity (BCVA), change in central retinal thickness (CRT) measured by optical coherence tomography, proportion achieving a 15-letter BCVA gain, and 12-month Visual Function Questionnaire-25 (VFQ-25) score. Safety was assessed with the incidence and severity of adverse events.
RESULTS: At 12 months, significant (p < 0.001) mean BCVA improvements were observed for both the ranibizumab monotherapy (+8.9 [95% confidence interval (CI) 7.0-10.7] letters) and the ranibizumab + laser (+8.2 [95% CI 6.0-10.4] letters) groups compared with the laser monotherapy group (+0.3 [95% CI -2.9 to 3.5] letters). Similarly, a better response in terms of CRT improvement, BCVA letter gain, and VFQ-25 was observed in both ranibizumab groups compared with laser monotherapy. The safety profile was comparable in the 2 ranibizumab groups.
CONCLUSIONS: Ranibizumab as monotherapy or combined with laser resulted in significantly higher improvements in visual acuity and vision-related quality of life at month 12 as compared with laser monotherapy. ||||| BACKGROUND: This study was designed to examine the clinical effects of treating diabetic macular edema with an intravitreal injection of ranibizumab in combination with retinal photocoagulation.
METHODS: Sixty-two cases (75 eyes) with confirmed severe proliferative diabetic retinopathy or proliferative diabetic retinopathy in combination with macular edema were randomly divided into the observation group (37 eyes were given an intravitreal injection of ranibizumab combined with retinal photocoagulation) and the control group (38 eyes received retinal photocoagulation only). Vision, fundus condition, central macular thickness, and the macular leakage area were recorded before and after treatment.
RESULTS: The best-corrected visual acuity and macular leakage area were similar between the observation and control groups (P>0.05). The best-corrected visual acuity in the observation group was higher than that in the control group 3 and 6 months after treatment (P<0.05) and showed a rising tendency. The macular leakage area in the observation group was significantly lower than that in the control group 1 and 3 months after treatment (P<0.05). However, the macular leakage area was similar 6 months after treatment (P>0.05). The central macular thickness of the observation group was lower than that in the control group 1, 3, and 6 months after treatment (P<0.05). The laser energy used in the observation group was also smaller than that in the control group (P<0.05). The intraocular pressure was not significantly different between the groups (P<0.05). No patients in the two groups developed eye or systemic complications, such as glaucoma, cataract, or vitreous hemorrhage during treatment.
CONCLUSION: Intravitreal injection of ranibizumab combined with retinal photocoagulation was proven to be effective in treating diabetic macular edema as it improved vision and resulted in fewer complications. ||||| OBJECTIVE: Evaluate intravitreal 0.5 mg ranibizumab or 4 mg triamcinolone combined with focal/grid laser compared with focal/grid laser alone for treatment of diabetic macular edema (DME).
DESIGN: Multicenter, randomized clinical trial.
PARTICIPANTS: A total of 854 study eyes of 691 participants with visual acuity (approximate Snellen equivalent) of 20/32 to 20/320 and DME involving the fovea.
METHODS: Eyes were randomized to sham injection + prompt laser (n=293), 0.5 mg ranibizumab + prompt laser (n=187), 0.5 mg ranibizumab + deferred (> or =24 weeks) laser (n=188), or 4 mg triamcinolone + prompt laser (n=186). Retreatment followed an algorithm facilitated by a web-based, real-time data-entry system.
MAIN OUTCOME MEASURES: Best-corrected visual acuity and safety at 1 year.
RESULTS: The 1-year mean change (+/-standard deviation) in the visual acuity letter score from baseline was significantly greater in the ranibizumab + prompt laser group (+9+/-11, P<0.001) and ranibizumab + deferred laser group (+9+/-12, P<0.001) but not in the triamcinolone + prompt laser group (+4+/-13, P=0.31) compared with the sham + prompt laser group (+3+/-13). Reduction in mean central subfield thickness in the triamcinolone + prompt laser group was similar to both ranibizumab groups and greater than in the sham + prompt laser group. In the subset of pseudophakic eyes at baseline (n=273), visual acuity improvement in the triamcinolone + prompt laser group appeared comparable to that in the ranibizumab groups. No systemic events attributable to study treatment were apparent. Three eyes (0.8%) had injection-related endophthalmitis in the ranibizumab groups, whereas elevated intraocular pressure and cataract surgery were more frequent in the triamcinolone + prompt laser group. Two-year visual acuity outcomes were similar to 1-year outcomes.
CONCLUSIONS: Intravitreal ranibizumab with prompt or deferred laser is more effective through at least 1 year compared with prompt laser alone for the treatment of DME involving the central macula. Ranibizumab as applied in this study, although uncommonly associated with endophthalmitis, should be considered for patients with DME and characteristics similar to those in this clinical trial. In pseudophakic eyes, intravitreal triamcinolone + prompt laser seems more effective than laser alone but frequently increases the risk of intraocular pressure elevation. ||||| BACKGROUND/AIM: Enlargement of laser scars after retinal argon laser photocoagulation can give rise to deterioration in visual acuity. Subthreshold micropulse diode laser may decrease this risk. The aim of this study was to compare the effectiveness of subthreshold micropulse diode laser (810 nm) and conventional argon laser (514 nm) photocoagulation for the treatment of clinically significant macular oedema in diabetic patients.
METHODS: 23 eyes of 16 patients were randomised to either treatment. Follow up was conducted for a minimum of 5 months. Changes in visual acuity and macular oedema measured by optical coherence tomography were examined.
RESULTS: Visual acuity remained stable in all treatment groups throughout the observation period. Changes in retinal thickness were small both foveally and perifoveally. In patients with focal macular oedema a significant reduction in retinal thickness (9% approximately -26 microm, p = 0.02) was seen foveally 3 months after diode laser photocoagulation.
CONCLUSION: Subthreshold micropulse diode laser and conventional argon laser treatment showed an equally good effect on visual acuity. Subthreshold micropulse diode laser showed a stabilising or even improving effect on macular oedema. The combination of primary diode laser and supplementary argon laser might be particularly favourable in reducing diabetic macular oedema. ||||| OBJECTIVES: To compare ranibizumab with focal/grid laser or a combination of both in diabetic macular edema (DME).
DESIGN: Prospective, randomized, interventional, multicenter clinical trial.
PARTICIPANTS: A total of 126 patients with DME.
METHODS: Subjects were randomized 1:1:1 to receive 0.5 mg of ranibizumab at baseline and months 1, 3, and 5 (group 1, 42 patients), focal/grid laser photocoagulation at baseline and month 3 if needed (group 2, 42 patients), or a combination of 0.5 mg of ranibizumab and focal/grid laser at baseline and month 3 (group 3, 42 patients).
MAIN OUTCOME MEASURES: The primary end point was the change from baseline in best-corrected visual acuity (BCVA) at month 6.
RESULTS: At month 6, the mean gain in BCVA was significantly greater in group 1 (+7.24 letters, P = 0.01, analysis of variance) compared with group 2 (-0.43 letters), and group 3 (+3.80 letters) was not statistically different from groups 1 or 2. For patients with data available at 6 months, improvement of 3 lines or more occurred in 8 of 37 (22%) in group 1 compared with 0 of 38 (0%) in group 2 (P = 0.002, Fisher exact test) and 3 of 40 (8%) in group 3. Excess foveal thickness was reduced by 50%, 33%, and 45% in groups 1, 2, and 3, respectively.
CONCLUSIONS: During a span of 6 months, ranibizumab injections by the current protocol had a significantly better visual outcome than focal/grid laser treatment in patients with DME. ||||| OBJECTIVE: The purpose of this study was to compare the efficacy of subthreshold micropulse diode (SDM) laser with double-frequency neodymium YAG (Nd:YAG) laser in treatment of clinically significant diabetic macular edema.
METHODS: Forty-six eyes of 33 patients with clinically significant macular edema (CSME) caused by diabetic retinopathy were randomized to either SDM (810?nm) laser or the conventional double-frequency Nd:YAG (532?nm) laser. Primary outcome measures were: change in the central macular thickness as measured by optical coherence tomography (OCT) and change in macular retinal sensitivity measured using multifocal electroretinography (MfERG). Secondary outcomes were: change in best corrected visual acuity (BCVA) and contrast sensitivity.
RESULTS: The group was divided in half, with 23 eyes assigned to SDM laser and 23 eyes assigned to double-frequency Nd:YAG laser. Mean follow-up period was 6 months. No statistically significant difference was noted in either the primary or the secondary outcome measures between the two groups. Macular thickness decreased from the baseline measures of 298.5?49.3 and 312.9?45.8??m to 274.9?62.9 and 286.7?32.8??m in the SDM laser and Nd:YAG laser groups, respectively. On MfERG, P1 implicit wave time delay at baseline changed from 46.27?4.9 to 45.27?3.4?ms in the SDM group and from 46.55?4.9 to 45.27?4.1?ms in the Nd:YAG group. MfERG recordings of 18 of the 23 eyes treated with double-frequency Nd:YAG laser showed areas of signal void as compared to 4 eyes treated with the SDM laser.
CONCLUSIONS: SDM laser photocoagulation showed an equally good effect on visual acuity, contrast sensitivity, and reduction of diabetic macular edema (DME) as compared to conventional Nd:YAG laser photocoagulation. MfERG recordings, however, suggest that SDM laser results in better preservation of electrophysiological indices. ||||| PURPOSE: To evaluate the efficacy of intravitreal injection of bevacizumab (IVB) followed by modified grid laser photocoagulation (MGP) versus each alone as a primary treatment of diffuse diabetic macular edema.
PATIENTS AND METHODS: A randomized 3-arm clinical trial in which 62 eyes of 48 patients with diffuse diabetic macular edema were enrolled. Eyes were randomly distributed to 1 of 3 study groups: 19 eyes underwent MGP (MGP group), 21 eyes received 1.25 mg of IVB (IVB group), and 22 eyes received IVB followed by MGP (combined group). All eyes underwent a complete ophthalmic examination including fluorescein angiography and optical coherence tomography at baseline and at 1, 3, and 6 months, after treatment. Fluorescein angiography was performed at the 3 and 6 months follow up visits. The outcome measures were the change compared with baseline in central macular thickness (CMT), changes in best-corrected visual acuity (BCVA), changes in fluorescein angiography leakage, and any reported complication. A P value less than 0.05 was considered statistically significant.
RESULTS: One month after treatment, the reduction in the mean CMT versus baseline was 49.88 μm (10.45%) in MGP group, 150.92 μm (31.30%) in IVB group, and 110.30 μm (23.77%) in the combined group, with a corresponding improvement in the mean BCVA. At 1 month, the improvement in CMT was better than baseline in all groups, yet only significant in the IVB group (P < 0.05) and the combined group (P < 0.05). The improvement in mean BCVA was significant in the IVB (P < 0.05) and the combined groups at 1 month (P < 0.05). At 3 months, the mean CMT was still better than baseline in all groups but this improvement was significant only in the combined group (P < 0.05). The improvement in the mean BCVA was significant only in the IVB and the combined groups (P < 0.05). Six months after treatment, the reduction in the mean CMT was significant in the combined group only (P < 0.05) and there was no significant improvement in the mean BCVA in all groups (P > 0.05). The BCVA did not deteriorate below baseline in all eyes included in the study, except three eyes in the MGP group. No complication related to the intravitreal injection was reported in the injected eyes.
CONCLUSION: Combined therapy with IVB and sequential MGP 3 weeks later appeared to be superior to MGP or IVB alone in reducing macular thickening and improving visual acuity. However, no significant improvement in BCVA occurs 6 months after treatment. A combination of IVB and sequential MGP could be used as an initial treatment of diffuse diabetic macular edema. ||||| PURPOSE: To compare the efficacy of panretinal photocoagulation (PRP) and intravitreal ranibizumab injection with PRP alone in patients with treatment-naive bilateral non-high-risk proliferative diabetic retinopathy.
METHODS: Sixty eyes of 30 patients were randomized either to the study group (SG) receiving PRP plus 2 ranibizumab injections or to the control group (CG) receiving PRP alone. Mean change in best-corrected visual acuity and in optical coherence tomography were compared at baseline and 1, 3, and 6 months.
RESULTS: Best-corrected visual acuity was significantly better at 6 months in the SG; however, there was decrease in best-corrected visual acuity in the CG. Central macula thickness decreased significantly at 6 months in SG when compared with baseline (-47.6 μm, P < 0.001) and did not reveal significant difference in the CG. In eyes with diabetic macular edema, best-corrected visual acuity increased by 3.6 letters (P = 0.06) in the SG and decreased by 4.4 letters in the CG (P = 0.003). Central macula thickness decreased by 69.3 μm (P = 0.001) in the SG and decreased by 45.5 μm (P = 0.11) in the CG.
CONCLUSION: Intravitreal ranibizumab in combination with PRP can be an effective treatment in eyes with non-high-risk proliferative diabetic retinopathy and diabetic macular edema. ||||| PURPOSE: The purpose of this study was to evaluate and compare microperimetry and fundus autofluorescence (FAF) after subthreshold micropulse diode laser versus modified Early Treatment Diabetic Retinopathy Study photocoagulation for clinically significant diabetic macular edema.
METHODS: A prospective randomized clinical trial including 62 eyes (50 patients) with untreated, center-involving, clinically significant diabetic macular edema was performed. All patients underwent best-corrected visual acuity determination (logarithm of the minimum angle of resolution), slit-lamp biomicroscopy, FAF, optical coherence tomography, microperimetry (macular sensitivity), and fluorescein angiography before and after treatment. Best-corrected visual acuity, optical coherence tomography, microperimetry, and FAF were repeated at 1-, 3-, 6-, 9-, and 12-month follow-up examinations. Fluorescein angiography was performed at baseline and at 6 and 12 months.
RESULTS: Before treatment, demographic and macular parameters were not different between the two treatment groups. At 12 months, best-corrected visual acuity remained stable in both groups (P = 0.41 and P = 0.82), mean central retinal thickness decreased in both groups (P = 0.0002 and P < 0.0001), and mean central 4 degrees and 12 degrees retinal sensitivity increased in the micropulse diode laser group (P = 0.02 and P = 0.0075) and decreased in the Early Treatment Diabetic Retinopathy Study group (P = 0.2 and P = 0.0026). There was no significant difference in either best-corrected visual acuity or central retinal thickness between the 2 treatment groups (P = 0.48 and P = 0.29), whereas there was a significant difference in 4 degrees and 12 degrees retinal sensitivity (P = 0.04 and P < 0.0001). Fundus autofluorescence never changed in the micropulse diode laser group even after retreatment. In the Early Treatment Diabetic Retinopathy Study group, FAF increased up to 9 months and decreased in 6 eyes (20%) at 12 months.
DISCUSSION: Micropulse diode laser seems to be as effective as modified Early Treatment Diabetic Retinopathy Study laser photocoagulation in the treatment of clinically significant diabetic macular edema. Micropulse diode laser treatment does not determine any change on FAF showing (at least) nonclinically visible damage of the retinal pigment epithelium. Microperimetry data encourage the use of a new, less aggressive laser therapeutic approach in the treatment of clinically significant diabetic macular edema. ||||| BACKGROUND: To assess the efficacy of a new nanopulse laser, retinal regeneration therapy for the treatment of diabetic macular oedema.
DESIGN: Randomized, non-inferiority, trial.
PARTICIPANTS: 20 eyes of 17 subjects in the retinal regeneration therapy group and 18 eyes of 14 subjects in the conventional group were analysed.
METHODS: The treatment group received retinal regeneration therapy laser, and the control group received photocoagulation.
MAIN OUTCOME MEASURES: The primary outcome was the optical coherence tomography-measured change in central retinal thickness at 6 months. A secondary outcome was the change in logarithm of minimum angle of resolution visual acuity at 6 months. Non-inferiority required the one-sided 95% confidence interval of the mean retinal thickness reduction after retinal regeneration therapy to be within 35 µm of the reduction after control laser.
RESULTS: When outliers were included in the dataset, the difference in retinal thickness reduction by analysis of covariance was 10.9 (standard deviation 17.6) mm in favour of the control laser. The difference between groups in retinal thickness reduction was 40.8 mm. If two extreme outliers were excluded, the difference was 5.6 (standard deviation 14.2) mm in favour of the retinal regeneration therapy laser, and the D optical coherence tomography was 18.5 mm. The visual acuity difference between groups was 0.059, meeting non-inferiority requirements.
CONCLUSIONS: Although retinal thickness reduction was not unambiguously non-inferior, in the short-term, retinal regeneration therapy approximates the clinical efficacy of conventional photocoagulation, stabilizing visual acuity and providing motivation for larger trials assessing retinal regeneration therapy. ||||| OBJECTIVE: To demonstrate superiority of ranibizumab 0.5 mg monotherapy or combined with laser over laser alone based on mean average change in best-corrected visual acuity (BCVA) over 12 months in diabetic macular edema (DME).
DESIGN: A 12-month, randomized, double-masked, multicenter, laser-controlled phase III study.
PARTICIPANTS: We included 345 patients aged ≥18 years, with type 1 or 2 diabetes mellitus and visual impairment due to DME.
METHODS: Patients were randomized to ranibizumab + sham laser (n = 116), ranibizumab + laser (n = 118), or sham injections + laser (n = 111). Ranibizumab/sham was given for 3 months then pro re nata (PRN); laser/sham laser was given at baseline then PRN (patients had scheduled monthly visits).
MAIN OUTCOME MEASURES: Mean average change in BCVA from baseline to month 1 through 12 and safety.
RESULTS: Ranibizumab alone and combined with laser were superior to laser monotherapy in improving mean average change in BCVA letter score from baseline to month 1 through 12 (+6.1 and +5.9 vs +0.8; both P<0.0001). At month 12, a significantly greater proportion of patients had a BCVA letter score ≥15 and BCVA letter score level >73 (20/40 Snellen equivalent) with ranibizumab (22.6% and 53%, respectively) and ranibizumab + laser (22.9% and 44.9%) versus laser (8.2% and 23.6%). The mean central retinal thickness was significantly reduced from baseline with ranibizumab (-118.7 μm) and ranibizumab + laser (-128.3 μm) versus laser (-61.3 μm; both P<0.001). Health-related quality of life, assessed through National Eye Institute Visual Function Questionnaire (NEI VFQ-25), improved significantly from baseline with ranibizumab alone and combined with laser (P<0.05 for composite score and vision-related subscales) versus laser. Patients received ∼7 (mean) ranibizumab/sham injections over 12 months. No endophthalmitis cases occurred. Increased intraocular pressure was reported for 1 patient each in the ranibizumab arms. Ranibizumab monotherapy or combined with laser was not associated with an increased risk of cardiovascular or cerebrovascular events in this study.
CONCLUSIONS: Ranibizumab monotherapy and combined with laser provided superior visual acuity gain over standard laser in patients with visual impairment due to DME. Visual acuity gains were associated with significant gains in VFQ-25 scores. At 1 year, no differences were detected between the ranibizumab and ranibizumab + laser arms. Ranibizumab monotherapy and combined with laser had a safety profile in DME similar to that in age-related macular degeneration. ||||| AIM: The study was a prospective randomised controlled double-masked trial performed in two centres to compare sub-threshold micropulse diode laser photocoagulation (MPDL) with conventional green laser photocoagulation (CGL) in the treatment of clinically significant diabetic macular oedema (CSMO).
METHODS: Fifty-three patients (84 eyes) with diabetic CSMO were randomly assigned to MPDL (n = 44) or CGL (n = 40) according to the modified Early Treatment Diabetic Retinopathy Study (ETDRS) protocol. Treatments were performed after baseline and re-treatments were allowed at or after the 4 month visit if necessary. Parameters noted included the best corrected visual acuity (BCVA), colour fundus photographs, central retinal thickness using optical coherence tomography (OCT), vision contrast sensitivity with Pelli-Robson charts and presence of visible laser scars at baseline and at 4 and 12 months. The primary outcome was BCVA at 12 months.
RESULTS: All patients completed 12 months of follow-up after treatment at baseline. There were no statistically significant differences in BCVA, contrast sensitivity and retinal thickness between the two laser modalities at 0, 4 and 12 months. We found that laser scarring was much more apparent with CGL than with the sub-threshold approach (MPDL). Laser scars were identified at the 12 month visits in 13.9% of the MPDL-treated eyes compared with 59.0% of the CGL-treated eyes (p<0.001).
CONCLUSION: Sub-threshold micropulse diode laser photocoagulation is equally as effective as CGL treatment for CSMO.
TRIAL REGISTRATION NUMBER: ISTRN 90646644. ||||| OBJECTIVE: The primary study hypothesis was that ranibizumab 0.5 mg monotherapy or combined with laser is superior to laser monotherapy based on mean average change in best-corrected visual acuity (BCVA) over 12 months in Asian patients with visual impairment resulting from diabetic macular edema (DME).
DESIGN: A 12-month, randomized, double-masked, multicenter, laser-controlled, phase III study.
PARTICIPANTS: Three hundred ninety-six patients aged ≥18 years, with type 1 or 2 diabetes mellitus, BCVA of 78-39 Early Treatment Diabetic Retinopathy Study (ETDRS) letters, and visual impairment resulting from DME.
METHODS: Patients were randomized to ranibizumab + sham laser (n = 133), ranibizumab + active laser (n = 132), or sham injection + active laser (n = 131). Ranibizumab/sham injections were administered on day 1 and continued monthly. As of month 3, monthly injections were continued if stable vision was not reached. Treatment was reinitiated if BCVA decreased because of DME progression. Active/sham laser was administered on day 1 and thereafter according to ETDRS guidelines.
MAIN OUTCOME MEASURES: Average change in BCVA from baseline to months 1 through 12, central retinal subfield thickness (CRST), and safety over 12 months.
RESULTS: Ranibizumab monotherapy or combined with laser was superior to laser in improving mean average change in BCVA from baseline to months 1 through 12 (+5.9 and +5.7 vs +1.4 letters). At month 12, greater proportion of patients gained ≥15 letters with ranibizumab and ranibizumab + laser compared with laser (18.8% and 17.8% vs 7.8%). Mean CRST reduced significantly from baseline to month 12 with ranibizumab (-134.6 μm) and ranibizumab + laser (-171.8 μm) versus laser (-57.2 μm). Patients received a mean of 7.8 and 7.0 ranibizumab injections in the ranibizumab and ranibizumab + laser arms, respectively, and 1.5-1.9 active laser across treatment arms over 12 months. Conjunctival hemorrhage was the most common ocular, whereas nasopharyngitis and hypertension were the most common nonocular adverse events. Ranibizumab was not associated with any cases of cerebrovascular hemorrhage and cerebrovascular ischemia. No death related to study treatment was reported.
CONCLUSIONS: Ranibizumab monotherapy or combined with laser showed superior BCVA improvements over laser treatment alone in Asian patients with visual impairment resulting from DME. No new ocular or nonocular safety findings were observed and treatment was well tolerated over 12 months. ||||| PURPOSE: To compare modified Early Treatment Diabetic Retinopathy Study (mETDRS) focal/grid laser photocoagulation with normal-density (ND-SDM) or high-density (HD-SDM) subthreshold diode-laser micropulse photocoagulation for the treatment diabetic macular edema (DME).
METHODS: A prospective, randomized, controlled, double-masked clinical trial with patients with previously untreated DME and best corrected visual acuity (BCVA) worse than 20/40 and better than 20/400. Patients were randomized to receive either mETDRS focal/grid photocoagulation (42 patients), ND-SDM (39 patients), or HD-SDM (42 patients). Before treatment and 1, 3, 6, and 12 months after treatment, all patients underwent ophthalmic examinations, BCVA, color fundus photography, fluorescein angiography, and optical coherence tomography (OCT).
RESULTS: At 12 months, the HD-SDM group had the best improvement in BCVA (0.25 logMAR), followed by the mETDRS group (0.08 logMAR), whereas no improvements were seen in the ND-SDM group (0.03 logMAR). All groups showed statistically significant progressive reduction of central macular thickness (CMT) throughout the study (P < 0.001). The HD-SDM group exhibited the greatest CMT reduction (154 μm), which was not significantly different from that of the mETDRS group (126 μm; P = 0.75).
CONCLUSIONS: At 1 year, the clinical performance of HD-SDM was superior to that of the mETDRS photocoagulation technique, according to the anatomic and functional measures of improvement used in this investigation. A rationale for this treatment modality as a preferable approach is suggested, and the precise role of subthreshold micropulse laser treatment may become more defined as experience grows, guided by optimized treatment guidelines and more comprehensive trials. (Clinicaltrials.gov number, NCT00552435.). | [
{
"source_pmid": "26040221",
"source_text": "OBJECTIVE: To compare the efficacy and safety of ranibizumab 0.5 mg intravitreal injection, as monotherapy or in combination with laser, with laser monotherapy in patients with visual impairment caused by diabetic macular edema.\nDESIGN: Twelve-month, multicentre... |
25036543 | CONCLUSIONS: Stratus OCT demonstrated good diagnostic capability in differentiating glaucomatous from normal eyes. However, we should be more cautious in applying this instrument in Asian groups in glaucoma management. | PURPOSE: To compare optic disk and retinal nerve fiber layer (RNFL) imaging methods to discriminate eyes with early glaucoma from normal eyes.
DESIGN: Retrospective, cross-sectional study.
METHODS: In a tertiary care academic glaucoma center, 92 eyes of 92 subjects (46 with early perimetric open-angle glaucoma and 46 controls) were studied. Diagnostic performance of optical coherence tomography (StratusOCT; Carl Zeiss Meditec, Dublin, California, USA), scanning laser polarimetry (GDx VCC; Laser Diagnostic Technologies, San Diego, California, USA), confocal laser ophthalmoscopy (Heidelberg Retinal Tomograph [HRT] III; Heidelberg Engineering GmbH, Heidelberg, Germany), and qualitative assessment of stereoscopic optic disk photographs were compared. Outcome measures were areas under receiver operator characteristic curves (AUCs) and sensitivities at fixed specificities. Classification and regression tree (CART) analysis was used to evaluate combinations of quantitative parameters.
RESULTS: The average (+/- standard deviation) visual field mean deviation for glaucomatous eyes was -4.0 +/- 2.5 dB (decibels). Parameters with largest AUCs (+/- standard error) were: average RNFL thickness for StratusOCT (0.96 +/- 0.02), nerve fiber indicator for GDx VCC (0.92 +/- 0.03), Frederick S. Mikelberg (FSM) discriminant function for HRT III (0.91 +/- 0.03), and 0.97 +/- 0.02 for disk photograph evaluation. At 95% specificity, sensitivity of disk photograph evaluation (90%) was greater than GDx VCC (P = .05) and HRT III (P = .002) results, but not significantly different than those of StratusOCT (P > .05). The combination of StratusOCT average RNFL thickness and HRT III cup-to-disk area with CART produced a sensitivity of 91% and specificity of 96%.
CONCLUSIONS: StratusOCT, GDx VCC, and HRT III performed as well as, but not better than, qualitative evaluation of optic disk stereophotographs for detection of early perimetric glaucoma. The combination of StratusOCT average RNFL thickness and HRT III cup-to-disk area ratio provided a high diagnostic precision. ||||| OBJECTIVE: To determine and validate the diagnostic ability of a linear discriminant function (LDF) based on the retinal nerve fiber layer thickness at each of the 12 clock-hour positions obtained using optical coherence tomography for discriminating between healthy eyes and eyes with early glaucomatous visual field loss.
METHODS: We prospectively selected 62 consecutive healthy individuals and 73 patients with open-angle glaucoma to calculate the LDF. Another independent prospective sample of 280 healthy eyes and 302 glaucomatous eyes was used to evaluate the diagnostic accuracy of the LDF.
RESULTS: The proposed function was LDF = 15.584 - (12-o'clock segment thickness x 0.032) - (7-o'clock segment thickness x 0.041) - (3-o'clock segment thickness [nasal side] x 0.121). The greatest area under the receiver operating characteristic curve was observed for our LDF in both populations: 0.962 and 0.922. Our LDF and the average thickness yielded sensitivities of 74.5% and 67.8%, respectively, at a fixed specificity of 95%.
CONCLUSIONS: The LDF increased the diagnostic ability of the isolated retinal nerve fiber layer thickness at the 12 clock-hour positions. Compared with optical coherence tomography-provided parameters, our LDF had the highest sensitivities at 85% and 95% fixed specificities to discriminate between healthy and early glaucomatous eyes. ||||| PURPOSE: To evaluate the diagnostic capability of optical coherence tomography (Stratus OCT 3) for early glaucoma in Asian Indian eyes.
DESIGN: Cross-sectional observational study.
PARTICIPANTS: Two groups of patients (early glaucoma and normal) who satisfied the inclusion and exclusion criteria were included. Early glaucoma was diagnosed in presence of open angles, characteristic glaucomatous optic disc changes correlating with the visual field on automated perimetry (visual field defect fulfilling at least 2 of Anderson and Patella's 3 criteria with mean deviation > or = -6 dB). Normals had visual acuity > or =20/30, intraocular pressure <22 mmHg with normal optic disc and fields and no ocular abnormality.
METHODS: All patients underwent complete ophthalmic evaluation including visual field examination (24-2/30-2 SITA standard program) and imaging with Stratus OCT 3.
MAIN OUTCOME MEASURES: Sensitivity, specificity, positive and negative predictive values, area under the receiving operating characteristic curve and likelihood ratios were calculated for various Stratus OCT 3 parameters.
RESULTS: Seventy-two eyes (72 patients) with early glaucoma and 96 eyes (96 normal subjects) were analyzed. The inferior maximum parameter had the best combination of sensitivity and specificity, 75% (95% confidence interval [CI], 70.2-79.8%) and 89.6% (95% CI, 82.6-96.6%), respectively. The 6-o'clock parameter had a sensitivity of 61.1% (95% CI, 52.3-69.9) and specificity of 99% (95% CI, 95-100); for an assumed prevalence of 5%, the positive and negative predictive values were 75% and 98%, respectively. The positive likelihood ratio for the 6-o'clock parameter (P<5%) in early glaucoma was 61.
CONCLUSIONS: Optical coherence tomography has moderate sensitivity with high specificity for the diagnosis of early glaucoma and may have a potential role in screening. ||||| PURPOSE: To identify the best combination of Stratus optical coherence tomography (OCT) retinal nerve fiber layer (RNFL) thickness parameters for the detection of glaucoma.
DESIGN: Observational cross-sectional study.
PARTICIPANTS: Eighty-nine age-matched normal and perimetric glaucoma participants enrolled in the Advanced Imaging for Glaucoma Study.
METHODS: The Zeiss Stratus OCT system was used to obtain the circumpapillary RNFL thickness in both eyes of each participant. Right and left eye clock-hour data are analyzed together, assuming mirror-image symmetry. The RNFL diagnostic parameters were combined using either or-logic or and-logic approaches.
MAIN OUTCOME MEASURES: Area under the receiver operating characteristic curve (AROC), sensitivity, and specificity are used to evaluate diagnostic performance.
RESULTS: Overall average RNFL thickness has the highest AROC value (0.89) of all single parameters evaluated, followed by the inferior and superior quadrants (0.88 and 0.86, respectively). The clock hours with the best AROC values are in the inferior and superior quadrants. The highest AROC (0.92) was achieved by the or-logic combination of overall, inferior, and superior quadrant RNFL thicknesses. The 3-parameter combination was significantly better than the overall average alone (P = 0.01). The addition of more quadrants or clock hours to the combination reduced diagnostic performance.
CONCLUSIONS: The best stand-alone diagnostic strategy for Stratus OCT RNFL data is to classify an eye as glaucomatous if the overall, inferior quadrant, or superior quadrant RNFL thickness average is below normal. ||||| OBJECTIVE: To evaluate and compare the retinal nerve fiber layer (RNFL) measurement variability, diagnostic sensitivity and specificity for glaucoma detection, and strength of the structure-function association obtained with a spectral-domain optical coherence tomography (OCT) device (Cirrus HD-OCT; Carl Zeiss Meditec, Inc., Dublin, CA) and a time-domain OCT device (Stratus OCT; Carl Zeiss Meditec, Inc.).
DESIGN: Prospective, cross-sectional study.
PARTICIPANTS: Ninety-seven normal subjects and 83 glaucoma patients.
METHODS: One eye from each subject was imaged with Cirrus HD-OCT and Stratus OCT. Sixteen and 31 normal eyes were selected randomly to evaluate intravisit repeatability and intervisit reproducibility, respectively. The agreement of RNFL measurements was evaluated with Bland-Altman plots. The diagnostic sensitivity and specificity was examined with the area under the receiver operating characteristic curve (AUC). The association between average RNFL thickness and visual field sensitivity was evaluated with a second-order regression model.
MAIN OUTCOME MEASURES: Retinal nerve fiber layer measurement variability, AUC, and coefficient of determination (R(2)).
RESULTS: The intravisit repeatability of Cirrus HD-OCT ranged between 5.12 and 15.02 mum, and the intervisit reproducibility ranged between 4.31 and 22.01 mum. The intervisit variabilities of sectoral and average RNFL thicknesses were lower in Cirrus HD-OCT compared with Stratus OCT with significant differences at 1, 3, 4, and 8 to 11 o'clock (P< or =0.021). There were proportional biases of RNFL measurements between the 2 OCT devices. The difference of RNFL thicknesses increased with the means. The average (AUC, 0.962 for Cirrus HD-OCT and 0.956 Stratus OCT), superior (AUC, 0.963 and 0.950, respectively), and inferior (AUC, 0.949 and 0.931, respectively) RNFL thicknesses demonstrated the greatest AUCs in both OCT devices with no significant difference detected between the respective measurements (P> or =0.120). The strength of the structure-function association was comparable between Cirrus HD-OCT (R(2) = 0.580) and Stratus OCT devices (R(2) = 0.623; P = 0.918).
CONCLUSIONS: Although the diagnostic performance and the strength of the structure-function association were comparable between Cirrus HD-OCT and Stratus OCT RNFL measurements, Cirrus HD-OCT demonstrated lower measurement variability compared with Stratus OCT with significant differences at 1, 3, 4, and 8 to 11 o'clock. The poor agreement was likely related to the different inherent characteristics of the 2 OCT systems. ||||| PURPOSE: To determine retinal nerve fiber layer (RNFL) thickness measurements in normal, ocular hypertensive (OHT), and glaucomatous Asian Indian eyes.
METHODS: This prospective observational cross-sectional study included patients with OHT, primary open angle glaucoma (POAG), and age-matched normal controls. The global and 4-quadrant average RNFL thickness was measured using the Stratus OCT. The main outcome measures were differences in RNFL thickness measurements between the 3 groups. The discriminating power of each parameter was evaluated by calculating areas under receiver operating characteristic curves (AROCs).
RESULTS: Twenty-three eyes of 23 POAG patients, 24 eyes of 24 OHT, and 48 eyes of 48 normal controls were analyzed. The superior, inferior, and global RNFL measurements were significantly thinner in OHTs compared with normals (P=0.031, 0.019, and 0.022, respectively). All 5 RNFL parameters were significantly thinner in the POAG group compared with OHT group (P<0.001). Parameters with largest AROCs for distinguishing glaucoma from OHT were average and inferior average RNFL measurements (0.989 and 0.979, respectively). Inferior and superior RNFL measurements had largest AROCs (0.717 and 0.700, respectively) to distinguish OHT from normal eyes.
CONCLUSIONS: Stratus OCT detected significant quantitative differences in RNFL thickness between normal, OHT, and glaucomatous Asian Indian eyes. ||||| PURPOSE: To determine the sensitivity and specificity of measurements of the retinal nerve fiber layer (RNFL) using the StratusOCT in glaucoma subjects with visual field (VF) defects.
DESIGN: Prospective cross-sectional study.
PARTICIPANTS: One hundred nine normal and 63 glaucoma subjects.
TESTING: Fast RNFL scans were performed in one eye of each patient using the StratusOCT.
MAIN OUTCOME MEASURES: Sensitivity and specificity of different optical coherence tomography (OCT) criteria for identifying glaucoma subjects with glaucomatous VF defects.
SECONDARY OUTCOME MEASURES: Areas under the receiver operating characteristic curves (AROCs) for various OCT parameters.
RESULTS: Severity of VF defects in the glaucoma group was distributed between mild (18 subjects), moderate (21 subjects), and severe (24 subjects). The average mean deviation of the glaucoma fields was -8.4 decibels (dB), with a standard deviation of 6.0 dB and a range from -0.14 to -28.0 dB. The sensitivity and specificity using a criterion of average RNFL thickness abnormal at the <5% level were 84% and 98%, respectively. The sensitivity and specificity using a criterion of average RNFL thickness abnormal at the <1% level were 68% and 100%. The sensitivity and specificity of using a criterion of >or=1 quadrants abnormal at the <5% level were 89% and 95%. The sensitivity and specificity of using a criterion of >or=1 quadrants abnormal at the <1% level were 83% and 100%. The sensitivity and specificity of using a criterion of >or=1 clock hours abnormal at the <5% level were 89% and 92%. The sensitivity and specificity of using a criterion of >or=1 quadrants abnormal at the <1% level were 83% and 100%. The AROC for mean RNFL thickness was 0.966. Other high AROC values included the superior quadrant (0.952), inferior quadrant (0.971), inferotemporal clock hour at 7-o'clock (right eye) and 5-o'clock (left eye) (0.959), 6-o'clock hour (0.940), superotemporal clock hour at 11-o'clock (right eye) and 1-o'clock (left eye) (0.935), and 12-o'clock hour (0.924).
CONCLUSIONS: The sensitivity and specificity of RNFL measurements using the new StratusOCT for glaucoma with manifest VF defects are excellent. The best parameters seem to be >or=1 quadrants abnormal at the <or=5% level or >or=1 clock hours abnormal at the <or=5% level. Future studies are needed to determine the sensitivity and specificity of this new technology for glaucoma without VF defects. ||||| PURPOSE: To compare retinal nerve fiber layer (RNFL) measurements between two ocular coherence tomography (OCT) instruments (OCT 2000 and Stratus OCT; Carl Zeiss Meditec, Dublin, CA) and compare their diagnostic precision.
METHODS: One hundred thirty-nine consecutive subjects were imaged (3 x 3.4-mm diameter circular scans) on the same day with each instrument. Thirty-five patients were excluded due to poor-quality images. RNFL thicknesses measured by the two instruments were compared, and receiver operating characteristic (ROC) curves were used to determine diagnostic precision.
RESULTS: A randomly selected eye of each of 104 participants (28 with open-angle glaucoma, 40 with suspected glaucoma, and 36 healthy subjects) was analyzed. RNFL thickness measurements generally were thicker with OCT 2000 than with Stratus OCT. The difference in global RNFL thickness between instruments was within 20 microm in 66 (65%) of subjects and within 10 microm (the instrument's limit of resolution) in 25 (25%) subjects. Application of a correction factor to OCT 2000 measurements predicted Stratus OCT RNFL thickness within 10 microm of the observed measurement in 75% of the eyes. For both instruments, highest ROC curve areas (better discrimination between glaucomatous and normal eyes) were found in the inferior sector. Discrimination using global RNFL thickness was better with Stratus OCT than OCT 2000 (P = 0.043).
CONCLUSIONS: RNFL thickness measurements measured by OCT 2000 can be approximated to measurements made by Stratus OCT using correction factors calculated by this study. However, there remains considerable variability that exceeds the limits of resolution afforded by the instruments themselves. Therefore comparisons between instruments using these approximations should be interpreted with caution. ||||| PURPOSE: To compare the performance of the retinal nerve fiber layer (RNFL) thickness and optic disk algorithms as determined by optical coherence tomography to detect glaucoma.
DESIGN: Observational cross-sectional study.
METHODS: setting: Academic tertiary-care center. study population: One eye from 42 control subjects and 65 patients with open-angle glaucoma with visual acuity of > or =20/40, and no other ocular pathologic condition. observation procedures: Two optical coherence tomography algorithms were used: "fast RNFL thickness" and "fast optic disk." main outcome measures: Area under the receiver operating characteristic curves and sensitivities at fixed specificities were used. Discriminating ability of the average RNFL thickness and RNFL thickness in clock-hour sectors and quadrants was compared with the parameters that were derived from the fast optic disk algorithm. Classification and regression trees were used to determine the best combination of parameters for the detection of glaucoma.
RESULTS: The average visual field mean deviation (+/-SD) was 0.0 +/- 1.3 and -5.3 +/- 5.0 dB in the control and glaucoma groups, respectively. The RNFL thickness at the 7 o'clock sector, inferior quadrant, and the vertical C/D ratio had the highest area under the receiver operating characteristic curves (0.93 +/- 0.02, 0.92 +/- 0.03, and 0.90 +/- 0.03, respectively). At 90% specificity, the best sensitivities (+/-SE) from each algorithm were 86% +/- 3% for RNFL thickness at the 7 o'clock sector and 79% +/- 4% for horizontal integrated rim width (estimated rim area). The combination of inferior quadrant RNFL thickness and vertical C/D ratio achieved the best classification (misclassification rate, 6.2%).
CONCLUSION: The fast optic disk algorithm performs as well as the fast RNFL thickness algorithm for discrimination of glaucoma from normal eyes. A combination of the two algorithms may provide enhanced diagnostic performance. ||||| PURPOSE: To compare retinal nerve fiber layer (RNFL) thickness and diagnostic capability of spectral-domain (CirrusTM) versus time-domain (Stratus®) optical coherence tomography (OCT).
METHODS: A total of 123 eyes of 123 subjects including 68 normal, 32 glaucoma suspect, and 23 patients with glaucoma were prospectively recruited for the study. All subjects were scanned by Stratus® and CirrusTM OCT in the same session. Average and quadrant peripapillary RNFL measurements by both machines were correlated using Spearman correlation coefficient, and agreement between testing methods was analyzed by Bland-Altman plots. The area under receiver operating characteristic curves (AUC) for glaucoma diagnosis was calculated.
RESULTS: Average RNFL thickness were significantly thinner on the CirrusTM compared to the Stratus® OCT in normal subjects and glaucoma suspects (p<0.001), but thicker on the CirrusTM OCT in glaucoma patients, though the difference was not statistically significant (p = 0.53). There was good correlation between the measurements in all 3 groups. In normal controls, the average, superior, nasal, inferior, and temporal correlations were r = 0.668, 0.601, 0.508, 0.620, and 0.660, p<0.001, respectively. In glaucomatous eyes, the corresponding values were r = 0.560, p = 0.005; r = 0.423, p = 0.04; r = 0.117, p = 0.596; r = 0.742, p<0.001; r = 0.669, p<0.001, respectively. The 95% limits of agreement of average RNFL thickness were -30.2 to 13.8 µm. Area under receiver operating characteristic curves for diagnosing glaucoma were comparable (superior RNFL thickness by CirrusTM 0.925; average RNFL thickness by Stratus® 0.987). Highest correlated AUCs were for inferior and temporal quadrants.
CONCLUSIONS: Retinal nerve fiber layer measurements on the CirrusTM and Stratus® OCT correlate well but do not have clinically acceptable agreement between their measurements. The instruments may not be used interchangeably. ||||| OBJECTIVE: To evaluate macular nerve fiber layer (NFL) thickness in glaucomatous damage by optical coherence tomography (OCT) and to compare its discriminating power for glaucoma and glaucoma suspects with that of total macular thickness and peripapillary NFL thickness.
DESIGN: Cross-sectional, case-control, comparative study.
PARTICIPANTS: A total of 133 eyes from 133 subjects including 46 normal eyes, 48 glaucoma-suspect eyes, and 39 glaucoma eyes were enrolled.
METHODS: Macular NFL thickness, total macular thickness, and peripapillary NFL thickness were measured by Stratus OCT in each diagnostic group.
MAIN OUTCOME MEASURES: The patterns and measurements of macular NFL, total macular, and peripapillary NFL thickness in total mean, 4 quadrants, and 12 clock hours. The discriminating power of each parameter for detection of glaucoma suspects and glaucoma was evaluated by areas under the receiver operating characteristic curve (AROC). Correspondence with visual field function was studied by linear regression analysis.
RESULTS: The macular NFL profile exhibited a double-hump pattern with peaks over superonasal and inferonasal sectors. A significant difference in macular NFL thickness between normal and glaucoma-suspect groups was found at the 6-o'clock position, whereas a difference was found in all except the temporal clock hours between normal and glaucoma subjects. No significant difference in AROCs for detection of glaucoma suspects or glaucoma was found when macular NFL thickness and total macular thickness measurements were compared. However, mean macular NFL thickness demonstrated a stronger correlation with visual function than mean macular thickness (r = 0.39/R2 = 0.15 vs. r = 0.23/R2 = 0.05, P =0.042). Among all the findings, inferior peripapillary NFL thickness had the best performance in discriminating glaucoma (AROC, 0.91) and glaucoma suspects (AROC, 0.67). It also had the strongest correlation with visual function (r = 0.60/R2 = 0.36, P<0.001).
CONCLUSIONS: Macular NFL thickness was significantly reduced in glaucoma. It had a similar discriminating power for glaucoma detection but a stronger correlation with visual function than total macular thickness. Peripapillary NFL thickness, however, outperformed both total macular and macular NFL thickness in terms of glaucoma detection and visual function correlation. Peripapillary NFL thickness, as a total measurement of both macular and peripheral NFL, is still the best surrogate marker in glaucoma assessment. ||||| OBJECTIVE: To evaluate the diagnostic performance of the retinal nerve fiber layer (RNFL) thickness deviation map imaged by a spectral-domain optical coherence tomography (OCT; Cirrus HD-OCT, Carl Zeiss Meditec Inc, Dublin, CA) and compare its sensitivity and specificity for glaucoma detection with circumpapillary RNFL measurement derived from the standard 3.46 mm diameter circle scan.
DESIGN: Prospective, cross-sectional study.
PARTICIPANTS: We included 102 normal subjects and 121 glaucoma patients.
METHODS: One eye from each individual was imaged with Cirrus HD-OCT and Stratus OCT (Carl Zeiss Meditec Inc.). Glaucoma was defined based on the presence of visual field defects with the Humphrey visual field analyzer (Carl Zeiss Meditec Inc.). A scoring system (0-5) was developed to analyze the RNFL thickness deviation map taking the defect size, shape, depth, location, and distance from the disc margin into consideration. Each of these features was scored independently by a masked observer with a highest total score of 5 (glaucomatous RNFL defect) and a lowest score of 0 (no RNFL defect). Sensitivity and specificity were computed with a score of > or =3, > or =4, or =5. The diagnostic performance of circumpapillary RNFL measurement was analyzed with clock-hour and average RNFL thickness categorical classification.
MAIN OUTCOME MEASURES: Diagnostic sensitivity and specificity.
RESULTS: The sensitivities of the RNFL thickness deviation map ranged between 95.0% and 97.5%. There were significant differences in specificity between a map score of 5, a map score of > or =4 (87.3%), and a map score > or =3 (72.5%; P< or =0.014). A map score of 5 attained a significantly higher sensitivity (95.0%) compared with clock-hour or average RNFL thickness categorical classification by Stratus OCT or Cirrus HD-OCT (46.3%-88.4%; P< or =0.033) at a comparable level of specificity (95.1%), except when glaucoma was detected as having > or =1 clock-hour at the < or =5% level by Cirrus HD-OCT in which an equally high sensitivity (93.4%) was found but at the expense of a significantly lower specificity (83.3%; P<0.001).
CONCLUSIONS: Analysis of the RNFL thickness deviation map provides additional spatial and morphologic information of RNFL damage and significantly improves the diagnostic sensitivity for glaucoma detection compared with conventional circumpapillary RNFL measurement. ||||| PURPOSE: To compare the peripapillary retinal nerve fiber layer (RNFL) thickness of normal patients and those with various glaucoma diseases by time domain (Stratus) and spectral domain (Spectralis) optical coherence tomography (OCT).
METHODS: The RNFL thickness as measured by the Stratus and Spectral OCT was compared (paired t-test). The relationship and agreement of RNFL thickness between the two OCT modalities were evaluated by Pearson correlation, Bland-Altman plot, and area under the receiver operating characteristic curve.
RESULTS: Two-hundred seventeen eyes of 217 patients, including twenty-four normal eyes, ninety-one glaucoma suspects, seventy-six normal tension glaucoma cases, and twenty-six primary open angle glaucoma cases (POAG) were analyzed. The peripapillary RNFL thicknesses as measured by Stratus OCT were significantly greater than those measured by Spectralis OCT. However, in quadrant comparisons, the temporal RNFL thickness obtained using Stratus OCT were significantly less than those obtained using Spectralis OCT. Correlations between RNFL parameters were strong (Pearson correlation coefficient for mean RNFL thickness = 0.88); a high degree of correlation was found in the POAG group. Bland-Altman plotting demonstrated that agreement in the temporal quadrant was greater than any other quadrant.
CONCLUSIONS: Both OCT systems were highly correlated and demonstrated strong agreement. However, absolute measurements of peripapillary RNFL thickness differed between Stratus OCT and Spectralis OCT. Thus, measurements with these instruments should not be considered interchangeable. The temporal quadrant was the only sector where RNFL thickness as measured by Spectralis OCT was greater than by Stratus OCT; this demonstrated greater agreement than other sectors. ||||| PURPOSE: To examine the association between scanning laser polarimetry (SLP), using enhanced (ECC) and variable corneal compensation (VCC) with optical coherence tomography (OCT), and to compare their discriminating ability in the diagnosis of glaucoma.
METHODS: Normal and glaucomatous eyes enrolled from four clinical sites underwent complete examination, automated perimetry, SLP-ECC, SLP-VCC, and OCT. Eyes were characterized in two groups based on the typical scan score (TSS): Normal birefringence pattern (NBP) was defined as a TSS of 80 to 100 and abnormal birefringence pattern (ABP) as TSS <or= 79. For each of the six SLP parameters and five OCT parameters the areas under the receiver operating characteristic curve (AUROCs) were calculated to compare the discriminating ability of each imaging modality, to differentiate between normal and glaucomatous eyes.
RESULTS: Ninety-five normal volunteers and 63 patients with glaucoma were enrolled. Average visual field mean deviation was -4.2 +/- 4.3 dB in the glaucoma group. In eyes with NBP, SLP-ECC had significantly (all P <or= 0.001) greater correlation with OCT average, superior, and inferior retinal nerve fiber layer (RNFL; r = 0.79, 0.67, 0.74) compared with SLP-VCC (r = 0.71, 0.43, 0.37). In eyes with ABP, SLP-ECC had a significantly greater (all P <or= 0.001) correlation with OCT average, superior, and inferior RNFL (r = 0.75, 0.73, 0.83) compared with SLP-VCC (r = 0.51, 0.22, 0.18). The AUROC for OCT inferior average thickness (0.91) was similar (P = 0.26) to the TSNIT (temporal, superior, nasal, inferior, temporal) average obtained using SLP-ECC (0.87) and significantly (P = 0.02) greater than SLP-VCC (0.81).
CONCLUSIONS: Compared with SLP-VCC, SLP-ECC has significantly stronger correlations with OCT and may improve the discriminating ability for early glaucoma diagnosis. ||||| PURPOSE: Several cross-sectional studies have demonstrated the capability of optical coherence tomography (OCT) to detect glaucomatous changes. OCT enables posterior pole scanning of three regions: macula, peripapillary, and optic nerve head (ONH). This study compared the ability of each region to detect glaucomatous damage.
DESIGN: Retrospective observational cross-sectional study.
METHODS: The study included 37 normal (37 subjects) and 37 glaucomatous eyes (26 subjects) that had comprehensive ocular examination, reliable and reproducible Swedish interactive thresholding algorithm standard 24-2 perimetry, and Stratus OCT scanning of macula, peripapillary, and ONH regions on the same visit. Optical nerve head (ONH) appearance did not form part of the inclusion criteria. The main outcome measure, was area under receiver operating characteristic curves (AROCs) that was calculated for each scanning region for distinguishing between normal and glaucomatous eyes.
RESULTS: The highest AROCs for distinguishing between groups were for ONH parameters (rim area = 0.97, horizontal integrated rim width = 0.96, vertical integrated rim area = 0.95) and peripapillary nerve fiber layer (NFL) thickness (0.94) followed by macular volume and thickness (both 0.80). A statistically significant difference existed in ONH and NFL AROCs when compared with macular AROCs (P < or = .007, for both)
CONCLUSIONS: OCT ONH and NFL parameters provided similar discrimination capabilities between healthy eyes and those of glaucoma patients and superior discrimination capabilities when compared with macular parameters. ||||| PURPOSE: To compare the ability of optical coherence tomography retinal nerve fiber layer (RNFL), optic nerve head, and macular thickness parameters to differentiate between healthy eyes and eyes with glaucomatous visual field loss.
DESIGN: Observational case-control study.
METHODS: Eighty-eight patients with glaucoma and 78 healthy subjects were included. All patients underwent ONH, RNFL thickness, and macular thickness scans with Stratus OCT during the same visit. ROC curves and sensitivities at fixed specificities were calculated for each parameter. A discriminant analysis was performed to develop a linear discriminant function designed to identify and combine the best parameters. This LDF was subsequently tested on an independent sample consisting of 63 eyes of 63 subjects (27 glaucomatous and 36 healthy individuals) from a different geographic area.
RESULTS: No statistically significant difference was found between the areas under the ROC curves (AUC) for the RNFL thickness parameter with the largest AUC (inferior thickness, AUC = 0.91) and the ONH parameter with largest AUC (cup/disk area ratio, AUC = 0.88) (P = .28). The RNFL parameter inferior thickness had a significantly larger AUC than the macular thickness parameter with largest AUC (inferior outer macular thickness, AUC = 0.81) (P = .004). A combination of selected RNFL and ONH parameters resulted in the best classification function for glaucoma detection with an AUC of 0.97 when applied to the independent sample.
CONCLUSIONS: RNFL and ONH measurements had the best discriminating performance among the several Stratus OCT parameters. A combination of ONH and RNFL parameters improved the diagnostic accuracy for glaucoma detection using this instrument. ||||| PURPOSE: To evaluate the relationship between optic nerve head (ONH) and peripapillary retinal nerve fiber layer (RNFL) parameters by optical coherence tomography (OCT) and confocal scanning laser ophthalmoscopy (Heidelberg retinal tomography; HRT; Heidelberg Engineering, Heidelberg, Germany) in early and moderate glaucoma and to compare several OCT-based automated classifiers with those inbuilt in HRT for detection of glaucomatous damage.
METHODS: This cross-sectional study included 60 eyes of 60 patients with glaucoma (30 early and 30 moderate visual field defects) and 60 eyes of 60 healthy subjects. All patients underwent Fast Optic Disc and Fast Peripapillary RNFL scans on the OCT and then HRT evaluation of the ONH during the same visit. Glaucoma variables obtained from OCT and HRT analyses were compared among the groups. Receiver operator characteristic (ROC) curves generated by performing linear discriminant analysis (LDA), artificial neural networks (ANNs), and classification and regression trees (CART) on OCT-based parameters were compared with the Moorfield regression analysis (MRA), R Bathija (RB), and FS Mickelberg (FSM) functions in the HRT, to classify eyes as either glaucomatous or normal.
RESULTS: No statistically significant difference was found in the disc area measured by the OCT and HRT analyses within each study group (P > 0.05). The areas under ROC curves were 0.9822 (LDF), 0.9791 (CART), and 0.9383 (ANN) as compared with 0.859 (FSM), 0.842 (RB) and 0.767 (MRA).
CONCLUSIONS: OCT-based automated classifiers performed better than HRT classifiers in distinguishing glaucomatous from healthy eyes. Such parameters should be integrated in the OCT to improve its diagnostic abilities. ||||| PURPOSE: To compare the retinal nerve fiber layer (RNFL) evaluation using Cirrus optical coherence tomography (OCT) and Stratus OCT in glaucoma diagnosis.
METHODS: One hundred thirty normal and 86 patients with glaucoma were included in this prospective study. The signal strengths of the OCTs were evaluated. The sensitivities and specificities of global RNFL average thickness were compared in the four quadrants and in each clock hour sector. Receiver operating characteristic (ROC) curves, areas under the ROC (AUC), and the likelihood ratio (LR) were plotted for RNFL thickness. Agreement between the OCTs was calculated by using the Bland-Altman method and kappa (kappa) coefficient.
RESULTS: Twenty-three percent of all cases examined with Stratus OCT and 1.9% examined with Cirrus OCT had a signal strength below 6 (P = 0.01). In cases with signal strengths > or =6, the mean signal strength was higher with Cirrus OCT than with Stratus OCT (P = 0.01). The RNFL measurements by Cirrus were thicker than those of Stratus OCT (P < 0.05). The AUCs were 0.829 for Stratus and 0.837 for Cirrus OCT (P = 0.706) for global RNFL average. LRs were similar in both OCTs in global RNFL classification but varied in quadrants. The widths of the limits of agreement varied between 42.16 and 97.79 microm. There was almost perfect agreement (kappa = 0.82) in the average RNFL classification.
CONCLUSIONS: Cirrus OCT has better scan quality than Stratus OCT, especially in glaucomatous eyes. In cases with good-quality scans, the sensitivity and specificity, and AUCs were similar. The best agreement was in the global average RNFL classification. The widths of limits of agreements exceed the limits of resolution of the OCTs. ||||| PURPOSE: To compare the glaucoma diagnostic power of Stratus and Cirrus optical coherence tomographies (OCTs) in a Taiwan Chinese population with different glaucoma types.
PATIENTS AND METHODS: One eye each was chosen from 21 ocular hypertension (OH) patients, 27 glaucoma-suspect (GS) patients, 35 primary open-angle glaucoma (POAG) patients, 26 primary angle-closure glaucoma (PACG) patients, and 52 normal subjects. Early glaucoma (EG) was identified among glaucomatous eyes on the basis of the visual field severity (better than -9 dB). All participants were imaged using 2 OCT units at the same visit. The area under the receiver operator characteristic (AROC) curve was used to differentiate normal eyes from OH, GS, POAG, PACG, and EG eyes, and the sensitivity and specificity of each parameter from internal normative classifications were analyzed.
RESULTS: For normal versus OH eyes, the best AROC value was the average thickness (Stratus, 0.693; Cirrus, 0.697). For normal versus GS eyes, the best AROC value was the average thickness (Stratus, 0.807; Cirrus, 0.776). For normal versus POAG eyes, the best AROC value was the average thickness (Stratus, 0.943; Cirrus, 0.930). For normal versus PACG eyes, the best AROC value was the 5-o'clock hour (Stratus, 0.830; Cirrus, 0.817). For normal versus EG eyes, the best AROC value was the average thickness with Stratus (0.868) and the 5-o'clock hour with Cirrus (0.876). All sensitivities in the 5 groups were fair on the basis of the internal normal classification database of both OCTs.
CONCLUSIONS: Cirrus and Stratus OCTs showed equal diagnostic power in EG, OH, GS, POAG, and PACG eyes in a Taiwan Chinese population. The utility of the current internal databases of both OCT units for the Chinese population is an interesting issue that needs to be addressed in the future. ||||| PURPOSE: To evaluate the role and ability of optical coherence tomography (OCT) to detect differences in peripapillary retinal nerve fiber layer (RNFL) thickness between normal and glaucomatous eyes and also between different severities of glaucoma.
METHOD: This cross-sectional observational study included 160 eyes of 160 healthy subjects and 134 eyes of 134 patients with primary open-angle glaucoma (POAG). Peripapillary RNFL thickness was measured on OCT using the fast RNFL thickness protocol. The RNFL thickness parameters used for evaluation included average RNFL thickness and inferior, superior, nasal, and temporal RNFL thickness. The glaucomatous eyes were subdivided into three subgroups on the basis of visual field defects and a fourth subgroup of eyes blinded by glaucoma. RNFL thickness parameters were compared among the normal eyes and the glaucoma subgroups. Correlation of global visual field indices with RNFL thickness parameters was also performed.
RESULTS: The average RNFL in control subjects, early glaucoma, moderate glaucoma, severe glaucoma, and blind glaucoma were 102.30 +/- 10.34, 77.68 +/- 15.7, 66.07 +/- 15.5, 53.65 +/- 14.2, and 44.93 +/- 4.95 microm, respectively. There was a significant difference in all RNFL thickness parameters between normal and all glaucoma subgroups (P < 0.001). Average and inferior RNFL thicknesses showed the highest area under the receiver operating characteristic curve, with 0.905 and 0.862 for normal versus early glaucoma, 0.705 and 0.722 for early versus moderate glaucoma, 0.737 and 0.717 for moderate versus severe glaucoma, and 0.635 and 0.584 for severe versus blind glaucoma. Both mean deviation (MD) and corrected pattern standard deviation (CPSD) showed a significant correlation with all the RNFL thickness parameters in eyes with glaucoma (P < 0.001).
CONCLUSIONS: RNFL thickness measured on OCT may serve as useful adjuncts in accurately and more objectively distinguishing normal from glaucomatous eyes, even in the early stages of glaucoma and may help to differentiate various severities of glaucoma. Average and inferior RNFL thicknesses are among the most efficient parameters for distinguishing such a differentiation. RNFL thicknesses in eyes blinded by glaucoma provide an estimate of the component of the RNFL thickness, which is not related to visual function. | [
{
"source_pmid": "17868631",
"source_text": "PURPOSE: To compare optic disk and retinal nerve fiber layer (RNFL) imaging methods to discriminate eyes with early glaucoma from normal eyes.\nDESIGN: Retrospective, cross-sectional study.\nMETHODS: In a tertiary care academic glaucoma center, 92 eyes of 92 subj... |
26173799 | CONCLUSIONS: There is, as yet, no convincing evidence that modern laser systems are more effective than the argon laser used in ETDRS, but they appear to have fewer adverse effects. We recommend a trial of PRP for severe NPDR and early PDR compared with deferring PRP till the HR-PDR stage. The trial would use modern laser technologies, and investigate the value adjuvant prophylactic anti-VEGF or steroid drugs. | The Early Treatment Diabetic Retinopathy Study (ETDRS), a multicenter collaborative clinical trial supported by the National Eye Institute, was designed to assess whether argon laser photocoagulation or aspirin treatment can reduce the risk of visual loss or slow the progression of diabetic retinopathy in patients with mild-to-severe nonproliferative or early proliferative diabetic retinopathy. The 3711 patients enrolled in the ETDRS were assigned randomly to either aspirin (650 mg per day) or placebo. One eye of each patient was assigned randomly to early argon laser photocoagulation and the other to deferral of photocoagulation. Both eyes were to be examined at least every 4 months and photocoagulation was to be initiated in eyes assigned to deferral as soon as high-risk proliferative retinopathy was detected. Examination of a large number of baseline ocular and patient characteristics indicated that there were no important differences between randomized treatment groups at baseline. ||||| Data from the Diabetic Retinopathy Study (DRS) show that photocoagulad inhibited the progression of retinopathy. These beneficial effects were noted to some degree in all those stages of diabetic retinopathy which were included in the Study. Some deleterious effects of treatment were also found, including losses of visual acuity and constriction of peripheral visual field. The risk of these harmful effects was considered acceptable in eyes with retinopathy in the moderate or severe retinopathy in the moderate or severe proliferative stage when the risk of severe visual loss without treatment was great. In early proliferative or severe nonproliferative retinopathy, when the risk of severe visual loss without treatment was less, the risks of harmful treatment effects assumed greater importance. In these earlier stages, DRS findings have not led to a clear choice between prompt treatment and deferral of treatment unless and until progression to a more severe stage occurs. ||||| PURPOSE: To evaluate 14-week effects of intravitreal ranibizumab or triamcinolone in eyes receiving focal/grid laser for diabetic macular edema and panretinal photocoagulation.
METHODS: Three hundred and forty-five eyes with a visual acuity of 20/320 or better, center-involved diabetic macular edema receiving focal/grid laser, and diabetic retinopathy receiving prompt panretinal photocoagulation were randomly assigned to sham (n = 123), 0.5-mg ranibizumab (n = 113) at baseline and 4 weeks, and 4-mg triamcinolone at baseline and sham at 4 weeks (n = 109). Treatment was at investigator discretion from 14 weeks to 56 weeks.
RESULTS: Mean changes (±SD) in visual acuity letter score from baseline were significantly better in the ranibizumab (+1 ± 11; P < 0.001) and triamcinolone (+2 ± 11; P < 0.001) groups compared with those in the sham group (-4 ± 14) at the 14-week visit, mirroring retinal thickening results. These differences were not maintained when study participants were followed for 56 weeks for safety outcomes. One eye (0.9%; 95% confidence interval, 0.02%-4.7%) developed endophthalmitis after receiving ranibizumab. Cerebrovascular/cardiovascular events occurred in 4%, 7%, and 3% of the sham, ranibizumab, and triamcinolone groups, respectively.
