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Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Ocular hypertension'. | Nonarteritic Anterior Ischemic Optic Neuropathy following Herpes Zoster Ophthalmicus and Steroid-Related Intraocular Pressure Spike.
A 61-year-old woman presented with sudden vision loss from a left anterior optic neuropathy in the context of severely elevated intraocular pressure after starting topical steroids for anterior uveitis related to herpes zoster ophthalmicus (HZO). The strong temporal relationship between the vision loss and elevated IOP suggested the vision loss was related to nonarteritic anterior ischemic optic neuropathy (NAION). Anterior chamber paracentesis did not detect varicella zoster virus (VZV) and magnetic resonance imaging of the orbits was normal. Her vision remained stable and the optic disc edema resolved within 3 months. The occurrence of NAION following an acute elevation of intraocular pressure (IOP) is well-documented in the context of surgical procedures, glaucoma, uveitis and trauma. This case indicates that not every optic neuropathy in close temporal relationship with HZO is directly attributable to the virus. NAION may also occur after steroid-related IOP spikes and ophthalmologists should ensure that patients on topical steroids are closely monitored for ocular complications.
Introduction
Vision loss is a rare complication of herpes zoster ophthalmicus (HZO) and can be a result of anterior segment of posterior segment involvement. Optic neuropathy is a rare complication of HZO seen in less than 0.5% of cases and can be anterior (associated with optic disc edema) or retrobulbar [1]. The diagnosis of herpes zoster optic neuropathy (HZON) is diagnosed in patients who develop an optic neuropathy in close temporal relationship with HZO with other causes of optic neuropathy being excluded. Supportive evidence for the diagnosis is helpful by means of magnetic resonance imaging (MRI) of the orbits with contrast demonstrating enhancement of the optic nerve in retrobulbar cases, or the detection of varicella zoster virus (VZV) in the aqueous humor or cerebrospinal fluid (CSF) [1]. However, the yield of detection of VZV in the CSF is low, especially in anterior cases. Treatment consists of oral or intravenous antivirals and the use of systemic corticosteroids remains controversial [1]. Patients with HZO may develop an anterior optic neuropathy that is not directly related to VZV, but secondarily related to HZO by means of other ocular complications. We report a case of nonarteritic anterior ischemic optic neuropathy (NAION) related to HZO, which was likely secondary to the development of a steroid response and elevated intraocular pressure (IOP) for the treatment of anterior uveitis. This indicates that not every optic neuropathy in close temporal relationship to HZO is directly related to the virus.
Case Report
A 61-year-old woman was seen in neuro-ophthalmology consultation for a left optic neuropathy. She had a history of hypertension and was taking amlodipine. She developed left HZO 1 month prior to presentation with skin lesions on the left forehead and tip and side of her nose. She was treated with valacyclovir 1 g PO TID for 10 days. She saw an ophthalmologist 3 days later and was found to have anterior uveitis (1+ cells), an intraocular pressure of 18, and was started on prednisolone acetate 1% eye drops QID. This was continued and the examination remained stable 1 week later. Two weeks later, she developed left eye pain and worsening vision. She saw an ophthalmologist and was found to have an intraocular pressure of 52 mm Hg without any signs of uveitis. Her refraction was −1.00 +0.50 × 172 OD and −1.50 +0.50 × 180 OS and the gonioscopy revealed open angles, grade 3 (Shaffer system) with the trabecular meshwork visible for 360 degrees in both eyes. She was started on acetazolamide 250 mg PO QID, brimonidine-timolol eye drops BID and topical prednisolone acetate was discontinued given the likelihood of a steroid response. Follow-up the next day revealed an improved intraocular pressure of 16, but she was noted to have a new relative afferent pupillary defect and optic disc edema in the left optic nerve. A neuro-ophthalmology consultation was requested. Acetazolamide and brimonidine-timolol eye drops were discontinued.
Neuro-ophthalmology assessment revealed a visual acuity of 20/20 OD and 20/100 OS, a left RAPD, and Humphrey visual field testing demonstrated a left inferior altitudinal visual field defect (Fig. 1a). Anterior segment revealed no signs of uveitis and dilated fundus examination demonstrated a normal appearing right optic nerve with a cup-to-disc ratio of 0.1 and left diffuse optic disc edema. Optical coherence tomography of the retinal nerve fiber layer showed an average thickness of 84 μm OD and 182 μm OS (Fig. 1b). The differential diagnosis considered was a left anterior optic neuropathy related to herpes zoster or NAION related to the recent IOP elevation. An anterior chamber paracentesis was performed and VZV was not detected by real-time PCR. She had an MRI of the brain and orbits with contrast that did not show enhancement of the optic nerves and was normal. Complete blood count, erythrocyte sedimentation rate and C-reactive protein were normal. She was treated with valacyclovir 1 g PO TID for 1 month as a precaution, but her vision did not improve. At 3-month follow-up, she continued to have a left inferior altitudinal visual field defect and the left optic disc edema had resolved.
Discussion
Vision loss is a feared complication of HZON and may affect almost any part of the eye including the anterior and posterior segments [1]. This may be a result of direct involvement of VZV or a secondary inflammatory component. This case highlights that optic nerve complications from VZV may not be due to direct involvement of the virus but can be a secondary result of another ocular complication. Our patient developed NAION related to elevated IOP that likely disrupted the perfusion to the optic nerve head. This was unlikely to be a direct result of the virus for a number of reasons including the absence of detectable virus in the aqueous humor by PCR, the absence of any optic nerve enhancement on orbital MRI with contrast and the absence of any improvement in her visual field, which is typical of NAION, despite antiviral treatment [2]. The patient also had a history of hypertension and a disc-at-risk, which is a requirement for the development of NAION [3]. The optic disc edema resolved in the expected time course for NAION, and the patient had no other signs or symptoms of another optic neuropathy. There was also a clear temporal relationship between the IOP spike and the loss of vision. Although CSF was not obtained, this would be an extremely low-yield test, especially with no retrobulbar involvement seen on MRI.
NAION has been previously described to develop in response to elevated IOP and subsequent disruption to the optic nerve head perfusion pressure [4, 5, 6]. This has been well-described in a number of situations including after ophthalmological procedures, acute glaucoma, hypertensive uveitis, or the administration of steroid eye drops [7, 8, 9, 10, 11]. Cases of ophthalmological procedures include cataract extraction complicated by capsular block, pars plana vitrectomy for macular hole, and trabeculectomy complicated by NAION have been described [7, 8, 9]. NAION after intravitreal injections have also been presumed to be related to elevated intraocular pressure, although the IOP has not been routinely measured in most of these cases [12]. The presumed mechanism of NAION after cataract surgery has also been thought to be related to elevated IOP, which is elevated intraoperatively and sometimes postoperatively [13]. Acute primary angle closure and traumatic angle recession glaucoma has been reported to be complicated by NAION and may be bilateral and severe [10, 11]. We were unable to retrieve any previously reported case of NAION secondary to herpes zoster anterior uveitis, but cases after Posner-Schlossman syndrome (PSS) have been described. Similar to our case, the PSS cases all had IOP in excess of 50 mmHg and some cases were in individuals younger than 50 years of age [5, 10]. We were unable to retrieve any cases of NAION that developed after steroid-related IOP spikes.
Elevated intraocular pressure is well-known complication of topical steroids and to a lesser extent systemic and topical steroid treatment [14, 15]. This typically onsets around 3–6 weeks after the initiation of topical steroids and is thought to be related to increased resistance to aqueous outflow at the trabecular meshwork. The mechanism of this IOP elevation is unclear but the discontinuation of steroid treatment predictably triggers the reversal of IOP elevation back to baseline [14]. Complications of elevated IOP, not only include glaucoma, but may also result in retinal vein occlusions, corneal edema and as we have shown in this case, NAION. It is important that ophthalmologists closely monitor patients on topical steroids since NAION may be a rare and irreversible complication of their use. This may even occur in younger patients who may be taking topical steroids postoperatively for eye surgery or for ocular inflammatory disorders. Treatment of steroid-induced ocular hypertension typically involves discontinuation of the steroid and use of topical and systemic IOP-lowering medications. The elevation of IOP in our patient was likely related to topical steroid use since there was no active inflammation at the time of vision loss and the IOP responded promptly to the discontinuation of steroids.
In summary, the development of an optic neuropathy in close temporal relationship may not necessarily be related to VZV. We report a case of steroid-induced ocular hypertension for initial treatment of herpes zoster-related anterior uveitis that was complicated by NAION. Patients on topical steroids should be closely monitored since irreversible optic nerve damage may occur in this context.
Statement of Ethics
This study was carried out in accordance with the World Medical Association Declaration of Helsinki. Verbal and written consent were obtained from the patient.
Conflict of Interest Statement
The authors have no conflicts of interest to declare.
Funding Sources
No funding was received.
Author Contributions
Conception and design (P.H.Y., J.A.M.), data extraction (P.H.Y., J.A.M.), manuscript preparation (P.H.Y.), final approval (J.A.M.). All authors have seen and approved the final version of the manuscript for publication.
Fig. 1 a Humphrey 24–2 SITA-Fast visual fields demonstrating a left inferior altitudinal visual field defect. b Optical coherence tomography of the retinal nerve fiber layer (RNFL) at presentation with left eye vision loss demonstrating an elevated RNFL due to optic disc edema in the left eye. | AMLODIPINE BESYLATE, PREDNISOLONE, VALACYCLOVIR HYDROCHLORIDE | DrugsGivenReaction | CC BY-NC | 33613245 | 19,401,072 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Visual impairment'. | Nonarteritic Anterior Ischemic Optic Neuropathy following Herpes Zoster Ophthalmicus and Steroid-Related Intraocular Pressure Spike.
A 61-year-old woman presented with sudden vision loss from a left anterior optic neuropathy in the context of severely elevated intraocular pressure after starting topical steroids for anterior uveitis related to herpes zoster ophthalmicus (HZO). The strong temporal relationship between the vision loss and elevated IOP suggested the vision loss was related to nonarteritic anterior ischemic optic neuropathy (NAION). Anterior chamber paracentesis did not detect varicella zoster virus (VZV) and magnetic resonance imaging of the orbits was normal. Her vision remained stable and the optic disc edema resolved within 3 months. The occurrence of NAION following an acute elevation of intraocular pressure (IOP) is well-documented in the context of surgical procedures, glaucoma, uveitis and trauma. This case indicates that not every optic neuropathy in close temporal relationship with HZO is directly attributable to the virus. NAION may also occur after steroid-related IOP spikes and ophthalmologists should ensure that patients on topical steroids are closely monitored for ocular complications.
Introduction
Vision loss is a rare complication of herpes zoster ophthalmicus (HZO) and can be a result of anterior segment of posterior segment involvement. Optic neuropathy is a rare complication of HZO seen in less than 0.5% of cases and can be anterior (associated with optic disc edema) or retrobulbar [1]. The diagnosis of herpes zoster optic neuropathy (HZON) is diagnosed in patients who develop an optic neuropathy in close temporal relationship with HZO with other causes of optic neuropathy being excluded. Supportive evidence for the diagnosis is helpful by means of magnetic resonance imaging (MRI) of the orbits with contrast demonstrating enhancement of the optic nerve in retrobulbar cases, or the detection of varicella zoster virus (VZV) in the aqueous humor or cerebrospinal fluid (CSF) [1]. However, the yield of detection of VZV in the CSF is low, especially in anterior cases. Treatment consists of oral or intravenous antivirals and the use of systemic corticosteroids remains controversial [1]. Patients with HZO may develop an anterior optic neuropathy that is not directly related to VZV, but secondarily related to HZO by means of other ocular complications. We report a case of nonarteritic anterior ischemic optic neuropathy (NAION) related to HZO, which was likely secondary to the development of a steroid response and elevated intraocular pressure (IOP) for the treatment of anterior uveitis. This indicates that not every optic neuropathy in close temporal relationship to HZO is directly related to the virus.
Case Report
A 61-year-old woman was seen in neuro-ophthalmology consultation for a left optic neuropathy. She had a history of hypertension and was taking amlodipine. She developed left HZO 1 month prior to presentation with skin lesions on the left forehead and tip and side of her nose. She was treated with valacyclovir 1 g PO TID for 10 days. She saw an ophthalmologist 3 days later and was found to have anterior uveitis (1+ cells), an intraocular pressure of 18, and was started on prednisolone acetate 1% eye drops QID. This was continued and the examination remained stable 1 week later. Two weeks later, she developed left eye pain and worsening vision. She saw an ophthalmologist and was found to have an intraocular pressure of 52 mm Hg without any signs of uveitis. Her refraction was −1.00 +0.50 × 172 OD and −1.50 +0.50 × 180 OS and the gonioscopy revealed open angles, grade 3 (Shaffer system) with the trabecular meshwork visible for 360 degrees in both eyes. She was started on acetazolamide 250 mg PO QID, brimonidine-timolol eye drops BID and topical prednisolone acetate was discontinued given the likelihood of a steroid response. Follow-up the next day revealed an improved intraocular pressure of 16, but she was noted to have a new relative afferent pupillary defect and optic disc edema in the left optic nerve. A neuro-ophthalmology consultation was requested. Acetazolamide and brimonidine-timolol eye drops were discontinued.
Neuro-ophthalmology assessment revealed a visual acuity of 20/20 OD and 20/100 OS, a left RAPD, and Humphrey visual field testing demonstrated a left inferior altitudinal visual field defect (Fig. 1a). Anterior segment revealed no signs of uveitis and dilated fundus examination demonstrated a normal appearing right optic nerve with a cup-to-disc ratio of 0.1 and left diffuse optic disc edema. Optical coherence tomography of the retinal nerve fiber layer showed an average thickness of 84 μm OD and 182 μm OS (Fig. 1b). The differential diagnosis considered was a left anterior optic neuropathy related to herpes zoster or NAION related to the recent IOP elevation. An anterior chamber paracentesis was performed and VZV was not detected by real-time PCR. She had an MRI of the brain and orbits with contrast that did not show enhancement of the optic nerves and was normal. Complete blood count, erythrocyte sedimentation rate and C-reactive protein were normal. She was treated with valacyclovir 1 g PO TID for 1 month as a precaution, but her vision did not improve. At 3-month follow-up, she continued to have a left inferior altitudinal visual field defect and the left optic disc edema had resolved.
Discussion
Vision loss is a feared complication of HZON and may affect almost any part of the eye including the anterior and posterior segments [1]. This may be a result of direct involvement of VZV or a secondary inflammatory component. This case highlights that optic nerve complications from VZV may not be due to direct involvement of the virus but can be a secondary result of another ocular complication. Our patient developed NAION related to elevated IOP that likely disrupted the perfusion to the optic nerve head. This was unlikely to be a direct result of the virus for a number of reasons including the absence of detectable virus in the aqueous humor by PCR, the absence of any optic nerve enhancement on orbital MRI with contrast and the absence of any improvement in her visual field, which is typical of NAION, despite antiviral treatment [2]. The patient also had a history of hypertension and a disc-at-risk, which is a requirement for the development of NAION [3]. The optic disc edema resolved in the expected time course for NAION, and the patient had no other signs or symptoms of another optic neuropathy. There was also a clear temporal relationship between the IOP spike and the loss of vision. Although CSF was not obtained, this would be an extremely low-yield test, especially with no retrobulbar involvement seen on MRI.
NAION has been previously described to develop in response to elevated IOP and subsequent disruption to the optic nerve head perfusion pressure [4, 5, 6]. This has been well-described in a number of situations including after ophthalmological procedures, acute glaucoma, hypertensive uveitis, or the administration of steroid eye drops [7, 8, 9, 10, 11]. Cases of ophthalmological procedures include cataract extraction complicated by capsular block, pars plana vitrectomy for macular hole, and trabeculectomy complicated by NAION have been described [7, 8, 9]. NAION after intravitreal injections have also been presumed to be related to elevated intraocular pressure, although the IOP has not been routinely measured in most of these cases [12]. The presumed mechanism of NAION after cataract surgery has also been thought to be related to elevated IOP, which is elevated intraoperatively and sometimes postoperatively [13]. Acute primary angle closure and traumatic angle recession glaucoma has been reported to be complicated by NAION and may be bilateral and severe [10, 11]. We were unable to retrieve any previously reported case of NAION secondary to herpes zoster anterior uveitis, but cases after Posner-Schlossman syndrome (PSS) have been described. Similar to our case, the PSS cases all had IOP in excess of 50 mmHg and some cases were in individuals younger than 50 years of age [5, 10]. We were unable to retrieve any cases of NAION that developed after steroid-related IOP spikes.
Elevated intraocular pressure is well-known complication of topical steroids and to a lesser extent systemic and topical steroid treatment [14, 15]. This typically onsets around 3–6 weeks after the initiation of topical steroids and is thought to be related to increased resistance to aqueous outflow at the trabecular meshwork. The mechanism of this IOP elevation is unclear but the discontinuation of steroid treatment predictably triggers the reversal of IOP elevation back to baseline [14]. Complications of elevated IOP, not only include glaucoma, but may also result in retinal vein occlusions, corneal edema and as we have shown in this case, NAION. It is important that ophthalmologists closely monitor patients on topical steroids since NAION may be a rare and irreversible complication of their use. This may even occur in younger patients who may be taking topical steroids postoperatively for eye surgery or for ocular inflammatory disorders. Treatment of steroid-induced ocular hypertension typically involves discontinuation of the steroid and use of topical and systemic IOP-lowering medications. The elevation of IOP in our patient was likely related to topical steroid use since there was no active inflammation at the time of vision loss and the IOP responded promptly to the discontinuation of steroids.
In summary, the development of an optic neuropathy in close temporal relationship may not necessarily be related to VZV. We report a case of steroid-induced ocular hypertension for initial treatment of herpes zoster-related anterior uveitis that was complicated by NAION. Patients on topical steroids should be closely monitored since irreversible optic nerve damage may occur in this context.
Statement of Ethics
This study was carried out in accordance with the World Medical Association Declaration of Helsinki. Verbal and written consent were obtained from the patient.
Conflict of Interest Statement
The authors have no conflicts of interest to declare.
Funding Sources
No funding was received.
Author Contributions
Conception and design (P.H.Y., J.A.M.), data extraction (P.H.Y., J.A.M.), manuscript preparation (P.H.Y.), final approval (J.A.M.). All authors have seen and approved the final version of the manuscript for publication.
Fig. 1 a Humphrey 24–2 SITA-Fast visual fields demonstrating a left inferior altitudinal visual field defect. b Optical coherence tomography of the retinal nerve fiber layer (RNFL) at presentation with left eye vision loss demonstrating an elevated RNFL due to optic disc edema in the left eye. | AMLODIPINE BESYLATE, PREDNISOLONE ACETATE | DrugsGivenReaction | CC BY-NC | 33613245 | 19,507,642 | 2021 |
What was the administration route of drug 'PREDNISOLONE ACETATE'? | Nonarteritic Anterior Ischemic Optic Neuropathy following Herpes Zoster Ophthalmicus and Steroid-Related Intraocular Pressure Spike.
A 61-year-old woman presented with sudden vision loss from a left anterior optic neuropathy in the context of severely elevated intraocular pressure after starting topical steroids for anterior uveitis related to herpes zoster ophthalmicus (HZO). The strong temporal relationship between the vision loss and elevated IOP suggested the vision loss was related to nonarteritic anterior ischemic optic neuropathy (NAION). Anterior chamber paracentesis did not detect varicella zoster virus (VZV) and magnetic resonance imaging of the orbits was normal. Her vision remained stable and the optic disc edema resolved within 3 months. The occurrence of NAION following an acute elevation of intraocular pressure (IOP) is well-documented in the context of surgical procedures, glaucoma, uveitis and trauma. This case indicates that not every optic neuropathy in close temporal relationship with HZO is directly attributable to the virus. NAION may also occur after steroid-related IOP spikes and ophthalmologists should ensure that patients on topical steroids are closely monitored for ocular complications.
Introduction
Vision loss is a rare complication of herpes zoster ophthalmicus (HZO) and can be a result of anterior segment of posterior segment involvement. Optic neuropathy is a rare complication of HZO seen in less than 0.5% of cases and can be anterior (associated with optic disc edema) or retrobulbar [1]. The diagnosis of herpes zoster optic neuropathy (HZON) is diagnosed in patients who develop an optic neuropathy in close temporal relationship with HZO with other causes of optic neuropathy being excluded. Supportive evidence for the diagnosis is helpful by means of magnetic resonance imaging (MRI) of the orbits with contrast demonstrating enhancement of the optic nerve in retrobulbar cases, or the detection of varicella zoster virus (VZV) in the aqueous humor or cerebrospinal fluid (CSF) [1]. However, the yield of detection of VZV in the CSF is low, especially in anterior cases. Treatment consists of oral or intravenous antivirals and the use of systemic corticosteroids remains controversial [1]. Patients with HZO may develop an anterior optic neuropathy that is not directly related to VZV, but secondarily related to HZO by means of other ocular complications. We report a case of nonarteritic anterior ischemic optic neuropathy (NAION) related to HZO, which was likely secondary to the development of a steroid response and elevated intraocular pressure (IOP) for the treatment of anterior uveitis. This indicates that not every optic neuropathy in close temporal relationship to HZO is directly related to the virus.
Case Report
A 61-year-old woman was seen in neuro-ophthalmology consultation for a left optic neuropathy. She had a history of hypertension and was taking amlodipine. She developed left HZO 1 month prior to presentation with skin lesions on the left forehead and tip and side of her nose. She was treated with valacyclovir 1 g PO TID for 10 days. She saw an ophthalmologist 3 days later and was found to have anterior uveitis (1+ cells), an intraocular pressure of 18, and was started on prednisolone acetate 1% eye drops QID. This was continued and the examination remained stable 1 week later. Two weeks later, she developed left eye pain and worsening vision. She saw an ophthalmologist and was found to have an intraocular pressure of 52 mm Hg without any signs of uveitis. Her refraction was −1.00 +0.50 × 172 OD and −1.50 +0.50 × 180 OS and the gonioscopy revealed open angles, grade 3 (Shaffer system) with the trabecular meshwork visible for 360 degrees in both eyes. She was started on acetazolamide 250 mg PO QID, brimonidine-timolol eye drops BID and topical prednisolone acetate was discontinued given the likelihood of a steroid response. Follow-up the next day revealed an improved intraocular pressure of 16, but she was noted to have a new relative afferent pupillary defect and optic disc edema in the left optic nerve. A neuro-ophthalmology consultation was requested. Acetazolamide and brimonidine-timolol eye drops were discontinued.
Neuro-ophthalmology assessment revealed a visual acuity of 20/20 OD and 20/100 OS, a left RAPD, and Humphrey visual field testing demonstrated a left inferior altitudinal visual field defect (Fig. 1a). Anterior segment revealed no signs of uveitis and dilated fundus examination demonstrated a normal appearing right optic nerve with a cup-to-disc ratio of 0.1 and left diffuse optic disc edema. Optical coherence tomography of the retinal nerve fiber layer showed an average thickness of 84 μm OD and 182 μm OS (Fig. 1b). The differential diagnosis considered was a left anterior optic neuropathy related to herpes zoster or NAION related to the recent IOP elevation. An anterior chamber paracentesis was performed and VZV was not detected by real-time PCR. She had an MRI of the brain and orbits with contrast that did not show enhancement of the optic nerves and was normal. Complete blood count, erythrocyte sedimentation rate and C-reactive protein were normal. She was treated with valacyclovir 1 g PO TID for 1 month as a precaution, but her vision did not improve. At 3-month follow-up, she continued to have a left inferior altitudinal visual field defect and the left optic disc edema had resolved.
Discussion
Vision loss is a feared complication of HZON and may affect almost any part of the eye including the anterior and posterior segments [1]. This may be a result of direct involvement of VZV or a secondary inflammatory component. This case highlights that optic nerve complications from VZV may not be due to direct involvement of the virus but can be a secondary result of another ocular complication. Our patient developed NAION related to elevated IOP that likely disrupted the perfusion to the optic nerve head. This was unlikely to be a direct result of the virus for a number of reasons including the absence of detectable virus in the aqueous humor by PCR, the absence of any optic nerve enhancement on orbital MRI with contrast and the absence of any improvement in her visual field, which is typical of NAION, despite antiviral treatment [2]. The patient also had a history of hypertension and a disc-at-risk, which is a requirement for the development of NAION [3]. The optic disc edema resolved in the expected time course for NAION, and the patient had no other signs or symptoms of another optic neuropathy. There was also a clear temporal relationship between the IOP spike and the loss of vision. Although CSF was not obtained, this would be an extremely low-yield test, especially with no retrobulbar involvement seen on MRI.
NAION has been previously described to develop in response to elevated IOP and subsequent disruption to the optic nerve head perfusion pressure [4, 5, 6]. This has been well-described in a number of situations including after ophthalmological procedures, acute glaucoma, hypertensive uveitis, or the administration of steroid eye drops [7, 8, 9, 10, 11]. Cases of ophthalmological procedures include cataract extraction complicated by capsular block, pars plana vitrectomy for macular hole, and trabeculectomy complicated by NAION have been described [7, 8, 9]. NAION after intravitreal injections have also been presumed to be related to elevated intraocular pressure, although the IOP has not been routinely measured in most of these cases [12]. The presumed mechanism of NAION after cataract surgery has also been thought to be related to elevated IOP, which is elevated intraoperatively and sometimes postoperatively [13]. Acute primary angle closure and traumatic angle recession glaucoma has been reported to be complicated by NAION and may be bilateral and severe [10, 11]. We were unable to retrieve any previously reported case of NAION secondary to herpes zoster anterior uveitis, but cases after Posner-Schlossman syndrome (PSS) have been described. Similar to our case, the PSS cases all had IOP in excess of 50 mmHg and some cases were in individuals younger than 50 years of age [5, 10]. We were unable to retrieve any cases of NAION that developed after steroid-related IOP spikes.
Elevated intraocular pressure is well-known complication of topical steroids and to a lesser extent systemic and topical steroid treatment [14, 15]. This typically onsets around 3–6 weeks after the initiation of topical steroids and is thought to be related to increased resistance to aqueous outflow at the trabecular meshwork. The mechanism of this IOP elevation is unclear but the discontinuation of steroid treatment predictably triggers the reversal of IOP elevation back to baseline [14]. Complications of elevated IOP, not only include glaucoma, but may also result in retinal vein occlusions, corneal edema and as we have shown in this case, NAION. It is important that ophthalmologists closely monitor patients on topical steroids since NAION may be a rare and irreversible complication of their use. This may even occur in younger patients who may be taking topical steroids postoperatively for eye surgery or for ocular inflammatory disorders. Treatment of steroid-induced ocular hypertension typically involves discontinuation of the steroid and use of topical and systemic IOP-lowering medications. The elevation of IOP in our patient was likely related to topical steroid use since there was no active inflammation at the time of vision loss and the IOP responded promptly to the discontinuation of steroids.
In summary, the development of an optic neuropathy in close temporal relationship may not necessarily be related to VZV. We report a case of steroid-induced ocular hypertension for initial treatment of herpes zoster-related anterior uveitis that was complicated by NAION. Patients on topical steroids should be closely monitored since irreversible optic nerve damage may occur in this context.
Statement of Ethics
This study was carried out in accordance with the World Medical Association Declaration of Helsinki. Verbal and written consent were obtained from the patient.
Conflict of Interest Statement
The authors have no conflicts of interest to declare.
Funding Sources
No funding was received.
Author Contributions
Conception and design (P.H.Y., J.A.M.), data extraction (P.H.Y., J.A.M.), manuscript preparation (P.H.Y.), final approval (J.A.M.). All authors have seen and approved the final version of the manuscript for publication.
Fig. 1 a Humphrey 24–2 SITA-Fast visual fields demonstrating a left inferior altitudinal visual field defect. b Optical coherence tomography of the retinal nerve fiber layer (RNFL) at presentation with left eye vision loss demonstrating an elevated RNFL due to optic disc edema in the left eye. | Ophthalmic | DrugAdministrationRoute | CC BY-NC | 33613245 | 19,507,642 | 2021 |
What was the administration route of drug 'PREDNISOLONE'? | Nonarteritic Anterior Ischemic Optic Neuropathy following Herpes Zoster Ophthalmicus and Steroid-Related Intraocular Pressure Spike.
A 61-year-old woman presented with sudden vision loss from a left anterior optic neuropathy in the context of severely elevated intraocular pressure after starting topical steroids for anterior uveitis related to herpes zoster ophthalmicus (HZO). The strong temporal relationship between the vision loss and elevated IOP suggested the vision loss was related to nonarteritic anterior ischemic optic neuropathy (NAION). Anterior chamber paracentesis did not detect varicella zoster virus (VZV) and magnetic resonance imaging of the orbits was normal. Her vision remained stable and the optic disc edema resolved within 3 months. The occurrence of NAION following an acute elevation of intraocular pressure (IOP) is well-documented in the context of surgical procedures, glaucoma, uveitis and trauma. This case indicates that not every optic neuropathy in close temporal relationship with HZO is directly attributable to the virus. NAION may also occur after steroid-related IOP spikes and ophthalmologists should ensure that patients on topical steroids are closely monitored for ocular complications.
Introduction
Vision loss is a rare complication of herpes zoster ophthalmicus (HZO) and can be a result of anterior segment of posterior segment involvement. Optic neuropathy is a rare complication of HZO seen in less than 0.5% of cases and can be anterior (associated with optic disc edema) or retrobulbar [1]. The diagnosis of herpes zoster optic neuropathy (HZON) is diagnosed in patients who develop an optic neuropathy in close temporal relationship with HZO with other causes of optic neuropathy being excluded. Supportive evidence for the diagnosis is helpful by means of magnetic resonance imaging (MRI) of the orbits with contrast demonstrating enhancement of the optic nerve in retrobulbar cases, or the detection of varicella zoster virus (VZV) in the aqueous humor or cerebrospinal fluid (CSF) [1]. However, the yield of detection of VZV in the CSF is low, especially in anterior cases. Treatment consists of oral or intravenous antivirals and the use of systemic corticosteroids remains controversial [1]. Patients with HZO may develop an anterior optic neuropathy that is not directly related to VZV, but secondarily related to HZO by means of other ocular complications. We report a case of nonarteritic anterior ischemic optic neuropathy (NAION) related to HZO, which was likely secondary to the development of a steroid response and elevated intraocular pressure (IOP) for the treatment of anterior uveitis. This indicates that not every optic neuropathy in close temporal relationship to HZO is directly related to the virus.
Case Report
A 61-year-old woman was seen in neuro-ophthalmology consultation for a left optic neuropathy. She had a history of hypertension and was taking amlodipine. She developed left HZO 1 month prior to presentation with skin lesions on the left forehead and tip and side of her nose. She was treated with valacyclovir 1 g PO TID for 10 days. She saw an ophthalmologist 3 days later and was found to have anterior uveitis (1+ cells), an intraocular pressure of 18, and was started on prednisolone acetate 1% eye drops QID. This was continued and the examination remained stable 1 week later. Two weeks later, she developed left eye pain and worsening vision. She saw an ophthalmologist and was found to have an intraocular pressure of 52 mm Hg without any signs of uveitis. Her refraction was −1.00 +0.50 × 172 OD and −1.50 +0.50 × 180 OS and the gonioscopy revealed open angles, grade 3 (Shaffer system) with the trabecular meshwork visible for 360 degrees in both eyes. She was started on acetazolamide 250 mg PO QID, brimonidine-timolol eye drops BID and topical prednisolone acetate was discontinued given the likelihood of a steroid response. Follow-up the next day revealed an improved intraocular pressure of 16, but she was noted to have a new relative afferent pupillary defect and optic disc edema in the left optic nerve. A neuro-ophthalmology consultation was requested. Acetazolamide and brimonidine-timolol eye drops were discontinued.
Neuro-ophthalmology assessment revealed a visual acuity of 20/20 OD and 20/100 OS, a left RAPD, and Humphrey visual field testing demonstrated a left inferior altitudinal visual field defect (Fig. 1a). Anterior segment revealed no signs of uveitis and dilated fundus examination demonstrated a normal appearing right optic nerve with a cup-to-disc ratio of 0.1 and left diffuse optic disc edema. Optical coherence tomography of the retinal nerve fiber layer showed an average thickness of 84 μm OD and 182 μm OS (Fig. 1b). The differential diagnosis considered was a left anterior optic neuropathy related to herpes zoster or NAION related to the recent IOP elevation. An anterior chamber paracentesis was performed and VZV was not detected by real-time PCR. She had an MRI of the brain and orbits with contrast that did not show enhancement of the optic nerves and was normal. Complete blood count, erythrocyte sedimentation rate and C-reactive protein were normal. She was treated with valacyclovir 1 g PO TID for 1 month as a precaution, but her vision did not improve. At 3-month follow-up, she continued to have a left inferior altitudinal visual field defect and the left optic disc edema had resolved.
Discussion
Vision loss is a feared complication of HZON and may affect almost any part of the eye including the anterior and posterior segments [1]. This may be a result of direct involvement of VZV or a secondary inflammatory component. This case highlights that optic nerve complications from VZV may not be due to direct involvement of the virus but can be a secondary result of another ocular complication. Our patient developed NAION related to elevated IOP that likely disrupted the perfusion to the optic nerve head. This was unlikely to be a direct result of the virus for a number of reasons including the absence of detectable virus in the aqueous humor by PCR, the absence of any optic nerve enhancement on orbital MRI with contrast and the absence of any improvement in her visual field, which is typical of NAION, despite antiviral treatment [2]. The patient also had a history of hypertension and a disc-at-risk, which is a requirement for the development of NAION [3]. The optic disc edema resolved in the expected time course for NAION, and the patient had no other signs or symptoms of another optic neuropathy. There was also a clear temporal relationship between the IOP spike and the loss of vision. Although CSF was not obtained, this would be an extremely low-yield test, especially with no retrobulbar involvement seen on MRI.
NAION has been previously described to develop in response to elevated IOP and subsequent disruption to the optic nerve head perfusion pressure [4, 5, 6]. This has been well-described in a number of situations including after ophthalmological procedures, acute glaucoma, hypertensive uveitis, or the administration of steroid eye drops [7, 8, 9, 10, 11]. Cases of ophthalmological procedures include cataract extraction complicated by capsular block, pars plana vitrectomy for macular hole, and trabeculectomy complicated by NAION have been described [7, 8, 9]. NAION after intravitreal injections have also been presumed to be related to elevated intraocular pressure, although the IOP has not been routinely measured in most of these cases [12]. The presumed mechanism of NAION after cataract surgery has also been thought to be related to elevated IOP, which is elevated intraoperatively and sometimes postoperatively [13]. Acute primary angle closure and traumatic angle recession glaucoma has been reported to be complicated by NAION and may be bilateral and severe [10, 11]. We were unable to retrieve any previously reported case of NAION secondary to herpes zoster anterior uveitis, but cases after Posner-Schlossman syndrome (PSS) have been described. Similar to our case, the PSS cases all had IOP in excess of 50 mmHg and some cases were in individuals younger than 50 years of age [5, 10]. We were unable to retrieve any cases of NAION that developed after steroid-related IOP spikes.
Elevated intraocular pressure is well-known complication of topical steroids and to a lesser extent systemic and topical steroid treatment [14, 15]. This typically onsets around 3–6 weeks after the initiation of topical steroids and is thought to be related to increased resistance to aqueous outflow at the trabecular meshwork. The mechanism of this IOP elevation is unclear but the discontinuation of steroid treatment predictably triggers the reversal of IOP elevation back to baseline [14]. Complications of elevated IOP, not only include glaucoma, but may also result in retinal vein occlusions, corneal edema and as we have shown in this case, NAION. It is important that ophthalmologists closely monitor patients on topical steroids since NAION may be a rare and irreversible complication of their use. This may even occur in younger patients who may be taking topical steroids postoperatively for eye surgery or for ocular inflammatory disorders. Treatment of steroid-induced ocular hypertension typically involves discontinuation of the steroid and use of topical and systemic IOP-lowering medications. The elevation of IOP in our patient was likely related to topical steroid use since there was no active inflammation at the time of vision loss and the IOP responded promptly to the discontinuation of steroids.
In summary, the development of an optic neuropathy in close temporal relationship may not necessarily be related to VZV. We report a case of steroid-induced ocular hypertension for initial treatment of herpes zoster-related anterior uveitis that was complicated by NAION. Patients on topical steroids should be closely monitored since irreversible optic nerve damage may occur in this context.
Statement of Ethics
This study was carried out in accordance with the World Medical Association Declaration of Helsinki. Verbal and written consent were obtained from the patient.
Conflict of Interest Statement
The authors have no conflicts of interest to declare.
Funding Sources
No funding was received.
Author Contributions
Conception and design (P.H.Y., J.A.M.), data extraction (P.H.Y., J.A.M.), manuscript preparation (P.H.Y.), final approval (J.A.M.). All authors have seen and approved the final version of the manuscript for publication.
Fig. 1 a Humphrey 24–2 SITA-Fast visual fields demonstrating a left inferior altitudinal visual field defect. b Optical coherence tomography of the retinal nerve fiber layer (RNFL) at presentation with left eye vision loss demonstrating an elevated RNFL due to optic disc edema in the left eye. | Topical | DrugAdministrationRoute | CC BY-NC | 33613245 | 19,401,072 | 2021 |
What was the administration route of drug 'VALACYCLOVIR HYDROCHLORIDE'? | Nonarteritic Anterior Ischemic Optic Neuropathy following Herpes Zoster Ophthalmicus and Steroid-Related Intraocular Pressure Spike.
A 61-year-old woman presented with sudden vision loss from a left anterior optic neuropathy in the context of severely elevated intraocular pressure after starting topical steroids for anterior uveitis related to herpes zoster ophthalmicus (HZO). The strong temporal relationship between the vision loss and elevated IOP suggested the vision loss was related to nonarteritic anterior ischemic optic neuropathy (NAION). Anterior chamber paracentesis did not detect varicella zoster virus (VZV) and magnetic resonance imaging of the orbits was normal. Her vision remained stable and the optic disc edema resolved within 3 months. The occurrence of NAION following an acute elevation of intraocular pressure (IOP) is well-documented in the context of surgical procedures, glaucoma, uveitis and trauma. This case indicates that not every optic neuropathy in close temporal relationship with HZO is directly attributable to the virus. NAION may also occur after steroid-related IOP spikes and ophthalmologists should ensure that patients on topical steroids are closely monitored for ocular complications.
Introduction
Vision loss is a rare complication of herpes zoster ophthalmicus (HZO) and can be a result of anterior segment of posterior segment involvement. Optic neuropathy is a rare complication of HZO seen in less than 0.5% of cases and can be anterior (associated with optic disc edema) or retrobulbar [1]. The diagnosis of herpes zoster optic neuropathy (HZON) is diagnosed in patients who develop an optic neuropathy in close temporal relationship with HZO with other causes of optic neuropathy being excluded. Supportive evidence for the diagnosis is helpful by means of magnetic resonance imaging (MRI) of the orbits with contrast demonstrating enhancement of the optic nerve in retrobulbar cases, or the detection of varicella zoster virus (VZV) in the aqueous humor or cerebrospinal fluid (CSF) [1]. However, the yield of detection of VZV in the CSF is low, especially in anterior cases. Treatment consists of oral or intravenous antivirals and the use of systemic corticosteroids remains controversial [1]. Patients with HZO may develop an anterior optic neuropathy that is not directly related to VZV, but secondarily related to HZO by means of other ocular complications. We report a case of nonarteritic anterior ischemic optic neuropathy (NAION) related to HZO, which was likely secondary to the development of a steroid response and elevated intraocular pressure (IOP) for the treatment of anterior uveitis. This indicates that not every optic neuropathy in close temporal relationship to HZO is directly related to the virus.
Case Report
A 61-year-old woman was seen in neuro-ophthalmology consultation for a left optic neuropathy. She had a history of hypertension and was taking amlodipine. She developed left HZO 1 month prior to presentation with skin lesions on the left forehead and tip and side of her nose. She was treated with valacyclovir 1 g PO TID for 10 days. She saw an ophthalmologist 3 days later and was found to have anterior uveitis (1+ cells), an intraocular pressure of 18, and was started on prednisolone acetate 1% eye drops QID. This was continued and the examination remained stable 1 week later. Two weeks later, she developed left eye pain and worsening vision. She saw an ophthalmologist and was found to have an intraocular pressure of 52 mm Hg without any signs of uveitis. Her refraction was −1.00 +0.50 × 172 OD and −1.50 +0.50 × 180 OS and the gonioscopy revealed open angles, grade 3 (Shaffer system) with the trabecular meshwork visible for 360 degrees in both eyes. She was started on acetazolamide 250 mg PO QID, brimonidine-timolol eye drops BID and topical prednisolone acetate was discontinued given the likelihood of a steroid response. Follow-up the next day revealed an improved intraocular pressure of 16, but she was noted to have a new relative afferent pupillary defect and optic disc edema in the left optic nerve. A neuro-ophthalmology consultation was requested. Acetazolamide and brimonidine-timolol eye drops were discontinued.
Neuro-ophthalmology assessment revealed a visual acuity of 20/20 OD and 20/100 OS, a left RAPD, and Humphrey visual field testing demonstrated a left inferior altitudinal visual field defect (Fig. 1a). Anterior segment revealed no signs of uveitis and dilated fundus examination demonstrated a normal appearing right optic nerve with a cup-to-disc ratio of 0.1 and left diffuse optic disc edema. Optical coherence tomography of the retinal nerve fiber layer showed an average thickness of 84 μm OD and 182 μm OS (Fig. 1b). The differential diagnosis considered was a left anterior optic neuropathy related to herpes zoster or NAION related to the recent IOP elevation. An anterior chamber paracentesis was performed and VZV was not detected by real-time PCR. She had an MRI of the brain and orbits with contrast that did not show enhancement of the optic nerves and was normal. Complete blood count, erythrocyte sedimentation rate and C-reactive protein were normal. She was treated with valacyclovir 1 g PO TID for 1 month as a precaution, but her vision did not improve. At 3-month follow-up, she continued to have a left inferior altitudinal visual field defect and the left optic disc edema had resolved.
Discussion
Vision loss is a feared complication of HZON and may affect almost any part of the eye including the anterior and posterior segments [1]. This may be a result of direct involvement of VZV or a secondary inflammatory component. This case highlights that optic nerve complications from VZV may not be due to direct involvement of the virus but can be a secondary result of another ocular complication. Our patient developed NAION related to elevated IOP that likely disrupted the perfusion to the optic nerve head. This was unlikely to be a direct result of the virus for a number of reasons including the absence of detectable virus in the aqueous humor by PCR, the absence of any optic nerve enhancement on orbital MRI with contrast and the absence of any improvement in her visual field, which is typical of NAION, despite antiviral treatment [2]. The patient also had a history of hypertension and a disc-at-risk, which is a requirement for the development of NAION [3]. The optic disc edema resolved in the expected time course for NAION, and the patient had no other signs or symptoms of another optic neuropathy. There was also a clear temporal relationship between the IOP spike and the loss of vision. Although CSF was not obtained, this would be an extremely low-yield test, especially with no retrobulbar involvement seen on MRI.
NAION has been previously described to develop in response to elevated IOP and subsequent disruption to the optic nerve head perfusion pressure [4, 5, 6]. This has been well-described in a number of situations including after ophthalmological procedures, acute glaucoma, hypertensive uveitis, or the administration of steroid eye drops [7, 8, 9, 10, 11]. Cases of ophthalmological procedures include cataract extraction complicated by capsular block, pars plana vitrectomy for macular hole, and trabeculectomy complicated by NAION have been described [7, 8, 9]. NAION after intravitreal injections have also been presumed to be related to elevated intraocular pressure, although the IOP has not been routinely measured in most of these cases [12]. The presumed mechanism of NAION after cataract surgery has also been thought to be related to elevated IOP, which is elevated intraoperatively and sometimes postoperatively [13]. Acute primary angle closure and traumatic angle recession glaucoma has been reported to be complicated by NAION and may be bilateral and severe [10, 11]. We were unable to retrieve any previously reported case of NAION secondary to herpes zoster anterior uveitis, but cases after Posner-Schlossman syndrome (PSS) have been described. Similar to our case, the PSS cases all had IOP in excess of 50 mmHg and some cases were in individuals younger than 50 years of age [5, 10]. We were unable to retrieve any cases of NAION that developed after steroid-related IOP spikes.
Elevated intraocular pressure is well-known complication of topical steroids and to a lesser extent systemic and topical steroid treatment [14, 15]. This typically onsets around 3–6 weeks after the initiation of topical steroids and is thought to be related to increased resistance to aqueous outflow at the trabecular meshwork. The mechanism of this IOP elevation is unclear but the discontinuation of steroid treatment predictably triggers the reversal of IOP elevation back to baseline [14]. Complications of elevated IOP, not only include glaucoma, but may also result in retinal vein occlusions, corneal edema and as we have shown in this case, NAION. It is important that ophthalmologists closely monitor patients on topical steroids since NAION may be a rare and irreversible complication of their use. This may even occur in younger patients who may be taking topical steroids postoperatively for eye surgery or for ocular inflammatory disorders. Treatment of steroid-induced ocular hypertension typically involves discontinuation of the steroid and use of topical and systemic IOP-lowering medications. The elevation of IOP in our patient was likely related to topical steroid use since there was no active inflammation at the time of vision loss and the IOP responded promptly to the discontinuation of steroids.
In summary, the development of an optic neuropathy in close temporal relationship may not necessarily be related to VZV. We report a case of steroid-induced ocular hypertension for initial treatment of herpes zoster-related anterior uveitis that was complicated by NAION. Patients on topical steroids should be closely monitored since irreversible optic nerve damage may occur in this context.
Statement of Ethics
This study was carried out in accordance with the World Medical Association Declaration of Helsinki. Verbal and written consent were obtained from the patient.
Conflict of Interest Statement
The authors have no conflicts of interest to declare.
Funding Sources
No funding was received.
Author Contributions
Conception and design (P.H.Y., J.A.M.), data extraction (P.H.Y., J.A.M.), manuscript preparation (P.H.Y.), final approval (J.A.M.). All authors have seen and approved the final version of the manuscript for publication.
Fig. 1 a Humphrey 24–2 SITA-Fast visual fields demonstrating a left inferior altitudinal visual field defect. b Optical coherence tomography of the retinal nerve fiber layer (RNFL) at presentation with left eye vision loss demonstrating an elevated RNFL due to optic disc edema in the left eye. | Oral | DrugAdministrationRoute | CC BY-NC | 33613245 | 19,401,072 | 2021 |
What was the dosage of drug 'PREDNISOLONE ACETATE'? | Nonarteritic Anterior Ischemic Optic Neuropathy following Herpes Zoster Ophthalmicus and Steroid-Related Intraocular Pressure Spike.
A 61-year-old woman presented with sudden vision loss from a left anterior optic neuropathy in the context of severely elevated intraocular pressure after starting topical steroids for anterior uveitis related to herpes zoster ophthalmicus (HZO). The strong temporal relationship between the vision loss and elevated IOP suggested the vision loss was related to nonarteritic anterior ischemic optic neuropathy (NAION). Anterior chamber paracentesis did not detect varicella zoster virus (VZV) and magnetic resonance imaging of the orbits was normal. Her vision remained stable and the optic disc edema resolved within 3 months. The occurrence of NAION following an acute elevation of intraocular pressure (IOP) is well-documented in the context of surgical procedures, glaucoma, uveitis and trauma. This case indicates that not every optic neuropathy in close temporal relationship with HZO is directly attributable to the virus. NAION may also occur after steroid-related IOP spikes and ophthalmologists should ensure that patients on topical steroids are closely monitored for ocular complications.
Introduction
Vision loss is a rare complication of herpes zoster ophthalmicus (HZO) and can be a result of anterior segment of posterior segment involvement. Optic neuropathy is a rare complication of HZO seen in less than 0.5% of cases and can be anterior (associated with optic disc edema) or retrobulbar [1]. The diagnosis of herpes zoster optic neuropathy (HZON) is diagnosed in patients who develop an optic neuropathy in close temporal relationship with HZO with other causes of optic neuropathy being excluded. Supportive evidence for the diagnosis is helpful by means of magnetic resonance imaging (MRI) of the orbits with contrast demonstrating enhancement of the optic nerve in retrobulbar cases, or the detection of varicella zoster virus (VZV) in the aqueous humor or cerebrospinal fluid (CSF) [1]. However, the yield of detection of VZV in the CSF is low, especially in anterior cases. Treatment consists of oral or intravenous antivirals and the use of systemic corticosteroids remains controversial [1]. Patients with HZO may develop an anterior optic neuropathy that is not directly related to VZV, but secondarily related to HZO by means of other ocular complications. We report a case of nonarteritic anterior ischemic optic neuropathy (NAION) related to HZO, which was likely secondary to the development of a steroid response and elevated intraocular pressure (IOP) for the treatment of anterior uveitis. This indicates that not every optic neuropathy in close temporal relationship to HZO is directly related to the virus.
Case Report
A 61-year-old woman was seen in neuro-ophthalmology consultation for a left optic neuropathy. She had a history of hypertension and was taking amlodipine. She developed left HZO 1 month prior to presentation with skin lesions on the left forehead and tip and side of her nose. She was treated with valacyclovir 1 g PO TID for 10 days. She saw an ophthalmologist 3 days later and was found to have anterior uveitis (1+ cells), an intraocular pressure of 18, and was started on prednisolone acetate 1% eye drops QID. This was continued and the examination remained stable 1 week later. Two weeks later, she developed left eye pain and worsening vision. She saw an ophthalmologist and was found to have an intraocular pressure of 52 mm Hg without any signs of uveitis. Her refraction was −1.00 +0.50 × 172 OD and −1.50 +0.50 × 180 OS and the gonioscopy revealed open angles, grade 3 (Shaffer system) with the trabecular meshwork visible for 360 degrees in both eyes. She was started on acetazolamide 250 mg PO QID, brimonidine-timolol eye drops BID and topical prednisolone acetate was discontinued given the likelihood of a steroid response. Follow-up the next day revealed an improved intraocular pressure of 16, but she was noted to have a new relative afferent pupillary defect and optic disc edema in the left optic nerve. A neuro-ophthalmology consultation was requested. Acetazolamide and brimonidine-timolol eye drops were discontinued.
Neuro-ophthalmology assessment revealed a visual acuity of 20/20 OD and 20/100 OS, a left RAPD, and Humphrey visual field testing demonstrated a left inferior altitudinal visual field defect (Fig. 1a). Anterior segment revealed no signs of uveitis and dilated fundus examination demonstrated a normal appearing right optic nerve with a cup-to-disc ratio of 0.1 and left diffuse optic disc edema. Optical coherence tomography of the retinal nerve fiber layer showed an average thickness of 84 μm OD and 182 μm OS (Fig. 1b). The differential diagnosis considered was a left anterior optic neuropathy related to herpes zoster or NAION related to the recent IOP elevation. An anterior chamber paracentesis was performed and VZV was not detected by real-time PCR. She had an MRI of the brain and orbits with contrast that did not show enhancement of the optic nerves and was normal. Complete blood count, erythrocyte sedimentation rate and C-reactive protein were normal. She was treated with valacyclovir 1 g PO TID for 1 month as a precaution, but her vision did not improve. At 3-month follow-up, she continued to have a left inferior altitudinal visual field defect and the left optic disc edema had resolved.
Discussion
Vision loss is a feared complication of HZON and may affect almost any part of the eye including the anterior and posterior segments [1]. This may be a result of direct involvement of VZV or a secondary inflammatory component. This case highlights that optic nerve complications from VZV may not be due to direct involvement of the virus but can be a secondary result of another ocular complication. Our patient developed NAION related to elevated IOP that likely disrupted the perfusion to the optic nerve head. This was unlikely to be a direct result of the virus for a number of reasons including the absence of detectable virus in the aqueous humor by PCR, the absence of any optic nerve enhancement on orbital MRI with contrast and the absence of any improvement in her visual field, which is typical of NAION, despite antiviral treatment [2]. The patient also had a history of hypertension and a disc-at-risk, which is a requirement for the development of NAION [3]. The optic disc edema resolved in the expected time course for NAION, and the patient had no other signs or symptoms of another optic neuropathy. There was also a clear temporal relationship between the IOP spike and the loss of vision. Although CSF was not obtained, this would be an extremely low-yield test, especially with no retrobulbar involvement seen on MRI.
NAION has been previously described to develop in response to elevated IOP and subsequent disruption to the optic nerve head perfusion pressure [4, 5, 6]. This has been well-described in a number of situations including after ophthalmological procedures, acute glaucoma, hypertensive uveitis, or the administration of steroid eye drops [7, 8, 9, 10, 11]. Cases of ophthalmological procedures include cataract extraction complicated by capsular block, pars plana vitrectomy for macular hole, and trabeculectomy complicated by NAION have been described [7, 8, 9]. NAION after intravitreal injections have also been presumed to be related to elevated intraocular pressure, although the IOP has not been routinely measured in most of these cases [12]. The presumed mechanism of NAION after cataract surgery has also been thought to be related to elevated IOP, which is elevated intraoperatively and sometimes postoperatively [13]. Acute primary angle closure and traumatic angle recession glaucoma has been reported to be complicated by NAION and may be bilateral and severe [10, 11]. We were unable to retrieve any previously reported case of NAION secondary to herpes zoster anterior uveitis, but cases after Posner-Schlossman syndrome (PSS) have been described. Similar to our case, the PSS cases all had IOP in excess of 50 mmHg and some cases were in individuals younger than 50 years of age [5, 10]. We were unable to retrieve any cases of NAION that developed after steroid-related IOP spikes.
Elevated intraocular pressure is well-known complication of topical steroids and to a lesser extent systemic and topical steroid treatment [14, 15]. This typically onsets around 3–6 weeks after the initiation of topical steroids and is thought to be related to increased resistance to aqueous outflow at the trabecular meshwork. The mechanism of this IOP elevation is unclear but the discontinuation of steroid treatment predictably triggers the reversal of IOP elevation back to baseline [14]. Complications of elevated IOP, not only include glaucoma, but may also result in retinal vein occlusions, corneal edema and as we have shown in this case, NAION. It is important that ophthalmologists closely monitor patients on topical steroids since NAION may be a rare and irreversible complication of their use. This may even occur in younger patients who may be taking topical steroids postoperatively for eye surgery or for ocular inflammatory disorders. Treatment of steroid-induced ocular hypertension typically involves discontinuation of the steroid and use of topical and systemic IOP-lowering medications. The elevation of IOP in our patient was likely related to topical steroid use since there was no active inflammation at the time of vision loss and the IOP responded promptly to the discontinuation of steroids.
In summary, the development of an optic neuropathy in close temporal relationship may not necessarily be related to VZV. We report a case of steroid-induced ocular hypertension for initial treatment of herpes zoster-related anterior uveitis that was complicated by NAION. Patients on topical steroids should be closely monitored since irreversible optic nerve damage may occur in this context.
Statement of Ethics
This study was carried out in accordance with the World Medical Association Declaration of Helsinki. Verbal and written consent were obtained from the patient.
Conflict of Interest Statement
The authors have no conflicts of interest to declare.
Funding Sources
No funding was received.
Author Contributions
Conception and design (P.H.Y., J.A.M.), data extraction (P.H.Y., J.A.M.), manuscript preparation (P.H.Y.), final approval (J.A.M.). All authors have seen and approved the final version of the manuscript for publication.
Fig. 1 a Humphrey 24–2 SITA-Fast visual fields demonstrating a left inferior altitudinal visual field defect. b Optical coherence tomography of the retinal nerve fiber layer (RNFL) at presentation with left eye vision loss demonstrating an elevated RNFL due to optic disc edema in the left eye. | 4 TIMES A DAY | DrugDosageText | CC BY-NC | 33613245 | 19,507,642 | 2021 |
What was the dosage of drug 'PREDNISOLONE'? | Nonarteritic Anterior Ischemic Optic Neuropathy following Herpes Zoster Ophthalmicus and Steroid-Related Intraocular Pressure Spike.
A 61-year-old woman presented with sudden vision loss from a left anterior optic neuropathy in the context of severely elevated intraocular pressure after starting topical steroids for anterior uveitis related to herpes zoster ophthalmicus (HZO). The strong temporal relationship between the vision loss and elevated IOP suggested the vision loss was related to nonarteritic anterior ischemic optic neuropathy (NAION). Anterior chamber paracentesis did not detect varicella zoster virus (VZV) and magnetic resonance imaging of the orbits was normal. Her vision remained stable and the optic disc edema resolved within 3 months. The occurrence of NAION following an acute elevation of intraocular pressure (IOP) is well-documented in the context of surgical procedures, glaucoma, uveitis and trauma. This case indicates that not every optic neuropathy in close temporal relationship with HZO is directly attributable to the virus. NAION may also occur after steroid-related IOP spikes and ophthalmologists should ensure that patients on topical steroids are closely monitored for ocular complications.
Introduction
Vision loss is a rare complication of herpes zoster ophthalmicus (HZO) and can be a result of anterior segment of posterior segment involvement. Optic neuropathy is a rare complication of HZO seen in less than 0.5% of cases and can be anterior (associated with optic disc edema) or retrobulbar [1]. The diagnosis of herpes zoster optic neuropathy (HZON) is diagnosed in patients who develop an optic neuropathy in close temporal relationship with HZO with other causes of optic neuropathy being excluded. Supportive evidence for the diagnosis is helpful by means of magnetic resonance imaging (MRI) of the orbits with contrast demonstrating enhancement of the optic nerve in retrobulbar cases, or the detection of varicella zoster virus (VZV) in the aqueous humor or cerebrospinal fluid (CSF) [1]. However, the yield of detection of VZV in the CSF is low, especially in anterior cases. Treatment consists of oral or intravenous antivirals and the use of systemic corticosteroids remains controversial [1]. Patients with HZO may develop an anterior optic neuropathy that is not directly related to VZV, but secondarily related to HZO by means of other ocular complications. We report a case of nonarteritic anterior ischemic optic neuropathy (NAION) related to HZO, which was likely secondary to the development of a steroid response and elevated intraocular pressure (IOP) for the treatment of anterior uveitis. This indicates that not every optic neuropathy in close temporal relationship to HZO is directly related to the virus.
Case Report
A 61-year-old woman was seen in neuro-ophthalmology consultation for a left optic neuropathy. She had a history of hypertension and was taking amlodipine. She developed left HZO 1 month prior to presentation with skin lesions on the left forehead and tip and side of her nose. She was treated with valacyclovir 1 g PO TID for 10 days. She saw an ophthalmologist 3 days later and was found to have anterior uveitis (1+ cells), an intraocular pressure of 18, and was started on prednisolone acetate 1% eye drops QID. This was continued and the examination remained stable 1 week later. Two weeks later, she developed left eye pain and worsening vision. She saw an ophthalmologist and was found to have an intraocular pressure of 52 mm Hg without any signs of uveitis. Her refraction was −1.00 +0.50 × 172 OD and −1.50 +0.50 × 180 OS and the gonioscopy revealed open angles, grade 3 (Shaffer system) with the trabecular meshwork visible for 360 degrees in both eyes. She was started on acetazolamide 250 mg PO QID, brimonidine-timolol eye drops BID and topical prednisolone acetate was discontinued given the likelihood of a steroid response. Follow-up the next day revealed an improved intraocular pressure of 16, but she was noted to have a new relative afferent pupillary defect and optic disc edema in the left optic nerve. A neuro-ophthalmology consultation was requested. Acetazolamide and brimonidine-timolol eye drops were discontinued.
Neuro-ophthalmology assessment revealed a visual acuity of 20/20 OD and 20/100 OS, a left RAPD, and Humphrey visual field testing demonstrated a left inferior altitudinal visual field defect (Fig. 1a). Anterior segment revealed no signs of uveitis and dilated fundus examination demonstrated a normal appearing right optic nerve with a cup-to-disc ratio of 0.1 and left diffuse optic disc edema. Optical coherence tomography of the retinal nerve fiber layer showed an average thickness of 84 μm OD and 182 μm OS (Fig. 1b). The differential diagnosis considered was a left anterior optic neuropathy related to herpes zoster or NAION related to the recent IOP elevation. An anterior chamber paracentesis was performed and VZV was not detected by real-time PCR. She had an MRI of the brain and orbits with contrast that did not show enhancement of the optic nerves and was normal. Complete blood count, erythrocyte sedimentation rate and C-reactive protein were normal. She was treated with valacyclovir 1 g PO TID for 1 month as a precaution, but her vision did not improve. At 3-month follow-up, she continued to have a left inferior altitudinal visual field defect and the left optic disc edema had resolved.
Discussion
Vision loss is a feared complication of HZON and may affect almost any part of the eye including the anterior and posterior segments [1]. This may be a result of direct involvement of VZV or a secondary inflammatory component. This case highlights that optic nerve complications from VZV may not be due to direct involvement of the virus but can be a secondary result of another ocular complication. Our patient developed NAION related to elevated IOP that likely disrupted the perfusion to the optic nerve head. This was unlikely to be a direct result of the virus for a number of reasons including the absence of detectable virus in the aqueous humor by PCR, the absence of any optic nerve enhancement on orbital MRI with contrast and the absence of any improvement in her visual field, which is typical of NAION, despite antiviral treatment [2]. The patient also had a history of hypertension and a disc-at-risk, which is a requirement for the development of NAION [3]. The optic disc edema resolved in the expected time course for NAION, and the patient had no other signs or symptoms of another optic neuropathy. There was also a clear temporal relationship between the IOP spike and the loss of vision. Although CSF was not obtained, this would be an extremely low-yield test, especially with no retrobulbar involvement seen on MRI.
NAION has been previously described to develop in response to elevated IOP and subsequent disruption to the optic nerve head perfusion pressure [4, 5, 6]. This has been well-described in a number of situations including after ophthalmological procedures, acute glaucoma, hypertensive uveitis, or the administration of steroid eye drops [7, 8, 9, 10, 11]. Cases of ophthalmological procedures include cataract extraction complicated by capsular block, pars plana vitrectomy for macular hole, and trabeculectomy complicated by NAION have been described [7, 8, 9]. NAION after intravitreal injections have also been presumed to be related to elevated intraocular pressure, although the IOP has not been routinely measured in most of these cases [12]. The presumed mechanism of NAION after cataract surgery has also been thought to be related to elevated IOP, which is elevated intraoperatively and sometimes postoperatively [13]. Acute primary angle closure and traumatic angle recession glaucoma has been reported to be complicated by NAION and may be bilateral and severe [10, 11]. We were unable to retrieve any previously reported case of NAION secondary to herpes zoster anterior uveitis, but cases after Posner-Schlossman syndrome (PSS) have been described. Similar to our case, the PSS cases all had IOP in excess of 50 mmHg and some cases were in individuals younger than 50 years of age [5, 10]. We were unable to retrieve any cases of NAION that developed after steroid-related IOP spikes.
Elevated intraocular pressure is well-known complication of topical steroids and to a lesser extent systemic and topical steroid treatment [14, 15]. This typically onsets around 3–6 weeks after the initiation of topical steroids and is thought to be related to increased resistance to aqueous outflow at the trabecular meshwork. The mechanism of this IOP elevation is unclear but the discontinuation of steroid treatment predictably triggers the reversal of IOP elevation back to baseline [14]. Complications of elevated IOP, not only include glaucoma, but may also result in retinal vein occlusions, corneal edema and as we have shown in this case, NAION. It is important that ophthalmologists closely monitor patients on topical steroids since NAION may be a rare and irreversible complication of their use. This may even occur in younger patients who may be taking topical steroids postoperatively for eye surgery or for ocular inflammatory disorders. Treatment of steroid-induced ocular hypertension typically involves discontinuation of the steroid and use of topical and systemic IOP-lowering medications. The elevation of IOP in our patient was likely related to topical steroid use since there was no active inflammation at the time of vision loss and the IOP responded promptly to the discontinuation of steroids.
In summary, the development of an optic neuropathy in close temporal relationship may not necessarily be related to VZV. We report a case of steroid-induced ocular hypertension for initial treatment of herpes zoster-related anterior uveitis that was complicated by NAION. Patients on topical steroids should be closely monitored since irreversible optic nerve damage may occur in this context.
Statement of Ethics
This study was carried out in accordance with the World Medical Association Declaration of Helsinki. Verbal and written consent were obtained from the patient.
Conflict of Interest Statement
The authors have no conflicts of interest to declare.
Funding Sources
No funding was received.
Author Contributions
Conception and design (P.H.Y., J.A.M.), data extraction (P.H.Y., J.A.M.), manuscript preparation (P.H.Y.), final approval (J.A.M.). All authors have seen and approved the final version of the manuscript for publication.
Fig. 1 a Humphrey 24–2 SITA-Fast visual fields demonstrating a left inferior altitudinal visual field defect. b Optical coherence tomography of the retinal nerve fiber layer (RNFL) at presentation with left eye vision loss demonstrating an elevated RNFL due to optic disc edema in the left eye. | UNK UNK, QID | DrugDosageText | CC BY-NC | 33613245 | 19,401,072 | 2021 |
What was the outcome of reaction 'Intraocular pressure increased'? | Nonarteritic Anterior Ischemic Optic Neuropathy following Herpes Zoster Ophthalmicus and Steroid-Related Intraocular Pressure Spike.
A 61-year-old woman presented with sudden vision loss from a left anterior optic neuropathy in the context of severely elevated intraocular pressure after starting topical steroids for anterior uveitis related to herpes zoster ophthalmicus (HZO). The strong temporal relationship between the vision loss and elevated IOP suggested the vision loss was related to nonarteritic anterior ischemic optic neuropathy (NAION). Anterior chamber paracentesis did not detect varicella zoster virus (VZV) and magnetic resonance imaging of the orbits was normal. Her vision remained stable and the optic disc edema resolved within 3 months. The occurrence of NAION following an acute elevation of intraocular pressure (IOP) is well-documented in the context of surgical procedures, glaucoma, uveitis and trauma. This case indicates that not every optic neuropathy in close temporal relationship with HZO is directly attributable to the virus. NAION may also occur after steroid-related IOP spikes and ophthalmologists should ensure that patients on topical steroids are closely monitored for ocular complications.
Introduction
Vision loss is a rare complication of herpes zoster ophthalmicus (HZO) and can be a result of anterior segment of posterior segment involvement. Optic neuropathy is a rare complication of HZO seen in less than 0.5% of cases and can be anterior (associated with optic disc edema) or retrobulbar [1]. The diagnosis of herpes zoster optic neuropathy (HZON) is diagnosed in patients who develop an optic neuropathy in close temporal relationship with HZO with other causes of optic neuropathy being excluded. Supportive evidence for the diagnosis is helpful by means of magnetic resonance imaging (MRI) of the orbits with contrast demonstrating enhancement of the optic nerve in retrobulbar cases, or the detection of varicella zoster virus (VZV) in the aqueous humor or cerebrospinal fluid (CSF) [1]. However, the yield of detection of VZV in the CSF is low, especially in anterior cases. Treatment consists of oral or intravenous antivirals and the use of systemic corticosteroids remains controversial [1]. Patients with HZO may develop an anterior optic neuropathy that is not directly related to VZV, but secondarily related to HZO by means of other ocular complications. We report a case of nonarteritic anterior ischemic optic neuropathy (NAION) related to HZO, which was likely secondary to the development of a steroid response and elevated intraocular pressure (IOP) for the treatment of anterior uveitis. This indicates that not every optic neuropathy in close temporal relationship to HZO is directly related to the virus.
Case Report
A 61-year-old woman was seen in neuro-ophthalmology consultation for a left optic neuropathy. She had a history of hypertension and was taking amlodipine. She developed left HZO 1 month prior to presentation with skin lesions on the left forehead and tip and side of her nose. She was treated with valacyclovir 1 g PO TID for 10 days. She saw an ophthalmologist 3 days later and was found to have anterior uveitis (1+ cells), an intraocular pressure of 18, and was started on prednisolone acetate 1% eye drops QID. This was continued and the examination remained stable 1 week later. Two weeks later, she developed left eye pain and worsening vision. She saw an ophthalmologist and was found to have an intraocular pressure of 52 mm Hg without any signs of uveitis. Her refraction was −1.00 +0.50 × 172 OD and −1.50 +0.50 × 180 OS and the gonioscopy revealed open angles, grade 3 (Shaffer system) with the trabecular meshwork visible for 360 degrees in both eyes. She was started on acetazolamide 250 mg PO QID, brimonidine-timolol eye drops BID and topical prednisolone acetate was discontinued given the likelihood of a steroid response. Follow-up the next day revealed an improved intraocular pressure of 16, but she was noted to have a new relative afferent pupillary defect and optic disc edema in the left optic nerve. A neuro-ophthalmology consultation was requested. Acetazolamide and brimonidine-timolol eye drops were discontinued.
Neuro-ophthalmology assessment revealed a visual acuity of 20/20 OD and 20/100 OS, a left RAPD, and Humphrey visual field testing demonstrated a left inferior altitudinal visual field defect (Fig. 1a). Anterior segment revealed no signs of uveitis and dilated fundus examination demonstrated a normal appearing right optic nerve with a cup-to-disc ratio of 0.1 and left diffuse optic disc edema. Optical coherence tomography of the retinal nerve fiber layer showed an average thickness of 84 μm OD and 182 μm OS (Fig. 1b). The differential diagnosis considered was a left anterior optic neuropathy related to herpes zoster or NAION related to the recent IOP elevation. An anterior chamber paracentesis was performed and VZV was not detected by real-time PCR. She had an MRI of the brain and orbits with contrast that did not show enhancement of the optic nerves and was normal. Complete blood count, erythrocyte sedimentation rate and C-reactive protein were normal. She was treated with valacyclovir 1 g PO TID for 1 month as a precaution, but her vision did not improve. At 3-month follow-up, she continued to have a left inferior altitudinal visual field defect and the left optic disc edema had resolved.
Discussion
Vision loss is a feared complication of HZON and may affect almost any part of the eye including the anterior and posterior segments [1]. This may be a result of direct involvement of VZV or a secondary inflammatory component. This case highlights that optic nerve complications from VZV may not be due to direct involvement of the virus but can be a secondary result of another ocular complication. Our patient developed NAION related to elevated IOP that likely disrupted the perfusion to the optic nerve head. This was unlikely to be a direct result of the virus for a number of reasons including the absence of detectable virus in the aqueous humor by PCR, the absence of any optic nerve enhancement on orbital MRI with contrast and the absence of any improvement in her visual field, which is typical of NAION, despite antiviral treatment [2]. The patient also had a history of hypertension and a disc-at-risk, which is a requirement for the development of NAION [3]. The optic disc edema resolved in the expected time course for NAION, and the patient had no other signs or symptoms of another optic neuropathy. There was also a clear temporal relationship between the IOP spike and the loss of vision. Although CSF was not obtained, this would be an extremely low-yield test, especially with no retrobulbar involvement seen on MRI.
NAION has been previously described to develop in response to elevated IOP and subsequent disruption to the optic nerve head perfusion pressure [4, 5, 6]. This has been well-described in a number of situations including after ophthalmological procedures, acute glaucoma, hypertensive uveitis, or the administration of steroid eye drops [7, 8, 9, 10, 11]. Cases of ophthalmological procedures include cataract extraction complicated by capsular block, pars plana vitrectomy for macular hole, and trabeculectomy complicated by NAION have been described [7, 8, 9]. NAION after intravitreal injections have also been presumed to be related to elevated intraocular pressure, although the IOP has not been routinely measured in most of these cases [12]. The presumed mechanism of NAION after cataract surgery has also been thought to be related to elevated IOP, which is elevated intraoperatively and sometimes postoperatively [13]. Acute primary angle closure and traumatic angle recession glaucoma has been reported to be complicated by NAION and may be bilateral and severe [10, 11]. We were unable to retrieve any previously reported case of NAION secondary to herpes zoster anterior uveitis, but cases after Posner-Schlossman syndrome (PSS) have been described. Similar to our case, the PSS cases all had IOP in excess of 50 mmHg and some cases were in individuals younger than 50 years of age [5, 10]. We were unable to retrieve any cases of NAION that developed after steroid-related IOP spikes.
Elevated intraocular pressure is well-known complication of topical steroids and to a lesser extent systemic and topical steroid treatment [14, 15]. This typically onsets around 3–6 weeks after the initiation of topical steroids and is thought to be related to increased resistance to aqueous outflow at the trabecular meshwork. The mechanism of this IOP elevation is unclear but the discontinuation of steroid treatment predictably triggers the reversal of IOP elevation back to baseline [14]. Complications of elevated IOP, not only include glaucoma, but may also result in retinal vein occlusions, corneal edema and as we have shown in this case, NAION. It is important that ophthalmologists closely monitor patients on topical steroids since NAION may be a rare and irreversible complication of their use. This may even occur in younger patients who may be taking topical steroids postoperatively for eye surgery or for ocular inflammatory disorders. Treatment of steroid-induced ocular hypertension typically involves discontinuation of the steroid and use of topical and systemic IOP-lowering medications. The elevation of IOP in our patient was likely related to topical steroid use since there was no active inflammation at the time of vision loss and the IOP responded promptly to the discontinuation of steroids.
In summary, the development of an optic neuropathy in close temporal relationship may not necessarily be related to VZV. We report a case of steroid-induced ocular hypertension for initial treatment of herpes zoster-related anterior uveitis that was complicated by NAION. Patients on topical steroids should be closely monitored since irreversible optic nerve damage may occur in this context.
Statement of Ethics
This study was carried out in accordance with the World Medical Association Declaration of Helsinki. Verbal and written consent were obtained from the patient.
Conflict of Interest Statement
The authors have no conflicts of interest to declare.
Funding Sources
No funding was received.
Author Contributions
Conception and design (P.H.Y., J.A.M.), data extraction (P.H.Y., J.A.M.), manuscript preparation (P.H.Y.), final approval (J.A.M.). All authors have seen and approved the final version of the manuscript for publication.
Fig. 1 a Humphrey 24–2 SITA-Fast visual fields demonstrating a left inferior altitudinal visual field defect. b Optical coherence tomography of the retinal nerve fiber layer (RNFL) at presentation with left eye vision loss demonstrating an elevated RNFL due to optic disc edema in the left eye. | Recovered | ReactionOutcome | CC BY-NC | 33613245 | 19,401,072 | 2021 |
What was the outcome of reaction 'Ocular hypertension'? | Nonarteritic Anterior Ischemic Optic Neuropathy following Herpes Zoster Ophthalmicus and Steroid-Related Intraocular Pressure Spike.
A 61-year-old woman presented with sudden vision loss from a left anterior optic neuropathy in the context of severely elevated intraocular pressure after starting topical steroids for anterior uveitis related to herpes zoster ophthalmicus (HZO). The strong temporal relationship between the vision loss and elevated IOP suggested the vision loss was related to nonarteritic anterior ischemic optic neuropathy (NAION). Anterior chamber paracentesis did not detect varicella zoster virus (VZV) and magnetic resonance imaging of the orbits was normal. Her vision remained stable and the optic disc edema resolved within 3 months. The occurrence of NAION following an acute elevation of intraocular pressure (IOP) is well-documented in the context of surgical procedures, glaucoma, uveitis and trauma. This case indicates that not every optic neuropathy in close temporal relationship with HZO is directly attributable to the virus. NAION may also occur after steroid-related IOP spikes and ophthalmologists should ensure that patients on topical steroids are closely monitored for ocular complications.
Introduction
Vision loss is a rare complication of herpes zoster ophthalmicus (HZO) and can be a result of anterior segment of posterior segment involvement. Optic neuropathy is a rare complication of HZO seen in less than 0.5% of cases and can be anterior (associated with optic disc edema) or retrobulbar [1]. The diagnosis of herpes zoster optic neuropathy (HZON) is diagnosed in patients who develop an optic neuropathy in close temporal relationship with HZO with other causes of optic neuropathy being excluded. Supportive evidence for the diagnosis is helpful by means of magnetic resonance imaging (MRI) of the orbits with contrast demonstrating enhancement of the optic nerve in retrobulbar cases, or the detection of varicella zoster virus (VZV) in the aqueous humor or cerebrospinal fluid (CSF) [1]. However, the yield of detection of VZV in the CSF is low, especially in anterior cases. Treatment consists of oral or intravenous antivirals and the use of systemic corticosteroids remains controversial [1]. Patients with HZO may develop an anterior optic neuropathy that is not directly related to VZV, but secondarily related to HZO by means of other ocular complications. We report a case of nonarteritic anterior ischemic optic neuropathy (NAION) related to HZO, which was likely secondary to the development of a steroid response and elevated intraocular pressure (IOP) for the treatment of anterior uveitis. This indicates that not every optic neuropathy in close temporal relationship to HZO is directly related to the virus.
Case Report
A 61-year-old woman was seen in neuro-ophthalmology consultation for a left optic neuropathy. She had a history of hypertension and was taking amlodipine. She developed left HZO 1 month prior to presentation with skin lesions on the left forehead and tip and side of her nose. She was treated with valacyclovir 1 g PO TID for 10 days. She saw an ophthalmologist 3 days later and was found to have anterior uveitis (1+ cells), an intraocular pressure of 18, and was started on prednisolone acetate 1% eye drops QID. This was continued and the examination remained stable 1 week later. Two weeks later, she developed left eye pain and worsening vision. She saw an ophthalmologist and was found to have an intraocular pressure of 52 mm Hg without any signs of uveitis. Her refraction was −1.00 +0.50 × 172 OD and −1.50 +0.50 × 180 OS and the gonioscopy revealed open angles, grade 3 (Shaffer system) with the trabecular meshwork visible for 360 degrees in both eyes. She was started on acetazolamide 250 mg PO QID, brimonidine-timolol eye drops BID and topical prednisolone acetate was discontinued given the likelihood of a steroid response. Follow-up the next day revealed an improved intraocular pressure of 16, but she was noted to have a new relative afferent pupillary defect and optic disc edema in the left optic nerve. A neuro-ophthalmology consultation was requested. Acetazolamide and brimonidine-timolol eye drops were discontinued.
Neuro-ophthalmology assessment revealed a visual acuity of 20/20 OD and 20/100 OS, a left RAPD, and Humphrey visual field testing demonstrated a left inferior altitudinal visual field defect (Fig. 1a). Anterior segment revealed no signs of uveitis and dilated fundus examination demonstrated a normal appearing right optic nerve with a cup-to-disc ratio of 0.1 and left diffuse optic disc edema. Optical coherence tomography of the retinal nerve fiber layer showed an average thickness of 84 μm OD and 182 μm OS (Fig. 1b). The differential diagnosis considered was a left anterior optic neuropathy related to herpes zoster or NAION related to the recent IOP elevation. An anterior chamber paracentesis was performed and VZV was not detected by real-time PCR. She had an MRI of the brain and orbits with contrast that did not show enhancement of the optic nerves and was normal. Complete blood count, erythrocyte sedimentation rate and C-reactive protein were normal. She was treated with valacyclovir 1 g PO TID for 1 month as a precaution, but her vision did not improve. At 3-month follow-up, she continued to have a left inferior altitudinal visual field defect and the left optic disc edema had resolved.
Discussion
Vision loss is a feared complication of HZON and may affect almost any part of the eye including the anterior and posterior segments [1]. This may be a result of direct involvement of VZV or a secondary inflammatory component. This case highlights that optic nerve complications from VZV may not be due to direct involvement of the virus but can be a secondary result of another ocular complication. Our patient developed NAION related to elevated IOP that likely disrupted the perfusion to the optic nerve head. This was unlikely to be a direct result of the virus for a number of reasons including the absence of detectable virus in the aqueous humor by PCR, the absence of any optic nerve enhancement on orbital MRI with contrast and the absence of any improvement in her visual field, which is typical of NAION, despite antiviral treatment [2]. The patient also had a history of hypertension and a disc-at-risk, which is a requirement for the development of NAION [3]. The optic disc edema resolved in the expected time course for NAION, and the patient had no other signs or symptoms of another optic neuropathy. There was also a clear temporal relationship between the IOP spike and the loss of vision. Although CSF was not obtained, this would be an extremely low-yield test, especially with no retrobulbar involvement seen on MRI.
NAION has been previously described to develop in response to elevated IOP and subsequent disruption to the optic nerve head perfusion pressure [4, 5, 6]. This has been well-described in a number of situations including after ophthalmological procedures, acute glaucoma, hypertensive uveitis, or the administration of steroid eye drops [7, 8, 9, 10, 11]. Cases of ophthalmological procedures include cataract extraction complicated by capsular block, pars plana vitrectomy for macular hole, and trabeculectomy complicated by NAION have been described [7, 8, 9]. NAION after intravitreal injections have also been presumed to be related to elevated intraocular pressure, although the IOP has not been routinely measured in most of these cases [12]. The presumed mechanism of NAION after cataract surgery has also been thought to be related to elevated IOP, which is elevated intraoperatively and sometimes postoperatively [13]. Acute primary angle closure and traumatic angle recession glaucoma has been reported to be complicated by NAION and may be bilateral and severe [10, 11]. We were unable to retrieve any previously reported case of NAION secondary to herpes zoster anterior uveitis, but cases after Posner-Schlossman syndrome (PSS) have been described. Similar to our case, the PSS cases all had IOP in excess of 50 mmHg and some cases were in individuals younger than 50 years of age [5, 10]. We were unable to retrieve any cases of NAION that developed after steroid-related IOP spikes.
Elevated intraocular pressure is well-known complication of topical steroids and to a lesser extent systemic and topical steroid treatment [14, 15]. This typically onsets around 3–6 weeks after the initiation of topical steroids and is thought to be related to increased resistance to aqueous outflow at the trabecular meshwork. The mechanism of this IOP elevation is unclear but the discontinuation of steroid treatment predictably triggers the reversal of IOP elevation back to baseline [14]. Complications of elevated IOP, not only include glaucoma, but may also result in retinal vein occlusions, corneal edema and as we have shown in this case, NAION. It is important that ophthalmologists closely monitor patients on topical steroids since NAION may be a rare and irreversible complication of their use. This may even occur in younger patients who may be taking topical steroids postoperatively for eye surgery or for ocular inflammatory disorders. Treatment of steroid-induced ocular hypertension typically involves discontinuation of the steroid and use of topical and systemic IOP-lowering medications. The elevation of IOP in our patient was likely related to topical steroid use since there was no active inflammation at the time of vision loss and the IOP responded promptly to the discontinuation of steroids.
In summary, the development of an optic neuropathy in close temporal relationship may not necessarily be related to VZV. We report a case of steroid-induced ocular hypertension for initial treatment of herpes zoster-related anterior uveitis that was complicated by NAION. Patients on topical steroids should be closely monitored since irreversible optic nerve damage may occur in this context.
Statement of Ethics
This study was carried out in accordance with the World Medical Association Declaration of Helsinki. Verbal and written consent were obtained from the patient.
Conflict of Interest Statement
The authors have no conflicts of interest to declare.
Funding Sources
No funding was received.
Author Contributions
Conception and design (P.H.Y., J.A.M.), data extraction (P.H.Y., J.A.M.), manuscript preparation (P.H.Y.), final approval (J.A.M.). All authors have seen and approved the final version of the manuscript for publication.
Fig. 1 a Humphrey 24–2 SITA-Fast visual fields demonstrating a left inferior altitudinal visual field defect. b Optical coherence tomography of the retinal nerve fiber layer (RNFL) at presentation with left eye vision loss demonstrating an elevated RNFL due to optic disc edema in the left eye. | Recovered | ReactionOutcome | CC BY-NC | 33613245 | 19,401,072 | 2021 |
What was the outcome of reaction 'Optic ischaemic neuropathy'? | Nonarteritic Anterior Ischemic Optic Neuropathy following Herpes Zoster Ophthalmicus and Steroid-Related Intraocular Pressure Spike.
A 61-year-old woman presented with sudden vision loss from a left anterior optic neuropathy in the context of severely elevated intraocular pressure after starting topical steroids for anterior uveitis related to herpes zoster ophthalmicus (HZO). The strong temporal relationship between the vision loss and elevated IOP suggested the vision loss was related to nonarteritic anterior ischemic optic neuropathy (NAION). Anterior chamber paracentesis did not detect varicella zoster virus (VZV) and magnetic resonance imaging of the orbits was normal. Her vision remained stable and the optic disc edema resolved within 3 months. The occurrence of NAION following an acute elevation of intraocular pressure (IOP) is well-documented in the context of surgical procedures, glaucoma, uveitis and trauma. This case indicates that not every optic neuropathy in close temporal relationship with HZO is directly attributable to the virus. NAION may also occur after steroid-related IOP spikes and ophthalmologists should ensure that patients on topical steroids are closely monitored for ocular complications.
Introduction
Vision loss is a rare complication of herpes zoster ophthalmicus (HZO) and can be a result of anterior segment of posterior segment involvement. Optic neuropathy is a rare complication of HZO seen in less than 0.5% of cases and can be anterior (associated with optic disc edema) or retrobulbar [1]. The diagnosis of herpes zoster optic neuropathy (HZON) is diagnosed in patients who develop an optic neuropathy in close temporal relationship with HZO with other causes of optic neuropathy being excluded. Supportive evidence for the diagnosis is helpful by means of magnetic resonance imaging (MRI) of the orbits with contrast demonstrating enhancement of the optic nerve in retrobulbar cases, or the detection of varicella zoster virus (VZV) in the aqueous humor or cerebrospinal fluid (CSF) [1]. However, the yield of detection of VZV in the CSF is low, especially in anterior cases. Treatment consists of oral or intravenous antivirals and the use of systemic corticosteroids remains controversial [1]. Patients with HZO may develop an anterior optic neuropathy that is not directly related to VZV, but secondarily related to HZO by means of other ocular complications. We report a case of nonarteritic anterior ischemic optic neuropathy (NAION) related to HZO, which was likely secondary to the development of a steroid response and elevated intraocular pressure (IOP) for the treatment of anterior uveitis. This indicates that not every optic neuropathy in close temporal relationship to HZO is directly related to the virus.
Case Report
A 61-year-old woman was seen in neuro-ophthalmology consultation for a left optic neuropathy. She had a history of hypertension and was taking amlodipine. She developed left HZO 1 month prior to presentation with skin lesions on the left forehead and tip and side of her nose. She was treated with valacyclovir 1 g PO TID for 10 days. She saw an ophthalmologist 3 days later and was found to have anterior uveitis (1+ cells), an intraocular pressure of 18, and was started on prednisolone acetate 1% eye drops QID. This was continued and the examination remained stable 1 week later. Two weeks later, she developed left eye pain and worsening vision. She saw an ophthalmologist and was found to have an intraocular pressure of 52 mm Hg without any signs of uveitis. Her refraction was −1.00 +0.50 × 172 OD and −1.50 +0.50 × 180 OS and the gonioscopy revealed open angles, grade 3 (Shaffer system) with the trabecular meshwork visible for 360 degrees in both eyes. She was started on acetazolamide 250 mg PO QID, brimonidine-timolol eye drops BID and topical prednisolone acetate was discontinued given the likelihood of a steroid response. Follow-up the next day revealed an improved intraocular pressure of 16, but she was noted to have a new relative afferent pupillary defect and optic disc edema in the left optic nerve. A neuro-ophthalmology consultation was requested. Acetazolamide and brimonidine-timolol eye drops were discontinued.
Neuro-ophthalmology assessment revealed a visual acuity of 20/20 OD and 20/100 OS, a left RAPD, and Humphrey visual field testing demonstrated a left inferior altitudinal visual field defect (Fig. 1a). Anterior segment revealed no signs of uveitis and dilated fundus examination demonstrated a normal appearing right optic nerve with a cup-to-disc ratio of 0.1 and left diffuse optic disc edema. Optical coherence tomography of the retinal nerve fiber layer showed an average thickness of 84 μm OD and 182 μm OS (Fig. 1b). The differential diagnosis considered was a left anterior optic neuropathy related to herpes zoster or NAION related to the recent IOP elevation. An anterior chamber paracentesis was performed and VZV was not detected by real-time PCR. She had an MRI of the brain and orbits with contrast that did not show enhancement of the optic nerves and was normal. Complete blood count, erythrocyte sedimentation rate and C-reactive protein were normal. She was treated with valacyclovir 1 g PO TID for 1 month as a precaution, but her vision did not improve. At 3-month follow-up, she continued to have a left inferior altitudinal visual field defect and the left optic disc edema had resolved.
Discussion
Vision loss is a feared complication of HZON and may affect almost any part of the eye including the anterior and posterior segments [1]. This may be a result of direct involvement of VZV or a secondary inflammatory component. This case highlights that optic nerve complications from VZV may not be due to direct involvement of the virus but can be a secondary result of another ocular complication. Our patient developed NAION related to elevated IOP that likely disrupted the perfusion to the optic nerve head. This was unlikely to be a direct result of the virus for a number of reasons including the absence of detectable virus in the aqueous humor by PCR, the absence of any optic nerve enhancement on orbital MRI with contrast and the absence of any improvement in her visual field, which is typical of NAION, despite antiviral treatment [2]. The patient also had a history of hypertension and a disc-at-risk, which is a requirement for the development of NAION [3]. The optic disc edema resolved in the expected time course for NAION, and the patient had no other signs or symptoms of another optic neuropathy. There was also a clear temporal relationship between the IOP spike and the loss of vision. Although CSF was not obtained, this would be an extremely low-yield test, especially with no retrobulbar involvement seen on MRI.
NAION has been previously described to develop in response to elevated IOP and subsequent disruption to the optic nerve head perfusion pressure [4, 5, 6]. This has been well-described in a number of situations including after ophthalmological procedures, acute glaucoma, hypertensive uveitis, or the administration of steroid eye drops [7, 8, 9, 10, 11]. Cases of ophthalmological procedures include cataract extraction complicated by capsular block, pars plana vitrectomy for macular hole, and trabeculectomy complicated by NAION have been described [7, 8, 9]. NAION after intravitreal injections have also been presumed to be related to elevated intraocular pressure, although the IOP has not been routinely measured in most of these cases [12]. The presumed mechanism of NAION after cataract surgery has also been thought to be related to elevated IOP, which is elevated intraoperatively and sometimes postoperatively [13]. Acute primary angle closure and traumatic angle recession glaucoma has been reported to be complicated by NAION and may be bilateral and severe [10, 11]. We were unable to retrieve any previously reported case of NAION secondary to herpes zoster anterior uveitis, but cases after Posner-Schlossman syndrome (PSS) have been described. Similar to our case, the PSS cases all had IOP in excess of 50 mmHg and some cases were in individuals younger than 50 years of age [5, 10]. We were unable to retrieve any cases of NAION that developed after steroid-related IOP spikes.
Elevated intraocular pressure is well-known complication of topical steroids and to a lesser extent systemic and topical steroid treatment [14, 15]. This typically onsets around 3–6 weeks after the initiation of topical steroids and is thought to be related to increased resistance to aqueous outflow at the trabecular meshwork. The mechanism of this IOP elevation is unclear but the discontinuation of steroid treatment predictably triggers the reversal of IOP elevation back to baseline [14]. Complications of elevated IOP, not only include glaucoma, but may also result in retinal vein occlusions, corneal edema and as we have shown in this case, NAION. It is important that ophthalmologists closely monitor patients on topical steroids since NAION may be a rare and irreversible complication of their use. This may even occur in younger patients who may be taking topical steroids postoperatively for eye surgery or for ocular inflammatory disorders. Treatment of steroid-induced ocular hypertension typically involves discontinuation of the steroid and use of topical and systemic IOP-lowering medications. The elevation of IOP in our patient was likely related to topical steroid use since there was no active inflammation at the time of vision loss and the IOP responded promptly to the discontinuation of steroids.
In summary, the development of an optic neuropathy in close temporal relationship may not necessarily be related to VZV. We report a case of steroid-induced ocular hypertension for initial treatment of herpes zoster-related anterior uveitis that was complicated by NAION. Patients on topical steroids should be closely monitored since irreversible optic nerve damage may occur in this context.
Statement of Ethics
This study was carried out in accordance with the World Medical Association Declaration of Helsinki. Verbal and written consent were obtained from the patient.
Conflict of Interest Statement
The authors have no conflicts of interest to declare.
Funding Sources
No funding was received.
Author Contributions
Conception and design (P.H.Y., J.A.M.), data extraction (P.H.Y., J.A.M.), manuscript preparation (P.H.Y.), final approval (J.A.M.). All authors have seen and approved the final version of the manuscript for publication.
Fig. 1 a Humphrey 24–2 SITA-Fast visual fields demonstrating a left inferior altitudinal visual field defect. b Optical coherence tomography of the retinal nerve fiber layer (RNFL) at presentation with left eye vision loss demonstrating an elevated RNFL due to optic disc edema in the left eye. | Recovering | ReactionOutcome | CC BY-NC | 33613245 | 19,507,642 | 2021 |
What was the outcome of reaction 'Visual impairment'? | Nonarteritic Anterior Ischemic Optic Neuropathy following Herpes Zoster Ophthalmicus and Steroid-Related Intraocular Pressure Spike.
A 61-year-old woman presented with sudden vision loss from a left anterior optic neuropathy in the context of severely elevated intraocular pressure after starting topical steroids for anterior uveitis related to herpes zoster ophthalmicus (HZO). The strong temporal relationship between the vision loss and elevated IOP suggested the vision loss was related to nonarteritic anterior ischemic optic neuropathy (NAION). Anterior chamber paracentesis did not detect varicella zoster virus (VZV) and magnetic resonance imaging of the orbits was normal. Her vision remained stable and the optic disc edema resolved within 3 months. The occurrence of NAION following an acute elevation of intraocular pressure (IOP) is well-documented in the context of surgical procedures, glaucoma, uveitis and trauma. This case indicates that not every optic neuropathy in close temporal relationship with HZO is directly attributable to the virus. NAION may also occur after steroid-related IOP spikes and ophthalmologists should ensure that patients on topical steroids are closely monitored for ocular complications.
Introduction
Vision loss is a rare complication of herpes zoster ophthalmicus (HZO) and can be a result of anterior segment of posterior segment involvement. Optic neuropathy is a rare complication of HZO seen in less than 0.5% of cases and can be anterior (associated with optic disc edema) or retrobulbar [1]. The diagnosis of herpes zoster optic neuropathy (HZON) is diagnosed in patients who develop an optic neuropathy in close temporal relationship with HZO with other causes of optic neuropathy being excluded. Supportive evidence for the diagnosis is helpful by means of magnetic resonance imaging (MRI) of the orbits with contrast demonstrating enhancement of the optic nerve in retrobulbar cases, or the detection of varicella zoster virus (VZV) in the aqueous humor or cerebrospinal fluid (CSF) [1]. However, the yield of detection of VZV in the CSF is low, especially in anterior cases. Treatment consists of oral or intravenous antivirals and the use of systemic corticosteroids remains controversial [1]. Patients with HZO may develop an anterior optic neuropathy that is not directly related to VZV, but secondarily related to HZO by means of other ocular complications. We report a case of nonarteritic anterior ischemic optic neuropathy (NAION) related to HZO, which was likely secondary to the development of a steroid response and elevated intraocular pressure (IOP) for the treatment of anterior uveitis. This indicates that not every optic neuropathy in close temporal relationship to HZO is directly related to the virus.