CONCLUSION: The addition of 1 intravitreal triamcinolone injection or 2 intravitreal ranibizumab injections in eyes receiving focal/grid laser for diabetic macular edema and panretinal photocoagulation is associated with better visual acuity and decreased macular edema by 14 weeks. Whether continued long-term intravitreal treatment is beneficial cannot be determined from this study. ||||| Analyses of visual acuity and visual field results in the Diabetic Retinopathy Study provide evidence that photocoagulation treatment as carried out according to the study protocol (extensive "scatter" photocoagulation and focal treatment of new vessels) is of benefit in preventing severe visual loss, over a two-year follow-up period, in eyes with proliferative retinopathy. Location of new vessels relative to the disk, severity on new vessels, and the presence of hemorrhage (vitreous or preretinal) all proved to be important prognostic factors. On the basis of these findings, these steps have been taken: All patients in the study have been informed of results to date and given an explanation of their implications. Photocoagulation treatment will be considered for the initially untreated eyes which now or in the future fulfill any one of the following criteria: (a) moderate or severe new vessels on or within 1-disk diameter of the optic disk; (b) mild new vessels on or within 1-disk diameter of the optic disk if fresh hemorrhage is present; and (c) moderate or severe new vessels elsewhere, if fresh hemorrhage is present. Follow-up of all patients will continue to allow long-term comparison between the argon- and xenon-treatment techniques employed. Further analyses of accumulating data will be performed to evaluate more completely the efficacy of photocoagulation therapy. ||||| PURPOSE: To compare the efficacy of therapy with panretinal photocoagulation (PRP) and intravitreal bevacizumab (IVB) injections versus PRP alone in patients with high-risk proliferative diabetic retinopathy (HR-PDR) with a 6-month follow-up.
METHODS: Forty-two patients with HR-PDR were prospectively studied in a randomised, masked, controlled trial. Both eyes of each patient were randomised either to the study group (SG) receiving PRP plus IVB injections or the control group (CG) receiving PRP alone. Mean change in visual acuity (VA), optical coherence tomography-measured foveal thickness (FT) and macular volume (MV) were compared.
RESULTS: Intergroup comparisons showed no significant difference in VA while FT exhibited a significant (p < 0.05) difference at 1 month of follow-up and MV was significantly reduced at the 1- and 3-month follow-up. Compared to baseline, VA was significantly worse at all follow-ups in the CG and was stable in the SG. FT increased significantly in the CG from baseline to the 1- and 6-month follow-ups and in the SG, no significant difference was observed. MV was significantly increased in the CG during all follow-up periods.
CONCLUSION: In HR-PDR, using IVB injections as adjuvant treatment to PRP reduces the VA deterioration and results in decreased FT and MV measurements compared to PRP alone. ||||| The Early Treatment Diabetic Retinopathy Study (ETDRS) enrolled 3711 patients with mild-to-severe nonproliferative or early proliferative diabetic retinopathy in both eyes. One eye of each patient was assigned randomly to early photocoagulation and the other to deferral of photocoagulation. Follow-up examinations were scheduled at least every 4 months and photocoagulation was initiated in eyes assigned to deferral as soon as high-risk proliferative retinopathy was detected. Eyes selected for early photocoagulation received one of four different combinations of scatter (panretinal) and focal treatment. This early treatment, compared with deferral of photocoagulation, was associated with a small reduction in the incidence of severe visual loss (visual acuity less than 5/200 at two consecutive visits), but 5-year rates were low in both the early treatment and deferral groups (2.6% and 3.7%, respectively). Adverse effects of scatter photocoagulation on visual acuity and visual field also were observed. These adverse effects were most evident in the months immediately following treatment and were less in eyes assigned to less extensive scatter photocoagulation. Provided careful follow-up can be maintained, scatter photocoagulation is not recommended for eyes with mild or moderate nonproliferative diabetic retinopathy. When retinopathy is more severe, scatter photocoagulation should be considered and usually should not be delayed if the eye has reached the high-risk proliferative stage. The ETDRS results demonstrate that, for eyes with macular edema, focal photocoagulation is effective in reducing the risk of moderate visual loss but that scatter photocoagulation is not. Focal treatment also increases the chance of visual improvement, decreases the frequency of persistent macular edema, and causes only minor visual field losses. Focal treatment should be considered for eyes with macular edema that involves or threatens the center of the macula. ||||| PURPOSE: To investigate the alterations of macular thickness during and after panretinal photocoagulation (PRP) in patients with severe diabetic retinopathy and good vision, and to compare the outcomes of weekly and biweekly treatments.
DESIGN: Prospective, comparative interventional case series.
PARTICIPANTS: Thirty-six patients with severe nonproliferative diabetic retinopathy or non-high-risk proliferative diabetic retinopathy whose visual acuity was 20/20 or better before PRP.
METHODS: Seventy-two eyes of 36 patients underwent scatter PRP in 4 sessions. The macular thickness was measured by optical coherence tomography. The photocoagulation sessions were performed weekly to one eye and biweekly to the other eye. Each eye was selected at random.
MAIN OUTCOME MEASURES: Best-corrected visual acuity and macular thickness.
RESULTS: Visual acuities were maintained in 89% of eyes with weekly treatments and 92% of eyes with biweekly treatments. Macular thickness was increased transiently in the central macula in both eyes, more in the weekly treated eyes, and then decreased to control levels in eyes treated biweekly but remained thickened in eyes treated weekly.
CONCLUSION: For eyes with severe diabetic retinopathy and good vision, PRP with either weekly or biweekly treatment did not affect postoperative visual acuity. However, biweekly treatments allowed faster recovery of macular thickening after PRP than weekly treatments. ||||| BACKGROUND: The Early Treatment Diabetic Retinopathy Study (ETDRS) enrolled 3711 patients with mild-to-severe nonproliferative or early proliferative diabetic retinopathy in both eyes. Patients were randomly assigned to aspirin 650 mg/day or placebo. One eye of each patient was assigned randomly to early photocoagulation and the other to deferral of photocoagulation. Follow-up examinations were scheduled at least every 4 months, and photocoagulation was initiated in eyes assigned to deferral as soon as high-risk proliferative retinopathy was detected. Aspirin was not found to have an effect on retinopathy progression or rates of vitreous hemorrhage. The risk of a combined end point, severe visual loss or vitrectomy, was low in eyes assigned to deferral (6% at 5 years) and was reduced by early photocoagulation (4% at 5 years). Vitrectomy was carried out in 208 patients during the 9 years of the study. This report presents baseline and previtrectomy characteristics and visual outcome in these patients.
METHODS: Information collected at baseline and during follow-up as part of the ETDRS protocol was supplemented by review of clinic charts for visual acuity and ocular status immediately before vitrectomy.
RESULTS: Vitrectomy was performed in 208 (5.6%) of the 3711 patients (243 eyes) enrolled in the ETDRS. The 5-year vitrectomy rates for eyes grouped by their initial photocoagulation assignment were as follows: 2.1% in the early full scatter photocoagulation group, 2.5% in the early mild scatter group, and 4.0% in the deferral group. The 5-year rates of vitrectomy (in one or both eyes) were 5.4% in patients assigned to aspirin and 5.2% in patients assigned to a placebo. The indications for vitrectomy were either vitreous hemorrhage (53.9%) or retinal detachment with or without vitreous hemorrhage (46.1%). Before vitrectomy, visual acuity was 5/200 or worse in 66.7% of eyes and better than 20/100 in 6.2%. One year after vitrectomy, the visual acuity was 20/100 or better in 47.6% of eyes, including 24.0% with visual acuity of 20/40 or better.
CONCLUSIONS: With frequent follow-up examinations and timely scatter (panretinal) photocoagulation, the 5-year cumulative rate of pars plana vitrectomy in ETDRS patients was 5.3%. Aspirin use did not influence the rate of vitrectomy. ||||| Six hundred sixteen eyes with recent severe diabetic vitreous hemorrhage reducing visual acuity to 5/200 or less for at least one month were randomly assigned to either early vitrectomy or deferral of vitrectomy for one year. After two years of follow-up, 25% of the early vitrectomy group had visual acuity of 10/20 or better compared with 15% in the deferral group (P = .01). In patients with Type I diabetes, who were on the average younger and had more-severe proliferative retinopathy, there was a clear-cut advantage for early vitrectomy, as reflected in the percentage of eyes recovering visual acuity of 10/20 or better (36% vs 12% in the deferral group, P = .0001). No such advantage was found in the Type II diabetes group (16% in the early group vs 18% in the deferral group), but evidence that this advantage differed by diabetes type was of borderline significance. ||||| AIMS: To evaluate the efficacy of a single posterior sub-Tenon capsule injection of triamcinolone acetonide (PSTA) before panretinal photocoagulation (PRP).
METHODS: This 6-month study involved the randomisation of 82 eyes of 41 patients, with bilateral severe non-proliferative diabetic retinopathy or proliferative diabetic retinopathy to a single PSTA 20 mg or to no injection before PRP. The primary end-point was change in best-corrected visual acuity (BCVA) at 6 months compared with that at baseline using the logarithm of the minimum angle of resolution (logMAR). Secondary end-points were changes in retinal thickness and intraocular pressure.
RESULTS: The mean changes in logMAR BCVA at 6 months compared with that at baseline were a worsening of 0.010 (SD 0.029) in the control group (no injection) and an improvement of 0.072 (0.028) in the PSTA group (p = 0.04). The mean changes in foveal thickness at 6 months compared with baseline measurements were an increase of 32.8 (82.8) mum in the control group and a lessening of 9.7 (85.6) mum in the PSTA group (p = 0.03).
CONCLUSIONS: PSTA before PRP appears to be beneficial in preventing PRP-induced visual loss in eyes with diabetic retinopathy by reducing the chance of macular thickening. ||||| OBJECTIVE: To investigate the effects of pattern scanning laser (Pascal; OptiMedica, Santa Clara, California) multispot panretinal photocoagulation given in a single-session (SS-PRP) vs single-spot multiple-session PRP (MS-PRP) on proliferative diabetic retinopathy (PDR).
METHODS: Single-center, randomized clinical trial of 40 eyes. Proliferative diabetic retinopathy was treated with a 400-mum spot size in 1500 burns given either as Pascal in 20-millisecond SS-PRP or in 3 sessions (100-millisecond MS-PRP) during a 4-week period. Visual acuity, central subfield retinal thickness (CRT), and 24-2 Swedish interactive thresholding algorithm visual fields were recorded at baseline and 4 and 12 weeks.
MAIN OUTCOME MEASURES: Central subfield retinal thickness, mean deviation, and PDR grade at 12 weeks.
RESULTS: There was a significant increase in mean CRT with MS-PRP (22 mum at 4 weeks, 95% CI, -32.25 to -10.75; 20 mum at 12 weeks, 95% CI, -28.75 to -10.82; P < .001) and no significant increase in the SS-PRP group. The mean deviation increased significantly in the SS-PRP group after 4 weeks (0.73 dB, P = .048), with no significant changes in either group at other points. A positive effect on PDR was observed in 74% of eyes in the SS-PRP group vs 53% in the MS-PRP group (P = .31). Mean treatment time for SS-PRP was 5.04 minutes (SD, 1.5 minutes) compared with 59.3 (SD, 12.7 minutes) in the MS-PRP group (P < .001).
CONCLUSIONS: There were no adverse outcomes (CRT, visual acuity, or visual field) from using multispot SS-PRP vs single-spot MS-PRP at 12 weeks postlaser, and treatment times were significantly shorter for multispot SS-PRP. Pascal SS-PRP was as effective as MS-PRP in the treatment of PDR.
APPLICATION TO CLINICAL PRACTICE: Twenty-millisecond Pascal SS-PRP may be safely and rapidly performed in 1500 burns with a similar efficacy to conventional MS-PRP. TRIAL IDENTIFIER: Research and Development Office PIN R00037, Central Manchester University Hospitals Foundation Trust. ||||| AIMS: To quantify the 20-ms Pattern Scan Laser (Pascal) panretinal laser photocoagulation (PRP) ablation dosage required for regression of proliferative diabetic retinopathy (PDR), and to explore factors related to long-term regression.
METHODS: We retrospectively studied a cohort of patients who participated in a randomised clinical trial, the Manchester Pascal Study. In all, 36 eyes of 22 patients were investigated over a follow-up period of 18 months. Primary outcome measures included visual acuity (VA) and complete PDR regression. Secondary outcomes included laser burn dosimetry, calculation of retinal PRP ablation areas, and effect of patient-related factors on disease regression. A PDR subgroup analysis was undertaken to assess all factors related to PDR regression according to disease severity.
RESULTS: There were no significant changes in logMAR VA for any group over time. In total, 10 eyes (28%) regressed after a single PRP. Following top-up PRP treatment, regression rates varied according to severity: 75% for mild PDR (n=6), 67% for moderate PDR (n=14), and 43% in severe PDR (n=3). To achieve complete disease regression, mild PDR required a mean of 2187 PRP burns and 264 mm(2) ablation area, moderate PDR required 3998 PRP burns and area 456 mm(2), and severe PDR needed 6924 PRP laser burns (836 mm(2); P<0.05).
CONCLUSIONS: Multiple 20-ms PRP treatments applied over time does not adversely affect visual outcomes, with favourable PDR regression rates and minimal laser burn expansion over 18 months. The average laser dosimetry and retinal ablation areas to achieve complete regression increased significantly with worsening PDR. ||||| PURPOSE: To evaluate prospectively the efficacy of a single sub-Tenon's capsule injection of triamcinolone acetonide (TA) against panretinal photocoagulation (PRP)-induced macular thickening and visual disturbance in patients with severe diabetic retinopathy and good vision.
DESIGN: Prospective, comparative, interventional case series.
PARTICIPANTS: Twenty eyes of 10 patients with severe nonproliferative diabetic retinopathy or non-high-risk proliferative diabetic retinopathy whose visual acuity was 20/40 or better (<0.3 in logarithm of the minimum angle of resolution [logMAR] acuity) before the PRP, whose retinopathy was bilateral and symmetrical. The averaged parafoveal retinal thickness was more than 300 microm, leading to a worse visual prognosis after PRP.
INTERVENTION: Sub-Tenon's capsule injection of 20 mg TA.
MAIN OUTCOME MEASURES: Best-corrected visual acuity (BCVA) with logMAR chart and averaged foveal thickness (FT) using the retinal mapping program of optical coherence tomography.
METHODS: In all patients, PRP was performed every other week for 4 sessions on both eyes, and 1 week before PRP; 1 eye received the TA injection, and the other eye served as a control. The clinical course of BCVA and FT was monitored for up to 24 weeks after beginning PRP.
RESULTS: Before TA injection, BCVA and FT were 0.055+/-0.072 and 235.5+/-37.5 microm in the TA-injected eye and 0.065+/-0.071 and 233.7+/-39.8 microm in the control eye, respectively; there was no significant difference between eyes. After the TA injection, FT in the TA-injected eyes was significantly decreased. During and after the PRP, FT in the control eye increased dramatically and reached 312.0+/-68.2 microm at 24 weeks, which was significantly different from that in the TA-injected eyes (235.3+/-38.6 microm at 24 weeks). Best-corrected visual acuity in the control eye decreased with time to 0.24+/-0.13; in contrast, and BCVA in the TA-injected eye was good (to 0.085+/-0.11) .
CONCLUSIONS: As a pretreatment for PRP, a single sub-Tenon's capsule injection of TA has beneficial effects for preventing PRP-induced foveal thickening and visual dysfunction in patients with severe diabetic retinopathy and good vision. ||||| PURPOSE: To evaluate the additional therapeutic effect of single intravitreal bevacizumab injection on standard laser treatment in the management of proliferative diabetic retinopathy.
METHODS: A prospective, fellow-eye sham controlled clinical trial was conducted on 80 eyes of 40 high-risk characteristic proliferative diabetic retinopathy type II diabetics. All cases received standard laser treatment according to Early Treatment Diabetic Retinopathy Study protocol. Avastin-assigned eyes received 1.25 mg intravitreal bevacizumab (Genentech Inc., San Francisco, CA) on the first session of their laser treatments. Fluorescein angiography was performed at baseline and at weeks 6 and 16, and proliferative diabetic retinopathy regression was evaluated in a masked fashion.
RESULTS: The median age was 52 years (range: 39-68) and 30% of the participants were male. All patients were followed for 16 weeks. A total of 87.5% of Avastin-injected eyes and 25% of sham group showed complete regression at week 6 of follow-up (p<0.005). However, at week 16, PDR recurred in a sizable number of the Avastin-treated eyes, and the complete regression rate in the two groups became identical (25%; p=1.000); partial regression rates were 70% vs 65%. In the subgroup of Avastin-treated eyes, multivariate analysis identified hemoglobin A1c as the strongest predictor of proliferative diabetic retinopathy recurrence (p=0.033).
CONCLUSIONS: Intravitreal bevacizumab remarkably augmented the short-term response to scatter panretinal laser photocoagulation in high-risk characteristic proliferative diabetic retinopathy but the effect was short-lived, as many of the eyes showed rapid recurrence. Alternative dosing (multiple and/or periodic intravitreal Avastin injections) is recommended for further evaluation. ||||| PURPOSE: To investigate the short-term effects of high-density 20-ms laser on macular thickness using Pascal-targeted retinal photocoagulation (TRP) and reduced fluence/minimally-traumatic panretinal photocoagulation (MT-PRP) compared to standard-intensity PRP (SI-PRP) in proliferative diabetic retinopathy (PDR).
METHODS: Prospective randomised clinical trial. Treatment-naive PDR was treated with single-session 20-ms Pascal 2500 burns photocoagulation randomised to one of three treatment arms (TRP:MT-PRP:SI-PRP). Primary outcome measure was change in central retinal thickness (CRT) on OCT. Secondary outcomes at 4 and 12 weeks post-laser included: OCT peripapillary nerve fibre layer (NFL) thickness; PDR disease regression on Optos angiography; SITA-Std visual fields (VF); and, visual acuity (VA).
RESULTS: 30 eyes of 24 patients were studied, ten eyes/arm. At 12 weeks, there were significant reductions in CRT after TRP (9.6 µm; 95% CI, 1.84 to 17.36; p=0.021) and MT-PRP (17.1 µm; 95% CI, 11 to 23.2; p=0.001), versus SI-PRP (+5.9 µm; 95% CI, -6.75 to 18.55; p=0.32). PDR regression was similar between groups (TRP 70%; MT-PRP 70%; SI-PRP 90%; κ=0.76). No significant changes in VA and NFL thickness developed between groups. The VF mean deviation scores increased significantly in all groups at 12 weeks ([TRP, +0.70dB; 95% CI, 0.07 to 1.48; p=0.07], [MT-PRP, +0.63dB; 95% CI, 0.12 to 1.15; p=0.02], [SI-PRP, +1.0dB; 95% CI, 0.19 to 1.74; p=0.02]). There were no laser-related ocular complications.
CONCLUSIONS: This pilot study reports that high-density 20-ms Pascal TRP and MT-PRP using 2500 burns did not produce increased macular thickness or any ocular adverse events during the short-term. ||||| PURPOSE: The purpose of this study was to compare the efficacy, collateral damage, and convenience of panretinal photocoagulation for proliferative diabetic retinopathy or severe nonproliferative diabetic retinopathy using a 532-nm solid-state green laser (GLX) versus a multispot 532-nm pattern scan laser (PASCAL).
METHODS: This study was a prospective randomized clinical trial. Sixty patients with bilaterally symmetrical proliferative diabetic retinopathy or severe nonproliferative diabetic retinopathy participated. Each patient underwent panretinal photocoagulation: one eye with GLX and the other with PASCAL, two sittings per eye. Grade 3 burns with a 200-mum spot size were placed with both modalities. The fluence, pain using the visual analog scale, time, laser spot spread with infrared images, and retinal sensitivity were compared.
RESULTS: Pattern scan laser and GLX required an average fluence of 40.33 vs 191 J/cm(2), respectively. Average time required per sitting was 1.43 minutes with PASCAL and 4.53 minutes with GLX. Average visual analog scale reading for GLX was 4.6, whereas that for PASCAL was 0.33. Heidelberg retinal angiography images showed the spot spread as being 430 versus 310 microm at 3 months with GLX and PASCAL. The eyes treated with PASCAL showed higher average retinal sensitivity in the central 15 degrees and 15 degrees to 30 degrees zones (25.08 and 22.08 dB, respectively) than the eyes treated with GLX (23.16 and 17.14 dB), respectively.
CONCLUSION: Pattern scan laser showed lesser collateral damage and similar regression of retinopathy compared with GLX. Pattern scan laser treatment was less time consuming and less painful for the patient compared with GLX. ||||| PURPOSE: To describe the causes of and risk factors for persistent severe visual loss occurring in the Early Treatment Diabetic Retinopathy Study (ETDRS).
METHODS: The ETDRS was a randomized clinical trial investigating photocoagulation and aspirin in 3,711 persons with mild to severe nonproliferative or early proliferative diabetic retinopathy. Severe visual loss, defined as best-corrected visual acuity of less than 5/200 on at least two consecutive 4-month follow-up visits, developed in 257 eyes (219 persons). Of these 257 eyes, 149 (127 persons) did not recover to 5/200 or better at any visit (persistent severe visual loss). Ocular characteristics of these eyes were compared with those of eyes with severe visual loss that improved to 5/200 or better at any subsequent visit. Characteristics of patients with severe visual loss that did and did not improve and those without severe visual loss were also compared.
RESULTS: Severe visual loss that persisted developed in 149 eyes of 127 persons. In order of decreasing frequency, reasons recorded for persistent visual loss included vitreous or preretinal hemorrhage, macular edema or macular pigmentary changes related to macular edema, macular or retinal detachment, and neovascular glaucoma. Compared with all patients without persistent severe visual loss, patients with persistent severe visual loss had higher mean levels of hemoglobin A1c (10.4% vs 9.7%; P = .001) and higher levels of cholesterol (244.1 vs 228.5 mg/dl; P = .0081) at baseline. Otherwise, patients with persistent severe visual loss were similar to patients with severe visual loss that improved and to those without severe visual loss.
CONCLUSIONS: Persistent severe visual loss was an infrequent occurrence in the ETDRS. Its leading cause was vitreous or preretinal hemorrhage, followed by macular edema or macular pigmentary changes related to macular edema and retinal detachment. The low frequency of persistent severe visual loss in the ETDRS is most likely related to the nearly universal intervention with scatter photocoagulation (either before or soon after high-risk proliferative diabetic retinopathy developed) and the intervention with vitreous surgery when clinically indicated. ||||| Additional follow-up confirms previous reports from the Diabetic Retinopathy Study (DRS) that photocoagulation, as used in the study, reduces the risk of severe visual loss by 50% or more. Decreases of visual acuity of one or more lines and constriction of peripheral visual field due to treatment were also observed in some eyes. These harmful effects were more frequent and more severe following the DRS xenon technique. The two-year risk of severe visual loss without treatment outweighs the risk of harmful treatment effects for two groups of eyes: (1) eyes with new vessels and preretinal or vitreous hemorrhage; and (2) eyes with new vessels on or within one disc diameter of the optic disc (NVD) equaling or exceeding 1/4 to 1/3 disc area in extent, (Fig 1), even in the absence of preretinal or vitreous hemorrhage. For eyes with these characteristics, prompt treatment is usually advisable. For eyes with less severe retinopathy, DRS findings do not provide a clear choice between prompt treatment or deferral unless progression to these more severe stages occurs. ||||| Results from the Diabetic Retinopathy Study (DRS) demonstrate that scatter photocoagulation is associated with some loss of visual acuity soon after treatment. This visual loss is especially prominent in eyes with preexisting macular edema. It is also associated with the intensity of treatment. Reducing macular edema by focal photocoagulation before initiating scatter treatment and dividing scatter treatment into multiple sessions with less intense burns may decrease the risk of the visual loss associated with photocoagulation. ||||| PURPOSE: We misled to verify whether a panretinal photocoagulation (PRP) performed using low levels of ARGON laser energy (light PRP) has the same efficacy as a PRP performed in a conventional fashion using argon green wavelengths (classic PRP) in eyes with high-risk proliferative diabetic retinopathy (HRPDR). Furthermore, we misled to compare the session number performed and the side effects produced by the two techniques.
METHODS: Sixty-five eyes with HRPDR of 50 consecutive patients were enrolled in a prospective randomized controlled trial. In eyes selected for light PRP, a very light biomicroscopic effect on the retina was obtained for each spot. In eyes assigned to classic PRP, each spot produced a white-yellow biomicroscopic effect. Mean follow-up was 22.4 months +/- 9.7 in the light PRP and 21.6 months +/- 9.3 in the classic PRP group (p = 0.727).
RESULTS: The initial mean logMAR visual acuity (VA) in the light PRP group was 0.12 +/- 0.13 and in the classic PRP group 0.14 +/- 0.15 (p = 0.493). The final mean VA in the former was 0.18 +/- 0.25, and in the latter 0.27 +/- 0.30 (p = 0.231). Median power was 235mW (100-540mW) for light and 420mW (200-950mW) for classic PRP (p < 0.001). Regression of HRPDR at the end of the follow-up was obtained in 30/31 eyes (97%) treated with classic PRP and in 31/34 eyes (91%) treated with light PRP (p = 0.615). The total mean session number was 7.4 +/- 2.4 for light and 9.9 +/- 2.2 for the classic PRP group (p < 0.001). Complications were more frequent in the classic PRP group.
CONCLUSIONS: The efficacy of Light PRP is similar to that of classic Light PRP in eyes with HRPDR. Light PRP is associated with fewer complications and allows the reduction of the number of treatment sessions. ||||| PURPOSE: To compare the safety and efficacy of Pascal laser photocoagulation in comparison with the conventional laser photocoagulation in the treatment of diabetic retinopathy.
PATIENTS AND METHODS: A prospective randomized case series study was done on 120 procedures done in 120 patients divided into two main groups, group A, patients undergoing focal or modified grid macular laser and group B, patients undergoing panretinal photocoagulation (PRP). Each of the two groups were subdivided into two subgroups randomly in the first we used conventional laser photocoagulation (groups A1 and B1) and in the other we used Pascal laser photocoagulation (groups A2 and B2).
RESULTS: Procedures in groups A1,2 and in groups B1,2 had successful outcomes. Significantly higher powers were required with the Pascal (groups A2 and B2) than with conventional laser (groups A1 and B1) (p < 0.001) in eyes that underwent PRP and focal/modified grid macular treatment with both systems. No adverse events were noted in all groups.
CONCLUSION: The Pascal photocoagulator is safe, rapid, effective, with rapid learning and had short exposure time. Although the shorter pulse duration of the Pascal necessitates the use of a higher power, it is not associated with adverse effects. ||||| AIMS: To evaluate pain responses following Pascal 20 ms multi-spot and 100 ms single-spot panretinal photocoagulation (PRP).
METHODS: Single-centre randomised clinical trial. 40 eyes of 24 patients with treatment-naive proliferative diabetic retinopathy randomised to 20 and 100 ms PRP under topical 0.4% oxybuprocaine. A masked grader used a pain questionnaire within 1 h (numerical pain score (NPS)) and 1 month after treatment (numerical headache score (NHS)). Primary outcome measure was NPS immediately post-PRP. Secondary outcome measures were mean NHS scores and levels of photophobia reported within 4 weeks of primary PRP.
RESULTS: Mean laser fluence was significantly lower using 20 ms PRP (4.8 J/cm²) compared to 100 ms PRP (11.8 J/cm²); p < 0.001). Mean NPS scores for treatment were 2.4 (2.3) (mild) for 20 ms PRP group compared to 4.9 (3.3) (moderate) in 100 ms PRP group-a significant difference (95% CI 4.3 to 0.68; p = 0.006). Mean NHS score within 1 month was 1.5 (2.7) in 20 ms PRP group compared to 3.2 (3.5) in the 100 ms PRP group (p < 0.05). The median duration of photophobia after 20 ms PRP was 3 h, and significantly less compared to 100 ms PRP after which 72 h of photophobia was reported (p < 0.001).
CONCLUSIONS: Multi-spot 20 ms PRP was associated with significantly lower levels of anxiety, headache, pain and photophobia compared to 100 ms single-spot PRP treatment. Possible reasons include lower fluence, shorter-pulse duration, and spatial summation of laser nociception with multi-spot Pascal technique. ||||| PURPOSE: To evaluate the effectiveness of selective photocoagulation (S-PC) for nonperfusion areas (NPA) in preproliferative diabetic retinopathy (PPDR).
SUBJECTS AND METHODS: A multicenter randomized controlled clinical trial of 69 patients with PPDR showing NPA comparable to or larger than those on reference photographs. The patients were assigned to 2 groups; one was treated with S-PC (PC group: 32 patients), while the other did not receive S-PS (non-PC group: 37 patients). In the non-PC group, panretinal photocoagulation (PRP) was performed whenever proliferative diabetic retinopathy (PDR) developed. In the PC group, S-PC of the NPA was performed followed by additional coagulation whenever the NPA extended, and PRP was performed whenever PDR developed. The primary outcome was the development of PDR.
RESULTS: During the entire course, PDR developed in 18 (26%) of the 69 patients. The incidence was significantly higher in the non-PC group than in the PC group. Comparison of the visual acuity at the time of registration and after 36 months showed no significant differences between the two groups.
CONCLUSIONS: S-PC for NPA in PPDR is effective at preventing PDR development. ||||| BACKGROUND: To compare pain score of single spot short duration time (20 milliseconds) panretinal photocoagulation (PRP) with conventional (100 milliseconds) PRP in diabetic retinopathy.
METHODS: Sixty-six eyes from 33 patients with symmetrical severe non-proliferative diabetic retinopathy (non-PDR) or proliferative diabetic retinopathy (PDR) were enrolled in this prospective randomized controlled trial. One eye of each patient was randomized to undergo conventional and the other eye to undergo short time PRP. Spot size of 200 μm was used in both laser types, and energy was adjusted to achieve moderate burn on the retina. Patients were asked to mark the level of pain felt during the PRP session for each eye on the visual analog scale (VAS) and were examined at 1 week, and at 1, 2, 4 and 6 months.
RESULTS: Sixteen women and 17 men with mean age 58.9 ± 7.8 years were evaluated. The conventional method required a mean power of 273 ± 107 mW, whereas the short duration method needed 721 ± 406 mW (P = 0.001). An average of 1,218 ± 441 spots were delivered with the conventional method and an average of 2,125 ± 503 spots were required with the short duration method (P = 0.001). Average pain score was 7.5 ± 1.14 in conventional group and 1.75 ± 0.87 in the short duration group (P = 0.001). At 1 week, 1 month, and 4 months following PRP, the mean changes of central macular thickness (CMT) from baseline in the conventional group remained 29.2 μm (P = 0.008), 40.0 μm (P = 0.001), and 40.2 μm (P = 0.007) greater than the changes in CMT for short time group.
CONCLUSION: Patient acceptance of short time single spot PRP was high, and well-tolerated in a single session by all patients. Moreover, this method is significantly less painful than but just as effective as conventional laser during 6 months of follow-up. The CMT change was more following conventional laser than short time laser. ||||| OBJECTIVE: To assess the visual results after surgical lens removal in patients with diabetic retinopathy.
DESIGN: A multicenter randomized clinical trial designed to assess the effect of photocoagulation and aspirin in patients with mild to severe nonproliferative or early proliferative diabetic retinopathy and/or macular edema.
PARTICIPANTS: Of the 3711 patients enrolled in the Early Treatment Diabetic Retinopathy Study, lens surgery was performed on 205 patients (270 eyes) during follow-up that ranged from 4 to 9 years.
OUTCOME MEASUREMENTS: Visual acuity, macular edema status, and degree of diabetic retinopathy. In addition, risk factors associated with lens extraction and with poor postoperative visual acuity (worse than 20/100) were assessed.
RESULTS: The risk of lens extraction increased with increasing age, female sex, and baseline proteinuria. Ocular variables associated with increased risk of lens surgery included poor baseline visual acuity and vitrectomy performed during the course of the study. At 1 year after lens surgery, visual acuity improvement of 2 or more lines from preoperative levels occurred in 64.3% of the operated-on eyes assigned to early photocoagulation and 59.3% of eyes assigned to deferral of photocoagulation. In eyes assigned to early photocoagulation, 46% of eyes achieved visual acuity better than 20/40; 73%, better than 20/100; and 8%, 5/200 or worse at 1 year after surgery. Visual acuity results for eyes assigned to deferral of laser photocoagulation at 1 year were not as favorable; 36% achieved visual acuity better than 20/40; 55%, better than 20/100; and 17%, 5/200 or worse at 1 year after surgery. Evaluation of 1-year postoperative visual acuities for all eyes with mild to moderate nonproliferative diabetic retinopathy at the annual visit before lens surgery showed that 53% were better than 20/40; 90%, better than 20/100; and 1%, 5/200 or worse. However, for eyes with severe nonproliferative or worse retinopathy at the annual visit before lens surgery, only 25% were better than 20/40; 42%, better than 20/100; and 22%, 5/200 or worse at 1 year after lens surgery. There was little change in visual acuity between 1 and 2 years postoperatively. Increased severity of retinopathy and poor visual acuity before surgery were associated with visual acuity of worse than 20/100 at 1 year after surgery. Lens surgery was associated with a borderline statistically significant increased risk of progression of diabetic retinopathy in the adjusted analyses (P = .03). No statistically significant long-term increased risk of macular edema was documented after lens surgery.
CONCLUSIONS: Visual acuity results after lens surgery in patients in the Early Treatment Diabetic Retinopathy Study were better than published results for similar patients. This may be because of more intensive photocoagulation for lesions of diabetic retinopathy in the Early Treatment Diabetic Retinopathy Study than in previously reported studies. Although patients with severe nonproliferative retinopathy or worse before lens surgery had poorer visual results, visual improvement was seen in 55% of these patients at 1-year follow-up. The main causes of poor visual results in eyes after lens surgery were complications of proliferative retinopathy and/or macular edema. ||||| PURPOSE: We performed a study of laser panretinal photocoagulation in 20 patients with proliferative retinopathy. We compared short exposure, high-energy laser settings with conventional settings, using a 532 nm, frequency doubled, Neodymium-Yag laser and assessed the patients in terms of pain experienced and effectiveness of treatment.
METHODS: Twenty patients having panretinal photocoagulation for the first time underwent random allocation to treatment of the superior and inferior hemi-retina. Treatment A used 'conventional' parameters: exposure time 0.1 s, power sufficient to produce a visible grey-white burns, spot size 300 microm. The other hemi- retina was treated with treatment B using exposure 0.02 s, 300 microm and sufficient power to have similar endpoint. All patients were asked to evaluate severity of pain on a visual analogue scale. (0=no pain, 10=most severe pain). All patients were masked as to the type of treatment and the order of carrying out the treatment on each patient was randomised. Patients underwent fundus photography and were followed up for 6-45 months.
RESULTS: Seventeen patients had proliferative diabetic retinopathy, two had ischaemic central retinal vein occlusion and one had ocular ischaemic syndrome. The mean response to treatment A was 5.11, compared to 1.40 treatment B, on the visual analogue scale, which was statistically significant (P=0.001). All patients preferred treatment B. Further treatments, if required, were performed with treatment B parameters and long-term follow-up has shown no evidence of undertreatment.
CONCLUSIONS: Shortening exposure time of retinal laser is significantly less painful but equally effective as conventional parameters. ||||| PURPOSE: To evaluate the outcomes in patients with diabetic retinopathy and cataract who had panretinal photocoagulation (PRP) first and cataract surgery second in 1 eye and cataract surgery followed by PRP in the fellow eye.
SETTING: Department of Ophthalmology, Saiseikai Kurihashi Hospital, Saitama, Japan.
METHODS: Fifty-eight eyes of 29 patients with similar bilateral cataracts and severe nonproliferative or early proliferative diabetic retinopathy were randomly assigned for treatment with cataract surgery performed after PRP (PRP-first group) or before PRP (surgery-first group). Treatment was performed in the opposite order in the contralateral eye. The main outcome measure was best corrected visual acuity (BCVA) 12 months after surgery. The secondary outcome measures were the laser parameters, progression of retinopathy and macular edema, and aqueous flare intensity.
RESULTS: The percentage of eyes with a BCVA of 20/40 or better was statistically significantly higher in the surgery-first group (96.6%) than in the PRP-first group (69.0%) (P = .012). The rate of the progression of macular edema was significantly decreased in the surgery-first group (P = .033). There was no significant difference between the 2 groups in the other outcome measures.
CONCLUSION: Although the order in which PRP and cataract surgery were performed had no effect on postoperative retinopathy, the BCVA was better and the rate of the progression of macular edema was decreased in the surgery-first group. ||||| PURPOSE: To evaluate laser combined with intravitreal triamcinolone acetonide (IVTA) for the management of patients with proliferative diabetic retinopathy (PDR) and clinically significant macular edema (CSME).
DESIGN: Randomized clinical trial.
METHODS: settings: Single center. study population: Twenty-two patients with bilateral treatment-naïve moderate PDR and CSME. intervention: Laser (panretinal and macular) photocoagulation was performed in each eye, followed by IVTA in one randomly assigned eye. Best-corrected visual acuity (BCVA), fundus photography, and optical coherence tomography were performed at baseline and at months 1, 3, 6, 9, and 12. main outcome measures: Changes in BCVA, central macular thickness (CMT), and total macular volume (TMV).
RESULTS: The mean logarithm of the minimal angle of resolution (logMAR) BCVA improved significantly, and mean CMT and TMV were significantly reduced in the IVTA group compared with the laser-only group (controls) at all study follow-up visits (P < .001). The mean logMAR BCVA (Snellen equivalent) was 0.44 (20/50(-2)) for the IVTA group and 0.38 (20/50(+1)) for the controls at baseline, and 0.12 (20/25(-1)) for the IVTA group and 0.32 (20/40(-1)) for the controls at 12 months (P < .001). The mean CMT and TMV were, respectively, 360 microm and 8.59 mm(3) for the IVTA group and 331 microm and 8.44 mm(3) for the controls at baseline, and 236 microm and 7.32 mm(3) for the IVTA group and 266 microm and 7.78 mm(3) for the controls at 12 months (P < .001).
CONCLUSIONS: The combination of laser photocoagulation with IVTA was associated with improved BCVA and decreased CMT and TMV when compared with laser photocoagulation alone for the treatment of moderate PDR with CSME. ||||| PURPOSE: To evaluate the efficacy and safety of combined intravitreal triamcinolone acetonide (IVTA) injection plus panretinal photocoagulation (PRP) and macular photocoagulation (MPC) in comparison with PRP and MPC in eyes with coexisting high-risk proliferative diabetic retinopathy (PDR) and clinically significant macular edema (CSME).
METHODS: Twenty-three patients diagnosed with both high-risk PDR and CSME were enrolled in our prospective, randomized clinical trial study. One eye of each patient was selected to undergo IVTA injection one week before initial PRP and MPC (IVTA eye), and the other eye was treated with PRP and MPC (control eye) based on block randomization. Panretinal photocoagulation was performed in 3 sessions at 1 week intervals. Baseline characteristics included best-corrected visual acuity (BCVA) using Snellen charts, intraocular pressure and patients were observed at 1, 4, and 6 months of treatment. Main outcome measures included change in central macular thickness (CMT) as measured by optical coherence tomography (OCT), logarithm of the minimum angle of resolution BCVA (logMAR), and complications occurring within the follow-up period.
RESULTS: Of 23 enrolled patients, 5 patients did not complete follow-up visits due to dense vitreous hemorrhage, tractional retinal detachment and loss of future follow-up. Mean baseline logMAR BCVA was 0.46 +/- 0.29 and 0.56 +/- 0.27 in IVTA eyes and controls. Final mean logMAR BCVA was 0.39 +/- 0.29 (IVTA eyes) and 0.55 +/- 0.33 (control eyes), which was not significantly different (P = 0.08). Mean baseline CMT was 319.2 +/- 79.1 microm (IVTA eyes) and 345.9 +/- 100.6 microm (control eyes). Significant reduction of CMT in IVTA eyes was observed at 1 month (P = 0.024), which had not remained stable after 6 months showing no significant difference as compared with baseline CMT (P = 0.06). In control eyes, CMT was not significantly reduced at 1 and 6 months of treatment. The standardized change in macular thickening (SCMT) was 29.4 +/- 52.2 (IVTA group) versus 5.66 +/- 31.5 (control group) (P = 0.12) at 1 month. At 6 months, SCMT was 16.8 +/- 55.8 (IVTA group) versus 5.03 +/- 47.4 (control group) (P = 0.51).
CONCLUSION: Combined IVTA plus PRP and MPC in coexisting high-risk PDR and CSME eyes do not have a significant beneficial effect on BCVA improvement and CMT reduction compared with standard treatment. ||||| OBJECTIVE: To determine the benefits of early photocoagulation in patients with type I versus type II diabetes.
DESIGN: One eye of each of 3,711 patients was randomly assigned to early photocoagulation; the other was assigned to deferral of photocoagulation, with follow-up visits scheduled every 4 months and photocoagulation to be carried out promptly if high-risk proliferative retinopathy developed. Patients were categorized by age and type of diabetes.
MAIN OUTCOME MEASURES: Best corrected visual acuity was measured at each study visit scheduled at 4-month intervals. Stereoscopic fundus photographs were taken and evaluated at baseline, 4 months, and yearly thereafter. Retinopathy severity was assessed from fundus photographs. Severe visual loss was defined as visual acuity of worse than 5/200 for at least two consecutive study visits.
RESULTS: Previously published results of the Early Treatment Diabetic Retinopathy Study (ETDRS) demonstrated a statistically significant benefit of early photocoagulation in preventing severe vision loss. Further analyses demonstrate that this benefit of early photocoagulation is greater in patients with type II diabetes than in those with type I. The relative benefit of early photocoagulation in patients with type II diabetes is also seen for other outcomes (development of high-risk proliferative retinopathy, development of the combined end point [severe visual loss or vitrectomy], development of moderate visual loss, or development of legal blindness). The patients most likely to benefit from early photocoagulation had severe nonproliferative retinopathy or early proliferative retinopathy. Analyses from the Diabetic Retinopathy Study confirm the relative benefit of scatter photocoagulation for type II patients. Because of the high correlation between age and type of diabetes, analyses sub-grouped by age show similar results.
CONCLUSION: These analyses suggest that patients with type II diabetes, or older patients with diabetes, are more likely to benefit from early scatter photocoagulation than patients with type I diabetes. The current standard of care is to initiate scatter photocoagulation as the severity of retinopathy approaches or reaches the high-risk stage, Provided careful follow-up is possible, ETDRS data do not show that initiating scatter photocoagulation prior to the development of high-risk proliferative diabetic retinopathy in patients with type I diabetes will reduce the risk of severe visual loss. ETDRS analyses do indicate that for patients with type II diabetes, it is especially important to consider scatter photocoagulation at the time of the development of severe nonproliferative or early proliferative retinopathy. ||||| BACKGROUND/AIMS: To evaluate efficacy of intravitreal triamcinolone (IVTA) and bevacizumab (IVB) as adjunctive treatments to panretinal photocoagulation (PRP).
METHODS: In 91 eyes of 76 patients (clinically significant macular oedema (CSME) 46 eyes; no CSME 45 eyes) with severe diabetic retinopathy, PRP with IVTA (IVTA group, 30 eyes) or PRP with IVB (IVB group, 31 eyes) or PRP only (PRP group, 30 eyes) was performed. Primary outcome measures were changes in best corrected visual acuity (BCVA) and central macular thickness (CMT) at 1 and 3 months. Secondary outcome measures were proportion of visual gain or loss, and decreased or increased CMT.
RESULTS: There was significant worsening in BCVA from 0.26 to 0.29 at 1 and 3 months (p=0.031) in the PRP group. In eyes with CSME, there was significant improvement of BCVA from 0.33 to 0.27 at 1 and 3 months (p=0.012) in IVTA group. In eyes without CSME, PRP group showed significant worsening in BCVA from 0.18 to 0.26 at 1 month (p=0.008) and 0.27 at 3 months (p=0.005). There was significant improvement in CMT in IVTA and IVB groups: in eyes without CSME, there was significant increase in CMT from 209.75 to 259.00 microm at 1 month (p=0.023) and to 276.14 microm at 3 months (p=0.011) in the PRP group; in eyes with CSME, the proportion of eyes with visual gain and decreased CMT was significantly higher in the IVTA group (75% and 100%, respectively) than in the IVB group (37.5% and 62.5%, respectively).
CONCLUSIONS: IVTA and IVB may be effective adjunctive treatments to PRP, minimising the risk of PRP-induced macular oedema and visual loss. ||||| BACKGROUND: Panretinal photocoagulation remains the gold standard for treatment of proliferative diabetic retinopathy, which can be done in a single session or in multiple sessions. However, because of different reasons, single session is less frequently practiced. We describe the results of a single session of pattern scan laser versus multiple sessions of conventional laser in cases of proliferative diabetic retinopathy.
METHODS: A prospective study was performed on 50 patients (100 eyes), in whom proliferative diabetic retinopathy was diagnosed recently. Two eyes of an individual patient were randomly assigned, one for a single session of panretinal photocoagulation using pattern scan laser and the other for multiple sessions of conventional laser.
RESULTS: Our study confirms that single session is effective and even better than conventional laser in relation to the effect of treatment.
CONCLUSION: Complications and the associated pain are less; thus, the patient's acceptance of PASCAL was high, and a single session was well tolerated with topical anesthesia alone. ||||| PURPOSE: To compare pain related to intravitreal injection and panretinal photocoagulation in the management of patients with high-risk proliferative diabetic retinopathy.
METHODS: Prospective study including patients with high-risk proliferative diabetic retinopathy and no prior laser treatment randomly assigned to receive panretinal photocoagulation (PRP group) or panretinal photocoagulation plus intravitreal ranibizumab (PRPplus group). In all patients, panretinal photocoagulation was administered in two sessions (weeks 0 and 2), and intravitreal ranibizumab was administered at the end of the first laser session in the PRPplus group. Retreatment was performed at weeks 16 and 32 if active new vessels were detected at fluorescein angiography. Patients in the PRPplus group received intravitreal ranibizumab and patients in the PRP group received 500-µm additional spots per quadrant of active new vessels. After the end of retreatment, a 100-degree Visual Analog Scale was used for pain score estimation. The patient was asked about the intensity of pain during the whole procedure (retinal photocoagulation session or intravitreal ranibizumab injection). Statistics for pain score comparison were performed using a non-parametric test (Wilcoxon rank sums).
RESULTS: Seventeen patients from PRPplus and 14 from PRP group were evaluated for pain scores. There were no significant differences between both groups regarding gender, glycosylated hemoglobin and disease duration. Mean intravitreal injection pain (±SEM) was 4.7 ± 2.1 and was significantly lower (p<0.0001) than mean panretinal photocoagulation pain (60.8 ± 7.8). Twelve out of 17 patients from the PRPplus group referred intensity pain score of zero, while the minimal score found in PRP group was found in one patient with 10.5.
CONCLUSION: In patients with high-risk proliferative diabetic retinopathy who needed retreatment for persistent new vessels, there was more comfort for the patient when retreatment was performed with an intravitreal injection in comparison with retinal photocoagulation. Further larger studies are necessary to confirm our preliminary findings. ||||| PURPOSE: To evaluate the effects of panretinal photocoagulation (PRP) compared with PRP plus intravitreal injection of 0.5 mg of ranibizumab (IVR) in patients with high-risk proliferative diabetic retinopathy (PDR).
METHODS: Prospective study included patients with high-risk PDR and no prior laser treatment randomly assigned to receive PRP (PRP group) or PRP plus IVR (PRPplus group). PRP was administered in two sessions (weeks 0 and 2), and IVR was administered at the end of the first laser session in the PRPplus group. Standardized ophthalmic evaluations including best-corrected visual acuity (BCVA) measured according to the methods used in the Early Treatment Diabetic Retinopathy Study (BCVA), fluorescein angiography to measure area of fluorescein leakage (FLA) and optical coherence tomography (OCT) for the assessment of central subfield macular thickness (CSMT), were performed at baseline and at weeks 16 (± 2), 32 (± 2) and 48 (± 2).
RESULTS: Twenty-nine of 40 patients (n = 29 eyes) completed the 48-week study follow-up period. At baseline, mean ± SE FLA (mm(2)) was 9.0 ± 1.3 and 11.7 ± 1.3 (p = 0.1502); BCVA (logMAR) was 0.31 ± 0.05 and 0.27 ± 0.06 (p = 0.6645); and CSMT (μm) was 216.3 ± 10.7 and 249.4 ± 36.1 (p = 0.3925), in the PRP and PRPplus groups, respectively. There was a significant (p < 0.05) FLA reduction at all study visits in both groups, with the reduction observed in the PRPplus group significantly larger than that in the PRP group at week 48 (PRP = 2.9 ± 1.3 mm(2) ; PRPplus = 5.8 ± 1.3 mm(2) ; p = 0.0291). Best-corrected visual acuity worsening was observed at 16, 32 and 48 weeks after treatment in the PRP group (p < 0.05), while no significant BCVA changes were observed in the PRPplus group. A significant CSMT increase was observed in the PRP group at all study visits, while a significant decrease in CSMT was observed in the PRPplus group at week 16, and no significant difference in CSMT from baseline was observed at weeks 32 and 48.
CONCLUSIONS: Intravitreal ranibizumab after PRP was associated with a larger reduction in FLA at week 48 compared with PRP alone in eyes with high-risk PDR, and the adjunctive use of IVR appears to protect against the modest visual acuity loss and macular swelling observed in eyes treated with PRP alone. ||||| PURPOSE: To evaluate the effects of panretinal photocoagulation (PRP) compared with PRP plus intravitreal bevacizumab on best corrected visual acuity (BCVA) and total area of fluorescein leakage from active new vessels (NVs) in patients with high-risk proliferative diabetic retinopathy (PDR).
METHODS: We carried out a prospective study of patients with high-risk PDR and no prior laser treatment who were randomly assigned to receive PRP (PRP group) or PRP plus intravitreal injection of 1.5 mg of bevacizumab (PRP-plus group). In all patients, the PRP was administered at two time-points (weeks 1 and 3), with the intravitreal bevacizumab delivered at the end of the second laser episode in the PRP-plus group. Standardized ophthalmic evaluation including Early Treatment Diabetic Retinopathy Study BCVA as well as stereoscopic fundus photography and fluorescein angiography were performed at baseline and at weeks 4, 9 (+/- 1) and 16 (+/- 2). Main outcome measures included changes in BCVA and in total area of fluorescein leakage from active NVs.
RESULTS: Twenty-two (n = 30 eyes) consecutive patients completed the 16-week follow-up. There was no significant difference between the PRP and PRP-plus groups with respect to age, gender, type or duration of diabetes, area of fluorescein leakage from active NVs or BCVA. No significant difference in BCVA was observed between the groups throughout the study period. However, the total area of actively leaking NVs was significantly reduced in the PRP-plus group compared with the PRP group at weeks 4, 9 and 16 (p < 0.001). No major adverse events were identified.
CONCLUSIONS: In the short-term, the adjunctive use of intravitreal bevacizumab with PRP was associated with a greater reduction in the area of active leaking NVs than PRP alone in patients with high-risk PDR. | [
{
"source_pmid": "2062510",
"source_text": "The Early Treatment Diabetic Retinopathy Study (ETDRS), a multicenter collaborative clinical trial supported by the National Eye Institute, was designed to assess whether argon laser photocoagulation or aspirin treatment can reduce the risk of visual loss or slow ... |
29794727 | CONCLUSIONS: Zinc-monocysteine and rheohemapheresis showed significantly better effects on BCVA (logMAR) improvement, and compared with the blank control, rheohemapheresis and the antioxidant complex showed better effects on BCVA (letters) improvement. Other treatments have potential effects on DAMD, including alprostadil, eculizumab, and lampalizumab. However, there is no effective treatment for GA area reduction. | BACKGROUND: To evaluate the efficacy and safety of topical isopropyl unoprostone (IU) in treating macular atrophy in age-related macular degeneration (AMD) patients.
METHODS: Fifty-two AMD patients with macular atrophy were included and randomly assigned (1:1) to the treatment (topical 0.15% IU) or placebo group. Subjects used study eye drops 3 times a day for 54 weeks. The macular atrophy was documented on fundus autofluorescence photographs and measured using RegionFinder. The enlargement rate of macular atrophy and the changes in visual acuity were examined statistically between baseline and 54 weeks.
RESULTS: Forty-eight subjects were included in the analyses because 4 subjects withdrew from the study. The differences between the IU and placebo groups in mean and median area of macular atrophy were not statistically significant at baseline. The baseline median lesion size of macular atrophy was 2.33 mm in the IU group and 1.63 mm in the placebo group (P = 0.51). The intergroup difference in the enlargement ratio of macular atrophy (21 ± 15% in the IU group and 111 ± 96% in the placebo group) was statistically significant (P < 0.001). Additionally, visual acuity tended to improve over baseline in the IU group. No serious adverse events were observed.
CONCLUSIONS: Topical IU therapy is safe and effective for treating macular atrophy in AMD patients. ||||| Dry form of age-related macular degeneration (AMD) constitutes 90% of AMD cases, and it is characterized by the formation of drusen under the retina and the slow breakdown of the light-sensing cells in the macula, which causes a gradual loss of central vision. Since oxidative stress is involved in the pathogenesis of dry AMD, α-lipoic acid (LA) with antioxidant properties was selected, and its effect on anti-oxidative markers and visual quality in patients with dry AMD was assessed. A total of 100 dry AMD patients (60-83 years old) were randomly assigned to LA treatment group (n = 50) and placebo control group (n = 50). We measured the serum superoxide dismutase (SOD) activity, an important marker of antioxidant defense, best-corrected visual acuity (BCVA), contrast sensitivity, and Chinese-Version Low Vision Quality of Life (CLVQOL) before and after LA or placebo intervention. Pearson correlation coefficients were calculated to explore the relationship between contrast sensitivity values and CLVQOL scores. There was a statistically significant increase in serum SOD activity after LA intervention. The CLVQOL score was improved significantly after LA treatment. The contrast sensitivity measured at middle and low spatial frequency was significantly higher after LA treatment. CLVQOL scores were positively correlated with contrast sensitivity at low spatial frequency (3 cyc/degree) in LA-treated group. These results indicate that LA treatment improves vision-related quality of life in patients with dry AMD probably by increasing antioxidant activity. Thus, LA can be regarded as a promising agent for the treatment of AMD. ||||| BACKGROUND: Excessive accumulation of retinol-based toxins has been implicated in the pathogenesis of geographic atrophy (GA). Fenretinide, an orally available drug that reduces retinol delivery to the eye through antagonism of serum retinol-binding protein (RBP), was used in a 2-year trial to determine whether retinol reduction would be effective in the management of geographic atrophy.
METHODS: The efficacy of fenretinide (100 and 300 mg daily, orally) to slow lesion growth in geographic atrophy patients was examined in a 2-year, placebo-controlled double-masked trial that enrolled 246 patients at 30 clinical sites in the United States.
RESULTS: Fenretinide treatment produced dose-dependent reversible reductions in serum RBP-retinol that were associated with trends in reduced lesion growth rates. Patients in the 300 mg group who achieved serum retinol levels of ≤ 1 μM (≤ 2 mg/dL RBP) showed a mean reduction of 0.33 mm in the yearly lesion growth rate compared with subjects in the placebo group (1.70 mm/year vs. 2.03 mm/year, respectively, P = 0.1848). Retinol-binding protein reductions <2 mg/dL correlated with further reductions in lesion growth rates (r = 0.478). Fenretinide treatment also reduced the incidence of choroidal neovascularization (approximately 45% reduction in incidence rate in the combined fenretinide groups vs. placebo, P = 0.0606). This therapeutic effect was not dose dependent and is consistent with anti-angiogenic properties of fenretinide, which have been observed in other disease states.
CONCLUSION: The findings of this study and the established safety profile of fenretinide in chronic dosing regimens warrant further study of fenretinide in the treatment of geographic atrophy. ||||| BACKGROUND: Age-related macular degeneration (ARMD) is the leading cause of vision loss in aging Westem societies. The objective of the lutein antioxidant supplementation trial (LAST) is to determine whether nutritional supplementation with lutein or lutein together with antioxidants, vitamins, and minerals, improves visual function and symptoms in atrophic ARMD.
METHODS: The study was a prospective, 12-month, randomized, double-masked, placebo-controlled trial conducted at an urban midwestern Veterans Administration Hospital from August 1999 to May 2001. Ninety patients with atrophic ARMD were referred by ophthalmologists at two Chicago-area veterans medical facilities. Patients in Group 1 received lutein 10 mg (L); in Group 2, a lutein 10 mg/antioxidants/vitamins and minerals broad spectrum supplementation formula (L/A); and in Group 3, a maltodextrin placebo (P) over 12 months.
RESULTS: In Groups 1 L and 2 L/A, mean eye macular pigment optical density increased approximately 0.09 log units from baseline, Snellen equivalent visual acuity improved 5.4 letters for Group 1 L and 3.5 letters for Group 2 L/A, and contrast sensitivity improved. There was a net subjective improvement in Amsler grid in Group 1 L. VFO-14 questionnaires conceming subjective glare recovery were nearly significant at 4 months for Group 2 L/A. Patients who received the placebo (Group 3) had no significant changes in any of the measured findings.
CONCLUSION: In this study, visual function is improved with lutein alone or lutein together with other nutrients. Further studies are needed with more patients, of both genders, and for longer periods of time to assess long-term effects of lutein or lutein together with a broad spectrum of antioxidants, vitamins, and minerals in the treatment of atrophic age-related macular degeneration. ||||| PURPOSE: To evaluate the experience with rheohaemapheresis (RH) in the treatment of age-related macular degeneration (AMD).
METHODS: Thirty-eight patients were each treated with 8 procedures of RH (14 males, 24 females). The control group consisted of 34 random patients (30 females, 4 males) with the dry form of AMD but not treated by RH. Our modification of the cascade method (named rheohaemapheresis) was used for plasma separation. After plasma separation (blood cell separator, Cobe Spectra, Denver, CO, USA), the separated plasma was pumped through a rheofilter (Evaflux 4A, Kuraray, Osaka, Japan) to remove lipoproteins and other high-molecular-weight rheologic factors.
RESULTS: In treated patients, best-corrected visual acuity (BCVA) increased significantly from 0.61 (0.06-1.00) to 0.68 (0.35-1.00) after 2.5 years (p = 0.035). We found no significant changes or differences in scotopic activity, whereas cone response and paramacular activity in the more peripheral region between 14° and 22° of eccentricity were significantly higher in treated patients after 2.5 years.
CONCLUSION: RH therapy favourably influenced BCVA. During 2.5 years after the therapy, no progression of dry to wet AMD was observed in our patients. RH reduced the area of drusenoid retinal pigment epithelium detachment (which increased during the natural course of dry form AMD). RH influenced rheological markers and probably improved metabolism in the affected retinal areas which lead to the aforementioned positive results. ||||| PURPOSE: To investigate the safety and effects of subconjunctival sirolimus, an mTOR inhibitor and immunosuppressive agent, for the treatment of geographic atrophy (GA).
METHODS: The study was a single-center, open-label phase II trial, enrolling 11 participants with bilateral GA; eight participants completed 24 months of follow-up. Sirolimus (440 μg) was administered every 3 months as a subconjunctival injection in only one randomly assigned eye in each participant for 24 months. Fellow eyes served as untreated controls. The primary efficacy outcome measure was the change in the total GA area at 24 months. Secondary outcomes included changes in visual acuity, macular sensitivity, central retinal thickness, and total drusen area.
RESULTS: The study drug was well tolerated with few symptoms and related adverse events. Study treatment in study eyes was not associated with structural or functional benefits relative to the control fellow eyes. At month 24, mean GA area increased by 54.5% and 39.7% in study and fellow eyes, respectively (P = 0.41), whereas mean visual acuity decreased by 21.0 letters and 3.0 letters in study and fellow eyes, respectively (P = 0.03). Substantial differences in mean changes in drusen area, central retinal thickness, and macular sensitivity were not detected for all analysis time points up to 24 months.
CONCLUSIONS: Repeated subconjunctival sirolimus was well-tolerated in patients with GA, although no positive anatomic or functional effects were identified. Subconjunctival sirolimus may not be beneficial in the prevention of GA progression, and may potentially be associated with effects detrimental to visual acuity. (ClinicalTrials.gov number, NCT00766649.). ||||| Geographic atrophy is an advanced form of age-related macular degeneration (AMD) and a leading cause of vision loss for which there are no approved treatments. Genetic studies in AMD patients have implicated dysregulation of the alternative complement pathway in the pathogenesis of geographic atrophy. Lampalizumab is a potential therapeutic that targets complement factor D, a pivotal activator of the alternative complement pathway. The MAHALO phase 2 clinical trial was a multicenter, randomized, controlled study that evaluated lampalizumab administered by intravitreal injection monthly ( ||||| AIM: To evaluate the effect of systemic ozonated major autohaemotherapy (O(3)-AHT) in patients affected by dry age related macular degeneration (AMD).
METHODS: This study was a randomized, controlled clinical study. One hundred and forty patients with the diagnosis of AMD in both eyes, with the study eye presenting dry AMD and soft drusen, were randomly assigned in a 1:1 ratio to either receive 27 major ozonated autohemotherapy treatments during 12-month period, or a standardized multi-vitamin therapy. Primary outcome was the change in best corrected visual acuity (mean logMar change) between the baseline and 6 and 12 months, end point of the study. In addition, to investigate the safety of prolonged ozonated autohaemotherapy, we measured the routine haematochemical parameters and biochemical oxidative stress values at baseline and after 12 months treatment time.
RESULTS: The mean baseline best corrected visual acuity in study eyes was 0.36 in the treatment group and 0.38 in the control group (difference not statistically significant). At the primary endpoint, 6 months post-baseline, the mean logMAR change in the treated group improved by 0.1 and the values of the control group at the same time impaired by 0.2 respect to the baseline. Four percent and twenty-five percent of eyes in the group treated with O(3)-AHT gained 1 or more lines after 6 and 12 months respectively compared to 0% in the eyes which received no treatment (P<0.05 at 12 months). None of the treated patients experienced a loss in visual acuity in their study eye at 6 and 12 months, compared to 16% and 40 % of patients in the control group who lost 2 lines or more at 6 months and 12 months respectively (P<0.05 treated vs control group)). Major ozonated autohemotherapy was shown to be safe and well- tolerated by the patients. Moreover, the haematochemical parameters showed a decrease in the Reactive Oxygen Metabolites (300±10.1 UCARR at 12 months compared to a baseline value of 380±10.4 UCARR, P<0.05) and an increase in Biological Antioxidant Potential plasma values (2100±34.8 micromoles/ C vitamin after 12 months compared to the baseline value of 1610±36.2, P<0.05) in the treated patients when compared to the control group. This data suggests that major ozonated autohaemotherapy may exert a role in reducing oxidative stress by endogenously stimulating the production of antioxidant molecules.
CONCLUSION: The results of this study suggests that major ozonated autohaemotherapy could be a safe and effective therapeutic option for high-risk patients with dry AMD, and that a series of such treatments could improve the natural course of AMD. ||||| BACKGROUND: The experimental design, subjects, procedures and baseline data for the prospective double blind dry ARMD-antioxidant intervention study have been described in Part 1.
METHODS: At eight DVA medical centers, 32 patients (group one) were assigned a placebo and 39 patients (group two) a "broad spectrum" antioxidant capsule. Data was collected in five areas: demographic; ophthalmic; dietary analysis of daily food intake; serum analysis; and adverse gastrointestinal symptoms. Data was serially acquired at baseline, 6 months, 12 months and 18 months, and was analyzed by univariate repeated factors ANOVA, p = 0.05.
RESULTS: Group two (antioxidant po BID) maintained their distance LogMAR visual acuity (p = 0.03), while there was a trend toward both stabilized near M print (p = 0.07) and 6 cycle/degree contrast sensitivity (p approximately 0.10), in left eyes. However, group two (antioxidant) also had increased cortical opacification of the right lens (p = 0.04), compared to group one (placebo). Self perceived stabilization of vision was reported by subjects in group two and supported the objective data (Pearson chi square; p = 0.05).