Case Report
A 61-year-old woman was seen in neuro-ophthalmology consultation for a left optic neuropathy. She had a history of hypertension and was taking amlodipine. She developed left HZO 1 month prior to presentation with skin lesions on the left forehead and tip and side of her nose. She was treated with valacyclovir 1 g PO TID for 10 days. She saw an ophthalmologist 3 days later and was found to have anterior uveitis (1+ cells), an intraocular pressure of 18, and was started on prednisolone acetate 1% eye drops QID. This was continued and the examination remained stable 1 week later. Two weeks later, she developed left eye pain and worsening vision. She saw an ophthalmologist and was found to have an intraocular pressure of 52 mm Hg without any signs of uveitis. Her refraction was −1.00 +0.50 × 172 OD and −1.50 +0.50 × 180 OS and the gonioscopy revealed open angles, grade 3 (Shaffer system) with the trabecular meshwork visible for 360 degrees in both eyes. She was started on acetazolamide 250 mg PO QID, brimonidine-timolol eye drops BID and topical prednisolone acetate was discontinued given the likelihood of a steroid response. Follow-up the next day revealed an improved intraocular pressure of 16, but she was noted to have a new relative afferent pupillary defect and optic disc edema in the left optic nerve. A neuro-ophthalmology consultation was requested. Acetazolamide and brimonidine-timolol eye drops were discontinued.
Neuro-ophthalmology assessment revealed a visual acuity of 20/20 OD and 20/100 OS, a left RAPD, and Humphrey visual field testing demonstrated a left inferior altitudinal visual field defect (Fig. 1a). Anterior segment revealed no signs of uveitis and dilated fundus examination demonstrated a normal appearing right optic nerve with a cup-to-disc ratio of 0.1 and left diffuse optic disc edema. Optical coherence tomography of the retinal nerve fiber layer showed an average thickness of 84 μm OD and 182 μm OS (Fig. 1b). The differential diagnosis considered was a left anterior optic neuropathy related to herpes zoster or NAION related to the recent IOP elevation. An anterior chamber paracentesis was performed and VZV was not detected by real-time PCR. She had an MRI of the brain and orbits with contrast that did not show enhancement of the optic nerves and was normal. Complete blood count, erythrocyte sedimentation rate and C-reactive protein were normal. She was treated with valacyclovir 1 g PO TID for 1 month as a precaution, but her vision did not improve. At 3-month follow-up, she continued to have a left inferior altitudinal visual field defect and the left optic disc edema had resolved.
Discussion
Vision loss is a feared complication of HZON and may affect almost any part of the eye including the anterior and posterior segments [1]. This may be a result of direct involvement of VZV or a secondary inflammatory component. This case highlights that optic nerve complications from VZV may not be due to direct involvement of the virus but can be a secondary result of another ocular complication. Our patient developed NAION related to elevated IOP that likely disrupted the perfusion to the optic nerve head. This was unlikely to be a direct result of the virus for a number of reasons including the absence of detectable virus in the aqueous humor by PCR, the absence of any optic nerve enhancement on orbital MRI with contrast and the absence of any improvement in her visual field, which is typical of NAION, despite antiviral treatment [2]. The patient also had a history of hypertension and a disc-at-risk, which is a requirement for the development of NAION [3]. The optic disc edema resolved in the expected time course for NAION, and the patient had no other signs or symptoms of another optic neuropathy. There was also a clear temporal relationship between the IOP spike and the loss of vision. Although CSF was not obtained, this would be an extremely low-yield test, especially with no retrobulbar involvement seen on MRI.
NAION has been previously described to develop in response to elevated IOP and subsequent disruption to the optic nerve head perfusion pressure [4, 5, 6]. This has been well-described in a number of situations including after ophthalmological procedures, acute glaucoma, hypertensive uveitis, or the administration of steroid eye drops [7, 8, 9, 10, 11]. Cases of ophthalmological procedures include cataract extraction complicated by capsular block, pars plana vitrectomy for macular hole, and trabeculectomy complicated by NAION have been described [7, 8, 9]. NAION after intravitreal injections have also been presumed to be related to elevated intraocular pressure, although the IOP has not been routinely measured in most of these cases [12]. The presumed mechanism of NAION after cataract surgery has also been thought to be related to elevated IOP, which is elevated intraoperatively and sometimes postoperatively [13]. Acute primary angle closure and traumatic angle recession glaucoma has been reported to be complicated by NAION and may be bilateral and severe [10, 11]. We were unable to retrieve any previously reported case of NAION secondary to herpes zoster anterior uveitis, but cases after Posner-Schlossman syndrome (PSS) have been described. Similar to our case, the PSS cases all had IOP in excess of 50 mmHg and some cases were in individuals younger than 50 years of age [5, 10]. We were unable to retrieve any cases of NAION that developed after steroid-related IOP spikes.
Elevated intraocular pressure is well-known complication of topical steroids and to a lesser extent systemic and topical steroid treatment [14, 15]. This typically onsets around 3–6 weeks after the initiation of topical steroids and is thought to be related to increased resistance to aqueous outflow at the trabecular meshwork. The mechanism of this IOP elevation is unclear but the discontinuation of steroid treatment predictably triggers the reversal of IOP elevation back to baseline [14]. Complications of elevated IOP, not only include glaucoma, but may also result in retinal vein occlusions, corneal edema and as we have shown in this case, NAION. It is important that ophthalmologists closely monitor patients on topical steroids since NAION may be a rare and irreversible complication of their use. This may even occur in younger patients who may be taking topical steroids postoperatively for eye surgery or for ocular inflammatory disorders. Treatment of steroid-induced ocular hypertension typically involves discontinuation of the steroid and use of topical and systemic IOP-lowering medications. The elevation of IOP in our patient was likely related to topical steroid use since there was no active inflammation at the time of vision loss and the IOP responded promptly to the discontinuation of steroids.
In summary, the development of an optic neuropathy in close temporal relationship may not necessarily be related to VZV. We report a case of steroid-induced ocular hypertension for initial treatment of herpes zoster-related anterior uveitis that was complicated by NAION. Patients on topical steroids should be closely monitored since irreversible optic nerve damage may occur in this context.
Statement of Ethics
This study was carried out in accordance with the World Medical Association Declaration of Helsinki. Verbal and written consent were obtained from the patient.
Conflict of Interest Statement
The authors have no conflicts of interest to declare.
Funding Sources
No funding was received.
Author Contributions
Conception and design (P.H.Y., J.A.M.), data extraction (P.H.Y., J.A.M.), manuscript preparation (P.H.Y.), final approval (J.A.M.). All authors have seen and approved the final version of the manuscript for publication.
Fig. 1 a Humphrey 24–2 SITA-Fast visual fields demonstrating a left inferior altitudinal visual field defect. b Optical coherence tomography of the retinal nerve fiber layer (RNFL) at presentation with left eye vision loss demonstrating an elevated RNFL due to optic disc edema in the left eye. | Not recovered | ReactionOutcome | CC BY-NC | 33613245 | 19,507,642 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Adenocarcinoma'. | Case Report: Findings Suggestive of Paraclinical Progressive Multifocal Leukoencephalopathy and Lung Cancer-Derived Brain Metastases in an MS Patient Treated With Fingolimod.
Fingolimod represents a highly effective disease-modifying drug in patients with active relapsing-remitting multiple sclerosis (RRMS). Its immunosuppressive effects can mediate adverse events like increased risk of cancer development or appearance of opportunistic infections. Progressive multifocal leukoencephalopathy (PML)-representing a severe opportunistic infection-has been only infrequently described during Fingolimod treatment. Here, we present a case of a 63-year-old women with pre-diagnosed RRMS who presented with new multiple cerebral lesions in a routine MRI scan, also including a tumefactive lesion in the left parietal lobe, eventually leading to the diagnosis of brain metastases derived by an adenocarcinoma of the lung. Additionally, a JCV-DNA-PCR in the cerebrospinal fluid revealed positive results, corresponding to a paraclinical progressive multifocal leukoencephalopathy. In conclusion, adverse events potentially associated with immunosuppression can occur during Fingolimod treatment. In this context, the occurrence of cancer and opportunistic infections should be carefully monitored. Here, we report a case in which JCV-DNA-PCR in the cerebrospinal fluid suggests asymptomatic PML and simultaneously lung cancer brain metastases developed. While it is rather unlikely that either event occurred as an adverse event of fingolimod treatment, a contributing effect cannot be formally excluded.
Introduction
Fingolimod (FTY720)—a sphingosine-1-phosphate-receptor modulator–is now commonly used in highly active relapsing-remitting multiple sclerosis (RRMS), due to its proven ability to prevent potential relapses (1). Despite the clear evidence for disease modifying effects, adverse events caused by the immunosuppressive effect potentially resulting in an increased risk of oncogenesis and appearance of opportunistic infections must be considered (2).
Case Presentation
A 63-year-old caucasian women with a prior diagnosis of MS (RRMS; initial diagnosis ~12 years ago) was admitted to our department because of a suspicious MRI scan, regularly arranged by her neurologist. This scan was now showing multiple new gray and white matter lesions. She had no new subjective complaints, still showing a relatively mild course of her disease (EDSS 1.5) with a slight cerebellar ataxia and slight sensory symptoms. At the age of 56 she was switched to fingolimod and had therapeutic attempts with different types of interferons and glatiramer acetate beforehand. Of note, the patient had never been treated with natalizumab.
Directly after admission, we performed a new MRI scan applying a gadolinium-based contrast agent now showing disseminated supra- and infratentorial T2/FLAIR hyperintensities, predominantly in the gray matter, also including a prominent tumefactive lesion in the left parietal lobe (Figures 1B,C). The MRI presentation itself did not allow to assign these new lesions to PML, MS activity or the development of metastases. MRI spectroscopy showed decreased N-acetylaspartate (NAA) indicating a neurodestructive, non-primarily-CNS-derived and thus malign process (Figure 1A).
Figure 1 (A–C) MRI scan revealing multiple T2/FLAIR hyperintensities; (D–G) Histopathological analysis of the brain biopsy. (A) MRI spectroscopy showing a decreased N-acetylaspartate (NAA) peak. (B) New prominent tumefactive lesion in the left parietal lobe (C) New disseminated supra- and infratentorial hyperintensities (D) Cytokeratin AE1/3+ positivity; 200x (E) Hematoxylin-eosin staining; 200x (F) TTF1+ positivity; 200x (G) Ki67 staining; 200x.
A peripheral immune cell quantification revealed a reduced white blood cell count (3,500/μl) with lymphopenia (318/μl) and a reduction in CD3+/CD4+ (22/μl) and CD19+ cells (7/μl), as well as normal numbers of CD56+ cells (146/μl).
Analyses of the cerebrospinal fluid (CSF) initially revealed typical RRMS-associated findings including a normal cell count, increased albumin levels and the detection of CSF-specific oligoclonal bands. An additional JCV-(John Cunningham virus)-DNA-PCR yielded the detection of 39 copies per mL, consistent with the laboratory finding of a paraclinical progressive multifocal leukoencephalopathy (PML).
Furthermore, we quantified carcinoembryonic antigen (CEA) in the CSF, revealing markedly increased levels, therefore pointing to probable carcinoma-derived metastases. A subsequent thoracic CT scan showed a suspicious pulmonal lesion (diameter of 2.9 cm) in the right apical lobe without radiological proof of lymphadenopathy. The patient was non-smoker and the family history was negative concerning the occurrence of lung cancer. No other risk factors have been reported by the patient.
To determine its origin, a stereotactic biopsy of the tumefactive lesion in the left parietal lobe was performed, revealing TTF1+, CK7+, AE1/3+ tissue, consistent with a metastasis derived from a bronchial adenocarcinoma. Additional immunohistochemistry analyses revealed negative results for SV40 and P53, therefore excluding an overlap with PML-associated changes in the region of the biopsy (Figures 1D–G).
Consequently, fingolimod treatment was immediately discontinued after positive JCV-DNA-PCR. Finally, the patient was admitted to the department of oncology for further diagnostic and interdisciplinary therapy initiation.
Discussion
Here, we report a case which highlights multiple challenges which can occur in active treatment of RRMS.
Occurrence of new cerebral lesions during fingolimod treatment must lead to the differential diagnosis of (1) an insufficient treatment effect associated with new disease activity or (2) a possible intracerebral adverse event.
With an estimated risk is of 0.069 per 1,000 patients, PML caused by JCV is quite rare during fingolimod treatment (3) and the MRI lesions in our case did not present with typical associated characteristics such as the prominent involvement of subcortical U-fibers (4). Nevertheless, low copy numbers of JCV-DNA could be detected in the CSF, potentially reflecting a subclinical stage of a developing PML. Such stages are rarely seen, because patients usually do not receive lumbar puncture in absence of new clinical signs and await to be better understood in the future. Limiting, an additional JCV-PCR on the biopsy material was not performed in this case. Verification of JCV-DNA in the brain biopsy would have reinforced the hypothesis of a potential subclinical PML, reflected by a low copy number of JCV-DNA in the CSF.
Because of the tumefactive characteristics of the lesion, CEA was quantified in the CSF. Increased levels can be detected especially in the presence of leptomeningeal infiltration by carcinoma but to a lesser extent also in the case of intraparenchymal infiltration (5). Due to similar molecular size, intrathecal CEA synthesis can be reliable assessed applying an IgA diagram (6).
Different types of skin cancer but also breast cancer were reported during fingolimod treatment (2). Lung cancer was less frequent and paradoxically, fingolimod is discussed to mediate lung tumor suppression by alteration of protein phosphatase 2A (7). Therefore, any causal relationship between lung cancer and fingolimod treatment in our current case is rather uncertain. The estimated incidence rate for invasive cancer development during Fingolimod treatment has been reported with 44.0 per 10,000 person-years, discussed to present an slightly increased risk compared to the general population with an incidence rate of 31.0 (8). Therefore, the usage of repeated preventive diagnostics might be not reasonable with Fingolimod treatment for patients with low risk of lung cancer development but should be considered in patients with high risk (e.g., smoker, positive family history).
Reports of concomitant occurrence of PML and primary central nervous system malignancies (e.g., primary CNS lymphoma) can be found in literature (9). Interestingly, JC-virus can also present with oncogenic potential in complete absence of a PML. Initially reported in animal models, JVC can induce tumors of glial origin. In humans, JCV seems to be especially associated with medulloblastomas among other primary brain tumors, e.g., glioblastoma multiforme and primary CNS lymphomas, as reviewed by Ahye et al. (10).
Conclusion
This case highlights that fingolimod represents a highly effective disease-modifying drug in prevention of MS relapses and accumulating disability, but that the concomitant occurrence of rare, but possibly severe adverse events such as neoplasia or opportunistic infections must be monitored. Furthermore, our case exemplifies that PML during fingolimod treatment can present with very mild, even isolated paraclinical disease course, and may accordingly be more frequent than reported.
Data Availability Statement
The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.
Ethics Statement
Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.
Author Contributions
FM, MW, PG, JF, CS, and MB: data acquisition, analysis, and revising the manuscript. PG, JF, and FM: figure design. FM and MW: drafting the manuscript. All authors read and approved the final manuscript.
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Funding. We acknowledge support by the Open Access Publication Funds of the Göttingen University. | FINGOLIMOD | DrugsGivenReaction | CC BY | 33613428 | 19,188,843 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Human polyomavirus infection'. | Case Report: Findings Suggestive of Paraclinical Progressive Multifocal Leukoencephalopathy and Lung Cancer-Derived Brain Metastases in an MS Patient Treated With Fingolimod.
Fingolimod represents a highly effective disease-modifying drug in patients with active relapsing-remitting multiple sclerosis (RRMS). Its immunosuppressive effects can mediate adverse events like increased risk of cancer development or appearance of opportunistic infections. Progressive multifocal leukoencephalopathy (PML)-representing a severe opportunistic infection-has been only infrequently described during Fingolimod treatment. Here, we present a case of a 63-year-old women with pre-diagnosed RRMS who presented with new multiple cerebral lesions in a routine MRI scan, also including a tumefactive lesion in the left parietal lobe, eventually leading to the diagnosis of brain metastases derived by an adenocarcinoma of the lung. Additionally, a JCV-DNA-PCR in the cerebrospinal fluid revealed positive results, corresponding to a paraclinical progressive multifocal leukoencephalopathy. In conclusion, adverse events potentially associated with immunosuppression can occur during Fingolimod treatment. In this context, the occurrence of cancer and opportunistic infections should be carefully monitored. Here, we report a case in which JCV-DNA-PCR in the cerebrospinal fluid suggests asymptomatic PML and simultaneously lung cancer brain metastases developed. While it is rather unlikely that either event occurred as an adverse event of fingolimod treatment, a contributing effect cannot be formally excluded.
Introduction
Fingolimod (FTY720)—a sphingosine-1-phosphate-receptor modulator–is now commonly used in highly active relapsing-remitting multiple sclerosis (RRMS), due to its proven ability to prevent potential relapses (1). Despite the clear evidence for disease modifying effects, adverse events caused by the immunosuppressive effect potentially resulting in an increased risk of oncogenesis and appearance of opportunistic infections must be considered (2).
Case Presentation
A 63-year-old caucasian women with a prior diagnosis of MS (RRMS; initial diagnosis ~12 years ago) was admitted to our department because of a suspicious MRI scan, regularly arranged by her neurologist. This scan was now showing multiple new gray and white matter lesions. She had no new subjective complaints, still showing a relatively mild course of her disease (EDSS 1.5) with a slight cerebellar ataxia and slight sensory symptoms. At the age of 56 she was switched to fingolimod and had therapeutic attempts with different types of interferons and glatiramer acetate beforehand. Of note, the patient had never been treated with natalizumab.
Directly after admission, we performed a new MRI scan applying a gadolinium-based contrast agent now showing disseminated supra- and infratentorial T2/FLAIR hyperintensities, predominantly in the gray matter, also including a prominent tumefactive lesion in the left parietal lobe (Figures 1B,C). The MRI presentation itself did not allow to assign these new lesions to PML, MS activity or the development of metastases. MRI spectroscopy showed decreased N-acetylaspartate (NAA) indicating a neurodestructive, non-primarily-CNS-derived and thus malign process (Figure 1A).
Figure 1 (A–C) MRI scan revealing multiple T2/FLAIR hyperintensities; (D–G) Histopathological analysis of the brain biopsy. (A) MRI spectroscopy showing a decreased N-acetylaspartate (NAA) peak. (B) New prominent tumefactive lesion in the left parietal lobe (C) New disseminated supra- and infratentorial hyperintensities (D) Cytokeratin AE1/3+ positivity; 200x (E) Hematoxylin-eosin staining; 200x (F) TTF1+ positivity; 200x (G) Ki67 staining; 200x.
A peripheral immune cell quantification revealed a reduced white blood cell count (3,500/μl) with lymphopenia (318/μl) and a reduction in CD3+/CD4+ (22/μl) and CD19+ cells (7/μl), as well as normal numbers of CD56+ cells (146/μl).
Analyses of the cerebrospinal fluid (CSF) initially revealed typical RRMS-associated findings including a normal cell count, increased albumin levels and the detection of CSF-specific oligoclonal bands. An additional JCV-(John Cunningham virus)-DNA-PCR yielded the detection of 39 copies per mL, consistent with the laboratory finding of a paraclinical progressive multifocal leukoencephalopathy (PML).
Furthermore, we quantified carcinoembryonic antigen (CEA) in the CSF, revealing markedly increased levels, therefore pointing to probable carcinoma-derived metastases. A subsequent thoracic CT scan showed a suspicious pulmonal lesion (diameter of 2.9 cm) in the right apical lobe without radiological proof of lymphadenopathy. The patient was non-smoker and the family history was negative concerning the occurrence of lung cancer. No other risk factors have been reported by the patient.
To determine its origin, a stereotactic biopsy of the tumefactive lesion in the left parietal lobe was performed, revealing TTF1+, CK7+, AE1/3+ tissue, consistent with a metastasis derived from a bronchial adenocarcinoma. Additional immunohistochemistry analyses revealed negative results for SV40 and P53, therefore excluding an overlap with PML-associated changes in the region of the biopsy (Figures 1D–G).
Consequently, fingolimod treatment was immediately discontinued after positive JCV-DNA-PCR. Finally, the patient was admitted to the department of oncology for further diagnostic and interdisciplinary therapy initiation.
Discussion
Here, we report a case which highlights multiple challenges which can occur in active treatment of RRMS.
Occurrence of new cerebral lesions during fingolimod treatment must lead to the differential diagnosis of (1) an insufficient treatment effect associated with new disease activity or (2) a possible intracerebral adverse event.
With an estimated risk is of 0.069 per 1,000 patients, PML caused by JCV is quite rare during fingolimod treatment (3) and the MRI lesions in our case did not present with typical associated characteristics such as the prominent involvement of subcortical U-fibers (4). Nevertheless, low copy numbers of JCV-DNA could be detected in the CSF, potentially reflecting a subclinical stage of a developing PML. Such stages are rarely seen, because patients usually do not receive lumbar puncture in absence of new clinical signs and await to be better understood in the future. Limiting, an additional JCV-PCR on the biopsy material was not performed in this case. Verification of JCV-DNA in the brain biopsy would have reinforced the hypothesis of a potential subclinical PML, reflected by a low copy number of JCV-DNA in the CSF.
Because of the tumefactive characteristics of the lesion, CEA was quantified in the CSF. Increased levels can be detected especially in the presence of leptomeningeal infiltration by carcinoma but to a lesser extent also in the case of intraparenchymal infiltration (5). Due to similar molecular size, intrathecal CEA synthesis can be reliable assessed applying an IgA diagram (6).
Different types of skin cancer but also breast cancer were reported during fingolimod treatment (2). Lung cancer was less frequent and paradoxically, fingolimod is discussed to mediate lung tumor suppression by alteration of protein phosphatase 2A (7). Therefore, any causal relationship between lung cancer and fingolimod treatment in our current case is rather uncertain. The estimated incidence rate for invasive cancer development during Fingolimod treatment has been reported with 44.0 per 10,000 person-years, discussed to present an slightly increased risk compared to the general population with an incidence rate of 31.0 (8). Therefore, the usage of repeated preventive diagnostics might be not reasonable with Fingolimod treatment for patients with low risk of lung cancer development but should be considered in patients with high risk (e.g., smoker, positive family history).
Reports of concomitant occurrence of PML and primary central nervous system malignancies (e.g., primary CNS lymphoma) can be found in literature (9). Interestingly, JC-virus can also present with oncogenic potential in complete absence of a PML. Initially reported in animal models, JVC can induce tumors of glial origin. In humans, JCV seems to be especially associated with medulloblastomas among other primary brain tumors, e.g., glioblastoma multiforme and primary CNS lymphomas, as reviewed by Ahye et al. (10).
Conclusion
This case highlights that fingolimod represents a highly effective disease-modifying drug in prevention of MS relapses and accumulating disability, but that the concomitant occurrence of rare, but possibly severe adverse events such as neoplasia or opportunistic infections must be monitored. Furthermore, our case exemplifies that PML during fingolimod treatment can present with very mild, even isolated paraclinical disease course, and may accordingly be more frequent than reported.
Data Availability Statement
The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.
Ethics Statement
Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.
Author Contributions
FM, MW, PG, JF, CS, and MB: data acquisition, analysis, and revising the manuscript. PG, JF, and FM: figure design. FM and MW: drafting the manuscript. All authors read and approved the final manuscript.
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Funding. We acknowledge support by the Open Access Publication Funds of the Göttingen University. | FINGOLIMOD | DrugsGivenReaction | CC BY | 33613428 | 20,226,478 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Leukoencephalopathy'. | Case Report: Findings Suggestive of Paraclinical Progressive Multifocal Leukoencephalopathy and Lung Cancer-Derived Brain Metastases in an MS Patient Treated With Fingolimod.
Fingolimod represents a highly effective disease-modifying drug in patients with active relapsing-remitting multiple sclerosis (RRMS). Its immunosuppressive effects can mediate adverse events like increased risk of cancer development or appearance of opportunistic infections. Progressive multifocal leukoencephalopathy (PML)-representing a severe opportunistic infection-has been only infrequently described during Fingolimod treatment. Here, we present a case of a 63-year-old women with pre-diagnosed RRMS who presented with new multiple cerebral lesions in a routine MRI scan, also including a tumefactive lesion in the left parietal lobe, eventually leading to the diagnosis of brain metastases derived by an adenocarcinoma of the lung. Additionally, a JCV-DNA-PCR in the cerebrospinal fluid revealed positive results, corresponding to a paraclinical progressive multifocal leukoencephalopathy. In conclusion, adverse events potentially associated with immunosuppression can occur during Fingolimod treatment. In this context, the occurrence of cancer and opportunistic infections should be carefully monitored. Here, we report a case in which JCV-DNA-PCR in the cerebrospinal fluid suggests asymptomatic PML and simultaneously lung cancer brain metastases developed. While it is rather unlikely that either event occurred as an adverse event of fingolimod treatment, a contributing effect cannot be formally excluded.
Introduction
Fingolimod (FTY720)—a sphingosine-1-phosphate-receptor modulator–is now commonly used in highly active relapsing-remitting multiple sclerosis (RRMS), due to its proven ability to prevent potential relapses (1). Despite the clear evidence for disease modifying effects, adverse events caused by the immunosuppressive effect potentially resulting in an increased risk of oncogenesis and appearance of opportunistic infections must be considered (2).
Case Presentation
A 63-year-old caucasian women with a prior diagnosis of MS (RRMS; initial diagnosis ~12 years ago) was admitted to our department because of a suspicious MRI scan, regularly arranged by her neurologist. This scan was now showing multiple new gray and white matter lesions. She had no new subjective complaints, still showing a relatively mild course of her disease (EDSS 1.5) with a slight cerebellar ataxia and slight sensory symptoms. At the age of 56 she was switched to fingolimod and had therapeutic attempts with different types of interferons and glatiramer acetate beforehand. Of note, the patient had never been treated with natalizumab.
Directly after admission, we performed a new MRI scan applying a gadolinium-based contrast agent now showing disseminated supra- and infratentorial T2/FLAIR hyperintensities, predominantly in the gray matter, also including a prominent tumefactive lesion in the left parietal lobe (Figures 1B,C). The MRI presentation itself did not allow to assign these new lesions to PML, MS activity or the development of metastases. MRI spectroscopy showed decreased N-acetylaspartate (NAA) indicating a neurodestructive, non-primarily-CNS-derived and thus malign process (Figure 1A).
Figure 1 (A–C) MRI scan revealing multiple T2/FLAIR hyperintensities; (D–G) Histopathological analysis of the brain biopsy. (A) MRI spectroscopy showing a decreased N-acetylaspartate (NAA) peak. (B) New prominent tumefactive lesion in the left parietal lobe (C) New disseminated supra- and infratentorial hyperintensities (D) Cytokeratin AE1/3+ positivity; 200x (E) Hematoxylin-eosin staining; 200x (F) TTF1+ positivity; 200x (G) Ki67 staining; 200x.
A peripheral immune cell quantification revealed a reduced white blood cell count (3,500/μl) with lymphopenia (318/μl) and a reduction in CD3+/CD4+ (22/μl) and CD19+ cells (7/μl), as well as normal numbers of CD56+ cells (146/μl).
Analyses of the cerebrospinal fluid (CSF) initially revealed typical RRMS-associated findings including a normal cell count, increased albumin levels and the detection of CSF-specific oligoclonal bands. An additional JCV-(John Cunningham virus)-DNA-PCR yielded the detection of 39 copies per mL, consistent with the laboratory finding of a paraclinical progressive multifocal leukoencephalopathy (PML).
Furthermore, we quantified carcinoembryonic antigen (CEA) in the CSF, revealing markedly increased levels, therefore pointing to probable carcinoma-derived metastases. A subsequent thoracic CT scan showed a suspicious pulmonal lesion (diameter of 2.9 cm) in the right apical lobe without radiological proof of lymphadenopathy. The patient was non-smoker and the family history was negative concerning the occurrence of lung cancer. No other risk factors have been reported by the patient.
To determine its origin, a stereotactic biopsy of the tumefactive lesion in the left parietal lobe was performed, revealing TTF1+, CK7+, AE1/3+ tissue, consistent with a metastasis derived from a bronchial adenocarcinoma. Additional immunohistochemistry analyses revealed negative results for SV40 and P53, therefore excluding an overlap with PML-associated changes in the region of the biopsy (Figures 1D–G).
Consequently, fingolimod treatment was immediately discontinued after positive JCV-DNA-PCR. Finally, the patient was admitted to the department of oncology for further diagnostic and interdisciplinary therapy initiation.
Discussion
Here, we report a case which highlights multiple challenges which can occur in active treatment of RRMS.
Occurrence of new cerebral lesions during fingolimod treatment must lead to the differential diagnosis of (1) an insufficient treatment effect associated with new disease activity or (2) a possible intracerebral adverse event.
With an estimated risk is of 0.069 per 1,000 patients, PML caused by JCV is quite rare during fingolimod treatment (3) and the MRI lesions in our case did not present with typical associated characteristics such as the prominent involvement of subcortical U-fibers (4). Nevertheless, low copy numbers of JCV-DNA could be detected in the CSF, potentially reflecting a subclinical stage of a developing PML. Such stages are rarely seen, because patients usually do not receive lumbar puncture in absence of new clinical signs and await to be better understood in the future. Limiting, an additional JCV-PCR on the biopsy material was not performed in this case. Verification of JCV-DNA in the brain biopsy would have reinforced the hypothesis of a potential subclinical PML, reflected by a low copy number of JCV-DNA in the CSF.
Because of the tumefactive characteristics of the lesion, CEA was quantified in the CSF. Increased levels can be detected especially in the presence of leptomeningeal infiltration by carcinoma but to a lesser extent also in the case of intraparenchymal infiltration (5). Due to similar molecular size, intrathecal CEA synthesis can be reliable assessed applying an IgA diagram (6).
Different types of skin cancer but also breast cancer were reported during fingolimod treatment (2). Lung cancer was less frequent and paradoxically, fingolimod is discussed to mediate lung tumor suppression by alteration of protein phosphatase 2A (7). Therefore, any causal relationship between lung cancer and fingolimod treatment in our current case is rather uncertain. The estimated incidence rate for invasive cancer development during Fingolimod treatment has been reported with 44.0 per 10,000 person-years, discussed to present an slightly increased risk compared to the general population with an incidence rate of 31.0 (8). Therefore, the usage of repeated preventive diagnostics might be not reasonable with Fingolimod treatment for patients with low risk of lung cancer development but should be considered in patients with high risk (e.g., smoker, positive family history).
Reports of concomitant occurrence of PML and primary central nervous system malignancies (e.g., primary CNS lymphoma) can be found in literature (9). Interestingly, JC-virus can also present with oncogenic potential in complete absence of a PML. Initially reported in animal models, JVC can induce tumors of glial origin. In humans, JCV seems to be especially associated with medulloblastomas among other primary brain tumors, e.g., glioblastoma multiforme and primary CNS lymphomas, as reviewed by Ahye et al. (10).
Conclusion
This case highlights that fingolimod represents a highly effective disease-modifying drug in prevention of MS relapses and accumulating disability, but that the concomitant occurrence of rare, but possibly severe adverse events such as neoplasia or opportunistic infections must be monitored. Furthermore, our case exemplifies that PML during fingolimod treatment can present with very mild, even isolated paraclinical disease course, and may accordingly be more frequent than reported.
Data Availability Statement
The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.
Ethics Statement
Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.
Author Contributions
FM, MW, PG, JF, CS, and MB: data acquisition, analysis, and revising the manuscript. PG, JF, and FM: figure design. FM and MW: drafting the manuscript. All authors read and approved the final manuscript.
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Funding. We acknowledge support by the Open Access Publication Funds of the Göttingen University. | FINGOLIMOD | DrugsGivenReaction | CC BY | 33613428 | 19,188,843 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Lung adenocarcinoma'. | Case Report: Findings Suggestive of Paraclinical Progressive Multifocal Leukoencephalopathy and Lung Cancer-Derived Brain Metastases in an MS Patient Treated With Fingolimod.
Fingolimod represents a highly effective disease-modifying drug in patients with active relapsing-remitting multiple sclerosis (RRMS). Its immunosuppressive effects can mediate adverse events like increased risk of cancer development or appearance of opportunistic infections. Progressive multifocal leukoencephalopathy (PML)-representing a severe opportunistic infection-has been only infrequently described during Fingolimod treatment. Here, we present a case of a 63-year-old women with pre-diagnosed RRMS who presented with new multiple cerebral lesions in a routine MRI scan, also including a tumefactive lesion in the left parietal lobe, eventually leading to the diagnosis of brain metastases derived by an adenocarcinoma of the lung. Additionally, a JCV-DNA-PCR in the cerebrospinal fluid revealed positive results, corresponding to a paraclinical progressive multifocal leukoencephalopathy. In conclusion, adverse events potentially associated with immunosuppression can occur during Fingolimod treatment. In this context, the occurrence of cancer and opportunistic infections should be carefully monitored. Here, we report a case in which JCV-DNA-PCR in the cerebrospinal fluid suggests asymptomatic PML and simultaneously lung cancer brain metastases developed. While it is rather unlikely that either event occurred as an adverse event of fingolimod treatment, a contributing effect cannot be formally excluded.
Introduction
Fingolimod (FTY720)—a sphingosine-1-phosphate-receptor modulator–is now commonly used in highly active relapsing-remitting multiple sclerosis (RRMS), due to its proven ability to prevent potential relapses (1). Despite the clear evidence for disease modifying effects, adverse events caused by the immunosuppressive effect potentially resulting in an increased risk of oncogenesis and appearance of opportunistic infections must be considered (2).
Case Presentation
A 63-year-old caucasian women with a prior diagnosis of MS (RRMS; initial diagnosis ~12 years ago) was admitted to our department because of a suspicious MRI scan, regularly arranged by her neurologist. This scan was now showing multiple new gray and white matter lesions. She had no new subjective complaints, still showing a relatively mild course of her disease (EDSS 1.5) with a slight cerebellar ataxia and slight sensory symptoms. At the age of 56 she was switched to fingolimod and had therapeutic attempts with different types of interferons and glatiramer acetate beforehand. Of note, the patient had never been treated with natalizumab.
Directly after admission, we performed a new MRI scan applying a gadolinium-based contrast agent now showing disseminated supra- and infratentorial T2/FLAIR hyperintensities, predominantly in the gray matter, also including a prominent tumefactive lesion in the left parietal lobe (Figures 1B,C). The MRI presentation itself did not allow to assign these new lesions to PML, MS activity or the development of metastases. MRI spectroscopy showed decreased N-acetylaspartate (NAA) indicating a neurodestructive, non-primarily-CNS-derived and thus malign process (Figure 1A).
Figure 1 (A–C) MRI scan revealing multiple T2/FLAIR hyperintensities; (D–G) Histopathological analysis of the brain biopsy. (A) MRI spectroscopy showing a decreased N-acetylaspartate (NAA) peak. (B) New prominent tumefactive lesion in the left parietal lobe (C) New disseminated supra- and infratentorial hyperintensities (D) Cytokeratin AE1/3+ positivity; 200x (E) Hematoxylin-eosin staining; 200x (F) TTF1+ positivity; 200x (G) Ki67 staining; 200x.
A peripheral immune cell quantification revealed a reduced white blood cell count (3,500/μl) with lymphopenia (318/μl) and a reduction in CD3+/CD4+ (22/μl) and CD19+ cells (7/μl), as well as normal numbers of CD56+ cells (146/μl).
Analyses of the cerebrospinal fluid (CSF) initially revealed typical RRMS-associated findings including a normal cell count, increased albumin levels and the detection of CSF-specific oligoclonal bands. An additional JCV-(John Cunningham virus)-DNA-PCR yielded the detection of 39 copies per mL, consistent with the laboratory finding of a paraclinical progressive multifocal leukoencephalopathy (PML).
Furthermore, we quantified carcinoembryonic antigen (CEA) in the CSF, revealing markedly increased levels, therefore pointing to probable carcinoma-derived metastases. A subsequent thoracic CT scan showed a suspicious pulmonal lesion (diameter of 2.9 cm) in the right apical lobe without radiological proof of lymphadenopathy. The patient was non-smoker and the family history was negative concerning the occurrence of lung cancer. No other risk factors have been reported by the patient.
To determine its origin, a stereotactic biopsy of the tumefactive lesion in the left parietal lobe was performed, revealing TTF1+, CK7+, AE1/3+ tissue, consistent with a metastasis derived from a bronchial adenocarcinoma. Additional immunohistochemistry analyses revealed negative results for SV40 and P53, therefore excluding an overlap with PML-associated changes in the region of the biopsy (Figures 1D–G).
Consequently, fingolimod treatment was immediately discontinued after positive JCV-DNA-PCR. Finally, the patient was admitted to the department of oncology for further diagnostic and interdisciplinary therapy initiation.
Discussion
Here, we report a case which highlights multiple challenges which can occur in active treatment of RRMS.
Occurrence of new cerebral lesions during fingolimod treatment must lead to the differential diagnosis of (1) an insufficient treatment effect associated with new disease activity or (2) a possible intracerebral adverse event.
With an estimated risk is of 0.069 per 1,000 patients, PML caused by JCV is quite rare during fingolimod treatment (3) and the MRI lesions in our case did not present with typical associated characteristics such as the prominent involvement of subcortical U-fibers (4). Nevertheless, low copy numbers of JCV-DNA could be detected in the CSF, potentially reflecting a subclinical stage of a developing PML. Such stages are rarely seen, because patients usually do not receive lumbar puncture in absence of new clinical signs and await to be better understood in the future. Limiting, an additional JCV-PCR on the biopsy material was not performed in this case. Verification of JCV-DNA in the brain biopsy would have reinforced the hypothesis of a potential subclinical PML, reflected by a low copy number of JCV-DNA in the CSF.
Because of the tumefactive characteristics of the lesion, CEA was quantified in the CSF. Increased levels can be detected especially in the presence of leptomeningeal infiltration by carcinoma but to a lesser extent also in the case of intraparenchymal infiltration (5). Due to similar molecular size, intrathecal CEA synthesis can be reliable assessed applying an IgA diagram (6).
Different types of skin cancer but also breast cancer were reported during fingolimod treatment (2). Lung cancer was less frequent and paradoxically, fingolimod is discussed to mediate lung tumor suppression by alteration of protein phosphatase 2A (7). Therefore, any causal relationship between lung cancer and fingolimod treatment in our current case is rather uncertain. The estimated incidence rate for invasive cancer development during Fingolimod treatment has been reported with 44.0 per 10,000 person-years, discussed to present an slightly increased risk compared to the general population with an incidence rate of 31.0 (8). Therefore, the usage of repeated preventive diagnostics might be not reasonable with Fingolimod treatment for patients with low risk of lung cancer development but should be considered in patients with high risk (e.g., smoker, positive family history).
Reports of concomitant occurrence of PML and primary central nervous system malignancies (e.g., primary CNS lymphoma) can be found in literature (9). Interestingly, JC-virus can also present with oncogenic potential in complete absence of a PML. Initially reported in animal models, JVC can induce tumors of glial origin. In humans, JCV seems to be especially associated with medulloblastomas among other primary brain tumors, e.g., glioblastoma multiforme and primary CNS lymphomas, as reviewed by Ahye et al. (10).
Conclusion
This case highlights that fingolimod represents a highly effective disease-modifying drug in prevention of MS relapses and accumulating disability, but that the concomitant occurrence of rare, but possibly severe adverse events such as neoplasia or opportunistic infections must be monitored. Furthermore, our case exemplifies that PML during fingolimod treatment can present with very mild, even isolated paraclinical disease course, and may accordingly be more frequent than reported.
Data Availability Statement
The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.
Ethics Statement
Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.
Author Contributions
FM, MW, PG, JF, CS, and MB: data acquisition, analysis, and revising the manuscript. PG, JF, and FM: figure design. FM and MW: drafting the manuscript. All authors read and approved the final manuscript.
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Funding. We acknowledge support by the Open Access Publication Funds of the Göttingen University. | FINGOLIMOD | DrugsGivenReaction | CC BY | 33613428 | 20,226,478 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Metastases to central nervous system'. | Case Report: Findings Suggestive of Paraclinical Progressive Multifocal Leukoencephalopathy and Lung Cancer-Derived Brain Metastases in an MS Patient Treated With Fingolimod.
Fingolimod represents a highly effective disease-modifying drug in patients with active relapsing-remitting multiple sclerosis (RRMS). Its immunosuppressive effects can mediate adverse events like increased risk of cancer development or appearance of opportunistic infections. Progressive multifocal leukoencephalopathy (PML)-representing a severe opportunistic infection-has been only infrequently described during Fingolimod treatment. Here, we present a case of a 63-year-old women with pre-diagnosed RRMS who presented with new multiple cerebral lesions in a routine MRI scan, also including a tumefactive lesion in the left parietal lobe, eventually leading to the diagnosis of brain metastases derived by an adenocarcinoma of the lung. Additionally, a JCV-DNA-PCR in the cerebrospinal fluid revealed positive results, corresponding to a paraclinical progressive multifocal leukoencephalopathy. In conclusion, adverse events potentially associated with immunosuppression can occur during Fingolimod treatment. In this context, the occurrence of cancer and opportunistic infections should be carefully monitored. Here, we report a case in which JCV-DNA-PCR in the cerebrospinal fluid suggests asymptomatic PML and simultaneously lung cancer brain metastases developed. While it is rather unlikely that either event occurred as an adverse event of fingolimod treatment, a contributing effect cannot be formally excluded.
Introduction
Fingolimod (FTY720)—a sphingosine-1-phosphate-receptor modulator–is now commonly used in highly active relapsing-remitting multiple sclerosis (RRMS), due to its proven ability to prevent potential relapses (1). Despite the clear evidence for disease modifying effects, adverse events caused by the immunosuppressive effect potentially resulting in an increased risk of oncogenesis and appearance of opportunistic infections must be considered (2).
Case Presentation
A 63-year-old caucasian women with a prior diagnosis of MS (RRMS; initial diagnosis ~12 years ago) was admitted to our department because of a suspicious MRI scan, regularly arranged by her neurologist. This scan was now showing multiple new gray and white matter lesions. She had no new subjective complaints, still showing a relatively mild course of her disease (EDSS 1.5) with a slight cerebellar ataxia and slight sensory symptoms. At the age of 56 she was switched to fingolimod and had therapeutic attempts with different types of interferons and glatiramer acetate beforehand. Of note, the patient had never been treated with natalizumab.
Directly after admission, we performed a new MRI scan applying a gadolinium-based contrast agent now showing disseminated supra- and infratentorial T2/FLAIR hyperintensities, predominantly in the gray matter, also including a prominent tumefactive lesion in the left parietal lobe (Figures 1B,C). The MRI presentation itself did not allow to assign these new lesions to PML, MS activity or the development of metastases. MRI spectroscopy showed decreased N-acetylaspartate (NAA) indicating a neurodestructive, non-primarily-CNS-derived and thus malign process (Figure 1A).
Figure 1 (A–C) MRI scan revealing multiple T2/FLAIR hyperintensities; (D–G) Histopathological analysis of the brain biopsy. (A) MRI spectroscopy showing a decreased N-acetylaspartate (NAA) peak. (B) New prominent tumefactive lesion in the left parietal lobe (C) New disseminated supra- and infratentorial hyperintensities (D) Cytokeratin AE1/3+ positivity; 200x (E) Hematoxylin-eosin staining; 200x (F) TTF1+ positivity; 200x (G) Ki67 staining; 200x.
A peripheral immune cell quantification revealed a reduced white blood cell count (3,500/μl) with lymphopenia (318/μl) and a reduction in CD3+/CD4+ (22/μl) and CD19+ cells (7/μl), as well as normal numbers of CD56+ cells (146/μl).
Analyses of the cerebrospinal fluid (CSF) initially revealed typical RRMS-associated findings including a normal cell count, increased albumin levels and the detection of CSF-specific oligoclonal bands. An additional JCV-(John Cunningham virus)-DNA-PCR yielded the detection of 39 copies per mL, consistent with the laboratory finding of a paraclinical progressive multifocal leukoencephalopathy (PML).
Furthermore, we quantified carcinoembryonic antigen (CEA) in the CSF, revealing markedly increased levels, therefore pointing to probable carcinoma-derived metastases. A subsequent thoracic CT scan showed a suspicious pulmonal lesion (diameter of 2.9 cm) in the right apical lobe without radiological proof of lymphadenopathy. The patient was non-smoker and the family history was negative concerning the occurrence of lung cancer. No other risk factors have been reported by the patient.
To determine its origin, a stereotactic biopsy of the tumefactive lesion in the left parietal lobe was performed, revealing TTF1+, CK7+, AE1/3+ tissue, consistent with a metastasis derived from a bronchial adenocarcinoma. Additional immunohistochemistry analyses revealed negative results for SV40 and P53, therefore excluding an overlap with PML-associated changes in the region of the biopsy (Figures 1D–G).
Consequently, fingolimod treatment was immediately discontinued after positive JCV-DNA-PCR. Finally, the patient was admitted to the department of oncology for further diagnostic and interdisciplinary therapy initiation.
Discussion
Here, we report a case which highlights multiple challenges which can occur in active treatment of RRMS.
Occurrence of new cerebral lesions during fingolimod treatment must lead to the differential diagnosis of (1) an insufficient treatment effect associated with new disease activity or (2) a possible intracerebral adverse event.
With an estimated risk is of 0.069 per 1,000 patients, PML caused by JCV is quite rare during fingolimod treatment (3) and the MRI lesions in our case did not present with typical associated characteristics such as the prominent involvement of subcortical U-fibers (4). Nevertheless, low copy numbers of JCV-DNA could be detected in the CSF, potentially reflecting a subclinical stage of a developing PML. Such stages are rarely seen, because patients usually do not receive lumbar puncture in absence of new clinical signs and await to be better understood in the future. Limiting, an additional JCV-PCR on the biopsy material was not performed in this case. Verification of JCV-DNA in the brain biopsy would have reinforced the hypothesis of a potential subclinical PML, reflected by a low copy number of JCV-DNA in the CSF.
Because of the tumefactive characteristics of the lesion, CEA was quantified in the CSF. Increased levels can be detected especially in the presence of leptomeningeal infiltration by carcinoma but to a lesser extent also in the case of intraparenchymal infiltration (5). Due to similar molecular size, intrathecal CEA synthesis can be reliable assessed applying an IgA diagram (6).
Different types of skin cancer but also breast cancer were reported during fingolimod treatment (2). Lung cancer was less frequent and paradoxically, fingolimod is discussed to mediate lung tumor suppression by alteration of protein phosphatase 2A (7). Therefore, any causal relationship between lung cancer and fingolimod treatment in our current case is rather uncertain. The estimated incidence rate for invasive cancer development during Fingolimod treatment has been reported with 44.0 per 10,000 person-years, discussed to present an slightly increased risk compared to the general population with an incidence rate of 31.0 (8). Therefore, the usage of repeated preventive diagnostics might be not reasonable with Fingolimod treatment for patients with low risk of lung cancer development but should be considered in patients with high risk (e.g., smoker, positive family history).
Reports of concomitant occurrence of PML and primary central nervous system malignancies (e.g., primary CNS lymphoma) can be found in literature (9). Interestingly, JC-virus can also present with oncogenic potential in complete absence of a PML. Initially reported in animal models, JVC can induce tumors of glial origin. In humans, JCV seems to be especially associated with medulloblastomas among other primary brain tumors, e.g., glioblastoma multiforme and primary CNS lymphomas, as reviewed by Ahye et al. (10).
Conclusion
This case highlights that fingolimod represents a highly effective disease-modifying drug in prevention of MS relapses and accumulating disability, but that the concomitant occurrence of rare, but possibly severe adverse events such as neoplasia or opportunistic infections must be monitored. Furthermore, our case exemplifies that PML during fingolimod treatment can present with very mild, even isolated paraclinical disease course, and may accordingly be more frequent than reported.
Data Availability Statement
The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.
Ethics Statement
Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.
Author Contributions
FM, MW, PG, JF, CS, and MB: data acquisition, analysis, and revising the manuscript. PG, JF, and FM: figure design. FM and MW: drafting the manuscript. All authors read and approved the final manuscript.
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Funding. We acknowledge support by the Open Access Publication Funds of the Göttingen University. | FINGOLIMOD | DrugsGivenReaction | CC BY | 33613428 | 20,226,478 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Progressive multifocal leukoencephalopathy'. | Case Report: Findings Suggestive of Paraclinical Progressive Multifocal Leukoencephalopathy and Lung Cancer-Derived Brain Metastases in an MS Patient Treated With Fingolimod.