CONCLUSIONS: A specific 14 component antioxidant capsule taken twice daily stabilized but did not improve dry ARMD over the study period of 1.5 years. The ARMD stabilized eyes had less advanced disease functionally but not by fundus appearance. Decreased intake of cardioprotective nutrients (vitamin E, zinc, magnesium, B6 and folate) in ARMD patients remained constant over the course of the trial. ||||| PURPOSE: To evaluate the effect of eculizumab, a systemic inhibitor of complement component (C5), on the growth of geographic atrophy (GA) in patients with age-related macular degeneration (AMD).
DESIGN: Prospective, double-masked, randomized clinical trial.
PARTICIPANTS: Patients with GA measuring from 1.25 to 18 mm(2) based on spectral-domain optical coherence tomography imaging.
METHODS: Patients were randomized 2:1 to receive intravenous eculizumab or placebo over 6 months. In the eculizumab treatment arm, the first 10 patients received a low-dose regimen of 600 mg weekly for 4 weeks followed by 900 mg every 2 weeks until week 24, and the next 10 patients received a high-dose regimen of 900 mg weekly for 4 weeks followed by 1200 mg every 2 weeks until week 24. The placebo group was infused with saline. Patients were observed off treatment for an additional 26 weeks. Both normal-luminance and low-luminance visual acuities were measured throughout the study, and the low-luminance deficits were calculated as the difference between the letter scores.
MAIN OUTCOME MEASURES: Change in area of GA at 26 weeks.
RESULTS: Thirty eyes of 30 patients were enrolled. Eighteen fellow eyes also met inclusion criteria and were analyzed as a secondary endpoint. For the 30 study eyes, mean square root of GA area measurements ± standard deviation at baseline were 2.55 ± 0.94 and 2.02 ± 0.74 mm in the eculizumab and placebo groups, respectively (P = 0.13). At 26 weeks, GA enlarged by a mean of 0.19 ± 0.12 and 0.18 ± 0.15 mm in the eculizumab and placebo groups, respectively (P = 0.96). At 52 weeks of follow-up, GA enlarged by a mean of 0.37 ± 0.22 mm in the eculizumab-treated eyes and by a mean of 0.37 ± 0.21 mm in the placebo group (P = 0.93, 2 sample t test). None of the eyes converted to wet AMD. No drug-related adverse events were identified.
CONCLUSIONS: Systemic complement inhibition with eculizumab was well tolerated through 6 months but did not decrease the growth rate of GA significantly. However, there was a statistically significant correlation between the low-luminance deficit at baseline and the progression of GA over 6 months. ||||| PURPOSE: To investigate the safety and effects of intravitreal sirolimus for the potential treatment of geographic atrophy (GA).
METHODS: The study was a single-center, open-label, phase I/II trial enrolling six participants with bilateral GA treated with intravitreal sirolimus in only one randomly assigned eye, with the fellow eye as control. The primary efficacy outcome measure was the change in total GA area from baseline on color fundus photography (CFP); secondary outcomes included changes in GA area on fundus autofluorescence (FAF), visual acuity, central retinal thickness (CRT), and macular sensitivity from baseline.
RESULTS: Although no systemic adverse events were attributed to treatment, two of six participants had ocular adverse events that were possibly associated. The treated eye of one participant developed abnormal paralesional changes on FAF that were associated with accelerated retinal thinning. This accelerated retinal thinning was also seen in the treated eye of a second participant. Because of concern that these events were associated with treatment, treatment was suspended. Comparisons of treated and fellow eyes for change in visual acuity, change in GA area, and change in CRT showed no evidence of treatment benefit and generally favored the untreated fellow eye.
CONCLUSIONS: While paralesional FAF changes and rapid retinal thinning observed are potentially part of the natural course of GA, they may possibly be related to treatment. No general evidence of anatomical or functional benefit was detected in treated eyes. Further data on intravitreal sirolimus for GA treatment will be available from a larger phase II trial. (ClinicalTrials.gov number, NCT01445548.). ||||| PURPOSE: To present an initial evaluation of the final data from the Multicenter Investigation of Rheopheresis for age-related macular degeneration (AMD) (MIRA-1) trial. This was a 12-month randomized, prospective, multicenter, double-masked, placebo-controlled, Food and Drug Administration approved clinical trial designed to compare rheopheresis treatment with placebo-control treatment.
METHODS: Patients that had nonexudative age-related macular degeneration (AMD) and certain hemorheologic abnormalities were randomized to either rheopheresis or sham treatment in a 2:1 fashion. Best-corrected visual acuity was determined before and at 3, 6, 9, and 12 months following treatment. Adverse events were also recorded.
RESULTS: A total of 216 patients were randomized. Of these, 18 were not included in the vision or adverse events evaluation because they did not complete one treatment. This decreased the number of patients that were evaluated for adverse events to 198 patients. In this group, there were 27 serious adverse events, but only 1.8 % of treatments were suspended because of adverse events. At 12 months, there were 104 treated patients and 63 placebo patients that had follow-up. The treated patients had a logMAR vision improvement of 0.02 +/- 0.213, and the placebo patients had a vision improvement of 0.02 +/- 0.20. This was not statistically significant (P = .977). The repeated measure P value for the entire time interval was not significant (P = .69). There appeared to be patients entered into the study that did not meet inclusion criteria. Excluding 37% of the treated patients and 29% of the placebo data from the analysis, there appeared to be statistically significant improvement in the treated patients compared to the control patients at 1 year with a P value of .001 (repeated measures P value = .01).
CONCLUSIONS: At best this was a flawed study in that 37% of the treated cases did not meet inclusion criteria, and at worst there was no evidence of effect. Even though the number of serious adverse events is small, because this study did not show an effect in the intent-to-treat group, rheopheresis should not be performed for AMD outside of an approved randomized controlled trial. ||||| PURPOSE: To determine the predictors of drusen reduction in eyes with nonexudative age-related macular degeneration (ARMD) treated with subthreshold infrared (810 nm) diode laser macular grid photocoagulation. Additionally, to determine the relationship of laser-induced drusen reduction and best-corrected visual acuity (BCVA) 18 months after laser treatment.
DESIGN: Randomized controlled clinical trial.
METHODS: Fifty patients (100 eyes) with bilateral nonexudative ARMD were enrolled at two centers. One eye of each patient was randomized to the observation; the other eye was treated with 48 subthreshold (invisible end point) applications of infrared (810 nm) diode laser in a macular grid pattern. The eyes that received subthreshold laser treatment were compared with the eyes that received no treatment. The baseline fundus characteristics (number, size, and distribution of drusen, as well as focal hyperpigmentation) from two macula areas (central 1500 micro diameter, pericentral 1500 micro ring area) on stereo color photographs, the number of laser-induced lesions, and the area of laser induced retinal pigment epithelial (RPE) lesions on fluorescein angiography 3 months after treatment were studied as predictors of major drusen reduction (> or = 50% drusen reduction from baseline) 18 months after laser treatment. BCVA at baseline and 18 months later was compared in observation eyes and in laser-treated eyes.
RESULTS: Eighteen months after randomization, 24 (48%) of 50 eyes treated with subthreshold laser had major drusen reduction compared with three (6%) of 50 observation eyes (P =.00001). At 3 months post-treatment in laser-treated eyes with major drusen reduction, the mean number of laser-induced lesions on fluorescein angiography was 30.7 and the mean area of RPE change was 0.81 mm(2) compared with 14.8 laser-induced lesions and 0.35 mm(2) area of RPE change in eyes without major drusen reduction (P =.0001 and P =.0003, respectively). At baseline, fundus characteristics were not significantly different between observation eyes and laser-treated eyes or between the major drusen reduction group and the nonmajor drusen reduction group. At 18 months after treatment, BCVA was not significantly different in laser-treated eyes and in observation eyes.
CONCLUSIONS: Subthreshold infrared (810 nm) diode laser macular grid photocoagulation in eyes with nonexudative ARMD significantly reduced drusen 18 months after laser treatment. Both the number of subthreshold laser lesions and the area of RPE changes visible on fluorescein angiography 3 months after treatment appeared to be predictors for major drusen reduction 18 months after treatment. However, it remains to be determined whether laser-induced drusen reduction is beneficial for visual acuity or reduces the incidence of choroidal neovascularization (CNV) in eyes with nonexudative ARMD. ||||| BACKGROUND: Age-related macular degeneration is the leading cause of blindness among elderly individuals in industrialized countries. New drugs and advanced concepts for the treatment of dry AMD (dAMD) are needed. A new approach is the application of intravenous infusions of prostaglandin E1.
OBJECTIVE: The aim of this study was to assess efficacy and safety of intravenous alprostadil infusion in patients with dAMD.
METHODS: This was a prospective, randomized, multi-center study. Patients were treated with intravenous infusion of either 60 µg alprostadil or placebo over 3 weeks. Main efficacy outcomes were mean differences in best corrected visual acuity (BCVA) from baseline assessed in early treatment diabetic retinopathy study (ETDRS) lines immediately, 3 months and 6 months after treatment.
RESULTS: In the full analysis set (FAS) a mean difference of 0.89 ± 0.537 ETDRS lines according to analysis of variance-covariance (ANCOVA) resulted in the alprostadil group (n = 16) and a mean difference of -0.05 ± 0.578 in the placebo group (n = 17) 3 months after end of treatment. Thus, effectiveness of alprostadil infusion was numerically superior to placebo treatment by a mean of 0.94 lines after 3 months (1.51 lines after 6 months). These findings were more pronounced in the per protocol set (PPS). Safety results were in line with the good safety profile of alprostadil.
CONCLUSION: A numerical treatment effect in favor of alprostadil was visible, which lasted until the end of follow up. These results provide further evidence that alprostadil probably has a therapeutic effect in the treatment of dAMD and justify further clinical studies. ||||| PURPOSE: This study assessed the safety, tolerability, and pharmacodynamics of emixustat hydrochloride (ACU-4429), a novel visual cycle modulator, in subjects with geographic atrophy associated with dry age-related macular degeneration.
METHODS: Subjects were randomly assigned to oral emixustat (2, 5, 7, or 10 mg once daily) or placebo (3:1 ratio) for 90 days. Recovery of rod photoreceptor sensitivity after a photobleach was measured by electroretinography. Safety evaluations included analysis of adverse events and ophthalmic examinations.
RESULTS: Seventy-two subjects (54 emixustat and 18 placebo) were evaluated. Emixustat suppressed rod photoreceptor sensitivity in a dose-dependent manner. Suppression plateaued by Day 14 and was reversible within 7 days to 14 days after drug cessation. Most systemic adverse events were not considered treatment related. Dose-related ocular adverse events (chromatopsia, 57% emixustat vs. 17% placebo and delayed dark adaptation, 48% emixustat vs. 6% placebo) were mild to moderate in severity, and the majority resolved on study or within 7 days to 14 days after study drug cessation. Reversibility of these adverse events with long-term administration, however, is undetermined.
CONCLUSION: In this Phase II study, emixustat produced a dose-dependent reversible effect on rod function that is consistent with the proposed mechanism of action. These results support further testing of emixustat for the treatment of geographic atrophy associated with dry age-related macular degeneration. ||||| Aim. To evaluate the long-term effect of rheohemapheresis (RHF) treatment of age-related macular degeneration (AMD) on photoreceptor IS/OS junction status. Methods. In our study, we followed 24 patients with dry AMD and drusenoid retinal pigment epithelium detachment (DPED) for a period of more than 2.5 years. Twelve patients (22 eyes) were treated by RHF and 12 controls (18 eyes) were randomized. The treated group underwent 8 RHF standardized procedures. We evaluated best-corrected visual acuity, IS/OS junction status (SD OCT), and macular function (multifocal electroretinography) at baseline and at 2.5-year follow-up. Results. RHF caused a decrease of whole-blood viscosity/plasma viscosity at about 15/12%. BCVA of treated patients increased insignificantly (P = 0.187) from median 74.0 letters (56.2 to 81.3 letters) to median 79.0 letters (57.3 to 83.4 letters), but it decreased significantly from 74.0 letters (25.2 to 82.6 letters) to 72.5 letters (23.4 to 83.1 letters) in the control group (P = 0.041). The mfERG responses in the region of eccentricity between 1.8° and 7° were significantly higher in treated patients (P = 0.04). Conclusions. RHF contributed to sparing of photoreceptor IS/OS junction integrity in the fovea, which is assumed to be a predictive factor for preservation of visual acuity. ||||| PURPOSE: To test the hypothesis that daily use of zinc-monocysteine (ZMC) supplement will be well tolerated and result in improved macular function in persons with dry age-related macular degeneration (AMD).
METHODS: Eligible, consenting subjects were randomized to either ZMC 25 mg or placebo twice daily for 6 months. Both ZMC and placebo groups enrolled 40 participants, with best corrected visual acuity 20/25 to 20/70, macular drusen, and pigment changes. Masked personnel determined baseline, 3- and 6-month best-corrected visual acuity, contrast sensitivity, and light flash recovery time. Differences between ZMC and placebo were analyzed by a one-sided unpaired t-test of the paired differences between baseline and 3- and 6-month timepoints for right and left eyes separately.
RESULTS: By 6 months the ZMC group showed improved visual acuity (p < 0.0001) and contrast sensitivity (p < 0.0001). Macular light flash recovery time shortened in the ZMC group at 3 months by 2.1 sec (left eye, p = 0.0001) to 3.6 sec (right eye, p < 0.0001), and at 6 months by 7.2 sec (left eye, p < 0.0001) to 7.4 sec (right eye, p < 0.0001). This variable had no improvement in the placebo group. ZMC had a gastrointestinal irritation rate of under 2%.
CONCLUSION: ZMC 25 mg twice daily was well tolerated and was associated with improved macular function in comparison to a placebo in persons with dry AMD. ||||| PURPOSE: To determine the safety and efficacy of AL-8309B (tandospirone) in the management of patients with geographic atrophy (GA) secondary to age-related macular degeneration (AMD) and obtain standardized data on GA lesion growth progression.
DESIGN: Prospective, controlled, double-masked, randomized, multicenter phase 3 clinical trial.
METHODS: setting: Forty-eight clinical sites.
PATIENTS: Patients with GA associated with AMD were enrolled. All patients were followed for a minimum of 30 months, and up to 36 months. intervention procedures: Patients were randomized (1:1:1) to receive AL-8309B ophthalmic solution 1.0%, 1.75%, or vehicle, administered as a twice-daily topical ocular drop.
MAIN OUTCOME MEASURES: The primary efficacy endpoint was mean annualized lesion enlargement from baseline as assessed with fundus autofluorescence (FAF) imaging.
RESULTS: A total of 768 eyes of 768 patients were enrolled and treated with AL-8309B 1.0% (n = 250), AL-8309B 1.75% (n = 258), or vehicle (n = 260). An increase in mean lesion size was observed in both the AL-8309B and vehicle treatment groups, and growth rates were similar in all treatment groups. Annualized lesion growth rates were 1.73, 1.76, and 1.71 mm(2) for AL-8309B 1.0%, AL-8309B 1.75%, and vehicle, respectively.
CONCLUSIONS: AL-8309B 1.0% and 1.75% did not affect lesion growth in eyes with GA secondary to AMD. There were no clinically relevant safety issues identified for AL-8309B. The large natural history dataset from this study is a valuable repository for future comparisons. ||||| BACKGROUND: The primary objective of LUTEGA is to determine the long-term effect of a supplementation with fixed combination of lutein, zeaxanthin, omega-3-longchain-polyunsaturated-fatty-acids (O-3-LCPUFAs) and antioxidants on macular pigment optical density (MPOD) in patients with non-exudative age-related macular degeneration (AMD).
METHODS: The LUTEGA study is a double-blind, placebo-controlled clinical trial. 172 patients with non-exudative AMD were enrolled and randomized to three treatment arms. Supplementation included either once (dosage D1) or twice daily (dosage D2) of 10 mg L / 1 mg Z/ O-3-LCPUFAs (thereof 100 mg DHA, 30 mg EPA)/ antioxidants, or placebo (P). After best-corrected visual acuity (BCVA) test, blood sample was collected and MPOD was measured using the 1-wavelength-reflection method and recording reflection images at 480 nm (modified Visucam(NM/FA), Carl Zeiss Meditec, Germany). During 1 year of intervention, AMD patients were followed up after 1, 3, 6 and 12 months. 145 AMD patients (D1 = 50, D2 = 55, P = 40) completed the study.
RESULTS: After 12 months of intervention, the MPOD parameters (volume, area, maxOD, meanOD) increased significantly in treatment arms D1 and D2 (p < 0.001). Volume of MPOD showed the highest within-group difference and increased significantly in D1 and D2, and decreased significantly in P (p = 0.041). Between-group comparison of absolute changes of all MPOD parameters were significantly different between D1 and P as well as D2 and P with p < 0.001 at end point (t = 12). BCVA, measured in log MAR, improved in D1 and in D2 (p < 0.001). After 12 months of intervention, the mean improvement in BCVA was significant in D2 (p = 0.006) and D1 (p = 0.038) compared to P.
CONCLUSIONS: The supplementation of L, Z, O-3-LCPUFAs and antioxidants resulted in considerable increase in MPOD. There was no difference in accumulation of MPOD between both dosages. Thus, we believe that the used supplementation with L and Z seems to reach a saturation level in retinal cell structure. Additionally, the constant supplementation of L, Z, O-3-LCPUFAs and antioxidants in AMD patients seems to be useful, because MPOD reduces without supplementation. We conclude that the supplementation caused an increase of MPOD, which results in an improvement and stabilization in BCVA in AMD patients. Thus, a protective effect on the macula in AMD patients is assumed. ||||| There is no treatment available for vision loss associated with advanced dry age-related macular degeneration (AMD) or geographic atrophy (GA). In a pilot, proof of concept phase 2 study, we evaluated ciliary neurotrophic factor (CNTF) delivered via an intraocular encapsulated cell technology implant for the treatment of GA. We designed a multicenter, 1-y, double-masked, sham-controlled dose-ranging study. Patients with GA were randomly assigned to receive a high-or low-dose implant or sham surgery. The primary endpoint was the change in best corrected visual acuity (BCVA) at 12 mo. CNTF treatment resulted in a dose-dependent increase in retinal thickness. This change was followed by visual acuity stabilization (loss of less than 15 letters) in the high-dose group (96.3%) compared with low-dose (83.3%) and sham (75%) group. A subgroup analysis of those with baseline BCVA at 20/63 or better revealed that 100% of patients in the high-dose group lost <15 letters compared with 55.6% in the combined low-dose/sham group (P = 0.033). There was a 0.8 mean letter gain in the high-dose group compared with a 9.7 mean letter loss in the combined low-dose/sham group (P = 0.0315). Both the implant and the implant procedure were well-tolerated. These findings suggest that CNTF delivered by the encapsulated cell technology implant appears to slow the progression of vision loss in GA, especially in eyes with 20/63 or better vision at baseline. ||||| PURPOSE: To evaluate the influence of haemorheopheresis on anatomical and functional findings in patients with soft-drusen maculopathy.
METHODS: We investigated 29 eyes (16 patients) and randomized 25 eyes (16 controls) with soft-drusen maculopathy [soft, confluent and reticular drusen, drusenoid retinal pigment epithelium detachment (RPED)]. Each patient received a series of eight haemorheophereses (cascade filtration of 1.5 plasma volume) within 10 weeks. The patients were followed up using Early Treatment Diabetic Retinopathy Study (ETDRS) charts, optical coherence tomography, fluorescein angiography, electroretinography and measurements of pulsed ocular blood flow.
RESULTS: After the procedures, there was a substantial reduction in rheologically active substances [lipoproteins, α2-macroglobulin, immunoglobulin M (IgM), fibrinogen], plasma and blood viscosity. At the 1.5-year follow-up, we noticed soft drusen absorption; reattachment of drusenoid RPED and stabilization or improvement of visual acuity occurred in 72% of patients in comparison to only 39% of patients in the control group. Full-field electroretinograms showed significantly higher scotopic activity of treated patients in comparison with the control group, and mainly insignificant differences in photopic activity between both groups. Despite the significant increase of activity in the paramacular retina in treated patients, the differences in amplitudes of multifocal electroretinography (mfERG) average responses were insignificant between groups.
CONCLUSION: Haemorheopheresis seems to be capable of changing the activity of promoters of the natural course of soft-drusen maculopathy, its development and progression. Visual acuity and electrical activity of the retina can be stabilized or even improved. The therapy has been shown to be effective and safe. ||||| PURPOSE: To evaluate Rheopheresis for the treatment of patients with high-risk dry age-related macular degeneration and no therapeutic alternative. Rheopheresis is a method of therapeutic apheresis using the methodology of double filtration plasmapheresis to treat microcirculatory disorders.
METHODS: The dry AMD treatment with Rheopheresis trial (ART) was a randomised, controlled clinical study. Patients with the diagnosis of AMD in both eyes, with the study eye presenting dry AMD and soft drusen (the fellow eye had advanced AMD) were randomly assigned in a 1:1 ratio to receive ten Rheopheresis treatments within 17 weeks or to remain untreated. The primary outcome was change in best-corrected ETDRS-visual acuity (mean logMar change) after 7.5 months compared to baseline visual acuity for both groups.
RESULTS: Forty-three eyes of 43 patients (22 treatment and 21 control group) were analysed. The mean baseline BCVA in study eyes was 0.58 in the treatment group and 0.66 in the control group (n.s. p = 0.19). At the primary efficacy endpoint 7.5 months post baseline, there was a statistically significant mean difference of 0.95 ETDRS lines (p = 0.01) between the Rheopheresis and control groups. Nine percent of eyes in the group treated with Rheopheresis gained 2 or more ETDRS lines, as compared with 0% of eyes with no treatment. None of the treated patients had a loss in visual acuity in their study eyes, as compared with 24% of patients without treatment who lost 1 ETDRS line or more; 19% lost 2 ETDRS lines or more. Rheopheresis treatment was safe and well-tolerated.
CONCLUSION: The results of ART provide further evidence that Rheopheresis is a safe and effective therapeutic option for high-risk patients with dry AMD and no therapeutic alternative. A series of Rheopheresis treatments can improve the natural course of AMD for selected patients. | [
{
"source_pmid": "28328847",
"source_text": "BACKGROUND: To evaluate the efficacy and safety of topical isopropyl unoprostone (IU) in treating macular atrophy in age-related macular degeneration (AMD) patients.\nMETHODS: Fifty-two AMD patients with macular atrophy were included and randomly assigned (1:1) t... |
25271776 | CONCLUSIONS: Our study indicated that rs1533428, rs12994401, rs10202118 polymorphism on chromosome 2p16.3 might not be a risk factor for POAG. Further studies with well-designed among different ethnicity populations are required. | PURPOSE: Genetic factors have been shown to play a remarkable role in the pathophysiology of glaucoma. Recently, two polymorphisms (rs1533428 and rs12994401) on chromosome 2p were found to be strongly associated with POAG in an Afro-Caribbean population in Barbados, West Indies. As data with regard to the role of these polymorphisms in a Caucasian population are lacking, the present study was set to investigate a hypothetical association between these polymorphisms and POAG in a Caucasian population.
METHODS: In total 723 participants were included in this study comprising 366 patients with POAG and 357 control subjects from the southern part of Austria. Genotyping of rs1533428 and rs12994401 was performed using polymerase chain reaction.
RESULTS: Allelic frequencies and genotype distributions of rs1533428 and rs12994401 did not show statistical significance between patients with POAG and control subjects (p < 0.05). Presence of the rs1533428 T-allele was associated with an odds ratio of 0.95 (95% CI: 0.76-1.19; p = 0.69) for POAG, while the rs12994401 T-allele was associated with an odds ratio of 0.94 (95% CI: 0.73-1.21; p = 0.65) for POAG.
CONCLUSION: Our data suggest that rs1533428 and rs12994401 themselves are unlikely major risk factors for POAG in a Central European population. ||||| PURPOSE: Susceptibility to primary open-angle glaucoma (POAG) has recently associated with three intergenic single-nucleotide polymorphisms (SNPs) on human chromosome 2p16.3, just outside of the POAG-linkage locus GLC1H (2p15-16.2), in an Afro-Caribbean population. Especially, association of one SNP (rs12994401) was very strong (odds ratio 35) and later replicated in Afro-Americans but not in Ghanaians or Japanese. An extended region was examined in this study to look for SNPs of cross-population association.
METHODS: The three reported SNPs and all 63 SNPs considerably correlating with rs12994401 (r(2)≥0.3) in the African-descendent Yoruba were examined for POAG susceptibility association in a Korean population of 1,159 unrelated participants including 226 cases with glaucoma. As these 66 SNPs were spread from 2p14 to 2p21, all SNPs in this extended region were imputed for susceptibility association tests.
RESULTS: No susceptibility association was detected with rs12994401 in comparisons between 933 controls and 188 POAG (or 175 high-tension glaucoma) cases (statistical power of 100%), as well as with all 19 other typed SNPs, using logistic regression with adjustment for age and gender. The other 46 SNPs were deemed non-polymorphic in Koreans. Among 21,201 SNPs located in 2p14-21, only 4,260 were imputed to be non-monomorphic, but none of them passed a significance level of multiple testing. No association was observed when the samples were stratified by age or gender.
CONCLUSIONS: No typed or imputed SNPs within 2p14-21 showed association with susceptibility to POAG, suggesting that the population inconsistency in 2p16.3 association was unlikely due to linkage disequilibrium differences. ||||| PURPOSE: To investigate the associations between gene variants in cholesterol 24S-hydroxylase (CYP46A1), LIM homeobox transcription factor 1-beta (LMX1B), plexin domain containing 2 (PLXDC2), toll-like receptor 4 (TLR4), transmembrane and tetratricopeptide repeat containing 2 (TMTC2), zona pellucida glycoprotein 4 (ZP4), chromosome 2p16.3, and primary open-angle glaucoma (POAG).
METHODS: We studied 462 POAG patients and 577 controls from three cohorts (Hong Kong, Shantou, and Beijing, China). Twelve single-nucleotide polymorphisms (SNPs) were genotyped in the Hong Kong cohort using TaqMan genotyping assay. Significant associations were validated in the Shantou and Beijing cohorts.
RESULTS: Association of POAG with TLR4 rs7037117, in a recessive model, was identified in the Hong Kong and Shantou cohorts (both southern Chinese, p(rec)=0.0019) but not the Beijing cohort (northern Chinese). rs1533428 at chromosome 2p16.3 showed a consistent trend of age-specific association in all three cohorts. Genotypes TT + CT conferred a 2.16 fold of significantly increased risk to late-onset POAG (p(dom)=0.00025), but no significant risk to POAG of younger ages of onset in the combined cohort. A joint effect was found between rs7037117 and rs1533428, with carriers of both higher-risk genotypes having a 4.53 fold of increased disease risk (p=0.00028).
CONCLUSIONS: Our study reveals discrepant association patterns of 12 candidate SNPs in 7 genes/loci with POAG in Chinese, provides positive replications for POAG markers rs1533428 at 2p16.3 and TLR4 rs7037117, and suggests that rs1533428 is a putative risk variant for late-onset POAG. The identification of an age-specific association between rs1533428 and late-onset POAG highlights a new genotype-phenotype association in POAG. Further studies are warranted to confirm the age-specific association. ||||| PURPOSE: Glaucoma comprises a heterogeneous group of optic neuropathies with a complex genetic basis. It is the second leading cause of irreversible blindness in the world. This study investigates the association of SNPs on chromosome 2p with primary open angle glaucoma (POAG) in a Southern Indian population.
METHODS: Case-control analysis was performed using 220 unrelated POAG cases and 220 age-matched unaffected controls recruited through the Aravind Eye Hospital and its outlying clinics. Five SNPs (rs1533428, rs12994401, rs10202118, rs11125375, and rs11889995) on chromosome 2p were evaluated in these two groups and genotyped using Taq Man SNP genotyping assay. Statistical analysis was performed using the SVS program package by Golden Helix to identify the distributions of allele and genotype frequencies, Fisher exact test P values, and odds ratios and to check Hardy-Weinberg equilibrium.
RESULTS: Among the five SNPs screened, SNP rs10202118, showed a P = 0.026 for the basic allelic test, P = 0.004 for the genotypic test, and P = 0.0014 for the recessive model. The second suggestive marker was rs11125375, which also showed P = 0.033 for the recessive model. The associated SNPs formed a common disease haplotype. The remaining three SNPs showed insignificant association in this study population.
CONCLUSIONS: This was the first study to demonstrate the association of SNPs on chromosome 2p in patients with POAG in the Indian population. The two tagging SNPs (rs10202118 and rs11125375) on chromosome 2p are the most likely sites underlying the significant association with POAG in this study population. ||||| Primary open-angle glaucoma (POAG) is the second leading cause of blindness worldwide. Although a number of genetic loci have shown association or genetic linkage to monogenic forms of POAG, the identified genes and loci do not appear to have a major role in the common POAG phenotype. We seek to identify genetic loci that appear to be major risk factors for POAG in the Afro-Caribbean population of Barbados, West Indies. We performed linkage analyses in 146 multiplex families ascertained through the Barbados Family Study of Glaucoma (BFSG) and identified a strong linkage signal on chromosome 2p (logarithm of odds score = 6.64 at = 0 with marker D2S2156). We subsequently performed case-control analyses using unrelated affected individuals and unaffected controls. A set of SNPs on chromosome 2p was evaluated in two independent groups of BFSG participants, a discovery group (130 POAG cases, 65 controls) and a replication group (122 POAG cases, 65 controls), and a strong association was identified with POAG and rs12994401 in both groups (P < 3.34 E-09 and P < 1.21E-12, respectively). The associated SNPs form a common disease haplotype. In summary, we have identified a locus with a major impact on susceptibility to the common POAG phenotype in an Afro-Caribbean population in Barbados. Our approach illustrates the merit of using an isolated population enriched with common disease variants as an efficient method to identify genetic underpinning of POAG. | [
{
"source_pmid": "23136999",
"source_text": "PURPOSE: Genetic factors have been shown to play a remarkable role in the pathophysiology of glaucoma. Recently, two polymorphisms (rs1533428 and rs12994401) on chromosome 2p were found to be strongly associated with POAG in an Afro-Caribbean population in Barbad... |
27151934 | The polymorphism rs1061170/Y402H might be a genetic predictor of treatment response to anti-VEGF therapy in AMD patients. Further prospective research including a larger number of patients is needed to validate this finding. | PURPOSE: To determine if prespecified genetic polymorphisms influence responsiveness to vascular endothelial growth factor (VEGF) inhibition in neovascular age-related macular degeneration (nAMD). The objectives were to replicate 3 reported pharmacogenetic associations of response in nAMD and to test for novel associations.
DESIGN: Cohort study, combining information about patients' genotypes with information from a randomized controlled trial about responsiveness to anti-VEGF therapy for nAMD.
PARTICIPANTS: Five hundred nine participants with nAMD, enrolled in the Alternative Treatments to Inhibit VEGF in Patients with Age-Related Choroidal Neovascularisation (IVAN) trial.
METHODS: Participants were classified as responders or nonresponders to VEGF inhibition based on the optical coherence tomography (OCT) metric of total retinal thickness (TRT). We computed the change in TRT from baseline to the latest time point for which OCT data were available (3, 6, 9, or 12 months). Eyes with changes in TRT greater than or equal to the 75th percentile or more were classified as responders, and those with changes less than or equal to the 25th percentile or lower were classified as non-responders. Three previously reported associations of response to VEGF inhibition in nAMD involving single nucleotide polymorphisms (SNPs) at the CFH, FZD4, and HTRA1/ARMS2 loci were tested for replication. An additional 482 SNPs also were tested using a candidate gene approach. Associations were estimated as odds ratios (ORs) with confidence intervals (CIs).
MAIN OUTCOME MEASURES: The primary outcome was evidence of a genetic association with response to VEGF inhibition as measured by change in TRT.
RESULTS: One hundred twenty-six participants were classified as responders and 128 were classified as nonresponders. The SNP rs10490924 in HTRA1/ARMS2 showed a borderline association with responsiveness after Bonferroni correction (OR, 1.53; CI, 0.99-2.36; P = 0.055, Bonferroni correction). None of the other 484 additional SNPs tested for association was significant after Bonferroni correction for multiple testing. The smallest corrected P value was 0.84 (P = 0.002, uncorrected) for rs9679290 in the EPAS1 (HIF2A) gene on chromosome 2. Four of the 10 most significant results were in this gene.
CONCLUSIONS: We estimated pharmacogenetic associations using high-quality phenotype data from a randomized controlled clinical trial of nAMD. No significant association or replication of previous associations were observed. Further investigation of the EPAS1 (HIF2A) gene, however, may, be merited. ||||| PURPOSE: To validate known and determine new predictors of non-response to ranibizumab in patients with neovascular age-related macular degeneration (AMD) and to incorporate these factors into a prediction rule.
METHODS: This multicenter, observational cohort study included 391 patients treated with ranibizumab for neovascular AMD. We performed genetic analysis for single nucleotide polymorphisms in AMD-associated genes and collected questionnaires regarding environmental factors and disease history. The primary outcome was non-response to treatment, defined as a loss of visual acuity ≥30% of letters.
RESULTS: Of the 391 patients, 47 were classified as non-responsive. Independent predictors for non-response were age, baseline visual acuity, diabetes mellitus and accumulation of risk alleles in the CFH, ARMS2 and VEGF-A genes. The area under the receiver operating characteristic curve was 0.77 (95% confidence interval 0.70-0.84). We derived a clinical prediction rule, with possible total risk scores ranging from 0-19 points. The absolute risk of non-response varied from 3-52% between risk score groups.
CONCLUSION: This is an important step towards a clinical prediction rule that can aid clinicians in identifying AMD patients with increased likelihood of non-response, and consequently contribute to making shared treatment decisions. ||||| PURPOSE: To study the association of single-nucleotide polymorphisms of interleukin 8, vascular endothelial growth factor, erythropoietin, complement factor H, complement component C3, and LOC387715 genes with the response to bevacizumab treatment in exudative age-related macular degeneration.
METHODS: Clinical records, smoking history, optical coherence tomography, and angiographies of 96 bevacizumab-treated exudative age-related macular degeneration patients were analyzed retrospectively. Blood DNA was collected. Based on the disappearance of intra- or subretinal fluid in optical coherence tomography, patients were graded as responders, partial responders, or nonresponders after 3 initial treatment visits and a median time of 3.5 months.
RESULTS: Interleukin 8 promoter polymorphism -251A/T was significantly associated with persisting fluid in optical coherence tomography. The A allele was more frequent in nonresponders than in responders (P = 0.033). In multivariate modeling, the AA genotype of -251A/T (P = 0.043) and occult (P = 0.042) or predominantly classic (P = 0.040) lesions predicted poorer outcome. Visual acuity change was better in responders than in nonresponders (P = 0.006). Baseline lesion size (P = 0.006) and retinal cysts after the treatment (P < 0.001) correlated with less visual acuity gain.
CONCLUSION: The A allele and the homozygous AA genotype of interleukin 8 -251A/T were associated with anatomical nonresponse to bevacizumab treatment. ||||| PURPOSE: To determine whether different complement factor H (CFH) genotypes play a role in treatment of age-related macular degeneration (AMD) with intravitreal bevacizumab.
METHODS: In this prospective study, we included 197 patients with exudative AMD and treated with 1.25 mg intravitreal bevacizumab at 6-week intervals until choroidal neovascularization (CNV) was no longer active. In all patients, ophthalmological examinations, visual acuity, optical coherence tomography (OCT), fundus photography and fluorescein angiography were performed. Single nucleotide polymorphism (SNP) genotyping was performed using restriction fragment length polymorphism (RFLP) analysis of polymerase chain reaction (PCR) products.
RESULTS: Age, gender and baseline mean visual acuity were similar among the three CFH genotypes. There was no significant difference in underlying lesion type of CNV, lesion size, number of injections or macula thickness. When examining the effect of genotype on post-treatment visual acuities, we observed a significant worse outcome for distance and reading visual acuity in the CFH 402HH genotype group. The number of patients who lost 3 or more lines in distance and reading visual acuity testing was significantly higher in the CFH 402HH (41%, 46%) genotype group than in patients with the CFH 402YY (28%, 26%) and CFH 402YH (26%, 24%) genotype.
CONCLUSIONS: In addition to the higher risk for exudative AMD in patients with the CFH 402HH genotype that was found in previous studies, our results show that the CFH 402HH genotype also correlates with lower visual acuity outcome after treatment with bevacizumab, suggesting that pharmacogenetics of CFH plays a role in response to treatment of wet AMD. ||||| OBJECTIVE: Factors influencing the outcome of anti-VEGF treatment in neovascular AMD are still investigated. We analyzed the impact of a loading phase, the significance of an initial response for the long-term and the effect of the CFH polymorphism (p.His402Tyr) on treatment outcome.
METHODS: Patients treated with ranibizumab for neovascular AMD were analyzed over a period of 24 months by assessing effects of loading phase, initial response and genotype of CFH rs1061170 (c.1204C>T, p.His402Tyr).
RESULTS: 204 eyes were included. A change of +5.0 [-1;+11] letters and +1.5 [-5.5;+9.5] was observed with a median of 4 [3]; [7] and 10 [7]; [14] ranibizumab injections during 12 and 24 months, respectively. Loading phase was no significant predictor for treatment as VA outcome in eyes with and without loading phase was similar (p = 0.846 and p = 0.729) at 12 and 24 months. In contrast, initial response was a significant predictor for improving vision of 5 or more letters at 12 (p = 0.001; OR = 6.75) and 24 months (p = 0.01; OR = 4.66). Furthermore, the CT genotype at CFH rs1061170 was identified as a significant predictor for a favorable VA outcome at 12 and 24 months (OR = 6.75, p = 0.001 and OR = 4.66, p = 0.01).
CONCLUSIONS: Our data suggest that clinical decisions regarding treatment may be guided by observing patients' initial response as well as their genotype of SNP rs1061170, while the criterion of loading phase may not bear the customary value. ||||| PURPOSE: To evaluate the pharmacogenetic relationship between genotypes of single nucleotide polymorphisms (SNPs) known to be associated with age-related macular degeneration (AMD) and response to treatment with ranibizumab (Lucentis; Genentech, South San Francisco, CA) or bevacizumab (Avastin; Genentech) for neovascular AMD.
DESIGN: Clinical trial.
PARTICIPANTS: Eight hundred thirty-four (73%) of 1149 patients participating in the Comparison of AMD Treatments Trials (CATT) were recruited through 43 CATT clinical centers.
METHODS: Each patient was genotyped for SNPs rs1061170 (CFH), rs10490924 (ARMS2), rs11200638 (HTRA1), and rs2230199 (C3), using TaqMan SNP genotyping assays (Applied Biosystems, Foster City, CA).
MAIN OUTCOMES MEASURES: Genotypic frequencies were compared with clinical measures of response to therapy at one year, including mean visual acuity (VA), mean change in VA, 15-letter or more increase in VA, retinal thickness, mean change in total foveal thickness, presence of fluid on OCT, presence of leakage on fluorescein angiography (FA), mean change in lesion size, and mean number of injections administered. Differences in response by genotype were evaluated with tests of linear trend calculated from logistic regression models for categorical outcomes and linear regression models for continuous outcomes. To adjust for multiple comparisons, P≤0.01 was considered statistically significant.
RESULTS: No statistically significant differences in response by genotype were identified for any of the clinical measures studied. Specifically, there were no high-risk alleles that predicted final VA or change in VA, the degree of anatomic response (fluid on OCT or FA, retinal thickness, change in total foveal thickness, change in lesion size), or the number of injections. Furthermore, a stepwise analysis failed to show a significant epistatic interaction among the variants analyzed; that is, response did not vary by the number of risk alleles present. The lack of association was similar whether patients were treated with ranibizumab or bevacizumab or whether they received monthly or pro re nata dosing.
CONCLUSIONS: Although specific alleles for CFH, ARMS2, HTRA1, and C3 may predict the development of AMD, they did not predict response to anti-vascular endothelial growth factor therapy. ||||| PURPOSE: To investigate whether there is an association between known age-related macular degeneration genetic risk variants in the CFH, ARMS2, and HTRA1 genes and response to anti-vascular endothelial growth factor (VEGF) (ranibizumab or bevacizumab) treatment for wet age-related macular degeneration.
METHODS: A retrospective review of 150 patients with documented wet age-related macular degeneration based on clinical examination and fluorescein angiogram was performed. Patients received anti-VEGF therapy with ranibizumab and/or bevacizumab. Patients were genotyped for the single-nucleotide polymorphism rs1061170, rs10490924, rs3750848, rs3793917, rs11200638, and rs932275 and for the indel del443ins54 spanning the CFH, ARMS2, and HTRA1 genes.
RESULTS: There were 57 patients who were characterized as negative responders to anti-VEGF therapy, and 93 patients who were characterized as positive responders. There was no significant difference in mean baseline visual acuity between the groups. Negative responders were followed for a mean duration of 24.0 months, while positive responders were followed for a mean duration of 22.0 months. Although the frequency of the at-risk alleles was higher in the positive responders when compared with the negative responder, this did not reach statistical significance. Additionally, there was no significant association between genotype and the number of injections or absolute change in visual acuity in both groups of responders.
CONCLUSION: In our patient cohort, there was no statistically significant association between response to anti-VEGF therapy and the genotype in both positive-responder and negative-responder groups. Larger studies with more power are necessary to further determine whether a pharmacogenetic association exists between wet age-related macular degeneration and anti-VEGF therapy. ||||| PURPOSE: To investigate whether there is an association between complement factor H (CFH) or LOC387715 genotypes with response to treatment with intravitreal bevacizumab for exudative age-related macular degeneration (AMD).
DESIGN: Retrospective cohort study.
PARTICIPANTS: The study cohort consisted of 86 patients being treated for neovascular AMD with bevacizumab alone.
METHODS: Genotype determination for the CFH Y402H and LOC387715 A69S polymorphisms was performed by allele-specific digestion of polymerase chain reaction products. All patients were treated with 1.25 mg intravitreal bevacizumab at 6-week intervals until choroidal neovascularization was no longer active.
MAIN OUTCOME MEASURES: CFH Y402H and LOC387715 A69S polymorphisms. Choroidal neovascular lesion characteristics were ascertained by fluorescein angiography. Snellen visual acuity (VA) was measured before and after treatment.
RESULTS: For the CFH Y402H polymorphism, patients with the CFH TT genotype had the largest choroidal neovascular lesions (P = 0.02). With treatment, VA improved from 20/248 to 20/166 for the CFH TT genotype and from 20/206 to 20/170 for the TC genotype, but fell from 20/206 to 20/341 for the CFH CC genotype (P = 0.016). Only 10.5% of patients with the CFH CC genotype demonstrated improved VA with treatment, compared with 53.7% of CFH TT and TC genotypes (P = 0.004). For the LOC387715 A69S variant, patients with the TT genotype had the largest choroidal neovascular lesions (P = 0.012). There was no significant difference in response to bevacizumab treatment according to LOC387715 genotype.
CONCLUSIONS: The AMD-associated CFH Y402H and LOC387715 A69S variants were associated with differences in choroidal neovascular lesion size in this study. Patients with the CFH CC genotype fared significantly worse with intravitreal bevacizumab than did those with the CFH TC and TT genotypes, suggesting a potential pharmacogenetic relationship. Prospective studies to confirm or refute this observation should be considered. ||||| AIMS: To investigate an association between genotype for three single nucleotide polymorphisms strongly associated with the development of age-related macular degeneration (AMD) and the early response to treatment with intravitreal ranibizumab for neovascular AMD.
METHODS: Best corrected visual acuity letter score was recorded at baseline and each subsequent visit. Age, sex, smoking history, lesion type and the number of injections were also recorded. Genotypes were obtained for rs11200638 in HTRA1, rs1061170 in CFH and rs1413711 in VEGF. Data were analysed with treatment response at month 6 as both a binary (>5 letter improvement vs ≤5 letter gain) and a linear trait.
RESULTS: This initial study cohort consisted of 104 Caucasian neovascular AMD patients treated with intravitreal ranibizumab. Trends towards a more favourable outcome were seen with the higher AMD risk genotypes in CFH and VEGF in both the linear and binary models and in HTRA1 in the linear model alone. For CFH, mean letter score change after 6 months was +1.6, +5.9 and +7.2 letters for the TT, TC and CC genotypes and a >5 letter gain was seen in 34.6%, 56.6% and 56%, respectively. For VEGF, mean letter score change after 6 months was +1.3, +5.8 and +7.4 letters for the TT, TC and CC genotypes and a >5 letter gain was seen in 40%, 55.8% and 51.9%, respectively. For HTRA1, mean letter score change was +2.2, +7.5 and +2.9 letters for the GG, GA and AA genotypes.
CONCLUSIONS: This study reports preliminary evidence suggesting that the higher AMD risk genotypes in CFH, VEGF and HTRA1 may influence the short-term response to treatment with ranibizumab for neovascular AMD. ||||| PURPOSE: The purpose of this study is to evaluate the effect of complement factor H (CFH) Y402H CC and TT polymorphisms on treatment response to intravitreal ranibizumab injection in patients with wet age-related macular degeneration (AMD).
METHODS: One hundred ninety-three patients with choroidal neovascularization (CNV) secondary to AMD who were monitored for at least 6 months of follow-up, and with at least three ranibizumab injections, were included in the study. At the final examination, an increase in visual acuity (VA) of five letters or more compared to the initial VA was regarded as a good response, and a decrease in VA of five letters or more compared to the initial VA was evaluated as a poor response. A genetic examination was performed with a PCR melting curve analysis. In the statistical evaluation, SPSS version 18 software was used.
RESULTS: The mean age of the patients was 71.01 (55-86) years, the mean follow-up was 13.34 (6-36) months, and the mean number of injections was 4.02 (3-15). There were 96 patients in the good response group (Group 1) and 97 patients in the poor response group (Group 2). The initial VA in Group 1 was 41.34 (10-64) letters, the initial central macular thickness (CMT) was 213.40 (126-494) µm, and the initial lesion width was 3760 (1430-6430) µm. The initial VA in Group 2 was 52.89 (26-82) letters, the initial CMT was 257.60 (115-882) µm, and the initial lesion width was 4460 (1000-7650) µm. There was no statistically significant difference between the two groups in terms of the initial VA and CMT (p=0.094, p=0.083). However, there was a statistically significant difference between the groups in the width of the initial lesion (p=0.003). In Group 1, 15 CC, 30 TT, and 51 TC alleles were found, and in Group 2, 49 CC, two TT, and 46 TC alleles were found, and the distribution was significantly different between the two groups (p=0.012). The change in the distribution of genotypes was not associated with either the lesion size or VA (p=0.841). Fibrosis developed in 12 patients who were all poor responders.
CONCLUSIONS: CFH Y402H CC accompanied a poor response, and TT accompanied a good response in this series of patients with AMD undergoing ranibizumab therapy. ||||| To evaluate a possible association between the complement factor H (CFH) Y402H polymorphism and susceptibility to age-related macular degeneration (AMD) in the Tunisian population, as well as the impact of the genotype distribution among different phenotypes and the response to treatment with intravitreal bevacizumab, exon 9 of CFH was analyzed for the Y402H polymorphism by direct sequencing in 135 healthy controls and 127 sporadic unrelated AMD patients classified into the following groups: 12 atrophic AMD (group G1), 115 exudative AMD (G2) and 10 AMD patients who had fibrovascular scarring (G3) that did not allow a precise grading of the phenotype. Seventy patients in G2 were treated with 1.25 mg intravitreal bevacizumab at 6-week intervals until choroidal neovascularization (CNV) was no longer active. The frequency of the CFH 402H allele was significantly higher in AMD patients than in controls (p = 2.62 × 10(-16)). However, subgroup analysis does not reveal any association between the variant allele H and phenotypes of AMD or CNV. Also, there was no significant difference in response to bevacizumab treatment according to Y402H CFH genotype (p = 0.59). A strong association of the 402H allele with susceptibility to AMD in the Tunisian population was confirmed; however, this variant does not appear to be involved in the clinical progression of this disease or in the postintravitreal bevacizumab response. ||||| AIM: This study was conducted to evaluate the possible clinical and genetic indicators for an early response to intravitreal ranibizumab (IVR) in exudative age-related macular degeneration (AMD).
PATIENTS & METHODS: The records of 120 eyes from 120 Japanese patients with treatment-naive exudative AMD were retrospectively reviewed. Three consecutive IVR treatments were performed every month. Achievement of anatomical resolution was evaluated by ophthalmoscopy and optical coherence tomography. Multivariable logistic regression analysis was conducted by analyzing SNPs in the ARMS2 locus (A69S) and in the CFH gene (I62V and Y402H), in addition to clinical factors.
RESULTS: The mean central retinal thickness of overall patients was significantly decreased (-120.1 ± 122.8 µm, p = 2.7 × 10(-19)) at 3 months after the initial treatment. In the logistic regression analysis, the poor anatomical resolution of the lesion at 3 months was associated with the combination of CFH I62V + CFH Y402H variants (p = 0.0021), and the polypoidal choroidal vasculopathy lesions (p = 0.044).
CONCLUSION: The CFH variants and the polypoidal choroidal vasculopathy lesion may influence the early anatomical resolution with IVR in exudative AMD. ||||| PURPOSE: To investigate factors affecting patient response to intravitreal ranibizumab treatment for age-related macular degeneration (AMD).
DESIGN: Retrospective chart review.
METHODS: We reviewed medical records of 105 consecutive eyes with AMD treated with intravitreal ranibizumab injections and followed for more than 1 year after treatment. Response to ranibizumab treatment was compared between typical neovascular AMD and polypoidal choroidal vasculopathy (PCV). Furthermore, we investigated associations of age, lesion size, and single nucleotide polymorphisms (SNPs) in CFH and ARMS2 genes with treatment response.
RESULTS: Forty-nine eyes were diagnosed with typical neovascular AMD and 56 eyes with PCV. Serous retinal detachment and retinal edema resolved similarly in both typical neovascular AMD and PCV after treatment. However, visual acuity (VA) significantly improved in eyes with PCV, whereas VA was maintained in typical neovascular AMD. At the third and twelfth months after injection, VA was better in PCV than in typical neovascular AMD (P = .027 and P = .044, respectively), although there were no differences in baseline VA between the 2 groups. Age and size of greatest linear dimension were significantly associated with visual prognosis in typical neovascular AMD but not in PCV. There was no clear association between 3 SNPs and responsiveness to ranibizumab treatment.
CONCLUSIONS: Although exudative changes were equivalent following ranibizumab treatment in both typical neovascular AMD and PCV, there was a significant increase in VA in PCV compared to typical neovascular AMD. Age and greatest linear dimension correlated with visual prognosis only in typical neovascular AMD and not in PCV. ||||| PURPOSE: To investigate the association between genetic risk variants for age-related macular degeneration (AMD) and response to intravitreal ranibizumab in Korean patients with neovascular AMD.
METHODS: This prospective study included 273 treatment-naive patients (273 eyes) who underwent 5 monthly injections (Months 0, 1, 2, 3, and 4) of intravitreal ranibizumab for neovascular AMD. Patients were genotyped for 23 single-nucleotide polymorphisms within 12 AMD-relevant genes. For each polymorphism, genotypic association with good response at Month 5, predetermined as visual improvement of ≥ 8 Early Treatment Diabetic Retinopathy Study letters from baseline, was investigated with logistic regression analysis adjusted for age, gender, smoking, baseline Early Treatment Diabetic Retinopathy Study letter, central retinal thickness, lesion area, and type of choroidal neovascularization.
RESULTS: At Month 5, visual acuity improved by 9.1 ± 17.6 letters from baseline, and 136 patients (49.8%) were classified as good responders. In logistic regression, no tested polymorphism showed statistically significant association with favorable visual outcome at Month 5. When unadjusted for multiple tests, AA genotype for VEGF rs699947 had an increased chance of good response compared with other genotypes (odds ratio, 3.61; 95% confidence interval, 1.42-9.18; P = 0.0071).
CONCLUSION: In this Korean neovascular AMD cohort, there was no statistically significant effect of genotype on early visual outcome after ranibizumab treatment. | [
{
"source_pmid": "24070809",
"source_text": "PURPOSE: To determine if prespecified genetic polymorphisms influence responsiveness to vascular endothelial growth factor (VEGF) inhibition in neovascular age-related macular degeneration (nAMD). The objectives were to replicate 3 reported pharmacogenetic associ... |
28693519 | CONCLUSIONS: The natural course of nAMD in both eyes needs to be considered when informing patients. Visual acuity in the best eye decreases to below 0.5 in 4.3 years. This affects QoL significantly. | PURPOSE: To evaluate safety and efficacy of the angiostatic agent anecortave acetate, compared with a placebo, for treatment of subfoveal choroidal neovascularization (CNV).
DESIGN: Ongoing masked, randomized, placebo-controlled, parallel evaluation of anecortave acetate (30 mg, 15 mg, and 3 mg) versus a placebo.
PARTICIPANTS: There were 128 eyes of 128 patients with subfoveal CNV secondary to age-related macular degeneration who were enrolled and treated, with 80% (102/128) of eyes presenting with predominantly classic lesions at baseline.
METHODS: All eyes received a posterior juxtascleral depot application of masked study medication or a placebo, with retreatment at 6-month intervals if the masked investigator believed the patient could benefit. Patients received periodic detailed ophthalmic examinations with both fluorescein and indocyanine green angiography, general physical examinations with electrocardiograms, and hematology/serum chemistry/urinalysis. All ophthalmic and systemic safety data were periodically reviewed by the Independent Safety Committee overseeing the study.
MAIN OUTCOME MEASURES: Best-corrected logarithm of the minimum angle of resolution (logMAR) vision and fluorescein angiographic lesion characteristics were compared over time and among treatment groups.
RESULTS: At month 12, anecortave acetate (15 mg) administered at 6-month intervals was statistically superior to the placebo for 3 measures of clinical efficacy: mean change from baseline vision (P = 0.0131), stabilization of vision (<3 logMAR line change; P = 0.0323), and prevention of severe vision loss (decrease of > or = 6 logMAR lines from baseline; P = 0.0224). Subgroup analysis of predominantly classic lesions revealed that anecortave acetate (15 mg) was also superior to the placebo at 1 year for each of these 3 measures of visual outcome (Ps = 0.0022, 0.0100, and 0.0299, respectively). Anecortave acetate (15 mg) trended toward significance over the placebo at month 12 for inhibition of total lesion growth and for inhibition of both the total CNV component and the classic CNV component in both the overall and subgroup analyses. The Independent Safety Committee identified no clinically relevant treatment-related safety issues.
CONCLUSIONS: Anecortave acetate (15 mg) is safe and clinically efficacious at 1 year for maintaining vision, preventing severe vision loss, and inhibiting subfoveal CNV lesion growth. ||||| PURPOSE: To identify factors affecting visual acuity and its decrease in eyes with subfoveal choroidal neovascularization (CNV) associated with age-related macular degeneration (AMD).
METHODS: Distance visual acuity was recorded at screening and up to five follow-up visits during the first year of a randomized, double-blind, placebo-controlled trial of oral prinomastat. Subjects had AMD in both eyes and neovascular AMD in at least one eye. Analysis employed a generalized linear mixed model.
RESULTS: Of 158 eligible subjects (age 56-90), 125 (79.1%) received prinomastat. Visual acuity was independently affected by relative acuity of the fellow eye, whether the study eye had been the first or second to develop CNV, age, current smoking, leakage area, and prior photocoagulation. Decrease in visual acuity score, unaffected by prinomastat, was less steep in eyes that had been second to develop CNV. Such eyes had a comparable time since CNV onset to other study eyes.
CONCLUSION: Fellow eye features independently affect visual acuity and its decrease in eyes with classic neovascular AMD. ||||| AIM: To evaluate the efficacy of radiotherapy in the treatment of subfoveal classic and occult choroidal neovascularization (CNV) in age-related macular degeneration (AMD) under strict fixation control.
METHODS: Twenty-seven eyes of 27 patients with subfoveal CNV as a result of AMD were treated with a total dose of 20 Gy in 10 fractions (10 well-defined, 17 occult). Fixation monitoring was achieved by installing a TV camera with an attached fixation light 3 cm from the cornea of the eye being treated. Visual acuity and fluorescein angiography were obtained before and 6 months after treatment. Fifteen eyes of 15 patients served as controls (4 well-defined, 11 occult).
RESULTS: After 6 months the treated group showed an average decrease in visual acuity of 27%; the control group experienced a decrease of 31%. Membrane size increased by 56% in the treated group and by 28% in the control group. There was no statistically significant difference. Within the subgroup analysis, however, patients with classic CNV suffered significantly less visual loss than in the control group.
CONCLUSION: Radiation therapy under optimized treatment conditions by fixation monitoring failed to control further growth in membrane size in both classic and occult CNV. Regarding visual acuity, however, patients with classic CNV seem to benefit from radiation treatment compared to the natural course. ||||| PURPOSE: To analyse the frequency of conversion from occult with no classic choroidal neovascularization (CNV) and occult with minimally classic CNV into predominantly classic CNV secondary to age-related macular degeneration.
METHODS: Retrospective evaluation of baseline and repeat angiograms of 54 eyes with a follow-up of 6-12 months.
RESULTS: In the group with initially occult with no classic CNV, nine of 40 eyes (23%) progressed to a predominantly classic lesion, whereas in the group of occult with a minimally classic CNV, 10 of 14 eyes (71%) eyes developed a predominantly classic CNV.
CONCLUSIONS: The proportion of eyes that develop predominantly classic CNV is much higher in eyes with initially occult and minimally classic CNV, compared with eyes with initially occult and no classic CNV. Our data suggest that the natural course of CNV secondary to AMD begins as occult and progresses to classic CNV. ||||| PURPOSE: To report results of 18-month follow up of external beam radiation therapy with photons for subfoveal classic or occult choroidal neovascularization (CNV) in age-related macular degeneration (ARMD).
DESIGN: Randomized clinical trial.
METHODS: A total of 161 patients with subfoveal CNV in ARMD were recruited in a prospective double-masked study. The posterior pole of the afflicted eye was given 1 Gy (4 x 0.25 Gy) in the control group and 8 Gy (4 x 2 Gy) or 16 Gy (4 x 4 Gy) in the treatment groups. At the time of treatment, and 6, 12, and 18 months post treatment, best-corrected visual acuity (BCVA), reading ability, and CNV size were measured.
RESULTS: At the completion of the study 150 (93.2%), 139 (86.3%), and 137 (85.1%) patients were followed for 6, 12, and 18 months, respectively. The mean number of lines lost in the BCVA was -1.69, -2.2, and -3.23 in the 1 Gy group; -0.94, -1.25, and -1.73 in the 8 Gy group; -0.51, -0.67, and -1.93 in the 16 Gy group. The difference was significant after 12 months (P =.016 for 8 Gy vs. 1 Gy; P =.006 for 16 Gy vs. 1 Gy), and 18 months (P =.011 for 8 Gy vs. 1 Gy; P =.05 for 16 Gy vs. 1 Gy). The patients with classic CNV, or with an initial distance visual acuity >or=20/100, benefited more from treatment. A significant difference was not found between control group and treatment groups in the reading ability and in the CNV size. No radiation-associated side effects were reported thus far.
CONCLUSION: The number of lines lost in the BCVA was less in the 8 Gy and 16 Gy treatment groups than in the control group during the complete follow up examination. Radiation therapy with 8 Gy and 16 Gy, without showing any difference in efficacy, resulted in a near stabilization of the BCVA in patients with subfoveal classic or occult CNV in ARMD. Further studies are necessary to determine the significance of repeated radiotherapy series with a dose of 8 Gy to improve the effect on the CNV size and thereby to prolong stabilization of distance visual acuity. ||||| PURPOSE: To study results of 2-year follow-up of radiotherapy for subfoveal choroidal neovascular membrane associated with age-related macular degeneration.
METHODS: In a randomized prospective clinical study, 101 patients received a low-dose radiotherapy or no treatment. In the treatment group, subfoveal choroidal neovascular membranes were treated with 20 Gy of 6-MV photons to the macula of the affected eye.
RESULTS: The overall complete follow-up rate was 84.2% (85/101). No measurable treatment-related morbidity was seen during or after treatment. Mean changes in log of minimal angle of resolution (logMAR) of visual acuity and area of choroidal neovascular membrane for 2-year follow-up were +0.226 +/- 0.373 and 143.5 +/- 53.1% in the treatment group, and +0.563 +/- 0.370 and 190. 3 +/- 81.4% in the control group; a significant difference was found (P <.0001; P =.0008). In patients with smaller choroidal neovascular membrane (</=1.5 mm(2)) or better visual acuity (>/=60/200) at baseline, the treatment group showed a significantly smaller increase in area of choroidal neovascular membrane and a significantly smaller decrease in LogMAR visual acuity for 2 years, whereas there was no significant difference in patients with larger choroidal neovascular membrane (>1.5 mm(2)) or poorer visual acuity (<60/200).
CONCLUSIONS: Radiotherapy appeared to have a favorable treatment effect in eyes with subfoveal neovascular membrane associated with AMD. Favorable factors for radiotherapy were a smaller area of choroidal neovascular membrane and better visual acuity. ||||| PURPOSE: To evaluate the 1-year effect of transpupillary thermotherapy (TTT) on occult choroidal neovascularization membranes (CNV).
METHODS: In this prospective, randomized, controlled pilot study of 28 patients with occult or minimally classic (< 10%) neovascularization membranes with a diameter less than 4500 microm, 19 patients were treated with TTT, while nine received sham treatment. Outcome measures were membrane diameter, visual acuity and reading ability.
RESULTS: The median age of patients randomized to TTT was 78 years (range 24 years); that of patients randomized to sham was 79 years (range 9 years). There was no difference regarding membrane diameter at baseline between the two groups; the median membrane diameters were 3400 microm (range 2400 microm) in the TTT group and 3200 microm (range 2300 microm) in the sham group (p = 0.639). Visual acuity (VA) was similar, with a median of 0.2 (minimum-maximum 0.08-0.5) in the TTT group and a median of 0.16 (min-max 0.10-0.32) in the sham group. A total of 21 patients were followed for 1 year, 13 in the TTT group (2.7 treatments/patient) and eight in the sham group. Membrane diameter increased in both groups, by a median of 350 microm (range 1600 microm) in the TTT group and 800 microm (range 1700 microm) in the sham group (p = 0.414), respectively, and there was a loss in VA of > or = 15 letters in 5/13 patients (38%) in the TTT group compared with 2/8 patients (25%) in the sham group (p = 0.266). Reading ability deteriorated equally over time in both groups. Seven patients were lost to follow-up due to reluctance to continue in the study (n = 4) or development of a classical component > 50% (n = 3) requiring photodynamic therapy (PDT).
CONCLUSION: The results from this randomized, prospective pilot study of TTT for occult CNV did not indicate that TTT has a beneficial effect on visual outcome 1 year after treatment compared with the visual outcome that results from the natural course of the disease. The small study size limits statistical power and results from large control studies are needed. ||||| OBJECTIVE: To determine whether verteporfin photodynamic therapy (PDT) can safely reduce the risk of vision loss in patients with subfoveal occult with no classic choroidal neovascularization (CNV) due to age-related macular degeneration.
RESEARCH DESIGN AND METHODS: Eligible patients were > or =50 years of age with lesion size < or =6 disc areas and best-corrected vision 20/40-20/200. A total of 364 patients with occult with no classic CNV were randomly assigned 2 : 1 to verteporfin PDT (n = 244) or placebo (n = 120). The primary outcome measures were loss of > or =15 and > or =30 letters of visual acuity (VA) from baseline at 12 and 24 months.
CLINICAL TRIAL REGISTRATION: This study was registered with ClinicalTrials.gov on 20 July 2005. ClinicalTrials.gov identifier: NCT00121407.
RESULTS: A total of 37% and 47% of verteporfin-treated patients versus 45% and 53% of placebo recipients lost > or =15 letters of VA at month 12 and month 24, respectively; 16% and 23% of verteporfin-treated patients versus 17% and 25% of placebo recipients lost > or =30 letters at month 12 and month 24, respectively. These differences were not statistically significant. Four (1.6%) verteporfin-treated patients and one placebo patient (who received verteporfin in error) experienced an acute severe VA decrease; all five patients recovered some degree of vision. No unexpected ocular or systemic adverse events were identified.
CONCLUSIONS: Verteporfin PDT in the treatment of occult with no classic CNV was safe and well-tolerated. The differences between the two groups in the primary efficacy variables were not significant. Baseline characteristics and patient selection methods may have contributed to the small treatment effect. ||||| PURPOSE: To determine whether differences in baseline lesion size and visual acuity might explain differing results found in three different lesion compositions (predominantly classic, minimally classic, and occult with no classic) among three placebo-controlled, randomized clinical trials evaluating photodynamic therapy with verteporfin (Visudyne, Novartis AG), also termed verteporfin therapy, in patients with subfoveal choroidal neovascularization (CNV) due to age-related macular degeneration (AMD).
METHODS: Exploratory analyses were conducted in patients with predominantly classic or minimally classic lesions at enrollment in the Treatment of AMD with Photodynamic Therapy (TAP) Investigation and in AMD patients with occult with no classic CNV in the Verteporfin In Photodynamic Therapy (VIP) Trial. Baseline characteristics of patients among these three lesion compositions were compared. In addition, multiple linear regression modeling was used to explore the effect of baseline lesion size, visual acuity, and lesion composition on mean change in visual acuity from baseline to 24 months.
RESULTS: At baseline, the mean size of predominantly classic lesions (3.4 disk areas) was smaller than that of minimally classic (4.7 disk areas) and occult with no classic lesions (4.3 disk areas). In the multiple linear regression model of individual lesion compositions, there was a significant treatment-by-lesion-size interaction for minimally classic and occult with no classic lesions, but not for predominantly classic lesions. Interaction between treatment and baseline visual acuity was not significant for any lesion composition. Small verteporfin-treated lesions lost less vision than large verteporfin-treated lesions in each lesion composition. In the multiple linear regression model that included all lesion compositions, lesion size was a more significant predictive factor for the magnitude of treatment benefit than either lesion composition or visual acuity. Smaller (4.0 disk areas or less) minimally classic and occult with no classic lesions had similar visual acuity outcomes to those observed in predominantly classic lesions.
CONCLUSIONS: Based on exploratory analyses, lesion size in the TAP Investigation and VIP Trial was an important predictor of the magnitude of treatment benefit with verteporfin therapy in occult with no classic and minimally classic lesion compositions. In patients with AMD, treating smaller rather than larger neovascular lesions, regardless of lesion composition, likely will result in a better level of visual acuity. ||||| OBJECTIVE: To determine the efficacy of strontium plaque (Sr90) brachytherapy for age-related macular degeneration (AMD) with subfoveal choroidal neovascularization (CNV).
DESIGN: Randomized clinical trial.
PARTICIPANTS: Eighty-eight eyes of 86 patients with subfoveal CNV secondary to AMD were randomized either to plaque radiotherapy or to observation.
INTERVENTION: Radiotherapy was given as episcleral brachytherapy using Sr90 plaques. Two different plaque types were used. Plaque I had a diameter of 8 mm and delivered a dose of 15 Gy at a depth of 1.75 mm in 54 minutes. With plaque II, the corresponding values were 4 mm, 12.6 Gy, and 11 minutes. The control group was observed without any treatment.
MAIN OUTCOME MEASURES: The primary outcome measure was visual acuity at 6, 12, 24, and 36 months. Other outcome variables were contrast sensitivity, fluorescein angiographic, and clinically evaluated changes in the macula.
RESULTS: Eighty-two patients (84 eyes [95%]) completed the 1-year follow-up, and 80 (93%) and 74 (86%) patients completed the 2- and 3-year follow-ups, respectively. At 6 months, visual loss of > or =3 lines occurred in 20% of treated patients and 42% of control patients (P = 0.031). At 12 months, a visual loss of > or =3 lines occurred in 45% (treated) and 56% (controls) (P = 0.325); at 24 months, in 73% and 71% (P = 0.914); and at 36 months, in 80% and 84% of patients (P = 0.591), respectively. Patients irradiated with plaque I had better results: a visual loss of > or =3 lines occurred in 6% at 6 months (P = 0.008, relative to controls), in 18% at 12 months (P = 0.007), in 59% at 24 months (P = 0.348), and in 71% at 36 months (P = 0.212). In patients treated with plaque II, the corresponding values were 29% (P = 0.032), 65% (P = 0.459), 83% (P = 0.317), and 80% (P = 0.687) at 6, 12, 24, and 36 months, respectively.
CONCLUSIONS: The short-term clinical course of exudative AMD is affected by Sr90 brachytherapy, but by 12 months, there was no treatment benefit. This article contains additional online-only material available at http://www.ophsource.org/periodicals/ophtha. ||||| BACKGROUND: Pegaptanib, an anti-vascular endothelial growth factor therapy, was evaluated in the treatment of neovascular age-related macular degeneration.
METHODS: We conducted two concurrent, prospective, randomized, double-blind, multicenter, dose-ranging, controlled clinical trials using broad entry criteria. Intravitreous injection into one eye per patient of pegaptanib (at a dose of 0.3 mg, 1.0 mg, or 3.0 mg) or sham injections were administered every 6 weeks over a period of 48 weeks. The primary end point was the proportion of patients who had lost fewer than 15 letters of visual acuity at 54 weeks.
RESULTS: In the combined analysis of the primary end point (for a total of 1186 patients), efficacy was demonstrated, without a dose-response relationship, for all three doses of pegaptanib (P<0.001 for the comparison of 0.3 mg with sham injection; P<0.001 for the comparison of 1.0 mg with sham injection; and P=0.03 for the comparison of 3.0 mg with sham injection). In the group given pegaptanib at 0.3 mg, 70 percent of patients lost fewer than 15 letters of visual acuity, as compared with 55 percent among the controls (P<0.001). The risk of severe loss of visual acuity (loss of 30 letters or more) was reduced from 22 percent in the sham-injection group to 10 percent in the group receiving 0.3 mg of pegaptanib (P<0.001). More patients receiving pegaptanib (0.3 mg), as compared with sham injection, maintained their visual acuity or gained acuity (33 percent vs. 23 percent; P=0.003). As early as six weeks after beginning therapy with the study drug, and at all subsequent points, the mean visual acuity among patients receiving 0.3 mg of pegaptanib was better than in those receiving sham injections (P<0.002). Among the adverse events that occurred, endophthalmitis (in 1.3 percent of patients), traumatic injury to the lens (in 0.7 percent), and retinal detachment (in 0.6 percent) were the most serious and required vigilance. These events were associated with a severe loss of visual acuity in 0.1 percent of patients.
CONCLUSIONS: Pegaptanib appears to be an effective therapy for neovascular age-related macular degeneration. Its long-term safety is not known. ||||| Little information is available on the natural history and no data have been published on laser treatment for occult neovascularization in age-related macular degeneration. The visual and angiographic outcomes were analyzed in 156 patients (82 untreated eyes; 81 treated eyes) with occult neovascularization who were followed for 1 to 8 years. Early laser treatment decreased visual acuity to less than 20/200 in 31 of the treated eyes (38%) compared with 20 of the untreated eyes (25%). Three years after the onset of symptoms, 24 treated eyes (29%) and 31 eyes untreated eyes (38%) retained 20/50 visual acuity or better, whereas their respective initial visual acuities were not statistically different. Severe loss of vision (6 or more lines of visual acuity) occurred in 43 treated eyes (53%) and in 33 untreated eyes (40%) at the end of follow-up (range, 12-84 months). A slow and gradual increase of the disciform lesion was demonstrated on fluorescein angiography in 60 untreated eyes, with subfoveal involvement noted in 39 eyes at the end of follow-up. In the treated group, subfoveal involvement occurred in 53 eyes, after a relatively short time (mean, 4 months). Only 28 of the 81 treated eyes had successful anatomic results. These findings suggested that laser treatment of occult neovascularization immediately after the onset of symptoms should not be recommended. ||||| PURPOSE: To evaluate whether transpupillary thermotherapy (TTT) reduces the risk of moderate visual loss in patients with occult choroidal neovascularization (CNV) secondary to age-related macular degeneration (AMD).
METHODS: A group of 25 patients were recruited and randomized into TTT or placebo groups. Patients were included if they had a subfoveal purely or predominantly (> 50%) occult CNV secondary to AMD with best corrected visual acuity (BCVA) of 6/60 or better and the lesion was not larger than 4.5 mm. Treatment was carried out using an 810-nm Oculight diode laser with a fixed spot size covering the whole lesion according to the standard protocol. The same procedure was used for the control group, except that the power was set at zero. The patients were followed up at 6 weeks, 3 months and then every 6 months for up to 2 years. A maximum of three treatments were administered in both groups if there was evidence of persistent leakage from CNV.
RESULTS: At the 12-month follow-up, there was no significant difference in the mean values for BCVA distance and near or contrast sensitivity between the treatment and control groups. The Mann-Whitney test was used to assess the differences in BCVA and contrast sensitivity between the groups, both at baseline and at the 12-month follow-up. No statistically significant difference was found; both groups lost on average two lines of BCVA.
CONCLUSION: Transpupillary thermotherapy appeared to have been of no benefit in preventing further visual loss in patients with occult CNV in this pilot study. ||||| OBJECTIVE: To determine the natural course of well-defined plaque choroidal neovascularization (CNV) using indocyanine green angiography.
METHODS: Two ophthalmologists, experts in macular diseases and indocyanine green angiography, examined 40 eyes with exudative age-related macular degeneration and a well-defined plaque CNV using complete ophthalmoscopic evaluation, fluorescein angiography, and indocyanine green angiography. The increase in the size of the plaques was analyzed using multivariate analysis, in relation to the worsening of visual acuity, with adjustment for age, sex, and length of follow-up.
RESULTS: Mean follow-up was 13.5 months (median, 11 months). Initial and final mean visual acuity were 20/46 (median, 20/50) and 20/65 (median, 20/100), respectively. The mean initial size of the plaque was 6.62 mm2 (median, 6.20 mm2), and the mean final size was 10.40 mm2 (median, 9.76 mm2). The enlargement was statistically significant (P<.001).
CONCLUSIONS: We found that plaque CNV tends to become larger with time, the enlargement reaching about 40% in 1 year of follow-up. The resulting loss of visual acuity, however, is not significant, and is slightly correlated with the extension of the lesion; it also does not appear to be directly related to sex. ||||| In a randomized clinical trial, the effects of laser treatment of subfoveal recurrent neovascularization have been compared with no additional laser treatment. Among eyes with age-related macular degeneration assigned to laser treatment of recurrent neovascularization (n = 97) and those assigned to no additional laser treatment (n = 109), average visual acuity was 20/125 (Snellen equivalent) at entry. Both at 3 and 24 months after enrollment, the average visual acuity of laser-treated eyes was 20/250, indicating a decrease in visual acuity of 3 lines immediately after treatment, but little further decrease in acuity thereafter. In contrast, the average visual acuity of eyes assigned to no additional treatment decreased by 2 lines to 20/200 by 3 months after entry. After 24 months, acuity had decreased an additional 2 lines to 20/320. By 24 months after enrollment, only three (9%) of 35 laser-treated eyes, but 13 (28%) of 46 untreated eyes, had decreased visual acuity of 6 or more lines from baseline (P = .03, chi 2 test). On average, treated eyes maintained the initial contrast threshold for large letters, while the contrast threshold of untreated eyes worsened steadily throughout 24 months of follow-up. This study was halted before the target number of patients had been enrolled because of the similarity of these findings to findings from a related Macular Photocoagulation Study clinical trial of laser treatment of subfoveal neovascularization secondary to age-related macular degeneration in eyes without previous laser treatment. Laser treatment is recommended for subfoveal recurrent neovascularization in eyes with age-related macular degeneration that meet the eligibility criteria for this study. ||||| We studied the clinical characteristics and the natural course of occult choroidal new vessels (CNV) in 78 eyes with age-related macular degeneration (AMD). Cases were included in 2 groups characterized respectively by ill-defined subretinal ooze (group 1) and serous detachment of the retinal pigment epithelium (RPE) with adjacent areas of mottled pigmentation (group 2). Both these forms of occult CNV showed to have a slower evolution compared to the classic CNV occurring in AMD, but they also led to disciform scar and severe visual loss. Occult CNV of group 2, contrary to those of group 1, were often multifocal and extrafoveal. They had a greater tendency to hemorrhages and a faster and less gradual progression to fibrovascular scarring and visual loss. Fluorescein angiography showed choroidal filling delay in the macular region of 47% of eyes of group 1. A perfusion defect of the macular choroid could be the basis of the low perfusion pressure and the consequent low activity of CNV with the angiographic pattern of ill-defined ooze. ||||| PURPOSE: The angiostatic cortisene anecortave acetate was evaluated in three safety and efficacy studies of patients with subfoveal choroidal neovascularization secondary to exudative age-related macular degeneration.
METHODS: The Anecortave Acetate Monotherapy Trial enrolled 128 patients randomized to anecortave acetate (3 mg, 15 mg, or 30 mg) or vehicle administered as a sub-Tenon's posterior juxtascleral depot (PJD) at 6-month intervals. The Anecortave Acetate and photodynamic therapy (PDT) with verteporfin Combination Trial enrolled 136 patients randomized to PDT with verteporfin followed by a single depot administration of anecortave acetate (15 mg or 30 mg) or vehicle. The Anecortave Acetate 15 mg versus PDT Comparison Trial enrolled 530 patients to receive either anecortave acetate 15 mg every 6 months + sham PDT every 3 months or PDT with verteporfin every 3 months + sham PJD administration every 6 months.
RESULTS: Anecortave acetate 15 mg was statistically superior to vehicle in the monotherapy trial at both 12 and 24 months for maintenance of vision and inhibition of CNV lesion growth. In the combination trial, a trend favored adding either anecortave acetate 15 mg or 30 mg to PDT for these two measures of clinical efficacy, but this short-duration study did not achieve statistical significance. Anecortave acetate 15 mg is comparable to PDT for maintaining vision over the 24-month period in the comparison trial.
CONCLUSIONS: Anecortave acetate is safe and effective treatment for exudative age-related macular degeneration. ||||| OBJECTIVE: To compare the treatment effect and safety of photodynamic therapy with verteporfin using a standard (SF) or reduced (RF) light fluence rate with that of placebo therapy in patients with subfoveal minimally classic choroidal neovascularization (CNV) with age-related macular degeneration.
DESIGN: Phase 2, multicenter, double-masked, placebo-controlled, randomized clinical trial.
SETTING: Nineteen ophthalmology practices in North America and Europe.
PARTICIPANTS: Patients with initial best-corrected visual acuity of at least 20/250 and a lesion size of no greater than 6 Macular Photocoagulation Study (MPS) disc areas.
METHODS: We randomly assigned 117 patients (1:1:1) to verteporfin infusion (6 mg/m(2)) and light application with an RF rate (300 mW/cm(2)) for 83 seconds (light dose of 25 J/cm(2)) or an SF rate (600 mW/cm(2)) for 83 seconds (light dose of 50 J/cm(2)) or to placebo infusion with RF or SF. Treatment was repeated every 3 months if the treating physician noted fluorescein leakage from CNV on angiography. Patients in whom a predominantly classic lesion developed could receive open-label standard verteporfin treatment. Best-corrected visual acuity was measured every 3 months, and angiographic changes were assessed by the Photograph Reading Center through the 3-month examination unless an ocular adverse event or conversion to a predominantly classic lesion was identified by an investigator. Safety was assessed throughout the study. All outcomes were on an intent-to-treat basis.
RESULTS: One hundred three (88%) of 117 patients completed the 24-month examination. Twelve (30%) of 40 patients assigned to placebo received open-label standard verteporfin treatment after confirmation of presence of predominantly classic CNV. At month 12, a loss of at least 3 lines of visual acuity occurred in 5 (14%) of 36 eyes assigned to RF and 10 (28%) of 36 eyes assigned to SF, compared with 18 (47%) of 38 eyes assigned to placebo (RF, P = .002; SF, P = .08; RF + SF, P = .004). At month 24, this loss occurred in 9 (26%) of 34 eyes assigned to RF and 17 (53%) of 32 assigned to SF, compared with 23 (62%) of 37 eyes assigned to placebo (RF, P = .003; SF, P = .45; RF + SF, P = .03). Progression to predominantly classic CNV by 24 months was more common in the placebo group (11 [28%] of 39 patients compared with 2 [5%] of 38 in the RF group [P = .007] and 1 [3%] of 37 in the SF group [P = .002]). No unexpected ocular or systemic adverse events were identified. Treatment-related, usually transient visual disturbances were 13% with SF, 10% with placebo, and 5% with RF.
CONCLUSIONS: Verteporfin therapy safely reduced the risks of losing at least 15 letters (> or =3 lines) of visual acuity and progression to predominantly classic CNV for at least 2 years in individuals with subfoveal minimally classic lesions due to age-related macular degeneration measuring 6 MPS disc areas or less. Based on the overall evidence available on verteporfin therapy for these lesions, the VIM Study Group would consider recommending verteporfin therapy for relatively small minimally classic lesions similar to those enrolled in the VIM Trial. ||||| We obtained follow-up data on 84 eyes with age-related macular degeneration and poorly defined angiographic leakage presumed to represent choroidal neovascularization. A poorly defined neovascular membrane was presumed to be present when subsensory retinal fluid was present in association with choroidal leakage on fluorescein angiography and in which the extent of leakage was not well defined. Among the 84 eyes, the average initial visual acuity was 20/80. In 75 (89%) of 84 eyes, the leakage involved the foveal center at initial presentation. At follow-up (average, 28 months; range, six to 53 months), the average visual acuity was 20/250; the final acuity declined at least three but less than six lines in 18 eyes (21%) and six or more lines in 35 eyes (42%). There was a statistically significant difference in the percentage of eyes that developed moderate or severe visual loss among eyes that progressed to disciform scarring compared with eyes that continued to manifest poorly defined leakage without evidence of scarring. Given that most severe visual loss associated with macular degeneration can be attributed to consequences of neovascular membranes and that many membranes associated with age-related macular degeneration are poorly defined, our study results support the possibility that poorly defined neovascular membranes represent a major cause of severe visual loss among the elderly in the United States. ||||| OBJECTIVE: To determine whether the presence of occult choroidal neovascularization (CNV) influenced the anatomic and visual acuity outcomes in a randomized clinical trial of krypton red laser photocoagulation to treat juxtafoveal neovascular lesions in age-related macular degeneration.
DESIGN, SETTING, AND PATIENTS: The fluorescein angiograms obtained at the baseline examination at tertiary retinal referral centers between April 1, 1981, and December 31, 1987, as part of the Macular Photocoagulation Study (MPS) Age-Related Macular Degeneration Study-Krypton Laser were evaluated retrospectively at the MPS Fundus Photograph Reading Center by two senior readers independently (with open adjudication of any differences) from 1992 to 1994. Criteria for classifying classic and occult CNV by the MPS Group were established in 1989, 2 years after the last patient had been assigned randomly to treatment or observation in the krypton laser study.
MAIN OUTCOME MEASURES: Treatment coverage of classic and occult CNV, persistent CNV, recurrent CNV, and visual acuity from scheduled follow-up examinations for up to 5 years were analyzed for the absence or presence of occult CNV at baseline.
RESULTS: The number of eyes with classic CNV but not occult CNV, classic and occult CNV, and occult CNV but no classic CNV were almost identical for the eyes assigned randomly to treatment or observation. Classic CNV almost always was covered completely with intense laser treatment; nevertheless, recurrent CNV developed in more than half of these eyes within 1 year after initial laser treatment. In contrast, in more than half of the eyes with occult CNV, more than 50% of the occult CNV was not covered with heavy laser treatment. Laser treatment was clearly beneficial for eyes with classic CNV but no occult CNV and almost equivalent to no treatment for eyes with classic and occult CNV. The few eyes with occult CNV but no classic CNV precluded conclusions about the value of treatment in this subgroup.
CONCLUSIONS: These results strengthen previous reports that laser treatment is beneficial for eyes with juxtafoveal choroidal neovascular lesions when classic CNV is present, even though CNV often recurs. Treatment of classic CNV alone in eyes with classic and occult CNV was not beneficial in this study. Distinguishing classic CNV from occult CNV can aid in the selection of patients who will benefit most from laser treatment. ||||| PURPOSE: The purpose of this study was to investigate the long-term effect of low-dose radiation therapy on subfoveal choroidal neovascularization associated with age-related macular degeneration.
METHODS: The clinical course and visual outcome were compared retrospectively among two treated groups and a control group; 15 patients (15 eyes) received 10 Gy, another 15 patients (15 eyes) received 20 Gy. The control group consisted of 15 patients (15 eyes) without treatment. All patients were followed up for at least 18 months, and most were followed up for 3 years. The macula was irradiated with either 10 Gy in 5 fractions or with 20 Gy in 10 fractions after computed tomography (CT) simulation enabled real-time treatment planning from multiple CT slices.
RESULTS: During the 3 years of follow-up, the lesions became better in 5 eyes, unchanged in 1, and worse in 9 with 10 Gy radiation; better in 7 eyes, unchanged in 1, and worse in 7 eyes with 20 Gy; and better in 1 eye and worse in 14 with no treatment. The difference between the groups treated with radiation and the control was statistically significant (P <.05). Visual acuity was also significantly better in the group receiving 20 Gy than in the control group up to 2 years after radiation (P <.01).
CONCLUSION: Radiation may extend the period of good visual function substantially by reducing subfoveal choroidal neovascularization activity. ||||| OBJECTIVE: An examination of clinically relevant subgroups of patients in the MARINA study of ranibizumab in treatment of minimally classic or occult with no classic choroidal neovascularization (CNV) secondary to age-related macular degeneration (AMD) was done. Objectives were to determine the effectiveness of ranibizumab across subgroups, compare the effectiveness of ranibizumab with that of sham injection within subgroups, and evaluate the relationship between selected baseline characteristics and visual acuity (VA) outcomes.
DESIGN: Retrospective subgroup analyses of 24-month data from the MARINA study.
PARTICIPANTS AND CONTROLS: Seven hundred sixteen patients were randomly assigned to 0.3 mg ranibizumab (n = 238), 0.5 mg ranibizumab (n = 240), or sham treatment (n = 238).
METHODS: Efficacy outcomes were compared across subgroups based on patients' gender, age, baseline VA score, baseline CNV lesion size, CNV lesion type, and duration of neovascular AMD using univariate analyses. Multivariate analyses were performed on the change from baseline to 24 months in VA score to assess further the correlation between baseline characteristics and VA outcome.
MAIN OUTCOME MEASURES: Proportion of patients losing <15 letters from baseline, proportion gaining > or =15 letters from baseline, and mean VA score change from baseline.
RESULTS: For each of the 3 VA end points, all subgroups of ranibizumab-treated patients did better on average than the sham-treated patients. Increasing age, larger CNV lesion size at baseline, and a higher baseline VA score were all associated with greater loss of letters in the sham group or less gain of letters in the ranibizumab groups. However, the net benefit of ranibizumab versus sham treatment was greater in patients who scored higher than in those who scored lower in baseline VA.
CONCLUSIONS: This subgroup analysis of 24-month data from the MARINA study indicates that ranibizumab treatment was associated with an average increase from baseline VA in all subgroups evaluated, and that ranibizumab treatment was superior to sham treatment across all subgroups. The most important predictors of VA outcomes were, in decreasing order of importance, baseline VA score, CNV lesion size, and age. ||||| PURPOSE: The aim of this investigation was to evaluate prognostic factors influencing the short-term prognosis of occult choroidal neovascularization (CNV).
METHODS: A consecutive series of 107 untreated occult CNV in 101 patients were evaluated in terms of the effect of their initial lesion characteristics, as determined with fluorescein angiography (FA), indocyanine green angiography (ICG-A) and optical coherence tomography (OCT), on the change in distance acuity, lesion size and retinal thickness over 1-3 months. Descriptive statistics, the Pearson Correlation Coefficient and a multiple linear regression analysis were applied to treat the data.
RESULTS: A total of 107 eyes (101 patients) were examined. The study cohort consisted of 35 males and 66 females, with a mean age of 77.6 years. During the 3-month study period the mean distance acuity decreased from 67.0 to 63.2 letters; the mean size of the lesion increased from 16.1 to 18.4 mm(2); the mean maximum retinal thickness increased from 374.5 to 387.5 mum. Of the lesions, 59.8% included pigment epithelial detachments (serous or fibrovascular) and 29.9% retinal angiomatous proliferation. A better distance acuity at both visits for the entire study population correlated significantly with smaller lesions, as determined by FA and ICG-A (p < 0.0001), and a lower maximum retinal thickness, as determined by the OCT (p < 0.0001).
CONCLUSIONS: A small and statistically insignificant change in distance acuity, lesion size and retinal thickness occurred over the 3 months of the study period. This reduced the ability of the study to examine the effect of baseline findings on outcome. Only two factors - the presence of a RAP lesion or the presence of CNV in the other eye - significantly and adversely affected the distance visual acuity at follow-up. ||||| AIM OF THE STUDY: Several pilot studies have indicated, that radiation therapy might have a beneficial effect on the course of CNV in AMD. This controlled study was aimed at the question, whether such treatment might halt progression of neovascular AMD and whether a low or a high radiation dose should be applied.
METHODS AND PATIENTS: Enclosed were patients aged > or = 60 and < or = 85 and eyes with a VA of > or = 0.1 and < or = 0.6, revealing a juxta/subfoveal CNV either of the occult or the classic type. Treatment was performed with a linear accelerator at fractions of 2 Gy up to a total dose of 10 Gy or 36 Gy. 95 eyes had completed follow-up of > or = 12 < or = 24 months.
RESULTS: Among eyes with occult CNV 8 received 36 Gy, 16 were treated with 10 Gy and 21 were in the control group. Mean visual loss was 3.5 lines after 12 months and 5 lines after 24 months with no difference between irradiated eyes and those in the control group. In the groups with classic CNV 8 eyes were treated with 36 Gy, 27 eyes received 10 Gy and 15 eyes were in the control group. Mean visual loss after 6 months was 2.2 lines in eyes of both groups treated with radiation and 5.7 lines in the control group. This was statistically significant (p < 0.05). VA was < 0.1 after 12 (24) months of follow-up in 50 (75)% of the cases with 36 Gy, in 48 (83)% with 10 Gy and in 60 (83)% of the controls. These results were statistically significant after 12 months only.
DISCUSSION AND CONCLUSIONS: The natural course of occult CNV could not be improved by irradiation with 10 or 36 Gy. In eyes with classic CNV a VA of > or = 0.1 was maintained significantly more often in irradiated eyes than in those of the control group. Treatment with 36 Gy however was associated with an unacceptable incidence of radiation retinopathy. | [
{
"source_pmid": "14644721",
"source_text": "PURPOSE: To evaluate safety and efficacy of the angiostatic agent anecortave acetate, compared with a placebo, for treatment of subfoveal choroidal neovascularization (CNV).\nDESIGN: Ongoing masked, randomized, placebo-controlled, parallel evaluation of anecortav... |
28665868 | CONCLUSION: This meta-analysis indicated that AMD, especially late AMD, was associated with increased risk of all-cause mortality and cardiovascular mortality based on comparisons with people who did not have AMD and who were of similar age and sex. | OBJECTIVE: To assess the association between mortality and cause-specific visual impairment in older people.
METHODS: Visual acuity and causes of visual impairment were collected in 13 569 participants 75 years and older participating in a randomized trial of health screening. Participants were followed up for mortality for a median of 6.1 years.
RESULTS: Compared with those with 6/6 (or 20/20 Snellen) or better visual acuity, the age- and sex-adjusted rate ratio for visually impaired people (binocular visual acuity <6/18 or <20/60 Snellen) was 1.60 (95% confidence interval, 1.47-1.74), which was markedly attenuated (rate ratio, 1.17; 95% confidence interval, 1.07-1.27) after adjustment for confounding factors. People whose visual impairment was due to cataract or age-related macular degeneration had excess risks of all-cause and cardiovascular mortality, which disappeared after adjustment. People with refractive error remained at small risk, despite adjustment, probably owing to residual confounding from factors associated with minimal use of eye services rather than underlying eye disease. There were no associations with cancer mortality.
CONCLUSION: Associations reported for visual impairment and mortality or for specific causes of visual impairment reflect confounding by comorbidities, risk factors, and other factors related to susceptibility to death rather than an independent biological association of vision problems or specific eye diseases. ||||| AIM: To describe predictors of mortality in the 5 year follow up of the Melbourne Visual Impairment Project (VIP) cohort.
METHODS: The Melbourne VIP was a population based study of the distribution and determinants of age related eye disease in a cluster random sample of Melbourne residents aged 40 years and older. Baseline examinations were conducted between 1992 and 1994. In 1997, 5 year follow up examinations of the original cohort commenced. Causes of death were obtained from the National Death Index for all reported deaths.
RESULTS: Of the original 3271 participants, 231 (7.1%) were reported to have died in the intervening 5 years. Of the remaining 3040 participants eligible to return for follow up examinations, 2594 (85% of eligible) did participate, 51 (2%) had moved interstate or overseas, 83 (3%) could not be traced, and 312 (10%) refused to participate. Best corrected visual acuity <6/12 (OR=2.34) was associated with a significantly increased risk of mortality, as were increasing age (OR=1.09), male sex (OR=1.62), increased duration of cigarette smoking (OR=2.06 for smoking >30 years), increased duration of hypertension (OR=1.51 for duration >10 years), and arthritis (OR=1.42).
CONCLUSIONS: Even mild visual impairment increases the risk of death more than twofold. Further research is needed to determine why decreased visual acuity is associated with increased risk of mortality. ||||| OBJECTIVE: We aimed to investigate the independent association between AMD and risk of ischemic heart disease (IHD), stroke, and cardiovascular (CVD) mortality, and all-cause mortality over 15 years.
METHODS: 3654 participants aged 49+ years at baseline were followed over 15 years. AMD was assessed from retinal photographs. Deaths and cause of death were confirmed by data linkage with the Australian National Death Index. Hazard ratios (HRs) and 95% confidence intervals (CIs) were assessed using Cox models.
RESULTS: 71.4% (n=162) and 34.6% (n=1037) of participants with any AMD and no AMD, respectively, died over 15 years. After multivariable-adjustment, no significant associations were observed between AMD and total- and cause-specific mortality in the overall cohort. However, among men, late AMD at baseline was associated with an increased risk of all-cause mortality (n=22; 95.7%), 15 years later: multivariable-adjusted HR, 1.80 (95% CI 1.04-3.11). Women with late AMD had 2-fold increased risk of stroke mortality (n=15; 28.9%), HR 2.10 (95% CI 1.08-4.06). Early-stage AMD was not associated with mortality risk.
CONCLUSION: Late AMD independently predicted all-cause mortality in men and stroke mortality in women, over 15 years. Although underlying mechanisms are unclear, these findings indicate that late AMD is a marker of biological aging. ||||| OBJECTIVES: To examine the association between age-related macular degeneration (AMD) and all-cause and cause-specific mortality in a population of older women.
DESIGN: Prospective cohort study.
SETTING: Four U.S. clinical centers.
PARTICIPANTS: A random sample of 1,202 women with graded fundus photographs at the Year 10 visit of the Study of Osteoporotic Fractures (mean age 79.5).
MEASUREMENTS: Forty-five-degree stereoscopic fundus photographs were graded for presence and severity (early vs late) of AMD. Vital status was adjudicated from death certificates. Cox proportional hazards models, adjusted for appropriate confounders, were used to estimate mortality hazards ratios.
RESULTS: Prevalence of any AMD was 40.5% at baseline, with 441 (36.7%) having early AMD and 46 (3.8%) having late AMD. Cumulative mortality was 51.6% over 15 years of follow-up. Overall, there was no significant association between AMD presence or severity and all-cause or cause-specific mortality. Because there was a significant interaction between AMD and age in predicting mortality (P<.05 for each mortality type), analyses were stratified according to age group. In women younger than 80, after adjusting for covariates, late AMD was associated with cardiovascular disease (CVD) mortality (hazard ratio (HR)=2.61, 95% confidence interval (CI)=1.05-6.46). In women aged 80 and older, early AMD was associated with all-cause (HR=1.39, 95% CI=1.11-1.75) and non-CVD, noncancer (HR=1.45, 95% CI=1.05-2.00) mortality. Any AMD was associated with all-cause (HR=1.42, 95% CI=1.13-1.78) and CVD (HR=1.45, 95% CI=1.01-2.09) mortality in women aged 80 and older.
CONCLUSION: AMD is a predictor of poorer survival in women, especially those aged 80 and older. Determination of shared risk factors may identify novel pathways for intervention that may reduce the risk of both conditions. ||||| PURPOSE: To examine patient survival in age-related maculopathy in a 14-year follow-up study.
DESIGN: Population-based 14-year cohort study.
PARTICIPANTS: Nine hundred forty-six residents, aged 60 to 80 years, living in the Osterbro district of Copenhagen, Denmark, participated in the first examination conducted from 1986 to 1988. These participants were followed until death or until May 1, 2002, whichever came first.
METHODS: Participants underwent an extensive ophthalmologic examination at Rigshospitalet, the National University Hospital of Copenhagen. Standardized protocols for physical examination, blood samples, and data from the National Central Person Register, the National Death Register, and the National Patient Register were used.
MAIN OUTCOME MEASURES: Mortality and age-related maculopathy.
RESULTS: By May 1, 2002, 60.9% (577 of 946) of the participants of the baseline study cohort had died. The adjusted 14-year cumulative mortality hazard ratio for subjects with early and late age-related maculopathy at baseline was 1.26 (95% confidence interval [CI], 1.06-1.51). We identified a strong correlation between mortality and age-related maculopathy among women (relative risk, 1.59; 95% CI, 1.23-2.07) but not among men.
CONCLUSIONS: When adjusting for survival-related factors, age-related maculopathy is a significant risk indicator for poorer survival in women and may be a marker of underlying serious systemic factors or aging processes specific to women. ||||| PURPOSE: To assess the association between age-related macular degeneration (AMD) and mortality in a population-based setting.
PROCEDURES: At baseline in 2001, the Beijing Eye Study examined 4,378 subjects for AMD with a detected frequency of 110/4,378 (2.5%) subjects for early AMD and of 12/4,378 (0.3%) subjects for late AMD. In 2006, all study participants were re-invited for a follow-up examination.
RESULTS: Out of the 4,378 subjects, 3,218 (73.5%) returned for a follow-up examination while 138 (3.2%) were dead and 1,022 (23.3%) did not agree to be re-examined or had moved away. Early AMD and late AMD were not significantly associated with mortality (p = 0.40 and 0.33, respectively), neither in univariate analysis nor in multivariate analysis.
CONCLUSIONS: AMD may not be associated with an increased mortality in adult Chinese. ||||| OBJECTIVE: To investigate the association between age-related macular degeneration (AMD) and mortality in older persons.
DESIGN: Population-based prospective cohort study.
PARTICIPANTS: Participants 67 to 96 years of age (43.1% male) enrolled between 2002 and 2006 in the Age, Gene/Environment Susceptibility-Reykjavik Study.
METHODS: Retinal photographs of the macula were acquired digitally and evaluated for the presence of AMD lesions using the Wisconsin Age-Related Maculopathy grading scheme. Mortality was assessed prospectively through 2013 with cause of death available through 2009. The association between AMD and death, resulting from any cause and specifically cardiovascular disease (CVD), was examined using Cox proportional hazards regression with age as the time scale, adjusted for significant risk factors and comorbid conditions. To address a violation in the proportional hazards assumption, analyses were stratified into 2 groups based on the mean age at death (83 years).
MAIN OUTCOME MEASURES: Mortality resulting from all causes and CVD.
RESULTS: Among 4910 participants, after a median follow-up of 8.6 years, 1742 died (35.5%), of whom 614 (35.2%) had signs of AMD at baseline. Cardiovascular disease was the cause of death for 357 people who died before the end of 2009, of whom 144 (40%) had AMD (101 with early disease and 43 with late disease). After considering covariates, including comorbid conditions, having early AMD at any age or having late AMD in individuals younger than 83 years (n = 4179) were not associated with all-cause or CVD mortality. In individuals 83 years of age and older (n = 731), late AMD was associated significantly with increased risk of all-cause mortality (hazard ratio [HR], 1.76; 95% confidence interval [CI], 1.20-2.57) and CVD-related mortality (HR, 2.37; 95% CI, 1.41-3.98). In addition to having AMD, older individuals who died were more likely to be male and to have low body mass index, impaired cognition, and microalbuminuria.
CONCLUSIONS: Competing risk factors and concomitant conditions are important in determining mortality risk resulting from AMD. Individuals with early AMD are not more likely to die than peers of comparable age. Late AMD becomes a predictor of mortality by the mid-octogenarian years. ||||| PURPOSE: To study mortality in subjects with age-related maculopathy (ARM), cataract, or open-angle glaucoma (OAG) in comparison with those without these disorders.
DESIGN: Population-based prospective cohort study.
PARTICIPANTS: Subjects (n = 6339) aged 55 years and older from the population-based Rotterdam Study for whom complete information on eye disease status was present.
MAIN OUTCOME MEASURES: Vital status continuously monitored from 1990 until January 1, 2000.
METHODS: The diagnosis of ARM was made according to the International Classification System. Cataract, determined on biomicroscopy, was defined as any sign of nuclear or (sub)cortical cataract, or both, in at least one eye with a visual acuity of 20/40 or less. Aphakia and pseudophakia in at least one eye were classified as operated cataract. Definite OAG was defined as a glaucomatous optic neuropathy combined with a glaucomatous visual field defect. Diagnoses were assessed at baseline. Mortality hazard ratios were computed using Cox proportional hazard regression analysis, adjusted for appropriate confounders (age, gender, smoking status, body mass index, cholesterol level, atherosclerosis, hypertension, history of cardiovascular disease, and diabetes mellitus).
RESULTS: The adjusted mortality hazard ratio for subjects with AMD (n = 104) was 0.94 (95% confidence interval [CI], 0.52-1.68), with biomicroscopic cataract (n = 951) was 0.94 (95% CI, 0.74-1.21), with surgical cataract (n = 298) was 1.20 (95% CI, 0.86-1.68), and with definite OAG (n = 44) was 0.39 (95% CI, 0.10-1.55).
CONCLUSIONS: Both ARM and cataract are predictors of shorter survival because they have risk factors that also affect mortality. When adjusted for these factors, ARM, cataract, and OAG were themselves not significantly associated with mortality. ||||| OBJECTIVES: To investigate the effect of age, sex, and the Y402H variant in the complement factor H (CFH) gene on the incidence, progression, and regression of age-related macular degeneration (AMD) as well as the effect of these factors and AMD on mortality, using multistate models.
METHODS: Analyses included 4379 persons aged 43 to 84 years at the time of the census. The status of AMD on a 5-level severity scale was graded from retinal photographs taken at up to 5 study visits between 1988 and 2010. Multistate models in continuous time were used to model the effects of age, sex, and CFH genotype on the incidence, progression, and regression of AMD and mortality.
RESULTS: The CFH Y402H genotype CC was associated, relative to genotype TT (reported as hazard ratio; 95% CI), with increased incidence of AMD (no to minimally severe early AMD, 1.98; 1.57-2.49), progression of AMD (minimally severe early to moderately severe early AMD, 1.73; 1.29-2.33; moderately severe early to severe early AMD, 1.30; 0.86-1.94; and severe early to late AMD, 1.72; 1.01-2.91) but not with regression of AMD or mortality. Late AMD was associated with increased mortality (1.37; 1.15-1.62) relative to no AMD, but earlier stages of AMD were not.
CONCLUSIONS: Using the multistate models, we show that the Y402H risk variant is associated with lifetime incidence of early AMD and progression of early to late AMD and that late AMD is associated with mortality risk. ||||| BACKGROUND: A large-scale prevalence survey of blindness and visual impairment (The Andhra Pradesh Eye Diseases Study [APEDS1]) was conducted between 1996-2000 on 10,293 individuals of all ages in three rural and one urban clusters in Andhra Pradesh, Southern India. More than a decade later (June 2009-March 2010), APEDS1 participants in rural clusters were traced (termed APEDS2) to determine ocular risk factors for mortality in this longitudinal cohort.
METHODS AND FINDINGS: Mortality hazard ratio (HR) analysis was performed for those aged >30 years at APEDS1, using Cox proportional hazard regression models to identify associations between ocular exposures and risk of mortality. Blindness and visual impairment (VI) were defined using Indian definitions. 799/4,188 (19.1%) participants had died and 308 (7.3%) had migrated. Mortality was higher in males than females (p<0.001). In multivariable analysis, after adjusting for age, gender, diabetes, hypertension, body mass index, smoking and education status the mortality HR was 1.9 (95% CI: 1.5-2.5) for blindness; 1.4 (95% CI: 1.2-1.7) for VI; 1.8 (95% CI: 1.4-2.3) for pure nuclear cataract, 1.5 (95% CI: 1.1-2.1) for pure cortical cataract; 1.96 (95% CI: 1.6-2.4) for mixed cataract, 2.0 (95% CI: 1.4-2.9) for history of cataract surgery, and 1.58 (95% CI: 1.3-1.9) for any cataract. When all these factors were included in the model, the HRs were attenuated, being 1.5 (95% CI: 1.1-2.0) for blindness and 1.2 (95% CI: 0.9-1.5) for VI. For lens type, the HRs were as follows: pure nuclear cataract, 1.6 (95% CI: 1.3-2.1); pure cortical cataract, 1.5 (95% CI: 1.1-2.1); mixed cataract, 1.8 (95% CI: 1.4-2.2), and history of previous cataract surgery, 1.8 (95% CI: 1.3-2.6).
CONCLUSIONS: All types of cataract, history of cataract surgery and VI had an increased risk of mortality that further suggests that these could be potential markers of ageing. ||||| OBJECTIVE: To examine the association of age-related macular degeneration (AMD) with incident coronary heart disease (CHD) and all-cause mortality.
DESIGN: Population-based prospective cohort study.
PARTICIPANTS: From the Atherosclerosis Risk in Communities Study (n = 12 536; age range, 49-73 years).
METHODS: Participants had retinal photographs of one eye taken between 1993 and 1995. Photographs were evaluated for the presence of early and late AMD signs according to the Wisconsin grading system. Incident CHD events (acute myocardial infarction, silent myocardial infarction, fatal CHD, and cardiac revascularization procedures) and all-cause mortality were identified prospectively using standardized methods.
MAIN OUTCOME MEASURES: Incident CHD events and all-cause mortality.
RESULTS: Of 11,414 persons at risk of CHD, there were 555 (4.9%) with AMD at baseline, of whom 540 were early AMD and 15 were late AMD cases. Over a 10-year follow-up, 922 persons developed an incident CHD event. After controlling for age, gender, race, systolic and diastolic blood pressure, pack-years of cigarette smoking, and other variables, early AMD was not associated with incident CHD (relative risk, 1.08; 95% confidence interval, 0.82-1.42). However, individuals with late AMD were significantly more likely to have an incident CHD event, with 4 CHD events among the 15 participants with late AMD at baseline (10-year cumulative incidence, 30.9%) as compared with 918 CHD events among the 11 399 participants without late AMD (incidence of 10.0%; P = 0.049, Fisher exact test). In the full cohort (n = 12 536), early AMD was not significantly associated with all-cause mortality. However, individuals with late AMD were more likely to die (10-year cumulative mortality rate, 23.5%) than those without late AMD (mortality rate, 8.9%; P = 0.088, Fisher exact test).
CONCLUSIONS: These data provide no evidence of an association between early AMD signs with incident CHD and all-cause mortality in middle-aged persons. Individuals with late AMD appear to have a higher rate of CHD events than those without late AMD, but due to a small number of late AMD cases, this finding should be interpreted cautiously. ||||| We investigated the relationship of visual impairment (VI) and age-related eye diseases with mortality in a prospective, population-based cohort study of 3,280 Malay adults aged 40-80 years between 2004-2006. Participants underwent a full ophthalmic examination and standardized lens and fundus photographic grading. Visual acuity was measured using logMAR chart. VI was defined as presenting (PVA) and best-corrected (BCVA) visual acuity worse than 0.30 logMAR in the better-seeing eye. Participants were linked with mortality records until 2012. During follow-up (median 7.24 years), 398 (12.2%) persons died. In Cox proportional-hazards models adjusting for relevant factors, participants with VI (PVA) had higher all-cause mortality (hazard ratio[HR], 1.57; 95% confidence interval[CI], 1.25-1.96) and cardiovascular (CVD) mortality (HR 1.75; 95% CI, 1.24-2.49) than participants without. Diabetic retinopathy (DR) was associated with increased all-cause (HR 1.70; 95% CI, 1.25-2.36) and CVD mortality (HR 1.57; 95% CI, 1.05-2.43). Retinal vein occlusion (RVO) was associated with increased CVD mortality (HR 3.14; 95% CI, 1.26-7.73). No significant associations were observed between cataract, glaucoma and age-related macular degeneration with mortality. We conclude that persons with VI were more likely to die than persons without. DR and RVO are markers of CVD mortality. | [
{
"source_pmid": "16219731",
"source_text": "OBJECTIVE: To assess the association between mortality and cause-specific visual impairment in older people.\nMETHODS: Visual acuity and causes of visual impairment were collected in 13 569 participants 75 years and older participating in a randomized trial of he... |
27927176 | CONCLUSIONS: Robust assessments of the diagnostic value of colour Doppler analysis remain uncommon, limiting the possibilities to extrapolate its true potential for clinical practice. PROSPERO 2014:CRD42014014027. | PURPOSE: To assess ocular blood flow in patients with primary open angle glaucoma (POAG) with or without progressive visual field loss in comparison with controls.
METHODS: Color Doppler imaging was performed on 78 eyes with established POAG (25 with progressive visual field loss and 53 with stable visual field) and 78 control eyes. Peak systolic velocity, end diastolic velocity (EDV), and resistance index (RI) were measured in the ophthalmic (OA), central-retinal, and medial and lateral posterior ciliary arteries.
RESULTS: Peak systolic velocity and EDV were lower and RI was higher in the ocular vessels of eyes with POAG (p < .01). The OA and medial posterior ciliary arteries RI was higher, and the OA EDV was lower in glaucomatous eyes with progressive than with stable visual field loss. The receiver operating characteristic curve showed the optimal cutoff RI to be 0.847.
CONCLUSIONS: Ocular blood flow appears compromised in eyes with POAG, particularly in those with progressive visual field loss. ||||| BACKGROUND/AIM: Retinal vein occlusion (RVO) is one of the most frequent ocular vascular diseases and leads to severe vision impairment. Colour Doppler imaging (CDI) is the first method which allows distinct evaluation of arterial and venous velocities in RVO. CDI is valuable for diagnosis of RVO and shows the effects of isovolaemic haemodilution. Patients with RVO were monitored by CDI for 1 year in order to clarify venous and arterial involvement in the pathogenesis of this disease.
METHODS: Patients with RVO were monitored prospectively for 1 year with clinical examinations, fluorescein angiography, and CDI every 3 months. 102 adults referred for RVO for less than 2 months were enrolled. Unaffected eyes were used as control. The maximum systolic and diastolic flow velocities and the resistance index (RI) were measured in the central retinal artery (CRA) and the maximum and minimum blood flow velocities in the central retinal vein (CRV).
RESULTS: During the year of observation, branch retinal vein occlusion (BRVO), ischaemic central retinal vein occlusion (CRVO), and non-ischaemic CRVO had a distinct pattern of venous velocity changes. BRVO had a similar profile to that observed in controls. Venous velocities were continuously lower in central forms, with the lowest values in ischaemic occlusion. In contrast, a brief decrease in arterial diastolic velocity was observed in ischaemic CRVO at presentation, correlated with arteriovenous passage time on fluorescein angiography, but with rapid normalisation.
CONCLUSIONS: CDI findings were correlated with the type of RVO at all times during follow up. CDI showed persistent impairment of central venous velocity in CRVO whereas there was a fast initial values recovery of the arterial velocity. These results using CDI show strong evidence of a primary venous mechanism in RVO. ||||| This longitudinal and prospective study analyzes the ability of orbital blood flow measured by color Doppler imaging (CDI) to predict glaucoma progression in patients with glaucoma risk factors. Patients with normal perimetry but having glaucoma risk factors and patients in the initial phase of glaucoma were prospectively included in the study and divided, after a five-year follow-up, into two groups: "Progression" and "No Progression" based on the changes in the Moorfields regression analysis (MRA) classification of Heidelberg retina tomograph (HRT). An orbital CDI was performed in all patients and the parameters obtained were correlated with changes in HRT. A logistic discrimination function (LDF) was calculated for ophthalmic artery (OA) and central retinal artery (CRA) parameters. Receiver operating characteristics curves (ROC) were used to assess the usefulness of LDFs to predict glaucomatous progression. A total of 71 eyes were included. End-diastolic velocity, time-averaged velocity, and resistive index in the OA and CRA were significantly different (P < 0.05) between the Progression and No Progression groups. The area under the ROC curves calculated for both LDFs was of 0.695 (OA) and 0.624 (CRA). More studies are needed to evaluate the ability of CDI to perform early diagnosis and to predict progression in glaucoma in eyes. ||||| BACKGROUND AND PURPOSE: Distal to a hemodynamically significant stenosis, the Doppler effect becomes dampened. Thus, measuring the flow profile in the ophthalmic artery and the central retinal artery with color Doppler imaging may provide hemodynamic information about the carotid circulation.
METHODS: To validate the flow profile measurement with color Doppler imaging in the ophthalmic and central retinal arteries and to determine the sensitivity and specificity of this examination in the detection of hemodynamically significant carotid stenosis, we compared color Doppler imaging examinations with ocular pneumoplethysmography and ophthalmodynamometry examinations in 66 patients with atherothrombotic ischemic cerebrovascular disease. The degree of carotid stenosis in these patients was determined by a duplex scan with color Doppler imaging, and 57 patients underwent angiography to verify the stenosis.
RESULTS: The flow velocities (systolic peak velocity and end-diastolic velocity) and pulsatility indices (A/B ratio and resistance index) in the ophthalmic and central retinal arteries decreased as the degree of carotid stenosis increased. There is a statistically significant difference in the mean of systolic peak velocity and the mean of end-diastolic velocity of the ophthalmic and central retinal arteries among groups with various degrees of carotid stenosis (P < .02). Using the flow velocities of the ophthalmic and central retinal arteries to diagnose carotid stenosis (> or = 75% stenosis and occlusion), 8 cm/s for systolic peak velocity in the central retinal artery and 29 cm/s for systolic peak velocity plus flow direction reversal in the ophthalmic artery gave the maximum accuracy (sensitivities, 84% and 85.7% and specificities, 89.6% and 81.7%, respectively). The systolic peak velocity in the central retinal artery varied directly with the systolic pressure of the ophthalmic and central retinal arteries.
CONCLUSIONS: The flow velocity and pulsatility in orbital arteries examined by color Doppler imaging provide further hemodynamic information; this test can be used to complement current sonographic examination of carotid disease. ||||| PURPOSE: To examine how an internal carotid artery (ICA) stenosis influences the orbital blood velocity and to determine which velocity parameters are most useful.
MATERIAL AND METHODS: The study group comprised 94 randomly selected patients examined with orbital US; most of the patients had a carotid artery stenosis. There were 58 men and 36 women, ranging in age from 22 to 88 years with a mean age of 63.1 years. The ICA stenosis grade was determined with carotid US. Peak systolic (Vp) and end-diastolic blood velocities, systolic acceleration, mean velocity, pulsatile index (PI) and resistance index (RI) were measured within the central retinal artery (CRA) and the ophthalmic artery (OA), and peak velocity was measured within the central retinal vein (CRV). The area under the ROC curve was used to compare the outcome of diagnostic tests.
RESULTS: Only a severe (> or =80%) ICA stenosis decreased orbital blood velocity significantly, while milder stenoses did not cause significant flow decrease or side differences. According to ROC curve analysis, the threshold values giving the highest accuracy in detecting a > or =80% ICA stenosis were Vp < or =0.08 cm/s for the CRA and Vp < or =0.14 cm/s for the OA. The sensitivities for detecting a > or =80% ICA stenosis were 45% for Vp CRA and 60% for Vp OA. Systolic acceleration also decreased in severe stenoses, but RI, PI and velocity in the CRV did not correlate with ICA pathology. Reversal of OA flow was seen in 92% of ICA occlusion and in 47% of severe ICA stenosis.
CONCLUSION: Orbital Doppler combined with carotid Doppler can be helpful in the diagnosis of the ocular ischaemic syndrome and in the evaluation of whether the symptoms are related to occlusion of the ophthalmic or central retinal vessels or are a consequence of carotid artery stenosis. ||||| PURPOSE: To determine pulsatile blood velocities in the orbital vasculature in patients with central retinal vein occlusion (CRVO).
METHODS: The ophthalmic artery, central retinal artery, and vein of 80 patients with CRVO and 95 control subjects were investigated by color Doppler imaging. The patients were examined by ophthalmoscopy, relative afferent pupillary measurement using cross-polarized filters, fundus fluorescein angiography, and electroretinography to estimate the degree of retinal ischemia.
RESULTS: Blood flow velocities in the central retinal vein and artery of eyes with CRVO were significantly lower than in fellow eyes and controls. The measurements from the vein were most reduced and in some cases absent in those eyes with "ischemic" CRVO. Velocities also were reduced in the central retinal artery of the affected eyes, but no correlation with "ischemia" was detected. The risk of iris neovascularization in patients examined within 3 months of onset of CRVO can be determined from the flow velocities with a high degree of predictability (75% sensitivity and 86% specificity).
CONCLUSIONS: Blood velocity was reduced in the retinal circulation of patients with CRVO and reduced even further in the "ischemic" variant of CRVO. The results indicate that noninvasive color Doppler imaging could play a major part in the routine assessment of patients with CRVO within 3 months of onset. ||||| PURPOSE: To assess the value of colour Doppler imaging (CDI) of the ophthalmic artery (OA) and short posterior ciliary arteries (SPCAs) in prognosis of disease progression in patients with primary open-angle glaucoma (POAG).
METHODS: A total of 49 eyes of 49 patients with POAG were included in a prospective cohort study. At baseline and every 6 months for 36 months, we measured the resistive indices (RIs) of the OA and SPCAs using CDI, visual field examination, intraocular pressure (IOP) and blood pressure measurements. The predictive capacity of the RIs of these vessels was investigated by Cox regression. Receiver operating characteristics curves were plotted for the OA and SPCAs RIs, and predictive values, likelihood ratios and post-test probabilities were calculated.
RESULTS: After 36 months, 23 eyes had progressed. In the eyes that progressed, the mean (SD) RI was 0.82 (0.007) for the OA and 0.73 (0.006) for the SPCAs; in the eyes that did not progress the mean RI was 0.70 (0.007) for the OA and 0.63 (0.006) for the SPCAs. The optimal points for the RIs were 0.72 for the OA and 0.65 for the SPCAs. With these cut-off points, the positive post-test probability was 90.5% in the OA.
CONCLUSION: In eyes with POAG and elevated IOP, the RIs of the OA or SPCAs may reliably predict visual field progression. ||||| PURPOSE: Previous studies have shown decreased retrobulbar blood flow in normal tension glaucoma (NTG) compared to healthy controls. This study evaluates the ability of colour Doppler imaging (CDI) to identify patients with NTG.
METHODS: Sixty-two patients with untreated NTG (mean age 57+/-14 years) and 40 age-matched controls (mean age 58+/-9 years) were included in a prospective cross-sectional institutional study. Peak systolic velocity (PSV), end-diastolic velocity (EDV), and resistive indices (RI=(PSV-EDV)/PSV) of the ophthalmic artery (OA), central retinal artery (CRA), and short posterior ciliary arteries (PCAs) were measured by means of CDI. Using receiver operating characteristic (ROC) curves, sensitivity was determined at 90% specificity.
RESULTS: Patients with NTG showed significantly decreased PSV (P<0.0001) and EDV (P<0.0001) of the CRA, significantly decreased EDV of the nasal (P=0.004) and temporal (P=0.002) PCA, and significantly increased RI of the temporal (P=0.003) PCAs compared to healthy controls. Sensitivity values at 90% specificity were calculated: PSV of the CRA, 30.6%; EDV of the CRA, 48.4%; EDV of the nasal PCA, 43.9%; EDV of the temporal PCA, 45.9%; and RI of the temporal PCA, 39.3%.
CONCLUSIONS: The power to identify NTG using CDI reaches 48% sensitivity at 90% specificity. Further longitudinal studies are needed to determine the prognostic value of CDI in glaucoma. ||||| OBJECTIVE: Resistive index (RI) is an indirect measurement of blood flow resistance that can be used to evaluate vascular damage in ophthalmologic diseases. The purpose of this study was to evaluate the association between RI values of orbital arteries by using the color Doppler imaging (CDI) in type II diabetes mellitus (DM) patients with microalbuminuria.
PATIENTS AND METHODS: We evaluated 91 type II DM patients with microalbuminuria and 27 healthy subjects. The DM patients with microalbuminuria were grouped into two: group 1 consisted of patients with retinopathy (n = 51) and group 2 consisted of patients without retinopathy (n = 40). Healthy subjects constituted group 3 (n = 27). The mean RI values of ophthalmic artery (OA), central retinal artery (CRA), and posterior ciliary artery (PCA) were measured using CDI.
RESULTS: Compared to diabetic group 2, group 1 had significantly higher mean RIs of OA, CRA, PCA, and HbA1c levels (p < 0.001 for all). Besides, there were no statistical differences in mean RIs of OA, CRA, and PCA between the control group and group 2 (p = 1.0; p = 0.44; p = 0.67, respectively). Mean RIs of OA and PCA were significantly correlated with age in group 1 (r = 0.549, p < 0.001; r = 0.407, p = 0.003, respectively). Mean RI of CRA was significantly correlated with the duration of diabetes and age in group 1 (r = 0.296, p = 0.035; r = 0.486, p < 0.001, respectively).
CONCLUSION: Our study indicates that RI might be a useful marker for early diagnosis and follow-up of diabetic retinopathy, and orbital RI assessment would be beneficial for diabetic patients with retinopathy. ||||| PURPOSE: We assessed early hemodynamic characteristics of various types of retinal vein occlusion using color Doppler imaging and spectral analysis.
METHODS: We measured the maximum systolic and diastolic blood flow velocities and the resistance index (RI) in the central retinal artery and the maximum and minimum blood flow velocities in the central retinal vein of affected eyes and contralateral unaffected eyes in 102 adults (63 men and 39 women; mean age, 61 +/- 14.6 years) who presented with retinal vein occlusion. Sixty-three control subjects (27 men and 36 women; mean age, 50 +/- 22.1 years) were also investigated.
RESULTS: No significant differences in hemodynamic characteristics were found between the control subjects' eyes and the patients' unaffected eyes. In the 18 cases of ischemic central retinal vein occlusion, the mean diastolic arterial flow velocity (p = 0.005) and venous flow velocity (p < 0.04) were lower and the mean RI was higher (p = 0. 0002) in the affected eyes than in the unaffected contralateral eyes. In the 51 cases of nonischemic central retinal vein occlusion, the mean diastolic arterial flow velocity (p < 0.0001) and venous flow velocity (p < 0.0001) also were lower and the mean RI (p < 0.0001) was higher in the affected eyes than in the unaffected contralateral eyes. These variables were different in the ischemic versus nonischemic types of central retinal vein occlusion. In the 33 cases of branch retinal vein occlusion, no significant differences were observed in arterial or venous blood flow velocities in the affected versus unaffected eyes. The mean RI in the affected eyes was significantly higher (p = 0.009) in patients with central versus branch retinal vein occlusion.
CONCLUSIONS: These results suggest that previous arterial disorders were not involved in the pathogenesis of central retinal vein occlusion in these patients. The findings also support the value of Doppler imaging and spectral analysis in the diagnosis and evaluation of retinal vein occlusion and confirm the involvement of arterial flow in venous occlusion. ||||| The purpose of this study was to investigate ocular blood flow hemodynamics in patients with diabetes mellitus. We used color Doppler sonography, in 22 normal subjects and 52 patients with (n = 25) or without (n = 27) diabetic retinopathy, to determine blood flow velocities and the resistive index of the central retinal artery. The resistive index of the central retinal artery in patients with diabetic retinopathy (0.85 +/- 0.09) was significantly greater (P < 0.01) than that in normal subjects (0.72 +/- 0.08) and in patients without diabetic retinopathy (0.81 +/- 0.09). The resistive index of the central retinal artery in the patients without diabetic retinopathy was also significantly greater than that of normal subjects (P < 0.01). The resistive index of ocular arterial flow was increased in the patients with diabetes mellitus and further increased in the presence of retinopathy. Increased resistance in the peripheral ocular vascular bed contributes to diabetic retinopathy, and this change is present before the appearance of overt diabetic retinopathy. | [
{
"source_pmid": "24898117",
"source_text": "PURPOSE: To assess ocular blood flow in patients with primary open angle glaucoma (POAG) with or without progressive visual field loss in comparison with controls.\nMETHODS: Color Doppler imaging was performed on 78 eyes with established POAG (25 with progressive... |
17073898 | CONCLUSION: According to data available, travoprost is more effective than timolol in lowering IOP in patients with open-angle glaucoma or ocular hypertension. Compared with other prostaglandin analogues, travoprost appears to be equivalent to bimatoprost and latanoprost. Although a limited number of local side-effects were reported, no serious treatment-related side-effects were reported. | PURPOSE: To compare the safety and intraocular pressure (IOP)-lowering efficacy of travoprost 0.004%/timolol 0.5% fixed combination ophthalmic solution (Trav/Tim) to its components travoprost 0.004% ophthalmic solution, TRAVATAN, (Trav) and timolol 0.5% ophthalmic solution (Tim) in patients with open-angle glaucoma or ocular hypertension.
DESIGN: Randomized multicenter, double-masked, active-controlled, parallel group study.
METHODS: Two hundred sixty-three patients with open-angle glaucoma or ocular hypertension were randomized to receive Trav/Tim once daily AM (and vehicle PM), Trav once daily PM (and vehicle AM), or Tim twice daily (AM and PM). Efficacy and safety were compared across treatment groups over 3 months.
RESULTS: Trav/Tim produced a mean IOP decrease from baseline of 1.9 mm Hg to 3.3 mm Hg more than Tim, with a significant decrease in mean IOP at each of the nine study visits (P < or = .003). Trav/Tim decreased mean IOP by 0.9 mm Hg to 2.4 mm Hg more than Trav, with a significant decrease in mean IOP at seven of the nine study visits (P < or = .05). The adverse event profile for Trav/Tim was comparable to Trav or Tim alone.
CONCLUSIONS: Over the 3 months of treatment, Trav/Tim produced clinically relevant IOP reductions in patients with open-angle glaucoma or ocular hypertension that were greater than those produced by either Trav or Tim alone. The clinical results that Trav/Tim was safe and well tolerated with an incidence of adverse events was comparable to the results of Trav or Tim alone. Trav/Tim provides both more effective IOP reduction than its components and the benefits of once-daily dosing. ||||| PURPOSE: This 9-month study compared the intraocular pressure (IOP)-lowering efficacy and safety of once-daily travoprost ophthalmic solutions (0.0015% and 0.004%) with twice-daily timolol 0.5%.
PATIENTS AND METHODS: This study was conducted using a double-masked, randomized, parallel-group design; adult patients with open-angle glaucoma or ocular hypertension (IOP between 24 and 36 mm Hg, inclusive at 9 am and between 21 and 36 mm Hg, inclusive, at 11 am and 4 pm on two eligibility visits after an appropriate washout of previous treatments). In both eyes, the travoprost vehicle (placebo) was instilled at 9 am and travoprost (0.0015% or 0.004%) was instilled at 9 pm, or timolol 0.5% was instilled at both times. The primary efficacy variable was mean IOP measured at 9 am, 11 am, and 4 pm at baseline and follow-up visits.
RESULTS: Five hundred seventy-three patients were randomized to the study treatments. Mean IOP, which was combined across study visits, was lower with travoprost 0.004% than with timolol 0.5% at 9 am (P = 0.0246), 11 am (P = 0.0039), and 4 pm (P = 0.0004). Intraocular pressure was lower with travoprost 0.004% than with travoprost 0.0015% at 11 am (P = 0.0314), the time of peak drug activity. Mean IOP was consistently lower with travoprost 0.0015% than with timolol 0.5%. Mean IOP reductions from baseline were significantly (P less than equal 0.0001) greater with travoprost 0.004% (8.0-8.9 mm Hg) than with timolol 0.5% (6.3-7.9 mm Hg). The most frequent related adverse events were hyperemia, pruritus, discomfort, pain, and iris pigmentation changes. The local tolerance was better in the timolol group compared with patients receiving travoprost. There were no serious unexpected treatment-related adverse events in any group.