Fingolimod represents a highly effective disease-modifying drug in patients with active relapsing-remitting multiple sclerosis (RRMS). Its immunosuppressive effects can mediate adverse events like increased risk of cancer development or appearance of opportunistic infections. Progressive multifocal leukoencephalopathy (PML)-representing a severe opportunistic infection-has been only infrequently described during Fingolimod treatment. Here, we present a case of a 63-year-old women with pre-diagnosed RRMS who presented with new multiple cerebral lesions in a routine MRI scan, also including a tumefactive lesion in the left parietal lobe, eventually leading to the diagnosis of brain metastases derived by an adenocarcinoma of the lung. Additionally, a JCV-DNA-PCR in the cerebrospinal fluid revealed positive results, corresponding to a paraclinical progressive multifocal leukoencephalopathy. In conclusion, adverse events potentially associated with immunosuppression can occur during Fingolimod treatment. In this context, the occurrence of cancer and opportunistic infections should be carefully monitored. Here, we report a case in which JCV-DNA-PCR in the cerebrospinal fluid suggests asymptomatic PML and simultaneously lung cancer brain metastases developed. While it is rather unlikely that either event occurred as an adverse event of fingolimod treatment, a contributing effect cannot be formally excluded.
Introduction
Fingolimod (FTY720)—a sphingosine-1-phosphate-receptor modulator–is now commonly used in highly active relapsing-remitting multiple sclerosis (RRMS), due to its proven ability to prevent potential relapses (1). Despite the clear evidence for disease modifying effects, adverse events caused by the immunosuppressive effect potentially resulting in an increased risk of oncogenesis and appearance of opportunistic infections must be considered (2).
Case Presentation
A 63-year-old caucasian women with a prior diagnosis of MS (RRMS; initial diagnosis ~12 years ago) was admitted to our department because of a suspicious MRI scan, regularly arranged by her neurologist. This scan was now showing multiple new gray and white matter lesions. She had no new subjective complaints, still showing a relatively mild course of her disease (EDSS 1.5) with a slight cerebellar ataxia and slight sensory symptoms. At the age of 56 she was switched to fingolimod and had therapeutic attempts with different types of interferons and glatiramer acetate beforehand. Of note, the patient had never been treated with natalizumab.
Directly after admission, we performed a new MRI scan applying a gadolinium-based contrast agent now showing disseminated supra- and infratentorial T2/FLAIR hyperintensities, predominantly in the gray matter, also including a prominent tumefactive lesion in the left parietal lobe (Figures 1B,C). The MRI presentation itself did not allow to assign these new lesions to PML, MS activity or the development of metastases. MRI spectroscopy showed decreased N-acetylaspartate (NAA) indicating a neurodestructive, non-primarily-CNS-derived and thus malign process (Figure 1A).
Figure 1 (A–C) MRI scan revealing multiple T2/FLAIR hyperintensities; (D–G) Histopathological analysis of the brain biopsy. (A) MRI spectroscopy showing a decreased N-acetylaspartate (NAA) peak. (B) New prominent tumefactive lesion in the left parietal lobe (C) New disseminated supra- and infratentorial hyperintensities (D) Cytokeratin AE1/3+ positivity; 200x (E) Hematoxylin-eosin staining; 200x (F) TTF1+ positivity; 200x (G) Ki67 staining; 200x.
A peripheral immune cell quantification revealed a reduced white blood cell count (3,500/μl) with lymphopenia (318/μl) and a reduction in CD3+/CD4+ (22/μl) and CD19+ cells (7/μl), as well as normal numbers of CD56+ cells (146/μl).
Analyses of the cerebrospinal fluid (CSF) initially revealed typical RRMS-associated findings including a normal cell count, increased albumin levels and the detection of CSF-specific oligoclonal bands. An additional JCV-(John Cunningham virus)-DNA-PCR yielded the detection of 39 copies per mL, consistent with the laboratory finding of a paraclinical progressive multifocal leukoencephalopathy (PML).
Furthermore, we quantified carcinoembryonic antigen (CEA) in the CSF, revealing markedly increased levels, therefore pointing to probable carcinoma-derived metastases. A subsequent thoracic CT scan showed a suspicious pulmonal lesion (diameter of 2.9 cm) in the right apical lobe without radiological proof of lymphadenopathy. The patient was non-smoker and the family history was negative concerning the occurrence of lung cancer. No other risk factors have been reported by the patient.
To determine its origin, a stereotactic biopsy of the tumefactive lesion in the left parietal lobe was performed, revealing TTF1+, CK7+, AE1/3+ tissue, consistent with a metastasis derived from a bronchial adenocarcinoma. Additional immunohistochemistry analyses revealed negative results for SV40 and P53, therefore excluding an overlap with PML-associated changes in the region of the biopsy (Figures 1D–G).
Consequently, fingolimod treatment was immediately discontinued after positive JCV-DNA-PCR. Finally, the patient was admitted to the department of oncology for further diagnostic and interdisciplinary therapy initiation.
Discussion
Here, we report a case which highlights multiple challenges which can occur in active treatment of RRMS.
Occurrence of new cerebral lesions during fingolimod treatment must lead to the differential diagnosis of (1) an insufficient treatment effect associated with new disease activity or (2) a possible intracerebral adverse event.
With an estimated risk is of 0.069 per 1,000 patients, PML caused by JCV is quite rare during fingolimod treatment (3) and the MRI lesions in our case did not present with typical associated characteristics such as the prominent involvement of subcortical U-fibers (4). Nevertheless, low copy numbers of JCV-DNA could be detected in the CSF, potentially reflecting a subclinical stage of a developing PML. Such stages are rarely seen, because patients usually do not receive lumbar puncture in absence of new clinical signs and await to be better understood in the future. Limiting, an additional JCV-PCR on the biopsy material was not performed in this case. Verification of JCV-DNA in the brain biopsy would have reinforced the hypothesis of a potential subclinical PML, reflected by a low copy number of JCV-DNA in the CSF.
Because of the tumefactive characteristics of the lesion, CEA was quantified in the CSF. Increased levels can be detected especially in the presence of leptomeningeal infiltration by carcinoma but to a lesser extent also in the case of intraparenchymal infiltration (5). Due to similar molecular size, intrathecal CEA synthesis can be reliable assessed applying an IgA diagram (6).
Different types of skin cancer but also breast cancer were reported during fingolimod treatment (2). Lung cancer was less frequent and paradoxically, fingolimod is discussed to mediate lung tumor suppression by alteration of protein phosphatase 2A (7). Therefore, any causal relationship between lung cancer and fingolimod treatment in our current case is rather uncertain. The estimated incidence rate for invasive cancer development during Fingolimod treatment has been reported with 44.0 per 10,000 person-years, discussed to present an slightly increased risk compared to the general population with an incidence rate of 31.0 (8). Therefore, the usage of repeated preventive diagnostics might be not reasonable with Fingolimod treatment for patients with low risk of lung cancer development but should be considered in patients with high risk (e.g., smoker, positive family history).
Reports of concomitant occurrence of PML and primary central nervous system malignancies (e.g., primary CNS lymphoma) can be found in literature (9). Interestingly, JC-virus can also present with oncogenic potential in complete absence of a PML. Initially reported in animal models, JVC can induce tumors of glial origin. In humans, JCV seems to be especially associated with medulloblastomas among other primary brain tumors, e.g., glioblastoma multiforme and primary CNS lymphomas, as reviewed by Ahye et al. (10).
Conclusion
This case highlights that fingolimod represents a highly effective disease-modifying drug in prevention of MS relapses and accumulating disability, but that the concomitant occurrence of rare, but possibly severe adverse events such as neoplasia or opportunistic infections must be monitored. Furthermore, our case exemplifies that PML during fingolimod treatment can present with very mild, even isolated paraclinical disease course, and may accordingly be more frequent than reported.
Data Availability Statement
The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.
Ethics Statement
Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.
Author Contributions
FM, MW, PG, JF, CS, and MB: data acquisition, analysis, and revising the manuscript. PG, JF, and FM: figure design. FM and MW: drafting the manuscript. All authors read and approved the final manuscript.
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Funding. We acknowledge support by the Open Access Publication Funds of the Göttingen University. | FINGOLIMOD | DrugsGivenReaction | CC BY | 33613428 | 20,226,478 | 2021 |
What was the dosage of drug 'FINGOLIMOD'? | Case Report: Findings Suggestive of Paraclinical Progressive Multifocal Leukoencephalopathy and Lung Cancer-Derived Brain Metastases in an MS Patient Treated With Fingolimod.
Fingolimod represents a highly effective disease-modifying drug in patients with active relapsing-remitting multiple sclerosis (RRMS). Its immunosuppressive effects can mediate adverse events like increased risk of cancer development or appearance of opportunistic infections. Progressive multifocal leukoencephalopathy (PML)-representing a severe opportunistic infection-has been only infrequently described during Fingolimod treatment. Here, we present a case of a 63-year-old women with pre-diagnosed RRMS who presented with new multiple cerebral lesions in a routine MRI scan, also including a tumefactive lesion in the left parietal lobe, eventually leading to the diagnosis of brain metastases derived by an adenocarcinoma of the lung. Additionally, a JCV-DNA-PCR in the cerebrospinal fluid revealed positive results, corresponding to a paraclinical progressive multifocal leukoencephalopathy. In conclusion, adverse events potentially associated with immunosuppression can occur during Fingolimod treatment. In this context, the occurrence of cancer and opportunistic infections should be carefully monitored. Here, we report a case in which JCV-DNA-PCR in the cerebrospinal fluid suggests asymptomatic PML and simultaneously lung cancer brain metastases developed. While it is rather unlikely that either event occurred as an adverse event of fingolimod treatment, a contributing effect cannot be formally excluded.
Introduction
Fingolimod (FTY720)—a sphingosine-1-phosphate-receptor modulator–is now commonly used in highly active relapsing-remitting multiple sclerosis (RRMS), due to its proven ability to prevent potential relapses (1). Despite the clear evidence for disease modifying effects, adverse events caused by the immunosuppressive effect potentially resulting in an increased risk of oncogenesis and appearance of opportunistic infections must be considered (2).
Case Presentation
A 63-year-old caucasian women with a prior diagnosis of MS (RRMS; initial diagnosis ~12 years ago) was admitted to our department because of a suspicious MRI scan, regularly arranged by her neurologist. This scan was now showing multiple new gray and white matter lesions. She had no new subjective complaints, still showing a relatively mild course of her disease (EDSS 1.5) with a slight cerebellar ataxia and slight sensory symptoms. At the age of 56 she was switched to fingolimod and had therapeutic attempts with different types of interferons and glatiramer acetate beforehand. Of note, the patient had never been treated with natalizumab.
Directly after admission, we performed a new MRI scan applying a gadolinium-based contrast agent now showing disseminated supra- and infratentorial T2/FLAIR hyperintensities, predominantly in the gray matter, also including a prominent tumefactive lesion in the left parietal lobe (Figures 1B,C). The MRI presentation itself did not allow to assign these new lesions to PML, MS activity or the development of metastases. MRI spectroscopy showed decreased N-acetylaspartate (NAA) indicating a neurodestructive, non-primarily-CNS-derived and thus malign process (Figure 1A).
Figure 1 (A–C) MRI scan revealing multiple T2/FLAIR hyperintensities; (D–G) Histopathological analysis of the brain biopsy. (A) MRI spectroscopy showing a decreased N-acetylaspartate (NAA) peak. (B) New prominent tumefactive lesion in the left parietal lobe (C) New disseminated supra- and infratentorial hyperintensities (D) Cytokeratin AE1/3+ positivity; 200x (E) Hematoxylin-eosin staining; 200x (F) TTF1+ positivity; 200x (G) Ki67 staining; 200x.
A peripheral immune cell quantification revealed a reduced white blood cell count (3,500/μl) with lymphopenia (318/μl) and a reduction in CD3+/CD4+ (22/μl) and CD19+ cells (7/μl), as well as normal numbers of CD56+ cells (146/μl).
Analyses of the cerebrospinal fluid (CSF) initially revealed typical RRMS-associated findings including a normal cell count, increased albumin levels and the detection of CSF-specific oligoclonal bands. An additional JCV-(John Cunningham virus)-DNA-PCR yielded the detection of 39 copies per mL, consistent with the laboratory finding of a paraclinical progressive multifocal leukoencephalopathy (PML).
Furthermore, we quantified carcinoembryonic antigen (CEA) in the CSF, revealing markedly increased levels, therefore pointing to probable carcinoma-derived metastases. A subsequent thoracic CT scan showed a suspicious pulmonal lesion (diameter of 2.9 cm) in the right apical lobe without radiological proof of lymphadenopathy. The patient was non-smoker and the family history was negative concerning the occurrence of lung cancer. No other risk factors have been reported by the patient.
To determine its origin, a stereotactic biopsy of the tumefactive lesion in the left parietal lobe was performed, revealing TTF1+, CK7+, AE1/3+ tissue, consistent with a metastasis derived from a bronchial adenocarcinoma. Additional immunohistochemistry analyses revealed negative results for SV40 and P53, therefore excluding an overlap with PML-associated changes in the region of the biopsy (Figures 1D–G).
Consequently, fingolimod treatment was immediately discontinued after positive JCV-DNA-PCR. Finally, the patient was admitted to the department of oncology for further diagnostic and interdisciplinary therapy initiation.
Discussion
Here, we report a case which highlights multiple challenges which can occur in active treatment of RRMS.
Occurrence of new cerebral lesions during fingolimod treatment must lead to the differential diagnosis of (1) an insufficient treatment effect associated with new disease activity or (2) a possible intracerebral adverse event.
With an estimated risk is of 0.069 per 1,000 patients, PML caused by JCV is quite rare during fingolimod treatment (3) and the MRI lesions in our case did not present with typical associated characteristics such as the prominent involvement of subcortical U-fibers (4). Nevertheless, low copy numbers of JCV-DNA could be detected in the CSF, potentially reflecting a subclinical stage of a developing PML. Such stages are rarely seen, because patients usually do not receive lumbar puncture in absence of new clinical signs and await to be better understood in the future. Limiting, an additional JCV-PCR on the biopsy material was not performed in this case. Verification of JCV-DNA in the brain biopsy would have reinforced the hypothesis of a potential subclinical PML, reflected by a low copy number of JCV-DNA in the CSF.
Because of the tumefactive characteristics of the lesion, CEA was quantified in the CSF. Increased levels can be detected especially in the presence of leptomeningeal infiltration by carcinoma but to a lesser extent also in the case of intraparenchymal infiltration (5). Due to similar molecular size, intrathecal CEA synthesis can be reliable assessed applying an IgA diagram (6).
Different types of skin cancer but also breast cancer were reported during fingolimod treatment (2). Lung cancer was less frequent and paradoxically, fingolimod is discussed to mediate lung tumor suppression by alteration of protein phosphatase 2A (7). Therefore, any causal relationship between lung cancer and fingolimod treatment in our current case is rather uncertain. The estimated incidence rate for invasive cancer development during Fingolimod treatment has been reported with 44.0 per 10,000 person-years, discussed to present an slightly increased risk compared to the general population with an incidence rate of 31.0 (8). Therefore, the usage of repeated preventive diagnostics might be not reasonable with Fingolimod treatment for patients with low risk of lung cancer development but should be considered in patients with high risk (e.g., smoker, positive family history).
Reports of concomitant occurrence of PML and primary central nervous system malignancies (e.g., primary CNS lymphoma) can be found in literature (9). Interestingly, JC-virus can also present with oncogenic potential in complete absence of a PML. Initially reported in animal models, JVC can induce tumors of glial origin. In humans, JCV seems to be especially associated with medulloblastomas among other primary brain tumors, e.g., glioblastoma multiforme and primary CNS lymphomas, as reviewed by Ahye et al. (10).
Conclusion
This case highlights that fingolimod represents a highly effective disease-modifying drug in prevention of MS relapses and accumulating disability, but that the concomitant occurrence of rare, but possibly severe adverse events such as neoplasia or opportunistic infections must be monitored. Furthermore, our case exemplifies that PML during fingolimod treatment can present with very mild, even isolated paraclinical disease course, and may accordingly be more frequent than reported.
Data Availability Statement
The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.
Ethics Statement
Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.
Author Contributions
FM, MW, PG, JF, CS, and MB: data acquisition, analysis, and revising the manuscript. PG, JF, and FM: figure design. FM and MW: drafting the manuscript. All authors read and approved the final manuscript.
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Funding. We acknowledge support by the Open Access Publication Funds of the Göttingen University. | STARTED AT THE AGE OF 56 YEAR | DrugDosageText | CC BY | 33613428 | 20,226,478 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Nephritis'. | Case Report: Adequate T and B Cell Responses in a SARS-CoV-2 Infected Patient After Immune Checkpoint Inhibition.
After the COVID-19 outbreak, non-evidence based guidelines were published to advise clinicians on the adjustment of oncological treatment during this pandemic. As immune checkpoint inhibitors directly affect the immune system, concerns have arisen about the safety of immunotherapy during this pandemic. However, data on the immune response in oncology patients treated with immunotherapy are still lacking. Here, we present the adaptive immune response in a SARS-CoV-2 infected patient who was treated with immune checkpoint inhibitors for advanced renal cell cancer. To evaluate the immune response in this patient, the number of T cells and their major subsets were measured according to expression of markers for co-signalling, maturation, and chemotaxis at baseline, during therapy, and during the SARS-CoV-2 infection. In addition, plasma samples were analyzed for IgM and IgG antibodies and the ability of these antibodies to neutralise SARS-CoV-2. Despite several risk factors for an impaired immune response to SARS-CoV-2, both T- and B-cell responses were observed. Moreover, after treatment with immune checkpoint inhibitors, a sufficient cellular and humoral immune response was achieved in this SARS-CoV-2 infected patient. These findings warrant renewed discussion on withholding of immune checkpoint inhibitors during an ongoing COVID-19 pandemic.
Introduction
The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is having significant impact on oncological care. Besides capacity issues, concerns have arisen about the safety of oncological treatment and an increased risk for a more severe outcome of COVID-19 in patients with cancer (1–7). Patients with an (active) malignancy may have an increased risk of severe COVID-19, and it is still not known whether treatment with anti-cancer drugs—including immune checkpoint inhibitors (ICIs)—is safe during this pandemic (1–5).
After the first COVID-19 outbreak, non-evidence based guidelines were published to advise clinicians on the adjustment of oncological treatment during this pandemic. As ICIs directly affect the immune cells, and symptoms of COVID-19 resemble adverse events of ICIs (8), these guidelines were rather conservative regarding the use of ICIs during this pandemic. However, data on the immune response in patients infected with SARS-CoV-2 and treated with ICIs are still lacking (9). Here, we present for the first time data of the T and B cell responses in a SARS-CoV-2 infected patient who was treated with nivolumab and ipilimumab for advanced renal cell cancer (RCC).
Case Description
In 2019, a 62-year-old male, with diabetes mellitus type II and hypertension, was diagnosed with primary metastatic RCC with lung and bone metastases. The disease was complicated by paraneoplastic pulmonary embolism for which therapeutic doses of low molecular weight heparin were started. Based on an interval of <1 year between diagnosis and systemic therapy, the patient had an “intermediate risk” according to the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) criteria. Therefore, first-line treatment with 3-weekly ipilimumab (1 mg/kg) plus nivolumab (3 mg/kg) was started while the primary tumor was in situ (
10). After four cycles of ipilimumab plus nivolumab, the first response evaluation showed progressive disease according to the Response Evaluation Criteria in Solid Tumours (RECIST) v1.1. However, as the patient experienced clinical benefit and some target lesions showed a reduction in tumor size with computed tomography (CT), maintenance treatment with nivolumab was started. After three cycles of 2-weekly maintenance treatment with nivolumab, creatinine levels increased from 126 µmol/L (i.e., baseline prior to ICI) to 265 µmol/L (>2x ULN) and the estimated glomerular filtration rate (eGFR) decreased from 53 ml/min (i.e., baseline prior to ICI) to 21 ml/min, which was accompanied by erythrocyturia and proteinuria. After the exclusion of other possible causes such as dehydration and contrast nephropathy, an immune related nephritis was considered most likely, although a biopsy to confirm this diagnosis could not be performed. According to the Common Terminology Criteria for Adverse Events Version 5 (CTCAE v5), the patient experienced a treatment-related nephritis grade 2 and treatment with steroids (prednisolone 1mg/kg) was started, whereas maintenance treatment with nivolumab was discontinued. In March 2020, the patient developed symptomatic COVID-19 with coughing and dyspnoea, infection with SARS-CoV-2 was confirmed by real-time polymerase chain reaction (RT-PCR). At the time of hospital admission (2 days after the onset of symptoms), the patient had been treated with prednisolone (1mg/kg daily) for four weeks and the last dose of nivolumab had been administered six weeks earlier. At that time, the creatinine level was decreased to 163 µmol/L with an eGFR of 38 ml/min. To prevent a potentially severe course of COVID-19, prednisolone was rapidly reduced to 60 mg daily within 3 days. As this dose reduction of prednisolone was accompanied by a grade 4 renal failure (creatinine level 500 µmol/L (>6.0 x ULN), eGFR 10 ml/min) according to CTCAE v5, high dose steroids (prednisolone 2 mg/kg daily, intravenously) was restarted. At hospital admission, empiric antibiotic treatment with cefuroxime and azithromycin was administered and minimal oxygen therapy was given for a few days. After 12 days of admission, the patient could be discharged. However, the patient was re-admitted within 7 days due to clinical deterioration. CT and magnetic resonance imaging (MRI) revealed extra- and intracranial progressive disease of RCC. MRI showed a newly diagnosed brain metastasis with bleeding. The patient experienced severe neurological deterioration and eventually died within 1 month after the first hospital admission for COVID-19. An autopsy was not performed.
Immune Response
To study the adaptive immune response in this patient, peripheral blood samples were collected in the context of the MULTOMAB study (Netherlands Trial Registry number NL6828). In this observational study, blood samples are prospectively collected from patients with cancer treated with monoclonal antibodies. The MULTOMAB study has been approved by the medical ethics committee at Erasmus Medical Centre and the patient had signed informed consent. Blood samples were collected at baseline (prior to the first administration of ipilimumab plus nivolumab), 3 weeks after the first administration of ipilimumab plus nivolumab (T1), and during hospital admission for COVID-19 (23 weeks after the first administration of ipilimumab plus nivolumab;T2).
After collection of these blood samples, peripheral blood mononuclear cells (PBMCs) and plasma were isolated for further analyses. Frequencies of T cells and their subsets prior to and during treatment with ICIs were determined by multiplex flow cytometry. The number of T cells and their major subsets were measured according to the expression of markers for co-signalling, maturation, and chemotaxis as previously described in detail (11). In addition, plasma samples were analyzed for IgM and total IgG antibodies directed against the receptor binding domain (RBD) of SARS-CoV-2 using an ELISA (Wantai) (12), and these antibodies were analyzed for their ability to neutralise SARS-CoV-2 by a plaque reduction test (PRNT50) (13). Upon diagnosis of COVID-19, the adaptive immune parameters changed drastically. First, the counts of total leukocytes showed a strong decrease from 6,9x103/µl at T1 to 3.9 x103/µl at T2, which was predominantly caused by a decrease in lymphocyte counts (
Supplementary Table 1
) (
14, 15). Second, for both CD4+ and CD8+ T cells the fractions of central (CD45RA-, CCR7+) and effector (CD45RA-, CCR7-) memory T cells decreased, whereas those of naïve T cells (CD45RA+, CCR7+) increased when comparing T2 versus T1 and baseline (
Figure 1
). As the total numbers of CD4+ and CD8+ T cells did not differ over time, the observed increase in naïve T cells may have been the result of apoptosis-mediated loss of more differentiated T cells. Third, the fractions of CD4+ and CD8+ T cells expressing multiple (≥2) types of co-inhibitory, co-stimulatory, and/or chemoattractant receptors increased when comparing T2 versus T1 (
Figures 2A–C
). The last two observations indicate that SARS-CoV-2 may have induced expression of multiple T cell receptors, which is often considered a measure of T cell differentiation. It is noteworthy that CD8+ T cells mainly expressed co-inhibitory and co-stimulatory receptors, whereas CD4+ T cells mainly expressed co-inhibitory receptors. In particular, fractions of CD4+ T cells expressing both programmed cell death protein 1 (PD-1) and B- and T-lymphocyte attenuator (BTLA) were high during infection with SARS-CoV-2 (
Figure 2D
). Fourth, the patient started to develop SARS-CoV-2 specific IgM and IgG antibodies at 10 days post onset of symptoms and neutralising antibodies were detectable at 15 days post onset of symptoms (
Supplementary Table 2
). Altogether, the above-mentioned T and B cell responses in this patient were assessed sufficient to clear the virus from the respiratory tract, as demonstrated by a negative virus culture at 15 days post onset of symptoms. The prolonged shedding of viral RNA is a phenomenon which is often observed, but does not necessarily indicate presence of infectious virus (16).
Figure 1 Percentages of different maturation stages of CD4+ and CD8+ T cells. Fractions of CD4+ T cells (A) and CD8+ T cells (B) in four differentiation stages at 3 time points: prior to ICIs (baseline), at 3 weeks after first administration of ipilimumab plus nivolumab (T1), and during SARS-CoV-2 infection (23 weeks after first administration of ipilimumab plus nivolumab; T2). The figure shows percentages of the following stages either within CD4+ and CD8+ T cells: naïve T cells (Tnaïve: CD45RA+, CCR7+), central memory T cells (Tcm: CD45RA-, CCR7+), effector memory T cells (Tem: CD45RA-, CCR7-), and effector memory T cells expressing CD45RA (Temra: CD45A+, CCR7-).
Figure 2 Percentages of CD4+ and CD8+ T cells expressing various classes of immune receptors. Fractions of CD4+ (left panels) and CD8+ (right panels) T cells expressing <2 versus ≥ 2 different co-inhibitory receptors. (A), co-stimulatory receptors (B), and chemoattractant receptors (C) at 3 different time points: prior to ICIs (baseline), at 3 weeks after first administration of ipilimumab plus nivolumab (T1), and during SARS-CoV-2 infection (23 weeks after first administration of ipilimumab plus nivolumab; T2). An example of the expression of co-inhibitory receptors is shown in (D), where the fraction of CD4+ T cells co-expressing BTLA (CD272) and PD-1 (CD279) at baseline, T1, and T2 is shown.
Discussion
In this patient, who was infected with SARS-CoV-2 and treated with ICIs for metastatic RCC, an adequate cellular and humoral immune response was measured, despite the presence of risk factors for an impaired immune response and a severe course of SARS-CoV-2. For instance, an increased risk for a severe course of COVID-19 has been reported in patients who were treated with high-dose steroids prior to hospital admission (7). In addition, patients with cancer have an increased risk for a severe outcome of COVID-19, and this further increases in patients with progressive disease (6). Furthermore, this patient presented with lymphopenia, which is considered a predictive marker for severe COVID-19 (14, 15). In particular, the patient had an increased neutrophil-to-lymphocyte ratio (NLR)(6.5) and an increased lymphocyte-to-monocyte ratio (LMR) (5.3) which are also considered markers of poor survival in patients with COVID-19 (15). Finally, oncological guidelines stress the enhanced risk of treatment with ICIs during this pandemic (9, 17).
Besides the fact that this patient had several risk factors for an impaired immune response and severe course of COVID-19, adequate responses for both T and B cells were observed. T cell activation and consequently differentiation (
Figure 1
) may have led to loss of T cells, and an indirect increase in the fraction of naïve CD4+ and CD8+ T cells. The increased frequencies of T cells expressing immune receptors is another sign of T cell activation and differentiation (
Figure 2
). In particular, the enhanced frequency of CD4+ T cells expressing the co-inhibitory receptors BTLA and PD-1 (
Figure 2D
), is considered the result of an adaptive feedback loop to counter regulate the initial activation of T cells (18, 19). In addition to T cells, also B cell activation was observed by the production of neutralizing antibodies. As the viral culture was already negative despite low titers of antibodies measured with ELISA and PRNT50, the T cell response has most likely contributed to the clearance of the virus. Overall, both the presence of cellular as well as humoral immune parameters was comparable to those observed in SARS-CoV-2 infected patients without cancer (18–20).
As shown, the patients’ immune system was sufficiently active against SARS-CoV-2, but failed to act upon the renal cell cancer effectively. The latter deficit may be due to the existence of immune suppressive actions in the renal cell cancer micro-environment, preventing effective infiltration and/or activation of anti-tumor T cells (21). Already before COVID-19, the patient had progressive disease according to RECIST v.1.1, indicating that the renal cell cancer did not respond to immunotherapy. These results underscore different obstacles to achieve anti-tumor versus anti-virus immunity, and importantly demonstrate that, at least in this case, treatment with ICI does not alter the anti-virus T and B cell immunity.
Several studies have investigated the immune response to SARS-CoV-2 (18–20), and have yielded limited and conflicting data regarding COVID-19 in patients treated with ICIs (4, 9, 22). To the best of our knowledge, this is the first report on adaptive immunity in a SARS-CoV-2 infected patient treated with ICIs. Limitations of this report include the description of only one patient who had already discontinued treatment with ICIs. Although the patient discontinued treatment with ICIs at 6 weeks prior to the onset of COVID-19, it is conceivable that this treatment still affected the immune response. The ongoing effects of ICIs are well-known and are usually illustrated by their durable tumor response and late onset of adverse events, even months to years after discontinuation of treatment. In addition, specific measurements, such as NLR and LMR, were only performed during COVID-19 and could not be compared to previous values at baseline and during treatment with ICIs. The role of innate immune cells in this patient could not be elucidated in this particular case, and deserves further attention.
In conclusion, the adequate B and T cell responses in this SARS-CoV-2 infected patient who was treated with ICIs, justify renewed discussion on withholding of ICIs during the ongoing COVID-19 pandemic and may guide inclusion of patients treated with ICIs for COVID-19 vaccination (23).
Data Availability Statement
The original contributions presented in the study are included in the article/
Supplementary Material
. Further inquiries can be directed to the corresponding author.
Ethics Statement
The studies involving human participants were reviewed and approved by the MULTOMAB study (Netherlands Trial Registry number NL6828). Approved by medical ethics committee of Erasmus Medical Centre. The patients/participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.
Author Contributions
KJ, AO, CG, RV and AV contributed to acquisition and analysis of the data. KJ and AV drafted the manuscript. RM and RD contributed to technical and material support. CG, RV, RM and RD contributed to critical revision of the manuscript for important intellectual content. All authors contributed to the article and approved the submitted version.
Conflict of Interest
AV reports advisory board of BMS, MSD, Merck, Pfizer, Ipsen, Eisai, Pierre Fabre, Roche, Novartis, Sanofi, outside the submitted work. RM reports unrestricted grants for investigator-initiated research from Astellas, Bayer, Boehringer-Ingelheim, Cristal Therapeutics, Novartis, Pamgene, Pfizer, Roche, Sanofi, and Servier outside the submitted work. RD has received grants from Merck and Pan-Cancer T BV outside the submitted work.
The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Supplementary Material
The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fimmu.2021.627186/full#supplementary-material
Click here for additional data file.
Click here for additional data file. | IPILIMUMAB, NIVOLUMAB, PREDNISOLONE | DrugsGivenReaction | CC BY | 33613575 | 19,133,955 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Rebound effect'. | Case Report: Adequate T and B Cell Responses in a SARS-CoV-2 Infected Patient After Immune Checkpoint Inhibition.
After the COVID-19 outbreak, non-evidence based guidelines were published to advise clinicians on the adjustment of oncological treatment during this pandemic. As immune checkpoint inhibitors directly affect the immune system, concerns have arisen about the safety of immunotherapy during this pandemic. However, data on the immune response in oncology patients treated with immunotherapy are still lacking. Here, we present the adaptive immune response in a SARS-CoV-2 infected patient who was treated with immune checkpoint inhibitors for advanced renal cell cancer. To evaluate the immune response in this patient, the number of T cells and their major subsets were measured according to expression of markers for co-signalling, maturation, and chemotaxis at baseline, during therapy, and during the SARS-CoV-2 infection. In addition, plasma samples were analyzed for IgM and IgG antibodies and the ability of these antibodies to neutralise SARS-CoV-2. Despite several risk factors for an impaired immune response to SARS-CoV-2, both T- and B-cell responses were observed. Moreover, after treatment with immune checkpoint inhibitors, a sufficient cellular and humoral immune response was achieved in this SARS-CoV-2 infected patient. These findings warrant renewed discussion on withholding of immune checkpoint inhibitors during an ongoing COVID-19 pandemic.
Introduction
The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is having significant impact on oncological care. Besides capacity issues, concerns have arisen about the safety of oncological treatment and an increased risk for a more severe outcome of COVID-19 in patients with cancer (1–7). Patients with an (active) malignancy may have an increased risk of severe COVID-19, and it is still not known whether treatment with anti-cancer drugs—including immune checkpoint inhibitors (ICIs)—is safe during this pandemic (1–5).
After the first COVID-19 outbreak, non-evidence based guidelines were published to advise clinicians on the adjustment of oncological treatment during this pandemic. As ICIs directly affect the immune cells, and symptoms of COVID-19 resemble adverse events of ICIs (8), these guidelines were rather conservative regarding the use of ICIs during this pandemic. However, data on the immune response in patients infected with SARS-CoV-2 and treated with ICIs are still lacking (9). Here, we present for the first time data of the T and B cell responses in a SARS-CoV-2 infected patient who was treated with nivolumab and ipilimumab for advanced renal cell cancer (RCC).
Case Description
In 2019, a 62-year-old male, with diabetes mellitus type II and hypertension, was diagnosed with primary metastatic RCC with lung and bone metastases. The disease was complicated by paraneoplastic pulmonary embolism for which therapeutic doses of low molecular weight heparin were started. Based on an interval of <1 year between diagnosis and systemic therapy, the patient had an “intermediate risk” according to the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) criteria. Therefore, first-line treatment with 3-weekly ipilimumab (1 mg/kg) plus nivolumab (3 mg/kg) was started while the primary tumor was in situ (
10). After four cycles of ipilimumab plus nivolumab, the first response evaluation showed progressive disease according to the Response Evaluation Criteria in Solid Tumours (RECIST) v1.1. However, as the patient experienced clinical benefit and some target lesions showed a reduction in tumor size with computed tomography (CT), maintenance treatment with nivolumab was started. After three cycles of 2-weekly maintenance treatment with nivolumab, creatinine levels increased from 126 µmol/L (i.e., baseline prior to ICI) to 265 µmol/L (>2x ULN) and the estimated glomerular filtration rate (eGFR) decreased from 53 ml/min (i.e., baseline prior to ICI) to 21 ml/min, which was accompanied by erythrocyturia and proteinuria. After the exclusion of other possible causes such as dehydration and contrast nephropathy, an immune related nephritis was considered most likely, although a biopsy to confirm this diagnosis could not be performed. According to the Common Terminology Criteria for Adverse Events Version 5 (CTCAE v5), the patient experienced a treatment-related nephritis grade 2 and treatment with steroids (prednisolone 1mg/kg) was started, whereas maintenance treatment with nivolumab was discontinued. In March 2020, the patient developed symptomatic COVID-19 with coughing and dyspnoea, infection with SARS-CoV-2 was confirmed by real-time polymerase chain reaction (RT-PCR). At the time of hospital admission (2 days after the onset of symptoms), the patient had been treated with prednisolone (1mg/kg daily) for four weeks and the last dose of nivolumab had been administered six weeks earlier. At that time, the creatinine level was decreased to 163 µmol/L with an eGFR of 38 ml/min. To prevent a potentially severe course of COVID-19, prednisolone was rapidly reduced to 60 mg daily within 3 days. As this dose reduction of prednisolone was accompanied by a grade 4 renal failure (creatinine level 500 µmol/L (>6.0 x ULN), eGFR 10 ml/min) according to CTCAE v5, high dose steroids (prednisolone 2 mg/kg daily, intravenously) was restarted. At hospital admission, empiric antibiotic treatment with cefuroxime and azithromycin was administered and minimal oxygen therapy was given for a few days. After 12 days of admission, the patient could be discharged. However, the patient was re-admitted within 7 days due to clinical deterioration. CT and magnetic resonance imaging (MRI) revealed extra- and intracranial progressive disease of RCC. MRI showed a newly diagnosed brain metastasis with bleeding. The patient experienced severe neurological deterioration and eventually died within 1 month after the first hospital admission for COVID-19. An autopsy was not performed.
Immune Response
To study the adaptive immune response in this patient, peripheral blood samples were collected in the context of the MULTOMAB study (Netherlands Trial Registry number NL6828). In this observational study, blood samples are prospectively collected from patients with cancer treated with monoclonal antibodies. The MULTOMAB study has been approved by the medical ethics committee at Erasmus Medical Centre and the patient had signed informed consent. Blood samples were collected at baseline (prior to the first administration of ipilimumab plus nivolumab), 3 weeks after the first administration of ipilimumab plus nivolumab (T1), and during hospital admission for COVID-19 (23 weeks after the first administration of ipilimumab plus nivolumab;T2).
After collection of these blood samples, peripheral blood mononuclear cells (PBMCs) and plasma were isolated for further analyses. Frequencies of T cells and their subsets prior to and during treatment with ICIs were determined by multiplex flow cytometry. The number of T cells and their major subsets were measured according to the expression of markers for co-signalling, maturation, and chemotaxis as previously described in detail (11). In addition, plasma samples were analyzed for IgM and total IgG antibodies directed against the receptor binding domain (RBD) of SARS-CoV-2 using an ELISA (Wantai) (12), and these antibodies were analyzed for their ability to neutralise SARS-CoV-2 by a plaque reduction test (PRNT50) (13). Upon diagnosis of COVID-19, the adaptive immune parameters changed drastically. First, the counts of total leukocytes showed a strong decrease from 6,9x103/µl at T1 to 3.9 x103/µl at T2, which was predominantly caused by a decrease in lymphocyte counts (
Supplementary Table 1
) (
14, 15). Second, for both CD4+ and CD8+ T cells the fractions of central (CD45RA-, CCR7+) and effector (CD45RA-, CCR7-) memory T cells decreased, whereas those of naïve T cells (CD45RA+, CCR7+) increased when comparing T2 versus T1 and baseline (
Figure 1
). As the total numbers of CD4+ and CD8+ T cells did not differ over time, the observed increase in naïve T cells may have been the result of apoptosis-mediated loss of more differentiated T cells. Third, the fractions of CD4+ and CD8+ T cells expressing multiple (≥2) types of co-inhibitory, co-stimulatory, and/or chemoattractant receptors increased when comparing T2 versus T1 (
Figures 2A–C
). The last two observations indicate that SARS-CoV-2 may have induced expression of multiple T cell receptors, which is often considered a measure of T cell differentiation. It is noteworthy that CD8+ T cells mainly expressed co-inhibitory and co-stimulatory receptors, whereas CD4+ T cells mainly expressed co-inhibitory receptors. In particular, fractions of CD4+ T cells expressing both programmed cell death protein 1 (PD-1) and B- and T-lymphocyte attenuator (BTLA) were high during infection with SARS-CoV-2 (
Figure 2D
). Fourth, the patient started to develop SARS-CoV-2 specific IgM and IgG antibodies at 10 days post onset of symptoms and neutralising antibodies were detectable at 15 days post onset of symptoms (
Supplementary Table 2
). Altogether, the above-mentioned T and B cell responses in this patient were assessed sufficient to clear the virus from the respiratory tract, as demonstrated by a negative virus culture at 15 days post onset of symptoms. The prolonged shedding of viral RNA is a phenomenon which is often observed, but does not necessarily indicate presence of infectious virus (16).
Figure 1 Percentages of different maturation stages of CD4+ and CD8+ T cells. Fractions of CD4+ T cells (A) and CD8+ T cells (B) in four differentiation stages at 3 time points: prior to ICIs (baseline), at 3 weeks after first administration of ipilimumab plus nivolumab (T1), and during SARS-CoV-2 infection (23 weeks after first administration of ipilimumab plus nivolumab; T2). The figure shows percentages of the following stages either within CD4+ and CD8+ T cells: naïve T cells (Tnaïve: CD45RA+, CCR7+), central memory T cells (Tcm: CD45RA-, CCR7+), effector memory T cells (Tem: CD45RA-, CCR7-), and effector memory T cells expressing CD45RA (Temra: CD45A+, CCR7-).
Figure 2 Percentages of CD4+ and CD8+ T cells expressing various classes of immune receptors. Fractions of CD4+ (left panels) and CD8+ (right panels) T cells expressing <2 versus ≥ 2 different co-inhibitory receptors. (A), co-stimulatory receptors (B), and chemoattractant receptors (C) at 3 different time points: prior to ICIs (baseline), at 3 weeks after first administration of ipilimumab plus nivolumab (T1), and during SARS-CoV-2 infection (23 weeks after first administration of ipilimumab plus nivolumab; T2). An example of the expression of co-inhibitory receptors is shown in (D), where the fraction of CD4+ T cells co-expressing BTLA (CD272) and PD-1 (CD279) at baseline, T1, and T2 is shown.
Discussion
In this patient, who was infected with SARS-CoV-2 and treated with ICIs for metastatic RCC, an adequate cellular and humoral immune response was measured, despite the presence of risk factors for an impaired immune response and a severe course of SARS-CoV-2. For instance, an increased risk for a severe course of COVID-19 has been reported in patients who were treated with high-dose steroids prior to hospital admission (7). In addition, patients with cancer have an increased risk for a severe outcome of COVID-19, and this further increases in patients with progressive disease (6). Furthermore, this patient presented with lymphopenia, which is considered a predictive marker for severe COVID-19 (14, 15). In particular, the patient had an increased neutrophil-to-lymphocyte ratio (NLR)(6.5) and an increased lymphocyte-to-monocyte ratio (LMR) (5.3) which are also considered markers of poor survival in patients with COVID-19 (15). Finally, oncological guidelines stress the enhanced risk of treatment with ICIs during this pandemic (9, 17).
Besides the fact that this patient had several risk factors for an impaired immune response and severe course of COVID-19, adequate responses for both T and B cells were observed. T cell activation and consequently differentiation (
Figure 1
) may have led to loss of T cells, and an indirect increase in the fraction of naïve CD4+ and CD8+ T cells. The increased frequencies of T cells expressing immune receptors is another sign of T cell activation and differentiation (
Figure 2
). In particular, the enhanced frequency of CD4+ T cells expressing the co-inhibitory receptors BTLA and PD-1 (
Figure 2D
), is considered the result of an adaptive feedback loop to counter regulate the initial activation of T cells (18, 19). In addition to T cells, also B cell activation was observed by the production of neutralizing antibodies. As the viral culture was already negative despite low titers of antibodies measured with ELISA and PRNT50, the T cell response has most likely contributed to the clearance of the virus. Overall, both the presence of cellular as well as humoral immune parameters was comparable to those observed in SARS-CoV-2 infected patients without cancer (18–20).
As shown, the patients’ immune system was sufficiently active against SARS-CoV-2, but failed to act upon the renal cell cancer effectively. The latter deficit may be due to the existence of immune suppressive actions in the renal cell cancer micro-environment, preventing effective infiltration and/or activation of anti-tumor T cells (21). Already before COVID-19, the patient had progressive disease according to RECIST v.1.1, indicating that the renal cell cancer did not respond to immunotherapy. These results underscore different obstacles to achieve anti-tumor versus anti-virus immunity, and importantly demonstrate that, at least in this case, treatment with ICI does not alter the anti-virus T and B cell immunity.
Several studies have investigated the immune response to SARS-CoV-2 (18–20), and have yielded limited and conflicting data regarding COVID-19 in patients treated with ICIs (4, 9, 22). To the best of our knowledge, this is the first report on adaptive immunity in a SARS-CoV-2 infected patient treated with ICIs. Limitations of this report include the description of only one patient who had already discontinued treatment with ICIs. Although the patient discontinued treatment with ICIs at 6 weeks prior to the onset of COVID-19, it is conceivable that this treatment still affected the immune response. The ongoing effects of ICIs are well-known and are usually illustrated by their durable tumor response and late onset of adverse events, even months to years after discontinuation of treatment. In addition, specific measurements, such as NLR and LMR, were only performed during COVID-19 and could not be compared to previous values at baseline and during treatment with ICIs. The role of innate immune cells in this patient could not be elucidated in this particular case, and deserves further attention.
In conclusion, the adequate B and T cell responses in this SARS-CoV-2 infected patient who was treated with ICIs, justify renewed discussion on withholding of ICIs during the ongoing COVID-19 pandemic and may guide inclusion of patients treated with ICIs for COVID-19 vaccination (23).
Data Availability Statement
The original contributions presented in the study are included in the article/
Supplementary Material
. Further inquiries can be directed to the corresponding author.
Ethics Statement
The studies involving human participants were reviewed and approved by the MULTOMAB study (Netherlands Trial Registry number NL6828). Approved by medical ethics committee of Erasmus Medical Centre. The patients/participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.
Author Contributions
KJ, AO, CG, RV and AV contributed to acquisition and analysis of the data. KJ and AV drafted the manuscript. RM and RD contributed to technical and material support. CG, RV, RM and RD contributed to critical revision of the manuscript for important intellectual content. All authors contributed to the article and approved the submitted version.
Conflict of Interest
AV reports advisory board of BMS, MSD, Merck, Pfizer, Ipsen, Eisai, Pierre Fabre, Roche, Novartis, Sanofi, outside the submitted work. RM reports unrestricted grants for investigator-initiated research from Astellas, Bayer, Boehringer-Ingelheim, Cristal Therapeutics, Novartis, Pamgene, Pfizer, Roche, Sanofi, and Servier outside the submitted work. RD has received grants from Merck and Pan-Cancer T BV outside the submitted work.
The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Supplementary Material
The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fimmu.2021.627186/full#supplementary-material
Click here for additional data file.
Click here for additional data file. | IPILIMUMAB, NIVOLUMAB, PREDNISOLONE | DrugsGivenReaction | CC BY | 33613575 | 19,133,955 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Renal failure'. | Case Report: Adequate T and B Cell Responses in a SARS-CoV-2 Infected Patient After Immune Checkpoint Inhibition.
After the COVID-19 outbreak, non-evidence based guidelines were published to advise clinicians on the adjustment of oncological treatment during this pandemic. As immune checkpoint inhibitors directly affect the immune system, concerns have arisen about the safety of immunotherapy during this pandemic. However, data on the immune response in oncology patients treated with immunotherapy are still lacking. Here, we present the adaptive immune response in a SARS-CoV-2 infected patient who was treated with immune checkpoint inhibitors for advanced renal cell cancer. To evaluate the immune response in this patient, the number of T cells and their major subsets were measured according to expression of markers for co-signalling, maturation, and chemotaxis at baseline, during therapy, and during the SARS-CoV-2 infection. In addition, plasma samples were analyzed for IgM and IgG antibodies and the ability of these antibodies to neutralise SARS-CoV-2. Despite several risk factors for an impaired immune response to SARS-CoV-2, both T- and B-cell responses were observed. Moreover, after treatment with immune checkpoint inhibitors, a sufficient cellular and humoral immune response was achieved in this SARS-CoV-2 infected patient. These findings warrant renewed discussion on withholding of immune checkpoint inhibitors during an ongoing COVID-19 pandemic.
Introduction
The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is having significant impact on oncological care. Besides capacity issues, concerns have arisen about the safety of oncological treatment and an increased risk for a more severe outcome of COVID-19 in patients with cancer (1–7). Patients with an (active) malignancy may have an increased risk of severe COVID-19, and it is still not known whether treatment with anti-cancer drugs—including immune checkpoint inhibitors (ICIs)—is safe during this pandemic (1–5).
After the first COVID-19 outbreak, non-evidence based guidelines were published to advise clinicians on the adjustment of oncological treatment during this pandemic. As ICIs directly affect the immune cells, and symptoms of COVID-19 resemble adverse events of ICIs (8), these guidelines were rather conservative regarding the use of ICIs during this pandemic. However, data on the immune response in patients infected with SARS-CoV-2 and treated with ICIs are still lacking (9). Here, we present for the first time data of the T and B cell responses in a SARS-CoV-2 infected patient who was treated with nivolumab and ipilimumab for advanced renal cell cancer (RCC).
Case Description
In 2019, a 62-year-old male, with diabetes mellitus type II and hypertension, was diagnosed with primary metastatic RCC with lung and bone metastases. The disease was complicated by paraneoplastic pulmonary embolism for which therapeutic doses of low molecular weight heparin were started. Based on an interval of <1 year between diagnosis and systemic therapy, the patient had an “intermediate risk” according to the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) criteria. Therefore, first-line treatment with 3-weekly ipilimumab (1 mg/kg) plus nivolumab (3 mg/kg) was started while the primary tumor was in situ (
10). After four cycles of ipilimumab plus nivolumab, the first response evaluation showed progressive disease according to the Response Evaluation Criteria in Solid Tumours (RECIST) v1.1. However, as the patient experienced clinical benefit and some target lesions showed a reduction in tumor size with computed tomography (CT), maintenance treatment with nivolumab was started. After three cycles of 2-weekly maintenance treatment with nivolumab, creatinine levels increased from 126 µmol/L (i.e., baseline prior to ICI) to 265 µmol/L (>2x ULN) and the estimated glomerular filtration rate (eGFR) decreased from 53 ml/min (i.e., baseline prior to ICI) to 21 ml/min, which was accompanied by erythrocyturia and proteinuria. After the exclusion of other possible causes such as dehydration and contrast nephropathy, an immune related nephritis was considered most likely, although a biopsy to confirm this diagnosis could not be performed. According to the Common Terminology Criteria for Adverse Events Version 5 (CTCAE v5), the patient experienced a treatment-related nephritis grade 2 and treatment with steroids (prednisolone 1mg/kg) was started, whereas maintenance treatment with nivolumab was discontinued. In March 2020, the patient developed symptomatic COVID-19 with coughing and dyspnoea, infection with SARS-CoV-2 was confirmed by real-time polymerase chain reaction (RT-PCR). At the time of hospital admission (2 days after the onset of symptoms), the patient had been treated with prednisolone (1mg/kg daily) for four weeks and the last dose of nivolumab had been administered six weeks earlier. At that time, the creatinine level was decreased to 163 µmol/L with an eGFR of 38 ml/min. To prevent a potentially severe course of COVID-19, prednisolone was rapidly reduced to 60 mg daily within 3 days. As this dose reduction of prednisolone was accompanied by a grade 4 renal failure (creatinine level 500 µmol/L (>6.0 x ULN), eGFR 10 ml/min) according to CTCAE v5, high dose steroids (prednisolone 2 mg/kg daily, intravenously) was restarted. At hospital admission, empiric antibiotic treatment with cefuroxime and azithromycin was administered and minimal oxygen therapy was given for a few days. After 12 days of admission, the patient could be discharged. However, the patient was re-admitted within 7 days due to clinical deterioration. CT and magnetic resonance imaging (MRI) revealed extra- and intracranial progressive disease of RCC. MRI showed a newly diagnosed brain metastasis with bleeding. The patient experienced severe neurological deterioration and eventually died within 1 month after the first hospital admission for COVID-19. An autopsy was not performed.
Immune Response
To study the adaptive immune response in this patient, peripheral blood samples were collected in the context of the MULTOMAB study (Netherlands Trial Registry number NL6828). In this observational study, blood samples are prospectively collected from patients with cancer treated with monoclonal antibodies. The MULTOMAB study has been approved by the medical ethics committee at Erasmus Medical Centre and the patient had signed informed consent. Blood samples were collected at baseline (prior to the first administration of ipilimumab plus nivolumab), 3 weeks after the first administration of ipilimumab plus nivolumab (T1), and during hospital admission for COVID-19 (23 weeks after the first administration of ipilimumab plus nivolumab;T2).
After collection of these blood samples, peripheral blood mononuclear cells (PBMCs) and plasma were isolated for further analyses. Frequencies of T cells and their subsets prior to and during treatment with ICIs were determined by multiplex flow cytometry. The number of T cells and their major subsets were measured according to the expression of markers for co-signalling, maturation, and chemotaxis as previously described in detail (11). In addition, plasma samples were analyzed for IgM and total IgG antibodies directed against the receptor binding domain (RBD) of SARS-CoV-2 using an ELISA (Wantai) (12), and these antibodies were analyzed for their ability to neutralise SARS-CoV-2 by a plaque reduction test (PRNT50) (13). Upon diagnosis of COVID-19, the adaptive immune parameters changed drastically. First, the counts of total leukocytes showed a strong decrease from 6,9x103/µl at T1 to 3.9 x103/µl at T2, which was predominantly caused by a decrease in lymphocyte counts (
Supplementary Table 1
) (
14, 15). Second, for both CD4+ and CD8+ T cells the fractions of central (CD45RA-, CCR7+) and effector (CD45RA-, CCR7-) memory T cells decreased, whereas those of naïve T cells (CD45RA+, CCR7+) increased when comparing T2 versus T1 and baseline (
Figure 1
). As the total numbers of CD4+ and CD8+ T cells did not differ over time, the observed increase in naïve T cells may have been the result of apoptosis-mediated loss of more differentiated T cells. Third, the fractions of CD4+ and CD8+ T cells expressing multiple (≥2) types of co-inhibitory, co-stimulatory, and/or chemoattractant receptors increased when comparing T2 versus T1 (
Figures 2A–C
). The last two observations indicate that SARS-CoV-2 may have induced expression of multiple T cell receptors, which is often considered a measure of T cell differentiation. It is noteworthy that CD8+ T cells mainly expressed co-inhibitory and co-stimulatory receptors, whereas CD4+ T cells mainly expressed co-inhibitory receptors. In particular, fractions of CD4+ T cells expressing both programmed cell death protein 1 (PD-1) and B- and T-lymphocyte attenuator (BTLA) were high during infection with SARS-CoV-2 (
Figure 2D
). Fourth, the patient started to develop SARS-CoV-2 specific IgM and IgG antibodies at 10 days post onset of symptoms and neutralising antibodies were detectable at 15 days post onset of symptoms (
Supplementary Table 2
). Altogether, the above-mentioned T and B cell responses in this patient were assessed sufficient to clear the virus from the respiratory tract, as demonstrated by a negative virus culture at 15 days post onset of symptoms. The prolonged shedding of viral RNA is a phenomenon which is often observed, but does not necessarily indicate presence of infectious virus (16).
Figure 1 Percentages of different maturation stages of CD4+ and CD8+ T cells. Fractions of CD4+ T cells (A) and CD8+ T cells (B) in four differentiation stages at 3 time points: prior to ICIs (baseline), at 3 weeks after first administration of ipilimumab plus nivolumab (T1), and during SARS-CoV-2 infection (23 weeks after first administration of ipilimumab plus nivolumab; T2). The figure shows percentages of the following stages either within CD4+ and CD8+ T cells: naïve T cells (Tnaïve: CD45RA+, CCR7+), central memory T cells (Tcm: CD45RA-, CCR7+), effector memory T cells (Tem: CD45RA-, CCR7-), and effector memory T cells expressing CD45RA (Temra: CD45A+, CCR7-).
Figure 2 Percentages of CD4+ and CD8+ T cells expressing various classes of immune receptors. Fractions of CD4+ (left panels) and CD8+ (right panels) T cells expressing <2 versus ≥ 2 different co-inhibitory receptors. (A), co-stimulatory receptors (B), and chemoattractant receptors (C) at 3 different time points: prior to ICIs (baseline), at 3 weeks after first administration of ipilimumab plus nivolumab (T1), and during SARS-CoV-2 infection (23 weeks after first administration of ipilimumab plus nivolumab; T2). An example of the expression of co-inhibitory receptors is shown in (D), where the fraction of CD4+ T cells co-expressing BTLA (CD272) and PD-1 (CD279) at baseline, T1, and T2 is shown.
Discussion
In this patient, who was infected with SARS-CoV-2 and treated with ICIs for metastatic RCC, an adequate cellular and humoral immune response was measured, despite the presence of risk factors for an impaired immune response and a severe course of SARS-CoV-2. For instance, an increased risk for a severe course of COVID-19 has been reported in patients who were treated with high-dose steroids prior to hospital admission (7). In addition, patients with cancer have an increased risk for a severe outcome of COVID-19, and this further increases in patients with progressive disease (6). Furthermore, this patient presented with lymphopenia, which is considered a predictive marker for severe COVID-19 (14, 15). In particular, the patient had an increased neutrophil-to-lymphocyte ratio (NLR)(6.5) and an increased lymphocyte-to-monocyte ratio (LMR) (5.3) which are also considered markers of poor survival in patients with COVID-19 (15). Finally, oncological guidelines stress the enhanced risk of treatment with ICIs during this pandemic (9, 17).
Besides the fact that this patient had several risk factors for an impaired immune response and severe course of COVID-19, adequate responses for both T and B cells were observed. T cell activation and consequently differentiation (
Figure 1
) may have led to loss of T cells, and an indirect increase in the fraction of naïve CD4+ and CD8+ T cells. The increased frequencies of T cells expressing immune receptors is another sign of T cell activation and differentiation (
Figure 2
). In particular, the enhanced frequency of CD4+ T cells expressing the co-inhibitory receptors BTLA and PD-1 (
Figure 2D
), is considered the result of an adaptive feedback loop to counter regulate the initial activation of T cells (18, 19). In addition to T cells, also B cell activation was observed by the production of neutralizing antibodies. As the viral culture was already negative despite low titers of antibodies measured with ELISA and PRNT50, the T cell response has most likely contributed to the clearance of the virus. Overall, both the presence of cellular as well as humoral immune parameters was comparable to those observed in SARS-CoV-2 infected patients without cancer (18–20).
As shown, the patients’ immune system was sufficiently active against SARS-CoV-2, but failed to act upon the renal cell cancer effectively. The latter deficit may be due to the existence of immune suppressive actions in the renal cell cancer micro-environment, preventing effective infiltration and/or activation of anti-tumor T cells (21). Already before COVID-19, the patient had progressive disease according to RECIST v.1.1, indicating that the renal cell cancer did not respond to immunotherapy. These results underscore different obstacles to achieve anti-tumor versus anti-virus immunity, and importantly demonstrate that, at least in this case, treatment with ICI does not alter the anti-virus T and B cell immunity.
Several studies have investigated the immune response to SARS-CoV-2 (18–20), and have yielded limited and conflicting data regarding COVID-19 in patients treated with ICIs (4, 9, 22). To the best of our knowledge, this is the first report on adaptive immunity in a SARS-CoV-2 infected patient treated with ICIs. Limitations of this report include the description of only one patient who had already discontinued treatment with ICIs. Although the patient discontinued treatment with ICIs at 6 weeks prior to the onset of COVID-19, it is conceivable that this treatment still affected the immune response. The ongoing effects of ICIs are well-known and are usually illustrated by their durable tumor response and late onset of adverse events, even months to years after discontinuation of treatment. In addition, specific measurements, such as NLR and LMR, were only performed during COVID-19 and could not be compared to previous values at baseline and during treatment with ICIs. The role of innate immune cells in this patient could not be elucidated in this particular case, and deserves further attention.
In conclusion, the adequate B and T cell responses in this SARS-CoV-2 infected patient who was treated with ICIs, justify renewed discussion on withholding of ICIs during the ongoing COVID-19 pandemic and may guide inclusion of patients treated with ICIs for COVID-19 vaccination (23).
Data Availability Statement
The original contributions presented in the study are included in the article/
Supplementary Material
. Further inquiries can be directed to the corresponding author.
Ethics Statement
The studies involving human participants were reviewed and approved by the MULTOMAB study (Netherlands Trial Registry number NL6828). Approved by medical ethics committee of Erasmus Medical Centre. The patients/participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.
Author Contributions
KJ, AO, CG, RV and AV contributed to acquisition and analysis of the data. KJ and AV drafted the manuscript. RM and RD contributed to technical and material support. CG, RV, RM and RD contributed to critical revision of the manuscript for important intellectual content. All authors contributed to the article and approved the submitted version.
Conflict of Interest
AV reports advisory board of BMS, MSD, Merck, Pfizer, Ipsen, Eisai, Pierre Fabre, Roche, Novartis, Sanofi, outside the submitted work. RM reports unrestricted grants for investigator-initiated research from Astellas, Bayer, Boehringer-Ingelheim, Cristal Therapeutics, Novartis, Pamgene, Pfizer, Roche, Sanofi, and Servier outside the submitted work. RD has received grants from Merck and Pan-Cancer T BV outside the submitted work.
The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Supplementary Material
The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fimmu.2021.627186/full#supplementary-material
Click here for additional data file.
Click here for additional data file. | IPILIMUMAB, NIVOLUMAB, PREDNISOLONE | DrugsGivenReaction | CC BY | 33613575 | 19,133,955 | 2021 |
What was the dosage of drug 'IPILIMUMAB'? | Case Report: Adequate T and B Cell Responses in a SARS-CoV-2 Infected Patient After Immune Checkpoint Inhibition.
After the COVID-19 outbreak, non-evidence based guidelines were published to advise clinicians on the adjustment of oncological treatment during this pandemic. As immune checkpoint inhibitors directly affect the immune system, concerns have arisen about the safety of immunotherapy during this pandemic. However, data on the immune response in oncology patients treated with immunotherapy are still lacking. Here, we present the adaptive immune response in a SARS-CoV-2 infected patient who was treated with immune checkpoint inhibitors for advanced renal cell cancer. To evaluate the immune response in this patient, the number of T cells and their major subsets were measured according to expression of markers for co-signalling, maturation, and chemotaxis at baseline, during therapy, and during the SARS-CoV-2 infection. In addition, plasma samples were analyzed for IgM and IgG antibodies and the ability of these antibodies to neutralise SARS-CoV-2. Despite several risk factors for an impaired immune response to SARS-CoV-2, both T- and B-cell responses were observed. Moreover, after treatment with immune checkpoint inhibitors, a sufficient cellular and humoral immune response was achieved in this SARS-CoV-2 infected patient. These findings warrant renewed discussion on withholding of immune checkpoint inhibitors during an ongoing COVID-19 pandemic.
Introduction
The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is having significant impact on oncological care. Besides capacity issues, concerns have arisen about the safety of oncological treatment and an increased risk for a more severe outcome of COVID-19 in patients with cancer (1–7). Patients with an (active) malignancy may have an increased risk of severe COVID-19, and it is still not known whether treatment with anti-cancer drugs—including immune checkpoint inhibitors (ICIs)—is safe during this pandemic (1–5).
After the first COVID-19 outbreak, non-evidence based guidelines were published to advise clinicians on the adjustment of oncological treatment during this pandemic. As ICIs directly affect the immune cells, and symptoms of COVID-19 resemble adverse events of ICIs (8), these guidelines were rather conservative regarding the use of ICIs during this pandemic. However, data on the immune response in patients infected with SARS-CoV-2 and treated with ICIs are still lacking (9). Here, we present for the first time data of the T and B cell responses in a SARS-CoV-2 infected patient who was treated with nivolumab and ipilimumab for advanced renal cell cancer (RCC).
Case Description
In 2019, a 62-year-old male, with diabetes mellitus type II and hypertension, was diagnosed with primary metastatic RCC with lung and bone metastases. The disease was complicated by paraneoplastic pulmonary embolism for which therapeutic doses of low molecular weight heparin were started. Based on an interval of <1 year between diagnosis and systemic therapy, the patient had an “intermediate risk” according to the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) criteria. Therefore, first-line treatment with 3-weekly ipilimumab (1 mg/kg) plus nivolumab (3 mg/kg) was started while the primary tumor was in situ (
10). After four cycles of ipilimumab plus nivolumab, the first response evaluation showed progressive disease according to the Response Evaluation Criteria in Solid Tumours (RECIST) v1.1. However, as the patient experienced clinical benefit and some target lesions showed a reduction in tumor size with computed tomography (CT), maintenance treatment with nivolumab was started. After three cycles of 2-weekly maintenance treatment with nivolumab, creatinine levels increased from 126 µmol/L (i.e., baseline prior to ICI) to 265 µmol/L (>2x ULN) and the estimated glomerular filtration rate (eGFR) decreased from 53 ml/min (i.e., baseline prior to ICI) to 21 ml/min, which was accompanied by erythrocyturia and proteinuria. After the exclusion of other possible causes such as dehydration and contrast nephropathy, an immune related nephritis was considered most likely, although a biopsy to confirm this diagnosis could not be performed. According to the Common Terminology Criteria for Adverse Events Version 5 (CTCAE v5), the patient experienced a treatment-related nephritis grade 2 and treatment with steroids (prednisolone 1mg/kg) was started, whereas maintenance treatment with nivolumab was discontinued. In March 2020, the patient developed symptomatic COVID-19 with coughing and dyspnoea, infection with SARS-CoV-2 was confirmed by real-time polymerase chain reaction (RT-PCR). At the time of hospital admission (2 days after the onset of symptoms), the patient had been treated with prednisolone (1mg/kg daily) for four weeks and the last dose of nivolumab had been administered six weeks earlier. At that time, the creatinine level was decreased to 163 µmol/L with an eGFR of 38 ml/min. To prevent a potentially severe course of COVID-19, prednisolone was rapidly reduced to 60 mg daily within 3 days. As this dose reduction of prednisolone was accompanied by a grade 4 renal failure (creatinine level 500 µmol/L (>6.0 x ULN), eGFR 10 ml/min) according to CTCAE v5, high dose steroids (prednisolone 2 mg/kg daily, intravenously) was restarted. At hospital admission, empiric antibiotic treatment with cefuroxime and azithromycin was administered and minimal oxygen therapy was given for a few days. After 12 days of admission, the patient could be discharged. However, the patient was re-admitted within 7 days due to clinical deterioration. CT and magnetic resonance imaging (MRI) revealed extra- and intracranial progressive disease of RCC. MRI showed a newly diagnosed brain metastasis with bleeding. The patient experienced severe neurological deterioration and eventually died within 1 month after the first hospital admission for COVID-19. An autopsy was not performed.
Immune Response
To study the adaptive immune response in this patient, peripheral blood samples were collected in the context of the MULTOMAB study (Netherlands Trial Registry number NL6828). In this observational study, blood samples are prospectively collected from patients with cancer treated with monoclonal antibodies. The MULTOMAB study has been approved by the medical ethics committee at Erasmus Medical Centre and the patient had signed informed consent. Blood samples were collected at baseline (prior to the first administration of ipilimumab plus nivolumab), 3 weeks after the first administration of ipilimumab plus nivolumab (T1), and during hospital admission for COVID-19 (23 weeks after the first administration of ipilimumab plus nivolumab;T2).
After collection of these blood samples, peripheral blood mononuclear cells (PBMCs) and plasma were isolated for further analyses. Frequencies of T cells and their subsets prior to and during treatment with ICIs were determined by multiplex flow cytometry. The number of T cells and their major subsets were measured according to the expression of markers for co-signalling, maturation, and chemotaxis as previously described in detail (11). In addition, plasma samples were analyzed for IgM and total IgG antibodies directed against the receptor binding domain (RBD) of SARS-CoV-2 using an ELISA (Wantai) (12), and these antibodies were analyzed for their ability to neutralise SARS-CoV-2 by a plaque reduction test (PRNT50) (13). Upon diagnosis of COVID-19, the adaptive immune parameters changed drastically. First, the counts of total leukocytes showed a strong decrease from 6,9x103/µl at T1 to 3.9 x103/µl at T2, which was predominantly caused by a decrease in lymphocyte counts (
Supplementary Table 1
) (
14, 15). Second, for both CD4+ and CD8+ T cells the fractions of central (CD45RA-, CCR7+) and effector (CD45RA-, CCR7-) memory T cells decreased, whereas those of naïve T cells (CD45RA+, CCR7+) increased when comparing T2 versus T1 and baseline (
Figure 1
). As the total numbers of CD4+ and CD8+ T cells did not differ over time, the observed increase in naïve T cells may have been the result of apoptosis-mediated loss of more differentiated T cells. Third, the fractions of CD4+ and CD8+ T cells expressing multiple (≥2) types of co-inhibitory, co-stimulatory, and/or chemoattractant receptors increased when comparing T2 versus T1 (
Figures 2A–C
). The last two observations indicate that SARS-CoV-2 may have induced expression of multiple T cell receptors, which is often considered a measure of T cell differentiation. It is noteworthy that CD8+ T cells mainly expressed co-inhibitory and co-stimulatory receptors, whereas CD4+ T cells mainly expressed co-inhibitory receptors. In particular, fractions of CD4+ T cells expressing both programmed cell death protein 1 (PD-1) and B- and T-lymphocyte attenuator (BTLA) were high during infection with SARS-CoV-2 (
Figure 2D
). Fourth, the patient started to develop SARS-CoV-2 specific IgM and IgG antibodies at 10 days post onset of symptoms and neutralising antibodies were detectable at 15 days post onset of symptoms (
Supplementary Table 2
). Altogether, the above-mentioned T and B cell responses in this patient were assessed sufficient to clear the virus from the respiratory tract, as demonstrated by a negative virus culture at 15 days post onset of symptoms. The prolonged shedding of viral RNA is a phenomenon which is often observed, but does not necessarily indicate presence of infectious virus (16).
Figure 1 Percentages of different maturation stages of CD4+ and CD8+ T cells. Fractions of CD4+ T cells (A) and CD8+ T cells (B) in four differentiation stages at 3 time points: prior to ICIs (baseline), at 3 weeks after first administration of ipilimumab plus nivolumab (T1), and during SARS-CoV-2 infection (23 weeks after first administration of ipilimumab plus nivolumab; T2). The figure shows percentages of the following stages either within CD4+ and CD8+ T cells: naïve T cells (Tnaïve: CD45RA+, CCR7+), central memory T cells (Tcm: CD45RA-, CCR7+), effector memory T cells (Tem: CD45RA-, CCR7-), and effector memory T cells expressing CD45RA (Temra: CD45A+, CCR7-).
Figure 2 Percentages of CD4+ and CD8+ T cells expressing various classes of immune receptors. Fractions of CD4+ (left panels) and CD8+ (right panels) T cells expressing <2 versus ≥ 2 different co-inhibitory receptors. (A), co-stimulatory receptors (B), and chemoattractant receptors (C) at 3 different time points: prior to ICIs (baseline), at 3 weeks after first administration of ipilimumab plus nivolumab (T1), and during SARS-CoV-2 infection (23 weeks after first administration of ipilimumab plus nivolumab; T2). An example of the expression of co-inhibitory receptors is shown in (D), where the fraction of CD4+ T cells co-expressing BTLA (CD272) and PD-1 (CD279) at baseline, T1, and T2 is shown.
Discussion
In this patient, who was infected with SARS-CoV-2 and treated with ICIs for metastatic RCC, an adequate cellular and humoral immune response was measured, despite the presence of risk factors for an impaired immune response and a severe course of SARS-CoV-2. For instance, an increased risk for a severe course of COVID-19 has been reported in patients who were treated with high-dose steroids prior to hospital admission (7). In addition, patients with cancer have an increased risk for a severe outcome of COVID-19, and this further increases in patients with progressive disease (6). Furthermore, this patient presented with lymphopenia, which is considered a predictive marker for severe COVID-19 (14, 15). In particular, the patient had an increased neutrophil-to-lymphocyte ratio (NLR)(6.5) and an increased lymphocyte-to-monocyte ratio (LMR) (5.3) which are also considered markers of poor survival in patients with COVID-19 (15). Finally, oncological guidelines stress the enhanced risk of treatment with ICIs during this pandemic (9, 17).
Besides the fact that this patient had several risk factors for an impaired immune response and severe course of COVID-19, adequate responses for both T and B cells were observed. T cell activation and consequently differentiation (
Figure 1
) may have led to loss of T cells, and an indirect increase in the fraction of naïve CD4+ and CD8+ T cells. The increased frequencies of T cells expressing immune receptors is another sign of T cell activation and differentiation (
Figure 2
). In particular, the enhanced frequency of CD4+ T cells expressing the co-inhibitory receptors BTLA and PD-1 (
Figure 2D
), is considered the result of an adaptive feedback loop to counter regulate the initial activation of T cells (18, 19). In addition to T cells, also B cell activation was observed by the production of neutralizing antibodies. As the viral culture was already negative despite low titers of antibodies measured with ELISA and PRNT50, the T cell response has most likely contributed to the clearance of the virus. Overall, both the presence of cellular as well as humoral immune parameters was comparable to those observed in SARS-CoV-2 infected patients without cancer (18–20).
As shown, the patients’ immune system was sufficiently active against SARS-CoV-2, but failed to act upon the renal cell cancer effectively. The latter deficit may be due to the existence of immune suppressive actions in the renal cell cancer micro-environment, preventing effective infiltration and/or activation of anti-tumor T cells (21). Already before COVID-19, the patient had progressive disease according to RECIST v.1.1, indicating that the renal cell cancer did not respond to immunotherapy. These results underscore different obstacles to achieve anti-tumor versus anti-virus immunity, and importantly demonstrate that, at least in this case, treatment with ICI does not alter the anti-virus T and B cell immunity.
Several studies have investigated the immune response to SARS-CoV-2 (18–20), and have yielded limited and conflicting data regarding COVID-19 in patients treated with ICIs (4, 9, 22). To the best of our knowledge, this is the first report on adaptive immunity in a SARS-CoV-2 infected patient treated with ICIs. Limitations of this report include the description of only one patient who had already discontinued treatment with ICIs. Although the patient discontinued treatment with ICIs at 6 weeks prior to the onset of COVID-19, it is conceivable that this treatment still affected the immune response. The ongoing effects of ICIs are well-known and are usually illustrated by their durable tumor response and late onset of adverse events, even months to years after discontinuation of treatment. In addition, specific measurements, such as NLR and LMR, were only performed during COVID-19 and could not be compared to previous values at baseline and during treatment with ICIs. The role of innate immune cells in this patient could not be elucidated in this particular case, and deserves further attention.
In conclusion, the adequate B and T cell responses in this SARS-CoV-2 infected patient who was treated with ICIs, justify renewed discussion on withholding of ICIs during the ongoing COVID-19 pandemic and may guide inclusion of patients treated with ICIs for COVID-19 vaccination (23).
Data Availability Statement
The original contributions presented in the study are included in the article/
Supplementary Material
. Further inquiries can be directed to the corresponding author.
Ethics Statement
The studies involving human participants were reviewed and approved by the MULTOMAB study (Netherlands Trial Registry number NL6828). Approved by medical ethics committee of Erasmus Medical Centre. The patients/participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.
Author Contributions
KJ, AO, CG, RV and AV contributed to acquisition and analysis of the data. KJ and AV drafted the manuscript. RM and RD contributed to technical and material support. CG, RV, RM and RD contributed to critical revision of the manuscript for important intellectual content. All authors contributed to the article and approved the submitted version.
Conflict of Interest
AV reports advisory board of BMS, MSD, Merck, Pfizer, Ipsen, Eisai, Pierre Fabre, Roche, Novartis, Sanofi, outside the submitted work. RM reports unrestricted grants for investigator-initiated research from Astellas, Bayer, Boehringer-Ingelheim, Cristal Therapeutics, Novartis, Pamgene, Pfizer, Roche, Sanofi, and Servier outside the submitted work. RD has received grants from Merck and Pan-Cancer T BV outside the submitted work.
The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Supplementary Material
The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fimmu.2021.627186/full#supplementary-material
Click here for additional data file.
Click here for additional data file. | RECEIVED 3?WEEKLY FIRST?LINE TREATMENT | DrugDosageText | CC BY | 33613575 | 19,133,955 | 2021 |
What was the dosage of drug 'PREDNISOLONE'? | Case Report: Adequate T and B Cell Responses in a SARS-CoV-2 Infected Patient After Immune Checkpoint Inhibition.
After the COVID-19 outbreak, non-evidence based guidelines were published to advise clinicians on the adjustment of oncological treatment during this pandemic. As immune checkpoint inhibitors directly affect the immune system, concerns have arisen about the safety of immunotherapy during this pandemic. However, data on the immune response in oncology patients treated with immunotherapy are still lacking. Here, we present the adaptive immune response in a SARS-CoV-2 infected patient who was treated with immune checkpoint inhibitors for advanced renal cell cancer. To evaluate the immune response in this patient, the number of T cells and their major subsets were measured according to expression of markers for co-signalling, maturation, and chemotaxis at baseline, during therapy, and during the SARS-CoV-2 infection. In addition, plasma samples were analyzed for IgM and IgG antibodies and the ability of these antibodies to neutralise SARS-CoV-2. Despite several risk factors for an impaired immune response to SARS-CoV-2, both T- and B-cell responses were observed. Moreover, after treatment with immune checkpoint inhibitors, a sufficient cellular and humoral immune response was achieved in this SARS-CoV-2 infected patient. These findings warrant renewed discussion on withholding of immune checkpoint inhibitors during an ongoing COVID-19 pandemic.
Introduction
The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is having significant impact on oncological care. Besides capacity issues, concerns have arisen about the safety of oncological treatment and an increased risk for a more severe outcome of COVID-19 in patients with cancer (1–7). Patients with an (active) malignancy may have an increased risk of severe COVID-19, and it is still not known whether treatment with anti-cancer drugs—including immune checkpoint inhibitors (ICIs)—is safe during this pandemic (1–5).
After the first COVID-19 outbreak, non-evidence based guidelines were published to advise clinicians on the adjustment of oncological treatment during this pandemic. As ICIs directly affect the immune cells, and symptoms of COVID-19 resemble adverse events of ICIs (8), these guidelines were rather conservative regarding the use of ICIs during this pandemic. However, data on the immune response in patients infected with SARS-CoV-2 and treated with ICIs are still lacking (9). Here, we present for the first time data of the T and B cell responses in a SARS-CoV-2 infected patient who was treated with nivolumab and ipilimumab for advanced renal cell cancer (RCC).
Case Description
In 2019, a 62-year-old male, with diabetes mellitus type II and hypertension, was diagnosed with primary metastatic RCC with lung and bone metastases. The disease was complicated by paraneoplastic pulmonary embolism for which therapeutic doses of low molecular weight heparin were started. Based on an interval of <1 year between diagnosis and systemic therapy, the patient had an “intermediate risk” according to the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) criteria. Therefore, first-line treatment with 3-weekly ipilimumab (1 mg/kg) plus nivolumab (3 mg/kg) was started while the primary tumor was in situ (
10). After four cycles of ipilimumab plus nivolumab, the first response evaluation showed progressive disease according to the Response Evaluation Criteria in Solid Tumours (RECIST) v1.1. However, as the patient experienced clinical benefit and some target lesions showed a reduction in tumor size with computed tomography (CT), maintenance treatment with nivolumab was started. After three cycles of 2-weekly maintenance treatment with nivolumab, creatinine levels increased from 126 µmol/L (i.e., baseline prior to ICI) to 265 µmol/L (>2x ULN) and the estimated glomerular filtration rate (eGFR) decreased from 53 ml/min (i.e., baseline prior to ICI) to 21 ml/min, which was accompanied by erythrocyturia and proteinuria. After the exclusion of other possible causes such as dehydration and contrast nephropathy, an immune related nephritis was considered most likely, although a biopsy to confirm this diagnosis could not be performed. According to the Common Terminology Criteria for Adverse Events Version 5 (CTCAE v5), the patient experienced a treatment-related nephritis grade 2 and treatment with steroids (prednisolone 1mg/kg) was started, whereas maintenance treatment with nivolumab was discontinued. In March 2020, the patient developed symptomatic COVID-19 with coughing and dyspnoea, infection with SARS-CoV-2 was confirmed by real-time polymerase chain reaction (RT-PCR). At the time of hospital admission (2 days after the onset of symptoms), the patient had been treated with prednisolone (1mg/kg daily) for four weeks and the last dose of nivolumab had been administered six weeks earlier. At that time, the creatinine level was decreased to 163 µmol/L with an eGFR of 38 ml/min. To prevent a potentially severe course of COVID-19, prednisolone was rapidly reduced to 60 mg daily within 3 days. As this dose reduction of prednisolone was accompanied by a grade 4 renal failure (creatinine level 500 µmol/L (>6.0 x ULN), eGFR 10 ml/min) according to CTCAE v5, high dose steroids (prednisolone 2 mg/kg daily, intravenously) was restarted. At hospital admission, empiric antibiotic treatment with cefuroxime and azithromycin was administered and minimal oxygen therapy was given for a few days. After 12 days of admission, the patient could be discharged. However, the patient was re-admitted within 7 days due to clinical deterioration. CT and magnetic resonance imaging (MRI) revealed extra- and intracranial progressive disease of RCC. MRI showed a newly diagnosed brain metastasis with bleeding. The patient experienced severe neurological deterioration and eventually died within 1 month after the first hospital admission for COVID-19. An autopsy was not performed.
Immune Response
To study the adaptive immune response in this patient, peripheral blood samples were collected in the context of the MULTOMAB study (Netherlands Trial Registry number NL6828). In this observational study, blood samples are prospectively collected from patients with cancer treated with monoclonal antibodies. The MULTOMAB study has been approved by the medical ethics committee at Erasmus Medical Centre and the patient had signed informed consent. Blood samples were collected at baseline (prior to the first administration of ipilimumab plus nivolumab), 3 weeks after the first administration of ipilimumab plus nivolumab (T1), and during hospital admission for COVID-19 (23 weeks after the first administration of ipilimumab plus nivolumab;T2).
After collection of these blood samples, peripheral blood mononuclear cells (PBMCs) and plasma were isolated for further analyses. Frequencies of T cells and their subsets prior to and during treatment with ICIs were determined by multiplex flow cytometry. The number of T cells and their major subsets were measured according to the expression of markers for co-signalling, maturation, and chemotaxis as previously described in detail (11). In addition, plasma samples were analyzed for IgM and total IgG antibodies directed against the receptor binding domain (RBD) of SARS-CoV-2 using an ELISA (Wantai) (12), and these antibodies were analyzed for their ability to neutralise SARS-CoV-2 by a plaque reduction test (PRNT50) (13). Upon diagnosis of COVID-19, the adaptive immune parameters changed drastically. First, the counts of total leukocytes showed a strong decrease from 6,9x103/µl at T1 to 3.9 x103/µl at T2, which was predominantly caused by a decrease in lymphocyte counts (
Supplementary Table 1
) (
14, 15). Second, for both CD4+ and CD8+ T cells the fractions of central (CD45RA-, CCR7+) and effector (CD45RA-, CCR7-) memory T cells decreased, whereas those of naïve T cells (CD45RA+, CCR7+) increased when comparing T2 versus T1 and baseline (
Figure 1
). As the total numbers of CD4+ and CD8+ T cells did not differ over time, the observed increase in naïve T cells may have been the result of apoptosis-mediated loss of more differentiated T cells. Third, the fractions of CD4+ and CD8+ T cells expressing multiple (≥2) types of co-inhibitory, co-stimulatory, and/or chemoattractant receptors increased when comparing T2 versus T1 (
Figures 2A–C
). The last two observations indicate that SARS-CoV-2 may have induced expression of multiple T cell receptors, which is often considered a measure of T cell differentiation. It is noteworthy that CD8+ T cells mainly expressed co-inhibitory and co-stimulatory receptors, whereas CD4+ T cells mainly expressed co-inhibitory receptors. In particular, fractions of CD4+ T cells expressing both programmed cell death protein 1 (PD-1) and B- and T-lymphocyte attenuator (BTLA) were high during infection with SARS-CoV-2 (
Figure 2D
). Fourth, the patient started to develop SARS-CoV-2 specific IgM and IgG antibodies at 10 days post onset of symptoms and neutralising antibodies were detectable at 15 days post onset of symptoms (
Supplementary Table 2
). Altogether, the above-mentioned T and B cell responses in this patient were assessed sufficient to clear the virus from the respiratory tract, as demonstrated by a negative virus culture at 15 days post onset of symptoms. The prolonged shedding of viral RNA is a phenomenon which is often observed, but does not necessarily indicate presence of infectious virus (16).
Figure 1 Percentages of different maturation stages of CD4+ and CD8+ T cells. Fractions of CD4+ T cells (A) and CD8+ T cells (B) in four differentiation stages at 3 time points: prior to ICIs (baseline), at 3 weeks after first administration of ipilimumab plus nivolumab (T1), and during SARS-CoV-2 infection (23 weeks after first administration of ipilimumab plus nivolumab; T2). The figure shows percentages of the following stages either within CD4+ and CD8+ T cells: naïve T cells (Tnaïve: CD45RA+, CCR7+), central memory T cells (Tcm: CD45RA-, CCR7+), effector memory T cells (Tem: CD45RA-, CCR7-), and effector memory T cells expressing CD45RA (Temra: CD45A+, CCR7-).
Figure 2 Percentages of CD4+ and CD8+ T cells expressing various classes of immune receptors. Fractions of CD4+ (left panels) and CD8+ (right panels) T cells expressing <2 versus ≥ 2 different co-inhibitory receptors. (A), co-stimulatory receptors (B), and chemoattractant receptors (C) at 3 different time points: prior to ICIs (baseline), at 3 weeks after first administration of ipilimumab plus nivolumab (T1), and during SARS-CoV-2 infection (23 weeks after first administration of ipilimumab plus nivolumab; T2). An example of the expression of co-inhibitory receptors is shown in (D), where the fraction of CD4+ T cells co-expressing BTLA (CD272) and PD-1 (CD279) at baseline, T1, and T2 is shown.
Discussion
In this patient, who was infected with SARS-CoV-2 and treated with ICIs for metastatic RCC, an adequate cellular and humoral immune response was measured, despite the presence of risk factors for an impaired immune response and a severe course of SARS-CoV-2. For instance, an increased risk for a severe course of COVID-19 has been reported in patients who were treated with high-dose steroids prior to hospital admission (7). In addition, patients with cancer have an increased risk for a severe outcome of COVID-19, and this further increases in patients with progressive disease (6). Furthermore, this patient presented with lymphopenia, which is considered a predictive marker for severe COVID-19 (14, 15). In particular, the patient had an increased neutrophil-to-lymphocyte ratio (NLR)(6.5) and an increased lymphocyte-to-monocyte ratio (LMR) (5.3) which are also considered markers of poor survival in patients with COVID-19 (15). Finally, oncological guidelines stress the enhanced risk of treatment with ICIs during this pandemic (9, 17).
Besides the fact that this patient had several risk factors for an impaired immune response and severe course of COVID-19, adequate responses for both T and B cells were observed. T cell activation and consequently differentiation (
Figure 1
) may have led to loss of T cells, and an indirect increase in the fraction of naïve CD4+ and CD8+ T cells. The increased frequencies of T cells expressing immune receptors is another sign of T cell activation and differentiation (
Figure 2
). In particular, the enhanced frequency of CD4+ T cells expressing the co-inhibitory receptors BTLA and PD-1 (
Figure 2D
), is considered the result of an adaptive feedback loop to counter regulate the initial activation of T cells (18, 19). In addition to T cells, also B cell activation was observed by the production of neutralizing antibodies. As the viral culture was already negative despite low titers of antibodies measured with ELISA and PRNT50, the T cell response has most likely contributed to the clearance of the virus. Overall, both the presence of cellular as well as humoral immune parameters was comparable to those observed in SARS-CoV-2 infected patients without cancer (18–20).
As shown, the patients’ immune system was sufficiently active against SARS-CoV-2, but failed to act upon the renal cell cancer effectively. The latter deficit may be due to the existence of immune suppressive actions in the renal cell cancer micro-environment, preventing effective infiltration and/or activation of anti-tumor T cells (21). Already before COVID-19, the patient had progressive disease according to RECIST v.1.1, indicating that the renal cell cancer did not respond to immunotherapy. These results underscore different obstacles to achieve anti-tumor versus anti-virus immunity, and importantly demonstrate that, at least in this case, treatment with ICI does not alter the anti-virus T and B cell immunity.
Several studies have investigated the immune response to SARS-CoV-2 (18–20), and have yielded limited and conflicting data regarding COVID-19 in patients treated with ICIs (4, 9, 22). To the best of our knowledge, this is the first report on adaptive immunity in a SARS-CoV-2 infected patient treated with ICIs. Limitations of this report include the description of only one patient who had already discontinued treatment with ICIs. Although the patient discontinued treatment with ICIs at 6 weeks prior to the onset of COVID-19, it is conceivable that this treatment still affected the immune response. The ongoing effects of ICIs are well-known and are usually illustrated by their durable tumor response and late onset of adverse events, even months to years after discontinuation of treatment. In addition, specific measurements, such as NLR and LMR, were only performed during COVID-19 and could not be compared to previous values at baseline and during treatment with ICIs. The role of innate immune cells in this patient could not be elucidated in this particular case, and deserves further attention.
In conclusion, the adequate B and T cell responses in this SARS-CoV-2 infected patient who was treated with ICIs, justify renewed discussion on withholding of ICIs during the ongoing COVID-19 pandemic and may guide inclusion of patients treated with ICIs for COVID-19 vaccination (23).
Data Availability Statement
The original contributions presented in the study are included in the article/
Supplementary Material
. Further inquiries can be directed to the corresponding author.
Ethics Statement
The studies involving human participants were reviewed and approved by the MULTOMAB study (Netherlands Trial Registry number NL6828). Approved by medical ethics committee of Erasmus Medical Centre. The patients/participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.
Author Contributions
KJ, AO, CG, RV and AV contributed to acquisition and analysis of the data. KJ and AV drafted the manuscript. RM and RD contributed to technical and material support. CG, RV, RM and RD contributed to critical revision of the manuscript for important intellectual content. All authors contributed to the article and approved the submitted version.
Conflict of Interest
AV reports advisory board of BMS, MSD, Merck, Pfizer, Ipsen, Eisai, Pierre Fabre, Roche, Novartis, Sanofi, outside the submitted work. RM reports unrestricted grants for investigator-initiated research from Astellas, Bayer, Boehringer-Ingelheim, Cristal Therapeutics, Novartis, Pamgene, Pfizer, Roche, Sanofi, and Servier outside the submitted work. RD has received grants from Merck and Pan-Cancer T BV outside the submitted work.
The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Supplementary Material
The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fimmu.2021.627186/full#supplementary-material
Click here for additional data file.
Click here for additional data file. | 60 MILLIGRAM DAILY; | DrugDosageText | CC BY | 33613575 | 19,133,955 | 2021 |
What was the outcome of reaction 'Nephritis'? | Case Report: Adequate T and B Cell Responses in a SARS-CoV-2 Infected Patient After Immune Checkpoint Inhibition.
After the COVID-19 outbreak, non-evidence based guidelines were published to advise clinicians on the adjustment of oncological treatment during this pandemic. As immune checkpoint inhibitors directly affect the immune system, concerns have arisen about the safety of immunotherapy during this pandemic. However, data on the immune response in oncology patients treated with immunotherapy are still lacking. Here, we present the adaptive immune response in a SARS-CoV-2 infected patient who was treated with immune checkpoint inhibitors for advanced renal cell cancer. To evaluate the immune response in this patient, the number of T cells and their major subsets were measured according to expression of markers for co-signalling, maturation, and chemotaxis at baseline, during therapy, and during the SARS-CoV-2 infection. In addition, plasma samples were analyzed for IgM and IgG antibodies and the ability of these antibodies to neutralise SARS-CoV-2. Despite several risk factors for an impaired immune response to SARS-CoV-2, both T- and B-cell responses were observed. Moreover, after treatment with immune checkpoint inhibitors, a sufficient cellular and humoral immune response was achieved in this SARS-CoV-2 infected patient. These findings warrant renewed discussion on withholding of immune checkpoint inhibitors during an ongoing COVID-19 pandemic.
Introduction
The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is having significant impact on oncological care. Besides capacity issues, concerns have arisen about the safety of oncological treatment and an increased risk for a more severe outcome of COVID-19 in patients with cancer (1–7). Patients with an (active) malignancy may have an increased risk of severe COVID-19, and it is still not known whether treatment with anti-cancer drugs—including immune checkpoint inhibitors (ICIs)—is safe during this pandemic (1–5).
After the first COVID-19 outbreak, non-evidence based guidelines were published to advise clinicians on the adjustment of oncological treatment during this pandemic. As ICIs directly affect the immune cells, and symptoms of COVID-19 resemble adverse events of ICIs (8), these guidelines were rather conservative regarding the use of ICIs during this pandemic. However, data on the immune response in patients infected with SARS-CoV-2 and treated with ICIs are still lacking (9). Here, we present for the first time data of the T and B cell responses in a SARS-CoV-2 infected patient who was treated with nivolumab and ipilimumab for advanced renal cell cancer (RCC).
Case Description
In 2019, a 62-year-old male, with diabetes mellitus type II and hypertension, was diagnosed with primary metastatic RCC with lung and bone metastases. The disease was complicated by paraneoplastic pulmonary embolism for which therapeutic doses of low molecular weight heparin were started. Based on an interval of <1 year between diagnosis and systemic therapy, the patient had an “intermediate risk” according to the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) criteria. Therefore, first-line treatment with 3-weekly ipilimumab (1 mg/kg) plus nivolumab (3 mg/kg) was started while the primary tumor was in situ (
10). After four cycles of ipilimumab plus nivolumab, the first response evaluation showed progressive disease according to the Response Evaluation Criteria in Solid Tumours (RECIST) v1.1. However, as the patient experienced clinical benefit and some target lesions showed a reduction in tumor size with computed tomography (CT), maintenance treatment with nivolumab was started. After three cycles of 2-weekly maintenance treatment with nivolumab, creatinine levels increased from 126 µmol/L (i.e., baseline prior to ICI) to 265 µmol/L (>2x ULN) and the estimated glomerular filtration rate (eGFR) decreased from 53 ml/min (i.e., baseline prior to ICI) to 21 ml/min, which was accompanied by erythrocyturia and proteinuria. After the exclusion of other possible causes such as dehydration and contrast nephropathy, an immune related nephritis was considered most likely, although a biopsy to confirm this diagnosis could not be performed. According to the Common Terminology Criteria for Adverse Events Version 5 (CTCAE v5), the patient experienced a treatment-related nephritis grade 2 and treatment with steroids (prednisolone 1mg/kg) was started, whereas maintenance treatment with nivolumab was discontinued. In March 2020, the patient developed symptomatic COVID-19 with coughing and dyspnoea, infection with SARS-CoV-2 was confirmed by real-time polymerase chain reaction (RT-PCR). At the time of hospital admission (2 days after the onset of symptoms), the patient had been treated with prednisolone (1mg/kg daily) for four weeks and the last dose of nivolumab had been administered six weeks earlier. At that time, the creatinine level was decreased to 163 µmol/L with an eGFR of 38 ml/min. To prevent a potentially severe course of COVID-19, prednisolone was rapidly reduced to 60 mg daily within 3 days. As this dose reduction of prednisolone was accompanied by a grade 4 renal failure (creatinine level 500 µmol/L (>6.0 x ULN), eGFR 10 ml/min) according to CTCAE v5, high dose steroids (prednisolone 2 mg/kg daily, intravenously) was restarted. At hospital admission, empiric antibiotic treatment with cefuroxime and azithromycin was administered and minimal oxygen therapy was given for a few days. After 12 days of admission, the patient could be discharged. However, the patient was re-admitted within 7 days due to clinical deterioration. CT and magnetic resonance imaging (MRI) revealed extra- and intracranial progressive disease of RCC. MRI showed a newly diagnosed brain metastasis with bleeding. The patient experienced severe neurological deterioration and eventually died within 1 month after the first hospital admission for COVID-19. An autopsy was not performed.
Immune Response
To study the adaptive immune response in this patient, peripheral blood samples were collected in the context of the MULTOMAB study (Netherlands Trial Registry number NL6828). In this observational study, blood samples are prospectively collected from patients with cancer treated with monoclonal antibodies. The MULTOMAB study has been approved by the medical ethics committee at Erasmus Medical Centre and the patient had signed informed consent. Blood samples were collected at baseline (prior to the first administration of ipilimumab plus nivolumab), 3 weeks after the first administration of ipilimumab plus nivolumab (T1), and during hospital admission for COVID-19 (23 weeks after the first administration of ipilimumab plus nivolumab;T2).