CONCLUSIONS: Travoprost 0.004% reduced diurnal mean intraocular pressure significantly more than timolol 0.5%. Both concentrations of travoprost were well tolerated and safe for use in patients with open-angle glaucoma or ocular hypertension. ||||| This randomized, investigator-masked, multicenter, parallel-design trial compared the IOP-lowering efficacy of bimatoprost 0.03% and travoprost 0.004% in African Americans with glaucoma or ocular hypertension. After a washout of all ocular hypotensive agents, patients were assigned to bimatoprost once daily (n=16) or travoprost once daily (n=15) for 3 months. Study visits were at baseline and at months 1, 2, and 3. Primary outcome measures were the percentage of patients who achieved selected target pressures and the mean reduction in IOP from baseline at month 3. Both drugs comparably lowered IOP, but bimatoprost was more likely than travoprost to allow achievement of every target pressure from 12 to 19 mm Hg at month 3. After 3 months, the mean IOP reduction from baseline was 8.4 mm Hg (34%) in the bimatoprost group and 7.9 mm Hg (30%) in the travoprost group. These results are being evaluated further in a larger clinical trial. ||||| PURPOSE: This study evaluated the safety and intraocular pressure-lowering efficacy of two concentrations of travoprost (0.0015% and 0.004%) compared with latanoprost 0.005% and timolol 0.5% in patients with open-angle glaucoma or ocular hypertension.
METHODS: Eight hundred one patients with open-angle glaucoma or ocular hypertension were randomly assigned to travoprost 0.0015%, travoprost 0.004%, latanoprost 0.005%, or timolol 0.5%. The efficacy and safety of travoprost (0.0015% and 0.004%) daily was compared with latanoprost daily and timolol twice daily for a period of 12 months.
RESULTS: Travoprost was equal or superior to latanoprost and superior to timolol with mean intraocular pressure over visits and time of day ranging from 17.9 to 19.1 mm Hg (travoprost 0.0015%), 17.7 to 19.1 mm Hg (travoprost 0.004%), 18.5 to 19.2 mm Hg (latanoprost), and 19.4 to 20.3 mm Hg (timolol). For all visits pooled, the mean intraocular pressure at 4 PM for travoprost was 0.7 mm Hg (0.0015%, P =.0502) and 0.8 mm Hg (0.004%, P =.0191) lower than for latanoprost. Travoprost 0.004% was more effective than latanoprost and timolol in reducing intraocular pressure in black patients by up to 2.4 mm Hg (versus latanoprost) and 4.6 mm Hg (versus timolol). Based on a criterion of 30% or greater intraocular pressure reduction from diurnal baseline or intraocular pressure 17 mm Hg or less, travoprost 0.0015% and 0.004% had an overall response to treatment of 49.3% and 54.7%, respectively, compared with 49.6% for latanoprost and 39.0% for timolol. Iris pigmentation change was observed in 10 of 201 of patients (5.0%) receiving travoprost 0.0015%, six of 196 of patients (3.1%) receiving travoprost 0.004%, 10 of 194 of patients (5.2%) receiving latanoprost, and none of the patients receiving timolol (0 of 196). The average ocular hyperemia score was less than 1 on a scale of 0 to 3, indicating that on average patients experienced between none/trace and mild for all treatment groups. There were no serious, unexpected, related adverse events reported for any therapy.
CONCLUSIONS: Travoprost (0.0015% and 0.004%), a highly selective, potent prostaglandin F (FP) receptor agonist, is equal or superior to latanoprost and superior to timolol in lowering intraocular pressure in patients with open-angle glaucoma or ocular hypertension. In addition, travoprost 0.004% is significantly better than either latanoprost or timolol in lowering intraocular pressure in black patients. Travoprost is safe and generally well tolerated in the studied patient population. ||||| OBJECTIVE: To compare the safety and intraocular pressure (IOP)-lowering efficacy of once-daily travoprost (0.0015% and 0.004%) to twice-daily timolol 0.5%.
DESIGN: Prospective, 6-month, randomized, controlled, multicenter, double-masked, phase III study.
PARTICIPANTS: Six hundred five patients with open-angle glaucoma or ocular hypertension.
METHODS: Patients with an 8 AM IOP between 24 to 36 mmHg in at least one eye (the same eye) at two eligibility visits received either travoprost 0.0015%, travoprost 0.004% (dosed every day), or timolol 0.5% (dosed twice daily).
MAIN OUTCOME MEASURES: Mean IOP at 8 AM, 10 AM, and 4 PM in the patient's eye with the higher baseline IOP.
RESULTS: The mean IOP was significantly lower for both concentrations of travoprost compared with timolol. Travoprost was statistically superior to timolol at 9 of 13 visits, with differences in IOP reductions ranging from 0.9 to 1.8 mmHg (0.0015%) and 10 of 13 visits with differences in IOP reductions from 0.9 to 2.4 mmHg (0.004%). Mean IOP changes from baseline ranged from -6.0 to -7.5 mmHg (0.0015%), -6.5 to -8.0 mmHg (0.004%), and -5.2 to -7.0 mmHg for timolol. Hyperemia was experienced at rates of 29.2% (59 of 202) for travoprost 0.0015%, 42.8% (86 of 201) for travoprost 0.004%, and 8.9% (18 of 202) for timolol. Iris pigmentation changes were observed in 1.0% (2 of 200) of patients receiving travoprost 0.004% with no changes noted in the travoprost 0.0015% group or the timolol group. A decrease in pulse and systolic blood pressure was observed in the timolol group. There were no other clinically relevant or statistically significant changes from baseline in ocular signs or laboratory values, and no serious, related, unexpected adverse events were reported for any group.
CONCLUSIONS: Travoprost (0.0015% and 0.004%), dosed once daily in the evening, is statistically superior or equal to timolol 0.5% dosed twice daily at all treatment visits during this 6-month study. IOP reductions of up to 2.0 mmHg greater than timolol were found in the travoprost 0.004% pooled data group. Travoprost is safe and well tolerated in patients with open-angle glaucoma or ocular hypertension. ||||| BACKGROUND: Prostaglandin analogues are effective ocular hypotensive agents and are being used increasingly in the treatment of elevated intraocular pressure (IOP). These agents are typically dosed once daily.
OBJECTIVES: A pilot study was conducted to evaluate the duration of travoprost's IOP-lowering efficacy up to 84 hours after the final dose in patients with open-angle glaucoma. A follow-up study was conducted to compare diurnal IOP control with travoprost and latanoprost over a 44-hour period.
METHODS: In the open label pilot study, patients received 0.004% travoprost in both eyes at 8 pm daily for 2 weeks. After 2 weeks, IOP was measured before administration of the last daily dose, every 4 hours thereafter for 36 hours, and 60 and 84 hours after the last dose, with no additional ocular hypotensive medication given. In the controlled, double-masked, parallel-group, follow-up study, patients were randomized to self-administer 1 drop of the marketed doses of 0.004% travoprost or 0.005% latanoprost in both eyes at 8 pm daily for 2 weeks. At the end of this period, patients returned to the facility at approximately 8 pm for IOP measurement and administration of the final dose of study medication. IOP was then measured at 4-hour intervals for 44 hours after the last dose, with no additional ocular hypotensive medication given.
RESULTS: The pilot study included 21 patients (67% female, 33% male; age range, 35-81 years) with open-angle glaucoma. IOP values were significantly below baseline at all time points up to 84 hours after the final dose of travoprost ( P<0.001). The follow-up study enrolled 35 patients, 1 of whom was excluded for missing data; thus, the intent-to-treat analysis included 34 patients (68% female, 32% male; age range, 36-72 years). At the unmedicated eligibility visit, mean IOP over 24 hours ranged from 21 to 26 mm Hg in each treatment group. After 2 weeks of treatment and 24 hours after the last dose, mean (SD) IOP was 13.1 (2.1) mm Hg (change from eligibility visit, -10.4 [2.7] mm Hg) in the travoprost group and 16.0 (3.1) mm Hg (change from eligibility visit, -7.1 [2.4] mm Hg) in the latanoprost group. The difference in change from baseline was statistically significant between treatment groups (P=0.006). Travoprost lowered IOP significantly at all time points throughout the 44-hour period after the last dose (mean IOP, <or=18 mm Hg; [P<0.001) and was statistically superior to latanoprost at 8 pm before the last dose (P=0.041) and 24 hours after the last dose (P=0.006). Latanoprost showed greater IOP-lowering efficacy compared with travoprost 4 hours after the last dose (P=0.040). IOP reductions were significantly different from zero at all time points with both treatments (P<0.001).
CONCLUSIONS: The results of the pilot study suggest that travoprost produces reductions in IOP that may be sustained for up to 84 hours after dosing. The results of the follow-up study suggest that both prostaglandin analogues significantly lower IOP from baseline in patients with open-angle glaucoma and provide excellent diurnal IOP control throughout a 24-hour period. ||||| PURPOSE: To Internet Advance publication at ajo.com Feb 13, 2003. compare the intraocular pressure (IOP)-lowering effect and safety of latanoprost, bimatoprost, and travoprost in patients with open-angle glaucoma (OAG) or ocular hypertension (OH).
DESIGN: Interventional study.
METHODS: This 12-week, randomized, parallel-group study was conducted at 45 US sites. Previously treated patients with OAG or OH and an IOP > or =23 mm Hg in one or both eyes after washout received either latanoprost 0.005%, bimatoprost 0.03%, or travoprost 0.004% once daily in the evening. At baseline and after 6 and 12 weeks of therapy, masked evaluators measured IOP in triplicate at 8:00 AM, 12 noon, 4:00 PM, and 8:00 PM, and masked investigators graded conjunctival hyperemia before the 8:00 AM IOP measurement. The primary efficacy outcome measure was change between baseline and Week 12 in the 8:00 AM IOP (time of peak drug effect).
RESULTS: In all, 410 of 411 randomized patients were included in intent-to-treat analyses (latanoprost, 136; bimatoprost, 136; travoprost, 138). Baseline mean 8:00 AM IOP levels were similar (P =.772); by week 12, reductions were observed in all 3 groups (P <.001 for each). Adjusted (ANCOVA) reductions in mean IOP at 8:00 AM were similar (P =.128) as were those at 12 noon, 4:00 PM, and 8:00 PM. Fewer latanoprost-treated patients reported ocular adverse events (P <.001, latanoprost vs bimatoprost), fewer reported hyperemia (P =.001, latanoprost vs bimatoprost), and average hyperemia scores were lower at week 12 (P =.001, latanoprost vs bimatoprost).
CONCLUSIONS: Latanoprost, bimatoprost, and travoprost were comparable in their ability to reduce IOP in OAG and OH patients. Latanoprost exhibited greater ocular tolerability. ||||| PURPOSE: To study, with an objective method, inflammation of the anterior segment of the glaucomatous eye after treatment with latanoprost, travoprost and bimatoprost.
MATERIALS AND METHODS: Sixty patients with chronic open-angle glaucoma aged between 38 and 76 years (mean 64.0 +/- 12.2) were randomly assigned to latanoprost 0.005, travoprost 0.004 and bimatoprost 0.03%. The study period lasted 6 months. Intraocular pressure (IOP) was measured every 2 weeks. We studied the intraocular inflammation before and after 3 and 6 months of therapy with an instrument composed of a He-Ne laser beam system, a photomultiplier mounted on a slitlamp microscope and a computer. This flare meter allows objective determination of the flare and the number of cells in the aqueous of the anterior chamber.
RESULTS: At the baseline, IOP was 26.4 +/- 3.6 mm Hg. After 3 months of treatment, mean IOP in the latanoprost group was 17.9 +/- 0.3 mm Hg (p < 0.001) with a mean cellularity of 12.638 +/- 3.284 photons/ms (p < 0.001). The travoprost group had an IOP of 17.2 +/- 0.3 mm Hg (p < 0.001) with a cellularity of 9.719 +/- 1.927 photons/ms (0.001). Finally, IOP in the bimatoprost group was 17.6 +/- 0.5 mm Hg (p < 0.001) with a cellularity of 6.138 +/- 1.475 photons/ms (p < 0.032). After 6 months of treatment, IOP in the latanoprost group was 18.1 +/- 0.3 (p < 0.001), in the travoprost group 17.3 +/- 0.3 (p < 0.001) and in the bimatoprost group 17.7 +/- 0.5 mm Hg (p < 0.001), whereas cellularity was 11.838 +/- 3.218 (p < 0.001), 8.950 +/- 3.692 (p < 0.001) and 7.617 +/- 2.603 photons/ms (p < 0.001), respectively. After 3 months, the travoprost (p < 0.013) and the bimatoprost groups (p < 0.001) had less flare compared with the latanoprost group and this remained so even at 6 months. When we compared the travoprost group with the bimatoprost group, we found significantly less flare at 3 months in the bimatoprost group (p < 0.001) but not at 6 months (p < 0.246).
CONCLUSIONS: The flare meter analysis shows that the eyes treated with bimatoprost and travoprost have a less significantly broken blood-aqueous barrier and their anterior chamber is also significantly less inflamed. ||||| OBJECTIVES: To investigate the effects of prostaglandin analogues on the blood-aqueous barrier and to evaluate the occurrence of cystoid macular edema in aphakic or pseudophakic patients with glaucoma.
METHODS: In this randomized, masked-observer, 6-month clinical trial, patients with primary open-angle, pseudophakic, or aphakic glaucoma were treated once daily with bimatoprost (n = 16), latanoprost (n = 15), or travoprost (n = 17) or twice daily with unoprostone (n = 16) or lubricant drops (control group) (n = 16). Blood-aqueous barrier status, which was assessed using a laser flare meter; intraocular pressure; the occurrence of angiographic cystoid macular edema; and conjunctival hyperemia were evaluated.
RESULTS: Mean flare values were significantly higher in the bimatoprost, latanoprost, and travoprost groups throughout follow-up (P < .02). Four latanoprost-treated eyes, 1 bimatoprost-treated eye, and 1 travoprost-treated eye developed cystoid macular edema; all cases resolved after discontinuation of the prostaglandin analogue and treatment with topical diclofenac sodium. Mean intraocular pressure reductions after 6 months were higher for the latanoprost (26%), bimatoprost (28%), and travoprost (29%) groups than for the control (3%) and unoprostone (14%) groups (P< .05). Bimatoprost induced significantly higher hyperemia scores than latanoprost, unoprostone, and placebo (P< .01).
CONCLUSION: Bimatoprost, latanoprost, and travoprost use may lead to disruption of the blood-aqueous barrier in patients with pseudophakia and aphakia. ||||| PURPOSE: To evaluate the IOP-lowering efficacy of bimatoprost and travoprost for the treatment of glaucoma and ocular hypertension.
METHODS: Randomized, investigator-masked, parallel-group clinical trial. After completing a washout from all glaucoma medications, patients (n=26) were randomized to bimatoprost or travoprost for 6 months. Visits were at baseline, week 1, and months 1, 3, and 6. IOP was measured at 9 am at each visit and also at 1 and 4 pm at baseline and months 3 and 6.
RESULTS: At the baseline visit, there were no significant between-group differences in IOP at 9 am, 1 pm, or 4 pm (P> or =.776). After 6 months of therapy, both medications provided significant mean reductions from baseline IOP at every time point (P< or =.007). Mean IOP reductions ranged from 7.4 mm Hg to 8.8 mm Hg (34% to 36%) with bimatoprost and from 4.6 mm Hg to 7.2 mm Hg (19% to 29%) with travoprost (P> or =.057) after 6 months of medication. At the final study visit, more patients achieved low target pressures with bimatoprost than with travoprost at each time point. Both study medications were well tolerated and ocular redness was the most commonly reported adverse event in both treatment groups.
CONCLUSION: Although both bimatoprost and travoprost effectively lowered IOP in patients with glaucoma or ocular hypertension, bimatoprost provided larger mean IOP reductions than travoprost. More patients achieved low target pressures with bimatoprost than with travoprost. The between-group differences were not statistically significant due to the small sample size. These findings are being further evaluated in an ongoing multicenter clinical trial. ||||| PURPOSE: To evaluate the intraocular pressure-lowering efficacy and safety of travoprost 0.0015% and 0.004%, dosed daily in the evening compared with vehicle, in patients with open-angle glaucoma or ocular hypertension, whose intraocular pressure was not adequately controlled on timolol 0.5% twice daily (twice daily).
METHODS: Subjects who qualified at screening began a run-in period dosing timolol twice daily for 3 weeks. If the subjects had an intraocular pressure of 24 to 36 mm Hg at 8 AM and 21 to 36 mm Hg at 10 AM and 4 pm in at least one eye on timolol, they were randomized to one of two concentrations of travoprost (0.0015% or 0.004%) or vehicle solution every day and were followed for 6 months. Four hundred twenty-six subjects were randomized. The mean intraocular pressure at 8 AM, 10 AM, and 4 PM in the patient's eye with the higher intraocular pressure was used for the analysis.
RESULTS: Mean baseline values (25 mm Hg) for subjects at eligibility (while maintained on timolol) were not significantly different (P <.0001) among the treatment groups. The intraocular pressure was lowered an additional -5.7 to -7.2 mm Hg and -5.1 to -6.7 mm Hg in the travoprost 0.004% and 0.0015% concentrations, respectively. These changes were significantly (P < or =.0001) different from the vehicle group (-1.3 to -2.8 mm Hg). The intraocular pressure range on treatment at all visit times over the 6-month treatment period ranged from 17.9 to 19.2 mm Hg for travoprost 0.004% and 18.3 to 20.1 mm Hg for travoprost 0.0015% compared with 22.4 to 24.1 mm Hg for vehicle. Average hyperemia scores ranged from trace to mild (mean 0.5 on a scale of 0 = none/trace; 1= mild; 2 = moderate; 3 = severe) for all treatment groups. No iris pigmentation changes were observed in any patient during this study. There were no clinically or statistically significant changes from baseline in visual acuity, ocular cells and flare, fundus parameter, cup-to-disk ratio and visual field between the treatment groups. There were no serious adverse events reported for any treatment group.
CONCLUSIONS: Travoprost produced clinically relevant and statistically significant additional intraocular pressure reductions from baseline when used adjunctively with timolol in subjects with open-angle glaucoma or ocular hypertension. | [
{
"source_pmid": "15990081",
"source_text": "PURPOSE: To compare the safety and intraocular pressure (IOP)-lowering efficacy of travoprost 0.004%/timolol 0.5% fixed combination ophthalmic solution (Trav/Tim) to its components travoprost 0.004% ophthalmic solution, TRAVATAN, (Trav) and timolol 0.5% ophthalmi... |
27763569 | This meta-analysis demonstrates that the T allele in the LIPC rs493258 polymorphism was significantly associated with the risk of any and late AMD. The associations of the locus with early and late AMD risk in various populations need further exploration. | Neovascular age-related macular degeneration (nAMD) and polypoidal choroidal vasculopathy (PCV) are both major serosanguinous maculopathies among the Asian elderly. They are similar in phenotype. Genetic variants in high-density lipoprotein (HDL) pathway were discovered to be associated with AMD in two genome-wide association studies. In this study with a Chinese Han cohort, we investigated the impacts of these genetic variants on nAMD and PCV separately. The missense coding variants and previously identified variants at LIPC, ABCA1, CETP, LPL and FADS1 loci were genotyped in 157 nAMD patients, 250 PCV patients and 204 controls without any macular abnormality. The known variants in CFH, ARMS2 and near HTRA1 were also genotyped. Fasting serum cholesterol levels were determined. The variants in CFH, ARMS2 and near HTRA1 were strongly associated with both PCV (P < 10(-6), 10(-7) and 10(-7) respectively) and nAMD (P < 10(-6), 10(-16) and 10(-17) respectively). None of the studied HDL-related variants were significantly associated with nAMD. A missense variant in CETP, rs5882, was significantly associated with PCV (P = 2.73 × 10(-4)). The rs5882 GG genotype had a 3.53-fold (95% CI: 1.93-6.45) increased risk for PCV, and conferred a significantly lower serum HDL-cholesterol level for PCV patients than the AA genotype (P = 0.048). These results suggest the need to separate PCV from nAMD in association studies especially with Asian cohorts, and that the HDL pathway may involve in the pathogenesis of PCV and nAMD differently. ||||| We executed a genome-wide association scan for age-related macular degeneration (AMD) in 2,157 cases and 1,150 controls. Our results validate AMD susceptibility loci near CFH (P < 10(-75)), ARMS2 (P < 10(-59)), C2/CFB (P < 10(-20)), C3 (P < 10(-9)), and CFI (P < 10(-6)). We compared our top findings with the Tufts/Massachusetts General Hospital genome-wide association study of advanced AMD (821 cases, 1,709 controls) and genotyped 30 promising markers in additional individuals (up to 7,749 cases and 4,625 controls). With these data, we identified a susceptibility locus near TIMP3 (overall P = 1.1 x 10(-11)), a metalloproteinase involved in degradation of the extracellular matrix and previously implicated in early-onset maculopathy. In addition, our data revealed strong association signals with alleles at two loci (LIPC, P = 1.3 x 10(-7); CETP, P = 7.4 x 10(-7)) that were previously associated with high-density lipoprotein cholesterol (HDL-c) levels in blood. Consistent with the hypothesis that HDL metabolism is associated with AMD pathogenesis, we also observed association with AMD of HDL-c-associated alleles near LPL (P = 3.0 x 10(-3)) and ABCA1 (P = 5.6 x 10(-4)). Multilocus analysis including all susceptibility loci showed that 329 of 331 individuals (99%) with the highest-risk genotypes were cases, and 85% of these had advanced AMD. Our studies extend the catalog of AMD associated loci, help identify individuals at high risk of disease, and provide clues about underlying cellular pathways that should eventually lead to new therapies. ||||| PURPOSE: To determine whether there is an association between hepatic lipase (LIPC) and age-related macular degeneration (AMD) in two independent Caucasian cohorts.
METHODS: A discovery cohort of 1626 patients with advanced AMD and 859 normal controls and a replication cohort of 2159 cases and 1150 controls were genotyped for two single-nucleotide polymorphisms (SNPs) in the promoter region of LIPC. The associations between the SNPs and AMD were examined by χ(2) tests.
RESULTS: In the discovery cohort, rs493258 and rs10468017 were both associated with advanced AMD (P=9.63E-3 and P=0.048, respectively). The association was corroborated in the replication cohort (P=4.48E-03 for rs493258 and P=0.015 for rs10468017). Combined analysis resulted in even more significant associations (P=1.21E-04 for rs493258 and P=1.67E-03 for rs10468017).
CONCLUSION: The LIPC promoter variants rs493258 and rs10468017 were associated with advanced AMD in two independent Caucasian populations, confirming that LIPC polymorphisms may be a genetic risk factor for AMD in the Caucasian population. ||||| Advanced age-related macular degeneration (AMD) is the leading cause of late onset blindness. We present results of a genome-wide association study of 979 advanced AMD cases and 1,709 controls using the Affymetrix 6.0 platform with replication in seven additional cohorts (totaling 5,789 unrelated cases and 4,234 unrelated controls). We also present a comprehensive analysis of copy-number variations and polymorphisms for AMD. Our discovery data implicated the association between AMD and a variant in the hepatic lipase gene (LIPC) in the high-density lipoprotein cholesterol (HDL) pathway (discovery P = 4.53e-05 for rs493258). Our LIPC association was strongest for a functional promoter variant, rs10468017, (P = 1.34e-08), that influences LIPC expression and serum HDL levels with a protective effect of the minor T allele (HDL increasing) for advanced wet and dry AMD. The association we found with LIPC was corroborated by the Michigan/Penn/Mayo genome-wide association study; the locus near the tissue inhibitor of metalloproteinase 3 was corroborated by our replication cohort for rs9621532 with P = 3.71e-09. We observed weaker associations with other HDL loci (ABCA1, P = 9.73e-04; cholesterylester transfer protein, P = 1.41e-03; FADS1-3, P = 2.69e-02). Based on a lack of consistent association between HDL increasing alleles and AMD risk, the LIPC association may not be the result of an effect on HDL levels, but it could represent a pleiotropic effect of the same functional component. Results implicate different biologic pathways than previously reported and provide new avenues for prevention and treatment of AMD. ||||| Age-related macular degeneration (AMD) is a leading cause of visual loss in Western populations. Susceptibility is influenced by age, environmental and genetic factors. Known genetic risk loci do not account for all the heritability. We therefore carried out a genome-wide association study of AMD in the UK population with 893 cases of advanced AMD and 2199 controls. This showed an association with the well-established AMD risk loci ARMS2 (age-related maculopathy susceptibility 2)-HTRA1 (HtrA serine peptidase 1) (P =2.7 × 10(-72)), CFH (complement factor H) (P =2.3 × 10(-47)), C2 (complement component 2)-CFB (complement factor B) (P =5.2 × 10(-9)), C3 (complement component 3) (P =2.2 × 10(-3)) and CFI (P =3.6 × 10(-3)) and with more recently reported risk loci at VEGFA (P =1.2 × 10(-3)) and LIPC (hepatic lipase) (P =0.04). Using a replication sample of 1411 advanced AMD cases and 1431 examined controls, we confirmed a novel association between AMD and single-nucleotide polymorphisms on chromosome 6p21.3 at TNXB (tenascin XB)-FKBPL (FK506 binding protein like) [rs12153855/rs9391734; discovery P =4.3 × 10(-7), replication P =3.0 × 10(-4), combined P =1.3 × 10(-9), odds ratio (OR) = 1.4, 95% confidence interval (CI) = 1.3-1.6] and the neighbouring gene NOTCH4 (Notch 4) (rs2071277; discovery P =3.2 × 10(-8), replication P =3.8 × 10(-5), combined P =2.0 × 10(-11), OR = 1.3, 95% CI = 1.2-1.4). These associations remained significant in conditional analyses which included the adjacent C2-CFB locus. TNXB, FKBPL and NOTCH4 are all plausible AMD susceptibility genes, but further research will be needed to identify the causal variants and determine whether any of these genes are involved in the pathogenesis of AMD. ||||| BACKGROUND: Several genes implicated in high-density lipoprotein (HDL) metabolism have been reported to be associated with age-related macular degeneration (AMD). Furthermore, HDL transport the two carotenoids, lutein and zeaxanthin, which are highly suspected to play a key-role in the protection against AMD. The objective is to confirm the associations of HDL-related loci with AMD and to assess their associations with plasma lutein and zeaxanthin concentrations.
METHODS: Alienor study is a prospective population-based study on nutrition and age-related eye diseases performed in 963 elderly residents of Bordeaux, France. AMD was graded according to the international classification, from non-mydriatic colour retinal photographs. Plasma lutein and zeaxanthin were determined by normal-phase high-performance liquid chromatography. The following polymorphisms were studied: rs493258 and rs10468017 (LIPC), rs3764261 (CETP), rs12678919 (LPL) and rs1883025 (ABCA1).
RESULTS: After multivariate adjustment, the TT genotype of the LIPC rs493258 variant was significantly associated with a reduced risk for early and late AMD (OR=0.64, 95%CI: 0.41-0.99; p=0.049 and OR=0.26, 95%CI: 0.08-0.85; p=0.03, respectively), and with higher plasma zeaxanthin concentrations (p=0.03), while plasma lipids were not significantly different according to this SNP. Besides, the LPL variant was associated with early AMD (OR=0.67, 95%CI: 0.45-1.00; p=0.05) and both with plasma lipids and plasma lutein (p=0.047). Associations of LIPC rs10468017, CETP and ABCA1 polymorphisms with AMD did not reach statistical significance.
CONCLUSION: These findings suggest that LIPC and LPL genes could both modify the risk for AMD and the metabolism of lutein and zeaxanthin. ||||| PURPOSE: To assess whether established and newly reported genetic variants, independent of known lifestyle factors, are associated with the risk of age-related macular degeneration (AMD) among women participating in the Women's Health Initiative Sight Exam (WHI-SE) Genetic Ancillary Study.
DESIGN: Multicenter case-control study.
METHODS: One hundred and forty-six women with intermediate and late stages of AMD and 1269 subjects without AMD underwent ocular examinations and fundus photography to determine stage of AMD. Fourteen polymorphisms at or near 11 genes, including previously confirmed genes CFH, ARMS2/HTRA1, C2, C3, and CFI; recently reported AMD genes in the high-density lipoprotein cholesterol (HDL) pathway LIPC, ABCA1, CETP, and LPL; TIMP3/SYN3, a known ocular gene recently linked with AMD; and APOE, were assessed using logistic regression analysis.
RESULTS: After adjustment for demographic, behavioral, and other genetic factors, a protective effect was detected among TT carriers compared with non-carriers for the HDL pathway gene, LIPC rs493258, for intermediate and late AMD (OR [95% confidence interval]: 0.3 [0.2-0.7], P = .003). Variants in CFH rs1410996, ARMS2/HTRA1 A69S, and C3 R102G were significantly associated with an increased risk of AMD. Individuals with the homozygous CFI rs10033900 TT genotype had a 2.9 [1.2-7.2]-fold increased risk, and those with the CFH Y402H GG genotype had a 2.2 [1.0-4.8]-fold higher risk of developing AMD compared with non-carriers. APOE4 carriers may have a reduced risk of intermediate/late AMD (OR = 0.5 [0.3-0.9], P = .015. Suggestive associations were seen between AMD and the HDL pathway genes CETP and LPL.
CONCLUSION: In this unique national cohort of women, we found associations with established AMD-related genetic factors and the recently reported LIPC gene in the HDL pathway. These findings may help develop novel therapeutic targets to treat or delay the onset of the disease. | [
{
"source_pmid": "23274582",
"source_text": "Neovascular age-related macular degeneration (nAMD) and polypoidal choroidal vasculopathy (PCV) are both major serosanguinous maculopathies among the Asian elderly. They are similar in phenotype. Genetic variants in high-density lipoprotein (HDL) pathway were dis... |
29069095 | CONCLUSIONS: The findings of this meta-analysis indicate that individuals with hypothyroidism have an increased risk of developing POAG. | PURPOSE: To determine if hypothyroidism is associated with an increased risk of glaucoma using a large cohort of patients.
DESIGN: Nested case-control study.
PARTICIPANTS: Patients seen at the Veterans Affairs Medical Center in Birmingham, Alabama with newly diagnosed glaucoma between 1997 and 2001 were selected (n = 590) and age-matched to nonglaucoma controls (n = 5897).
METHODS: Patient information was extracted from the Birmingham Veterans Affairs Medical Center data files containing demographic, clinical, and medication information. An index date was assigned to the glaucoma subjects corresponding to the time of diagnosis. Patients who had a glaucoma diagnosis before the observation period of the study were excluded. Ten controls were randomly selected for each patient and matched on age (+/-1 year) and an encounter on or before the index date of the matched case.
MAIN OUTCOME MEASURES: Odds ratios (ORs) for the association between the prior diagnosis of hypothyroidism and the risk of developing glaucoma with adjustment for the presence of diabetes, lipid metabolism disorders, hypertension, cardiovascular disease, cerebrovascular disease, arterial disease, and migraines.
RESULTS: After adjustment for the other potential risk factors, patients were significantly more likely to have prior hypothyroidism than controls (OR, 1.40; 95% confidence interval, 1.01-1.97).
CONCLUSIONS: Our study has demonstrated a significantly greater risk of subjects with a preexisting diagnosis of hypothyroidism developing glaucoma, compared with controls, in a large Veterans Affairs Medical Center population. ||||| PURPOSE: To investigate the risk factors for primary open-angle glaucoma (POAG) in the Namil study population.
METHODS: A cross-sectional, population-based epidemiological study of residents aged ≥40 years from Namil-myon, South Korea, was conducted. Fifty-five subjects with POAG and 1,409 controls were enrolled in this study. Univariate and multivariate logistic regression analyses were performed to identify ocular and systemic factors associated with POAG.
RESULTS: Multivariate logistic regression analysis demonstrated that older age, a history of thyroid disease and higher IOP were associated with an increased risk of POAG. Subgroup analysis showed that older age (OR 1.033, 95 % CI 1.003-1.063 per year), a history of thyroid disease (OR 7.373, 95 % CI 1.407-38.636) and higher IOP (OR 1.132, 95 % CI 1.011-1.268 per mmHg) were risk factors for normal tension glaucoma (NTG, POAG with IOP ≤21 mmHg).
CONCLUSIONS: In the Namil study, higher IOP, older age and a history of thyroid disease were significant risk factors for POAG. ||||| OBJECTIVE: To test if there is an association between hypothyroidism and primary open-angle glaucoma (POAG) and the utility of routine study of thyroid function in these patients.
METHODS: The study was conducted in a case-control fashion. Seventy-five consecutive patients with a previous diagnosis of POAG and 75 control patients were prospectively evaluated for hypothyroidism. The levels of thyroid-stimulating hormone and free thyroxin were measured.
RESULTS: Hypothyroidism was revealed in only 2 patients with previous diagnosis of POAG (2.67%) and 3 patients of the control group (4%).
CONCLUSIONS: As we have not been able to demonstrate the previously reported relationship between hypothyroidism and POAG, we cannot recommend the systematic screening for hypothyroidism in patients with POAG. ||||| OBJECTIVE: To investigate the risk of open-angle glaucoma (OAG) after a diagnosis of hypothyroidism.
DESIGN: A retrospective, population-based follow-up study using an administrative database.
PARTICIPANTS: The study group comprised 257 hypothyroidism patients. The comparison group included 2056 subjects.
METHODS: Data were retrospectively collected from the Taiwan Longitudinal Health Insurance Database. The study cohort comprised patients aged ≥ 60 who received a first diagnosis of hypothyroidism (International Classification of Diseases, Ninth Revision, Clinical Modification code 244.9) from 1997 to 2001 (n = 257). The comparison cohort consisted of randomly selected patients without hypothyroidism who were aged ≥ 60 and had no diagnosis of glaucoma before 2001 (8 for every OAG patient; n = 2056). Each sampled patient was tracked for 5 years from their index visit. Cox proportional hazard regressions were used to compute the 5-year OAG-free survival rate, after adjusting for possible confounding factors.
MAIN OUTCOME MEASURES: The risk of developing OAG during the 5-year follow-up period.
RESULTS: Open-angle glaucoma developed in 7.4% of patients with hypothyroidism and 3.8% of patients in the comparison cohort during the follow-up period. Hypothyroid patients had a significantly lower 5-year OAG-free survival rate than patients in the comparison cohort. After adjusting for patients' age, gender, monthly income, urbanization level, and comorbid medical disorders, hypothyroidism patients were found to have a 1.78-fold (95% confidence interval [CI], 1.04-3.06) greater risk of developing OAG than the comparison cohort. This association remained significant in untreated hypothyroidism patients (adjusted hazard ratio [HR], 2.37; 95% CI, 1.10-5.09) and became statistically nonsignificant in patients treated with levothyroxine (adjusted HR, 1.73; 95% CI, 0.89-3.38).
CONCLUSIONS: Hypothyroid patients had a significantly increased risk of OAG development during the 5-year follow-up period. Levothyroxine seemed to be protective. ||||| OBJECTIVE: To determine the prevalence of selected comorbidities in patients with open-angle glaucoma (OAG) and whether these comorbidities are more prevalent among individuals with OAG than those without OAG.
DESIGN: A retrospective, nationwide, case-control study using an administrative database.
PARTICIPANTS: The study group comprised 76,673 OAG patients. The comparison group comprised 230,019 subjects matched to the study cohort.
METHODS: Data were collected retrospectively from the Taiwan National Health Insurance Research Database. The study cohort comprised all patients with a diagnosis of OAG (International Classification of Diseases, 9th Revision, Clinical Modification codes 365.1-365.11) in 2005 (n = 76,673). The comparison cohort comprised randomly selected patients (3 for every 1 OAG patient; n = 230,019) matched with the study group in terms of age, gender, urbanization level, and monthly income. In total, 31 medical comorbidities were selected based mainly on the Elixhauser Comorbidity Index. Separate conditional logistic regression analyses were used to estimate the adjusted odds ratio for each of the medical comorbidities between patients with and without OAG.
MAIN OUTCOME MEASURES: The prevalences of selected comorbidities.
RESULTS: More than half (50.5%) of the OAG patients had hypertension, and more than 30% had hyperlipidemia or diabetes (30.5% and 30.2%, respectively). The prevalences of 28 of 31 comorbidities were significantly higher for OAG patients than subjects without glaucoma after adjusting for age, gender, urbanization level, and monthly income. The adjusted odds ratio was more than 1.50 for hypertension, hyperlipidemia, systemic lupus erythematosus, diabetes, hypothyroidism, fluid and electrolyte disorders, depression, and psychosis. Among the studied comorbidities, the prevalence difference of the OAG group minus the control group was 3% or higher for hypertension, hyperlipidemia, stroke, diabetes, liver disease, and peptic ulcer.
CONCLUSIONS: Open-angle glaucoma patients are significantly more likely to have comorbidities, many of which can be life threatening or can affect the quality of life appreciably.
FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussedin this article ||||| BACKGROUND: Despite many reports linking allergic rhinitis (AR) to problems of the eye, the relationship between AR and open-angle glaucoma (OAG) has not been studied. The purpose of this epidemiology study was to provide an estimation of the association of OAG with AR by using a population-based data set in Taiwan.
METHODS: We retrieved our study sample for this case-control study from the Longitudinal Health Insurance Database 2000. We extracted 7063 subjects with OAG as cases and 21,189 matched controls (three controls per case). We used conditional logistic regression analyses to calculate the odds ratio (OR) and corresponding 95% confidence interval (CI) to describe the association between OAG and having previously been diagnosed with AR.
RESULTS: A chi-squared test showed that there was a significant difference in the prevalence of prior AR between cases and controls (28.8% versus 22.3%; p < 0.001). A conditional logistic regression analysis suggested that the OR of having previously been diagnosed with AR for cases was 1.40 (95% CI, 1.31∼1.48; p < 0.001) compared with controls after adjusting for monthly income, geographic region, urbanization level, hypertension, diabetes, asthma, coronary heart disease, hyperlipidemia, and hypothyroidism. It also revealed that OAG was consistently and significantly associated with prior AR across all age groups. In particular, subjects aged 50∼59 years had the highest OR for prior AR among cases compared with controls (OR, 1.77; 95% CI, 1.53∼2.06; p < 0.001).
CONCLUSION: This outcome research found that there was an association between AR and OAG. ||||| PURPOSE: To investigate the association between hypothyroidism and glaucomatous disease.
METHODS: This cross-sectional study included all subjects above the age of 40 years from two nationwide surveys: the 2008 National Health Interview Survey (NHIS) as well as the 2007 and 2008 National Health and Nutrition Examination Survey (NHANES). The presence or absence of glaucoma, thyroid disease and other demographic and health-related information including comorbidities was ascertained via interview. Blood samples were collected from NHANES subjects and analyzed for thyrotropin (TSH).
RESULTS: A total of 13,599 and 3,839 NHIS and NHANES participants respectively were analyzed to assess for a possible relationship between self-reported glaucoma, and self-reported hypothyroidism as well as self-reported thyroid disease. The unadjusted odds ratio (OR) for NHIS showed a significant association between self-reported glaucoma and self-reported hypothyroidism (OR 1.46, 95% confidence interval [CI] 1.07-1.99). Multivariate logistic regression analysis adjusted for age, gender, race, comorbidities, and health-related behavior, however, showed no association between self-reported glaucoma and hypothyroidism or thyroid disease in both surveys (OR 1.60, 95%CI 0.87-2.95 for NHIS; OR 1.05, 95%CI 0.59-1.88 for NHANES).
CONCLUSION: A previously reported association between hypothyroidism and glaucomatous disease was not confirmed in two large U.S. health survey populations. While such an association was noted in the univariate analysis for the NHIS survey, such a relationship was not found in the multivariate analysis after adjustment for potential confounding variables. ||||| PURPOSE: To evaluate the association between platelet function and disc hemorrhage in patients with normal-tension glaucoma.
DESIGN: Prospective, cross-sectional study.
METHODS: Study involved a total of 315 subjects, including patients with normal-tension glaucoma and disc hemorrhage (n = 120), patients with normal-tension glaucoma without disc hemorrhage (n = 75), and healthy individuals (control group, n = 120). A detailed eye examination including visual field testing, color disc photography, optical coherence tomography scanning, and measurement of collagen/epinephrine closure time using a platelet function analyzer were performed for all subjects.
RESULTS: The collagen/epinephrine closure time (s) as measured by the platelet function analyzer was approximately 14%-24% longer in the normal-tension glaucoma and disc hemorrhage group compared with the other groups (141.92 ± 53.44 [with normal-tension glaucoma and disc hemorrhage] vs 124.60 ± 46.72 [with normal-tension glaucoma without disc hemorrhage] vs 114.84 ± 34.84 [healthy individuals], 1-way analysis of variance test, P < .001). The activated partial thromboplastin time (s) value of the normal-tension glaucoma with disc hemorrhage group was also higher than the control group. Stepwise multiple logistic regression analysis revealed that only a longer collagen/epinephrine closure time (OR adjusted for age, sex, prothrombin time, activated partial thromboplastin time, diabetes mellitus, hypertension, hypotension, heart disease, hypothyroidism, migraine, stroke, hypercholesterolemia: 2.94; 95% CI: 1.40-6.17) was independently associated with disc hemorrhage. A similar trend was observed when platelet function was compared among the 3 groups with respect to age.
CONCLUSIONS: Our results suggest that platelet function is significantly associated with disc hemorrhage in patients with normal-tension glaucoma. Delayed absorption resulted from prolonged bleeding due to delayed platelet aggregation may have an effect on the detectability of disc hemorrhage in patients with normal-tension glaucoma. ||||| PURPOSE: To assess whether thyroid disease is independently associated with open-angle glaucoma (OAG), using history of thyroid disease and current thyroxine use.
METHODS: The Blue Mountains Eye Study examined 3654 persons, aged 49-97 years. Interviewers collected self-reported history of diagnosis and treatment for thyroid disease. Eye examinations included applanation tonometry, stereoscopic optic disc photography and automated perimetry. OAG was diagnosed from the presence of matching typical glaucomatous field changes and optic disc cupping, independent of intraocular pressure. Associations between thyroid disease (history and treatment) and OAG were assessed in a multivariate model.
RESULTS: Of 324 participants (8.9%) reporting history of thyroid disease, 147 (4.0%) were currently using thyroxine. Although we could not accurately categorize the thyroid disorder for all cases, current use of thyroxine suggests a prior hypothyroid state. All thyroid disease subgroups affected women more frequently than men, P=0.001. OAG was diagnosed in 108 subjects (3.0%) and was more frequent in those reporting past thyroid disease (4.6 vs 2.8%). This relationship was not statistically significant after adjusting for potential confounders, multivariate odds ratio (OR) 1.6; 95% confidence interval (95% CI) 0.9-2.9. OAG was significantly more frequent, however, in subjects reporting current thyroxine use (6.8 vs 2.8%), multivariate OR 2.1; 95% CI 1.0-4.4, or history of thyroid surgery (6.5 vs 2.8%), multivariate OR 2.5; 95% CI 1.0-6.2.
CONCLUSIONS: This population-based study suggests that thyroid disease, indicated by current thyroxine use or past thyroid surgery, could be independently related to OAG. ||||| PURPOSE: There have been conflicting reports pertaining to the association between hypothyroidism and open-angle glaucoma (OAG). The purpose of this study was to assess the hypothesized association between preexisting hypothyroidism and development of OAG in a population-based setting.
DESIGN: Case-control study.
PARTICIPANTS: The study population and controls were taken from all patients in a large US managed care database aged >or=60 years with 4 years of continuous eligibility dating from January 1, 2001, through December 31, 2004.
METHODS: A total of 4728 newly diagnosed OAG patients were matched with 14 184 controls (3:1 matching) based on age and gender.
MAIN OUTCOME MEASURES: Conditional logistic regression was used to assess the relationship between hypothyroidism and OAG while controlling for various risk factors (ischemic heart disease, cerebrovascular disease, hyperlipidemia, hypertension, arterial disease, diabetes, and migraines).
RESULTS: Based on a diagnosis of hypothyroidism or use of a thyroid replacement therapy, prior hypothyroidism was found in 815 (17.2%) OAG subjects and in 2498 (17.6%) control subjects. After adjusting for the specified risk factors, patients with OAG were not found to be associated with a prior hypothyroid diagnosis when compared with control subjects (odds ratio, 0.93; 95% confidence interval, 0.85-1.01).
CONCLUSIONS: An association between prior hypothyroidism and OAG development was not found. The large proportion of patients receiving thyroid replacement therapy may have negated any OAG-related consequences of hypothyroidism. ||||| PURPOSE: To test the hypothesis that there is an association between hypothyroidism and primary open-angle glaucoma.
METHODS: The study was conducted in a case-control fashion. Sixty-four patients with primary open-angle glaucoma were evaluated for hypothyroidism by history and by undergoing a thyroid-stimulating hormone immunoradiometric assay. Sixty-four control subjects from the general eye clinic were evaluated in the same manner. Patients found to have elevated thyroid-stimulating hormone immunoradiometric assay were evaluated by an endocrinologist for hypothyroidism.
RESULTS: Of the primary open-angle glaucoma group, 23.4% had hypothyroidism. A diagnosis was made previously in 12.5% patients, and 10.9% were newly diagnosed. Of the control subjects, 4.7% had hypothyroidism. A diagnosis had been made previously in 1.6% of the control subjects, and 3.1% were newly diagnosed. The difference between the two groups was found to be statistically significant.
CONCLUSION: A statistically significant association between hypothyroidism and primary open-angle glaucoma is demonstrated. There is a large group (10.9%) of patients with primary open-angle glaucoma with undiagnosed hypothyroidism. | [
{
"source_pmid": "15350317",
"source_text": "PURPOSE: To determine if hypothyroidism is associated with an increased risk of glaucoma using a large cohort of patients.\nDESIGN: Nested case-control study.\nPARTICIPANTS: Patients seen at the Veterans Affairs Medical Center in Birmingham, Alabama with newly di... |
31775144 | CONCLUSIONS: Inferior vision outcomes were observed in clinical practice compared with RCTs and might be partly attributable to administration of fewer anti-VEGF injections. Physicians should be aware that early and appropriate anti-VEGF treatment regimens are necessary to obtain the results reported in RCTs and help prevent irreversible vision loss in DME patients. | BACKGROUND: The relative efficacy and safety of intravitreous aflibercept, bevacizumab, and ranibizumab in the treatment of diabetic macular edema are unknown.
METHODS: At 89 clinical sites, we randomly assigned 660 adults (mean age, 61±10 years) with diabetic macular edema involving the macular center to receive intravitreous aflibercept at a dose of 2.0 mg (224 participants), bevacizumab at a dose of 1.25 mg (218 participants), or ranibizumab at a dose of 0.3 mg (218 participants). The study drugs were administered as often as every 4 weeks, according to a protocol-specified algorithm. The primary outcome was the mean change in visual acuity at 1 year.
RESULTS: From baseline to 1 year, the mean visual-acuity letter score (range, 0 to 100, with higher scores indicating better visual acuity; a score of 85 is approximately 20/20) improved by 13.3 with aflibercept, by 9.7 with bevacizumab, and by 11.2 with ranibizumab. Although the improvement was greater with aflibercept than with the other two drugs (P<0.001 for aflibercept vs. bevacizumab and P=0.03 for aflibercept vs. ranibizumab), it was not clinically meaningful, because the difference was driven by the eyes with worse visual acuity at baseline (P<0.001 for interaction). When the initial visual-acuity letter score was 78 to 69 (equivalent to approximately 20/32 to 20/40) (51% of participants), the mean improvement was 8.0 with aflibercept, 7.5 with bevacizumab, and 8.3 with ranibizumab (P>0.50 for each pairwise comparison). When the initial letter score was less than 69 (approximately 20/50 or worse), the mean improvement was 18.9 with aflibercept, 11.8 with bevacizumab, and 14.2 with ranibizumab (P<0.001 for aflibercept vs. bevacizumab, P=0.003 for aflibercept vs. ranibizumab, and P=0.21 for ranibizumab vs. bevacizumab). There were no significant differences among the study groups in the rates of serious adverse events (P=0.40), hospitalization (P=0.51), death (P=0.72), or major cardiovascular events (P=0.56).
CONCLUSIONS: Intravitreous aflibercept, bevacizumab, or ranibizumab improved vision in eyes with center-involved diabetic macular edema, but the relative effect depended on baseline visual acuity. When the initial visual-acuity loss was mild, there were no apparent differences, on average, among study groups. At worse levels of initial visual acuity, aflibercept was more effective at improving vision. (Funded by the National Institutes of Health; ClinicalTrials.gov number, NCT01627249.). ||||| PURPOSE: To report 36-month outcomes of RIDE (NCT00473382) and RISE (NCT00473330), trials of ranibizumab in diabetic macular edema (DME).
DESIGN: Phase III, randomized, multicenter, double-masked, 3-year trials, sham injection-controlled for 2 years.
PARTICIPANTS: Adults with DME (n=759), baseline best-corrected visual acuity (BCVA) 20/40 to 20/320 Snellen equivalent, and central foveal thickness (CFT) ≥ 275 μm on optical coherence tomography.
METHODS: Patients were randomized equally (1 eye per patient) to monthly 0.5 mg or 0.3 mg ranibizumab or sham injection. In the third year, sham patients, while still masked, were eligible to cross over to monthly 0.5 mg ranibizumab. Macular laser was available to all patients starting at month 3; panretinal laser was available as necessary.
MAIN OUTCOME MEASURES: The proportion of patients gaining ≥15 Early Treatment Diabetic Retinopathy Study letters in BCVA from baseline at month 24.
RESULTS: Visual acuity (VA) outcomes seen at month 24 in ranibizumab groups were consistent through month 36; the proportions of patients who gained ≥15 letters from baseline at month 36 in the sham/0.5 mg, 0.3 mg, and 0.5 mg ranibizumab groups were 19.2%, 36.8%, and 40.2%, respectively, in RIDE and 22.0%, 51.2%, and 41.6%, respectively, in RISE. In the ranibizumab arms, reductions in CFT seen at 24 months were, on average, sustained through month 36. After crossover to 1 year of treatment with ranibizumab, average VA gains in the sham/0.5 mg group were lower compared with gains seen in the ranibizumab patients after 1 year of treatment (2.8 vs. 10.6 and 11.1 letters). Per-injection rates of endophthalmitis remained low over time (∼0.06% per injection). The incidence of serious adverse events potentially related to systemic vascular endothelial growth factor inhibition was 19.7% in patients who received 0.5 mg ranibizumab compared with 16.8% in the 0.3 mg group.
CONCLUSIONS: The strong VA gains and improvement in retinal anatomy achieved with ranibizumab at month 24 were sustained through month 36. Delayed treatment in patients receiving sham treatment did not seem to result in the same extent of VA improvement observed in patients originally randomized to ranibizumab. Ocular and systemic safety was generally consistent with the results seen at month 24.
FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references. ||||| OBJECTIVE: To compare the efficacy and safety of ranibizumab 0.5 mg intravitreal injection, as monotherapy or in combination with laser, with laser monotherapy in patients with visual impairment caused by diabetic macular edema.
DESIGN: Twelve-month, multicentre, open-label, parallel-group, randomized, active-control study.
PARTICIPANTS: A total of 220 (ranibizumab monotherapy: n = 75, ranibizumab + laser: n = 73, laser monotherapy: n = 72) patients with a diagnosis of type I or II diabetes and visual impairment caused by macular edema were included in the efficacy analysis.
METHODS: Ranibizumab was initiated with a fixed loading phase of 3 monthly injections followed by as needed therapy until stable vision achievement. Efficacy end points were the change in best corrected visual acuity (BCVA), change in central retinal thickness (CRT) measured by optical coherence tomography, proportion achieving a 15-letter BCVA gain, and 12-month Visual Function Questionnaire-25 (VFQ-25) score. Safety was assessed with the incidence and severity of adverse events.
RESULTS: At 12 months, significant (p < 0.001) mean BCVA improvements were observed for both the ranibizumab monotherapy (+8.9 [95% confidence interval (CI) 7.0-10.7] letters) and the ranibizumab + laser (+8.2 [95% CI 6.0-10.4] letters) groups compared with the laser monotherapy group (+0.3 [95% CI -2.9 to 3.5] letters). Similarly, a better response in terms of CRT improvement, BCVA letter gain, and VFQ-25 was observed in both ranibizumab groups compared with laser monotherapy. The safety profile was comparable in the 2 ranibizumab groups.
CONCLUSIONS: Ranibizumab as monotherapy or combined with laser resulted in significantly higher improvements in visual acuity and vision-related quality of life at month 12 as compared with laser monotherapy. ||||| BACKGROUND: To compare the efficacy of intravitreal conbercept and ranibizumab in the treatment of diabetic macular edema (DME) in a real-life clinical practice.
METHODS: This was a retrospective study. Among 62 Chinese patients with DME, 32 patients (36 eyes) received intravitreal conbercept (IVC) injections and 30 patients (32 eyes) received intravitreal ranibizumab (IVR) injections, once a month for 3 months followed by as needed therapy. All participants had at least 12 months of follow-up. We compared the changes in best-corrected visual acuity (BCVA) letter score and central retinal thickness (CRT) between groups, as well as the number of intravitreal injections delivered. Safety was assessed with the incidence of adverse events (AEs).
RESULTS: At month 12, the mean BCVA letter score improved by 9.3 ± 5.2 with conbercept, and by 8.9 ± 4.4 with ranibizumab, the mean CRT reduction was 138.4 ± 97.7 μm and 145.2 ± 72.5 μm, respectively. There was no statistically significant difference of improvement in BCVA (P = 0.756) and decrease in CRT (P = 0.748) between the two groups. The number of intravitreal injections delivered was significantly higher (P = 0.027) in the IVR group (7.2 ± 1.0 per eye) than in the IVC group (6.6 ± 0.9 per eye). There were no severe ocular adverse reactions or systemic adverse events.
CONCLUSIONS: Both conbercept and ranibizumab are effective in the treatment of DME, achieving the similar clinical efficacy. In comparison to ranibizumab, conbercept shows a longer treatment interval and fewer intravitreal conbercept injections are needed. ||||| PURPOSE: To compare monthly dosing with a treat and extend algorithm using ranibizumab 0.3 mg with and without angiography-guided macular laser photocoagulation for center-involving diabetic macular edema (DME).
DESIGN: Multicenter, prospective, randomized clinical trial.
PARTICIPANTS: A total of 150 eyes from 116 subjects were randomized into 3 cohorts: Monthly (n = 30), TReat and EXtend without macular laser photocoagulation (TREX; n = 60), and treat and extend with angiography-GuIded macular LAser photocoagulation (GILA; n = 60).
METHODS: Monthly cohort eyes received ranibizumab 0.3 mg every 4 weeks. Eyes in the TREX and GILA cohorts received 4 monthly injections of ranibizumab 0.3 mg followed by a treat and extend algorithm based on disease activity. Eyes in the GILA cohort also received angiography-guided macular laser photocoagulation at month 1 and again every 3 months for microaneurysm leakage.
MAIN OUTCOME MEASURES: Change in mean best-corrected visual acuity (BCVA), mean central retinal thickness (CRT), number of injections from baseline to 1 year, and percentage gaining/losing 2 and 3 lines of vision.
RESULTS: Baseline demographics were well balanced among the cohorts. A total of 137 eyes (91%) completed the 1-year end point visit. At 1 year, the mean BCVA improved by 8.6, 9.6, and 9.5 letters in the Monthly, TREX, and GILA cohorts, respectively (P = 0.8). There was no significant difference between the cohorts in the percentage gaining/losing 2 and 3 lines of vision. The CRT improved by 123 μm, 146 μm, and 166 μm in the Monthly, TREX, and GILA cohorts, respectively (P = 0.47). The mean number of macular laser treatments in the GILA cohort at 1 year was 2.9 (range, 1-4). The number of injections was significantly reduced in both the TREX (10.7) and GILA (10.1) cohorts compared with the Monthly cohort (13.1, P < 0.001). There were no cases of endophthalmitis, and the total incidence of Anti-Platelet Trialists' Collaboration events was 4.7%.
CONCLUSIONS: This prospective, randomized trial found that treat and extend dosing of ranibizumab 0.3 mg with and without angiography-guided macular laser photocoagulation significantly decreased the number of injections given while providing similar visual and anatomic outcomes compared with monthly dosing at 1 year. Adding angiography-guided laser photocoagulation to this dosing algorithm did not significantly improve outcomes at 1 year. ||||| PURPOSE: To compare 2.0 mg ranibizumab (RBZ) injections with 0.5 mg RBZ for eyes with center-involved diabetic macular edema (DME).
DESIGN: Randomized, controlled, double-masked (to the dose), interventional, multicenter clinical trial.
PARTICIPANTS: A total of 152 patients (152 eyes) with DME.
METHODS: Eligible eyes were randomized in a 1:1 ratio to 0.5 mg (n = 77) or 2.0 mg (n = 75) RBZ. Study eyes received 6 monthly mandatory injections followed by as-needed injections until month 24.
MAIN OUTCOME MEASURES: The primary efficacy end point of the study was mean change in best-corrected visual acuity (BCVA) and central foveal thickness (CFT) at month 6. Secondary outcomes included the mean change in BCVA and CFT at month 24, and incidence and severity of systemic and ocular adverse events through month 24.
RESULTS: A total of 152 eyes were randomized in the study. At month 24, the mean improvement from baseline BCVA was +11.06 letters in the 0.5 mg RBZ group (n = 59) and +6.78 letters in the 2.0 mg RBZ group (n = 54) (P = 0.02). The mean numbers of RBZ injections through month 24 were 18.4 and 17.3 in the 0.5 mg and 2.0 mg RBZ groups, respectively (P = 0.08). The mean change in CFT was -192.53 μm in the 0.5 mg RBZ group and -170.64 μm in the 2.0 mg RBZ group (P = 0.41). By month 24, 3 deaths had occurred in the 0.5 mg RBZ group and 3 deaths had occurred in the 2.0 mg RBZ group; 5 of these 6 deaths occurred secondary to cardiovascular causes, and 1 death occurred as the result of severe pneumonia. All 5 patients with a cardiovascular cause of death had a history of coronary heart disease.
CONCLUSIONS: At month 24, there were significant visual and anatomic improvements in both groups, with subjects in the 0.5 mg RBZ group gaining more vision. Visual and anatomic gains achieved at month 6 were largely maintained through month 24. No new safety events were identified. In this study population, 2.0 mg RBZ does not appear to provide additional benefit over 0.5 mg RBZ. ||||| PURPOSE: To evaluate whether treatment with dexamethasone intravitreal implant (DEX implant) 0.7 mg every 5 months provides a similar average change in best-corrected visual acuity (BCVA) from baseline as ranibizumab 0.5 mg administered as per its European Summary of Product Characteristics in patients with diabetic macular edema (DME).
METHODS: This was a multicenter, open-label, 12-month, randomized, parallel-group, noninferiority study in patients with DME (one eye/patient). The primary efficacy measure was BCVA using the Early Treatment Diabetic Retinopathy Study (ETDRS) method. Secondary efficacy measures included area of leakage on fluorescein angiography and central retinal thickness (CRT) on optical coherence tomography.
RESULTS: Baseline patient characteristics were similar in the two treatment groups (DEX implant, n = 181; ranibizumab, n = 182); mean DME duration was ∼33 months. The mean average BCVA change from baseline over 12 months was 4.34 letters with DEX implant and 7.60 letters with ranibizumab. The lower limit of the 95 % confidence interval of the between-group difference was -4.74 letters, and therefore, DEX was demonstrated to be noninferior to ranibizumab based on the prespecified noninferiority margin of 5 letters. At monthly follow-up visits, the percentage of patients with ≥15-letter BCVA gain from baseline ranged from 7.2 to 17.7 % with DEX implant and 4.4 to 26.9 % with ranibizumab. Both DEX implant and ranibizumab effectively reduced CRT and reduced the area of fluorescein leakage. Between-group differences in change from baseline CRT favored DEX implant at 1, 2, 6, and 7 months (p ≤ 0.007) and ranibizumab at 4, 5, 9, and 10 months (p < 0.001); the decrease in fluorescein leakage area was greater with DEX implant than ranibizumab at month 12 (p < 0.001). Ocular adverse events in the study eye were more frequent in the DEX implant group because of the occurrence of intraocular pressure (IOP) increases and cataract. IOP increases were transient and generally managed with topical medication.
CONCLUSIONS: Both DEX implant and ranibizumab were well tolerated and improved BCVA and anatomic outcomes in patients with DME. DEX implant met the a priori criterion for noninferiority to ranibizumab in average change from baseline BCVA over 12 months. Noninferiority was achieved with an average of 2.85 DEX implant injections and 8.70 ranibizumab injections per patient. ||||| Intravitreal ranibizumab (IVR) has been approved for treating diabetic macular edema (DME), and is used in daily clinical practice. However, the treatment efficacies of IVR monotherapy in real-world clinical settings are not well known.The medical records of 56 eyes from 38 patients who received their first IVR for DME between April 2014 and March 2015, and were retreated with IVR monotherapy as needed with no rescue treatment, such as laser photocoagulation, were retrospectively reviewed. The clinical course, best-corrected visual acuity (BCVA), and fundus findings at baseline, before the initial IVR injection, and at 12 months, were evaluated.Twenty-five eyes from 25 patients (16 men; mean age 68.7 ± 9.8 years) who received IVR in the first eye, or unilaterally, without any other treatments during follow-up were included. After 12 months, mean central retinal thickness (CRT), which includes edema, was reduced (P = .003), although mean BCVA remained unchanged. There was a negative correlation between individual changes in BCVA (r = -0.57; P = .003) and CRT (r = -0.60; P = .002) at 12 months compared with baseline values. BCVA changes were greater in individuals with a history of pan-retinal photocoagulation at baseline (P = .026). After adjusting for age and sex, CRT improvement >100 μm at 12 months was associated with a greater CRT at baseline (OR 0.87 per 10 μm [95% CI 0.72-0.97]; P = .018) according to logistic regression analyses; however, better BCVA and CRT at 12 months were associated with a better BCVA (r = 0.77; P < .001) and lower CRT (r = 0.41; P = .039) at baseline, respectively, according to linear regression analyses.IVR monotherapy suppressed DME, and the effects varied according to baseline conditions. Eyes that had poorer BCVA or greater CRT, or a history of pan-retinal photocoagulation at baseline, demonstrated greater improvement with IVR monotherapy. In contrast, to achieve better outcome values, DME eyes should be treated before the BCVA and CRT deteriorate. These findings advance our understanding of the optimal use of IVR for DME in daily clinical practice, although further study is warranted. ||||| PURPOSE: To evaluate ranibizumab 0.5 mg using bimonthly monitoring and individualized re-treatment after monthly follow-up for 6 months in patients with visual impairment due to diabetic macular edema (DME).
DESIGN: A phase IIIb, 18-month, prospective, open-label, multicenter, single-arm study in the United Kingdom.
PARTICIPANTS: Participants (N = 109) with visual impairment due to DME.
METHODS: Participants received 3 initial monthly ranibizumab 0.5 mg injections (day 0 to month 2), followed by individualized best-corrected visual acuity (BCVA) and optical coherence tomography-guided re-treatment with monthly (months 3-5) and subsequent bimonthly follow-up (months 6-18). Laser was allowed after month 6.
MAIN OUTCOME MEASURES: Mean change in BCVA from baseline to month 12 (primary end point), mean change in BCVA and central retinal thickness (CRT) from baseline to month 18, gain of ≥10 and ≥15 letters, treatment exposure, and incidence of adverse events over 18 months.
RESULTS: Of 109 participants, 100 (91.7%) and 99 (90.8%) completed the 12 and 18 months of the study, respectively. The mean age was 63.7 years, the mean duration of DME was 40 months, and 77.1% of the participants had received prior laser treatment (study eye). At baseline, mean BCVA was 62.9 letters, 20% of patients had a baseline BCVA of >73 letters, and mean baseline CRT was 418.1 μm, with 32% of patients having a baseline CRT <300 μm. The mean change in BCVA from baseline to month 6 was +6.6 letters (95% confidence interval [CI], 4.9-8.3), and after institution of bimonthly treatment the mean change in BCVA at month 12 was +4.8 letters (95% CI, 2.9-6.7; P < 0.001) and +6.5 letters (95% CI, 4.2-8.8) at month 18. The proportion of participants gaining ≥10 and ≥15 letters was 24.8% and 13.8% at month 12 and 34.9% and 19.3% at month 18, respectively. Participants received a mean of 6.8 and 8.5 injections over 12 and 18 months, respectively. No new ocular or nonocular safety findings were observed during the study.