After collection of these blood samples, peripheral blood mononuclear cells (PBMCs) and plasma were isolated for further analyses. Frequencies of T cells and their subsets prior to and during treatment with ICIs were determined by multiplex flow cytometry. The number of T cells and their major subsets were measured according to the expression of markers for co-signalling, maturation, and chemotaxis as previously described in detail (11). In addition, plasma samples were analyzed for IgM and total IgG antibodies directed against the receptor binding domain (RBD) of SARS-CoV-2 using an ELISA (Wantai) (12), and these antibodies were analyzed for their ability to neutralise SARS-CoV-2 by a plaque reduction test (PRNT50) (13). Upon diagnosis of COVID-19, the adaptive immune parameters changed drastically. First, the counts of total leukocytes showed a strong decrease from 6,9x103/µl at T1 to 3.9 x103/µl at T2, which was predominantly caused by a decrease in lymphocyte counts (
Supplementary Table 1
) (
14, 15). Second, for both CD4+ and CD8+ T cells the fractions of central (CD45RA-, CCR7+) and effector (CD45RA-, CCR7-) memory T cells decreased, whereas those of naïve T cells (CD45RA+, CCR7+) increased when comparing T2 versus T1 and baseline (
Figure 1
). As the total numbers of CD4+ and CD8+ T cells did not differ over time, the observed increase in naïve T cells may have been the result of apoptosis-mediated loss of more differentiated T cells. Third, the fractions of CD4+ and CD8+ T cells expressing multiple (≥2) types of co-inhibitory, co-stimulatory, and/or chemoattractant receptors increased when comparing T2 versus T1 (
Figures 2A–C
). The last two observations indicate that SARS-CoV-2 may have induced expression of multiple T cell receptors, which is often considered a measure of T cell differentiation. It is noteworthy that CD8+ T cells mainly expressed co-inhibitory and co-stimulatory receptors, whereas CD4+ T cells mainly expressed co-inhibitory receptors. In particular, fractions of CD4+ T cells expressing both programmed cell death protein 1 (PD-1) and B- and T-lymphocyte attenuator (BTLA) were high during infection with SARS-CoV-2 (
Figure 2D
). Fourth, the patient started to develop SARS-CoV-2 specific IgM and IgG antibodies at 10 days post onset of symptoms and neutralising antibodies were detectable at 15 days post onset of symptoms (
Supplementary Table 2
). Altogether, the above-mentioned T and B cell responses in this patient were assessed sufficient to clear the virus from the respiratory tract, as demonstrated by a negative virus culture at 15 days post onset of symptoms. The prolonged shedding of viral RNA is a phenomenon which is often observed, but does not necessarily indicate presence of infectious virus (16).
Figure 1 Percentages of different maturation stages of CD4+ and CD8+ T cells. Fractions of CD4+ T cells (A) and CD8+ T cells (B) in four differentiation stages at 3 time points: prior to ICIs (baseline), at 3 weeks after first administration of ipilimumab plus nivolumab (T1), and during SARS-CoV-2 infection (23 weeks after first administration of ipilimumab plus nivolumab; T2). The figure shows percentages of the following stages either within CD4+ and CD8+ T cells: naïve T cells (Tnaïve: CD45RA+, CCR7+), central memory T cells (Tcm: CD45RA-, CCR7+), effector memory T cells (Tem: CD45RA-, CCR7-), and effector memory T cells expressing CD45RA (Temra: CD45A+, CCR7-).
Figure 2 Percentages of CD4+ and CD8+ T cells expressing various classes of immune receptors. Fractions of CD4+ (left panels) and CD8+ (right panels) T cells expressing <2 versus ≥ 2 different co-inhibitory receptors. (A), co-stimulatory receptors (B), and chemoattractant receptors (C) at 3 different time points: prior to ICIs (baseline), at 3 weeks after first administration of ipilimumab plus nivolumab (T1), and during SARS-CoV-2 infection (23 weeks after first administration of ipilimumab plus nivolumab; T2). An example of the expression of co-inhibitory receptors is shown in (D), where the fraction of CD4+ T cells co-expressing BTLA (CD272) and PD-1 (CD279) at baseline, T1, and T2 is shown.
Discussion
In this patient, who was infected with SARS-CoV-2 and treated with ICIs for metastatic RCC, an adequate cellular and humoral immune response was measured, despite the presence of risk factors for an impaired immune response and a severe course of SARS-CoV-2. For instance, an increased risk for a severe course of COVID-19 has been reported in patients who were treated with high-dose steroids prior to hospital admission (7). In addition, patients with cancer have an increased risk for a severe outcome of COVID-19, and this further increases in patients with progressive disease (6). Furthermore, this patient presented with lymphopenia, which is considered a predictive marker for severe COVID-19 (14, 15). In particular, the patient had an increased neutrophil-to-lymphocyte ratio (NLR)(6.5) and an increased lymphocyte-to-monocyte ratio (LMR) (5.3) which are also considered markers of poor survival in patients with COVID-19 (15). Finally, oncological guidelines stress the enhanced risk of treatment with ICIs during this pandemic (9, 17).
Besides the fact that this patient had several risk factors for an impaired immune response and severe course of COVID-19, adequate responses for both T and B cells were observed. T cell activation and consequently differentiation (
Figure 1
) may have led to loss of T cells, and an indirect increase in the fraction of naïve CD4+ and CD8+ T cells. The increased frequencies of T cells expressing immune receptors is another sign of T cell activation and differentiation (
Figure 2
). In particular, the enhanced frequency of CD4+ T cells expressing the co-inhibitory receptors BTLA and PD-1 (
Figure 2D
), is considered the result of an adaptive feedback loop to counter regulate the initial activation of T cells (18, 19). In addition to T cells, also B cell activation was observed by the production of neutralizing antibodies. As the viral culture was already negative despite low titers of antibodies measured with ELISA and PRNT50, the T cell response has most likely contributed to the clearance of the virus. Overall, both the presence of cellular as well as humoral immune parameters was comparable to those observed in SARS-CoV-2 infected patients without cancer (18–20).
As shown, the patients’ immune system was sufficiently active against SARS-CoV-2, but failed to act upon the renal cell cancer effectively. The latter deficit may be due to the existence of immune suppressive actions in the renal cell cancer micro-environment, preventing effective infiltration and/or activation of anti-tumor T cells (21). Already before COVID-19, the patient had progressive disease according to RECIST v.1.1, indicating that the renal cell cancer did not respond to immunotherapy. These results underscore different obstacles to achieve anti-tumor versus anti-virus immunity, and importantly demonstrate that, at least in this case, treatment with ICI does not alter the anti-virus T and B cell immunity.
Several studies have investigated the immune response to SARS-CoV-2 (18–20), and have yielded limited and conflicting data regarding COVID-19 in patients treated with ICIs (4, 9, 22). To the best of our knowledge, this is the first report on adaptive immunity in a SARS-CoV-2 infected patient treated with ICIs. Limitations of this report include the description of only one patient who had already discontinued treatment with ICIs. Although the patient discontinued treatment with ICIs at 6 weeks prior to the onset of COVID-19, it is conceivable that this treatment still affected the immune response. The ongoing effects of ICIs are well-known and are usually illustrated by their durable tumor response and late onset of adverse events, even months to years after discontinuation of treatment. In addition, specific measurements, such as NLR and LMR, were only performed during COVID-19 and could not be compared to previous values at baseline and during treatment with ICIs. The role of innate immune cells in this patient could not be elucidated in this particular case, and deserves further attention.
In conclusion, the adequate B and T cell responses in this SARS-CoV-2 infected patient who was treated with ICIs, justify renewed discussion on withholding of ICIs during the ongoing COVID-19 pandemic and may guide inclusion of patients treated with ICIs for COVID-19 vaccination (23).
Data Availability Statement
The original contributions presented in the study are included in the article/
Supplementary Material
. Further inquiries can be directed to the corresponding author.
Ethics Statement
The studies involving human participants were reviewed and approved by the MULTOMAB study (Netherlands Trial Registry number NL6828). Approved by medical ethics committee of Erasmus Medical Centre. The patients/participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.
Author Contributions
KJ, AO, CG, RV and AV contributed to acquisition and analysis of the data. KJ and AV drafted the manuscript. RM and RD contributed to technical and material support. CG, RV, RM and RD contributed to critical revision of the manuscript for important intellectual content. All authors contributed to the article and approved the submitted version.
Conflict of Interest
AV reports advisory board of BMS, MSD, Merck, Pfizer, Ipsen, Eisai, Pierre Fabre, Roche, Novartis, Sanofi, outside the submitted work. RM reports unrestricted grants for investigator-initiated research from Astellas, Bayer, Boehringer-Ingelheim, Cristal Therapeutics, Novartis, Pamgene, Pfizer, Roche, Sanofi, and Servier outside the submitted work. RD has received grants from Merck and Pan-Cancer T BV outside the submitted work.
The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Supplementary Material
The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fimmu.2021.627186/full#supplementary-material
Click here for additional data file.
Click here for additional data file. | Recovering | ReactionOutcome | CC BY | 33613575 | 19,133,955 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Hypophysitis'. | Testosterone deficiency in men receiving immunotherapy for malignant melanoma.
Immunotherapy has been established as a standard of care for patients with malignant melanoma, however, the long-term side-effects of immunotherapy are still emerging. Studies over the last decade have documented increasing reports of endocrine dysfunction following the initiation of immunotherapy. Our study aimed to detect the proportion of men who have low testosterone before, during, and or/after receiving immunotherapy for malignant melanoma, and to determine the proportion of men who receive testosterone replacement therapy after detection of low testosterone. We performed retrospective chart review of patients with malignant melanoma treated with immunotherapy. Low testosterone was identified in 34 out of 49 patients at some point during their treatment with immunotherapy. Despite low testosterone levels in two-thirds of patients, only three patients were treated with testosterone replacement therapy. In addition to laboratory evidence of low testosterone, patients were also symptomatic as 43 out of 49 patients reported fatigue to their providers. Four patients developed hypophysitis and subsequent hypopituitarism, all of whom were receiving Ipilimumab. We conclude that patients with stage 3 or 4 melanoma treated with immunotherapy appear to be at an increased risk of developing testosterone deficiency during their treatment.
INTRODUCTION
Malignant melanoma is one of the fastest growing cancers worldwide and men account for 60% of new diagnoses [1]. Fortunately, cancer treatments have greatly improved and those impacted by cancer are now living longer. Immunotherapy has been established as a standard of care for patients with malignant melanoma, however, the long-term side-effects of immunotherapy are still emerging [2].
It has been well documented that cancer treatment-related toxicities create short and long-term side effects, which can significantly impair the quality of life of cancer survivors. Conventional chemotherapy agents have been thoroughly studied, and there are an abundance of data detailing the negative effects of chemotherapy on testosterone levels, fertility, and the quality of life of cancer patients [3–5]. As immunotherapy is a relatively new treatment for cancer, their side effects on testosterone levels have not been as extensively explored.
Immune checkpoint inhibitors, which are intravenously administered therapies used to treat melanoma, include anti-programmed death-1 (anti-PD-1) antibodies (Pembrolizumab, Nivolumab) and anti-cytotoxic T-lymphocyte antigen-4 inhibition (anti-CTLA4) antibodies (Ipilimumab). There have also been recent developments of investigational therapies, including Indoximod and intratumoral SD-101. Intratumoral SD-101, a synthetic CpG oligonucleotide that stimulates Toll-like receptor 9 (TLR9) and is directly injected into the tumor site, has been shown to increase effectiveness of immune activation at the tumor site when used in combination with PD-1 inhibitors [6]. Indoximod, an inhibitor of the indoleamine 2,3-dioxygenase (IDO) pathway and is administered orally, has many effects on immune regulation allowing for the restoration of immune reactivity against cancer after there has been primary treatment with an active immunization processes (i.e., checkpoint inhibitor therapy) [7, 8]. The duration of treatment for unresectable and metastatic melanoma is currently recommended to continue until there is either disease progression or unacceptable toxicity, however, it is recommended to continue for approximately one year if used as an adjuvant therapy.
While side effects of immunotherapy have not been as comprehensively studied as older therapies, there are known adverse effects related to the attempted modulation of the immune system, including nonspecific inflammation and autoimmunity [9]. Studies over the last decade have begun documenting increasing reports of endocrine dysfunction following the initiation of immunotherapy. Specifically, hypophysitis, or inflammation of the pituitary gland, has been reported in 9–13% of patients treated with immunotherapy [3, 10–15]. Most of the patients who developed hypophysitis received Ipilimumab and there were higher rates observed in males (16.1%) than females (8.7%) [15–17]. Hypophysitis results in dysfunction of the pituitary gland and can cause a deficiency of one or more pituitary hormones, including luteinizing hormone (LH), which may then lead to testosterone deficiency. Thus far, no studies have specifically focused on androgen levels associated with immunotherapy or the clinical significance of androgen hormone deficiency. In our literature review, there was only one study which investigated testosterone levels following immunotherapy. The study reported incidences of Ipilimumab-associated low testosterone, in the absence of hypophysitis, in nine out of 256 patients assessed [15]. However, this study did not routinely assess testosterone levels and few measurements were actually obtained. Additionally, reassessment of testosterone levels was not always performed, so it is difficult to ascertain whether the low testosterone levels were transient or permanent.
Symptoms of low testosterone can be nonspecific and include fatigue, weight fluctuations, muscle loss, depression, insomnia, and sexual dysfunction [4, 18]. Sexual symptoms of androgen deficiency include decreased libido and erectile dysfunction [18, 19]. The implications of sexual dysfunction are far reaching, and may include reduction in self-esteem, impact on relationships, anxiety, and depression [4, 18]. It has been documented that male cancer survivors are likely to experience fatigue, impaired quality of life, and sexual dysfunction, regardless of type of cancer treatment received, and these effects are exacerbated by those with concurrent androgen deficiency [4, 5].
While the impact from chemotherapy agents on patients’ reproductive potential is well known, the impact from immunotherapy still needs to be established, as melanoma is becoming more prevalent in the AYA (adolescent and young adult) population [20–22]. Preclinical studies of Ipilimumab in monkeys demonstrated a clinically significant decrease in testicular weight, with no evidence of sperm histopathology changes [20]. A small study assessing testicular histopathology after immunotherapy for metastatic melanoma found evidence that spermatogenesis may be impacted by immunotherapies, however, the mechanism remains unclear [23]. While it is difficult to calculate fertility risk based on these small studies, there is concern for some level of gonadal dysfunction that needs to be further explored [24].
While immunotherapy has proven to be a successful treatment option for melanoma, there is concern for treatment-related dysfunction of the hypothalamic-pituitary-gonadal axis, which may impair quality of life [4, 5, 18, 20]. As immunotherapy is now widely used for a variety of cancers specifically in early stages, including non-small cell lung cancer, bladder cancer, renal cell carcinoma, and Hodgkin’s lymphoma [13], understanding the side effects associated with immunotherapy, while keeping in mind the direct impact of the treated malignancy, will allow for better recognition and earlier treatment for adverse effects in many future patients.
The aims of our study include: (1) detect the proportion of men who have low testosterone levels before, during, and or/after receiving immunotherapy for malignant melanoma; (2) identify risk factors for development of low testosterone levels during treatment with immunotherapy; (3) and determine the proportion of men who receive testosterone replacement therapy after detection of low testosterone levels.
RESULTS
Forty-nine patients met inclusion criteria. Patient demographics are reported in Table 1. Median age at diagnosis was 64 (33–92) years. Fifteen patients had stage 3, 33 patients had stage 4, and one patient had a primary pineal gland melanoma that was not staged. At the time of analysis, 16 patients were deceased and 31 patients were alive, 13 of whom were tumor free. Two patients transferred care to a local cancer center and their status was unknown. Patients were treated with Pembrolizumab, Ipilimumab, Nivolumab, or investigational immunotherapy agents Indoximod and intratumoral SD-101 (Figure 1). Of the 49 patients who received immunotherapy, 45 of these patients had metastatic disease. The other four patients received immunotherapy as adjuvant therapy for melanoma.
Table 1 Patient demographics at time of diagnosis
Patient Demographics
n, %
Number of patients, male 49 (100%)
Staging:
Stage 3 15 (30.6%)
Stage 4 33 (67%)
Primary pineal gland melanoma 1 (0.2%)
Previous history of melanoma 3 (6.1%)
Obesity 26 (53.1%)
Diabetes 10 (20.4%)
Heart disease (CAD, HTN) 35 (71.4%)
Hypothyroidism 8 (16.3%)
Obstructive sleep apnea 5 (10.2%)
Chronic kidney disease 3 (6.1%)
Corticosteroid use 1 (2.0%)
Opioid use 4 (8.2%)
Pre-existing autoimmune disease 2 (4.1%)
Previous cancer diagnosis 10 (20.4%)
Type of cancer:
Basal cell carcinoma 2 (20.0%)
Bladder cancer 1 (10.0%)
Colon cancer 1 (10.0%)
Diffuse large B cell lymphoma 1 (10.0%)
Hodgkin’s lymphoma 1 (10.0%)
Neuroendocrine tumor 1 (10.0%)
Prostate cancer 3 (30.0%)
Received radiation therapy 26 (53.1%)
Type of radiation:
Local 12 (46.2%)
Brain 14 (53.8%)
Enrolled in clinical trial 14 (28.6%)
Figure 1 The different rows demonstrate each patient’s treatment paradigm across time.
The heterogeneity in treatment regimens made it difficult to distinguish how each individual immunotherapy agent affected testosterone levels. On covariate analysis, there was no significant association between testosterone levels and treatment modality.
Low testosterone was identified in 34 out of 49 patients at some point during treatment with immunotherapy (Figure 2). Of these 34 patients with low testosterone, eight had their testosterone levels return to > 300 ng/dL within three months after detection. One patient’s testosterone level returned to normal after one year. Twenty-five patients with low testosterone did not see a complete recovery in their testosterone levels throughout the remainder of their follow-up. Four patients developed hypophysitis and subsequent hypopituitarism, all of whom received Ipilimumab. All patients who developed hypophysitis began showing evidence of hypopituitarism after 2–3 doses of Ipilimumab. Forty-three patients reported fatigue to their provider during their treatment with immunotherapy. Only three patients, all diagnosed with hypopituitarism, were treated with testosterone replacement therapy. The fourth patient diagnosed with hypopituitarism was treated with corticosteroids. Ten (29%) of the patients who developed low testosterone had normal testosterone levels prior to initiation of immunotherapy (Table 2). Eight (24%) of the patients had a low baseline testosterone prior to immunotherapy initiation, and their levels remained low throughout their treatment. Thirteen (38%) of the patients identified with low testosterone did not have a baseline testosterone level checked prior to starting immunotherapy. Three (9%) of the patients had low baseline testosterone levels, however, they also had brain radiation within two months prior to checking their baseline level.
Figure 2 Testosterone levels assessed after initiation of immunotherapy.
The red line is a reference for 300 ng/dL. There was large intrapersonal variability in testosterone levels, as demonstrated by the oscillating values within each patient. However, it is evident many patients had testosterone levels drop below 300 ng/dL, with many of those patients dipping well below 200 ng/dL.
Table 2 Additional clinical information of the patients with previously normal testosterone who subsequently developed low testosterone after treatment with immunotherapy
Clinical information of patients with normal T who developed low T after immunotherapy
Pt Age at diagnosis Immunotherapy Agent(s) Baseline T Lowest T value Resolution of low T Comorbidities Radiation Clinical trial Endocrine dysfunction during tx
1 50 Ipilimumab, Pembrolizumab Normal (314) 55 No Heart disease Local - -
2 72 Ipilimumab Normal (498) 78 No - - - -
3 66 Pembrolizumab Normal (319) 144 No Heart disease Brain - Pituitary, adrenal
4 61 Ipilimumab, Pembrolizumab Normal (338) 69 No Obese, heart disease, diabetes, hypothyroid Brain Yes -
5 82 Pembrolizumab Normal (399) 181 No Heart disease, diabetes - - -
6 59 Ipilimumab, Pembrolizumab Normal (419) < 5 No Obesity, heart disease Local - Hypophysitis
7 35 Ipilimumab, Pembrolizumab Normal (524) 170 Yes Obesity Brain Yes Pituitary, thyroid
8 85 Pembrolizumab Normal (351) 206 Yes Obesity, heart disease, previous prostate cancer - - Pituitary, adrenal
9 46 Pembrolizumab Normal (369) 22 Yes - - - Adrenal
10 52 Pembrolizumab Normal (456) 133 Yes Obesity, heart disease, OSA, previous melanoma Local - Pituitary, adrenal, and thyroid
Avg:
60.8
398.7
105.8
While these patients had diverse treatment courses, most of these patients had multiple comorbidities prior to their development of low testosterone.
Covariate analysis demonstrated no significant association between low testosterone and treatment with either Ipilimumab, Pembrolizumab, or Nivolumab. On univariate analysis, obesity and enrollment in a clinical trial were associated with lower testosterone levels (Table 3). During the treatment course with immunotherapy, 19 patients had evidence of pituitary dysfunction, 16 patients had evidence of adrenal dysfunction, and 18 patients had evidence of thyroid dysfunction. On univariate analysis, a trend was noted between testosterone and adrenal dysfunction and thyroid dysfunction. On multivariable analysis (Table 4), participation in a clinical trial and weeks since immunotherapy initiation were significant (p < 0.01), and a trend was noted for thyroid dysfunction (p = 0.08) and adrenal dysfunction (p = 0.08). More specifically, clinical trial patients had testosterone levels that were 80.38 ng/dL lower on average. There was not a clinically significant difference between clinical trial enrollment and cancer stage. Of the 15 patients with stage 3, five were enrolled in a clinical trial; while there were nine out of 33 patients with stage 4 enrolled in a clinical trial. Testosterone levels declined at a rate of 0.71 ng/dL per week, on average. Obesity, adrenal dysfunction, and thyroid dysfunction tended to be associated with lower testosterone levels.
Table 3 Univariate analysis assessing for associations with low testosterone and patient demographics, co-morbidities, treatment modalities, and treatment complications
Covariate Univariate Analysis
Testosterone (ng/dL)
Level Beta 95% CI
P-value
Obesity Yes –56.71 –110.41 –3.01 0.04
No Ref - -
Diabetes Yes –18.77 –89.16 51.63 0.60
No Ref - -
Heart Disease (CAD, HTN) Yes –16.97 –78.93 44.99 0.59
No Ref - -
Cancer Stage 4 –18.05 –81.07 44.97 0.57
3 Ref - -
Other Cancer Diagnoses Yes 40.46 –27.45 108.37 0.24
No Ref - -
Clinical trial Yes –87.04 –143.19 –30.88 < 0.01
No Ref - -
Radiation Yes –17.80 –65.16 29.56 0.46
No Ref - -
Radiation Local –2.81 –63.67 58.04 0.56
Brain –34.24 –97.67 29.20
Pituitary Yes –22.01 –64.11 20.08 0.30
No Ref - -
Adrenal Yes –45.52 –96.51 5.47 0.08
No Ref - -
Thyroid Yes –40.99 –86.22 4.23 0.08
No Ref - -
Testosterone Replacement Yes 98.91 –11.35 209.17 0.08
No Ref - -
Age Units = 1 0.64 –1.35 2.63 0.52
BMI at diagnosis Units = 1 –4.22 –9.80 1.36 0.14
Months Since Diagnosis Units = 1 –2.13 –5.02 0.75 0.14
Time obtained (minutes) Units = 60 0.06 –2.81 2.93 0.97
Weeks Since Immunotherapy Initiation Units = 1 0.44 –0.11 0.99 0.12
Obesity and enrollment in a clinical trial were associated with low testosterone. A trend is observed between low testosterone and adrenal and thyroid dysfunction.
Table 4 Multivariable model was utilized to include variables that were significant or nearly significant on univariate analysis
Multivariable analysis
Covariate Testosterone (ng/dL)
Level Beta 95% CI
P-value
Intercept 348.53 300.37 396.69
< 0.01
Obesity Yes –36.72 –90.57 17.13 0.18
No Ref - -
Clinical trial Yes –80.35 –139.85 –20.86
< 0.01
No Ref - -
Adrenal Yes –50.54 –108.60 7.53 0.08
No Ref - -
Thyroid Yes –43.84 –94.37 6.69 0.08
No Ref - -
Testosterone Replacement Yes 135.84 –109.79 381.48 0.14
No Ref - -
Weeks Since Immunotherapy Initiation Units = 1 0.71 0.18 1.25
< 0.01
Enrollment in a clinical trial and weeks since immunotherapy initiation were significant.
DISCUSSION
In our cohort, roughly two-thirds of patients developed low testosterone at some point during their treatment with immunotherapy. While some patients did have a recovery in their testosterone levels after a few months, over half of the patients continued to have low testosterone levels throughout the remainder of their follow-up. Despite persistently low testosterone levels in 25 patients, only three patients were treated with testosterone replacement therapy, all of whom had hypophysitis and testosterone levels < 5 ng/dL. In addition to laboratory evidence of low testosterone, patients were also symptomatic as the vast majority of patients reported fatigue to their providers. The three patients who received testosterone replacement therapy reported improved energy levels after treatment, however, they also received steroids and thyroid replacement therapy so it cannot be determined from our study whether testosterone replacement directly improves energy in these patients. While many factors contribute to fatigue, low testosterone levels may be playing an important role in the development of fatigue in these cancer patients. There was no chart documentation of whether providers assessed for other symptoms of low testosterone, including low libido or sexual dysfunction. These findings suggest that providers may be under-diagnosing and under-treating low testosterone in melanoma patients receiving immunotherapy.
Out of our patient population, 8% developed hypophysitis. All four patients showed evidence of hypopituitarism within three months of initiation of Ipilimumab, which has been documented in previous studies [15–17]. These data suggest that patients being treated with Ipilimumab need diligent monitoring of their endocrine function during the first three months of their treatment and up to 12 months after completion of their immunotherapy treatment [25].
In our study, there were clinically significant associations of low testosterone with obesity and patients that were enrolled in a clinical trial. It has been well documented that obesity is associated with low testosterone due to the high expression of aromatase in adipocytes, which converts testosterone to estradiol and lowers circulating androgens [26]. Of the 14 patients enrolled in a clinical trial, 10 of these patients developed low testosterone. The type of clinical trial each patient participated in was extremely variable, however, Indoximod and high dose (10 mg/kg) Ipilimumab were utilized most frequently. These patients may have been more likely to develop lower testosterone levels due to the higher dose of immunotherapy and the use of investigational immunotherapy agents, the side effects of which have not been completely studied. Additionally, Indoximod was used in conjunction with an anti-PD1 immunotherapy agent. The use of two immunotherapy agents has typically shown to have a synergistic effect on cancer control. This synergy may also reflect how immunotherapy affects testosterone levels, and therefore, those patients who are receiving two types of immunotherapy could be more susceptible to developing low testosterone. There may have also been a delayed effect of prior therapeutic agents used to treat melanoma on testosterone levels. On multivariable analysis, there was also an association with decreasing testosterone levels and weeks since initiation of immunotherapy. On average, the testosterone levels declined at a rate of 0.71 ng/dL per week. This change is minimal and most likely not clinically significant.
To our knowledge, this is the first study directly analyzing the effect of immunotherapy on testosterone levels in patients with melanoma. One limitation of this study is the low number of analyzed patients. While there were 143 male patients with malignant melanoma that received immunotherapy from 2009–2019, only 49 patients had at least two testosterone levels drawn. There were also inconsistencies as to when these patients had their testosterone levels checked. Only 30 of the 49 patients had a baseline testosterone level checked prior to initiation of immunotherapy. The other 19 patients had their level checked some variable amount of time after receiving immunotherapy. Additionally, further assessments of testosterone levels were not at regular intervals. Because roughly half of the patients had irregular assessment of testosterone levels, we are unable to report the causality of low testosterone.
Another limitation of this study is the heterogeneity within each patient’s treatment course, which made it difficult to analyze patients based on specific treatment received. Specifically, of the 34 patients identified with low testosterone during immunotherapy treatment, two patients were also being treated with steroids and five patients received concurrent radiation therapy (one received retroperitoneal radiation while the other four received brain radiation). It cannot be determined whether the low testosterone was due to immunotherapy and/or the concurrent treatment with steroids or radiation therapy.
As this was a retrospective study, fertility was not assessed in these patients. However, as melanoma is becoming more prevalent in the AYA population, future work needs to be completed to addresses any potential fertility risk in melanoma patients receiving immunotherapy, with particular attention to sperm count and function.
In conclusion, patients with stage 3 or 4 melanoma treated with immunotherapy appear to be at an increased risk of developing testosterone deficiency during their treatment. The majority of patients also report fatigue, which is commonly associated with low testosterone levels, yet only a minority of those with low levels received testosterone supplementation. Patients who are obese and have been enrolled in a clinical trial appear to be at increased risk of developing low testosterone during treatment with immunotherapy, and these patients would benefit from close observation and potentially testosterone replacement therapy. Encouraging weight loss in obese patients diagnosed with low testosterone should also be considered in conjunction with testosterone replacement therapy. Regardless of the reason for the development of low testosterone, our study has identified that this patient population is at risk for under-diagnosis and under-treatment of low testosterone. Further research needs to be performed to assess whether or not testosterone supplementation improves patient-reported outcomes in this patient population.
MATERIALS AND METHODS
After seeking Institutional Review Board and Ethics approval, we performed a retrospective chart review of patients with malignant melanoma treated with immunotherapy at Holden Comprehensive Cancer Center from 2009–2019 using the Melanoma Molecular Epidemiology Resource database. Patients were included in the analysis if they had at least two testosterone levels checked while on immunotherapy (Figure 3). Low testosterone was defined in this study as total testosterone < 300 ng/dL upon two consecutive lab draws, according to American Urological Association (AUA) guidelines on testosterone deficiency [27]. Blood was collected and total testosterone was assessed via electrochemiluminscence immunoassay.
Figure 3 Systematic review of 149 patients.
Patients were excluded in the study if they had fewer than two assessments of testosterone levels.
Patients were also evaluated for pituitary, adrenal, and thyroid dysfunction, based on the reference ranges from Clinical Laboratory Improvement Amendments certified laboratory at the University of Iowa Hospitals and Clinics. Pituitary dysfunction was defined as adrenocorticotropic hormone (ACTH) < 7 pg/mL. Adrenal dysfunction was defined as cortisol < 3 μg/dL. Thyroid dysfunction was defined as TSH < 0.27 or > 4.20 μIU/mL. Patient demographics and co-morbidities were gathered from chart review. Obesity was classified as BMI > 30 at the time of initial office visit.
Mixed effects regression models were applied to assess for changes in serum testosterone levels over time while adjusting for potential confounders. Time-dependent covariates were incorporated to capture changes in treatment and onset of other medical conditions. Random effects were included to account for the longitudinally correlated nature of repeat assessment and unequal time spacing between visits. Beta coefficients and 95% confidence intervals are reported. All statistical testing was two-sided and assessed for significance at the 5% level using SAS v9.4 (SAS Institute, Cary, NC). Power calculations were not performed, as this was a retrospective study meant to gain preliminary estimates of the true underlying population values.
Author contributions
A.P., V.M., and W.T. conceived the presented idea. M.P. collected the data for analysis. S.M. analyzed the data and performed the computations. All authors discussed the results. M.P. wrote the manuscript with support from A.P., V.M., W.T., and S.M.
CONFLICTS OF INTEREST
Authors have no conflicts of interest to declare.
FUNDING
This project was in part supported by the National Cancer Institute Cancer Center Support Grant 5P30CA086862-09 (P30). | IPILIMUMAB, PEMBROLIZUMAB | DrugsGivenReaction | CC BY | 33613847 | 19,055,902 | 2021-02-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Hypothalamo-pituitary disorder'. | Testosterone deficiency in men receiving immunotherapy for malignant melanoma.
Immunotherapy has been established as a standard of care for patients with malignant melanoma, however, the long-term side-effects of immunotherapy are still emerging. Studies over the last decade have documented increasing reports of endocrine dysfunction following the initiation of immunotherapy. Our study aimed to detect the proportion of men who have low testosterone before, during, and or/after receiving immunotherapy for malignant melanoma, and to determine the proportion of men who receive testosterone replacement therapy after detection of low testosterone. We performed retrospective chart review of patients with malignant melanoma treated with immunotherapy. Low testosterone was identified in 34 out of 49 patients at some point during their treatment with immunotherapy. Despite low testosterone levels in two-thirds of patients, only three patients were treated with testosterone replacement therapy. In addition to laboratory evidence of low testosterone, patients were also symptomatic as 43 out of 49 patients reported fatigue to their providers. Four patients developed hypophysitis and subsequent hypopituitarism, all of whom were receiving Ipilimumab. We conclude that patients with stage 3 or 4 melanoma treated with immunotherapy appear to be at an increased risk of developing testosterone deficiency during their treatment.
INTRODUCTION
Malignant melanoma is one of the fastest growing cancers worldwide and men account for 60% of new diagnoses [1]. Fortunately, cancer treatments have greatly improved and those impacted by cancer are now living longer. Immunotherapy has been established as a standard of care for patients with malignant melanoma, however, the long-term side-effects of immunotherapy are still emerging [2].
It has been well documented that cancer treatment-related toxicities create short and long-term side effects, which can significantly impair the quality of life of cancer survivors. Conventional chemotherapy agents have been thoroughly studied, and there are an abundance of data detailing the negative effects of chemotherapy on testosterone levels, fertility, and the quality of life of cancer patients [3–5]. As immunotherapy is a relatively new treatment for cancer, their side effects on testosterone levels have not been as extensively explored.
Immune checkpoint inhibitors, which are intravenously administered therapies used to treat melanoma, include anti-programmed death-1 (anti-PD-1) antibodies (Pembrolizumab, Nivolumab) and anti-cytotoxic T-lymphocyte antigen-4 inhibition (anti-CTLA4) antibodies (Ipilimumab). There have also been recent developments of investigational therapies, including Indoximod and intratumoral SD-101. Intratumoral SD-101, a synthetic CpG oligonucleotide that stimulates Toll-like receptor 9 (TLR9) and is directly injected into the tumor site, has been shown to increase effectiveness of immune activation at the tumor site when used in combination with PD-1 inhibitors [6]. Indoximod, an inhibitor of the indoleamine 2,3-dioxygenase (IDO) pathway and is administered orally, has many effects on immune regulation allowing for the restoration of immune reactivity against cancer after there has been primary treatment with an active immunization processes (i.e., checkpoint inhibitor therapy) [7, 8]. The duration of treatment for unresectable and metastatic melanoma is currently recommended to continue until there is either disease progression or unacceptable toxicity, however, it is recommended to continue for approximately one year if used as an adjuvant therapy.
While side effects of immunotherapy have not been as comprehensively studied as older therapies, there are known adverse effects related to the attempted modulation of the immune system, including nonspecific inflammation and autoimmunity [9]. Studies over the last decade have begun documenting increasing reports of endocrine dysfunction following the initiation of immunotherapy. Specifically, hypophysitis, or inflammation of the pituitary gland, has been reported in 9–13% of patients treated with immunotherapy [3, 10–15]. Most of the patients who developed hypophysitis received Ipilimumab and there were higher rates observed in males (16.1%) than females (8.7%) [15–17]. Hypophysitis results in dysfunction of the pituitary gland and can cause a deficiency of one or more pituitary hormones, including luteinizing hormone (LH), which may then lead to testosterone deficiency. Thus far, no studies have specifically focused on androgen levels associated with immunotherapy or the clinical significance of androgen hormone deficiency. In our literature review, there was only one study which investigated testosterone levels following immunotherapy. The study reported incidences of Ipilimumab-associated low testosterone, in the absence of hypophysitis, in nine out of 256 patients assessed [15]. However, this study did not routinely assess testosterone levels and few measurements were actually obtained. Additionally, reassessment of testosterone levels was not always performed, so it is difficult to ascertain whether the low testosterone levels were transient or permanent.
Symptoms of low testosterone can be nonspecific and include fatigue, weight fluctuations, muscle loss, depression, insomnia, and sexual dysfunction [4, 18]. Sexual symptoms of androgen deficiency include decreased libido and erectile dysfunction [18, 19]. The implications of sexual dysfunction are far reaching, and may include reduction in self-esteem, impact on relationships, anxiety, and depression [4, 18]. It has been documented that male cancer survivors are likely to experience fatigue, impaired quality of life, and sexual dysfunction, regardless of type of cancer treatment received, and these effects are exacerbated by those with concurrent androgen deficiency [4, 5].
While the impact from chemotherapy agents on patients’ reproductive potential is well known, the impact from immunotherapy still needs to be established, as melanoma is becoming more prevalent in the AYA (adolescent and young adult) population [20–22]. Preclinical studies of Ipilimumab in monkeys demonstrated a clinically significant decrease in testicular weight, with no evidence of sperm histopathology changes [20]. A small study assessing testicular histopathology after immunotherapy for metastatic melanoma found evidence that spermatogenesis may be impacted by immunotherapies, however, the mechanism remains unclear [23]. While it is difficult to calculate fertility risk based on these small studies, there is concern for some level of gonadal dysfunction that needs to be further explored [24].
While immunotherapy has proven to be a successful treatment option for melanoma, there is concern for treatment-related dysfunction of the hypothalamic-pituitary-gonadal axis, which may impair quality of life [4, 5, 18, 20]. As immunotherapy is now widely used for a variety of cancers specifically in early stages, including non-small cell lung cancer, bladder cancer, renal cell carcinoma, and Hodgkin’s lymphoma [13], understanding the side effects associated with immunotherapy, while keeping in mind the direct impact of the treated malignancy, will allow for better recognition and earlier treatment for adverse effects in many future patients.
The aims of our study include: (1) detect the proportion of men who have low testosterone levels before, during, and or/after receiving immunotherapy for malignant melanoma; (2) identify risk factors for development of low testosterone levels during treatment with immunotherapy; (3) and determine the proportion of men who receive testosterone replacement therapy after detection of low testosterone levels.
RESULTS
Forty-nine patients met inclusion criteria. Patient demographics are reported in Table 1. Median age at diagnosis was 64 (33–92) years. Fifteen patients had stage 3, 33 patients had stage 4, and one patient had a primary pineal gland melanoma that was not staged. At the time of analysis, 16 patients were deceased and 31 patients were alive, 13 of whom were tumor free. Two patients transferred care to a local cancer center and their status was unknown. Patients were treated with Pembrolizumab, Ipilimumab, Nivolumab, or investigational immunotherapy agents Indoximod and intratumoral SD-101 (Figure 1). Of the 49 patients who received immunotherapy, 45 of these patients had metastatic disease. The other four patients received immunotherapy as adjuvant therapy for melanoma.
Table 1 Patient demographics at time of diagnosis
Patient Demographics
n, %
Number of patients, male 49 (100%)
Staging:
Stage 3 15 (30.6%)
Stage 4 33 (67%)
Primary pineal gland melanoma 1 (0.2%)
Previous history of melanoma 3 (6.1%)
Obesity 26 (53.1%)
Diabetes 10 (20.4%)
Heart disease (CAD, HTN) 35 (71.4%)
Hypothyroidism 8 (16.3%)
Obstructive sleep apnea 5 (10.2%)
Chronic kidney disease 3 (6.1%)
Corticosteroid use 1 (2.0%)
Opioid use 4 (8.2%)
Pre-existing autoimmune disease 2 (4.1%)
Previous cancer diagnosis 10 (20.4%)
Type of cancer:
Basal cell carcinoma 2 (20.0%)
Bladder cancer 1 (10.0%)
Colon cancer 1 (10.0%)
Diffuse large B cell lymphoma 1 (10.0%)
Hodgkin’s lymphoma 1 (10.0%)
Neuroendocrine tumor 1 (10.0%)
Prostate cancer 3 (30.0%)
Received radiation therapy 26 (53.1%)
Type of radiation:
Local 12 (46.2%)
Brain 14 (53.8%)
Enrolled in clinical trial 14 (28.6%)
Figure 1 The different rows demonstrate each patient’s treatment paradigm across time.
The heterogeneity in treatment regimens made it difficult to distinguish how each individual immunotherapy agent affected testosterone levels. On covariate analysis, there was no significant association between testosterone levels and treatment modality.
Low testosterone was identified in 34 out of 49 patients at some point during treatment with immunotherapy (Figure 2). Of these 34 patients with low testosterone, eight had their testosterone levels return to > 300 ng/dL within three months after detection. One patient’s testosterone level returned to normal after one year. Twenty-five patients with low testosterone did not see a complete recovery in their testosterone levels throughout the remainder of their follow-up. Four patients developed hypophysitis and subsequent hypopituitarism, all of whom received Ipilimumab. All patients who developed hypophysitis began showing evidence of hypopituitarism after 2–3 doses of Ipilimumab. Forty-three patients reported fatigue to their provider during their treatment with immunotherapy. Only three patients, all diagnosed with hypopituitarism, were treated with testosterone replacement therapy. The fourth patient diagnosed with hypopituitarism was treated with corticosteroids. Ten (29%) of the patients who developed low testosterone had normal testosterone levels prior to initiation of immunotherapy (Table 2). Eight (24%) of the patients had a low baseline testosterone prior to immunotherapy initiation, and their levels remained low throughout their treatment. Thirteen (38%) of the patients identified with low testosterone did not have a baseline testosterone level checked prior to starting immunotherapy. Three (9%) of the patients had low baseline testosterone levels, however, they also had brain radiation within two months prior to checking their baseline level.
Figure 2 Testosterone levels assessed after initiation of immunotherapy.
The red line is a reference for 300 ng/dL. There was large intrapersonal variability in testosterone levels, as demonstrated by the oscillating values within each patient. However, it is evident many patients had testosterone levels drop below 300 ng/dL, with many of those patients dipping well below 200 ng/dL.
Table 2 Additional clinical information of the patients with previously normal testosterone who subsequently developed low testosterone after treatment with immunotherapy
Clinical information of patients with normal T who developed low T after immunotherapy
Pt Age at diagnosis Immunotherapy Agent(s) Baseline T Lowest T value Resolution of low T Comorbidities Radiation Clinical trial Endocrine dysfunction during tx
1 50 Ipilimumab, Pembrolizumab Normal (314) 55 No Heart disease Local - -
2 72 Ipilimumab Normal (498) 78 No - - - -
3 66 Pembrolizumab Normal (319) 144 No Heart disease Brain - Pituitary, adrenal
4 61 Ipilimumab, Pembrolizumab Normal (338) 69 No Obese, heart disease, diabetes, hypothyroid Brain Yes -
5 82 Pembrolizumab Normal (399) 181 No Heart disease, diabetes - - -
6 59 Ipilimumab, Pembrolizumab Normal (419) < 5 No Obesity, heart disease Local - Hypophysitis
7 35 Ipilimumab, Pembrolizumab Normal (524) 170 Yes Obesity Brain Yes Pituitary, thyroid
8 85 Pembrolizumab Normal (351) 206 Yes Obesity, heart disease, previous prostate cancer - - Pituitary, adrenal
9 46 Pembrolizumab Normal (369) 22 Yes - - - Adrenal
10 52 Pembrolizumab Normal (456) 133 Yes Obesity, heart disease, OSA, previous melanoma Local - Pituitary, adrenal, and thyroid
Avg:
60.8
398.7
105.8
While these patients had diverse treatment courses, most of these patients had multiple comorbidities prior to their development of low testosterone.
Covariate analysis demonstrated no significant association between low testosterone and treatment with either Ipilimumab, Pembrolizumab, or Nivolumab. On univariate analysis, obesity and enrollment in a clinical trial were associated with lower testosterone levels (Table 3). During the treatment course with immunotherapy, 19 patients had evidence of pituitary dysfunction, 16 patients had evidence of adrenal dysfunction, and 18 patients had evidence of thyroid dysfunction. On univariate analysis, a trend was noted between testosterone and adrenal dysfunction and thyroid dysfunction. On multivariable analysis (Table 4), participation in a clinical trial and weeks since immunotherapy initiation were significant (p < 0.01), and a trend was noted for thyroid dysfunction (p = 0.08) and adrenal dysfunction (p = 0.08). More specifically, clinical trial patients had testosterone levels that were 80.38 ng/dL lower on average. There was not a clinically significant difference between clinical trial enrollment and cancer stage. Of the 15 patients with stage 3, five were enrolled in a clinical trial; while there were nine out of 33 patients with stage 4 enrolled in a clinical trial. Testosterone levels declined at a rate of 0.71 ng/dL per week, on average. Obesity, adrenal dysfunction, and thyroid dysfunction tended to be associated with lower testosterone levels.
Table 3 Univariate analysis assessing for associations with low testosterone and patient demographics, co-morbidities, treatment modalities, and treatment complications
Covariate Univariate Analysis
Testosterone (ng/dL)
Level Beta 95% CI
P-value
Obesity Yes –56.71 –110.41 –3.01 0.04
No Ref - -
Diabetes Yes –18.77 –89.16 51.63 0.60
No Ref - -
Heart Disease (CAD, HTN) Yes –16.97 –78.93 44.99 0.59
No Ref - -
Cancer Stage 4 –18.05 –81.07 44.97 0.57
3 Ref - -
Other Cancer Diagnoses Yes 40.46 –27.45 108.37 0.24
No Ref - -
Clinical trial Yes –87.04 –143.19 –30.88 < 0.01
No Ref - -
Radiation Yes –17.80 –65.16 29.56 0.46
No Ref - -
Radiation Local –2.81 –63.67 58.04 0.56
Brain –34.24 –97.67 29.20
Pituitary Yes –22.01 –64.11 20.08 0.30
No Ref - -
Adrenal Yes –45.52 –96.51 5.47 0.08
No Ref - -
Thyroid Yes –40.99 –86.22 4.23 0.08
No Ref - -
Testosterone Replacement Yes 98.91 –11.35 209.17 0.08
No Ref - -
Age Units = 1 0.64 –1.35 2.63 0.52
BMI at diagnosis Units = 1 –4.22 –9.80 1.36 0.14
Months Since Diagnosis Units = 1 –2.13 –5.02 0.75 0.14
Time obtained (minutes) Units = 60 0.06 –2.81 2.93 0.97
Weeks Since Immunotherapy Initiation Units = 1 0.44 –0.11 0.99 0.12
Obesity and enrollment in a clinical trial were associated with low testosterone. A trend is observed between low testosterone and adrenal and thyroid dysfunction.
Table 4 Multivariable model was utilized to include variables that were significant or nearly significant on univariate analysis
Multivariable analysis
Covariate Testosterone (ng/dL)
Level Beta 95% CI
P-value
Intercept 348.53 300.37 396.69
< 0.01
Obesity Yes –36.72 –90.57 17.13 0.18
No Ref - -
Clinical trial Yes –80.35 –139.85 –20.86
< 0.01
No Ref - -
Adrenal Yes –50.54 –108.60 7.53 0.08
No Ref - -
Thyroid Yes –43.84 –94.37 6.69 0.08
No Ref - -
Testosterone Replacement Yes 135.84 –109.79 381.48 0.14
No Ref - -
Weeks Since Immunotherapy Initiation Units = 1 0.71 0.18 1.25
< 0.01
Enrollment in a clinical trial and weeks since immunotherapy initiation were significant.
DISCUSSION
In our cohort, roughly two-thirds of patients developed low testosterone at some point during their treatment with immunotherapy. While some patients did have a recovery in their testosterone levels after a few months, over half of the patients continued to have low testosterone levels throughout the remainder of their follow-up. Despite persistently low testosterone levels in 25 patients, only three patients were treated with testosterone replacement therapy, all of whom had hypophysitis and testosterone levels < 5 ng/dL. In addition to laboratory evidence of low testosterone, patients were also symptomatic as the vast majority of patients reported fatigue to their providers. The three patients who received testosterone replacement therapy reported improved energy levels after treatment, however, they also received steroids and thyroid replacement therapy so it cannot be determined from our study whether testosterone replacement directly improves energy in these patients. While many factors contribute to fatigue, low testosterone levels may be playing an important role in the development of fatigue in these cancer patients. There was no chart documentation of whether providers assessed for other symptoms of low testosterone, including low libido or sexual dysfunction. These findings suggest that providers may be under-diagnosing and under-treating low testosterone in melanoma patients receiving immunotherapy.
Out of our patient population, 8% developed hypophysitis. All four patients showed evidence of hypopituitarism within three months of initiation of Ipilimumab, which has been documented in previous studies [15–17]. These data suggest that patients being treated with Ipilimumab need diligent monitoring of their endocrine function during the first three months of their treatment and up to 12 months after completion of their immunotherapy treatment [25].
In our study, there were clinically significant associations of low testosterone with obesity and patients that were enrolled in a clinical trial. It has been well documented that obesity is associated with low testosterone due to the high expression of aromatase in adipocytes, which converts testosterone to estradiol and lowers circulating androgens [26]. Of the 14 patients enrolled in a clinical trial, 10 of these patients developed low testosterone. The type of clinical trial each patient participated in was extremely variable, however, Indoximod and high dose (10 mg/kg) Ipilimumab were utilized most frequently. These patients may have been more likely to develop lower testosterone levels due to the higher dose of immunotherapy and the use of investigational immunotherapy agents, the side effects of which have not been completely studied. Additionally, Indoximod was used in conjunction with an anti-PD1 immunotherapy agent. The use of two immunotherapy agents has typically shown to have a synergistic effect on cancer control. This synergy may also reflect how immunotherapy affects testosterone levels, and therefore, those patients who are receiving two types of immunotherapy could be more susceptible to developing low testosterone. There may have also been a delayed effect of prior therapeutic agents used to treat melanoma on testosterone levels. On multivariable analysis, there was also an association with decreasing testosterone levels and weeks since initiation of immunotherapy. On average, the testosterone levels declined at a rate of 0.71 ng/dL per week. This change is minimal and most likely not clinically significant.
To our knowledge, this is the first study directly analyzing the effect of immunotherapy on testosterone levels in patients with melanoma. One limitation of this study is the low number of analyzed patients. While there were 143 male patients with malignant melanoma that received immunotherapy from 2009–2019, only 49 patients had at least two testosterone levels drawn. There were also inconsistencies as to when these patients had their testosterone levels checked. Only 30 of the 49 patients had a baseline testosterone level checked prior to initiation of immunotherapy. The other 19 patients had their level checked some variable amount of time after receiving immunotherapy. Additionally, further assessments of testosterone levels were not at regular intervals. Because roughly half of the patients had irregular assessment of testosterone levels, we are unable to report the causality of low testosterone.
Another limitation of this study is the heterogeneity within each patient’s treatment course, which made it difficult to analyze patients based on specific treatment received. Specifically, of the 34 patients identified with low testosterone during immunotherapy treatment, two patients were also being treated with steroids and five patients received concurrent radiation therapy (one received retroperitoneal radiation while the other four received brain radiation). It cannot be determined whether the low testosterone was due to immunotherapy and/or the concurrent treatment with steroids or radiation therapy.
As this was a retrospective study, fertility was not assessed in these patients. However, as melanoma is becoming more prevalent in the AYA population, future work needs to be completed to addresses any potential fertility risk in melanoma patients receiving immunotherapy, with particular attention to sperm count and function.
In conclusion, patients with stage 3 or 4 melanoma treated with immunotherapy appear to be at an increased risk of developing testosterone deficiency during their treatment. The majority of patients also report fatigue, which is commonly associated with low testosterone levels, yet only a minority of those with low levels received testosterone supplementation. Patients who are obese and have been enrolled in a clinical trial appear to be at increased risk of developing low testosterone during treatment with immunotherapy, and these patients would benefit from close observation and potentially testosterone replacement therapy. Encouraging weight loss in obese patients diagnosed with low testosterone should also be considered in conjunction with testosterone replacement therapy. Regardless of the reason for the development of low testosterone, our study has identified that this patient population is at risk for under-diagnosis and under-treatment of low testosterone. Further research needs to be performed to assess whether or not testosterone supplementation improves patient-reported outcomes in this patient population.
MATERIALS AND METHODS
After seeking Institutional Review Board and Ethics approval, we performed a retrospective chart review of patients with malignant melanoma treated with immunotherapy at Holden Comprehensive Cancer Center from 2009–2019 using the Melanoma Molecular Epidemiology Resource database. Patients were included in the analysis if they had at least two testosterone levels checked while on immunotherapy (Figure 3). Low testosterone was defined in this study as total testosterone < 300 ng/dL upon two consecutive lab draws, according to American Urological Association (AUA) guidelines on testosterone deficiency [27]. Blood was collected and total testosterone was assessed via electrochemiluminscence immunoassay.
Figure 3 Systematic review of 149 patients.
Patients were excluded in the study if they had fewer than two assessments of testosterone levels.
Patients were also evaluated for pituitary, adrenal, and thyroid dysfunction, based on the reference ranges from Clinical Laboratory Improvement Amendments certified laboratory at the University of Iowa Hospitals and Clinics. Pituitary dysfunction was defined as adrenocorticotropic hormone (ACTH) < 7 pg/mL. Adrenal dysfunction was defined as cortisol < 3 μg/dL. Thyroid dysfunction was defined as TSH < 0.27 or > 4.20 μIU/mL. Patient demographics and co-morbidities were gathered from chart review. Obesity was classified as BMI > 30 at the time of initial office visit.
Mixed effects regression models were applied to assess for changes in serum testosterone levels over time while adjusting for potential confounders. Time-dependent covariates were incorporated to capture changes in treatment and onset of other medical conditions. Random effects were included to account for the longitudinally correlated nature of repeat assessment and unequal time spacing between visits. Beta coefficients and 95% confidence intervals are reported. All statistical testing was two-sided and assessed for significance at the 5% level using SAS v9.4 (SAS Institute, Cary, NC). Power calculations were not performed, as this was a retrospective study meant to gain preliminary estimates of the true underlying population values.
Author contributions
A.P., V.M., and W.T. conceived the presented idea. M.P. collected the data for analysis. S.M. analyzed the data and performed the computations. All authors discussed the results. M.P. wrote the manuscript with support from A.P., V.M., W.T., and S.M.
CONFLICTS OF INTEREST
Authors have no conflicts of interest to declare.
FUNDING
This project was in part supported by the National Cancer Institute Cancer Center Support Grant 5P30CA086862-09 (P30). | IPILIMUMAB, PEMBROLIZUMAB | DrugsGivenReaction | CC BY | 33613847 | 19,057,747 | 2021-02-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Thyroid disorder'. | Testosterone deficiency in men receiving immunotherapy for malignant melanoma.
Immunotherapy has been established as a standard of care for patients with malignant melanoma, however, the long-term side-effects of immunotherapy are still emerging. Studies over the last decade have documented increasing reports of endocrine dysfunction following the initiation of immunotherapy. Our study aimed to detect the proportion of men who have low testosterone before, during, and or/after receiving immunotherapy for malignant melanoma, and to determine the proportion of men who receive testosterone replacement therapy after detection of low testosterone. We performed retrospective chart review of patients with malignant melanoma treated with immunotherapy. Low testosterone was identified in 34 out of 49 patients at some point during their treatment with immunotherapy. Despite low testosterone levels in two-thirds of patients, only three patients were treated with testosterone replacement therapy. In addition to laboratory evidence of low testosterone, patients were also symptomatic as 43 out of 49 patients reported fatigue to their providers. Four patients developed hypophysitis and subsequent hypopituitarism, all of whom were receiving Ipilimumab. We conclude that patients with stage 3 or 4 melanoma treated with immunotherapy appear to be at an increased risk of developing testosterone deficiency during their treatment.
INTRODUCTION
Malignant melanoma is one of the fastest growing cancers worldwide and men account for 60% of new diagnoses [1]. Fortunately, cancer treatments have greatly improved and those impacted by cancer are now living longer. Immunotherapy has been established as a standard of care for patients with malignant melanoma, however, the long-term side-effects of immunotherapy are still emerging [2].
It has been well documented that cancer treatment-related toxicities create short and long-term side effects, which can significantly impair the quality of life of cancer survivors. Conventional chemotherapy agents have been thoroughly studied, and there are an abundance of data detailing the negative effects of chemotherapy on testosterone levels, fertility, and the quality of life of cancer patients [3–5]. As immunotherapy is a relatively new treatment for cancer, their side effects on testosterone levels have not been as extensively explored.
Immune checkpoint inhibitors, which are intravenously administered therapies used to treat melanoma, include anti-programmed death-1 (anti-PD-1) antibodies (Pembrolizumab, Nivolumab) and anti-cytotoxic T-lymphocyte antigen-4 inhibition (anti-CTLA4) antibodies (Ipilimumab). There have also been recent developments of investigational therapies, including Indoximod and intratumoral SD-101. Intratumoral SD-101, a synthetic CpG oligonucleotide that stimulates Toll-like receptor 9 (TLR9) and is directly injected into the tumor site, has been shown to increase effectiveness of immune activation at the tumor site when used in combination with PD-1 inhibitors [6]. Indoximod, an inhibitor of the indoleamine 2,3-dioxygenase (IDO) pathway and is administered orally, has many effects on immune regulation allowing for the restoration of immune reactivity against cancer after there has been primary treatment with an active immunization processes (i.e., checkpoint inhibitor therapy) [7, 8]. The duration of treatment for unresectable and metastatic melanoma is currently recommended to continue until there is either disease progression or unacceptable toxicity, however, it is recommended to continue for approximately one year if used as an adjuvant therapy.
While side effects of immunotherapy have not been as comprehensively studied as older therapies, there are known adverse effects related to the attempted modulation of the immune system, including nonspecific inflammation and autoimmunity [9]. Studies over the last decade have begun documenting increasing reports of endocrine dysfunction following the initiation of immunotherapy. Specifically, hypophysitis, or inflammation of the pituitary gland, has been reported in 9–13% of patients treated with immunotherapy [3, 10–15]. Most of the patients who developed hypophysitis received Ipilimumab and there were higher rates observed in males (16.1%) than females (8.7%) [15–17]. Hypophysitis results in dysfunction of the pituitary gland and can cause a deficiency of one or more pituitary hormones, including luteinizing hormone (LH), which may then lead to testosterone deficiency. Thus far, no studies have specifically focused on androgen levels associated with immunotherapy or the clinical significance of androgen hormone deficiency. In our literature review, there was only one study which investigated testosterone levels following immunotherapy. The study reported incidences of Ipilimumab-associated low testosterone, in the absence of hypophysitis, in nine out of 256 patients assessed [15]. However, this study did not routinely assess testosterone levels and few measurements were actually obtained. Additionally, reassessment of testosterone levels was not always performed, so it is difficult to ascertain whether the low testosterone levels were transient or permanent.
Symptoms of low testosterone can be nonspecific and include fatigue, weight fluctuations, muscle loss, depression, insomnia, and sexual dysfunction [4, 18]. Sexual symptoms of androgen deficiency include decreased libido and erectile dysfunction [18, 19]. The implications of sexual dysfunction are far reaching, and may include reduction in self-esteem, impact on relationships, anxiety, and depression [4, 18]. It has been documented that male cancer survivors are likely to experience fatigue, impaired quality of life, and sexual dysfunction, regardless of type of cancer treatment received, and these effects are exacerbated by those with concurrent androgen deficiency [4, 5].
While the impact from chemotherapy agents on patients’ reproductive potential is well known, the impact from immunotherapy still needs to be established, as melanoma is becoming more prevalent in the AYA (adolescent and young adult) population [20–22]. Preclinical studies of Ipilimumab in monkeys demonstrated a clinically significant decrease in testicular weight, with no evidence of sperm histopathology changes [20]. A small study assessing testicular histopathology after immunotherapy for metastatic melanoma found evidence that spermatogenesis may be impacted by immunotherapies, however, the mechanism remains unclear [23]. While it is difficult to calculate fertility risk based on these small studies, there is concern for some level of gonadal dysfunction that needs to be further explored [24].
While immunotherapy has proven to be a successful treatment option for melanoma, there is concern for treatment-related dysfunction of the hypothalamic-pituitary-gonadal axis, which may impair quality of life [4, 5, 18, 20]. As immunotherapy is now widely used for a variety of cancers specifically in early stages, including non-small cell lung cancer, bladder cancer, renal cell carcinoma, and Hodgkin’s lymphoma [13], understanding the side effects associated with immunotherapy, while keeping in mind the direct impact of the treated malignancy, will allow for better recognition and earlier treatment for adverse effects in many future patients.
The aims of our study include: (1) detect the proportion of men who have low testosterone levels before, during, and or/after receiving immunotherapy for malignant melanoma; (2) identify risk factors for development of low testosterone levels during treatment with immunotherapy; (3) and determine the proportion of men who receive testosterone replacement therapy after detection of low testosterone levels.
RESULTS
Forty-nine patients met inclusion criteria. Patient demographics are reported in Table 1. Median age at diagnosis was 64 (33–92) years. Fifteen patients had stage 3, 33 patients had stage 4, and one patient had a primary pineal gland melanoma that was not staged. At the time of analysis, 16 patients were deceased and 31 patients were alive, 13 of whom were tumor free. Two patients transferred care to a local cancer center and their status was unknown. Patients were treated with Pembrolizumab, Ipilimumab, Nivolumab, or investigational immunotherapy agents Indoximod and intratumoral SD-101 (Figure 1). Of the 49 patients who received immunotherapy, 45 of these patients had metastatic disease. The other four patients received immunotherapy as adjuvant therapy for melanoma.
Table 1 Patient demographics at time of diagnosis
Patient Demographics
n, %
Number of patients, male 49 (100%)
Staging:
Stage 3 15 (30.6%)
Stage 4 33 (67%)
Primary pineal gland melanoma 1 (0.2%)
Previous history of melanoma 3 (6.1%)
Obesity 26 (53.1%)
Diabetes 10 (20.4%)
Heart disease (CAD, HTN) 35 (71.4%)
Hypothyroidism 8 (16.3%)
Obstructive sleep apnea 5 (10.2%)
Chronic kidney disease 3 (6.1%)
Corticosteroid use 1 (2.0%)
Opioid use 4 (8.2%)
Pre-existing autoimmune disease 2 (4.1%)
Previous cancer diagnosis 10 (20.4%)
Type of cancer:
Basal cell carcinoma 2 (20.0%)
Bladder cancer 1 (10.0%)
Colon cancer 1 (10.0%)
Diffuse large B cell lymphoma 1 (10.0%)
Hodgkin’s lymphoma 1 (10.0%)
Neuroendocrine tumor 1 (10.0%)
Prostate cancer 3 (30.0%)
Received radiation therapy 26 (53.1%)
Type of radiation:
Local 12 (46.2%)
Brain 14 (53.8%)
Enrolled in clinical trial 14 (28.6%)
Figure 1 The different rows demonstrate each patient’s treatment paradigm across time.
The heterogeneity in treatment regimens made it difficult to distinguish how each individual immunotherapy agent affected testosterone levels. On covariate analysis, there was no significant association between testosterone levels and treatment modality.
Low testosterone was identified in 34 out of 49 patients at some point during treatment with immunotherapy (Figure 2). Of these 34 patients with low testosterone, eight had their testosterone levels return to > 300 ng/dL within three months after detection. One patient’s testosterone level returned to normal after one year. Twenty-five patients with low testosterone did not see a complete recovery in their testosterone levels throughout the remainder of their follow-up. Four patients developed hypophysitis and subsequent hypopituitarism, all of whom received Ipilimumab. All patients who developed hypophysitis began showing evidence of hypopituitarism after 2–3 doses of Ipilimumab. Forty-three patients reported fatigue to their provider during their treatment with immunotherapy. Only three patients, all diagnosed with hypopituitarism, were treated with testosterone replacement therapy. The fourth patient diagnosed with hypopituitarism was treated with corticosteroids. Ten (29%) of the patients who developed low testosterone had normal testosterone levels prior to initiation of immunotherapy (Table 2). Eight (24%) of the patients had a low baseline testosterone prior to immunotherapy initiation, and their levels remained low throughout their treatment. Thirteen (38%) of the patients identified with low testosterone did not have a baseline testosterone level checked prior to starting immunotherapy. Three (9%) of the patients had low baseline testosterone levels, however, they also had brain radiation within two months prior to checking their baseline level.
Figure 2 Testosterone levels assessed after initiation of immunotherapy.
The red line is a reference for 300 ng/dL. There was large intrapersonal variability in testosterone levels, as demonstrated by the oscillating values within each patient. However, it is evident many patients had testosterone levels drop below 300 ng/dL, with many of those patients dipping well below 200 ng/dL.
Table 2 Additional clinical information of the patients with previously normal testosterone who subsequently developed low testosterone after treatment with immunotherapy
Clinical information of patients with normal T who developed low T after immunotherapy
Pt Age at diagnosis Immunotherapy Agent(s) Baseline T Lowest T value Resolution of low T Comorbidities Radiation Clinical trial Endocrine dysfunction during tx
1 50 Ipilimumab, Pembrolizumab Normal (314) 55 No Heart disease Local - -
2 72 Ipilimumab Normal (498) 78 No - - - -
3 66 Pembrolizumab Normal (319) 144 No Heart disease Brain - Pituitary, adrenal
4 61 Ipilimumab, Pembrolizumab Normal (338) 69 No Obese, heart disease, diabetes, hypothyroid Brain Yes -
5 82 Pembrolizumab Normal (399) 181 No Heart disease, diabetes - - -
6 59 Ipilimumab, Pembrolizumab Normal (419) < 5 No Obesity, heart disease Local - Hypophysitis
7 35 Ipilimumab, Pembrolizumab Normal (524) 170 Yes Obesity Brain Yes Pituitary, thyroid
8 85 Pembrolizumab Normal (351) 206 Yes Obesity, heart disease, previous prostate cancer - - Pituitary, adrenal
9 46 Pembrolizumab Normal (369) 22 Yes - - - Adrenal
10 52 Pembrolizumab Normal (456) 133 Yes Obesity, heart disease, OSA, previous melanoma Local - Pituitary, adrenal, and thyroid
Avg:
60.8
398.7
105.8
While these patients had diverse treatment courses, most of these patients had multiple comorbidities prior to their development of low testosterone.
Covariate analysis demonstrated no significant association between low testosterone and treatment with either Ipilimumab, Pembrolizumab, or Nivolumab. On univariate analysis, obesity and enrollment in a clinical trial were associated with lower testosterone levels (Table 3). During the treatment course with immunotherapy, 19 patients had evidence of pituitary dysfunction, 16 patients had evidence of adrenal dysfunction, and 18 patients had evidence of thyroid dysfunction. On univariate analysis, a trend was noted between testosterone and adrenal dysfunction and thyroid dysfunction. On multivariable analysis (Table 4), participation in a clinical trial and weeks since immunotherapy initiation were significant (p < 0.01), and a trend was noted for thyroid dysfunction (p = 0.08) and adrenal dysfunction (p = 0.08). More specifically, clinical trial patients had testosterone levels that were 80.38 ng/dL lower on average. There was not a clinically significant difference between clinical trial enrollment and cancer stage. Of the 15 patients with stage 3, five were enrolled in a clinical trial; while there were nine out of 33 patients with stage 4 enrolled in a clinical trial. Testosterone levels declined at a rate of 0.71 ng/dL per week, on average. Obesity, adrenal dysfunction, and thyroid dysfunction tended to be associated with lower testosterone levels.
Table 3 Univariate analysis assessing for associations with low testosterone and patient demographics, co-morbidities, treatment modalities, and treatment complications
Covariate Univariate Analysis
Testosterone (ng/dL)
Level Beta 95% CI
P-value
Obesity Yes –56.71 –110.41 –3.01 0.04
No Ref - -
Diabetes Yes –18.77 –89.16 51.63 0.60
No Ref - -
Heart Disease (CAD, HTN) Yes –16.97 –78.93 44.99 0.59
No Ref - -
Cancer Stage 4 –18.05 –81.07 44.97 0.57
3 Ref - -
Other Cancer Diagnoses Yes 40.46 –27.45 108.37 0.24
No Ref - -
Clinical trial Yes –87.04 –143.19 –30.88 < 0.01
No Ref - -
Radiation Yes –17.80 –65.16 29.56 0.46
No Ref - -
Radiation Local –2.81 –63.67 58.04 0.56
Brain –34.24 –97.67 29.20
Pituitary Yes –22.01 –64.11 20.08 0.30
No Ref - -
Adrenal Yes –45.52 –96.51 5.47 0.08
No Ref - -
Thyroid Yes –40.99 –86.22 4.23 0.08
No Ref - -
Testosterone Replacement Yes 98.91 –11.35 209.17 0.08
No Ref - -
Age Units = 1 0.64 –1.35 2.63 0.52
BMI at diagnosis Units = 1 –4.22 –9.80 1.36 0.14
Months Since Diagnosis Units = 1 –2.13 –5.02 0.75 0.14
Time obtained (minutes) Units = 60 0.06 –2.81 2.93 0.97
Weeks Since Immunotherapy Initiation Units = 1 0.44 –0.11 0.99 0.12
Obesity and enrollment in a clinical trial were associated with low testosterone. A trend is observed between low testosterone and adrenal and thyroid dysfunction.
Table 4 Multivariable model was utilized to include variables that were significant or nearly significant on univariate analysis
Multivariable analysis
Covariate Testosterone (ng/dL)
Level Beta 95% CI
P-value
Intercept 348.53 300.37 396.69
< 0.01
Obesity Yes –36.72 –90.57 17.13 0.18
No Ref - -
Clinical trial Yes –80.35 –139.85 –20.86
< 0.01
No Ref - -
Adrenal Yes –50.54 –108.60 7.53 0.08
No Ref - -
Thyroid Yes –43.84 –94.37 6.69 0.08
No Ref - -
Testosterone Replacement Yes 135.84 –109.79 381.48 0.14
No Ref - -
Weeks Since Immunotherapy Initiation Units = 1 0.71 0.18 1.25
< 0.01
Enrollment in a clinical trial and weeks since immunotherapy initiation were significant.
DISCUSSION
In our cohort, roughly two-thirds of patients developed low testosterone at some point during their treatment with immunotherapy. While some patients did have a recovery in their testosterone levels after a few months, over half of the patients continued to have low testosterone levels throughout the remainder of their follow-up. Despite persistently low testosterone levels in 25 patients, only three patients were treated with testosterone replacement therapy, all of whom had hypophysitis and testosterone levels < 5 ng/dL. In addition to laboratory evidence of low testosterone, patients were also symptomatic as the vast majority of patients reported fatigue to their providers. The three patients who received testosterone replacement therapy reported improved energy levels after treatment, however, they also received steroids and thyroid replacement therapy so it cannot be determined from our study whether testosterone replacement directly improves energy in these patients. While many factors contribute to fatigue, low testosterone levels may be playing an important role in the development of fatigue in these cancer patients. There was no chart documentation of whether providers assessed for other symptoms of low testosterone, including low libido or sexual dysfunction. These findings suggest that providers may be under-diagnosing and under-treating low testosterone in melanoma patients receiving immunotherapy.
Out of our patient population, 8% developed hypophysitis. All four patients showed evidence of hypopituitarism within three months of initiation of Ipilimumab, which has been documented in previous studies [15–17]. These data suggest that patients being treated with Ipilimumab need diligent monitoring of their endocrine function during the first three months of their treatment and up to 12 months after completion of their immunotherapy treatment [25].
In our study, there were clinically significant associations of low testosterone with obesity and patients that were enrolled in a clinical trial. It has been well documented that obesity is associated with low testosterone due to the high expression of aromatase in adipocytes, which converts testosterone to estradiol and lowers circulating androgens [26]. Of the 14 patients enrolled in a clinical trial, 10 of these patients developed low testosterone. The type of clinical trial each patient participated in was extremely variable, however, Indoximod and high dose (10 mg/kg) Ipilimumab were utilized most frequently. These patients may have been more likely to develop lower testosterone levels due to the higher dose of immunotherapy and the use of investigational immunotherapy agents, the side effects of which have not been completely studied. Additionally, Indoximod was used in conjunction with an anti-PD1 immunotherapy agent. The use of two immunotherapy agents has typically shown to have a synergistic effect on cancer control. This synergy may also reflect how immunotherapy affects testosterone levels, and therefore, those patients who are receiving two types of immunotherapy could be more susceptible to developing low testosterone. There may have also been a delayed effect of prior therapeutic agents used to treat melanoma on testosterone levels. On multivariable analysis, there was also an association with decreasing testosterone levels and weeks since initiation of immunotherapy. On average, the testosterone levels declined at a rate of 0.71 ng/dL per week. This change is minimal and most likely not clinically significant.
To our knowledge, this is the first study directly analyzing the effect of immunotherapy on testosterone levels in patients with melanoma. One limitation of this study is the low number of analyzed patients. While there were 143 male patients with malignant melanoma that received immunotherapy from 2009–2019, only 49 patients had at least two testosterone levels drawn. There were also inconsistencies as to when these patients had their testosterone levels checked. Only 30 of the 49 patients had a baseline testosterone level checked prior to initiation of immunotherapy. The other 19 patients had their level checked some variable amount of time after receiving immunotherapy. Additionally, further assessments of testosterone levels were not at regular intervals. Because roughly half of the patients had irregular assessment of testosterone levels, we are unable to report the causality of low testosterone.
Another limitation of this study is the heterogeneity within each patient’s treatment course, which made it difficult to analyze patients based on specific treatment received. Specifically, of the 34 patients identified with low testosterone during immunotherapy treatment, two patients were also being treated with steroids and five patients received concurrent radiation therapy (one received retroperitoneal radiation while the other four received brain radiation). It cannot be determined whether the low testosterone was due to immunotherapy and/or the concurrent treatment with steroids or radiation therapy.
As this was a retrospective study, fertility was not assessed in these patients. However, as melanoma is becoming more prevalent in the AYA population, future work needs to be completed to addresses any potential fertility risk in melanoma patients receiving immunotherapy, with particular attention to sperm count and function.
In conclusion, patients with stage 3 or 4 melanoma treated with immunotherapy appear to be at an increased risk of developing testosterone deficiency during their treatment. The majority of patients also report fatigue, which is commonly associated with low testosterone levels, yet only a minority of those with low levels received testosterone supplementation. Patients who are obese and have been enrolled in a clinical trial appear to be at increased risk of developing low testosterone during treatment with immunotherapy, and these patients would benefit from close observation and potentially testosterone replacement therapy. Encouraging weight loss in obese patients diagnosed with low testosterone should also be considered in conjunction with testosterone replacement therapy. Regardless of the reason for the development of low testosterone, our study has identified that this patient population is at risk for under-diagnosis and under-treatment of low testosterone. Further research needs to be performed to assess whether or not testosterone supplementation improves patient-reported outcomes in this patient population.
MATERIALS AND METHODS
After seeking Institutional Review Board and Ethics approval, we performed a retrospective chart review of patients with malignant melanoma treated with immunotherapy at Holden Comprehensive Cancer Center from 2009–2019 using the Melanoma Molecular Epidemiology Resource database. Patients were included in the analysis if they had at least two testosterone levels checked while on immunotherapy (Figure 3). Low testosterone was defined in this study as total testosterone < 300 ng/dL upon two consecutive lab draws, according to American Urological Association (AUA) guidelines on testosterone deficiency [27]. Blood was collected and total testosterone was assessed via electrochemiluminscence immunoassay.
Figure 3 Systematic review of 149 patients.
Patients were excluded in the study if they had fewer than two assessments of testosterone levels.
Patients were also evaluated for pituitary, adrenal, and thyroid dysfunction, based on the reference ranges from Clinical Laboratory Improvement Amendments certified laboratory at the University of Iowa Hospitals and Clinics. Pituitary dysfunction was defined as adrenocorticotropic hormone (ACTH) < 7 pg/mL. Adrenal dysfunction was defined as cortisol < 3 μg/dL. Thyroid dysfunction was defined as TSH < 0.27 or > 4.20 μIU/mL. Patient demographics and co-morbidities were gathered from chart review. Obesity was classified as BMI > 30 at the time of initial office visit.
Mixed effects regression models were applied to assess for changes in serum testosterone levels over time while adjusting for potential confounders. Time-dependent covariates were incorporated to capture changes in treatment and onset of other medical conditions. Random effects were included to account for the longitudinally correlated nature of repeat assessment and unequal time spacing between visits. Beta coefficients and 95% confidence intervals are reported. All statistical testing was two-sided and assessed for significance at the 5% level using SAS v9.4 (SAS Institute, Cary, NC). Power calculations were not performed, as this was a retrospective study meant to gain preliminary estimates of the true underlying population values.
Author contributions
A.P., V.M., and W.T. conceived the presented idea. M.P. collected the data for analysis. S.M. analyzed the data and performed the computations. All authors discussed the results. M.P. wrote the manuscript with support from A.P., V.M., W.T., and S.M.
CONFLICTS OF INTEREST
Authors have no conflicts of interest to declare.
FUNDING
This project was in part supported by the National Cancer Institute Cancer Center Support Grant 5P30CA086862-09 (P30). | IPILIMUMAB, PEMBROLIZUMAB | DrugsGivenReaction | CC BY | 33613847 | 19,057,747 | 2021-02-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Pulmonary hypertension'. | Diazoxide-associated pulmonary hypertension in a patient with noncompaction cardiomyopathy.
Development of pulmonary hypertension after initiation of diazoxide for the treatment of neonatal hyperinsulinemic hypoglycemia is a rare, but previously described association. Risk factors for development of diazoxide-associated pulmonary hypertension include lower gestational age and congenital heart disease. This novel case report describes an infant with noncompaction cardiomyopathy who developed pulmonary hypertension shortly after initiation of diazoxide for hyperinsulinemic hypoglycemia which resolved upon cessation of the drug. This case highlights the benefit of having pre-treatment knowledge of underlying cardiac anatomy and makes a case for routine echocardiographic screening for neonates initiating diazoxide treatment.
Case description
A term male infant, followed prenatally for a single umbilical artery and cerebral ventriculomegaly, presented with hypoglycemia at 8 h of age. Initially controlled on intravenous dextrose containing fluids, he ultimately maintained appropriate blood glucose levels on fortified ad lib feeds at one week of age. Postnatal workup for multiple congenital anomalies revealed mild cerebral ventriculomegaly and mild bilateral hydronephrosis. Initial echocardiogram demonstrated mild aortic isthmus hypoplasia without discrete coarctation, biventricular hypertrophy with prominent biventricular myocardial trabeculations, and an ostium secundum atrial septal defect (ASD) without signs of pulmonary hypertension.
On day of life 11, repeat echocardiogram more clearly demonstrated noncompaction cardiomyopathy with moderately diminished left ventricular function (ejection fraction 40%), mildly diminished right ventricular function, and no evidence of pulmonary hypertension. N-terminal-pro B-type natriuretic peptide (NT-pro-BNP) was elevated at 1760 pg/mL (lab normal <350 pg/mL), and enalapril was started for afterload reduction. He was hospitalized at three weeks of age for continued hypoglycemia and started on diazoxide when workup confirmed hyperinsulinism. He transiently required furosemide for pulmonary edema; however, prior to hospital discharge had clinically improved with NT-pro-BNP of 494 pg/mL and was discharged without diuretics.
At one month of age, he returned to cardiology clinic with lethargy and hypoxia with a systemic saturation of 62%. Echocardiogram demonstrated severe pulmonary hypertension with severe right atrial and ventricular dilation, interventricular septal flattening, mild right ventricular hypertrophy, mildly diminished right ventricular function, dilated main and branch pulmonary arteries, and bidirectional shunting at the ASD (Fig. 1). NT-pro-BNP was markedly elevated at 26,600 pg/mL. Saturations improved to 95% on supplemental oxygen via nasal cannula, and he was admitted. Due to concern for diazoxide-induced pulmonary hypertension given the temporal relation to drug initiation, diazoxide was discontinued. Three days after diazoxide discontinuation, echocardiogram demonstrated improvement in secondary findings of pulmonary hypertension, with improved right heart dilation and function, improved interventricular septal position, and left to right shunting across the ASD (Fig. 1). NT-pro-BNP had decreased to 1340 pg/mL. He weaned off supplemental oxygen and discharged after four days on no pulmonary vasodilator therapy with stable blood glucose off diazoxide.
Fig. 1. Panel (a) demonstrates Echocardiographic evidence of severe pulmonary hypertension after diazoxide initiation with severe interventricular septal flattening (a). Panel (b) shows Complete resolution of pulmonary hypertension within nine months of diazoxide discontinuation with normal interventricular septal configuration.
Within nine months following hospital discharge, he had no further evidence of pulmonary hypertension, and his left ventricular function normalized on ACE inhibitor monotherapy. Additionally, he was diagnosed with idiopathic interstitial lung disease based on chest CT demonstrating diffuse bilateral ground glass opacities with interlobular septal thickening and a new oxygen requirement well after resolution of his pulmonary hypertension. To date, no additional pulmonary laboratory or invasive testing has been pursued given mild nature of symptoms and no further evidence of pulmonary hypertension. He continues with routine pulmonary follow-up. Genetic testing revealed an unbalanced chromosomal translocation, with chromosome 1p36 deletion and 4q32 duplication. Regions involved in this translocation do not overlap with genes on commercially available gene panels for pulmonary hypertension, congenital hyperinsulinism, or left ventricular noncompaction.
Discussion
This case report describes a patient with noncompaction cardiomyopathy and chromosomal translocation who developed diazoxide-associated pulmonary hypertension. Immediate recognition and discontinuation of the diazoxide led to clinical improvement and resolution of pulmonary hypertension within several days.
Diazoxide, a KATP channel opener, is the first-line therapy for the treatment of hyperinsulinemic hypoglycemia by inhibiting release of insulin from the pancreas. It also leads to smooth muscle cell relaxation with both systemic and pulmonary vasodilation.1 While diazoxide is well tolerated in the majority of infants receiving this therapy, there is a known association with the development of pulmonary hypertension. In 2015, the Federal Drug Agency (FDA) issued a drug safety communication citing 11 cases of diazoxide associated pulmonary hypertension.2
The first case report describing pulmonary hypertension in a patient treated with diazoxide was noted in 2004.3 Since that time, even in light of the FDA drug safety communication, less than 50 cases of diazoxide-associated pulmonary hypertension are reported in the literature. In series published from single centers or regional cohorts, the incidence of diazoxide-associated pulmonary hypertension is estimated to be 2.4–7%.4–6 Potential risk factors for development of diazoxide-associated pulmonary hypertension include lower gestational age, fluid overload, and congenital heart disease.4–6 Reported concomitant congenital heart disease diagnoses are variable in terms of hemodynamic significance and likelihood of potential contribution to pulmonary hypertension in the neonatal period, ranging from small ASD to patent ductus arteriosus to more complex lesions such as double outlet right ventricle and atrioventricular septal defect.3–8 There is one reported case associated with a restrictive cardiomyopathy.5
Diazoxide’s initial clinical use was as an antihypertensive via its action as a systemic vasodilator. This prompted evaluation of diazoxide as a pulmonary vasodilator, with some report of efficacy in idiopathic pulmonary hypertension.9 The relationship between KATP channels and the development of pulmonary hypertension is complex, with differential expression of different channel subtypes depending on tissue type and physiologic state. Loss of function in one subtype can lead to heritable pulmonary hypertension.10 Gain of function in a different subtype causes a genetic disorder called Cantu syndrome, which manifests similarly to the side effects of diazoxide with edema, hypertrichosis, and pulmonary hypertension.10 One can speculate that some predisposition (e.g. a KATP channel gene mutation or overexpression) may lead to the diazoxide-associated pulmonary hypertension when stimulated by initiation of diazoxide therapy, similar to a “two-hit hypothesis” in other fields.
To the best of our knowledge, this report is the first case described in a patient with noncompaction cardiomyopathy in addition to an ASD. Noncompaction cardiomyopathy with left ventricular diastolic dysfunction may predispose to pulmonary arterial hypertension secondary to elevated post-capillary pressure; however, this is usually not a primary feature in young infants with cardiomyopathy. Importantly, our patient’s pulmonary hypertension was detected on what was intended as routine follow-up for his known cardiomyopathy, and he had not had prior echocardiographic or clinical evidence of significant diastolic dysfunction or restrictive physiology. Our center does not have routine echocardiogram protocols for initiating diazoxide treatment for neonatal hyperinsulinemic hypoglycemia. This case highlights the benefit of pre-treatment knowledge of underlying cardiac concerns and makes a case for routine post-treatment echocardiographic screening, particularly in patients with identifiable risk factors for development of pulmonary hypertension. Further, this adds to the body of literature of potential associations in this rare clinical entity.
Contributorship: Sullivan was a fellow at the time of data collection and patient involvement and was responsible for the primary composition of the written manuscript draft. Tillman and Kindel contributed with review of patient-specific details with regard to pulmonary hypertension and underlying cardiomyopathy, respectively. Handler contributed as senior author, with primary role in case selection and case report oversight. All authors were involved in review and final approval of this article.
Declaration of conflicting interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Ethical approval: Written informed consent was obtained from the patient’s parent for patient information to be published.
Guarantor: SH.
Funding: The author(s) received no financial support for the research, authorship, and/or publication of this article.
ORCID iD: Rachel T. Sullivan https://orcid.org/0000-0003-4580-9965 | DIAZOXIDE, ENALAPRIL | DrugsGivenReaction | CC BY-NC | 33614015 | 19,066,362 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Right atrial dilatation'. | Diazoxide-associated pulmonary hypertension in a patient with noncompaction cardiomyopathy.
Development of pulmonary hypertension after initiation of diazoxide for the treatment of neonatal hyperinsulinemic hypoglycemia is a rare, but previously described association. Risk factors for development of diazoxide-associated pulmonary hypertension include lower gestational age and congenital heart disease. This novel case report describes an infant with noncompaction cardiomyopathy who developed pulmonary hypertension shortly after initiation of diazoxide for hyperinsulinemic hypoglycemia which resolved upon cessation of the drug. This case highlights the benefit of having pre-treatment knowledge of underlying cardiac anatomy and makes a case for routine echocardiographic screening for neonates initiating diazoxide treatment.
Case description
A term male infant, followed prenatally for a single umbilical artery and cerebral ventriculomegaly, presented with hypoglycemia at 8 h of age. Initially controlled on intravenous dextrose containing fluids, he ultimately maintained appropriate blood glucose levels on fortified ad lib feeds at one week of age. Postnatal workup for multiple congenital anomalies revealed mild cerebral ventriculomegaly and mild bilateral hydronephrosis. Initial echocardiogram demonstrated mild aortic isthmus hypoplasia without discrete coarctation, biventricular hypertrophy with prominent biventricular myocardial trabeculations, and an ostium secundum atrial septal defect (ASD) without signs of pulmonary hypertension.
On day of life 11, repeat echocardiogram more clearly demonstrated noncompaction cardiomyopathy with moderately diminished left ventricular function (ejection fraction 40%), mildly diminished right ventricular function, and no evidence of pulmonary hypertension. N-terminal-pro B-type natriuretic peptide (NT-pro-BNP) was elevated at 1760 pg/mL (lab normal <350 pg/mL), and enalapril was started for afterload reduction. He was hospitalized at three weeks of age for continued hypoglycemia and started on diazoxide when workup confirmed hyperinsulinism. He transiently required furosemide for pulmonary edema; however, prior to hospital discharge had clinically improved with NT-pro-BNP of 494 pg/mL and was discharged without diuretics.
At one month of age, he returned to cardiology clinic with lethargy and hypoxia with a systemic saturation of 62%. Echocardiogram demonstrated severe pulmonary hypertension with severe right atrial and ventricular dilation, interventricular septal flattening, mild right ventricular hypertrophy, mildly diminished right ventricular function, dilated main and branch pulmonary arteries, and bidirectional shunting at the ASD (Fig. 1). NT-pro-BNP was markedly elevated at 26,600 pg/mL. Saturations improved to 95% on supplemental oxygen via nasal cannula, and he was admitted. Due to concern for diazoxide-induced pulmonary hypertension given the temporal relation to drug initiation, diazoxide was discontinued. Three days after diazoxide discontinuation, echocardiogram demonstrated improvement in secondary findings of pulmonary hypertension, with improved right heart dilation and function, improved interventricular septal position, and left to right shunting across the ASD (Fig. 1). NT-pro-BNP had decreased to 1340 pg/mL. He weaned off supplemental oxygen and discharged after four days on no pulmonary vasodilator therapy with stable blood glucose off diazoxide.
Fig. 1. Panel (a) demonstrates Echocardiographic evidence of severe pulmonary hypertension after diazoxide initiation with severe interventricular septal flattening (a). Panel (b) shows Complete resolution of pulmonary hypertension within nine months of diazoxide discontinuation with normal interventricular septal configuration.
Within nine months following hospital discharge, he had no further evidence of pulmonary hypertension, and his left ventricular function normalized on ACE inhibitor monotherapy. Additionally, he was diagnosed with idiopathic interstitial lung disease based on chest CT demonstrating diffuse bilateral ground glass opacities with interlobular septal thickening and a new oxygen requirement well after resolution of his pulmonary hypertension. To date, no additional pulmonary laboratory or invasive testing has been pursued given mild nature of symptoms and no further evidence of pulmonary hypertension. He continues with routine pulmonary follow-up. Genetic testing revealed an unbalanced chromosomal translocation, with chromosome 1p36 deletion and 4q32 duplication. Regions involved in this translocation do not overlap with genes on commercially available gene panels for pulmonary hypertension, congenital hyperinsulinism, or left ventricular noncompaction.
Discussion
This case report describes a patient with noncompaction cardiomyopathy and chromosomal translocation who developed diazoxide-associated pulmonary hypertension. Immediate recognition and discontinuation of the diazoxide led to clinical improvement and resolution of pulmonary hypertension within several days.
Diazoxide, a KATP channel opener, is the first-line therapy for the treatment of hyperinsulinemic hypoglycemia by inhibiting release of insulin from the pancreas. It also leads to smooth muscle cell relaxation with both systemic and pulmonary vasodilation.1 While diazoxide is well tolerated in the majority of infants receiving this therapy, there is a known association with the development of pulmonary hypertension. In 2015, the Federal Drug Agency (FDA) issued a drug safety communication citing 11 cases of diazoxide associated pulmonary hypertension.2
The first case report describing pulmonary hypertension in a patient treated with diazoxide was noted in 2004.3 Since that time, even in light of the FDA drug safety communication, less than 50 cases of diazoxide-associated pulmonary hypertension are reported in the literature. In series published from single centers or regional cohorts, the incidence of diazoxide-associated pulmonary hypertension is estimated to be 2.4–7%.4–6 Potential risk factors for development of diazoxide-associated pulmonary hypertension include lower gestational age, fluid overload, and congenital heart disease.4–6 Reported concomitant congenital heart disease diagnoses are variable in terms of hemodynamic significance and likelihood of potential contribution to pulmonary hypertension in the neonatal period, ranging from small ASD to patent ductus arteriosus to more complex lesions such as double outlet right ventricle and atrioventricular septal defect.3–8 There is one reported case associated with a restrictive cardiomyopathy.5
Diazoxide’s initial clinical use was as an antihypertensive via its action as a systemic vasodilator. This prompted evaluation of diazoxide as a pulmonary vasodilator, with some report of efficacy in idiopathic pulmonary hypertension.9 The relationship between KATP channels and the development of pulmonary hypertension is complex, with differential expression of different channel subtypes depending on tissue type and physiologic state. Loss of function in one subtype can lead to heritable pulmonary hypertension.10 Gain of function in a different subtype causes a genetic disorder called Cantu syndrome, which manifests similarly to the side effects of diazoxide with edema, hypertrichosis, and pulmonary hypertension.10 One can speculate that some predisposition (e.g. a KATP channel gene mutation or overexpression) may lead to the diazoxide-associated pulmonary hypertension when stimulated by initiation of diazoxide therapy, similar to a “two-hit hypothesis” in other fields.
To the best of our knowledge, this report is the first case described in a patient with noncompaction cardiomyopathy in addition to an ASD. Noncompaction cardiomyopathy with left ventricular diastolic dysfunction may predispose to pulmonary arterial hypertension secondary to elevated post-capillary pressure; however, this is usually not a primary feature in young infants with cardiomyopathy. Importantly, our patient’s pulmonary hypertension was detected on what was intended as routine follow-up for his known cardiomyopathy, and he had not had prior echocardiographic or clinical evidence of significant diastolic dysfunction or restrictive physiology. Our center does not have routine echocardiogram protocols for initiating diazoxide treatment for neonatal hyperinsulinemic hypoglycemia. This case highlights the benefit of pre-treatment knowledge of underlying cardiac concerns and makes a case for routine post-treatment echocardiographic screening, particularly in patients with identifiable risk factors for development of pulmonary hypertension. Further, this adds to the body of literature of potential associations in this rare clinical entity.
Contributorship: Sullivan was a fellow at the time of data collection and patient involvement and was responsible for the primary composition of the written manuscript draft. Tillman and Kindel contributed with review of patient-specific details with regard to pulmonary hypertension and underlying cardiomyopathy, respectively. Handler contributed as senior author, with primary role in case selection and case report oversight. All authors were involved in review and final approval of this article.
Declaration of conflicting interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Ethical approval: Written informed consent was obtained from the patient’s parent for patient information to be published.
Guarantor: SH.
Funding: The author(s) received no financial support for the research, authorship, and/or publication of this article.
ORCID iD: Rachel T. Sullivan https://orcid.org/0000-0003-4580-9965 | DIAZOXIDE, ENALAPRIL | DrugsGivenReaction | CC BY-NC | 33614015 | 19,066,362 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Right ventricular dysfunction'. | Diazoxide-associated pulmonary hypertension in a patient with noncompaction cardiomyopathy.
Development of pulmonary hypertension after initiation of diazoxide for the treatment of neonatal hyperinsulinemic hypoglycemia is a rare, but previously described association. Risk factors for development of diazoxide-associated pulmonary hypertension include lower gestational age and congenital heart disease. This novel case report describes an infant with noncompaction cardiomyopathy who developed pulmonary hypertension shortly after initiation of diazoxide for hyperinsulinemic hypoglycemia which resolved upon cessation of the drug. This case highlights the benefit of having pre-treatment knowledge of underlying cardiac anatomy and makes a case for routine echocardiographic screening for neonates initiating diazoxide treatment.
Case description
A term male infant, followed prenatally for a single umbilical artery and cerebral ventriculomegaly, presented with hypoglycemia at 8 h of age. Initially controlled on intravenous dextrose containing fluids, he ultimately maintained appropriate blood glucose levels on fortified ad lib feeds at one week of age. Postnatal workup for multiple congenital anomalies revealed mild cerebral ventriculomegaly and mild bilateral hydronephrosis. Initial echocardiogram demonstrated mild aortic isthmus hypoplasia without discrete coarctation, biventricular hypertrophy with prominent biventricular myocardial trabeculations, and an ostium secundum atrial septal defect (ASD) without signs of pulmonary hypertension.
On day of life 11, repeat echocardiogram more clearly demonstrated noncompaction cardiomyopathy with moderately diminished left ventricular function (ejection fraction 40%), mildly diminished right ventricular function, and no evidence of pulmonary hypertension. N-terminal-pro B-type natriuretic peptide (NT-pro-BNP) was elevated at 1760 pg/mL (lab normal <350 pg/mL), and enalapril was started for afterload reduction. He was hospitalized at three weeks of age for continued hypoglycemia and started on diazoxide when workup confirmed hyperinsulinism. He transiently required furosemide for pulmonary edema; however, prior to hospital discharge had clinically improved with NT-pro-BNP of 494 pg/mL and was discharged without diuretics.