CONCLUSIONS: The BCVA gain achieved in the initial 6-month treatment period was maintained with an additional 12 months of bimonthly ranibizumab PRN treatment. ||||| PURPOSE: To compare visual acuity and spectral-domain optical coherence tomography (SDOCT) outcomes associated with intravitreal (IV) bevacizumab vs IV ranibizumab for the management of diabetic macular edema (DME).
DESIGN: Prospective randomized trial.
METHODS: Forty-eight patients (63 eyes) with center-involved DME were randomly assigned to receive 1.5 mg (0.06 cc) IV bevacizumab or 0.5 mg (0.05 cc) IV ranibizumab at baseline and monthly if central subfield thickness was greater than 275 μm.
RESULTS: Forty-five patients (60 eyes) completed 48 weeks of follow-up. At baseline, mean ± standard error best-corrected visual acuity (BCVA) (logMAR) was 0.60 (20/80) ± 0.05 in the IV bevacizumab group and 0.63 (20/85) ± 0.05 in the IV ranibizumab group. A significant improvement in mean BCVA was observed in both groups at all study visits (P < .05); this improvement was significantly greater in the IV ranibizumab group compared with the IV bevacizumab group at weeks 8 (P = .032) and 32 (P = .042). A significant reduction in mean central subfield thickness was observed in both groups at all study visits compared with baseline (P < .05), with no significant difference in the magnitude of macular thickness reduction between groups. The mean number of injections was significantly higher (P = .005) in the IV bevacizumab group (9.84) than in the IV ranibizumab group (7.67).
CONCLUSIONS: IV bevacizumab and IV ranibizumab are associated with similar effects on central subfield thickness in patients with DME through 1 year of follow-up. IV ranibizumab is associated with greater improvement in BCVA at some study visits, and the mean number of injections is higher in the IV bevacizumab group. ||||| OBJECTIVE: To evaluate long-term efficacy and safety profiles during 3 years of individualized ranibizumab treatment in patients with visual impairment due to diabetic macular edema (DME).
DESIGN: Phase IIIb, multicenter, 12-month, randomized core study and 24-month open-label extension study.
PARTICIPANTS: Of the 303 patients who completed the randomized RESTORE 12-month core study, 240 entered the extension study.
METHODS: In the extension study, patients were eligible to receive individualized ranibizumab treatment as of month 12 guided by best-corrected visual acuity (BCVA) and disease progression criteria at the investigators' discretion. Concomitant laser treatment was allowed according to the Early Treatment Diabetic Retinopathy Study guidelines. Based on the treatments received in the core study, the extension study groups were referred to as prior ranibizumab, prior ranibizumab + laser, and laser.
MAIN OUTCOME MEASURES: Change in BCVA and incidence of ocular and nonocular adverse events (AEs) over 3 years.
RESULTS: Overall, 208 patients (86.7%) completed the extension study. In patients treated with ranibizumab during the core study, consecutive individualized ranibizumab treatment during the extension study led to an overall maintenance of BCVA and central retinal subfield thickness (CRST) observed at month 12 over the 2-year extension study (+8.0 letters, -142.1 μm [prior ranibizumab] and +6.7 letters, -145.9 μm [prior ranibizumab + laser] from baseline at month 36) with a median of 6.0 injections (mean, 6.8 injections; prior ranibizumab) and 4.0 (mean, 6.0 injections; prior ranibizumab + laser). In the prior laser group, a progressive BCVA improvement (+6.0 letters) and CRST reduction (-142.7 μm) at month 36 were observed after allowing ranibizumab during the extension study, with a median of 4.0 injections (mean, 6.5 injections) from months 12 to 35. Patients in all 3 treatment groups received a mean of <3 injections in the final year. No cases of endophthalmitis, retinal tear, or retinal detachment were reported. The most frequently reported ocular and nonocular adverse effects over 3 years were cataract (16.3%) and nasopharyngitis (23.3%). Eight deaths were reported during the extension study, but none were suspected to be related to the study drug/procedure.
CONCLUSIONS: Ranibizumab was effective in improving and maintaining BCVA and CRST outcomes with a progressively declining number of injections over 3 years of individualized dosing. Ranibizumab was generally well tolerated with no new safety concerns over 3 years. ||||| PURPOSE: To determine visual acuity (VA) and spectral-domain optical coherence tomography (OCT) outcomes with intravitreal ranibizumab for diabetic macular edema (DME) in a United Kingdom National Health Service clinical setting.
DESIGN: Retrospective interventional case series.
PARTICIPANTS: Consecutive patients with DME, treated with the first ranibizumab injection between August 2013 and March 2014 across 4 sites of Moorfields Eye Hospital, London.
METHODS: Two hundred eyes of 164 consecutive patients with center-involving DME and VA ≤79 ETDRS letters, central subfield macular thickness (CST) ≥350 μm on Topcon 3D OCT 2000, initiated on a loading phase of 3 intravitreal ranibizumab injections and who had at least 6 months follow-up were reviewed. Subsequent retreatment was guided by VA and OCT with the aim of treating to stability. VA, OCT CST, and macular volume (MV) were recorded at baseline and monthly to 12 months.
RESULTS: The mean VA, mean CST, and mean MV at baseline were 54.4 (± 15.26) letters, 490.16 (± 116.54) μm, and 10.46 (± 2.28) mm
CONCLUSIONS: Outcomes with 3 loading injections of 0.5 mg ranibizumab given monthly followed by pro re nata retreatment in a clinical setting are comparable with outcomes from clinical trials. ||||| OBJECTIVE: The expression of vascular endothelial growth factor (VEGF) is elevated in diabetic macular edema (DME). Ranibizumab binds to and inhibits multiple VEGF variants. We investigated the safety and efficacy of ranibizumab in DME involving the foveal center.
RESEARCH DESIGN AND METHODS: This was a 12-month, multicenter, sham-controlled, double-masked study with eyes (age>18 years, type 1 or 2 diabetes, central retinal thickness [CRT]≥300 μm, and best corrected visual acuity [BCVA] of 73-39 ETDRS letters [Early Treatment Diabetic Retinopathy Study]) randomly assigned to intravitreal ranibizumab (0.3 or 0.5 mg; n=51 each) or sham (n=49). The treatment schedule comprised three monthly injections, after which treatment could be stopped/reinitiated with an opportunity for rescue laser photocoagulation (protocol-defined criteria). After month 1, dose-doubling was permitted (protocol-defined criteria, injection volume increased from 0.05 to 0.1 ml and remained at 0.1 ml thereafter). Efficacy (BCVA and CRT) and safety were compared between pooled ranibizumab and sham arms using the full analysis set (n=151, patients receiving≥1 injection).
RESULTS: At month 12, mean±SD BCVA improved from baseline by 10.3±9.1 letters with ranibizumab and declined by 1.4±14.2 letters with sham (P<0.0001). Mean CRT reduction was 194.2±135.1 μm with ranibizumab and 48.4±153.4 μm with sham (P<0.0001). Gain of ≥10 letters BCVA from baseline occurred in 60.8% of ranibizumab and 18.4% of sham eyes (P<0.0001). Safety data were consistent with previous studies of intravitreal ranibizumab.
CONCLUSIONS: Ranibizumab is effective in improving BCVA and is well tolerated in DME. Future clinical trials are required to confirm its long-term efficacy and safety. ||||| PURPOSE: To assess the 2-year effectiveness of intravitreal ranibizumab combined with a dietary supplement rich in docosahexaenoic acid (DHA) plus antioxidants in 62 patients with diabetic macular edema.
METHODS: In a randomized single-blind controlled study, 33 subjects (42 eyes) received intravitreal ranibizumab alone and 29 (34 eyes) combined with DHA (1,050 mg/day). Monthly ranibizumab (0.5 mg) was given for the first 4 months followed by on as-needed treatment.
RESULTS: At 24 months, the difference between groups in the decrease of central subfield macular thickness was significant in favor of the DHA supplementation group (95% confidence interval of the difference 7.20-97.656; P = 0.024), although improvement in best-corrected visual acuity measured in the Early Treatment Diabetic Retinopathy Study letters did not reach statistical significance (95% confidence interval 5.4-11.2, P < 0.66). At 24 months, gains of >5 and >10 letters were significantly higher in the DHA supplementation group as compared with controls when the worse and better seeing eyes were considered but other differences at 12 months and 24 months were not found.
CONCLUSION: Intravitreal ranibizumab combined with DHA supplementation reduced central subfield macular thickness after 2 years of follow-up as compared with ranibizumab alone in patients with diabetic macular edema. This anatomical improvement was accompanied by a trend for an amelioration of vision. ||||| PurposeTo determine the average time-point at which it is best to define 'sub-optimal response' after ranibizumab treatment for diabetic macular edema (DME) based on the data obtained from real-life clinical practice.MethodsIn this retrospective observational study, 322 consecutive treatment naïve eyes with DME were treated with three loading doses of intravitreal ranibizumab followed by re-treatment based on decision of the treating physician on a case-by-case basis. The demographic data, clinic-based visual acuity measurements and central subfield thickness (CST) assessed on spectral domain optical coherence tomography (OCT) were evaluated at baseline (month 0), 1, 2, 3, 6, and 12 months.ResultsOn an average, the improvement in visual acuity and CST was first seen after the loading dose. However, the maximal response in terms of proportion of patients with improvement in visual acuity and/ or CST in this cohort was observed at 12 months. Patients who presented with low visual acuity at baseline (<37 ETDRS letters) were unlikely to attain driving vision with ranibizumab therapy.ConclusionsOn an average, a 'sub-optimal response' after ranibizumab therapy is best defined at month 12 as patients may continue to improve with treatment. ||||| PURPOSE: To assess the efficacy of intravitreal 0.5 mg ranibizumab for the treatment of center-involving macular edema secondary to branch retinal vein occlusion (BRVO) over 1 year compared with standard-of-care grid laser.
DESIGN: A prospective randomized controlled clinical trial.
METHODS: A total of 36 patients with vision loss in 1 eye attributable to macular edema following BRVO were recruited from 5 institutions. Patients were randomized 1:1 to a treatment group that received 6 monthly injections of 0.5 mg ranibizumab and thereafter monthly as needed based on best-corrected visual acuity (BCVA) and central foveal thickness (CFT) assessments on optical coherence tomography scans, or a standard-of-care group that received monthly sham injections for the 1-year duration of the study. Grid laser was administered at 13 and 25 weeks in both groups if criteria for laser treatment were met. Main outcome measures included mean change in BCVA in Early Treatment Diabetic Retinopathy Study (ETDRS) letter scores from baseline to month 12. Secondary outcomes included anatomic outcomes and the percentage of patients requiring grid laser in both groups.
RESULTS: Mean BCVA change from baseline was significantly greater in the treatment compared with the standard-of-care group at 12 months (12.5 ETDRS letters vs -1.6 ETDRS letters, P = .032). The mean CFT was significantly reduced in the treatment compared with standard-of-care group (361.7 μm vs 175.6 μm, P = .025). At 13 and 25 weeks, more patients in the standard-of-care group (68.4%, 50.0%) received grid laser than in the treatment group (6.7%, 8.3%). No new ocular or systemic adverse events were observed.
CONCLUSIONS: Compared with standard grid laser, intravitreal ranibizumab provided significant and sustained benefits in visual acuity gain and anatomic improvement in eyes with macular edema secondary to BRVO. ||||| AIMS: To demonstrate non-inferiority of ranibizumab treat-and-extend (T&E) with/without laser to ranibizumab pro re nata (PRN) for best-corrected visual acuity (BCVA) in patients with diabetic macular oedema (DMO).
METHODS: A 24-month single-masked study with patients randomised 1:1:1 to T&E+laser (n=121), T&E (n=128) or PRN (control; n=123). All patients received monthly injections until BCVA stabilisation. The investigator decided on re-treatment in the PRN and treatment-interval adaptations in the T&E groups based on loss of BCVA stability due to DMO activity. Likewise, laser treatment was at investigator's discretion. Collectively, these features reflect a real-life scenario. Endpoints included mean average change in BCVA from baseline to months 1-12 (primary), mean BCVA change from baseline to months 12 and 24, treatment exposure and safety profile.
RESULTS: Both T&E regimens were non-inferior to PRN based on mean average BCVA change from baseline to months 1-12 (T&E+laser: +5.9 and T&E: +6.1 vs PRN: +6.2 letters; both p<0.0001). Mean BCVA change at month 24 was similar across groups (+8.3, +6.5 and +8.1 letters, respectively). The mean number of injections was 12.4 and 12.8 in the T&E+laser and T&E groups and 10.7 in the PRN group. The T&E regimens showed 46% reduction in the number of clinic visits. Over 70% of patients maintained their BCVA, with treatment intervals of ≥2 months over 24 months. Safety profile was consistent with that described in the product information.
CONCLUSIONS: T&E is a feasible treatment option for patients with DMO, with a potential to reduce treatment burden. Slightly more injections were required versus PRN, likely due to the specifics of the T&E regimen applied here.
TRIAL REGISTRATION NUMBER: NCT01171976. ||||| OBJECTIVE: To report 5-year results from a previously reported trial evaluating intravitreal 0.5 mg ranibizumab with prompt versus deferred (for ≥24 weeks) focal/grid laser treatment for diabetic macular edema (DME).
DESIGN: Multicenter, randomized clinical trial.
PARTICIPANTS: Among participants from the trial with 3 years of follow-up who subsequently consented to a 2-year extension and survived through 5 years, 124 (97%) and 111 (92%) completed the 5-year visit in the prompt and deferred groups, respectively.
METHODS: Random assignment to ranibizumab every 4 weeks until no longer improving (with resumption if worsening) and prompt or deferred (≥24 weeks) focal/grid laser treatment.
MAIN OUTCOME MEASURES: Best-corrected visual acuity at the 5-year visit.
RESULTS: The mean change in visual acuity letter score from baseline to the 5-year visit was +7.2 letters in the prompt laser group compared with +9.8 letters in the deferred laser group (mean difference, -2.6 letters; 95% confidence interval, -5.5 to +0.4 letters; P = 0.09). At the 5-year visit in the prompt versus deferred laser groups, there was vision loss of ≥10 letters in 9% versus 8%, an improvement of ≥10 letters in 46% versus 58%, and an improvement of ≥15 letters in 27% versus 38% of participants, respectively. From baseline to 5 years, 56% of participants in the deferred group did not receive laser. The median number of injections was 13 versus 17 in the prompt and deferral groups, including 54% and 45% receiving no injections during year 4 and 62% and 52% receiving no injections during year 5, respectively.
CONCLUSIONS: Five-year results suggest focal/grid laser treatment at the initiation of intravitreal ranibizumab is no better than deferring laser treatment for ≥24 weeks in eyes with DME involving the central macula with vision impairment. Although more than half of eyes in which laser treatment is deferred may avoid laser for at least 5 years, such eyes may require more injections to achieve these results when following this protocol. Most eyes treated with ranibizumab and either prompt or deferred laser maintain vision gains obtained by the first year through 5 years with little additional treatment after 3 years. ||||| IMPORTANCE: Comparisons of the relative effect of 3 anti-vascular endothelial growth factor agents to treat diabetic macular edema warrant further assessment.
OBJECTIVE: To provide additional outcomes from a randomized trial evaluating 3 anti-vascular endothelial growth factor agents for diabetic macular edema within subgroups based on baseline visual acuity (VA) and central subfield thickness (CST) as evaluated on optical coherence tomography.
DESIGN, SETTING, AND PARTICIPANTS: Post hoc exploratory analyses were conducted of randomized trial data on 660 adults with diabetic macular edema and decreased VA (Snellen equivalent, approximately 20/32 to 20/320). The original study was conducted between August 22, 2012, and August 28, 2013. Analysis was conducted from January 7 to June 2, 2015.
INTERVENTIONS: Repeated 0.05-mL intravitreous injections of 2.0 mg of aflibercept (224 eyes), 1.25 mg of bevacizumab (218 eyes), or 0.3 mg of ranibizumab (218 eyes) as needed per protocol.
MAIN OUTCOMES AND MEASURES: One-year VA and CST outcomes within prespecified subgroups based on both baseline VA and CST thresholds, defined as worse (20/50 or worse) or better (20/32 to 20/40) VA and thicker (≥400 µm) or thinner (250 to 399 µm) CST.
RESULTS: In the subgroup with worse baseline VA (n = 305), irrespective of baseline CST, aflibercept showed greater improvement than bevacizumab or ranibizumab for several VA outcomes. In the subgroup with better VA and thinner CST at baseline (61-73 eyes across 3 treatment groups), VA outcomes showed little difference between groups; mean change was +7.2, +8.4, and +7.6 letters in the aflibercept, bevacizumab, and ranibizumab groups, respectively. However, in the subgroup with better VA and thicker CST at baseline (31-43 eyes), there was a suggestion of worse VA outcomes in the bevacizumab group; mean change from baseline to 1 year was +9.5, +5.4, and +9.5 letters in the aflibercept, bevacizumab, and ranibizumab groups, respectively, and VA letter score was greater than 84 (approximately 20/20) in 21 of 33 (64%), 7 of 31 (23%), and 21 of 43 (49%) eyes, respectively. The adjusted differences and 95% CIs were 39% (17% to 60%) for aflibercept vs bevacizumab, 25% (5% to 46%) for ranibizumab vs bevacizumab, and 13% (-8% to 35%) for aflibercept vs ranibizumab.
CONCLUSIONS AND RELEVANCE: These post hoc secondary findings suggest that for eyes with better initial VA and thicker CST, some VA outcomes may be worse in the bevacizumab group than in the aflibercept and ranibizumab groups. Given the exploratory nature of these analyses and the small sample size within subgroups, caution is suggested when using the data to guide treatment considerations for patients.
TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01627249. ||||| PURPOSE Diabetic macular oedema (DMO) is a leading cause for visual impairment in the working age population in the UK. Ranibizumab has been shown to be effective in treatment of DMO in studies based on mainly Caucasian populations. This study reports the 12-month outcome in a cohort of South Asian subjects with DMO treated with ranibizumab.MethodsDMO in 51 eyes of 41 South Asian patients was treated with ranibizumab 0.5 mg according to the modified DRCRnet protocol I. Visual acuity (VA) and central macular thickness (CMT) were recorded at baseline, 3, 6, and 12 months. Results were compared for eyes with different baseline visual acuities and different baseline macular thicknesses.RESULTS Over the 12-month period, the mean ETDRS VA increased from 55.3±13.4 letters to 63.8±15.2 letters for all eyes. At 12 months, 70.6% eyes gained 5 or more letters acuity and 17.6% eyes gained 15 letters or more. During the same period, the mean CMT decreased from 532±129 to 318±136 μm. Eyes that had received previous laser treatments had a mean letter gain of 9.2 letters, compared with 8.5 for all eyes at 12 months.CONCLUSIONS Ranibizumab 0.5 mg is safe and effective at reversing vision loss due to DMO in patients of South Asian origin at 12 months. Ranibizumab treatment appears to be effective in patients with longstanding DMO who received prior laser treatments. Further studies are needed to define the long-term outcome in patients of different ethnicity and DMO. ||||| OBJECTIVE: To compare the visual and anatomical outcomes of intravitreal ranibizumab (group 1), bevacizumab (group 2), and triamcinolone (group 3) for center-involving diabetic macular edema.
METHODS: We retrospectively enrolled 275 eyes of 208 consecutive patients. Visual acuity (VA) in Early Treatment Diabetic Retinopathy Study (ETDRS) letters and central macular thickness (CMT) values on optical coherence tomography were extracted. Reported side effects were noted.
RESULTS: At 6 months, the mean changes in VA in group 1, group 2, and group 3 were +4.9, +4.3, and +4.6 letters, respectively (p = 0.911). Improvement of CMT at 6 and 24 months was significantly better in group 3 compared to groups 1 and 2 (p = 0.012 and p = 0.001, respectively). At 24 months, the only independent variable affecting the change in VA was initial VA (p = 0.020). Cataract and glaucoma prevalences were higher in group 3 (p = 0.000 and p = 0.001, respectively).
CONCLUSIONS: Three treatment methods had similar effects with regard to improvement in VA; however, intravitreal triamcinolone provided additional anatomical improvement. ||||| OBJECTIVE: To demonstrate superiority of ranibizumab 0.5 mg monotherapy or combined with laser over laser alone based on mean average change in best-corrected visual acuity (BCVA) over 12 months in diabetic macular edema (DME).
DESIGN: A 12-month, randomized, double-masked, multicenter, laser-controlled phase III study.
PARTICIPANTS: We included 345 patients aged ≥18 years, with type 1 or 2 diabetes mellitus and visual impairment due to DME.
METHODS: Patients were randomized to ranibizumab + sham laser (n = 116), ranibizumab + laser (n = 118), or sham injections + laser (n = 111). Ranibizumab/sham was given for 3 months then pro re nata (PRN); laser/sham laser was given at baseline then PRN (patients had scheduled monthly visits).
MAIN OUTCOME MEASURES: Mean average change in BCVA from baseline to month 1 through 12 and safety.
RESULTS: Ranibizumab alone and combined with laser were superior to laser monotherapy in improving mean average change in BCVA letter score from baseline to month 1 through 12 (+6.1 and +5.9 vs +0.8; both P<0.0001). At month 12, a significantly greater proportion of patients had a BCVA letter score ≥15 and BCVA letter score level >73 (20/40 Snellen equivalent) with ranibizumab (22.6% and 53%, respectively) and ranibizumab + laser (22.9% and 44.9%) versus laser (8.2% and 23.6%). The mean central retinal thickness was significantly reduced from baseline with ranibizumab (-118.7 μm) and ranibizumab + laser (-128.3 μm) versus laser (-61.3 μm; both P<0.001). Health-related quality of life, assessed through National Eye Institute Visual Function Questionnaire (NEI VFQ-25), improved significantly from baseline with ranibizumab alone and combined with laser (P<0.05 for composite score and vision-related subscales) versus laser. Patients received ∼7 (mean) ranibizumab/sham injections over 12 months. No endophthalmitis cases occurred. Increased intraocular pressure was reported for 1 patient each in the ranibizumab arms. Ranibizumab monotherapy or combined with laser was not associated with an increased risk of cardiovascular or cerebrovascular events in this study.
CONCLUSIONS: Ranibizumab monotherapy and combined with laser provided superior visual acuity gain over standard laser in patients with visual impairment due to DME. Visual acuity gains were associated with significant gains in VFQ-25 scores. At 1 year, no differences were detected between the ranibizumab and ranibizumab + laser arms. Ranibizumab monotherapy and combined with laser had a safety profile in DME similar to that in age-related macular degeneration. ||||| IMPORTANCE: The prevalence of persistent diabetic macular edema (DME) after months of anti-vascular endothelial growth factor therapy and its effect on visual acuity are unknown.
OBJECTIVE: To assess subsequent outcomes of eyes with DME persisting for 24 weeks after initiating treatment with 0.5 mg of ranibizumab.
DESIGN, SETTING, AND PARTICIPANTS: We performed post hoc, exploratory analyses of a randomized clinical trial from March 20, 2007, through January 29, 2014, from 117 of 296 eyes (39.5%) randomly assigned to receive ranibizumab with persistent DME (central subfield thickness ≥250 μm on time domain optical coherence tomography) through the 24-week visit.
INTERVENTIONS: Four monthly intravitreous injections of ranibizumab and then as needed per protocol.
MAIN OUTCOMES AND MEASURES: Cumulative 3-year probabilities of chronic persistent DME (failure to achieve a central subfield thickness <250 μm and at least a 10% reduction from the 24-week visit on at least 2 consecutive study visits) determined by life-table analyses, and at least 10 letter (≥2 line) gain or loss of visual acuity among those eyes.
RESULTS: The probability of chronic persistent DME among eyes with persistent DME at the 24-week visit decreased from 100% at the 32-week visit to 81.1% (99% CI, 69.6%-88.6%), 55.8% (99% CI, 42.9%-66.9%), and 40.1% (99% CI, 27.4%-52.4%) at the 1-, 2-, and 3-year visits, respectively. At 3 years, visual acuity improved in eyes with and without chronic persistent DME through the follow-up period, respectively, by a mean of 7 letters and 13 letters from baseline. Among 40 eyes with chronic persistent edema through 3 years, 17 (42.5%) (99% CI, 23.1%-63.7%) gained 10 letters or more from baseline, whereas 5 (12.5%) (99% CI, 2.8%-31.5%) lost 10 letters or more from baseline.
CONCLUSIONS AND RELEVANCE: These data suggest less than half of eyes treated for DME with intravitreous ranibizumab have persistent central-involved DME through 24 weeks after initiating treatment. Among the 40% that then have chronic persistent central-involved DME through 3 years, longer-term visual acuity outcomes appear to be slightly worse than in the 60% in which DME does not persist. Nevertheless, when following the treatment protocol used in this trial among eyes with vision impairment from DME, long-term improvement in visual acuity from baseline is typical and substantial (≥2-line) loss of visual acuity is likely uncommon through 3 years, even when central-involved DME chronically persists. ||||| PURPOSE: To evaluate the efficacy, safety, and injection frequency of vascular endothelial growth factor (VEGF) inhibitors as used in clinical practice for the treatment of diabetic macular edema.
METHODS: Multicenter (10 sites), retrospective chart review in patients (n=156) who received ≥3 anti-VEGF injections. Data collected for ≥6 months after the first injection included Snellen best-corrected visual acuity (BCVA) and central retinal thickness (CRT) by time-domain or spectral-domain optical coherence tomography (TD-OCT or SD-OCT).
RESULTS: Mean number of anti-VEGF injections (627 bevacizumab, 594 ranibizumab, 1 aflibercept) was 5.8 (year 1), 5.0 (year 2), and 3.4 (year 3). Percentage of patients with BCVA of 20/40 or better and CRT ≤250 μm on TD-OCT or ≤300 μm on SD-OCT at the same visit (primary endpoint) ranged from 16.4% to 38.9% after the first 10 injections; 51.9%-62.3% achieved ≥20/40 BCVA and 26.2%-48.0% met CRT criteria. Therapy was well tolerated with 19 treatment-related adverse events (all ocular) reported.
CONCLUSION: Anti-VEGF injections were administered less frequently and were less effective than those in the ranibizumab registration trials. After each of the first 9 injections, <25% of patients achieved both BCVA of 20/40 or better and a dry macula. A substantial proportion of patients are suboptimal responders to anti-VEGF therapy; these patients may be candidates for other therapies, including intravitreal corticosteroid and laser therapy. ||||| PURPOSE: To evaluate the effect of systemic factors on best-corrected visual acuity (BCVA) achieved with ranibizumab (Lucentis; Genentech, Inc, South San Francisco, CA) for treatment of diabetic macular edema (DME) in the RIDE and RISE phase 3 studies.
DESIGN: Exploratory, post hoc analysis of 2 randomized, double-masked, sham-injection controlled studies.
PARTICIPANTS: Adults with DME, BCVA of 20/40 to 20/320 Snellen equivalent, and central foveal thickness of 275 μm or more.
METHODS: Analysis of RIDE (clinicaltrials.gov identifier, NCT00473382) and RISE (clinicaltrials.gov identifier, NCT00473330) pooled ranibizumab data through month 24. Change in BCVA was assessed for association with the following covariates: age, body mass index (BMI), blood pressure, serum glucose, glycosylated hemoglobin (HbA1c), blood urea nitrogen, serum creatinine, estimated glomerular filtration rate, and blood chemistry variables. Change in BCVA at month 24 was assessed according to the following categories of diabetes medication use history: insulin only (n = 193), insulin plus other medications (n = 221), or other noninsulin medications (n = 331).
MAIN OUTCOME MEASURES: Change in BCVA from baseline assessed by randomized treatment group in pooled 0.3- and 0.5-mg monthly ranibizumab groups.
RESULTS: In patients with DME, vision improvement with ranibizumab was not influenced by systemic factors such as diabetes medication history, serum glucose, HbA1c, renal function, BMI, and blood pressure. Patients taking insulin with or without other medications at baseline had longer diabetes disease duration (mean, 17.4 and 20.9 years, respectively) compared with those taking other noninsulin medications (mean, 11.9 years). At month 24, among ranibizumab-treated patients, the mean BCVA change from baseline (Early Treatment Diabetic Retinopathy Study letters ± standard deviation) was not different between patients taking only insulin (12.6±11.2 letters), insulin plus other medications (12.2±12.4 letters), or other noninsulin medications (14.0±13.7 letters). Mean BCVA change also was comparable among patients taking thiazolidinediones (12.9±9.7 letters) and those not taking thiazolidinediones (13.2±13.3 letters).
CONCLUSIONS: There were no associations between systemic factors (baseline values or change from baseline) and mean change of BCVA at month 24. These results suggest that visual response to ranibizumab therapy in DME was not influenced by nonocular factors related to systemic management of diabetes in the RIDE and RISE studies. ||||| OBJECTIVES: To determine the long-term effects of ranibizumab (RBZ) in patients with diabetic macular edema (DME).
DESIGN: Prospective, randomized, interventional, multicenter clinical trial.
PARTICIPANTS: One hundred twenty-six patients with DME.
METHODS: Subjects were randomized 1:1:1 to receive 0.5 mg RBZ at baseline and months 1, 3, and 5 (group 1), focal or grid laser photocoagulation at baseline and month 3 if needed (group 2), or a combination of 0.5 mg RBZ and focal or grid laser at baseline and month 3 (group 3). Starting at month 6, if retreatment criteria were met, all subjects could be treated with RBZ.
MAIN OUTCOME MEASURES: The mean change from baseline in best-corrected visual acuity (BCVA) at month 24.
RESULTS: After the primary end point at month 6, most patients in all groups were treated only with RBZ, and the mean number of injections was 5.3, 4.4, and 2.9 during the 18-month follow-up period in groups 1, 2, and 3, respectively. For the 33 patients in group 1, 34 patients in group 2, and 34 patients in group 3 who remained in the study through 24 months, the mean improvement in BCVA was 7.4, 0.5, and 3.8 letters at the 6-month primary end point, compared with 7.7, 5.1, and 6.8 letters at month 24, and the percentage of patients who gained 3 lines or more of BCVA was 21, 0, and 6 at month 6, compared with 24, 18, and 26 at month 24. The percentage of patients with 20/40 or better Snellen equivalent at month 24 was 45% in group 1, 44% in group 2, and 35% in group 3. Mean foveal thickness (FTH), defined as center subfield thickness, at month 24 was 340 μm, 286 μm, and 258 μm for groups 1, 2, and 3, respectively, and the percentage of patients with center subfield thickness of 250 μm or less was 36%, 47%, and 68%, respectively.
CONCLUSIONS: Intraocular injections of RBZ provided benefit for patients with DME for at least 2 years, and when combined with focal or grid laser treatments, the amount of residual edema was reduced, as were the frequency of injections needed to control edema.
FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references. ||||| Purpose: To assess the effect of serous retinal detachment (SRD) on functional and anatomical outcomes in ranibizumab-treated patients with diabetic macular edema (DME).
Methods: All consecutive ranibizumab-treated patients with SRD were included in this retrospective study. For each patient with SRD, a patient without SRD with the same baseline best-corrected visual acuity (BCVA) was randomly included for adjustment on their baseline BCVA. All patients with SRD were included in group 1 (G1) and those without SRD in G2. The primary endpoint was the mean change in BCVA between baseline and month 12 (M12). Secondary endpoints were the mean change in central retinal thickness (CRT) between baseline and M12, injection number, and proportion of patients who gained/lost ≥15 letters.
Results: Seventy-eight eyes were included, 39 in each group. Baseline BCVA was similar in both groups (45.2 and 45.3 letters). Mean change in BCVA between baseline and M12 was not statistically different: 11 ± 12 letters in G1 and 12 ± 13 letters in G2 (P = 0.78). Baseline CRT was 650 ± 130 μm in G1 and 480 ± 79 μm in G2. Mean change in CRT was -235 ± 170 μm in G1 and -130 ± 96 μm in G2 (P = 0.013). Patients received 5.2 and 5.5 injections in G1 and G2 (P = 0.46). In group 1, 38.5% and 2.6% of patients respectively gained and lost ≥15 letters versus 41% (P = 0.1) and 5.1% (P = 0.1) in G2.
Conclusions: Similar BCVA gains were observed regardless of the presence of SRD. The higher visual gain usually observed in DME with SRD could be associated with a lower baseline BCVA. ||||| PURPOSE: To provide 2-year results comparing anti-vascular endothelial growth factor (VEGF) agents for center-involved diabetic macular edema (DME) using a standardized follow-up and retreatment regimen.
DESIGN: Randomized clinical trial.
PARTICIPANTS: Six hundred sixty participants with visual acuity (VA) impairment from DME.
METHODS: Randomization to 2.0-mg aflibercept, 1.25-mg repackaged (compounded) bevacizumab, or 0.3-mg ranibizumab intravitreous injections performed up to monthly using a protocol-specific follow-up and retreatment regimen. Focal/grid laser photocoagulation was added after 6 months if DME persisted. Visits occurred every 4 weeks during year 1 and were extended up to every 4 months thereafter when VA and macular thickness were stable.
MAIN OUTCOME MEASURES: Change in VA, adverse events, and retreatment frequency.
RESULTS: Median numbers of injections were 5, 6, and 6 in year 2 and 15, 16, and 15 over 2 years in the aflibercept, bevacizumab, and ranibizumab groups, respectively (global P = 0.08). Focal/grid laser photocoagulation was administered in 41%, 64%, and 52%, respectively (aflibercept vs. bevacizumab, P < 0.001; aflibercept vs. ranibizumab, P = 0.04; bevacizumab vs. ranibizumab, P = 0.01). At 2 years, mean VA improved by 12.8, 10.0, and 12.3 letters, respectively. Treatment group differences varied by baseline VA (P = 0.02 for interaction). With worse baseline VA (20/50 to 20/320), mean improvement was 18.1, 13.3, and 16.1 letters, respectively (aflibercept vs. bevacizumab, P = 0.02; aflibercept vs. ranibizumab, P = 0.18; ranibizumab vs. bevacizumab, P = 0.18). With better baseline VA (20/32 to 20/40), mean improvement was 7.8, 6.8, and 8.6 letters, respectively (P > 0.10, for pairwise comparisons). Anti-Platelet Trialists' Collaboration (APTC) events occurred in 5% with aflibercept, 8% with bevacizumab, and 12% with ranibizumab (global P = 0.047; aflibercept vs. bevacizumab, P = 0.34; aflibercept vs. ranibizumab, P = 0.047; ranibizumab vs. bevacizumab, P = 0.20; global P = 0.09 adjusted for potential confounders).
CONCLUSIONS: All 3 anti-VEGF groups showed VA improvement from baseline to 2 years with a decreased number of injections in year 2. Visual acuity outcomes were similar for eyes with better baseline VA. Among eyes with worse baseline VA, aflibercept had superior 2-year VA outcomes compared with bevacizumab, but superiority of aflibercept over ranibizumab, noted at 1 year, was no longer identified. Higher APTC event rates with ranibizumab over 2 years warrants continued evaluation in future trials. ||||| PURPOSE: Intravitreal anti-vascular endothelial growth factor (VEGF) agents are effective in the treatment of central involving diabetic macular oedema (DMO). Vitreoretinal interface abnormalities (VRIA) are common in patients with DMO, and the effect of these on the response to anti-VEGF treatment is unclear. Furthermore the effect of anti-VEGF agents on the VRIA itself is uncertain.
METHOD: Prospective study of consecutive patients treated with ranibizumab (RZB) for DMO as part of routine clinical care in one eye unit over a 1-year period. Visual acuity (Va), central retinal thickness (CRT) and injection frequency data was recorded on an electronic database. Treatment was initiated with four monthly RZB injections and then a monthly PRN regime. All patients underwent high-density spectral-domain optical coherence tomography (SDOCT) at baseline and 12 months. The SDOCTs were graded by two observers masked to the outcome.
RESULTS: One hundred and four eyes (77 patients) were included in the analysis. The mean age was 62 years, and 62% were male. The mean presenting vision was 62 letters and CRT 472 μm. Eighty eyes retained stable Va, and 17 had an improvement in Va. At baseline, 39 eyes had associated focal vitreomacular adhesion (VMA) and by 12 months this reduced to 30 (p = 0.04), with 12 releasing VMA and three developing it. Patients with VMA had significantly better final Va than those without VMA. Improvement in CRT was greatest in those where VMA released during the study. Forty-five eyes had some degree of foveal involving epiretinal membrane (ERM) at baseline, and 28 were considered to have clinically significant ERM. There was no clinically relevant change in ERM during the study. Patients with significant ERM at baseline had a lower final vision. Multivariate analysis showed that ERM and more severe retinopathy at baseline were predictive of less visual improvement (p < 0.01). Shorter intraretinal cyst length, ERM and the absence of VMA at baseline were predictive of a worsened anatomical response (p < 0.001).
CONCLUSION: VRIA are related to outcome in patients treated with RZB. ERM was associated with a worsened visual and anatomic response, and VMA with an improved anatomical response particularly when spontaneous VMA release occurred during treatment. The presence and severity of ERM was not affected by RZB treatment. ||||| OBJECTIVE: The primary study hypothesis was that ranibizumab 0.5 mg monotherapy or combined with laser is superior to laser monotherapy based on mean average change in best-corrected visual acuity (BCVA) over 12 months in Asian patients with visual impairment resulting from diabetic macular edema (DME).
DESIGN: A 12-month, randomized, double-masked, multicenter, laser-controlled, phase III study.
PARTICIPANTS: Three hundred ninety-six patients aged ≥18 years, with type 1 or 2 diabetes mellitus, BCVA of 78-39 Early Treatment Diabetic Retinopathy Study (ETDRS) letters, and visual impairment resulting from DME.
METHODS: Patients were randomized to ranibizumab + sham laser (n = 133), ranibizumab + active laser (n = 132), or sham injection + active laser (n = 131). Ranibizumab/sham injections were administered on day 1 and continued monthly. As of month 3, monthly injections were continued if stable vision was not reached. Treatment was reinitiated if BCVA decreased because of DME progression. Active/sham laser was administered on day 1 and thereafter according to ETDRS guidelines.
MAIN OUTCOME MEASURES: Average change in BCVA from baseline to months 1 through 12, central retinal subfield thickness (CRST), and safety over 12 months.
RESULTS: Ranibizumab monotherapy or combined with laser was superior to laser in improving mean average change in BCVA from baseline to months 1 through 12 (+5.9 and +5.7 vs +1.4 letters). At month 12, greater proportion of patients gained ≥15 letters with ranibizumab and ranibizumab + laser compared with laser (18.8% and 17.8% vs 7.8%). Mean CRST reduced significantly from baseline to month 12 with ranibizumab (-134.6 μm) and ranibizumab + laser (-171.8 μm) versus laser (-57.2 μm). Patients received a mean of 7.8 and 7.0 ranibizumab injections in the ranibizumab and ranibizumab + laser arms, respectively, and 1.5-1.9 active laser across treatment arms over 12 months. Conjunctival hemorrhage was the most common ocular, whereas nasopharyngitis and hypertension were the most common nonocular adverse events. Ranibizumab was not associated with any cases of cerebrovascular hemorrhage and cerebrovascular ischemia. No death related to study treatment was reported.
CONCLUSIONS: Ranibizumab monotherapy or combined with laser showed superior BCVA improvements over laser treatment alone in Asian patients with visual impairment resulting from DME. No new ocular or nonocular safety findings were observed and treatment was well tolerated over 12 months. ||||| BACKGROUND: Anti vascular endothelial growth factor (VEGF) therapy is an established treatment for various retinal diseases. Long-term data on injection frequencies and visual acuity (VA), however, are still rare.
METHODS: Five-year analysis of real-life VA developments and injection patterns from 2072 patients (2577 eyes; 33 187 injections) with chronically active disease undergoing pro-re-nata treatment for age-related macular degeneration (AMD), diabetic macular oedema (DME), retinal vein occlusion (RVO) and myopic choroidal neovascularisation (CNV).
RESULTS: Maximum mean VA gain in year 1 was+5.2 letters in AMD, +6.2 in DME, +10 in RVO and+7.2 in myopic CNV. Over 5 years, however, VA in patients with AMD declined. By year 5, 34% of patients with AMD had experienced VA loss of >15 letters, 56% had remained stable and 10% had gained >15 letters. Long-term VA developments in DME and RVO were more favourable with 81% of DME and 79% of patients with RVO gaining or maintaining vision at 5 years. In AMD, median injection frequency was six in year 1 and between four and five in consecutive years. In DME and RVO, median injection frequency was six in year 1 but lower compared with AMD in consecutive years. Injection frequency in DME was weakly associated with patient age (r
CONCLUSIONS: In AMD, the initial VA gain was not maintained long term despite higher injection numbers compared with DME, RVO and myopic CNV. The presented real-world data provide a peer-group-based estimate of VA developments and injection frequencies for counselling patients undergoing long-term anti-VEGF therapy. ||||| AIMS: To describe baseline characteristics and visual outcome for eyes treated with ranibizumab for diabetic macular oedema (DMO) from a multicentre database.
METHODS: Structured clinical data were anonymised and extracted from an electronic medical record from 19 participating UK centres: age at first injection, ETDRS visual acuity (VA), number of injections, ETDRS diabetic retinopathy (DR) and maculopathy grade at baseline and visits. The main outcomes were change in mean VA from baseline, number of injections and clinic visits and characteristics affecting VA change and DR grade.
RESULTS: Data from 12 989 clinic visits was collated from baseline and follow-up for 3103 eyes. Mean age at first treatment was 66 years. Mean VA (letters) for eyes followed at least 2 years was 51.1 (SD=19.3) at baseline, 54.2 (SD: 18.6) and 52.5 (SD: 19.4) at 1 and 2 years, respectively. Mean visual gain was five letters. The proportion of eyes with VA of 72 letters or better was 25% (baseline) and 33% (1 year) for treatment naïve eyes. Eyes followed for at least 6 months received a mean of 3.3 injections over a mean of 6.9 outpatient visits in 1 year.
CONCLUSIONS: In a large cohort of eyes with DMO treated with ranibizumab injections in the UK, 33% of patients achieved better than or equal to 6/12 in the treated eye at 12 months compared with 25% at baseline. The mean visual gain was five letters. Eyes with excellent VA at baseline maintain good vision at 18 months. ||||| Importance: Post hoc analyses from the Diabetic Retinopathy Clinical Research Network randomized clinical trial comparing aflibercept, bevacizumab, and ranibizumab for diabetic macular edema (DME) might influence interpretation of study results.
Objective: To provide additional outcomes comparing 3 anti-vascular endothelial growth factor (VEGF) agents for DME.
Design, Setting, and Participants: Post hoc analyses performed from May 3, 2016, to June 21, 2016, of a randomized clinical trial performed from August 22, 2012, to September 23, 2015, of 660 participants comparing 3 anti-VEGF treatments in eyes with center-involved DME causing vision impairment.
Exposures: Randomization to intravitreous aflibercept (2.0 mg), bevacizumab (1.25 mg), or ranibizumab (0.3 mg) administered up to monthly based on a structured retreatment regimen. Focal/grid laser treatment was added after 6 months for the treatment of persistent DME.
Main Outcomes and Measures: Change in visual acuity (VA) area under the curve and change in central subfield thickness (CST) within subgroups based on whether an eye received laser treatment for DME during the study.
Results: Post hoc analyses were performed for 660 participants (mean [SD] age, 61 [10] years; 47% female, 65% white, 16% black or African American, 16% Hispanic, and 3% other). For eyes with an initial VA of 20/50 or worse, VA improvement was greater with aflibercept than the other agents at 1 year but superior only to bevacizumab at 2 years. Mean (SD) letter change in VA over 2 years (area under curve) was greater with aflibercept (+17.1 [9.7]) than with bevacizumab (+12.1 [9.4]; 95% CI, +1.6 to +7.3; P < .001) or ranibizumab (+13.6 [8.5]; 95% CI, +0.7 to +6.0; P = .009). When VA was 20/50 or worse at baseline, bevacizumab reduced CST less than the other agents at 1 year, but at 2 years the differences had diminished. In subgroups stratified by baseline VA, anti-VEGF agent, and whether focal/grid laser treatment was performed for DME, the only participants to have a substantial reduction in mean CST between 1 and 2 years were those with a baseline VA of 20/50 or worse receiving bevacizumab and laser treatment (mean [SD], -55 [108] µm; 95% CI, -82 to -28 µm; P < .001).
Conclusions and Relevance: Although post hoc analyses should be viewed with caution given the potential for bias, in eyes with a VA of 20/50 or worse, aflibercept has the greatest improvement in VA over 2 years. Focal/grid laser treatment, ceiling and floor effects, or both may account for mean thickness reductions noted only in bevacizumab-treated eyes between 1 and 2 years.
Trial Registration: clinicaltrials.gov Identifier NCT01627249. | [
{
"source_pmid": "25692915",
"source_text": "BACKGROUND: The relative efficacy and safety of intravitreous aflibercept, bevacizumab, and ranibizumab in the treatment of diabetic macular edema are unknown.\nMETHODS: At 89 clinical sites, we randomly assigned 660 adults (mean age, 61±10 years) with diabetic m... |
19410949 | CONCLUSIONS: Intravitreal triamcinolone acetonide injection is effective in improving VA in patients with refractory DME in the short-term, but the benefits do not seem to persist in the long-term. | OBJECTIVE: To report 2-year safety and efficacy outcomes from a trial of intravitreal triamcinolone acetonide (TA) injections (4 mg) in eyes with diabetic macular edema and impaired vision that persisted or recurred after laser treatment.
DESIGN: Prospective, double-masked, placebo-controlled, randomized clinical trial.
PARTICIPANTS AND CONTROLS: Sixty-nine eyes of 43 patients were entered into the study, with 34 eyes randomized to receive active treatment and 35 placebo. Two-year data were available for 60 of 69 (87%) eyes of 35 of 41 (85%) patients; 9 eyes of 6 patients were lost to follow-up, of which 6 received a placebo and 3 received intravitreal TA.
INTERVENTION: Triamcinolone acetonide (0.1 ml) was injected through the pars plana using a 27-gauge needle. Eyes randomized to placebo received a subconjunctival injection of saline.
MAIN OUTCOME MEASURES: Improvement of best-corrected logarithm of the minimum angle of resolution visual acuity (VA) by > or =5 letters after 2 years and incidence of moderate or severe adverse events.
RESULTS: Improvement of > or =5 letters' best-corrected VA was found in 19 of 34 (56%) eyes treated with intravitreal TA, compared with 9 of 35 (26%) eyes treated with the placebo (z(generalized estimating equation) = 2.73, P = 0.006). The mean improvement in VA was 5.7 letters (95% confidence interval, 1.4-9.9) more in the intravitreal TA-treated eyes than in those treated with the placebo. An increase of intraocular pressure (IOP) of > or =5 mmHg was observed in 23 of 34 (68%) treated versus 3 of 30 (10%) untreated eyes (P<0.0001). Glaucoma medication was required in 15 of 34 (44%) treated versus 1 of 30 (3%) untreated eyes (P = 0.0002). Cataract surgery was performed in 15 of 28 (54%) treated versus 0 of 21 (0%) untreated eyes (P<0.0001). Two eyes in the intravitreal TA-treated group required trabeculectomy. There was one case of infectious endophthalmitis in the treatment group.
CONCLUSION: Intravitreal TA improves vision and reduces macular thickness in eyes with refractory diabetic macular edema. This beneficial effect persists for up to 2 years with repeated treatment. Progression of cataract and elevation of IOP commonly occur but appear manageable. Spontaneous improvement over years can still occur in eyes that are apparently severely affected by diabetic macular edema. ||||| PURPOSE: To compare the safety and efficacy of intravitreal versus posterior Sub-Tenon's capsule injection of triamcinolone acetonide for diffuse diabetic macular edema.
DESIGN: Prospective, double-masked, randomized controlled trial.
PARTICIPANTS: Twelve patients (24 eyes) with bilateral diffuse diabetic macular edema.
INTERVENTION: One eye of each patient was randomly assigned to receive a single 4-mg triamcinolone acetonide intravitreal injection and the fellow eye to receive a 40-mg triamcinolone acetonide posterior Sub-Tenon's capsule injection.
MAIN OUTCOME MEASURES: Changes in visual acuity and central macular thickness obtained using optical coherence tomography were measured during a 6-month follow-up. Potential treatment complications were monitored, including increases in intraocular pressure (IOP) and cataract progression.
RESULTS: Both intravitreal and Sub-Tenon's capsule injections of triamcinolone acetonide resulted in significant but transient improvements in central macular thickness. The mean (+/-standard deviation [SD]) central macular thickness in eyes with intravitreal injection was significantly thinner than in the Sub-Tenon's capsule-injected eyes at 1 month (226.8+/-41.7 microm and 431.5+/-165.8 microm, respectively; P = 0.002) and 3 months (242.3 +/- 93.9 microm and 364.7+/-78.2 microm, respectively; P = 0.005) after triamcinolone acetonide injection. The mean visual acuity (logarithm of the minimum angle of resolution) in the intravitreally injected eyes was significantly better than in the Sub-Tenon's capsule-injected eyes at 3 months post injection (0.832+/-0.293 and 1.107+/-0.339, respectively; P = 0.004). Intraocular pressure did not show any significant difference between the 2 forms of triamcinolone acetonide delivery at any follow-up visit, and no eyes had IOPs >25 mmHg.
CONCLUSIONS: The findings from our study neither advocate nor support the use of corticosteroids for the treatment of diabetic macular edema, but do imply that both intravitreal and Sub-Tenon's capsule injections of triamcinolone acetonide may be equally tolerated, with short-term performance clearly favoring the intravitreal (4 mg) more than the SBT capsule (40 mg) route for the anatomic and functional aspects of improvement tested in this investigation. ||||| PURPOSE: The aim of this study was to examine the visual outcome of patients receiving an intravitreal injection of triamcinolone acetonide (TA) as treatment of diffuse diabetic macular edema (DDME).
METHODS: This prospective, placebo-controlled, randomized, clinical interventional study included 40 eyes (38 patients) with DDME, with 28 (70%) eyes randomized to treatment and 12 (30%) eyes randomized to receive a placebo injection. Thirty-six (36) (90%) eyes completed the 3-month study visit, and 32 (80%) eyes completed the 6-month study visit. The treatment group received an intravitreal injection of approximately 20 mg of TA.
RESULTS: Visual acuity increased significantly (P < 0.001) in the study group by 3.4 +/- 2.5 Snellen lines. In the control group, visual acuity did not change significantly (P = 0.07) during follow-up. Difference in change of best visual acuity was significant (P < 0.001) between both groups. At 3 months after baseline, 11 (11/26; 42%) eyes and 10 (10/26; 39%) eyes, respectively, improved by at least 2 and 3 lines, respectively, in the study group, versus 2 (2/10; 20%) eyes and 1 (1/10; 10%) eye in the control group. At 6 months after baseline, 11 (11/23; 48%) eyes and 9 (9/23; 39%) eyes, respectively, improved by at least 2 and 3 lines, respectively, in the study group, versus 0 (0%) eyes and 0 (0%) eyes in the control group. The difference was significant for the 2-line improvement (P = 0.01) and 3-line improvement (P = 0.03).
CONCLUSIONS: Using a dosage of approximately 20 mg of intravitreal TA, visual acuity temporarily increases for 6 months after injection. ||||| PURPOSE: To evaluate prospectively the efficacy and safety of one intravitreal injection of 4 mg triamcinolone acetonide for refractory diffuse diabetic macular edema.
METHODS: Seventeen patients with bilateral diabetic macular edema unresponsive to laser photocoagulation. In all patients, one eye was injected, and the other served as a control. The intervention consisted in intravitreal injection of 4 mg triamcinolone acetonide. The main outcome measure was central macular thickness (CMT) at 4, 12 and 24 weeks, measured by Optical Coherence Tomography. Secondary outcomes were Early Treatment Diabetic Rentinopathy Study (ETDRS) scores, intraocular pressure and cataract PROGRESSION.
RESULTS: Before injection, mean +/- SD CMT was 566.4 +/- 182.4 mum in injected eyes. Four, 12, and 24 weeks after injection, it was 228.4 +/- 47.5 mum, 210.9 +/- 87.2 mum and 358.5 +/- 160.5 mum respectively. CMT was significantly lower in injected eyes vs. control eyes except 24 weeks after injection because of a recurrence of macular edema in 9/17 injected eyes. Mean +/- SD gain in ETDRS score was significantly better in injected eyes vs. control eyes 4, 12 and 24 weeks after TA injection. In 9 of the 17 injected eyes, intraocular pressure exceeded 24 mmHg and was controlled by topical medication.
CONCLUSION: In the short-term, intravitreal injection of triamcinolone effectively reduces macular thickening due to diffuse diabetic macular edema and improves visual acuity in most cases. The long-term effect of this treatment and predictive factors of visual recovery remain to be elucidated. ||||| PURPOSE: To compare the effectiveness of posterior sub-Tenon's infusion (STi) and intravitreal injection (IVI) of triamcinolone acetonide (TA) for treatment of refractory diffuse diabetic macular edema.
METHODS: Thirty-six phakic diabetic patients with refractory diffuse diabetic macular edema were prospectively enrolled. Patients randomly received either 40 mg STi or 4 mg IVI of TA. Comprehensive ophthalmic evaluation was performed at baseline and 1, 2, 4, 8 +/- 1, 12 +/- 2 and 24 +/- 2 weeks after treatment. Macular morphologic changes detected by optical coherence tomography and visual acuity, intraocular pressure, and lens status were evaluated.
RESULTS: Twenty-eight patients (28 eyes) completed the 24-week study. Central macular thickness was significantly reduced in the IVI group when compared with the STi group at 2, 4, 8, 12, and 24 weeks after treatment (P < 0.01). Mean visual acuities (in logarithm of the minimum angle of resolution [logMAR]) at week-4, -8, and -12 follow-up examinations were significantly higher in the IVI group (0.74, 0.75, and 0.82, respectively) when compared with the STi group (0.88, 0.88, and 0.90, respectively; P < 0.01). A significant change from baseline in mean intraocular pressure (mm Hg) was seen at weeks 4 (+/-3.21) and 8 (+/-3.35) in STi the group (P < 0.01), and at week 8 (+/-2.78) in the IVI group (P < 0.05). No patient had cataract progression during the study.
CONCLUSIONS: Although the number of patients and length of follow-up in this preliminary study were limited, the changes in central macular thickness and visual acuity observed after treatment suggest that IVI TA may be more effective than STi for the management of refractory diffuse diabetic macular edema. Further studies are needed to confirm these preliminary findings. ||||| PURPOSE: To evaluate the effect of intravitreal triamcinolone acetonide (IVT) on refractory diabetic macular edema (DME).
METHODS: In a prospective, placebo-controlled, randomized clinical trial, 88 eyes of 61 patients with clinically significant macular edema that would have responded unfavourably to laser photocoagulation were randomly assigned to two groups. The treatment group (45 eyes) received 4 mg IVT and the control group (43 eyes) received a placebo subconjunctival injection. The primary outcome was central macular thickness (CMT) measured by optical coherence tomography. Complete examination was repeated at 2 and 4 months post-intervention.
RESULTS: The mean (SD) CMT before the intervention and at the 2- and 4-month follow-ups was 393 (151), 293 (109) and 362 (119) microm in the treatment group and 393 (166), 404 (134) and 405 (160) microm in the placebo group, respectively. The second month difference was significant (P=0.01). The difference between visual acuity changes (0.15 logarithm of the minimum angle of resolution, logMAR) was significant at 2 months (P=0.02) but reduced to 0.11 logMAR (P=0.08) after 4 months. Reduction for hard exudates and petaloid pattern were significantly greater in cases at 4 months.
CONCLUSIONS: The therapeutic effect of IVT on DME is greatest at 2 months and decreases up to the fourth month post-intervention. However, in terms of cystoid macular edema and hard exudates, the effect is maintained up to 4 months. | [
{
"source_pmid": "16828501",
"source_text": "OBJECTIVE: To report 2-year safety and efficacy outcomes from a trial of intravitreal triamcinolone acetonide (TA) injections (4 mg) in eyes with diabetic macular edema and impaired vision that persisted or recurred after laser treatment.\nDESIGN: Prospective, do... |
22562509 | CONCLUSIONS: This meta-analysis showed the evidence that TP53 codon 72 (CC versus CG+GG) and intron 3 16-bp insertion (Ins versus Del) polymorphisms may affect individual susceptibility to POAG. Moreover, stratified analyses that detected the effect of TP53 codon 72 polymorphism seemed to be varied by ethnicity. Given the limited sample size, further investigations are needed to validate the association. | PURPOSE: Glaucoma is a complex neurodegenerative disorder of the eye. Primary Open Angle Glaucoma (POAG) is the most common type, accounting for over half of the total cases. Recently, a significant difference in the distribution of the codon 72 polymorphism of the tumor suppressor gene p53 between control subjects and POAG patients of Chinese origin (p=0.00782) was demonstrated. The proline residue at codon 72 of the p53 gene was significantly over represented in the POAG patients relative to healthy controls. The purpose of this study was to investigate whether the reported association between the p53 polymorphism and POAG is a common phenomenon irrespective of geographical location or ethnicity of the population.
METHODS: Sixty seven unrelated POAG patients, ranging from 10-65 years of age (mean+/-SD of 41.16+/-18.52 years), and 112 control subjects having a similar age range of 18-63 years (mean+/-SD of 36.64+/-14.65 years) were enrolled in this study. A region of the p53 gene encompassing two polymorphic sites, a 16 bp duplication in intron 3 and a BstU I RFLP in exon 4, were amplified by polymerase chain reaction from Indian POAG patients and normal healthy controls. A single base change (G to C) in codon 72 alters the amino acid residue from arginine to proline and removes the polymorphic BstU I site mentioned above. The amplified DNA fragments were digested with the restriction enzyme and the digestion patterns of the fragments were used to identify the alleles for both the polymorphic sites.
RESULTS: No significant association between p53 alleles and Indian POAG patients were observed by analyzing either codon 72 polymorphism (p=0.5627) or the intronic 16 bp duplication polymorphism (p=0.059). Haplotype analysis, reported to be a better predictor of association of the p53 gene with different types of cancer, was also performed and no association of any haplotype was detected with POAG (p=0.1831).
CONCLUSIONS: Association between the p53 gene encoding for proline at codon 72 and POAG presumably exists in some ethnic populations but cannot be used as a predictor for the role of the gene as a common regulator of cell death of retinal ganglions leading to POAG. ||||| PURPOSE: To investigate the association between Apolipoprotein E (APOE), tumor suppressor protein p53 (p53), and cyclin-dependent kinase inhibitor 1A (p21) genes and primary open-angle glaucoma (POAG) in a cohort of Turkish subjects.
METHODS: Seventy-five POAG patients (49 women, 26 men) and 119 healthy subjects (67 women, 52 men) were genotyped with polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Allele and genotype frequencies between healthy subjects and glaucoma patients were compared by the chi(2) test, and intraocular pressure (IOP), cup/disc ratio (C/D) and visual field indices (MD and PSD) were compared among different APOE, p53, and p21 genotypes in POAG group. A p value <0.05 was considered as statistically significant.
RESULTS: The mean ages were 63.8+/-9.5 and 61.8+/-10.2 years in POAG and control groups, respectively (p=0.18). There were no significant differences in the distribution of APOE, p53, and p21 genotypes between the healthy subjects and POAG patients (p=0.38, p=0.12, and p=0.2, respectively). There were no significant differences in maximum IOP, MD, and PSD values among different groups of p53 and p21 genotypes (p>0.05). POAG subjects with the epsilon2epsilon3 genotype had a worse PSD value (median=2.2) than those with the epsilon3epsilon4 genotype (median=1.77; p=0.01) and POAG subjects with the epsilon3epsilon3 genotype had worse MD and PSD values (median= -7.4 and 3.4, respectively) than those with the epsilon3epsilon4 genotype (median= -4.1 and 1.77, respectively; p=0.034 and 0.028, respectively).
CONCLUSIONS: Our study found no link between polymorphisms in APOE, p53, and p21 genes and POAG in Turkish patients, although a larger sample is required to elucidate the role of these polymorphisms in the pathogenesis and course of glaucoma. ||||| PURPOSE: To evaluate the variants of 10 genes for association with primary open-angle glaucoma (POAG) in a Chinese population.
METHODS: A total of 405 unrelated patients with POAG (255 high-tension glaucoma [HTG], 100 normal-tension glaucoma [NTG], and 50 juvenile-onset open-angle glaucoma [JOAG]) and 201 control subjects were recruited. Seventeen variants in 10 genes with reported association with POAG were genotyped for analysis of allele and haplotype frequencies between cases and control subjects. These genes included CDH1 (cadherin 1, type 1, E-cadherin), CDKN1A (cyclin-dependent kinase inhibitor 1A), CYP1B1 (cytochrome P450, family 1, subfamily B, polypeptide 1), GSTM1 (glutathione S-transferase mu 1), GSTT1 (glutathione S-transferase theta 1), MTHFR (5,10-methylenetetrahydrofolate reductase), NOS3 (nitric oxide synthase 3), OPA1 (optic atrophy 1), TNF (tumor necrosis factor), and TP53 (tumor protein p53).
RESULTS: One SNP (-308G>A; rs1800629) in TNF demonstrated a significant association with HTG (P = 0.012). The allele G frequency was higher in HTG patients than in control subjects (94.6% vs. 90.3%; OR = 1.89). One haplotype consisting of rs1799724 and rs1800629 was significantly associated with HTG (P = 0.015, corrected P = 0.045). One SNP (R72P; rs1042522) in TP53 was significantly associated with NTG (P = 0.018). The allele G frequency was higher in NTG patients than in control subjects (56.1% vs. 45.8%; OR = 1.52). The significance of these associations survived the Bonferroni correction (corrected P < 0.024). Other gene variants were not significantly associated with HTG (P > 0.063) or NTG (P > 0.13). None of the studied variants was significantly associated with JOAG (P > 0.17).
CONCLUSIONS: The findings suggest that variants in TNF and TP53 are risk factors for POAG, whereas variants in other studied genes are not major risk factors for POAG, at least in the Chinese population. ||||| PURPOSE: Apoptosis has been implicated as the mechanism for retinal ganglion cell death in primary open-angle glaucoma (POAG), a complex neurodegenerative disease. There have been inconsistent reports regarding increased risk of POAG and a polymorphism (Arg72Pro) within the tumor suppressor gene, p53. The goal of this study was to examine the role of this polymorphism in susceptibility to POAG in a Caucasian population from the United States.
METHODS: We generated genotypes in 191 unrelated Caucasian POAG patients and 167 unrelated Caucasian controls for the following polymorphisms within p53: rs1042522 (Arg72Pro), rs17878362 (16 bp Ins/Del), and rs1800371 (Pro47Ser) by PCR amplification followed by restriction digestion and sequence analysis.
RESULTS: There was a significant difference in genotypic frequencies for rs1042522 (Arg72Pro) between POAG patients and controls (chi(2)= 9.56, p=0.008). Individuals who were homozygous for the arginine allele have a 1.9 fold significantly increased risk of developing glaucoma (95%CI: 1.16-2.82, p=0.01). Interestingly, we found that the frequency of the arginine allele was even higher in the normal-tension glaucoma (NTG) subtype compared to high-tension POAG (0.81 versus 0.76).
CONCLUSIONS: Our preliminary results indicate that the arginine variant of rs1042522 within p53 is associated with increased risk of POAG. This variant has increased apoptotic potential, thus the retinal ganglion cells in carriers of the arginine allele may have greater susceptibility to apoptosis. ||||| PURPOSE: To assess whether tumor protein p53 gene (p53) polymorphisms are associated with primary open angle glaucoma (POAG) in the Japanese population.
METHODS: Four hundred and twenty-five Japanese patients with POAG, including normal tension glaucoma (NTG, n=213) and high tension glaucoma (HTG, n=212) and 189 control subjects without glaucoma were analyzed for two p53 polymorphisms (rs1042522; a G-->C substitution at codon 72 in exon 4 and rs59758982; a 16 base pair insertion in intron 3) using allele specific primer PCR and a pyrosequencing technique respectively. The genotypic and allelic frequencies were compared between NTG or HTG patients and control subjects.
RESULTS: No significant difference (NTG versus control, p=0.99, and HTG versus control, p=0.69, chi(2) test) was observed regarding the p53 genotype frequencies at codon 72 between the NTG (GG: 43.2%, GC: 44.6%, CC: 12.2%) or HTG (GG: 40.1%, GC: 48.1%, CC: 11.8%) patients and the control subjects (GG: 43.9%, GC: 43.9%, CC: 12.2%). In addition, there was no significant difference (NTG versus control, p=0.94; and HTG versus control, p=0.66, Fisher's exact test) in the p53 allele frequencies at codon 72 between the NTG (G allele: 65.5%, C allele: 34.5%) or HTG (G allele: 64.2%, C allele: 35.8%) patients and the control subjects (G allele: 65.9%, C allele: 34.1%). No 16 base pair insertion in intron 3 was found in this study.
CONCLUSION: p53 polymorphisms were not associated with POAG in the Japanese population. Further studies in the other ethnic populations should therefore be performed to elucidate whether the p53 intron 3 insertion polymorphism is a genetic risk factor for POAG, because the intron 3 insertion polymorphism occurs very rarely in the Japanese population. ||||| PURPOSE: To investigate the role of WDR36 and P53 sequence variations in POAG susceptibility.
METHODS: The authors performed a case-control genetic association study in 268 unrelated Spanish patients (POAG1) and 380 control subjects matched for sex, age, and ethnicity. WDR36 sequence variations were screened by either direct DNA sequencing or denaturing high-performance liquid chromatography. P53 polymorphisms p.R72P and c.97-147ins16bp were analyzed by single-nucleotide polymorphism (SNP) genotyping and PCR, respectively. Positive SNP and haplotype associations were reanalyzed in a second sample of 211 patients and in combined cases (n = 479).
RESULTS: The authors identified almost 50 WDR36 sequence variations, of which approximately two-thirds were rare and one-third were polymorphisms. Approximately half the variants were novel. Eight patients (2.9%) carried rare mutations that were not identified in the control group (P = 0.001). Six Tag SNPs were expected to be structured in three common haplotypes. Haplotype H2 was consistently associated with the disease (P = 0.0024 in combined cases). According to a dominant model, genotypes containing allele P of the P53 p.R72P SNP slightly increased glaucoma risk. Glaucoma susceptibility associated with different WDR36 genotypes also increased significantly in combination with the P53 RP risk genotype, indicating the existence of a genetic interaction. For instance, the OR of the H2 diplotype estimated for POAG1 and combined cases rose approximately 1.6 times in the two-locus genotype H2/RP.
CONCLUSIONS: Rare WDR36 variants and the P53 p.R72P polymorphism behaved as moderate glaucoma risk factors in Spanish patients. The authors provide evidence for a genetic interaction between WDR36 and P53 variants in POAG susceptibility, although this finding must be confirmed in other populations. ||||| Primary open angle glaucoma (POAG) is the most common type of glaucoma. The p53 codon 72 Arg-Pro (CGC to CCC) polymorphism of exon 4 affects various biological properties; recently, it was reported that this polymorphism affects the ability to induce apoptosis in vitro. Various genotypes have been found to be significantly associated with POAG. We examined the distribution of this polymorphism in 104 unrelated POAG patients and in 58 normal healthy individuals without history of POAG at the Pronto Clínica de Olhos in Goiânia, Brazil. The controls were recruited among individuals undergoing ophthalmological examination. Their genomic DNA was analyzed for p53 gene codon 72 polymorphism by polymerase chain reaction. The Arg72 allele was more common than the Pro72 allele in both groups. There was no significant difference in the distribution of the codon 72 polymorphism between groups (p= 0.3311). The genotype distribution in the POAG group was 23.07 Arg homozygote, 75 heterozygote, and 1.93% Pro homozygote, while in the control group it was 31.04 Arg homozygote, 68.96 heterozygote, and 0% Pro homozygote. We concluded that the p53 codon 72 Arg/Pro polymorphism is not associated with glaucoma in Brazilian patients. ||||| BACKGROUND: Glaucomatous neuropathy is a type of cell death by apoptosis. The p53 gene is one of the regulatory genes of apoptosis. Recently, p53 codon 72 polymorphism has been extensively studied to determine the risk factors responsible for many diseases. In the p53 gene, a single base change from G to C causes the alternation of amino acid residue 72 from arginine to proline. In this study the association between p53 codon 72 polymorphism and primary open angle glaucoma (POAG) patients was evaluated.
METHODS: 58 POAG patients and 59 healthy volunteers were enrolled in this study. Polymerase chain reaction based analysis was used to resolve the p53 codon 72 polymorphism.
RESULTS: There were significant differences in the distribution of the polymorphism between the control subjects and the POAG patients (p = 0.00782). The proline form of p53 gene codon 72 appears to be a significant risk factor in the development of POAG (odds ratio 2.389, 95% confidence interval: 1.14 to 5.01).
CONCLUSIONS: Retinal ganglion cells die during POAG by apoptosis. The tumour suppressor protein, p53, is one of the primary regulators steps of apoptosis, and the results of our study are compatible with this concept. ||||| BACKGROUND: The final common pathway for open angle glaucoma (OAG) is retinal ganglion cell apoptosis. Polymorphisms in p53, a major regulator of apoptosis, affect the efficiency of cell death induction. Association studies of p53 haplotypes and OAG have had conflicting results.
OBJECTIVE: To examine the association between p53 haplotypes and OAG in a larger white population than in previous reports, and extend the analysis to normal tension glaucoma.
METHODS: 345 unrelated people with OAG were recruited (283 subjects with high tension glaucoma and 62 with normal tension glaucoma) and compared with 178 age matched controls. Genomic DNA was analysed for the p53 codon 72 Arg/Pro polymorphism as well as for the presence or absence of a 16 bp intron 3 insertion.
RESULTS: In this white cohort no association was found between glaucoma (high or normal tension) and either sequence variant or haplotype.
CONCLUSIONS: The p53 codon 72 Arg/Pro polymorphism is not associated with age of onset or severity of glaucoma. | [
{
"source_pmid": "12368717",
"source_text": "PURPOSE: Glaucoma is a complex neurodegenerative disorder of the eye. Primary Open Angle Glaucoma (POAG) is the most common type, accounting for over half of the total cases. Recently, a significant difference in the distribution of the codon 72 polymorphism of t... |
19588397 | AUTHORS' CONCLUSIONS: The trials included in this review confirm the clinical observation that laser photocoagulation of drusen leads to their disappearance. However, there is no evidence that this subsequently results in a reduction in the risk of developing CNV, geographic atrophy or visual acuity loss. | [] | |
25044139 | CONCLUSIONS: Travoprost and bimatoprost are superior in IOP control than latanoprost, but latanoprost is better tolerated in patients with CACG. | BACKGROUND/AIMS: To compare the intraocular pressure (IOP) lowering efficacy and side effects of latanoprost 0.005% and bimatoprost 0.03% in subjects with chronic primary angle closure glaucoma (PACG).
METHODS: This was an observer-masked randomised crossover study of 60 PACG subjects who received either latanoprost or bimatoprost for 6 weeks, after which they were crossed over to the other medication for another 6 weeks. The IOP-reducing effect of the medications was assessed by the reduction in IOP after 6 weeks of treatment compared with baseline.
RESULTS: Fifty-four subjects (80 eyes) completed the study. Latanoprost reduced IOP (mean (SD)) by 8.4 (3.8) mm Hg and bimatoprost by 8.9 (3.9) mm Hg from a baseline of 25.2 (3.6) mm Hg and 25.2 (3.6) mm Hg respectively (p = 0.23). Adverse events were mild in both groups; however there were twice as many reports of an adverse event in the bimatoprost group (81%) compared with the latanoprost group (40%, p<0.01). Ocular irritation was the most frequently reported adverse event in both groups; 22 subjects (37.9%) treated with bimatoprost experienced ocular hyperaemia as compared with 13 subjects (22.4%) treated with latanoprost (p = 0.11).
CONCLUSIONS: Bimatoprost once daily was similarly effective in reducing IOP compared with latanoprost once daily in subjects with chronic PACG. Both drugs were well tolerated with mild ocular adverse events. ||||| PURPOSE: To compare the efficacy and safety of latanoprost and timolol in Chinese patients with chronic angle-closure glaucoma (CACG), who had undergone laser or surgical peripheral iridotomy but who continued to experience elevated intraocular pressure (IOP) levels.
PATIENTS AND METHODS: This 8-week, randomized, open-label, parallel, active-controlled study was conducted at 4 sites in China. Subjects were 18 to 75 years of age; had primary, unilateral, or bilateral CACG with an IOP between 21 and 35 mm Hg inclusive at screening; and had undergone peripheral iridotomy at least 1 month before study entry. Subjects were randomized (1:1) to receive 1 drop of latanoprost 0.005% (PM) or 1 drop of timolol 0.5% twice daily (AM and PM). Follow-up was at weeks 1, 2, 4, and 8. Primary efficacy endpoint: change in average IOP from baseline to week 8.
RESULTS: One hundred forty-two subjects were randomized into the latanoprost and timolol group; the analysis population included 141 subjects (latanoprost, n=71; timolol, n=70). Mean baseline average IOP levels were 24 mm Hg in both groups. The least square mean change from baseline to week 8 was -6.7 mm Hg for latanoprost versus -4.9 mm Hg for timolol [least square mean difference=1.8 mm Hg (95% confidence interval, 0.7-2.9); P<0.001]. Latanoprost was associated with significantly lower mean average IOP levels at each visit (P<0.05). Both treatments were well tolerated and no treatment-emergent adverse event was considered by investigators to be severe.
CONCLUSIONS: Once-daily administration of latanoprost 0.005% was significantly more effective in reducing IOP in Chinese patients with CACG than twice-daily instillation of timolol 0.5%. Both agents were well tolerated. ||||| OBJECTIVE: To compare the intraocular pressure (IOP)-reducing effect and side effects of 0.005% latanoprost once daily to 0.5% timolol twice daily in patients with primary chronic angle closure glaucoma (CACG).
DESIGN: Randomized, double-masked two-center clinical trial.
PARTICIPANTS: Thirty-two Asian patients with CACG, defined as glaucomatous optic neuropathy with a compatible visual field defect and at least 6 clock hours of synechial angle closure on gonioscopy were recruited. All patients had previous peripheral iridotomy (PI) with IOP >21 mmHg after PI and were thereafter controlled (IOP <22 mmHg) with one or two pressure-reducing drugs.
INTERVENTION: After a washout period, the patients were randomized to a 2-week treatment period with either placebo in the morning and 0.005% latanoprost in the evening or 0.5% timolol twice daily.
MAIN OUTCOME MEASURES: The short-term IOP reduction of latanoprost and timolol in patients with CACG. IOP was measured at baseline, and after 2, 7, and 14 days of treatment. In addition, the short-term ocular and systemic adverse events of the two drugs were evaluated.
RESULTS: Thirty patients completed the study. Two patients in the timolol group were withdrawn because of inadequate IOP control. Compared with baseline, the IOP after 2 weeks of treatment was statistically significantly reduced by 8.8 +/- 1.1 mmHg (mean +/- SEM, P < 0.001) in the latanoprost group, and by 5.7 +/- 0.9 mmHg (P < 0.001) in the timolol group. The difference in IOP reduction between the two treatment groups was 3.1 +/- 1.5 mm Hg in favor of latanoprost (P = 0.04). The main ocular adverse events reported in both treatment groups were conjunctival hyperemia and discomfort.
CONCLUSIONS: In this preliminary study, a significantly greater IOP reduction was achieved with 0.005% latanoprost once daily compared with 0.5% timolol twice daily in patients with CACG. The results suggest that latanoprost may be a therapeutic choice for the medical treatment of primary CACG. ||||| PURPOSE: The aim of this study was to compare the intraocular pressure (IOP)-lowering effect of latanoprost and bimatoprost as primary therapy in patients with chronic angle-closure glaucoma (CACG) after peripheral iridotomy.
METHODS: Eighty-two (82) consecutive CACG patients with an IOP greater than 19 mmHg after a peripheral iridotomy were recruited. CACG was defined as chronic elevated IOP, glaucomatous optic neuropathy, and a corresponding visual field defect in eyes with occludable angle and peripheral anterior synechiae on gonioscopy. Patients were randomly assigned to two groups based on daily treatment with either latanoprost 0.005% or bimatoprost 0.03% in the evening for 12 weeks. The IOP was measured at 9 AM and 4 PM on the same day at baseline and also at 4, 8, and 12 weeks. Between-group differences in mean diurnal IOP and IOP reduction were analyzed.
RESULTS: After 12 weeks of treatment, mean IOP for both the latanoprost and bimatoprost groups was significantly reduced when compared to the baseline value (21.6 +/- 1.9 to 16.4 +/- 2.5 mmHg and 22.1 +/- 2.0 to 16.9 +/- 2.4 mmHg, respectively; P < 0.001 for both). There was no significant difference in IOP reduction between the two treatment groups (P = 0.40). At 4 and 8 weeks, the IOP changes from baseline were statistically significant at both times for both drugs (all P < 0.001).
CONCLUSIONS: Both latanoprost and bimatoprost significantly reduced IOP in CACG patients who were inadequately treated by laser peripheral iridotomy. ||||| To compare the efficacy, adverse effects, and patient compliance of latanoprost monotherapy with unfixed combination therapy with 0.5% timolol maleate and 1% dorzolamide in the treatment of chronic primary angle-closure glaucoma (CACG), 36 Japanese patients with CACG following laser iridotomy (LPI) were treated for 12 weeks with instillation of latanoprost alone or with unfixed combination therapy of 0.5% timolol maleate and 1% dorzolamide hydrochloride. After 12 weeks of treatment, latanoprost reduced intraocular pressure (IOP) from 22.2 +/- 2.0 mmHg to 14.8 +/- 1.9 mmHg (33% reduction); timolol maleate and dorzolamide hydrochloride also reduced IOP from 22.5 +/- 2.2 mmHg to 17.1 +/- 2.7 mmHg (24% reduction). Latanoprost monotherapy significantly lowered IOP compared with unfixed combination therapy of 0.5% timolol maleate and 1% dorzolamide hydrochloride. Furthermore, a systemic adverse effect of bradycardia was not observed in the latanoprost monotherapy group. Concerning compliance, no significant difference was observed between the two groups. Thus, latanoprost monotherapy is more effective than unfixed combination therapy with 0.5% timolol maleate and 1% dorzolamide in the treatment of CACG following relief of pupillary block in Japanese patients. ||||| OBJECTIVE: To compare latanoprost and timolol maleate as primary therapy in 60 eyes with chronic primary angle-closure glaucoma after a laser iridotomy.
METHODS: We performed a prospective, randomized, crossover study of 60 eyes of 30 patients with chronic primary angle-closure glaucoma after laser iridotomy. Patients were randomized to 2 groups: those taking latanoprost once daily or those taking timolol twice daily. Three months after treatment with the first drug, the second drug was substituted. The circadian rhythm of intraocular pressure (IOP) was recorded before the start of therapy, at 3 months, and at 7 months. The fourth month was the washout period for the first drug.
RESULTS: The mean baseline IOP was 23.5 +/- 2.1 mm Hg, which decreased by 8.2 +/- 2.0 mm Hg with latanoprost (P<.001) and by 6.1 +/- 1.7 mm Hg with timolol (P =.01). The decrease in IOP was greater for patients taking latanoprost (P<.001). Latanoprost was significantly more effective in eyes having morning and afternoon peaks of IOP. A total of 43 eyes (72%) of patients taking latanoprost and 26 (43%) on timolol achieved a reduction of more than 30% from baseline IOP.
CONCLUSION: There were greater mean and peak IOP reductions achieved with 0.005% latanoprost once daily compared with 0.5% timolol twice daily. ||||| OBJECTIVE: To demonstrate that the intraocular pressure (IOP)-reducing effect of latanoprost once daily is at least as good as that of timolol twice daily in patients with chronic angle-closure glaucoma (CACG).
DESIGN: Randomized, double-masked, multicenter 12-week study.
PARTICIPANTS: In all, 137 patients with unilateral or bilateral CACG were treated with latanoprost, and 138 were treated with timolol.
METHODS: Patients received either latanoprost (9 pm) and a placebo (9 am) or timolol (both 9 am and 9 pm). Intraocular pressure was measured at 9 am and 5 pm at baseline and weeks 2, 6, and 12.
MAIN OUTCOME MEASURES: The difference between groups in daily IOP (average of 9 am and 5 pm measures) reduction was the primary outcome. Secondary outcomes included differences between groups in IOP reductions at 9 am and 5 pm, and in proportions of patients reaching specified daily IOP levels.
RESULTS: Using repeated measures (analysis of covariance: intent to treat), mean changes from baseline in daily IOP levels during 12 weeks were -8.2 mmHg and -5.2 mmHg for latanoprost- and timolol-treated patients, respectively (difference: -3.0 mmHg [95% confidence interval: -4.0, -2.1], P<0.001). Greater reductions in IOP levels at both 9 am and 5 pm were found in latanoprost-treated patients (P<0.001 for both), and greater proportions of patients receiving latanoprost reached prespecified target daily IOP levels (P<0.001 for all 3 target levels tested). Both drugs were well tolerated.
CONCLUSION: Latanoprost administered once daily provides significantly greater IOP reduction in CACG patients than does timolol instilled twice daily. ||||| PURPOSE: The aim of this study was to compare the intraocular pressure (IOP)-lowering effect of latanoprost and travoprost as primary therapy in patients with chronic angle-closure glaucoma (CACG) after peripheral iridotomy.
METHODS: Seventy-three (73) CACG patients with IOP>19 mmHg after peripheral iridotomy and without previous antiglaucoma medication were consecutively recruited. CACG was defined as the presence of chronically elevated IOP, glaucomatous optic neuropathy, and a corresponding visual field defect in eyes with occludable angle and peripheral anterior synechiae on gonioscopy. Patients were randomly assigned to 2 groups, based on daily treatment with either latanoprost 0.005% or travoprost 0.004% in the evening for 12 weeks. The IOP was measured at 9 AM and 4 PM at baseline and at 4, 8, and 12 weeks. Between-group differences in mean diurnal IOP and IOP reduction were analyzed.
RESULTS: After 12 weeks of treatment, mean IOP for both the latanoprost and travoprost groups was significantly reduced, when compared to the baseline IOP (from 21.3+/-1.8 mmHg to 16.0+/-2.3 mmHg and 21.7+/-1.7 to 16.7+/-2.2 mmHg; P<0.001 for both). There was no significant difference in IOP reduction between the 2 treatment groups (P=0.19). At 4 and 8 weeks, the IOP changes from the baseline were statistically significant at all time points for both drugs (all P<0.001).
CONCLUSIONS: Both latanoprost and travoprost significantly reduced IOP in our sample of CACG patients after peripheral iridotomy. | [
{
"source_pmid": "19336424",
"source_text": "BACKGROUND/AIMS: To compare the intraocular pressure (IOP) lowering efficacy and side effects of latanoprost 0.005% and bimatoprost 0.03% in subjects with chronic primary angle closure glaucoma (PACG).\nMETHODS: This was an observer-masked randomised crossover st... |
18591929 | CONCLUSIONS: Evidence for an association between MYOC.mt1 and the risk of POAG is limited. These results suggest that MYOC.mt1 polymorphism does not have significant influence on the risk of POAG development or its severity. However, the evidence of publication bias suggests that more large prospective cohort studies with precise design are required to confirm an association between MYOC.mt1 and POAG. | PURPOSE: To investigate the proximal 2.5 kb promoter in the myocilin (MYOC) gene for mutations in Chinese patients with primary open-angle glaucoma (POAG).
PATIENTS AND METHODS: We screened for sequence alterations in the MYOC promoter in 88 unrelated Chinese patients with POAG and 94 unrelated individuals without glaucoma, aged 50 years or above, as control subjects. In addition, the specific MYOC.mt1 polymorphism was determined in a total of 212 POAG patients and 221 control subjects. The relationships between POAG phenotype and the identified polymorphisms were studied by univariate analysis, multivariable logistic regression analysis, and haplotype analysis.
RESULTS: All polymorphisms identified in this study followed Hardy-Weinberg equilibrium (P > 0.12) both in POAG patients and controls. Both univariate and multivariable logistic regression analyses showed no polymorphism that was significantly associated with the risk of POAG, P > 0.08 and P > 0.044 respectively. Haplotype analysis further indicated no association of MYOC promoter polymorphisms with the susceptibility for POAG (P > 0.1). On the other hand, there was no difference of POAG phenotypes among different genotypes of MYOC.mt1 (P > 0.31).
CONCLUSIONS: In this study on the Chinese population, polymorphisms in the MYOC promoter are not related to the risk of POAG. There is no association between the MYOC.mt1 promoter polymorphism with the severity of POAG. ||||| Primary open-angle glaucoma (POAG) is a highly prevalent optic neuropathy and a major cause of irreversible blindness, with elevation of intraocular pressure (IOP) being a primary risk factor. The trabecular meshwork-inducible glucocorticoid response (TIGR)/MYOCILIN (MYOC) gene coding region is mutated in 3-4% of POAG patients. Here, in a retrospective study of 142 POAG patients, we evaluated the influence on glaucoma phenotype of a novel biallelic polymorphism (-1000C/G) located in the upstream region of the MYOC gene. Allele frequencies were similar among patients and controls. However, the G allele (frequency 17.6%), also designated as MYOC.mt1, was associated with an increased IOP (+4.9 mmHg, p=0.0004) and a more damaged visual field (p=0.02). Both effects were predominant in females. Moreover, whereas IOP in MYOC.mt1 noncarriers decreased very markedly to the normal range between diagnosis and inclusion in the study (p=3 x 10(-5) in both males and females), reflecting successful therapy, it decreased less noticeably in MYOC.mt1+ male patients (p=0.005) and not at all in MYOC.mt1+ female patients. MYOC.mt1 appears therefore to be an indicator of poor IOP control and greater visual field damage in diagnosed POAG patients, potentially due to a lack of response to therapeutic intervention. Its typing might help in the selection of treatment paradigms for the management of POAG patients. ||||| OBJECTIVE: To determine the prevalence and associated phenotype of myocilin (MYOC) coding sequence variations and a specific promoter polymorphism (MYOC.mt1) in patients with glaucoma and glaucoma suspects.
METHODS: A consecutive, unselected series of 779 patients (652 with open-angle glaucoma and 127 glaucoma suspects) were recruited from a university medical center and clinically characterized. The coding sequences of the MYOC gene and the MYOC.mt1 locus in the promoter region were screened for sequence variations. We determined the prevalence of MYOC coding sequence mutations and the MYOC.mt1 promoter polymorphism. We also compared the clinical features of individuals with and without mutations and the MYOC.mt1 promoter polymorphism.
RESULTS: Plausible disease-causing sequence variations (DCVs) in the MYOC gene were found in 3.0% of the entire group. Such variations were found in patients with most forms of open-angle glaucoma studied. Patients with primary open-angle glaucoma (POAG) who harbored coding sequence DCVs were clinically similar to patients without them. Patients who harbored the rarer allele of the MYOC.mt1 promoter polymorphism were no different in any measure of disease severity from those who harbored the more common allele.
CONCLUSIONS: MYOC DCVs were found in approximately 3% of patients with glaucoma and glaucoma suspects. The 2 alleles of the MYOC.mt1 promoter polymorphism were equally distributed among patients with POAG and healthy control subjects. Patients with POAG who harbored the rarer allele of the MYOC.mt1 promoter polymorphism were no different from those with the more common variant in any measure of disease severity.
CLINICAL RELEVANCE: Testing for the MYOC.mt1 promoter polymorphism appears to be of no value in the evaluation of patients with glaucoma. ||||| PURPOSE: To evaluate the association of the myocilin gene promoter variant -1000C>G (MYOC.mt1) with primary open angle glaucoma (POAG) and its possible role on the phenotype and the severity of glaucoma in Turkish patients.
METHODS: Eighty eight POAG patients and 123 healthy subjects were included in the study. All subjects were genotyped by PCR-RFLP. Allele and genotype frequencies between healthy subjects and glaucoma patients were compared by the chi2 test. The age at diagnosis, the age at inclusion, the maximum IOP at diagnosis and the number of antiglaucomatous medications were compared between MYOC.mt1 carriers and non-carriers using the Student's t-test; C/D ratio, mean deviation (MD), and pattern standard deviation values were compared with the Mann-Whitney U-test. Statistical significance was defined as p<0.05.
RESULTS: MYOC.mt1 genotype and allele frequencies did not differ in POAG and healthy subjects (p=0.204 and p=0.083, respectively). In the control group, 17.1% of the subjects were MYOC.mt1 carriers, while 27.3% of the POAG patients were MYOC.mt1 carriers (p=0.107). The odds ratio for CG was 1.859 (95% CI: 0.9-3.7; p=0.084) and for GG 1.594 (95% CI: 0.31-8.13; p=0.575). The phenotype variables were quite similar in MYOC.mt1 carriers and non-carriers. Gender by itself or with the MYOC.mt1 did not have any effect on IOP, C/D ratio, or MD values (univariate analysis of variance, p>0.05). No significant difference was found in the distribution of genotypes between different stages of glaucoma groups (p=0.93).
CONCLUSIONS: Our results suggest that in our Turkish glaucoma patients, MYOC.mt1 is not a risk factor for the development of POAG and is not associated with the phenotype and severity of glaucoma. | [
{
"source_pmid": "15354075",
"source_text": "PURPOSE: To investigate the proximal 2.5 kb promoter in the myocilin (MYOC) gene for mutations in Chinese patients with primary open-angle glaucoma (POAG).\nPATIENTS AND METHODS: We screened for sequence alterations in the MYOC promoter in 88 unrelated Chinese pa... |
22440158 | CONCLUSIONS: Our meta-analysis indicated strong protective effects of the variant alleles of four SNPs in CFB/C2 gene (rs9332739, rs547154, rs4151667, and rs641153) against AMD. The disease risk descended to nearly one half for individuals carrying at least one copy of the rare alleles. The protective effects seemed to be stronger in Caucasians, of which the genotype frequencies were also higher. | BACKGROUND: Age-related maculopathy (ARM) is a common cause of visual impairment in the elderly populations of industrialized countries and significantly affects the quality of life of those suffering from the disease. Variants within two genes, the complement factor H (CFH) and the poorly characterized LOC387715 (ARMS2), are widely recognized as ARM risk factors. CFH is important in regulation of the alternative complement pathway suggesting this pathway is involved in ARM pathogenesis. Two other complement pathway genes, the closely linked complement component receptor (C2) and complement factor B (CFB), were recently shown to harbor variants associated with ARM.
METHODS/PRINCIPAL FINDINGS: We investigated two SNPs in C2 and two in CFB in independent case-control and family cohorts of white subjects and found rs547154, an intronic SNP in C2, to be significantly associated with ARM in both our case-control (P-value 0.00007) and family data (P-value 0.00001). Logistic regression analysis suggested that accounting for the effect at this locus significantly (P-value 0.002) improves the fit of a genetic risk model of CFH and LOC387715 effects only. Modeling with the generalized multifactor dimensionality reduction method showed that adding C2 to the two-factor model of CFH and LOC387715 increases the sensitivity (from 63% to 73%). However, the balanced accuracy increases only from 71% to 72%, and the specificity decreases from 80% to 72%.
CONCLUSIONS/SIGNIFICANCE: C2/CFB significantly influences AMD susceptibility and although accounting for effects at this locus does not dramatically increase the overall accuracy of the genetic risk model, the improvement over the CFH-LOC387715 model is statistically significant. ||||| Genome-wide association studies (GWASs) assess correlation between traits and DNA sequence variation using large numbers of genetic variants such as single nucleotide polymorphisms (SNPs) distributed across the genome. A GWAS produces many trait-SNP associations with low p-values, but few are replicated in subsequent studies. We sought to determine if characteristics of the genomic loci associated with a trait could be used to identify initial associations with a higher chance of replication in a second cohort. Data from the age-related eye disease study (AREDS) of 100,000 SNPs on 395 subjects with and 198 without age-related macular degeneration (AMD) were employed. Loci highly associated with AMD were characterized based on the distribution of genotypes, level of significance, and clustering of adjacent SNPs also associated with AMD suggesting linkage disequilibrium or multiple effects. Forty nine loci were highly associated with AMD, including 3 loci (CFH, C2/BF, LOC387715/HTRA1) already known to contain important genetic risks for AMD. One additional locus (C3) reported during the course of this study was identified and replicated in an additional study group. Tag-SNPs and haplotypes for each locus were evaluated for association with AMD in additional cohorts to account for population differences between discovery and replication subjects, but no additional clearly significant associations were identified. Relying on a significant genotype tests using a log-additive model would have excluded 57% of the non-replicated and none of the replicated loci, while use of other SNP features and clustering might have missed true associations. ||||| Dysregulation of the alternative pathway (AP) of complement cascade has been implicated in the pathogenesis of age-related macular degeneration (AMD), the leading cause of blindness in the elderly. To further test the hypothesis that defective control of complement activation underlies AMD, parameters of complement activation in blood plasma were determined together with disease-associated genetic markers in AMD patients. Plasma concentrations of activation products C3d, Ba, C3a, C5a, SC5b-9, substrate proteins C3, C4, factor B and regulators factor H and factor D were quantified in patients (n = 112) and controls (n = 67). Subjects were analyzed for single nucleotide polymorphisms in factor H (CFH), factor B-C2 (BF-C2) and complement C3 (C3) genes which were previously found to be associated with AMD. All activation products, especially markers of chronic complement activation Ba and C3d (p<0.001), were significantly elevated in AMD patients compared to controls. Similar alterations were observed in factor D, but not in C3, C4 or factor H. Logistic regression analysis revealed better discriminative accuracy of a model that is based only on complement activation markers Ba, C3d and factor D compared to a model based on genetic markers of the complement system within our study population. In both the controls' and AMD patients' group, the protein markers of complement activation were correlated with CFH haplotypes.This study is the first to show systemic complement activation in AMD patients. This suggests that AMD is a systemic disease with local disease manifestation at the ageing macula. Furthermore, the data provide evidence for an association of systemic activation of the alternative complement pathway with genetic variants of CFH that were previously linked to AMD susceptibility. ||||| BACKGROUND: Age related macular degeneration (AMD) is a leading cause of blindness. AMD is a complex disorder caused by genetic and environmental factors in which single nucleotide polymorphisms (SNPs) in the genes CFH and LOC387715/HTRA1/ARMS2 have prognostic importance for progression to advanced AMD (with visual loss). CFH may also have a pharmacogenetic role by affecting treatment response to widely used nutritional supplements. This paper examines other AMD susceptibility genes to determine if these genotypes influenced disease progression and treatment response.
METHODS: Three cohorts, totalling 3137 individuals, were genotyped for SNPs in 13 genes previously published to be associated with advanced AMD (other than CFH and LOC387715/ARMS2/HTRA1). Those genes found associated were then evaluated for their involvement in disease progression. Interactions between the genes and with AREDS (Age-Related Eye Disease Study) nutritional supplements were investigated.
RESULTS: Positive independent associations were noted in SNPs in the genes C2 (p = 0.0001, odds ratio (OR) 0.35, 95% confidence interval (CI) 0.2 to 0.6), CFB (p = 0.0001, OR 0.35, 95% CI 0.2 to 0.6), C3 (p = 0.0001, OR 3.91, 95% CI 1.94 to 7.88), APOE (epsilon4, p = 0.01, OR 0.50, 95% CI 0.29 to 0.86) and VEGFA (p = 0.01, OR 2.23, 95% CI 1.06 to 4.68). C2/CFB and C3 were independently related to progression from early/intermediate to advanced AMD with OR 0.32 (95% CI 0.14 to 0.73) and 3.32 (95% CI 1.46 to 7.59), respectively. Gene-gene and pharmacogenetic interactions were not observed. No preferential associations were observed with geographic atrophy or choroidal neovascularisation.
CONCLUSION: This study provides insights into the genetic pathogenesis of AMD. Five genes have now been shown to be independently involved in progression from intermediate disease (before vision loss has occurred) to advanced disease in which blindness is frequent. ||||| BACKGROUND: The present study was undertaken to replicate the associations of representative polymorphisms in three genes (complement factor H (CFH), complement factor B (BF) and HtrA serine peptidase 1 (HTRA1)) with exudative age-related macular degeneration (AMD) in a Han Chinese population, and to test if the modifiable environmental factors affect AMD susceptibility associated with different type of genotype in these genes.
METHODS: An age, gender and ethnicity matched case-control study was conducted to genotype the representative single neucleotide polymorphisms (SNPs) loci including rs1061170 and rs1410996 in CFH, rs641153 and rs4151667 in BF and rs11200638 in HTRA1 gene in 144 exudative AMD patients and 126 normal controls using PCR-RFLP and direct resequencing. The demographic characteristics and behavioral risk factors were also recorded. Allelic and genotypic associations for individual SNP and joint associations with two loci were performed. The gene-gene and gene-environment interactions were analyzed using multivariate non-conditional Logistic regression analysis.
RESULTS: The C risk allele frequencies for CFH Y402H (rs1061170) in cases and controls were 12.5% and 5.4% respectively, which were much lower than those in Caucasians (P < 0.001). Compared with TT homozygous genotype, the CT heterozygous genotype was positively associated with AMD with odds ratio (OR) of 3.23 (1.36 - 5.07). However, the population attributable risk (PAR) of C allele was only 3.3% (1.4% - 4.3%). rs1410996 was also associated with AMD independent of Y402H. The ORs of exudative AMD for individuals carrying one copy risk allele and two copy risk alleles were 2.57 (1.21 - 5.45) and 4.76 (2.15 - 10.55) respectively, with correspondent PARs of 28.3% (2.0% - 40.5%) and 38.2% (21.8% - 45.4%). rs11200638 in HTRA1 was another susceptible locus for AMD and the risk homozygotes were significantly susceptible for exudutive AMD (OR = 3.98, 1.88 - 8.43) with PAR of 38.9% (24.3% - 45.8%). Education status and cigarette smoking were also related to exudative AMD. After controlling for environmental risk factors, CFH and HTRA1 SNPs were independently associated with exudative AMD, with OR of 3.50 (1.45 - 8.45) for CT genotype in Y402H, 3.34 (1.33 - 8.36) for GG genotype in rs1410996 and 3.85 (1.58 - 9.42) for AA genotype in rs11200638 respectively. The interaction analysis between gene and environmental factors showed that smoking synergistically increased susceptibility of AMD for heterozygotes of rs1410996, with OR(interaction) of 7.33 (P(interaction) = 0.029).
CONCLUSIONS: In a Han Chinese population, CFH and HTRA1 polymorphisms appear to be independently and possibly additively hereditary contributors to exudative AMD. Y402H polymorphism conferred a significant but relatively lower contribution in Chinese than in Caucasians with a low frequency of risk allele. The gene-environment interaction may be a best way to encourage those with a high genetic risk to prevent AMD by avoiding modifiable factors until there is effective treatment for AMD. ||||| PURPOSE: Polymorphic variation in genes involved in regulation of the complement system has been implicated as a major cause of genetic risk, in addition to the LOC387715/HTRA1 locus and other environmental influences. Previous studies have identified polymorphisms in the complement component 2 (CC2) and factor B (CFB) genes, as potential functional variants associated with AMD, in particular CFB R32Q and CC2 rs547154, both of which share strong linkage disequilibrium (LD).
METHODS: Data derived from the HapMap Project were used to select 18 haplotype-tagging SNPs across the extended CC2/CFB region for genotyping, to measure the strength of LD in 318 patients with neovascular AMD and 243 age-matched control subjects to identify additional potential functional variants in addition to those originally reported.
RESULTS: Strong LD was measured across this region as far as the superkiller viralicidic activity 2-like gene (SKIV2L). Nine SNPs were identified to be significantly associated with the genetic effect observed at this locus. Of these, a nonsynonymous coding variant SKIV2L R151Q (rs438999; OR, 0.48; 95% confidence interval [CI], 0.31-0.74; P<0.001), was in strong LD with CFB R32Q, rs641153 (r(2)=0.95) and may exert a functional effect. When assessed within a logistic regression model measuring the effects of genetic variation at the CFH and LOC387715/HTRA1 loci and smoking, the effect remained significant (OR, 0.38; 95% CI, 0.22-0.65; P<0.001). Additional variation identified within this region may also confer a weaker but independent effect and implicate additional genes within the pathogenesis of AMD.
CONCLUSIONS: Because of the high level of LD within the extended CC2/CFB region, variation within SKIV2L may exert a functional effect in AMD. ||||| PURPOSE: Genes in the complement pathway, including complement factor H (CFH), C2/BF, and C3, have been reported to be associated with age-related macular degeneration (AMD). Genetic variants, single-nucleotide polymorphisms (SNPs), in these genes were geno-typed for a case-control association study in a mainland Han Chinese population.
METHODS: One hundred and fifty-eight patients with wet AMD, 80 patients with soft drusen, and 220 matched control subjects were recruited among Han Chinese in mainland China. Seven SNPs in CFH and two SNPs in C2, CFB', and C3 were genotyped using the ABI SNaPshot method. A deletion of 84,682 base pairs covering the CFHR1 and CFHR3 genes was detected by direct polymerase chain reaction and gel electrophoresis.
RESULTS: Four SNPs, including rs3753394 (P = 0.0276), rs800292 (P = 0.0266), rs1061170 (P = 0.00514), and rs1329428 (P = 0.0089), in CFH showed a significant association with wet AMD in the cohort of this study. A haplotype containing these four SNPs (CATA) significantly increased protection of wet AMD with a P value of 0.0005 and an odds ratio of 0.29 (95% confidence interval: 0.15-0.60). Unlike in other populations, rs2274700 and rs1410996 did not show a significant association with AMD in the Chinese population of this study. None of the SNPs in CFH showed a significant association with drusen, and none of the SNPs in CFH, C2, CFB, and C3 showed a significant association with either wet AMD or drusen in the cohort of this study. The CFHR1 and CFHR3 deletion was not polymorphic in the Chinese population and was not associated with wet AMD or drusen.
CONCLUSION: This study showed that SNPs rs3753394 (P = 0.0276), rs800292 (P = 0.0266), rs1061170 (P = 0.00514), and rs1329428 (P = 0.0089), but not rs7535263, rs1410996, or rs2274700, in CFH were significantly associated with wet AMD in a mainland Han Chinese population. This study showed that CFH was more likely to be AMD susceptibility gene at Chr.1q31 based on the finding that the CFHR1 and CFHR3 deletion was not polymorphic in the cohort of this study, and none of the SNPs that were significantly associated with AMD in a white population in C2, CFB, and C3 genes showed a significant association with AMD. ||||| Age-related macular degeneration (AMD) is the most common form of irreversible blindness in developed countries. Variants in the factor H gene (CFH, also known as HF1), which encodes a major inhibitor of the alternative complement pathway, are associated with the risk for developing AMD. Here we test the hypothesis that variation in genes encoding other regulatory proteins of the same pathway is associated with AMD. We screened factor B (BF) and complement component 2 (C2) genes, located in the major histocompatibility complex class III region, for genetic variation in two independent cohorts comprising approximately 900 individuals with AMD and approximately 400 matched controls. Haplotype analyses identify a statistically significant common risk haplotype (H1) and two protective haplotypes. The L9H variant of BF and the E318D variant of C2 (H10), as well as a variant in intron 10 of C2 and the R32Q variant of BF (H7), confer a significantly reduced risk of AMD (odds ratio = 0.45 and 0.36, respectively). Combined analysis of the C2 and BF haplotypes and CFH variants shows that variation in the two loci can predict the clinical outcome in 74% of the affected individuals and 56% of the controls. These data expand and refine our understanding of the genetic risk for AMD. ||||| PURPOSE: Several single-nucleotide polymorphisms (SNPs) in the C2 and BF genes have been associated with age-related macular degeneration (AMD) in Caucasian populations from the United States. The study was conducted to evaluate whether these SNPs are also associated with AMD in persons of Anglo-Celtic ethnicity in an Australian population.
METHODS: Included in the study were 565 persons with AMD and 204 ethnically matched control subjects. All participants completed a standard health questionnaire, were given a fundus examination, and provided a blood sample for DNA extraction. Alleles were determined by a matrix-assisted desorption ionization-time of flight (MALDI-TOF)-based approach followed by statistical analysis.
RESULTS: The C2 and BF genes indicated significant association with AMD of only two SNPs; rs547154 (IVS10) in the C2 gene (P=9.1 x 10(-5)) and rs641153 (R32Q) in the BF gene (P=7.0 x 10(-5)). No association with AMD was found for SNP rs9332739 (E318D) in the C2 gene or for rs4151667 (L9H), rs1048709 (R150R), rs4151659 (K565E), or rs2072633 (IVS17) in the BF gene. A protective haplotype of variants IVS10 and R32Q was associated with AMD (OR 0.29, 95% CI 0.20-0.42).
CONCLUSIONS: In this study, the association of the IVS10 and R32Q variants in the C2 and BF genes in AMD was replicated. Haplotype analysis indicated association of these variants with AMD in an Australian population. Both IVS10 and R32Q variants were in strong linkage disequilibrium with each other (r(2)=0.96). Although the E318D and L9H variants have shown association with AMD in previous studies, the findings were not in agreement. This demonstrates a refined pattern of association of these rare variants with AMD. ||||| Age-related macular degeneration (AMD) is a late onset vision disorder. Recent studies demonstrate that alterations in complement cascade genes are associated with AMD. Of the three identified complement loci, variants in complement factor H (CFH) have the highest impact as does an independent locus at 10q26. Our matched case-control study using the Age-Related Eye Disease Study (AREDS) cohort confirms and extends the associations in these loci. Subjects were genotyped for single nucleotide polymorphisms (SNPs) from CFH, complement component 2 (C2), complement component 3 (C3), complement factor B (CFB), age-related maculopathy susceptibility (ARMS2), HtrA serine peptidase 1 (HTRA1), and apolipoprotein E (APOE). Individual SNPs, and haplotypes showed risk trends consistent with those seen in other population studies for CFH, C3, C2, and CFB. SNP rs10490924 on chromosome 10 in exon 1 of the ARMS2 gene showed a highly significant association with an odds ratio (OR) of 3.2 (95% CI 2.4-4.2) for the risk allele and rs11200638 located in the proximal promoter region of HTRA1 showed a higher significant association with an OR of 3.4 (95% CI 2.5-4.6) with our AMD cases. We found that APOE haplotypes were not significantly associated with disease status. Adjustments for other risk factors did not significantly alter the observed associations. This study validates the complement pathway's involvement in AMD and suggests that allelic variants in complement genes have a direct role in disease. These results also support previous findings that variants in the region of 10q26 exert an independent risk for AMD. ||||| PURPOSE: Genes involved in the complement cascade such as complement factor B (CFB) and complement component C2 have been implicated in age-related macular degeneration (AMD) worldwide. In continuation of the analysis of CFH and LOC387715/HTRA1, this study was conducted to gain understanding of the role of CFB and C2 in an Indian AMD cohort.
METHODS: Single nucleotide polymorphisms in CFB and C2 were screened in a cohort of clinically well-characterized patients with AMD (n = 177) and unaffected normal control subjects (n = 175). Screening was accomplished by a combination of customized genotyping followed by validation through resequencing. In addition, genotyping of two CFB variants (rs12614 and rs641153) that were in close proximity had to be resolved by resequencing. Estimates of allele and genotype frequencies, odds ratios, Hardy-Weinberg equilibrium, linkage disequilibrium (LD), and haplotype frequencies were also performed.
RESULTS: Three SNPs in C2 (rs547154 [IVS10]; P = 5.4 x 10(-11)) and CFB (rs641153 [R32Q], P = 2.2 x 10(-7) and rs2072633 [IVS17]; P = 2.0 x 10(-4)) were strongly associated with reduced risk of AMD. The rs547154 and rs641153 were in strong LD (D' = 0.90, 95% CI = 0.81-0.96) and a protective haplotype T-A was observed (OR = 0.10, 95% CI = 0.05-0.20). LD was moderate (D' = 0.77, 95% CI = 0.67-0.85) between the rs547154 and the rs2072633 SNPs, and the haplotype T-T generated with these SNPs was relatively less protective (OR = 0.28, 95% CI = 0.18-0.44).
CONCLUSIONS: The results of the present study provide an independent validation of the association of rs547154 (C2) and rs641153 (CFB) SNPs with reduced risk of AMD in an Indian cohort. ||||| OBJECTIVE: A genetic variant in the high-density lipoprotein (HDL) cholesterol pathway, hepatic lipase (LIPC), was discovered to be associated with advanced age-related macular degeneration (AMD) in a genome-wide association study. In this study, we evaluated whether LIPC is associated with serum lipids, and whether this gene and serum lipids are independently associated with AMD.
DESIGN: Case-control study.
PARTICIPANTS: A total of 458 participants from the Progression Study of Macular Degeneration and the Age-Related Eye Disease Ancillary Biomarker Study, including 318 advanced AMD cases with either geographic atrophy (n = 123) or neovascular disease (n = 195) and 140 controls.
METHODS: Participants were genotyped for 8 variants associated with AMD: 2 CFH variants, C2, CFB, C3, CFI, the ARMS2/HTRA1 gene region, and LIPC. Fasting blood specimens were obtained at study onset, and serum levels of total cholesterol, low-density lipoprotein (LDL), HDL, and triglycerides were determined. Logistic and linear regression were used to evaluate associations between serum lipids, LIPC genotype, and AMD.
MAIN OUTCOME MEASURES: LIPC and serum lipid associations with AMD.
RESULTS: The minor T allele of the LIPC gene was associated with a reduced risk of AMD (odds ratio, 0.4; 95% confidence interval, 0.2-0.9; P = 0.01, trend for number of T alleles, controlling for age and gender). Mean level of HDL was lower (P = 0.05) and mean level of LDL (P = 0.03) was higher in cases of advanced AMD compared with controls. Higher total cholesterol and LDL levels were associated with increased risk of AMD, with P for trend = 0.01 for both, in models controlling for environmental and genetic covariates. The T allele of LIPC was associated with higher levels of HDL, although LIPC was associated with advanced AMD independent of HDL level.
CONCLUSIONS: The HDL-raising allele of the LIPC gene (T) was associated with a reduced risk of AMD. Higher total cholesterol and LDL levels were associated with increased risk, whereas higher HDL levels tended to reduce the risk of AMD. The specific mechanisms underlying the association between AMD and LIPC require further investigation. ||||| Age-related macular degeneration (AMD) is a devastating disorder of the central retina, causing significant visual impairment for 7.5 million elderly Americans. Abnormal regulation of the complement system likely caused by the Y402H polymorphism in the complement factor H gene is a recognized risk factor for AMD, as is the A69S variant in the poorly characterized LOC387715 gene. Recently, polymorphisms in the factor B (CFB) and complement component 2 (CC2) genes were associated with decreased susceptibility to AMD. To validate this association in independent family-based and case-control Caucasian data sets, we genotyped two single-nucleotide polymorphisms (SNPs) in CC2 and four SNPs in CFB. The R32Q variant of CFB was significantly associated with protection from AMD in the family-based data set (P = 0.025). Three SNPs in CC2 and CFB were strongly associated with decreased risk of AMD in the case-control data set (CC2 E318D: P = 0.02; CC2 rs547154: P = 9 x 10(-6); and CFB R32Q P = 2 x 10(-5)). The minor alleles at CC2 rs547154 and CFB R32Q are present in 4% of cases versus 10% of controls, and as these SNPs are in strong linkage disequilibrium (r(2)=0.92), these results likely represent the same protective signal. After controlling for age, Y402H, A69S and smoking, the effect of CFB R32Q remained quite strong (OR 0.21, 95% confidence interval 0.11-0.39; P < 10(-4)). Likelihood ratio testing and conditional analyses in the case-control data set suggest that a weaker, independent protective effect exists for CC2 E318D. ||||| AIMS: Little is known about the role of genetic variants in the early stages of age-related macular degeneration (AMD). We aimed to investigate how genetic variations within five well-defined genes relate to AMD severity.
METHODS: We analysed SNPs in the genes for complement factor H (CFH), age-related maculopathy susceptibility (ARMS2), HtrA serine peptidase 1 (HtrA1), complement factor B (CFB), and complement component 2 (C2)in 183 controls and 730 patients with increasing severity of AMD from the Muenster aging and retina study (MARS). Severity scoring was based on the Rotterdam classification of fundus photographs.
RESULTS: Compared with controls, patients with very early AMD showed a significantly increased minor allele frequency (MAF) only for CFH-rs1061170. With increasing severity of AMD, SNPs in CFH-rs1061170,as well as ARMS2-rs10490924, became consistently more common (P<0.001). Likewise, HtrA1-rs11200638 was less clearly associated with AMD severity, whereas C2-rs9332739 and CFB-rs641153 showed no relation. Multifactorial models confirmed CFH and ARMS2 as major determinants of AMD severity, whereas addition of HtrA1, C2 and CFB did not improve model prediction. In the models, age did not contribute to very early but to all more severe AMD stages, whereas smoking history had a significant impact only for late AMD.
CONCLUSION: Our findings indicate that the CFH gene is involved in the onset of AMD, whereas both, the CFH and ARMS2 genes, and more weakly, the HtrA1 gene, appear to account for the advancement of AMD. The results for SNPs in the C2 and CFB genes were inconclusive. Genetic factors dominated in their impact over age and smoking history. ||||| PURPOSE: The joint effects of genetic, ocular, and environmental variables were evaluated and predictive models for prevalence and incidence of AMD were assessed.
METHODS: Participants in the multicenter Age-Related Eye Disease Study (AREDS) were included in a prospective evaluation of 1446 individuals, of which 279 progressed to advanced AMD (geographic atrophy or neovascular disease) and 1167 did not progress during 6.3 years of follow-up. For prevalent AMD, 509 advanced cases were compared with 222 controls. Covariates for the incidence analysis included age, sex, education, smoking, body mass index (BMI), baseline AMD grade, and the AREDS vitamin-mineral treatment assignment. DNA specimens were evaluated for six variants in five genes related to AMD. Unconditional logistic regression analyses were performed for prevalent and incident advanced AMD. An algorithm was developed and receiver operating characteristic curves and C statistics were calculated to assess the predictive ability of risk scores to discriminate progressors from nonprogressors.
RESULTS: All genetic polymorphisms were independently related to prevalence of advanced AMD, controlling for genetic factors, smoking, BMI, and AREDS treatment. Multivariate odds ratios (ORs) were 3.5 (95% confidence interval [CI], 1.7-7.1) for CFH Y402H; 3.7 (95% CI, 1.6-8.4) for CFH rs1410996; 25.4 (95% CI, 8.6-75.1) for LOC387715 A69S (ARMS2); 0.3 (95% CI, 0.1-0.7) for C2 E318D; 0.3 (95% CI, 0.1-0.5) for CFB; and 3.6 (95% CI, 1.4-9.4) for C3 R102G, comparing the homozygous risk/protective genotypes to the referent genotypes. For incident AMD, all these variants except CFB were significantly related to progression to advanced AMD, after controlling for baseline AMD grade and other factors, with ORs from 1.8 to 4.0 for presence of two risk alleles and 0.4 for the protective allele. An interaction was seen between CFH402H and treatment, after controlling for all genotypes. Smoking was independently related to AMD, with a multiplicative joint effect with genotype on AMD risk. The C statistic for the full model with all variables was 0.831 for progression to advanced AMD.
CONCLUSIONS: Factors reflective of nature and nurture are independently related to prevalence and incidence of advanced AMD, with excellent predictive power. ||||| PURPOSE: To present genome-wide association analyses of genotypic and environmental risks on age-related macular degeneration (AMD) using 593 subjects from the age-related eye disease study (AREDS), after adjusting for population stratification and including questionable controls.
METHODS: Single nucleotide polymorphism (SNP) associations with AMD for the non-Hispanic white population were investigated using a log-additive model after adjusting for population stratification. Replication of possible SNP-disease association was performed by genotyping an independent group of 444 AMD case and 300 control subjects. Logistic regression models were used to assess interaction effects between smoking and SNPs associated with AMD. Independent genetic risk effects among the disease-associated SNPs were also investigated using multiple logistic regression models.
RESULTS: Population stratification was observed among the individuals having a self-reported race of non-Hispanic white. Risk allele frequencies at established AMD loci demonstrated that questionable control subjects were similar to control subjects in the AREDS, suggesting that they could be used as true controls in the analyses. Genetic loci (complement factor H [CFH], complement factor B [CFB], the age-related maculopathy susceptibility 2 locus containing the hypothetical gene [LOC387715]/the high-temperature requirement A-1 [HTRA1], and complement component 3 [C3]) that were already known to be associated with AMD were identified. An additional 26 novel SNPs potentially associated with AMD were identified, but none were definitely replicated in a second independent group of subjects. Smoking did not interact with known AMD loci, but was associated with late AMD. Statistically independent genetic signals were observed within the Pleckstrin homology domain-containing family A member 1 (PLEKHA1) region near LOC387715/HTRA1 and within a haplotype spanning exon 19 of the C3 gene.
CONCLUSIONS: Population stratification among Caucasian subjects from the multicentered AREDS was observed, suggesting that it should be adjusted for in future studies. The AREDS questionable control subjects can be used as control subjects in the AREDS genome-wide association study (GWAS). Smoking was an independent risk factor for advanced AMD in the AREDS subjects. There continues to be evidence that the 10q26 (age-related maculopathy susceptibility 2 gene [ARMS2]) locus spanning PLEKHA1-LOC387715-HTRA1 and the C3 gene may contain multiple independent genetic risks contributing to AMD. ||||| PURPOSE: The purpose of this study was to determine whether the genetic polymorphisms of complement factor 3 (C3) are associated with neovascular age-related macular degeneration (AMD) in the Chinese population.
METHODS: A total of 123 unrelated Chinese Han patients with neovascular AMD and 130 control subjects were recruited. Their six single-nucleotide polymorphisms (SNPs) in the C3 gene, one in the complement factor H (CFH) gene and two in the complement factor B (CFB) gene were characterized. Their genotypes, allele frequencies, and odds ratios were analyzed.
RESULTS: The G allele of the C3 IVS2 rs2250656, but not other tested C3 SNPs of rs2230205, rs10411506, rs2230199, rs339392, and rs163913, was significantly associated with a reduced risk for AMD in the Chinese population (OR 0.605, 95% CI 0.39-0.93, p = 0.023), even after adjusting for age, gender, smoking status, CFH rs1061170, CFB rs4151667, and CFB rs641153 allele status (OR 0.58, 95% CI 0.35-0.96, p = 0.033). However, the C3 haplotype of A-A-C-A-T-T was identified as a statistically significant risk factor for neovascular AMD (OR 1.41, 95% CI 1.02-1.94). Furthermore, the C allele of the CFH rs1061170, but not the CFB rs4151667 and rs641153, was significnatly associated with increased risk for AMD (OR 3.09, 95% CI 1.55-6.15, p < 0.001).
CONCLUSION: The G allele of C3 IVS2 rs2250656 may be a significantly protective factor for neovascular AMD in the Chinese population. This, together with low MAF of C3 R102G, may be partially responsible for the low prevalence of AMD in the Chinese population. | [
{
"source_pmid": "18493315",
"source_text": "BACKGROUND: Age-related maculopathy (ARM) is a common cause of visual impairment in the elderly populations of industrialized countries and significantly affects the quality of life of those suffering from the disease. Variants within two genes, the complement fa... |
22268800 | CONCLUSION: Quit smoking is an important advice to patients to prevent or slow the progress of AMD. There is no recommendation for routine nutritional or vitamins supplementation for primary prevention. However, patients with documented intermediate risk of AMD or advanced AMD in one eye are recommended to take AREDS-type vitamin supplements. | OBJECTIVE: To evaluate the relationship between dietary lutein plus zeaxanthin and intermediate age-related macular degeneration (AMD).
DESIGN: Women aged 50 to 79 years in Iowa, Wisconsin, and Oregon with intake of lutein plus zeaxanthin above the 78th (high) and below the 28th (low) percentiles at baseline in the Women's Health Initiative Observational Study were recruited 4 to 7 years later into the Carotenoids in Age-Related Eye Disease Study (CAREDS), when the presence of AMD was determined by fundus photographs. Logistic regression analyses examined the prevalence of AMD in 1787 CAREDS participants, after accounting for potential covariates.
RESULTS: The prevalence of intermediate AMD was not statistically different between the high and low lutein plus zeaxanthin intake recruitment groups after adjusting for age (odds ratio, 0.96; 95% confidence interval, 0.75-1.23). Limiting analyses to women younger than 75 years with stable intake of lutein plus zeaxanthin, without a history of chronic diseases that are often associated with diet changes, substantially lowered odds ratios (0.57; 95% confidence interval, 0.34-0.95). Exploratory analyses of advanced AMD in 34 participants resulted in protective, but statistically nonsignificant, associations in the overall sample and in women younger than 75 years.
CONCLUSION: Diets rich in lutein plus zeaxanthin may protect against intermediate AMD in healthy women younger than 75 years. ||||| BACKGROUND: Lutein and docosahexaenoic acid (DHA) may protect against age-related macular degeneration (AMD). Lutein is a component of macular pigment. DHA is in the retina.
OBJECTIVE: The objective of this 4-mo study was to determine the effects of lutein (12 mg/d) and DHA (800 mg/d) on their serum concentrations and macular pigment optical density (MPOD).
DESIGN: Forty-nine women (60-80 y) were randomly assigned to placebo, DHA, lutein, or lutein + DHA supplement. Serum was analyzed for lutein and DHA (0, 2, and 4 mo). MPOD was determined (0 and 4 mo) at 0.4, 1.5, 3, and 5 degrees temporal retinal eccentricities. Serum was analyzed for lipoproteins (4 mo).
RESULTS: There was no interaction between lutein and DHA supplementations for serum lutein and MPOD. The lutein supplementation x DHA supplementation x month interaction was significant for serum DHA response (P < 0.05). In the lutein group, serum lutein increased from baseline at 2 and 4 mo (P < 0.001), and MPOD increased at 3.0 degrees (P < 0.01). In the DHA group, serum DHA increased at 2 and 4 mo (P < 0.0001), and MPOD increased at 0.4 degrees (P < 0.05). In the lutein + DHA group, serum lutein and DHA increased at 2 and 4 mo (P < 0.01), and MPOD increased at 0.4, 1.5, and 3 degrees (P = 0.06, 0.08, and 0.09, respectively). Differences from placebo in lipoprotein subfractions were greatest for the lutein + DHA group (4 mo).
CONCLUSIONS: Lutein supplementation increased MPOD eccentrically. DHA resulted in central increases. These results may be due to changes in lipoproteins. Lutein and DHA may aid in prevention of age-related macular degeneration. ||||| BACKGROUND: Observational and experimental data suggest that antioxidant and/or zinc supplements may delay progression of age-related macular degeneration (AMD) and vision loss.
OBJECTIVE: To evaluate the effect of high-dose vitamins C and E, beta carotene, and zinc supplements on AMD progression and visual acuity.
DESIGN: The Age-Related Eye Disease Study, an 11-center double-masked clinical trial, enrolled participants in an AMD trial if they had extensive small drusen, intermediate drusen, large drusen, noncentral geographic atrophy, or pigment abnormalities in 1 or both eyes, or advanced AMD or vision loss due to AMD in 1 eye. At least 1 eye had best-corrected visual acuity of 20/32 or better. Participants were randomly assigned to receive daily oral tablets containing: (1) antioxidants (vitamin C, 500 mg; vitamin E, 400 IU; and beta carotene, 15 mg); (2) zinc, 80 mg, as zinc oxide and copper, 2 mg, as cupric oxide; (3) antioxidants plus zinc; or (4) placebo.
MAIN OUTCOME MEASURES: (1) Photographic assessment of progression to or treatment for advanced AMD and (2) at least moderate visual acuity loss from baseline (> or =15 letters). Primary analyses used repeated-measures logistic regression with a significance level of.01, unadjusted for covariates. Serum level measurements, medical histories, and mortality rates were used for safety monitoring.
RESULTS: Average follow-up of the 3640 enrolled study participants, aged 55-80 years, was 6.3 years, with 2.4% lost to follow-up. Comparison with placebo demonstrated a statistically significant odds reduction for the development of advanced AMD with antioxidants plus zinc (odds ratio [OR], 0.72; 99% confidence interval [CI], 0.52-0.98). The ORs for zinc alone and antioxidants alone are 0.75 (99% CI, 0.55-1.03) and 0.80 (99% CI, 0.59-1.09), respectively. Participants with extensive small drusen, nonextensive intermediate size drusen, or pigment abnormalities had only a 1.3% 5-year probability of progression to advanced AMD. Odds reduction estimates increased when these 1063 participants were excluded (antioxidants plus zinc: OR, 0.66; 99% CI, 0.47-0.91; zinc: OR, 0.71; 99% CI, 0.52-0.99; antioxidants: OR, 0.76; 99% CI, 0.55-1.05). Both zinc and antioxidants plus zinc significantly reduced the odds of developing advanced AMD in this higher-risk group. The only statistically significant reduction in rates of at least moderate visual acuity loss occurred in persons assigned to receive antioxidants plus zinc (OR, 0.73; 99% CI, 0.54-0.99). No statistically significant serious adverse effect was associated with any of the formulations.
CONCLUSIONS: Persons older than 55 years should have dilated eye examinations to determine their risk of developing advanced AMD. Those with extensive intermediate size drusen, at least 1 large druse, noncentral geographic atrophy in 1 or both eyes, or advanced AMD or vision loss due to AMD in 1 eye, and without contraindications such as smoking, should consider taking a supplement of antioxidants plus zinc such as that used in this study. ||||| BACKGROUND: Observational epidemiologic studies indicate a direct association between homocysteine concentration in the blood and the risk of age-related macular degeneration (AMD), but randomized trial data to examine the effect of therapy to lower homocysteine levels in AMD are lacking. Our objective was to examine the incidence of AMD in a trial of combined folic acid, pyridoxine hydrochloride (vitamin B(6)), and cyanocobalamin (vitamin B(12)) therapy.
METHODS: We conducted a randomized, double-blind, placebo-controlled trial including 5442 female health care professionals 40 years or older with preexisting cardiovascular disease or 3 or more cardiovascular disease risk factors. A total of 5205 of these women did not have a diagnosis of AMD at baseline and were included in this analysis. Participants were randomly assigned to receive a combination of folic acid (2.5 mg/d), pyridoxine hydrochloride (50 mg/d), and cyanocobalamin (1 mg/d) or placebo. Our main outcome measures included total AMD, defined as a self-report documented by medical record evidence of an initial diagnosis after randomization, and visually significant AMD, defined as confirmed incident AMD with visual acuity of 20/30 or worse attributable to this condition.
RESULTS: After an average of 7.3 years of treatment and follow-up, there were 55 cases of AMD in the combination treatment group and 82 in the placebo group (relative risk, 0.66; 95% confidence interval, 0.47-0.93 [P = .02]). For visually significant AMD, there were 26 cases in the combination treatment group and 44 in the placebo group (relative risk, 0.59; 95% confidence interval, 0.36-0.95 [P = .03]).
CONCLUSIONS: These randomized trial data from a large cohort of women at high risk of cardiovascular disease indicate that daily supplementation with folic acid, pyridoxine, and cyanocobalamin may reduce the risk of AMD. ||||| OBJECTIVE: To assess the relationship between baseline dietary fatty acids and 10-year incident age-related macular degeneration (AMD).
METHODS: In an elderly Australian cohort, 3654 participants were examined at baseline and 2454 were examined 5 and/or 10 years later. We assessed AMD from retinal photographs. Participants completed a semiquantitative food frequency questionnaire.
RESULTS: After adjusting for age, sex, and smoking, 1 serving of fish per week was associated with reduced risk of incident early AMD (relative risk, 0.69 [95% confidence interval, 0.49-0.98]), primarily among participants with less than the median linoleic acid consumption (0.57 [0.36-0.89]). Findings were similar for intake of long-chain omega-3 polyunsaturated fatty acids. One to 2 servings of nuts per week was associated with reduced risk of incident early AMD (relative risk, 0.65 [95% confidence interval, 0.47-0.91]). Protective associations between the intake of nuts and reduced risk of pigmentary abnormalities were seen among nonsmokers, participants with less than the median ratio of serum total to high-density lipoprotein cholesterol, and those with beta carotene intake greater than the median level.
CONCLUSIONS: This study provides evidence of protection against early AMD from regularly eating fish, greater consumption of omega-3 polyunsaturated fatty acids, and low intakes of foods rich in linoleic acid. Regular consumption of nuts may also reduce AMD risk. Joint effects from multiple factors are suggested. ||||| BACKGROUND: Dietary supplementation with B vitamins that lower blood homocysteine concentrations is expected to reduce cardiovascular disease risk, but there has been uncertainty about the optimum regimen to use for this purpose.
OBJECTIVE: The objectives were to ascertain the lowest dose of folic acid associated with the maximum reduction in homocysteine concentrations and to determine the additional relevance of vitamins B-12 and B-6.
DESIGN: A meta-analysis of 25 randomized controlled trials involving individual data on 2596 subjects assessed the effect on plasma homocysteine concentrations of different doses of folic acid and of the addition of vitamins B-12 and B-6.
RESULTS: The proportional reductions in plasma homocysteine concentrations produced by folic acid were greater at higher homocysteine (P < 0.001) and lower folate (P < 0.001) pretreatment concentrations; they were also greater in women than in men (P < 0.001). After standardization for sex and to pretreatment plasma concentrations of 12 micromol homocysteine/L and 12 nmol folate/L, daily doses of 0.2, 0.4, 0.8, 2.0, and 5.0 mg folic acid were associated with reductions in homocysteine of 13% (95% CI: 10%, 16%), 20% (17%, 22%), 23% (21%, 26%), 23% (20%, 26%), and 25% (22%, 28%), respectively. Vitamin B-12 (x: 0.4 mg/d) produced 7% (95% CI: 4%, 9%) further reduction in homocysteine concentrations, but vitamin B-6 had no significant effect.
CONCLUSIONS: Daily doses of > or =0.8 mg folic acid are typically required to achieve the maximal reduction in plasma homocysteine concentrations produced by folic acid supplementation. Doses of 0.2 and 0.4 mg are associated with 60% and 90%, respectively, of this maximal effect. ||||| BACKGROUND: Some observational studies have suggested that people who eat a diet rich in antioxidant vitamins (carotenoids, vitamins C and E) or minerals (selenium and zinc) may be less likely to develop age-related macular degeneration (AMD).
OBJECTIVES: The aim of this review was to examine the evidence as to whether or not taking vitamin or mineral supplements prevents the development of AMD.
SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (which contains the Cochrane Eyes and Vision Group Trials Register) in The Cochrane Library (2007, Issue 3), MEDLINE (1966 to August 2007), SIGLE (1980 to 2005/03), EMBASE (1980 to August 2007), National Research Register (2007, Issue 3), AMED (1985 to January 2006) and PubMed (on 24 January 2006 covering last 60 days), reference lists of identified reports and the Science Citation Index. We contacted investigators and experts in the field for details of unpublished studies.
SELECTION CRITERIA: We included all randomised trials comparing an antioxidant vitamin and/or mineral supplement (alone or in combination) to control. We included only studies where supplementation had been given for at least one year.
DATA COLLECTION AND ANALYSIS: Both review authors independently extracted data and assessed trial quality. Data were pooled using a fixed-effect model.
MAIN RESULTS: Three randomised controlled trials were included in this review (23,099 people randomised). These trials investigated alpha-tocopherol and beta-carotene supplements. There was no evidence that antioxidant vitamin supplementation prevented or delayed the onset of AMD. The pooled risk ratio for any age-related maculopathy (ARM) was 1.04 (95% CI 0.92 to 1.18), for AMD (late ARM) was 1.03 (95% CI 0.74 to 1.43). Similar results were seen when the analyses were restricted to beta-carotene and alpha-tocopherol.
AUTHORS' CONCLUSIONS: There is no evidence to date that the general population should take antioxidant vitamin and mineral supplements to prevent or delay the onset of AMD. There are several large ongoing trials. People with AMD should see the related Cochrane review "Antioxidant vitamin and mineral supplements for slowing the progression of age-related macular degeneration" written by the same author. ||||| OBJECTIVE: To systematically review the evidence on dietary omega-3 fatty acid and fish intake in the primary prevention of age-related macular degeneration (AMD).
METHODS: Seven databases were systematically searched with no limits on publication year or language using standardized criteria. Randomized controlled trials and prospective cohort, case-control, and cross-sectional studies were included. Of 2754 abstracts identified, 3 prospective cohort, 3 case-control, and 3 cross-sectional studies met the criteria. Measures of associations were pooled quantitatively using meta-analytic methods.
RESULTS: Nine studies provided data on a total sample of 88 974 people, including 3203 AMD cases. A high dietary intake of omega-3 fatty acids was associated with a 38% reduction in the risk of late AMD (pooled odds ratio [OR], 0.62; 95% confidence interval [CI], 0.48-0.82). Fish intake at least twice a week was associated with a reduced risk of both early AMD (pooled OR, 0.76; 95% CI, 0.64-0.90) and late AMD (pooled OR, 0.67; 95% CI, 0.53-0.85).
CONCLUSIONS: Although this meta-analysis suggests that consumption of fish and foods rich in omega-3 fatty acids may be associated with a lower risk of AMD, there is insufficient evidence from the current literature, with few prospective studies and no randomized clinical trials, to support their routine consumption for AMD prevention. ||||| BACKGROUND: Lung cancer and cardiovascular disease are major causes of death in the United States. It has been proposed that carotenoids and retinoids are agents that may prevent these disorders.
METHODS: We conducted a multicenter, randomized, double-blind, placebo-controlled primary prevention trial -- the Beta Carotene and Retinol Efficacy Trial -- involving a total of 18,314 smokers, former smokers, and workers exposed to asbestos. The effects of a combination of 30 mg of beta carotene per day and 25,000 IU of retinol (vitamin A) in the form of retinyl palmitate per day on the primary end point, the incidence of lung cancer, were compared with those of placebo.
RESULTS: A total of 388 new cases of lung cancer were diagnosed during the 73,135 person-years of follow-up (mean length of follow-up, 4.0 years). The active-treatment group had a relative risk of lung cancer of 1.28 (95 percent confidence interval, 1.04 to 1.57; P=0.02), as compared with the placebo group. There were no statistically significant differences in the risks of other types of cancer. In the active-treatment group, the relative risk of death from any cause was 1.17 (95 percent confidence interval, 1.03 to 1.33); of death from lung cancer, 1.46 (95 percent confidence interval, 1.07 to 2.00); and of death from cardiovascular disease, 1.26 (95 percent confidence interval, 0.99 to 1.61). On the basis of these findings, the randomized trial was stopped 21 months earlier than planned; follow-up will continue for another 5 years.
CONCLUSIONS: After an average of four years of supplementation, the combination of beta carotene and vitamin A had no benefit and may have had an adverse effect on the incidence of lung cancer and on the risk of death from lung cancer, cardiovascular disease, and any cause in smokers and workers exposed to asbestos. ||||| The prevalence of obesity has reached epidemic proportions in many countries. Although its impact on overall health is well documented, less is known about the ocular manifestations of obesity. Among different eye diseases, obesity has been linked with age-related cataract, glaucoma, age-related maculopathy, and diabetic retinopathy. Numerous population-based and prospective studies support an association between obesity and risk of age-related cataract. However, the nature and strength of these associations, particularly with the different cataract subtypes, remains to be determined. There is strong evidence that obesity is associated with elevated intraocular pressure, but there is no convincing data to support a more direct association between obesity and glaucomatous optic neuropathy. Studies to date have not found a consistent pattern of association between obesity and risk of age-related maculopathy or diabetic retinopathy. Thus, although obesity may be a risk factor for many ocular conditions, the present literature is inadequate to establish any convincing associations. Furthermore, whether weight loss reduces the risk of eye diseases remains unresolved. Because of the potential public health impact of obesity, there is a greater need to understand its ocular effects. ||||| PURPOSE: To examine the association between intermediate age-related macular degeneration (AMD) and the optical density of macular pigment (MPOD), which is composed of lutein and zeaxanthin from the diet.
DESIGN: Cross-sectional cohort study.
PARTICIPANTS: We included 1698 of 2005 women ages 54 to 86 years and participating in the Carotenoids in Age-Related Eye Disease Study, an ancillary study of the Women's Health Initiative.
METHODS: The MPOD was measured noninvasively by heterochromatic flicker photometry. Fundus photographs were taken to document prevalent AMD.
MAIN OUTCOME MEASURES: Intermediate AMD (n = 305) and two subtypes-large drusen (n = 233) and pigmentary abnormalities (n = 157).
RESULTS: After adjusting for covariates, the odds ratio (OR) and 95% confidence interval (CI) for AMD among women in quintile (Q) 5 (n = 339) versus 1 (n = 340) for MPOD was 1.4 (0.9, 2.1). However, after excluding women with possible unstable diets and recent supplement use due to chronic disease history, associations reversed (OR Q2-5 vs. 1, 0.8; 95% CI, 0.5-1.2), but remained nonsignificant. Associations also differed between middle-aged (54-69 years) and older (> or =70 years) women (P-interaction = 0.09), but less so, after excluding women who were likely to have unstable diets: adjusted ORs (95% CI) were 0.5 (0.3-1.0; P = 0.08) for intermediate AMD among middle-aged women (n = 516) with MPOD in Q2 to Q5 versus 1 and 1.0 (0.5-2.0; P = 0.90) for older women (n = 422).
CONCLUSIONS: The MPOD is not cross-sectionally associated with AMD. The inconsistency of relationships across age groups and in subgroups of women who are likely to have more stable diets suggests that cross-sectional associations may be biased and highlights the need to study these relationships prospectively. ||||| BACKGROUND: Epidemiologic evidence indicates that diets high in carotenoid-rich fruits and vegetables, as well as high serum levels of vitamin E (alpha-tocopherol) and beta carotene, are associated with a reduced risk of lung cancer.
METHODS: We performed a randomized, double-blind, placebo-controlled primary-prevention trial to determine whether daily supplementation with alpha-tocopherol, beta carotene, or both would reduce the incidence of lung cancer and other cancers. A total of 29,133 male smokers 50 to 69 years of age from southwestern Finland were randomly assigned to one of four regimens: alpha-tocopherol (50 mg per day) alone, beta carotene (20 mg per day) alone, both alpha-tocopherol and beta carotene, or placebo. Follow-up continued for five to eight years.
RESULTS: Among the 876 new cases of lung cancer diagnosed during the trial, no reduction in incidence was observed among the men who received alpha-tocopherol (change in incidence as compared with those who did not, -2 percent; 95 percent confidence interval, -14 to 12 percent). Unexpectedly, we observed a higher incidence of lung cancer among the men who received beta carotene than among those who did not (change in incidence, 18 percent; 95 percent confidence interval, 3 to 36 percent). We found no evidence of an interaction between alpha-tocopherol and beta carotene with respect to the incidence of lung cancer. Fewer cases of prostate cancer were diagnosed among those who received alpha-tocopherol than among those who did not. Beta carotene had little or no effect on the incidence of cancer other than lung cancer. Alpha-tocopherol had no apparent effect on total mortality, although more deaths from hemorrhagic stroke were observed among the men who received this supplement than among those who did not. Total mortality was 8 percent higher (95 percent confidence interval, 1 to 16 percent) among the participants who received beta carotene than among those who did not, primarily because there were more deaths from lung cancer and ischemic heart disease.
CONCLUSIONS: We found no reduction in the incidence of lung cancer among male smokers after five to eight years of dietary supplementation with alpha-tocopherol or beta carotene. In fact, this trial raises the possibility that these supplements may actually have harmful as well as beneficial effects. ||||| OBJECTIVE: To evaluate the relationship between cigarette smoking and incidence of age-related macular degeneration (AMD) among women.
DESIGN: Prospective cohort study with 12 years of follow-up (1980 to 1992), in which information on smoking habits was updated every 2 years.
SETTING: Eleven states throughout the United States.
PARTICIPANTS: A total of 31 843 registered nurses enrolled in the Nurses' Health Study who were aged 50 to 59 years in 1980 and did not report a diagnosis of cancer or AMD at the beginning of the study. Additional women entered the analytic cohort as they reached 50 years of age.
MAIN OUTCOME MEASURE: Incidence of AMD with visual loss.
RESULTS: During 556 338 person-years of follow-up, 215 women were newly diagnosed as having AMD. After adjusting for other risk factors for AMD, women who currently smoked 25 or more cigarettes per day had a relative risk (RR) of AMD of 2.4 (95% confidence interval [CI], 1.4-4.0) compared with women who never smoked. Past smokers of this amount also had a 2-fold increased risk (RR=2.0; 95% CI, 1.2-3.4) relative to never smokers. Compared with current smokers, little reduction in risk was suggested even after quitting smoking for 15 or more years. Risk of AMD also increased with an increasing number of pack-years smoked (P for trend <.001); among women who smoked for 65 or more pack-years, the risk was 2.4 times the risk of never smokers (95% CI, 1.5-3.8). Analyses of dry and exudative types of AMD and other alternative definitions of AMD revealed similar results.
CONCLUSIONS: Cigarette smoking is an independent and avoidable risk factor for AMD among women. Because AMD is the most common cause of severe visual impairment among the elderly and treatment is not available or is ineffective for most patients, reducing the risk of this disease is another important reason to avoid smoking. ||||| The pyridinium bisretinoid A2E, an autofluorescent pigment that accumulates in retinal pigment epithelial cells with age and in some retinal disorders, can mediate a detergent-like perturbation of cell membranes and light-induced damage to the cell. The photodynamic events initiated by the sensitization of A2E include the generation of singlet oxygen and the oxidation of A2E at carbon-carbon double bonds. To assess the ability of plant-derived anthocyanins to modulate adverse effects of A2E accumulation on retinal pigment epithelium (RPE) cells, these flavylium salts were isolated from extracts of bilberry. Nine anthocyanin fractions reflecting monoglycosides of delphinidin, cyanidin, petunidin and malvidin were obtained and all were shown to suppress the photooxidation of A2E at least in part by quenching singlet oxygen. The anthocyanins tested exhibited antioxidant activity of variable efficiency. The structural characteristics relevant to this variability likely included the ability to form a stable quinonoidal anhydro base at neutral pH, a conjugated diene structure in the C (pyrane) ring, the presence of hydroxyl groups on the B (benzene) ring and the relative hydrophobicity conferred by the arrangement of substituents on the B ring. Cells that had taken up anthocyanins also exhibited a resistance to the membrane permeabilization that occurs as a result of the detergent-like action of A2E. ||||| PURPOSE: The purpose of this study was to investigate the association of age-related macular degeneration (AMD) with plasma homocysteine, vitamin B12, and folate levels.
METHODS: Sixty patients diagnosed with AMD at our clinic between March 2004 and September 2004 were assessed in a prospective cross-sectional study. Plasma homocysteine, vitamin B12, and folate levels taken after 8 h of fasting from 30 patients with exudative AMD and 30 patients with dry AMD were compared with the results of 30 age- and sex-matched healthy participants.
RESULTS: Patients with both exudative and dry types of AMD had significantly higher plasma homocysteine levels (mean 14.19+/-3.11 micromol/l; 13.07+/-2.90 micromol/l respectively) compared with the controls (mean 10.79+/-2.56 micromol/l; (p=0.000 and p=0.008 respectively). Homocysteine levels were higher in the exudative AMD group compared with the dry AMD group, but the difference was not statistically significant (p=0.290). Plasma vitamin B12 levels were found to be significantly lower in the exudative AMD group (289.14+/-113.44 pg/l) compared with the controls (436.17+/-204.12 pg/l) and dry AMD group (443.47+/-190.83 pg/l; (p=0.000). Plasma folate levels were comparable among groups (p=0.106).
CONCLUSION: This study suggests an association between elevated plasma homocysteine and AMD regardless of the subtype. Further controlled prospective studies are needed to investigate the possible role of homocysteine in AMD and the effect of vitamin B12 and folate supplementation in this process. ||||| This study aimed at assessing the associations of dietary fat with the risk of age-related maculopathy (ARM), in the framework of a population-based study from southern France. Nutritional data were collected using a dietitian-administered food-frequency questionnaire. ARM was classified from retinal photographs using the international classification and included neovascular age-related macular degeneration, geographic atrophy, soft indistinct drusen, soft distinct drusen associated with pigmentary abnormalities. After multivariate adjustment, high total, saturated and monounsaturated fat intake were associated with increased risk for ARM (odds ratio (OR)=4.74, P=0.007; OR=2.70, P=0.04; and OR= 3.50, P=0.03, respectively). Total polyunsaturated fatty acid was not significantly associated with ARM. Total and white fish intake was not significantly associated with ARM, but fatty fish intake (more than once a month versus less than once a month) was associated with a 60% reduction in risk for ARM (OR=0.42, P=0.01). ||||| PURPOSE: To review systematically the evidence currently available on alcohol consumption and the risk of age-related macular degeneration (AMD).
DESIGN: Systematic review and meta-analysis of observational studies.
METHODS: Seven databases were searched systematically with no limits on the year or language of publication for prospective cohort studies. References identified from pertinent reviews and articles also were retrieved. Two reviewers independently searched the above databases and selected the studies using prespecified standardized criteria. These criteria included appropriate adjustment for age and smoking in the analysis. Of the 441 studies identified initially, five cohort studies met the selection criteria. Data extraction and study quality evaluation were performed independently by two reviewers and results were pooled quantitatively using meta-analytic methods.
RESULTS: The five cohort studies included 136,946 people, among whom AMD developed in 1923 (1,513 early and 410 late). Pooled results showed that heavy alcohol consumption was associated with an increased risk of early AMD (pooled odds ratio, 1.47; 95% confidence interval, 1.10 to 1.95), whereas the association between heavy alcohol consumption and risk of late AMD was inconclusive. There were insufficient data to evaluate a dose-response association between alcohol consumption and AMD or the association between moderate alcohol consumption and AMD.
CONCLUSIONS: Heavy alcohol consumption (more than three standard drinks per day) is associated with an increased risk of early AMD. Although this association seems to be independent of smoking, residual confounding effects from smoking cannot be excluded completely. ||||| OBJECTIVE: To assess the relation between cigarette smoking and age-related macular degeneration (AMD) in a population of elderly persons.
DESIGN: A cross-sectional, community-based study.
SETTING: City district of Rotterdam, the Netherlands.
PARTICIPANTS: A total of 6174 persons 55 years and older who participated in the Rotterdam Study. In 36 persons atrophic AMD and in 65 persons neovascular AMD were diagnosed.
MAIN OUTCOME MEASURES: Age-related macular degeneration was diagnosed by evaluating fundus transparencies, smoking behavior was identified by interviewing subjects, and the presence of atherosclerosis was assessed by the ankle-arm systolic blood pressure index. Relative risks and 95% confidence intervals (CIs) were calculated using multivariate logistic regression analysis.
RESULTS: In subjects younger than 85 years, current smokers had a 6.6-fold increased risk of neovascular AMD vs those who had never smoked (95% CI, 2.8-15.9). Former smokers had a 3.2-fold increased risk of neovascular AMD vs nonsmokers in this age group (95% CI, 1.4-7.4). These associations were not observed in subjects 85 years or older. Smoking was not associated with atrophic AMD. A strong increased risk of neovascular AMD was present in those who had smoked more than 10 pack-years (relative risk, 6.5; 95% CI, 2.9-14.8). Adjusting the results for atherosclerosis did not change the association. Persons who had quit smoking 20 or more years before the eye examination had no increased risk.
CONCLUSIONS: The results provide evidence for a dose-response relationship between smoking and AMD, particularly in persons with the neovascular form of the disease. ||||| PURPOSE: To assess the relationship between plasma homocysteine levels and exudative neovascular age-related macular degeneration (AMD).
DESIGN: Cross-sectional study.
METHODS: A prospective comparative cross-sectional study was conducted in outpatient ophthalmology clinics in a university-affiliated medical institution. The cohort consisted of 59 patients (25 male, 34 female) with a mean age of 78 years (standard deviation [SD] = 8.4) with neovascular AMD who were candidates for photodynamic treatment. Patients were compared for plasma homocysteine levels with 58 patients who had dry AMD (24 male, 34 female) with a mean age of 76.3 years (SD = 8.4) and with a control group of 56 age-matched subjects (27 male, 29 female), with a mean age of 77.3 years (SD = 8.2). A 3-ml venous blood sample was obtained from each participant after an 8-hour fast. Levels of plasma homocysteine were measured by high performance liquid chromatography. The main outcome measure was hyperhomocysteinemia, defined as a plasma homocysteine level above 15 micromol/l.
RESULTS: Homocysteine levels were higher by 27.9% in the neovascular AMD than in the dry AMD group, and by 21.9% than in the control group (P <.02). Hyperhomocysteinemia was found in 44.1% of the study group, in 22.4% of the dry AMD group, and in 21.4% of the control group (P =.011).
CONCLUSIONS: This study suggests an association between an elevated plasma level of homocysteine and exudative neovascular AMD but not dry AMD. ||||| OBJECTIVE: To investigate the relationships between lifestyle behaviors of diet, smoking, and physical activity and the subsequent prevalence of age-related macular degeneration (AMD).
METHODS: The population included 1313 participants (aged 55-74 years) in the Carotenoids in Age-Related Eye Disease Study, an ancillary study of the Women's Health Initiative Observational Study. Scores on a modified 2005 Healthy Eating Index were assigned using responses to a food frequency questionnaire administered at baseline of the Women's Health Initiative Observational Study (1994-1998). Physical activity and lifetime smoking history were queried. An average of 6 years later, stereoscopic fundus photographs were taken to assess the presence and severity of AMD; it was present in 202 women, 94% of whom had early AMD, the primary outcome.
RESULTS: In multivariate models, women whose diets scored in the highest quintile compared with the lowest quintile on the modified 2005 Healthy Eating Index had 46% lower odds for early AMD. Women in the highest quintile compared with those in the lowest quintile for physical activity (in metabolic energy task hours per week) had 54% lower odds for early AMD. Although smoking was not independently associated with AMD on its own, having a combination of 3 healthy behaviors (healthy diet, physical activity, and not smoking) was associated with 71% lower odds for AMD compared with having high-risk scores (P < .001).
CONCLUSION: Modifying lifestyles might reduce risk for early AMD as much as 3-fold, lowering the risk for advanced AMD in a person's lifetime and the social and economic costs of AMD to society. ||||| BACKGROUND: Age-related macular degeneration (AMD) is the major cause of irreversible blindness. AMD appears to share several carbohydrate-related mechanisms and risk factors with diabetes-related diseases, including retinopathy and cardiovascular disease (CVD); however, to date, only one small study has addressed this issue.
OBJECTIVE: The objective was to test the hypothesis that dietary glycemic index (dGI), which has been related to the risk of diabetes and CVD, is associated with the risk and severity of AMD in nondiabetic elderly populations.
DESIGN: Dietary information was obtained from 4099 participants aged 55-80 y (56% women) in the Age-Related Eye Disease Study (AREDS). A total of 8125 eligible eyes at baseline were classified into 1 of 5 AMD groups according to the size and extent of drusen, the presence of geographic atrophy, and neovascular changes. We used a generalized estimating approach to evaluate the relations between dGI and risk and severity of AMD with eyes as the unit of analysis.
RESULTS: Compared with eyes in the first quintile of dGI, eyes in the fourth and fifth quintiles had a significantly or suggestively higher risk of large drusen, geographic atrophy, and neovascularization. The multivariate-adjusted odds ratios (95% CIs) for the highest quintile were 1.42 (1.09, 1.84), 1.78 (0.81, 3.90), and 1.41 (0.95, 2.08), respectively, of which only the odds ratio for large drusen was significant. A significant positive relation between dGI and severity of AMD was also noted (P for trend < 0.001). There was a 49% increase in the risk of advanced AMD (geographic atrophy plus neovascularization) for persons with a dGI higher than the sex median (women: >or=77.9; men: >or=79.3). This result indicated that 20% of prevalent cases of AMD would have been eliminated if the AREDS participants consumed diets with a dGI below the median.
CONCLUSION: The association between dGI and AMD from the AREDS cross-sectional analysis at baseline suggests that a reduction in the dGI, a modifiable risk factor, may provide a means of diminishing the risk of AMD. ||||| Age-related macular degeneration (AMD) is a common disorder that causes irreversible loss of central vision. Increased intake of foods containing zeaxanthin may be effective in preventing AMD because the macula accumulates zeaxanthin and lutein, oxygenated carotenoids with antioxidant and blue light-absorbing properties. Lycium barbarum L. is a small red berry known as Fructus lycii and wolfberry in the West, and Kei Tze and Gou Qi Zi in Asia. Wolfberry is rich in zeaxanthin dipalmitate, and is valued in Chinese culture for being good for vision. The aim of this study, which was a single-blinded, placebo-controlled, human intervention trial of parallel design, was to provide data on how fasting plasma zeaxanthin concentration changes as a result of dietary supplementation with whole wolfberries. Fasting blood was collected from healthy, consenting subjects; fourteen subjects took 15 g/d wolfberry (estimated to contain almost 3 mg zeaxanthin) for 28 d. Repeat fasting blood was collected on day 29. Age- and sex-matched controls (n 13) took no wolfberry. Responses in the two groups were compared using the Mann-Whitney test. After supplementation, plasma zeaxanthin increased 2.5-fold: mean values on day 1 and 29 were 0.038 (sem 0.003) and 0.096 (sem 0.009) micromol/l (P<0.01), respectively, for the supplementation group; and 0.038 (sem 0.003) and 0.043 (sem 0.003) micromol/l (P>0.05), respectively, for the control group. This human supplementation trial shows that zeaxanthin in whole wolfberries is bioavailable and that intake of a modest daily amount markedly increases fasting plasma zeaxanthin levels. These new data will support further study of dietary strategies to maintain macular pigment density. ||||| BACKGROUND: Information on concentrations of retinal carotenoids (macular pigment, or MP) is of particular interest because MP protects against age-related macular degeneration, the leading cause of irreversible blindness in the United States.
OBJECTIVE: This study was designed to evaluate the relation between dietary intake, blood concentrations, and retinal concentrations of carotenoids in a large group of volunteers.
DESIGN: Two hundred eighty volunteers in the Indianapolis area completed health and diet questionnaires, donated a blood sample, and participated in MP density assessment to determine retinal carotenoid status. Dietary intake was assessed by food-frequency questionnaire. Serum concentrations of lutein, zeaxanthin, and beta-carotene were measured by HPLC. MP optical density (MPOD) was determined psychophysically with a 460-nm, 1 degrees test stimulus.
RESULTS: Average MPOD was 0.21 +/- 0.13. Average intakes of lutein + zeaxanthin and beta-carotene were 1101 +/- 838 and 2935 +/- 2698 microg/d, respectively. Although several key dietary intake variables (eg, lutein + zeaxanthin and beta-carotene) differed by sex, no significant sex differences were found in either serum concentrations of lutein and zeaxanthin or MPOD. Serum beta-carotene concentrations were significantly higher in women than in men. Serum lutein + zeaxanthin and dietary intake of lutein + zeaxanthin were significantly correlated and significantly related to variations in MPOD (r = 0.21, P < 0.001, and r = 0.25, P < 0.001, respectively).
CONCLUSIONS: Retinal carotenoids can be measured in epidemiologic studies. In this study, MPOD was associated with lutein + zeaxanthin in the diet and the serum. Retinal concentrations, however, were influenced by other factors as well. To understand the effect of dietary lutein + zeaxanthin intake on the retina and risk of age-related eye disease, future studies should include measures of macular concentrations of these pigments. ||||| OBJECTIVE: To evaluate the relationship of dietary carotenoids, vitamin A, alpha-tocopherol, and vitamin C with prevalent age-related macular degeneration (AMD) in the Age-Related Eye Disease Study (AREDS).
METHODS: Demographic, lifestyle, and medical characteristics were ascertained on 4519 AREDS participants aged 60 to 80 years at enrollment. Stereoscopic color fundus photographs were used to categorize participants into 4 AMD severity groups and a control group (participants with < 15 small drusen). Nutrient intake was estimated from a self-administered semiquantitative food frequency questionnaire at enrollment. Intake values were energy adjusted and classified by quintiles. The relationship between diet and AMD status was assessed using logistic regression analyses.
RESULTS: Dietary lutein/zeaxanthin intake was inversely associated with neovascular AMD (odds ratio [OR], 0.65; 95% confidence interval [CI], 0.45-0.93), geographic atrophy (OR, 0.45; 95% CI, 0.24-0.86), and large or extensive intermediate drusen (OR, 0.73; 95% CI, 0.56-0.96), comparing the highest vs lowest quintiles of intake, after adjustment for total energy intake and nonnutrient-based covariates. Other nutrients were not independently related to AMD.
CONCLUSION: Higher dietary intake of lutein/zeaxanthin was independently associated with decreased likelihood of having neovascular AMD, geographic atrophy, and large or extensive intermediate drusen. ||||| PURPOSE: To determine whether anthocyanin-enriched bilberry extracts modulate pre- or posttranslational levels of oxidative stress defense enzymes heme-oxygenase (HO)-1 and glutathione S-transferase-pi (GST-pi) in cultured human retinal pigment epithelial (RPE) cells.
METHODS: Confluent ARPE-19 cells were preincubated with anthocyanin and nonanthocyanin phenolic fractions of a 25% enriched extract of bilberry (10(-6)-1.0 mg/mL) and, after phenolic removal, cells were oxidatively challenged with H(2)O(2). The concentration of intracellular glutathione was measured by HPLC and free radical production determined by the dichlorofluorescin diacetate assay. HO-1 and GST-pi protein and mRNA levels were determined by Western blot and RT-PCR, respectively.
RESULTS: Preincubation with bilberry extract ameliorated the intracellular increase of H(2)O(2)-induced free radicals in RPE, though H(2)O(2) cytotoxicity was not affected. By 4 hours, the extract had upregulated HO-1 and GST-pi protein by 2.8- and 2.5-fold, respectively, and mRNA by 5.5- and 7.1-fold, respectively, in a dose-dependent manner. Anthocyanin and nonanthocyanin phenolic fractions contributed similarly to mRNA upregulation.
CONCLUSIONS: Anthocyanins and other phenolics from bilberry upregulate the oxidative stress defense enzymes HO-1 and GST-pi in RPE, suggesting that they stimulate signal transduction pathways influencing genes controlled by the antioxidant response element. ||||| BACKGROUND: Several dietary factors have been linked to age-related maculopathy (ARM), the early form of age-related macular degeneration, and there is reason to think that dietary carbohydrate may play a role in the development of ARM.
OBJECTIVE: The purpose of the present study was to examine the relation between dietary carbohydrate quality, as measured by dietary glycemic index (GI) or total carbohydrate intake, and ARM.
DESIGN: From the Nurses' Health Study, 1036 eyes from 526 Boston-area participants without a previous ARM diagnosis were included in the present study. The presence and degree of ARM were classified by the Age-Related Eye Diseases Study system. Long-term dietary information was based on data from an average of 4 food-frequency questionnaires collected over a 10-y period before the assessment of ARM. With eyes as the unit of analysis, we used a generalized estimating approach to logistic regression to estimate the odds ratios for ARM in a manner that accounted for the lack of independence between the 2 eyes from the same subject.
RESULTS: After multivariate adjustment, dietary GI was related to ARM (specifically to retinal pigmentary abnormalities), whereas total carbohydrate intake was not. The odds ratio for ARM being in the highest tertile of dietary GI (> or =77.0) versus the lowest (<74.6) was 2.71 (95% CI: 1.24, 5.93; P for trend = 0.01). Neither dietary GI nor total carbohydrate intake was related to drusen.
CONCLUSION: Our results suggest that dietary GI may be an independent risk factor for ARM. ||||| BACKGROUND: Fish intake, the major source of docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), may reduce the risk of age-related macular degeneration (AMD).
OBJECTIVE: We investigated the association of oily fish and dietary DHA and EPA with neovascular AMD (NV-AMD).
DESIGN: Participants aged >/=65 y in the cross-sectional population-based EUREYE study underwent fundus photography and were interviewed by using a food-frequency questionnaire. Fundus images were graded by the International Classification System for Age Related Maculopathy. Questionnaire data were converted to nutrient intakes with the use of food-composition tables. Survey logistic regression was used to calculate odds ratios (ORs) and 95% CIs of energy-adjusted quartiles of EPA or DHA with NV-AMD, taking into account potential confounders.
RESULTS: Dietary intake data and fundus images were available for 105 cases with NV-AMD and for 2170 controls without any features of early or late AMD. Eating oily fish at least once per week compared with less than once per week was associated with a halving of the odds of NV-AMD (OR = 0.47; 95% CI: 0.33, 0.68; P = 0.002). Compared with the lowest quartile, there was a significant trend for decreased odds with increasing quartiles of either DHA or EPA. ORs in the highest quartiles were 0.32 (95% CI: 0.12, 0.87; P = 0.03) for DHA and 0.29 (95% CI: 0.11, 0.73; P = 0.02) for EPA.
CONCLUSIONS: Eating oily fish at least once per week compared with less than once per week was associated with a halving of the OR for NV-AMD. ||||| PURPOSE: To assess the relationship between plasma levels of homocysteine and age-related macular degeneration (AMD).
DESIGN: Cross-sectional, case-control study.
METHODS: Fasting plasma homocysteine levels were measured at two centers in 934 individuals who were participating in an ancillary study of the Age-Related Eye Disease Study. There were 547 cases and 387 control subjects, who were determined by fundus photography. Conditional logistic regression analyses were conducted to assess the association of homocysteine with AMD.
RESULTS: Median values of homocysteine were higher among advanced AMD cases (9.51 mmol/l) compared with persons with no AMD (8.81 mmol/l; P = .01). Values of >12 mmol/l vs < or =12 mmol/l were also associated with an increased risk of AMD (P = .023), when controlled for other covariates.
CONCLUSION: Results are consistent with a possible small, independent association between higher homocysteine levels and AMD. Homocysteine may be a modifiable risk factor for AMD. ||||| PURPOSE: To investigate whether dietary supplementation with IH636 grape seed proanthocyanidin extract (GSPE) prevents selenite-induced cataract.
SETTING: Department of Ophthalmology, Gulhane Military Medical Academy, Ankara, Turkey.
METHODS: Thirty Spraque-Dawley rat litters were put randomly into 3 groups. In group 1 (n = 10), sodium selenite (30 nmol/g body weight) was injected subcutaneously on postpartum day 10. In group 2 (n = 10), sodium selenite (30 nmol/g body weight) was injected on postpartum day 10 and oral GSPE (100 mg/kg body weight) was given for 1 week after sodium selenite injection. Only subcutaneous saline was injected in group 3 (control, n = 10). The development of cataract was assessed for 3 weeks, and its density was graded and photographed with a slitlamp. Removed rat lenses were analyzed for glutathione (GSH) and malondialdehyde (MDA).
RESULTS: All of the rats in group 1 had cataract between stage 6 and stage 3. In group 2, only 5 of 10 eyes had cataract between stage 3 and stage 2 and no cataract occurred in the remaining 5 rats. The difference between mean cataract stages in group 1 and group 2 was significant (P<.05). The mean GSH level in group 1 was significantly lower than in group 2 and controls (P<.05). The mean MDA level in group 1 was significantly higher than in group 2 and controls (P<.05).
CONCLUSIONS: IH636 grape seed proanthocyanidin extract effectively suppressed cataract formation in rats. Routine consumption of grape seed proanthocyanidin extract in the form of food or dietary supplement may offer a prophylactic measure against onset and progression of cataract. ||||| Elevated plasma homocysteine concentrations are associated with an increased risk of cardiovascular disease, but the relationship has not been proven to be causal. Folate is the strongest nutritional and pharmacological determinant of plasma homocysteine concentrations, which also interact with the genetic variation in methylenetetrahydrofolate reductase (MTHFR). Endothelial dysfunction due to reduced nitric oxide bioavailability is an early feature of vascular pathology. This can be assessed noninvasively by measurement of flow-mediated dilatation. Human studies on folic acid, homocysteine and endothelial function are reported. It is proposed that folic acid in high doses may have beneficial effects on endothelial function, which are independent of homocysteine lowering. ||||| BACKGROUND: Dietary factors are known risk factors for age-related macular degeneration (AMD) -- the leading cause of visual loss among persons aged > or =65 y. High-glycemic-index diets have been hypothesized as a risk factor for AMD, but prospective data are unavailable.
OBJECTIVE: The objective was to examine the association between dietary glycemic index and the 10-y incidence of AMD in the Blue Mountain Eye Study population.
DESIGN: This was a population-based cohort study with 3,654 participants (> or =49 y) examined at baseline (1992-1994); 2,335 patients were reexamined after 5 y and 1952 after 10 y. The Wisconsin System was used to grade 10-y incident early and late AMD from retinal photographs. A food-frequency questionnaire was used to collect dietary information at baseline, and an Australian database was used to calculate the mean glycemic index.
RESULTS: Over 10 y, 208 of 1,810 persons (cumulative incidence: 14.1%) developed early AMD. After age, smoking, other risk factors, and dietary constituents were adjusted for, a higher mean dietary glycemic index was associated with an increased 10-y risk of early AMD in a comparison of quartiles 1 and 4 [relative risk (RR): 1.77; 95% CI: 1.13, 2.78; P for trend = 0.03]. Conversely, a greater consumption of cereal fiber (RR: 0.68; 95% CI: 0.44, 1.04; P for trend = 0.05) and breads and cereals (predominantly lower glycemic index foods such as oatmeal) (RR: 0.67; 95% CI: 0.44, 1.02; P for trend = 0.03) was associated with a reduced risk of incident early AMD. No relation was observed with late AMD.
CONCLUSIONS: A high-glycemic-index diet is a risk factor for early AMD -- the recognized precursor of sight-threatening late AMD. Low-glycemic-index foods such as oatmeal may protect against early AMD. ||||| BACKGROUND: Ginkgo is used in the treatment of peripheral vascular disease and 'cerebral insufficiency'. It is thought to have several potential mechanisms of action including increased blood flow, platelet activating factor antagonism and prevention of membrane damage caused by free radicals. Vascular factors and oxidative damage are thought to be two potential mechanisms in the pathology of age-related macular degeneration.
OBJECTIVES: The objective of this review is to determine the effect of Ginkgo biloba extract on the progression of age-related macular degeneration.
SEARCH STRATEGY: The Cochrane Eyes and Vision Group specialised register, the Cochrane Controlled Trials Register - Central, MEDLINE, reference lists of identified trial reports, and the Science Citation Index were searched. The reviewer contacted Investigators of included studies for additional information. The most recent searches were performed in February 2000.
SELECTION CRITERIA: All randomised trials where Ginkgo biloba extract had been compared to control in people with age-related macular degeneration were included.
DATA COLLECTION AND ANALYSIS: The reviewer extracted data using a standardised form. The data were verified with the trial investigator.
MAIN RESULTS: One published trial was identified. Although a beneficial effect was observed, as only 20 people were enrolled in the trial, and assessment of outcome was not masked, its results must be considered equivocal. Adverse effects and quality of life for people with age-related macular degeneration have not been addressed. One unpublished trial is awaiting translation and assessment.
REVIEWER'S CONCLUSIONS: The question as to whether people with age-related macular degeneration should take Ginkgo biloba extract to prevent progression of the disease has not been answered by research to date. ||||| Observational studies have suggested an inverse relationship between dietary or serum lutein and risk for age-related macular degeneration and cataracts. This evidence has stimulated interest in the biological and other characteristics of lutein, and also zeaxanthin, a structurally similar carotenoid; together, they comprise the macular pigment. Accurate interpretation of data linking dietary intake or serum concentrations of lutein and zeaxanthin and risk for eye disease in epidemiologic and clinical studies requires knowledge of biological and nondietary factors influencing these intake data or concentrations. The primary aims of this study were to identify the correlates of dietary lutein + zeaxanthin intake and the determinants of serum lutein and zeaxanthin concentrations in a heterogeneous community-based sample of adults aged 18-92 y, recruited and examined at three U.S. sites (n = 2786). An additional aim was to identify the determinants of change in serum lutein concentration from baseline to 1 y in a subset of 1368 study participants followed prospectively. Demographic characteristics (age, sex, race/ethnicity, education), body mass index and lifestyle factors (exercise, sun exposure, smoking, alcohol consumption) were significantly (P < 0.05) associated with dietary lutein + zeaxanthin intake. Demographic characteristics, dietary intake, serum cholesterol concentration, body mass index and smoking explained 24% of the variance in serum lutein concentration. Race/ethnicity, education level and smoking had the strongest associations with serum lutein concentration. Every 10% increase in dietary lutein + zeaxanthin intake was associated with a 2.4% increase in serum lutein concentration. Notably, however, the amount of variance in serum concentration that is explained by demographic characteristics, health-related behaviors and lifestyle factors remains substantial. ||||| Dietary intervention with anthocyanins may confer benefits in brain function, including vision. Research to date indicates that animals have only a limited capacity to absorb anthocyanins, compared to other types of flavonoids. Pigs, which are a suitable model for human digestive absorption, were used to examine the deposition of anthocyanins in tissues including the liver, eye, and brain tissue. Pigs were fed diets supplemented with 0, 1, 2, or 4% w/w blueberries ( Vaccinium corymbosum L. 'Jersey') for 4 weeks. Prior to euthanasia, pigs were fasted for 18-21 h. Although no anthocyanins were detected in the plasma or urine of the fasted animals, intact anthocyanins were detected in all tissues where they were sought. LC-MS/MS results are presented for the relative concentration of 11 intact anthocyanins in the liver, eye, cortex, and cerebellum. The results suggest that anthocyanins can accumulate in tissues, including tissues beyond the blood-brain barrier. ||||| PURPOSE: To assess the relationship between baseline dietary and supplement intakes of antioxidants and the long-term risk of incident age-related macular degeneration (AMD).
DESIGN: Australian population-based cohort study.
PARTICIPANTS: Of 3654 baseline (1992-1994) participants initially 49 years of older, 2454 were reexamined after 5 years, 10 years, or both.
METHODS: Stereoscopic retinal photographs were graded using the Wisconsin Grading System. Data on potential risk factors were collected. Energy-adjusted intakes of alpha-carotene; beta-carotene; beta-cryptoxanthin; lutein and zeaxanthin; lycopene; vitamins A, C, and E; and iron and zinc were the study factors. Discrete logistic models assessed AMD risk. Risk ratios (RRs) and 95% confidence intervals (CIs) were calculated after adjusting for age, gender, smoking, and other risk factors.
MAIN OUTCOME MEASURES: Incident early, late, and any AMD.
RESULTS: For dietary lutein and zeaxanthin, participants in the top tertile of intake had a reduced risk of incident neovascular AMD (RR, 0.35; 95% CI, 0.13-0.92), and those with above median intakes had a reduced risk of indistinct soft or reticular drusen (RR, 0.66; 95% CI, 0.48-0.92). For total zinc intake the RR comparing the top decile intake with the remaining population was 0.56 (95% CI, 0.32-0.97) for any AMD and 0.54 (95% CI, 0.30-0.97) for early AMD. The highest compared with the lowest tertile of total beta-carotene intake predicted incident neovascular AMD (RR, 2.68; 95% CI, 1.03-6.96; P = 0.029, for trend). Similarly, beta-carotene intake from diet alone predicted neovascular AMD (RR comparing tertile 3 with tertile 1, 2.40; 95% CI, 0.98-5.91; P = 0.027, for trend). This association was evident in both ever and never smokers. Higher intakes of total vitamin E predicted late AMD (RR compared with the lowest tertile, 2.83; 95% CI, 1.28-6.23; and RR, 2.55; 95% CI, 1.14-5.70 for the middle and highest tertiles, respectively; P = 0.22, for trend).
CONCLUSIONS: In this population-based cohort study, higher dietary lutein and zeaxanthin intake reduced the risk of long-term incident AMD. This study confirmed the Age-Related Eye Disease Study finding of protective influences from zinc against AMD. Higher beta-carotene intake was associated with an increased risk of AMD. ||||| BACKGROUND: omega-3 (n-3) Long-chain polyunsaturated fatty acids (LCPUFAs) affect processes implicated in vascular and neural retinal pathogenesis and thus may influence the risk of developing age-related macular degeneration (AMD).
OBJECTIVE: We investigated whether omega-3 LCPUFA intake was associated with a reduced likelihood of developing central geographic atrophy (CGA) and neovascular (NV) AMD.
DESIGN: We undertook a nested cohort study within a multicenter phase 3 clinical trial, the Age-Related Eye Disease Study (AREDS), to study progression to advanced AMD in 1837 persons at moderate-to-high risk of this condition. The AREDS was designed to assess the clinical course, prognosis, risk factors, and nutrient-based treatments of AMD and ran from November 1992 to December 2005. We obtained baseline data on omega-3 LCPUFA intake with a validated food-frequency questionnaire. Trained fundus graders ascertained AMD status from annual stereoscopic color photographs by using standardized methods at a single reading center across a 12-y period. We applied multivariable repeated-measures logistic regression with the incorporation of generalized estimating equation methods, because this permitted determination of progression to outcome at each visit.
RESULTS: Participants who reported the highest omega-3 LCPUFA intake (median: 0.11% of total energy intake) were 30% less likely than their peers to develop CGA and NV AMD. The respective odds ratios were 0.65 (95% CI: 0.45, 0.92; P <or= 0.02) and 0.68 (95% CI: 0.49, 0.94; P <or= 0.02).
CONCLUSIONS: The 12-y incidence of CGA and NV AMD in participants at moderate-to-high risk of these outcomes was lowest for those reporting the highest consumption of omega-3 LCPUFAs. If these results are generalizable, they may guide the development of low-cost and easily implemented preventive interventions for progression to advanced AMD. This trial was registered at clinicaltrials.gov as NCT00594672. ||||| BACKGROUND: Cross-sectional studies indicate that diets that provide a higher dietary glycemic index (dGI) are associated with a greater risk of age-related macular degeneration (AMD). No prospective studies have addressed this issue.
OBJECTIVE: The objective was to prospectively evaluate the effect of baseline dGI on the progression of AMD.
DESIGN: dGI was calculated as the weighted average of GIs from foods and was evaluated as being above or below the sex median (women: 77.9; men: 79.3) for 3977 participants aged 55-80 y (58% women) in the Age-Related Eye Disease Study. The 7232 eligible eyes without advanced AMD were classified into 1 of 3 AMD categories: group 1 (nonextensive small drusen), group 2 (intermediate drusen, extensive small drusen, or pigmentary abnormalities), or group 3 (large drusen or extensive intermediate drusen). With the use of multifailure Cox proportional-hazards regression, we modeled the time to the maximal progression to evaluate the relation between dGI and the risk of AMD.
RESULTS: Overall, the multivariate-adjusted risk of progression over 8 y of follow-up (x: 5.4 y) was significantly higher (risk ratio: 1.10; 95% CI: 1.00, 1.20; P = 0.047) in the high-dGI group than in the low-dGI group. The risk of progression for groups 1, 2, and 3 eyes was 5%, 8%, and 17% greater, respectively (P for trend < 0.001). The latter gives an estimate that 7.8% of new advanced AMD cases would be prevented in 5 y if people consumed the low-dGI diet.
CONCLUSION: Persons at risk of AMD progression, especially those at high risk of advanced AMD, may benefit from consuming a smaller amount of refined carbohydrates. ||||| BACKGROUND: The Cochrane Collaboration, an international not-for-profit organization that prepares and maintains systematic reviews of randomized trials of health care therapies, has produced reviews summarizing much of the evidence on Traditional Chinese Medicine (TCM). Our objective was to review the evidence base according to Cochrane systematic reviews.
METHODS: In order to detect reviews focusing on TCM, we searched the titles and abstracts of all reviews in Issue 4, 2008 of the Cochrane Database of Systematic Reviews. For each review, we extracted data on the number of trials included and the total number of participants. We provided an indication of the strength of the review findings by assessing the reviewers' abstract conclusions statement. We supplemented our assessment of the abstract conclusions statements with a listing of the comparisons and outcomes showing statistically significant meta-analyses results.
RESULTS: We identified 70 Cochrane systematic reviews of TCM, primarily acupuncture (n = 26) and Chinese herbal medicine (n = 42), and 1 each of moxibustion and t'ai chi. Nineteen (19) of 26 acupuncture reviews and 22/42 herbal medicine reviews concluded that there was not enough good quality trial evidence to make any conclusion about the efficacy of the evaluated treatment, while the remaining 7 acupuncture and 20 herbal medicine reviews and each of the moxibustion and t'ai chi reviews indicated a suggestion of benefit, which was qualified by a caveat about the poor quality and quantity of studies. Most reviews included many distinct interventions, controls, outcomes, and populations, and a large number of different comparisons were made, each with a distinct forest plot.
CONCLUSIONS: Most Cochrane systematic reviews of TCM are inconclusive, due specifically to the poor methodology and heterogeneity of the studies reviewed. Some systematic reviews provide preliminary evidence of Chinese medicine's benefits to certain patient populations, underscoring the importance and appropriateness of further research. These preliminary findings should be considered tentative and need to be confirmed with rigorous randomized controlled trials. ||||| PURPOSE: To assess associations between increased serum homocysteine, low vitamin B12, low folate, and age-related macular degeneration (AMD).
DESIGN: Population-based, cross-sectional analysis.
METHODS: Serum homocysteine, vitamin B12, and folate were measured in 2,335 participants of the Blue Mountains Eye Study second survey. AMD detected from retinal photographs included atrophic or neovascular lesions.
RESULTS: After adjusting for age, gender, and smoking in logistic regression models, homocysteine >15 micromol/l was associated with an increased likelihood of AMD in participants aged <75 years (odds ratio [OR] 3.21, 95% confidence interval [95% CI] 1.09 to 9.43). A similar association was found for vitamin B12 <125 pmol/l (OR 2.30, 95% CI 1.08 to 4.89) among all participants. In participants with homocysteine < or =15 micromol/l, low serum B12 was associated with nearly four-fold higher odds of AMD (OR 3.74, 95% CI 1.06 to 13.24). Folate was not statistically significantly associated with AMD.
CONCLUSIONS: Increased homocysteine and low vitamin B12 were independently associated with an increased risk of AMD in this study population. | [
{
"source_pmid": "16908818",
"source_text": "OBJECTIVE: To evaluate the relationship between dietary lutein plus zeaxanthin and intermediate age-related macular degeneration (AMD).\nDESIGN: Women aged 50 to 79 years in Iowa, Wisconsin, and Oregon with intake of lutein plus zeaxanthin above the 78th (high) a... |
24312416 | Our meta-analysis provides strong evidence that the APOE ε2/ε3/ε4 polymorphism is not associated with POAG susceptibility in any populations. | PURPOSE: To evaluate the association of myocilin (MYOC), optineurin (OPTN), and apolipoprotein E (APOE) genes and their interactions in primary open angle glaucoma (POAG).
METHODS: A cohort of 400 unrelated POAG patients (294 high tension glaucoma, HTG, and 106 normal tension glaucoma, NTG) and 281 unrelated control subjects were recruited. All coding exons and splicing junctions in MYOC and OPTN were screened for sequence alterations. Common polymorphisms in APOE were genotyped. Single genes were investigated by univariate and haplotype analysis, and gene-gene interactions by logistic regression and stratified analysis. Multiple comparisons were corrected by the Bonferroni method. Bioinformatics analysis was performed to assess the conservation of mutation sites across species and to predict putative motifs and secondary structures in mutated proteins.
RESULTS: Disease-causing mutations in MYOC and OPTN were identified in 1.75% and 1% of POAG patients, respectively. Most of these mutations were highly conserved across species, many predicted to create new motifs or change protein secondary structures. No individual MYOC polymorphisms significantly contributed to HTG or NTG. A haplotype containing the minor allele of the MYOC IVS2+35A>G increased NTG risk (p=0.0001). Three OPTN polymorphisms, T34T, IVS5+38T>G, and IVS8-53T>C increased NTG risk (p<0.0008), while IVS5+38T>G increased HTG risk (p=0.0006). One haplotype that contains the minor alleles of 3 OPTN polymorphisms, T34T, IVS5+38T>G, and IVS7+24G>A, increased NTG risk (p=0.0002). APOE epsilon4 carriers had a decreased NTG risk (p=0.007). Possible gene-gene interactions were found between MYOC, OPTN, and APOE.
CONCLUSIONS: Disease-causing mutations in MYOC and OPTN accounted for only a small proportion of Chinese POAG patients. Common polymorphisms in MYOC, OPTN, and APOE might interactively contribute to POAG, indicating a polygenic etiology. ||||| PURPOSE: Inheritance of a particular apolipoprotein E gene polymorphism, the epsilon4 allele, has been associated with elevated risk for Alzheimer's disease and a poor outcome following head injury. The neuronal injury associated with Alzheimer's disease and brain injury may have a number of similarities with the nerve cell changes associated with glaucoma. Thus, we have investigated the association of inheritance of apolipoprotein E allelic isoforms (epsilon2, [epsilon]3, and epsilon4) with relative risk for different forms of glaucoma.
METHODS: Apolipoprotein E genotype was examined in a Tasmanian population sample comprised of glaucoma sufferers with elevated or normal intraocular pressure and compared to a control sample of elderly Tasmanians without glaucoma.
RESULTS: Approximately twice as many normal tension (38.0%) and high tension (34.2%) glaucoma cases possessed an epsilon4 allele compared to control cases (18.9%). The odds of epsilon4 carriers having normal tension glaucoma were significantly greater than for epsilon3 homozygotes (odds ratio 2.45, 95% confidence interval [1.02-5.91]) even after adjusting for age and gender (odd ratio 2.87 [1.02-8.05]). The increased odds of high tension glaucoma among [epsilon]4 allele carriers were not significant (adjusted odds ratio 1.53 [0.64-3.68]).
CONCLUSIONS: The data indicate that, in the Tasmanian population, inheritance of the [epsilon]4 allele is associated with elevated risk for glaucomatous changes that are not related to increased intraocular pressure. ||||| PURPOSE: To investigate apolipoprotein E (APOE) polymorphisms, which are known to influence the risk of Alzheimer disease (AD), in patients with primary open-angle glaucoma (POAG).
DESIGN: Retrospective case-control association study.
METHODS: Patients with POAG (n = 242) and controls (n = 187) were analyzed for the APOE epsilon 2/epsilon 3/epsilon 4 polymorphisms using minisequencing technique.
RESULTS: The Alzheimer-associated APOE epsilon 4 allele had similar frequencies in the POAG group and in the control group. There was no difference between cases and controls with regard to APOE genotypes.
CONCLUSIONS: If a common pathogenic mechanism exists for the two age-related neurodegenerative diseases, POAG and AD, it does not involve APOE polymorphisms. ||||| The clinical and genetic relationships between Alzheimer's disease (AD) and glaucoma remain obscure. The aim of this study was to determine the prevalence of open-angle glaucoma (OAG) in patients with AD and whether the apolipoprotein E (APOE) 4 allele is associated with AD, with or without OAG, in Japanese. The groups consisted of 172 patients with the diagnostic criteria of AD and 176 age-matched controls. Ophthalmic examinations were conducted, and genomic analysis was performed by PCR and digestion of products with an enzyme. OAG was found in 41 (23.8%) of the AD patients, which was a significantly (p = 0.0002) higher prevalence than that in the controls (9.9%). Furthermore, there was no significant difference between intraocular pressures (IOPs) in AD patients with OAG and without OAG. The percentage of AD patients who carried an APOE epsilon4 allele (29.5%) was significantly (p = 0.0007) higher than that of the controls (9.1%). However, the percentage of AD patients with OAG who carried an APOE epsilon4 allele (35.7%) was not significantly different than that of AD patients without OAG (27.7%, p = 0.42). In summary, the prevalence of OAG is high in Japanese patients with AD, suggesting that common factors other than APOE may contribute to the two diseases. ||||| PURPOSE: To assess whether genetic polymorphisms of the apolipoprotein E (APOE) gene are associated with open angle glaucoma (OAG) in the Japanese population.
METHODS: Genomic DNA was examined in a cohort of 310 Japanese patients with OAG and 179 control subjects. The average age was 63.5+/-14.4 years (mean+/-SD) for the OAG patients and 65.5+/-11.6 years for the control subjects. The presence or absence of OAG in patients and controls was based on clinical examination and/or ophthalmic records. The APOE allele frequency (epsilon2, epsilon3, and epsilon4 alleles) was studied by restriction fragment length polymorphism, and compared between OAG patients and control subjects. The association between the intraocular pressure (IOP) and the APOE alleles was also evaluated.
RESULTS: There was a significant difference in the APOE genotype frequencies between these groups (p=0.0006 chi2 test). The frequencies of the epsilon2 and epsilon4 alleles were significantly lower in the OAG patients (epsilon2: 2.6%; epsilon4: 6.0%) compared to the control subjects (epsilon2: 5.0%, p=0.048; epsilon4: 10.6%, p=0.012; Fisher's exact test). The frequency of the epsilon3 allele was significantly higher in the OAG patients (91.4%) compared to the control subjects (84.4%, p=0.0010; Fisher's exact test). Adjusted for age, gender, and IOP, an appropriate three fold reduction in OAG risk (odds ratio [OR] 0.29, 95% confidence interval [CI] 0.10 to 0.80; p=0.018) was found with the epsilon2 allele and a two fold increased risk of OAG (OR 1.97, 95% CI 1.06 to 3.67; p=0.033) was found with the epsilon3 allele. The maximum IOP (18.3+/-6.0 mm Hg) in patients with the epsilon4 allele was significantly lower than that (21.3+/-9.1 mm Hg) in patients without the epsilon4 allele (p=0.006, Student's t-test).
CONCLUSIONS: The APOE gene polymorphism is associated with OAG in the Japanese population. Further studies in the other ethnic populations should be performed to elucidate the relationship between APOE and OAG. ||||| PURPOSE: To investigate the association between Apolipoprotein E (APOE), tumor suppressor protein p53 (p53), and cyclin-dependent kinase inhibitor 1A (p21) genes and primary open-angle glaucoma (POAG) in a cohort of Turkish subjects.
METHODS: Seventy-five POAG patients (49 women, 26 men) and 119 healthy subjects (67 women, 52 men) were genotyped with polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Allele and genotype frequencies between healthy subjects and glaucoma patients were compared by the chi(2) test, and intraocular pressure (IOP), cup/disc ratio (C/D) and visual field indices (MD and PSD) were compared among different APOE, p53, and p21 genotypes in POAG group. A p value <0.05 was considered as statistically significant.
RESULTS: The mean ages were 63.8+/-9.5 and 61.8+/-10.2 years in POAG and control groups, respectively (p=0.18). There were no significant differences in the distribution of APOE, p53, and p21 genotypes between the healthy subjects and POAG patients (p=0.38, p=0.12, and p=0.2, respectively). There were no significant differences in maximum IOP, MD, and PSD values among different groups of p53 and p21 genotypes (p>0.05). POAG subjects with the epsilon2epsilon3 genotype had a worse PSD value (median=2.2) than those with the epsilon3epsilon4 genotype (median=1.77; p=0.01) and POAG subjects with the epsilon3epsilon3 genotype had worse MD and PSD values (median= -7.4 and 3.4, respectively) than those with the epsilon3epsilon4 genotype (median= -4.1 and 1.77, respectively; p=0.034 and 0.028, respectively).
CONCLUSIONS: Our study found no link between polymorphisms in APOE, p53, and p21 genes and POAG in Turkish patients, although a larger sample is required to elucidate the role of these polymorphisms in the pathogenesis and course of glaucoma. ||||| PURPOSE: To evaluate the individual and interactive effects of polymorphisms in the myocilin (MYOC),optineurin (OPTN), WD repeat domain 36 (WDR36), and apolipoprotein E (APOE) genes on primary open-angle glaucoma (POAG) in northern Chinese.
METHODS: Northern Chinese study subjects, 176 POAG patients and 200 controls, were recruited for screening of the coding exons and splicing regions of MYOC. Five single nucleotide polymorphisms (SNPs) in OPTN (M98K, R545Q, IVS5+38T>G, IVS8-53T>C, and IVS15+10G>A), one SNP in WDR36 (IVS5+30C>T) as well as the APOE promoter and epsilon2/epsilon3/epsilon4 polymorphisms were also examined. Association analysis was performed by using chi(2) analysis. High-order gene-gene interaction was also analyzed using the multifactor dimensionality reduction (MDR) method.
RESULTS: In MYOC, 22 variants were identified. Four of them were novel but found in controls only. The missense mutation, Val53Ala, is likely a glaucoma causing mutation, accounting for 0.6% of cases. No individual polymorphism in OPTN, WDR36, or APOE was associated with POAG. MDR analysis identified a best 6-factor model for POAG: MYOC IVS2+35A>G, OPTN Met98Lys, OPTN IVS5+38T>G, OPTN IVS8-53T>C, WDR36 IVS5+30C>T, and APOE -491A>T.
CONCLUSIONS: The association pattern between the genes, MYOC, OPTN, WDR36, and APOE, and POAG in northern Chinese is different from that of southern Chinese. Disease-causing mutations in MYOC accounted for a small proportion of northern Chinese POAG patients. Common polymorphisms in these genes were not associated with POAG individually but might interactively contribute to the disorder, supporting a polygenic etiology. ||||| BACKGROUND: /aims: In normal tension glaucoma (NTG) factors other than raised intraocular pressure have a role in the pathogenesis of the optic neuropathy. Because particular apolipoprotein E (ApoE) gene polymorphisms have been associated with cell death and survival in neurological degenerative diseases, the purpose of this study was to determine the ApoE allele frequencies in patients with normal tension glaucoma.
METHODS: The apolipoprotein E genotype of 155 patients with normal tension glaucoma was compared to that of 349 non-affected, control subjects from the same geographical area. A similar comparison was made between 53 patients with normal tension glaucoma who demonstrated progressive visual field loss, and control subjects. The frequencies of genotypes was compared with the chi(2) test and Mantel-Haenszel coefficent.
RESULTS: There was no significant difference in the frequency of ApoE alleles or genotypes in the normal tension glaucoma population compared to the control group. The ApoE alleles and genotypes in NTG patients with progressive disease were not different from the control group.
CONCLUSION: ApoE gene polymorphisms are not linked to normal tension glaucoma, suggesting that this gene does not have a role in the pathogenesis of optic neuropathy in this disease. ||||| PURPOSE: To evaluate the role of apolipoprotein E (APOE) polymorphisms in primary open angle glaucoma (POAG).
METHODS: A cohort of 400 unrelated Chinese POAG patients was examined, including 294 cases of high tension glaucoma (HTG) and 106 with normal tension glaucoma (NTG). Also studied were 300 unrelated Chinese control subjects. The genotypes of the APOE polymorphisms in exon 4 and in the promoter at positions -491, -427, and -219 were determined by polymerase chain reaction and restriction endonuclease analysis. Frequencies of the genotypes were compared between patients and controls by chi test or Fisher exact test. The association of APOE polymorphisms with POAG phenotypes including age at diagnosis, intraocular pressure (IOP) at diagnosis, highest IOP, cup-disc ratio, and visual field score was investigated by the Kruskal-Wallis test.
RESULTS: No significant difference was detected in the frequencies of APOE promoter polymorphisms between POAG patients and control subjects (P>0.0125). For the exon 4 polymorphism, when compared with control subjects, the frequency of epsilon 4 carriers was significantly lower in patients with NTG (P=0.008; odds ratio=0.36, 95% confidence interval=0.17, 0.79) but not in HTG (P=0.07). Compared with -219TT, the -219G carriers had a significant higher age at diagnosis (P=0.0046). No significant association was found between other APOE polymorphisms and POAG phenotypes (P>0.07).
CONCLUSIONS: Our findings suggest that the APOE epsilon 4 allele confers a protective effect against NTG, whereas the APOE promoter polymorphisms do not contribute to POAG risk. However, the APOE -219G carriers tended to have later-onset POAG. | [
{
"source_pmid": "16148883",
"source_text": "PURPOSE: To evaluate the association of myocilin (MYOC), optineurin (OPTN), and apolipoprotein E (APOE) genes and their interactions in primary open angle glaucoma (POAG).\nMETHODS: A cohort of 400 unrelated POAG patients (294 high tension glaucoma, HTG, and 106 ... |
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