At one month of age, he returned to cardiology clinic with lethargy and hypoxia with a systemic saturation of 62%. Echocardiogram demonstrated severe pulmonary hypertension with severe right atrial and ventricular dilation, interventricular septal flattening, mild right ventricular hypertrophy, mildly diminished right ventricular function, dilated main and branch pulmonary arteries, and bidirectional shunting at the ASD (Fig. 1). NT-pro-BNP was markedly elevated at 26,600 pg/mL. Saturations improved to 95% on supplemental oxygen via nasal cannula, and he was admitted. Due to concern for diazoxide-induced pulmonary hypertension given the temporal relation to drug initiation, diazoxide was discontinued. Three days after diazoxide discontinuation, echocardiogram demonstrated improvement in secondary findings of pulmonary hypertension, with improved right heart dilation and function, improved interventricular septal position, and left to right shunting across the ASD (Fig. 1). NT-pro-BNP had decreased to 1340 pg/mL. He weaned off supplemental oxygen and discharged after four days on no pulmonary vasodilator therapy with stable blood glucose off diazoxide.
Fig. 1. Panel (a) demonstrates Echocardiographic evidence of severe pulmonary hypertension after diazoxide initiation with severe interventricular septal flattening (a). Panel (b) shows Complete resolution of pulmonary hypertension within nine months of diazoxide discontinuation with normal interventricular septal configuration.
Within nine months following hospital discharge, he had no further evidence of pulmonary hypertension, and his left ventricular function normalized on ACE inhibitor monotherapy. Additionally, he was diagnosed with idiopathic interstitial lung disease based on chest CT demonstrating diffuse bilateral ground glass opacities with interlobular septal thickening and a new oxygen requirement well after resolution of his pulmonary hypertension. To date, no additional pulmonary laboratory or invasive testing has been pursued given mild nature of symptoms and no further evidence of pulmonary hypertension. He continues with routine pulmonary follow-up. Genetic testing revealed an unbalanced chromosomal translocation, with chromosome 1p36 deletion and 4q32 duplication. Regions involved in this translocation do not overlap with genes on commercially available gene panels for pulmonary hypertension, congenital hyperinsulinism, or left ventricular noncompaction.
Discussion
This case report describes a patient with noncompaction cardiomyopathy and chromosomal translocation who developed diazoxide-associated pulmonary hypertension. Immediate recognition and discontinuation of the diazoxide led to clinical improvement and resolution of pulmonary hypertension within several days.
Diazoxide, a KATP channel opener, is the first-line therapy for the treatment of hyperinsulinemic hypoglycemia by inhibiting release of insulin from the pancreas. It also leads to smooth muscle cell relaxation with both systemic and pulmonary vasodilation.1 While diazoxide is well tolerated in the majority of infants receiving this therapy, there is a known association with the development of pulmonary hypertension. In 2015, the Federal Drug Agency (FDA) issued a drug safety communication citing 11 cases of diazoxide associated pulmonary hypertension.2
The first case report describing pulmonary hypertension in a patient treated with diazoxide was noted in 2004.3 Since that time, even in light of the FDA drug safety communication, less than 50 cases of diazoxide-associated pulmonary hypertension are reported in the literature. In series published from single centers or regional cohorts, the incidence of diazoxide-associated pulmonary hypertension is estimated to be 2.4–7%.4–6 Potential risk factors for development of diazoxide-associated pulmonary hypertension include lower gestational age, fluid overload, and congenital heart disease.4–6 Reported concomitant congenital heart disease diagnoses are variable in terms of hemodynamic significance and likelihood of potential contribution to pulmonary hypertension in the neonatal period, ranging from small ASD to patent ductus arteriosus to more complex lesions such as double outlet right ventricle and atrioventricular septal defect.3–8 There is one reported case associated with a restrictive cardiomyopathy.5
Diazoxide’s initial clinical use was as an antihypertensive via its action as a systemic vasodilator. This prompted evaluation of diazoxide as a pulmonary vasodilator, with some report of efficacy in idiopathic pulmonary hypertension.9 The relationship between KATP channels and the development of pulmonary hypertension is complex, with differential expression of different channel subtypes depending on tissue type and physiologic state. Loss of function in one subtype can lead to heritable pulmonary hypertension.10 Gain of function in a different subtype causes a genetic disorder called Cantu syndrome, which manifests similarly to the side effects of diazoxide with edema, hypertrichosis, and pulmonary hypertension.10 One can speculate that some predisposition (e.g. a KATP channel gene mutation or overexpression) may lead to the diazoxide-associated pulmonary hypertension when stimulated by initiation of diazoxide therapy, similar to a “two-hit hypothesis” in other fields.
To the best of our knowledge, this report is the first case described in a patient with noncompaction cardiomyopathy in addition to an ASD. Noncompaction cardiomyopathy with left ventricular diastolic dysfunction may predispose to pulmonary arterial hypertension secondary to elevated post-capillary pressure; however, this is usually not a primary feature in young infants with cardiomyopathy. Importantly, our patient’s pulmonary hypertension was detected on what was intended as routine follow-up for his known cardiomyopathy, and he had not had prior echocardiographic or clinical evidence of significant diastolic dysfunction or restrictive physiology. Our center does not have routine echocardiogram protocols for initiating diazoxide treatment for neonatal hyperinsulinemic hypoglycemia. This case highlights the benefit of pre-treatment knowledge of underlying cardiac concerns and makes a case for routine post-treatment echocardiographic screening, particularly in patients with identifiable risk factors for development of pulmonary hypertension. Further, this adds to the body of literature of potential associations in this rare clinical entity.
Contributorship: Sullivan was a fellow at the time of data collection and patient involvement and was responsible for the primary composition of the written manuscript draft. Tillman and Kindel contributed with review of patient-specific details with regard to pulmonary hypertension and underlying cardiomyopathy, respectively. Handler contributed as senior author, with primary role in case selection and case report oversight. All authors were involved in review and final approval of this article.
Declaration of conflicting interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Ethical approval: Written informed consent was obtained from the patient’s parent for patient information to be published.
Guarantor: SH.
Funding: The author(s) received no financial support for the research, authorship, and/or publication of this article.
ORCID iD: Rachel T. Sullivan https://orcid.org/0000-0003-4580-9965 | DIAZOXIDE, ENALAPRIL | DrugsGivenReaction | CC BY-NC | 33614015 | 19,066,362 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Right ventricular hypertrophy'. | Diazoxide-associated pulmonary hypertension in a patient with noncompaction cardiomyopathy.
Development of pulmonary hypertension after initiation of diazoxide for the treatment of neonatal hyperinsulinemic hypoglycemia is a rare, but previously described association. Risk factors for development of diazoxide-associated pulmonary hypertension include lower gestational age and congenital heart disease. This novel case report describes an infant with noncompaction cardiomyopathy who developed pulmonary hypertension shortly after initiation of diazoxide for hyperinsulinemic hypoglycemia which resolved upon cessation of the drug. This case highlights the benefit of having pre-treatment knowledge of underlying cardiac anatomy and makes a case for routine echocardiographic screening for neonates initiating diazoxide treatment.
Case description
A term male infant, followed prenatally for a single umbilical artery and cerebral ventriculomegaly, presented with hypoglycemia at 8 h of age. Initially controlled on intravenous dextrose containing fluids, he ultimately maintained appropriate blood glucose levels on fortified ad lib feeds at one week of age. Postnatal workup for multiple congenital anomalies revealed mild cerebral ventriculomegaly and mild bilateral hydronephrosis. Initial echocardiogram demonstrated mild aortic isthmus hypoplasia without discrete coarctation, biventricular hypertrophy with prominent biventricular myocardial trabeculations, and an ostium secundum atrial septal defect (ASD) without signs of pulmonary hypertension.
On day of life 11, repeat echocardiogram more clearly demonstrated noncompaction cardiomyopathy with moderately diminished left ventricular function (ejection fraction 40%), mildly diminished right ventricular function, and no evidence of pulmonary hypertension. N-terminal-pro B-type natriuretic peptide (NT-pro-BNP) was elevated at 1760 pg/mL (lab normal <350 pg/mL), and enalapril was started for afterload reduction. He was hospitalized at three weeks of age for continued hypoglycemia and started on diazoxide when workup confirmed hyperinsulinism. He transiently required furosemide for pulmonary edema; however, prior to hospital discharge had clinically improved with NT-pro-BNP of 494 pg/mL and was discharged without diuretics.
At one month of age, he returned to cardiology clinic with lethargy and hypoxia with a systemic saturation of 62%. Echocardiogram demonstrated severe pulmonary hypertension with severe right atrial and ventricular dilation, interventricular septal flattening, mild right ventricular hypertrophy, mildly diminished right ventricular function, dilated main and branch pulmonary arteries, and bidirectional shunting at the ASD (Fig. 1). NT-pro-BNP was markedly elevated at 26,600 pg/mL. Saturations improved to 95% on supplemental oxygen via nasal cannula, and he was admitted. Due to concern for diazoxide-induced pulmonary hypertension given the temporal relation to drug initiation, diazoxide was discontinued. Three days after diazoxide discontinuation, echocardiogram demonstrated improvement in secondary findings of pulmonary hypertension, with improved right heart dilation and function, improved interventricular septal position, and left to right shunting across the ASD (Fig. 1). NT-pro-BNP had decreased to 1340 pg/mL. He weaned off supplemental oxygen and discharged after four days on no pulmonary vasodilator therapy with stable blood glucose off diazoxide.
Fig. 1. Panel (a) demonstrates Echocardiographic evidence of severe pulmonary hypertension after diazoxide initiation with severe interventricular septal flattening (a). Panel (b) shows Complete resolution of pulmonary hypertension within nine months of diazoxide discontinuation with normal interventricular septal configuration.
Within nine months following hospital discharge, he had no further evidence of pulmonary hypertension, and his left ventricular function normalized on ACE inhibitor monotherapy. Additionally, he was diagnosed with idiopathic interstitial lung disease based on chest CT demonstrating diffuse bilateral ground glass opacities with interlobular septal thickening and a new oxygen requirement well after resolution of his pulmonary hypertension. To date, no additional pulmonary laboratory or invasive testing has been pursued given mild nature of symptoms and no further evidence of pulmonary hypertension. He continues with routine pulmonary follow-up. Genetic testing revealed an unbalanced chromosomal translocation, with chromosome 1p36 deletion and 4q32 duplication. Regions involved in this translocation do not overlap with genes on commercially available gene panels for pulmonary hypertension, congenital hyperinsulinism, or left ventricular noncompaction.
Discussion
This case report describes a patient with noncompaction cardiomyopathy and chromosomal translocation who developed diazoxide-associated pulmonary hypertension. Immediate recognition and discontinuation of the diazoxide led to clinical improvement and resolution of pulmonary hypertension within several days.
Diazoxide, a KATP channel opener, is the first-line therapy for the treatment of hyperinsulinemic hypoglycemia by inhibiting release of insulin from the pancreas. It also leads to smooth muscle cell relaxation with both systemic and pulmonary vasodilation.1 While diazoxide is well tolerated in the majority of infants receiving this therapy, there is a known association with the development of pulmonary hypertension. In 2015, the Federal Drug Agency (FDA) issued a drug safety communication citing 11 cases of diazoxide associated pulmonary hypertension.2
The first case report describing pulmonary hypertension in a patient treated with diazoxide was noted in 2004.3 Since that time, even in light of the FDA drug safety communication, less than 50 cases of diazoxide-associated pulmonary hypertension are reported in the literature. In series published from single centers or regional cohorts, the incidence of diazoxide-associated pulmonary hypertension is estimated to be 2.4–7%.4–6 Potential risk factors for development of diazoxide-associated pulmonary hypertension include lower gestational age, fluid overload, and congenital heart disease.4–6 Reported concomitant congenital heart disease diagnoses are variable in terms of hemodynamic significance and likelihood of potential contribution to pulmonary hypertension in the neonatal period, ranging from small ASD to patent ductus arteriosus to more complex lesions such as double outlet right ventricle and atrioventricular septal defect.3–8 There is one reported case associated with a restrictive cardiomyopathy.5
Diazoxide’s initial clinical use was as an antihypertensive via its action as a systemic vasodilator. This prompted evaluation of diazoxide as a pulmonary vasodilator, with some report of efficacy in idiopathic pulmonary hypertension.9 The relationship between KATP channels and the development of pulmonary hypertension is complex, with differential expression of different channel subtypes depending on tissue type and physiologic state. Loss of function in one subtype can lead to heritable pulmonary hypertension.10 Gain of function in a different subtype causes a genetic disorder called Cantu syndrome, which manifests similarly to the side effects of diazoxide with edema, hypertrichosis, and pulmonary hypertension.10 One can speculate that some predisposition (e.g. a KATP channel gene mutation or overexpression) may lead to the diazoxide-associated pulmonary hypertension when stimulated by initiation of diazoxide therapy, similar to a “two-hit hypothesis” in other fields.
To the best of our knowledge, this report is the first case described in a patient with noncompaction cardiomyopathy in addition to an ASD. Noncompaction cardiomyopathy with left ventricular diastolic dysfunction may predispose to pulmonary arterial hypertension secondary to elevated post-capillary pressure; however, this is usually not a primary feature in young infants with cardiomyopathy. Importantly, our patient’s pulmonary hypertension was detected on what was intended as routine follow-up for his known cardiomyopathy, and he had not had prior echocardiographic or clinical evidence of significant diastolic dysfunction or restrictive physiology. Our center does not have routine echocardiogram protocols for initiating diazoxide treatment for neonatal hyperinsulinemic hypoglycemia. This case highlights the benefit of pre-treatment knowledge of underlying cardiac concerns and makes a case for routine post-treatment echocardiographic screening, particularly in patients with identifiable risk factors for development of pulmonary hypertension. Further, this adds to the body of literature of potential associations in this rare clinical entity.
Contributorship: Sullivan was a fellow at the time of data collection and patient involvement and was responsible for the primary composition of the written manuscript draft. Tillman and Kindel contributed with review of patient-specific details with regard to pulmonary hypertension and underlying cardiomyopathy, respectively. Handler contributed as senior author, with primary role in case selection and case report oversight. All authors were involved in review and final approval of this article.
Declaration of conflicting interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Ethical approval: Written informed consent was obtained from the patient’s parent for patient information to be published.
Guarantor: SH.
Funding: The author(s) received no financial support for the research, authorship, and/or publication of this article.
ORCID iD: Rachel T. Sullivan https://orcid.org/0000-0003-4580-9965 | DIAZOXIDE, ENALAPRIL | DrugsGivenReaction | CC BY-NC | 33614015 | 19,066,362 | 2021 |
What was the outcome of reaction 'Pulmonary hypertension'? | Diazoxide-associated pulmonary hypertension in a patient with noncompaction cardiomyopathy.
Development of pulmonary hypertension after initiation of diazoxide for the treatment of neonatal hyperinsulinemic hypoglycemia is a rare, but previously described association. Risk factors for development of diazoxide-associated pulmonary hypertension include lower gestational age and congenital heart disease. This novel case report describes an infant with noncompaction cardiomyopathy who developed pulmonary hypertension shortly after initiation of diazoxide for hyperinsulinemic hypoglycemia which resolved upon cessation of the drug. This case highlights the benefit of having pre-treatment knowledge of underlying cardiac anatomy and makes a case for routine echocardiographic screening for neonates initiating diazoxide treatment.
Case description
A term male infant, followed prenatally for a single umbilical artery and cerebral ventriculomegaly, presented with hypoglycemia at 8 h of age. Initially controlled on intravenous dextrose containing fluids, he ultimately maintained appropriate blood glucose levels on fortified ad lib feeds at one week of age. Postnatal workup for multiple congenital anomalies revealed mild cerebral ventriculomegaly and mild bilateral hydronephrosis. Initial echocardiogram demonstrated mild aortic isthmus hypoplasia without discrete coarctation, biventricular hypertrophy with prominent biventricular myocardial trabeculations, and an ostium secundum atrial septal defect (ASD) without signs of pulmonary hypertension.
On day of life 11, repeat echocardiogram more clearly demonstrated noncompaction cardiomyopathy with moderately diminished left ventricular function (ejection fraction 40%), mildly diminished right ventricular function, and no evidence of pulmonary hypertension. N-terminal-pro B-type natriuretic peptide (NT-pro-BNP) was elevated at 1760 pg/mL (lab normal <350 pg/mL), and enalapril was started for afterload reduction. He was hospitalized at three weeks of age for continued hypoglycemia and started on diazoxide when workup confirmed hyperinsulinism. He transiently required furosemide for pulmonary edema; however, prior to hospital discharge had clinically improved with NT-pro-BNP of 494 pg/mL and was discharged without diuretics.
At one month of age, he returned to cardiology clinic with lethargy and hypoxia with a systemic saturation of 62%. Echocardiogram demonstrated severe pulmonary hypertension with severe right atrial and ventricular dilation, interventricular septal flattening, mild right ventricular hypertrophy, mildly diminished right ventricular function, dilated main and branch pulmonary arteries, and bidirectional shunting at the ASD (Fig. 1). NT-pro-BNP was markedly elevated at 26,600 pg/mL. Saturations improved to 95% on supplemental oxygen via nasal cannula, and he was admitted. Due to concern for diazoxide-induced pulmonary hypertension given the temporal relation to drug initiation, diazoxide was discontinued. Three days after diazoxide discontinuation, echocardiogram demonstrated improvement in secondary findings of pulmonary hypertension, with improved right heart dilation and function, improved interventricular septal position, and left to right shunting across the ASD (Fig. 1). NT-pro-BNP had decreased to 1340 pg/mL. He weaned off supplemental oxygen and discharged after four days on no pulmonary vasodilator therapy with stable blood glucose off diazoxide.
Fig. 1. Panel (a) demonstrates Echocardiographic evidence of severe pulmonary hypertension after diazoxide initiation with severe interventricular septal flattening (a). Panel (b) shows Complete resolution of pulmonary hypertension within nine months of diazoxide discontinuation with normal interventricular septal configuration.
Within nine months following hospital discharge, he had no further evidence of pulmonary hypertension, and his left ventricular function normalized on ACE inhibitor monotherapy. Additionally, he was diagnosed with idiopathic interstitial lung disease based on chest CT demonstrating diffuse bilateral ground glass opacities with interlobular septal thickening and a new oxygen requirement well after resolution of his pulmonary hypertension. To date, no additional pulmonary laboratory or invasive testing has been pursued given mild nature of symptoms and no further evidence of pulmonary hypertension. He continues with routine pulmonary follow-up. Genetic testing revealed an unbalanced chromosomal translocation, with chromosome 1p36 deletion and 4q32 duplication. Regions involved in this translocation do not overlap with genes on commercially available gene panels for pulmonary hypertension, congenital hyperinsulinism, or left ventricular noncompaction.
Discussion
This case report describes a patient with noncompaction cardiomyopathy and chromosomal translocation who developed diazoxide-associated pulmonary hypertension. Immediate recognition and discontinuation of the diazoxide led to clinical improvement and resolution of pulmonary hypertension within several days.
Diazoxide, a KATP channel opener, is the first-line therapy for the treatment of hyperinsulinemic hypoglycemia by inhibiting release of insulin from the pancreas. It also leads to smooth muscle cell relaxation with both systemic and pulmonary vasodilation.1 While diazoxide is well tolerated in the majority of infants receiving this therapy, there is a known association with the development of pulmonary hypertension. In 2015, the Federal Drug Agency (FDA) issued a drug safety communication citing 11 cases of diazoxide associated pulmonary hypertension.2
The first case report describing pulmonary hypertension in a patient treated with diazoxide was noted in 2004.3 Since that time, even in light of the FDA drug safety communication, less than 50 cases of diazoxide-associated pulmonary hypertension are reported in the literature. In series published from single centers or regional cohorts, the incidence of diazoxide-associated pulmonary hypertension is estimated to be 2.4–7%.4–6 Potential risk factors for development of diazoxide-associated pulmonary hypertension include lower gestational age, fluid overload, and congenital heart disease.4–6 Reported concomitant congenital heart disease diagnoses are variable in terms of hemodynamic significance and likelihood of potential contribution to pulmonary hypertension in the neonatal period, ranging from small ASD to patent ductus arteriosus to more complex lesions such as double outlet right ventricle and atrioventricular septal defect.3–8 There is one reported case associated with a restrictive cardiomyopathy.5
Diazoxide’s initial clinical use was as an antihypertensive via its action as a systemic vasodilator. This prompted evaluation of diazoxide as a pulmonary vasodilator, with some report of efficacy in idiopathic pulmonary hypertension.9 The relationship between KATP channels and the development of pulmonary hypertension is complex, with differential expression of different channel subtypes depending on tissue type and physiologic state. Loss of function in one subtype can lead to heritable pulmonary hypertension.10 Gain of function in a different subtype causes a genetic disorder called Cantu syndrome, which manifests similarly to the side effects of diazoxide with edema, hypertrichosis, and pulmonary hypertension.10 One can speculate that some predisposition (e.g. a KATP channel gene mutation or overexpression) may lead to the diazoxide-associated pulmonary hypertension when stimulated by initiation of diazoxide therapy, similar to a “two-hit hypothesis” in other fields.
To the best of our knowledge, this report is the first case described in a patient with noncompaction cardiomyopathy in addition to an ASD. Noncompaction cardiomyopathy with left ventricular diastolic dysfunction may predispose to pulmonary arterial hypertension secondary to elevated post-capillary pressure; however, this is usually not a primary feature in young infants with cardiomyopathy. Importantly, our patient’s pulmonary hypertension was detected on what was intended as routine follow-up for his known cardiomyopathy, and he had not had prior echocardiographic or clinical evidence of significant diastolic dysfunction or restrictive physiology. Our center does not have routine echocardiogram protocols for initiating diazoxide treatment for neonatal hyperinsulinemic hypoglycemia. This case highlights the benefit of pre-treatment knowledge of underlying cardiac concerns and makes a case for routine post-treatment echocardiographic screening, particularly in patients with identifiable risk factors for development of pulmonary hypertension. Further, this adds to the body of literature of potential associations in this rare clinical entity.
Contributorship: Sullivan was a fellow at the time of data collection and patient involvement and was responsible for the primary composition of the written manuscript draft. Tillman and Kindel contributed with review of patient-specific details with regard to pulmonary hypertension and underlying cardiomyopathy, respectively. Handler contributed as senior author, with primary role in case selection and case report oversight. All authors were involved in review and final approval of this article.
Declaration of conflicting interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Ethical approval: Written informed consent was obtained from the patient’s parent for patient information to be published.
Guarantor: SH.
Funding: The author(s) received no financial support for the research, authorship, and/or publication of this article.
ORCID iD: Rachel T. Sullivan https://orcid.org/0000-0003-4580-9965 | Recovered | ReactionOutcome | CC BY-NC | 33614015 | 19,066,362 | 2021 |
What was the outcome of reaction 'Right atrial dilatation'? | Diazoxide-associated pulmonary hypertension in a patient with noncompaction cardiomyopathy.
Development of pulmonary hypertension after initiation of diazoxide for the treatment of neonatal hyperinsulinemic hypoglycemia is a rare, but previously described association. Risk factors for development of diazoxide-associated pulmonary hypertension include lower gestational age and congenital heart disease. This novel case report describes an infant with noncompaction cardiomyopathy who developed pulmonary hypertension shortly after initiation of diazoxide for hyperinsulinemic hypoglycemia which resolved upon cessation of the drug. This case highlights the benefit of having pre-treatment knowledge of underlying cardiac anatomy and makes a case for routine echocardiographic screening for neonates initiating diazoxide treatment.
Case description
A term male infant, followed prenatally for a single umbilical artery and cerebral ventriculomegaly, presented with hypoglycemia at 8 h of age. Initially controlled on intravenous dextrose containing fluids, he ultimately maintained appropriate blood glucose levels on fortified ad lib feeds at one week of age. Postnatal workup for multiple congenital anomalies revealed mild cerebral ventriculomegaly and mild bilateral hydronephrosis. Initial echocardiogram demonstrated mild aortic isthmus hypoplasia without discrete coarctation, biventricular hypertrophy with prominent biventricular myocardial trabeculations, and an ostium secundum atrial septal defect (ASD) without signs of pulmonary hypertension.
On day of life 11, repeat echocardiogram more clearly demonstrated noncompaction cardiomyopathy with moderately diminished left ventricular function (ejection fraction 40%), mildly diminished right ventricular function, and no evidence of pulmonary hypertension. N-terminal-pro B-type natriuretic peptide (NT-pro-BNP) was elevated at 1760 pg/mL (lab normal <350 pg/mL), and enalapril was started for afterload reduction. He was hospitalized at three weeks of age for continued hypoglycemia and started on diazoxide when workup confirmed hyperinsulinism. He transiently required furosemide for pulmonary edema; however, prior to hospital discharge had clinically improved with NT-pro-BNP of 494 pg/mL and was discharged without diuretics.
At one month of age, he returned to cardiology clinic with lethargy and hypoxia with a systemic saturation of 62%. Echocardiogram demonstrated severe pulmonary hypertension with severe right atrial and ventricular dilation, interventricular septal flattening, mild right ventricular hypertrophy, mildly diminished right ventricular function, dilated main and branch pulmonary arteries, and bidirectional shunting at the ASD (Fig. 1). NT-pro-BNP was markedly elevated at 26,600 pg/mL. Saturations improved to 95% on supplemental oxygen via nasal cannula, and he was admitted. Due to concern for diazoxide-induced pulmonary hypertension given the temporal relation to drug initiation, diazoxide was discontinued. Three days after diazoxide discontinuation, echocardiogram demonstrated improvement in secondary findings of pulmonary hypertension, with improved right heart dilation and function, improved interventricular septal position, and left to right shunting across the ASD (Fig. 1). NT-pro-BNP had decreased to 1340 pg/mL. He weaned off supplemental oxygen and discharged after four days on no pulmonary vasodilator therapy with stable blood glucose off diazoxide.
Fig. 1. Panel (a) demonstrates Echocardiographic evidence of severe pulmonary hypertension after diazoxide initiation with severe interventricular septal flattening (a). Panel (b) shows Complete resolution of pulmonary hypertension within nine months of diazoxide discontinuation with normal interventricular septal configuration.
Within nine months following hospital discharge, he had no further evidence of pulmonary hypertension, and his left ventricular function normalized on ACE inhibitor monotherapy. Additionally, he was diagnosed with idiopathic interstitial lung disease based on chest CT demonstrating diffuse bilateral ground glass opacities with interlobular septal thickening and a new oxygen requirement well after resolution of his pulmonary hypertension. To date, no additional pulmonary laboratory or invasive testing has been pursued given mild nature of symptoms and no further evidence of pulmonary hypertension. He continues with routine pulmonary follow-up. Genetic testing revealed an unbalanced chromosomal translocation, with chromosome 1p36 deletion and 4q32 duplication. Regions involved in this translocation do not overlap with genes on commercially available gene panels for pulmonary hypertension, congenital hyperinsulinism, or left ventricular noncompaction.
Discussion
This case report describes a patient with noncompaction cardiomyopathy and chromosomal translocation who developed diazoxide-associated pulmonary hypertension. Immediate recognition and discontinuation of the diazoxide led to clinical improvement and resolution of pulmonary hypertension within several days.
Diazoxide, a KATP channel opener, is the first-line therapy for the treatment of hyperinsulinemic hypoglycemia by inhibiting release of insulin from the pancreas. It also leads to smooth muscle cell relaxation with both systemic and pulmonary vasodilation.1 While diazoxide is well tolerated in the majority of infants receiving this therapy, there is a known association with the development of pulmonary hypertension. In 2015, the Federal Drug Agency (FDA) issued a drug safety communication citing 11 cases of diazoxide associated pulmonary hypertension.2
The first case report describing pulmonary hypertension in a patient treated with diazoxide was noted in 2004.3 Since that time, even in light of the FDA drug safety communication, less than 50 cases of diazoxide-associated pulmonary hypertension are reported in the literature. In series published from single centers or regional cohorts, the incidence of diazoxide-associated pulmonary hypertension is estimated to be 2.4–7%.4–6 Potential risk factors for development of diazoxide-associated pulmonary hypertension include lower gestational age, fluid overload, and congenital heart disease.4–6 Reported concomitant congenital heart disease diagnoses are variable in terms of hemodynamic significance and likelihood of potential contribution to pulmonary hypertension in the neonatal period, ranging from small ASD to patent ductus arteriosus to more complex lesions such as double outlet right ventricle and atrioventricular septal defect.3–8 There is one reported case associated with a restrictive cardiomyopathy.5
Diazoxide’s initial clinical use was as an antihypertensive via its action as a systemic vasodilator. This prompted evaluation of diazoxide as a pulmonary vasodilator, with some report of efficacy in idiopathic pulmonary hypertension.9 The relationship between KATP channels and the development of pulmonary hypertension is complex, with differential expression of different channel subtypes depending on tissue type and physiologic state. Loss of function in one subtype can lead to heritable pulmonary hypertension.10 Gain of function in a different subtype causes a genetic disorder called Cantu syndrome, which manifests similarly to the side effects of diazoxide with edema, hypertrichosis, and pulmonary hypertension.10 One can speculate that some predisposition (e.g. a KATP channel gene mutation or overexpression) may lead to the diazoxide-associated pulmonary hypertension when stimulated by initiation of diazoxide therapy, similar to a “two-hit hypothesis” in other fields.
To the best of our knowledge, this report is the first case described in a patient with noncompaction cardiomyopathy in addition to an ASD. Noncompaction cardiomyopathy with left ventricular diastolic dysfunction may predispose to pulmonary arterial hypertension secondary to elevated post-capillary pressure; however, this is usually not a primary feature in young infants with cardiomyopathy. Importantly, our patient’s pulmonary hypertension was detected on what was intended as routine follow-up for his known cardiomyopathy, and he had not had prior echocardiographic or clinical evidence of significant diastolic dysfunction or restrictive physiology. Our center does not have routine echocardiogram protocols for initiating diazoxide treatment for neonatal hyperinsulinemic hypoglycemia. This case highlights the benefit of pre-treatment knowledge of underlying cardiac concerns and makes a case for routine post-treatment echocardiographic screening, particularly in patients with identifiable risk factors for development of pulmonary hypertension. Further, this adds to the body of literature of potential associations in this rare clinical entity.
Contributorship: Sullivan was a fellow at the time of data collection and patient involvement and was responsible for the primary composition of the written manuscript draft. Tillman and Kindel contributed with review of patient-specific details with regard to pulmonary hypertension and underlying cardiomyopathy, respectively. Handler contributed as senior author, with primary role in case selection and case report oversight. All authors were involved in review and final approval of this article.
Declaration of conflicting interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Ethical approval: Written informed consent was obtained from the patient’s parent for patient information to be published.
Guarantor: SH.
Funding: The author(s) received no financial support for the research, authorship, and/or publication of this article.
ORCID iD: Rachel T. Sullivan https://orcid.org/0000-0003-4580-9965 | Recovered | ReactionOutcome | CC BY-NC | 33614015 | 19,066,362 | 2021 |
What was the outcome of reaction 'Right ventricular dysfunction'? | Diazoxide-associated pulmonary hypertension in a patient with noncompaction cardiomyopathy.
Development of pulmonary hypertension after initiation of diazoxide for the treatment of neonatal hyperinsulinemic hypoglycemia is a rare, but previously described association. Risk factors for development of diazoxide-associated pulmonary hypertension include lower gestational age and congenital heart disease. This novel case report describes an infant with noncompaction cardiomyopathy who developed pulmonary hypertension shortly after initiation of diazoxide for hyperinsulinemic hypoglycemia which resolved upon cessation of the drug. This case highlights the benefit of having pre-treatment knowledge of underlying cardiac anatomy and makes a case for routine echocardiographic screening for neonates initiating diazoxide treatment.
Case description
A term male infant, followed prenatally for a single umbilical artery and cerebral ventriculomegaly, presented with hypoglycemia at 8 h of age. Initially controlled on intravenous dextrose containing fluids, he ultimately maintained appropriate blood glucose levels on fortified ad lib feeds at one week of age. Postnatal workup for multiple congenital anomalies revealed mild cerebral ventriculomegaly and mild bilateral hydronephrosis. Initial echocardiogram demonstrated mild aortic isthmus hypoplasia without discrete coarctation, biventricular hypertrophy with prominent biventricular myocardial trabeculations, and an ostium secundum atrial septal defect (ASD) without signs of pulmonary hypertension.
On day of life 11, repeat echocardiogram more clearly demonstrated noncompaction cardiomyopathy with moderately diminished left ventricular function (ejection fraction 40%), mildly diminished right ventricular function, and no evidence of pulmonary hypertension. N-terminal-pro B-type natriuretic peptide (NT-pro-BNP) was elevated at 1760 pg/mL (lab normal <350 pg/mL), and enalapril was started for afterload reduction. He was hospitalized at three weeks of age for continued hypoglycemia and started on diazoxide when workup confirmed hyperinsulinism. He transiently required furosemide for pulmonary edema; however, prior to hospital discharge had clinically improved with NT-pro-BNP of 494 pg/mL and was discharged without diuretics.
At one month of age, he returned to cardiology clinic with lethargy and hypoxia with a systemic saturation of 62%. Echocardiogram demonstrated severe pulmonary hypertension with severe right atrial and ventricular dilation, interventricular septal flattening, mild right ventricular hypertrophy, mildly diminished right ventricular function, dilated main and branch pulmonary arteries, and bidirectional shunting at the ASD (Fig. 1). NT-pro-BNP was markedly elevated at 26,600 pg/mL. Saturations improved to 95% on supplemental oxygen via nasal cannula, and he was admitted. Due to concern for diazoxide-induced pulmonary hypertension given the temporal relation to drug initiation, diazoxide was discontinued. Three days after diazoxide discontinuation, echocardiogram demonstrated improvement in secondary findings of pulmonary hypertension, with improved right heart dilation and function, improved interventricular septal position, and left to right shunting across the ASD (Fig. 1). NT-pro-BNP had decreased to 1340 pg/mL. He weaned off supplemental oxygen and discharged after four days on no pulmonary vasodilator therapy with stable blood glucose off diazoxide.
Fig. 1. Panel (a) demonstrates Echocardiographic evidence of severe pulmonary hypertension after diazoxide initiation with severe interventricular septal flattening (a). Panel (b) shows Complete resolution of pulmonary hypertension within nine months of diazoxide discontinuation with normal interventricular septal configuration.
Within nine months following hospital discharge, he had no further evidence of pulmonary hypertension, and his left ventricular function normalized on ACE inhibitor monotherapy. Additionally, he was diagnosed with idiopathic interstitial lung disease based on chest CT demonstrating diffuse bilateral ground glass opacities with interlobular septal thickening and a new oxygen requirement well after resolution of his pulmonary hypertension. To date, no additional pulmonary laboratory or invasive testing has been pursued given mild nature of symptoms and no further evidence of pulmonary hypertension. He continues with routine pulmonary follow-up. Genetic testing revealed an unbalanced chromosomal translocation, with chromosome 1p36 deletion and 4q32 duplication. Regions involved in this translocation do not overlap with genes on commercially available gene panels for pulmonary hypertension, congenital hyperinsulinism, or left ventricular noncompaction.
Discussion
This case report describes a patient with noncompaction cardiomyopathy and chromosomal translocation who developed diazoxide-associated pulmonary hypertension. Immediate recognition and discontinuation of the diazoxide led to clinical improvement and resolution of pulmonary hypertension within several days.
Diazoxide, a KATP channel opener, is the first-line therapy for the treatment of hyperinsulinemic hypoglycemia by inhibiting release of insulin from the pancreas. It also leads to smooth muscle cell relaxation with both systemic and pulmonary vasodilation.1 While diazoxide is well tolerated in the majority of infants receiving this therapy, there is a known association with the development of pulmonary hypertension. In 2015, the Federal Drug Agency (FDA) issued a drug safety communication citing 11 cases of diazoxide associated pulmonary hypertension.2
The first case report describing pulmonary hypertension in a patient treated with diazoxide was noted in 2004.3 Since that time, even in light of the FDA drug safety communication, less than 50 cases of diazoxide-associated pulmonary hypertension are reported in the literature. In series published from single centers or regional cohorts, the incidence of diazoxide-associated pulmonary hypertension is estimated to be 2.4–7%.4–6 Potential risk factors for development of diazoxide-associated pulmonary hypertension include lower gestational age, fluid overload, and congenital heart disease.4–6 Reported concomitant congenital heart disease diagnoses are variable in terms of hemodynamic significance and likelihood of potential contribution to pulmonary hypertension in the neonatal period, ranging from small ASD to patent ductus arteriosus to more complex lesions such as double outlet right ventricle and atrioventricular septal defect.3–8 There is one reported case associated with a restrictive cardiomyopathy.5
Diazoxide’s initial clinical use was as an antihypertensive via its action as a systemic vasodilator. This prompted evaluation of diazoxide as a pulmonary vasodilator, with some report of efficacy in idiopathic pulmonary hypertension.9 The relationship between KATP channels and the development of pulmonary hypertension is complex, with differential expression of different channel subtypes depending on tissue type and physiologic state. Loss of function in one subtype can lead to heritable pulmonary hypertension.10 Gain of function in a different subtype causes a genetic disorder called Cantu syndrome, which manifests similarly to the side effects of diazoxide with edema, hypertrichosis, and pulmonary hypertension.10 One can speculate that some predisposition (e.g. a KATP channel gene mutation or overexpression) may lead to the diazoxide-associated pulmonary hypertension when stimulated by initiation of diazoxide therapy, similar to a “two-hit hypothesis” in other fields.
To the best of our knowledge, this report is the first case described in a patient with noncompaction cardiomyopathy in addition to an ASD. Noncompaction cardiomyopathy with left ventricular diastolic dysfunction may predispose to pulmonary arterial hypertension secondary to elevated post-capillary pressure; however, this is usually not a primary feature in young infants with cardiomyopathy. Importantly, our patient’s pulmonary hypertension was detected on what was intended as routine follow-up for his known cardiomyopathy, and he had not had prior echocardiographic or clinical evidence of significant diastolic dysfunction or restrictive physiology. Our center does not have routine echocardiogram protocols for initiating diazoxide treatment for neonatal hyperinsulinemic hypoglycemia. This case highlights the benefit of pre-treatment knowledge of underlying cardiac concerns and makes a case for routine post-treatment echocardiographic screening, particularly in patients with identifiable risk factors for development of pulmonary hypertension. Further, this adds to the body of literature of potential associations in this rare clinical entity.
Contributorship: Sullivan was a fellow at the time of data collection and patient involvement and was responsible for the primary composition of the written manuscript draft. Tillman and Kindel contributed with review of patient-specific details with regard to pulmonary hypertension and underlying cardiomyopathy, respectively. Handler contributed as senior author, with primary role in case selection and case report oversight. All authors were involved in review and final approval of this article.
Declaration of conflicting interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Ethical approval: Written informed consent was obtained from the patient’s parent for patient information to be published.
Guarantor: SH.
Funding: The author(s) received no financial support for the research, authorship, and/or publication of this article.
ORCID iD: Rachel T. Sullivan https://orcid.org/0000-0003-4580-9965 | Recovered | ReactionOutcome | CC BY-NC | 33614015 | 19,066,362 | 2021 |
What was the outcome of reaction 'Right ventricular hypertrophy'? | Diazoxide-associated pulmonary hypertension in a patient with noncompaction cardiomyopathy.
Development of pulmonary hypertension after initiation of diazoxide for the treatment of neonatal hyperinsulinemic hypoglycemia is a rare, but previously described association. Risk factors for development of diazoxide-associated pulmonary hypertension include lower gestational age and congenital heart disease. This novel case report describes an infant with noncompaction cardiomyopathy who developed pulmonary hypertension shortly after initiation of diazoxide for hyperinsulinemic hypoglycemia which resolved upon cessation of the drug. This case highlights the benefit of having pre-treatment knowledge of underlying cardiac anatomy and makes a case for routine echocardiographic screening for neonates initiating diazoxide treatment.
Case description
A term male infant, followed prenatally for a single umbilical artery and cerebral ventriculomegaly, presented with hypoglycemia at 8 h of age. Initially controlled on intravenous dextrose containing fluids, he ultimately maintained appropriate blood glucose levels on fortified ad lib feeds at one week of age. Postnatal workup for multiple congenital anomalies revealed mild cerebral ventriculomegaly and mild bilateral hydronephrosis. Initial echocardiogram demonstrated mild aortic isthmus hypoplasia without discrete coarctation, biventricular hypertrophy with prominent biventricular myocardial trabeculations, and an ostium secundum atrial septal defect (ASD) without signs of pulmonary hypertension.
On day of life 11, repeat echocardiogram more clearly demonstrated noncompaction cardiomyopathy with moderately diminished left ventricular function (ejection fraction 40%), mildly diminished right ventricular function, and no evidence of pulmonary hypertension. N-terminal-pro B-type natriuretic peptide (NT-pro-BNP) was elevated at 1760 pg/mL (lab normal <350 pg/mL), and enalapril was started for afterload reduction. He was hospitalized at three weeks of age for continued hypoglycemia and started on diazoxide when workup confirmed hyperinsulinism. He transiently required furosemide for pulmonary edema; however, prior to hospital discharge had clinically improved with NT-pro-BNP of 494 pg/mL and was discharged without diuretics.
At one month of age, he returned to cardiology clinic with lethargy and hypoxia with a systemic saturation of 62%. Echocardiogram demonstrated severe pulmonary hypertension with severe right atrial and ventricular dilation, interventricular septal flattening, mild right ventricular hypertrophy, mildly diminished right ventricular function, dilated main and branch pulmonary arteries, and bidirectional shunting at the ASD (Fig. 1). NT-pro-BNP was markedly elevated at 26,600 pg/mL. Saturations improved to 95% on supplemental oxygen via nasal cannula, and he was admitted. Due to concern for diazoxide-induced pulmonary hypertension given the temporal relation to drug initiation, diazoxide was discontinued. Three days after diazoxide discontinuation, echocardiogram demonstrated improvement in secondary findings of pulmonary hypertension, with improved right heart dilation and function, improved interventricular septal position, and left to right shunting across the ASD (Fig. 1). NT-pro-BNP had decreased to 1340 pg/mL. He weaned off supplemental oxygen and discharged after four days on no pulmonary vasodilator therapy with stable blood glucose off diazoxide.
Fig. 1. Panel (a) demonstrates Echocardiographic evidence of severe pulmonary hypertension after diazoxide initiation with severe interventricular septal flattening (a). Panel (b) shows Complete resolution of pulmonary hypertension within nine months of diazoxide discontinuation with normal interventricular septal configuration.
Within nine months following hospital discharge, he had no further evidence of pulmonary hypertension, and his left ventricular function normalized on ACE inhibitor monotherapy. Additionally, he was diagnosed with idiopathic interstitial lung disease based on chest CT demonstrating diffuse bilateral ground glass opacities with interlobular septal thickening and a new oxygen requirement well after resolution of his pulmonary hypertension. To date, no additional pulmonary laboratory or invasive testing has been pursued given mild nature of symptoms and no further evidence of pulmonary hypertension. He continues with routine pulmonary follow-up. Genetic testing revealed an unbalanced chromosomal translocation, with chromosome 1p36 deletion and 4q32 duplication. Regions involved in this translocation do not overlap with genes on commercially available gene panels for pulmonary hypertension, congenital hyperinsulinism, or left ventricular noncompaction.
Discussion
This case report describes a patient with noncompaction cardiomyopathy and chromosomal translocation who developed diazoxide-associated pulmonary hypertension. Immediate recognition and discontinuation of the diazoxide led to clinical improvement and resolution of pulmonary hypertension within several days.
Diazoxide, a KATP channel opener, is the first-line therapy for the treatment of hyperinsulinemic hypoglycemia by inhibiting release of insulin from the pancreas. It also leads to smooth muscle cell relaxation with both systemic and pulmonary vasodilation.1 While diazoxide is well tolerated in the majority of infants receiving this therapy, there is a known association with the development of pulmonary hypertension. In 2015, the Federal Drug Agency (FDA) issued a drug safety communication citing 11 cases of diazoxide associated pulmonary hypertension.2
The first case report describing pulmonary hypertension in a patient treated with diazoxide was noted in 2004.3 Since that time, even in light of the FDA drug safety communication, less than 50 cases of diazoxide-associated pulmonary hypertension are reported in the literature. In series published from single centers or regional cohorts, the incidence of diazoxide-associated pulmonary hypertension is estimated to be 2.4–7%.4–6 Potential risk factors for development of diazoxide-associated pulmonary hypertension include lower gestational age, fluid overload, and congenital heart disease.4–6 Reported concomitant congenital heart disease diagnoses are variable in terms of hemodynamic significance and likelihood of potential contribution to pulmonary hypertension in the neonatal period, ranging from small ASD to patent ductus arteriosus to more complex lesions such as double outlet right ventricle and atrioventricular septal defect.3–8 There is one reported case associated with a restrictive cardiomyopathy.5
Diazoxide’s initial clinical use was as an antihypertensive via its action as a systemic vasodilator. This prompted evaluation of diazoxide as a pulmonary vasodilator, with some report of efficacy in idiopathic pulmonary hypertension.9 The relationship between KATP channels and the development of pulmonary hypertension is complex, with differential expression of different channel subtypes depending on tissue type and physiologic state. Loss of function in one subtype can lead to heritable pulmonary hypertension.10 Gain of function in a different subtype causes a genetic disorder called Cantu syndrome, which manifests similarly to the side effects of diazoxide with edema, hypertrichosis, and pulmonary hypertension.10 One can speculate that some predisposition (e.g. a KATP channel gene mutation or overexpression) may lead to the diazoxide-associated pulmonary hypertension when stimulated by initiation of diazoxide therapy, similar to a “two-hit hypothesis” in other fields.
To the best of our knowledge, this report is the first case described in a patient with noncompaction cardiomyopathy in addition to an ASD. Noncompaction cardiomyopathy with left ventricular diastolic dysfunction may predispose to pulmonary arterial hypertension secondary to elevated post-capillary pressure; however, this is usually not a primary feature in young infants with cardiomyopathy. Importantly, our patient’s pulmonary hypertension was detected on what was intended as routine follow-up for his known cardiomyopathy, and he had not had prior echocardiographic or clinical evidence of significant diastolic dysfunction or restrictive physiology. Our center does not have routine echocardiogram protocols for initiating diazoxide treatment for neonatal hyperinsulinemic hypoglycemia. This case highlights the benefit of pre-treatment knowledge of underlying cardiac concerns and makes a case for routine post-treatment echocardiographic screening, particularly in patients with identifiable risk factors for development of pulmonary hypertension. Further, this adds to the body of literature of potential associations in this rare clinical entity.
Contributorship: Sullivan was a fellow at the time of data collection and patient involvement and was responsible for the primary composition of the written manuscript draft. Tillman and Kindel contributed with review of patient-specific details with regard to pulmonary hypertension and underlying cardiomyopathy, respectively. Handler contributed as senior author, with primary role in case selection and case report oversight. All authors were involved in review and final approval of this article.
Declaration of conflicting interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Ethical approval: Written informed consent was obtained from the patient’s parent for patient information to be published.
Guarantor: SH.
Funding: The author(s) received no financial support for the research, authorship, and/or publication of this article.
ORCID iD: Rachel T. Sullivan https://orcid.org/0000-0003-4580-9965 | Recovered | ReactionOutcome | CC BY-NC | 33614015 | 19,066,362 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Agitation'. | Amantadine withdrawal syndrome masquerading as COVID-19 encephalopathy: a case report and review of the literature.
Amantadine withdrawal syndrome (AWS) is a rare but recognized cause of severe and persistent altered mental status sometimes with co-occurring extrapyramidal symptoms. First described in a case series from 1987, its clinical manifestations have been characterized along a spectrum ranging from profound hypoactive delirium to hyperactive delirium with hallucinations. Risk factors for withdrawal include abrupt medication discontinuation, prolonged use, older age and underlying dementia. Herein we describe a case of a 52-year-old woman who presented with confusion, hallucinations, and coronavirus disease-2019 infection. She subsequently developed a prolonged hypoactive delirium after her amantadine was tapered and held. Her hypoactive delirium entirely resolved with resumption of amantadine confirming the diagnosis of AWS. This case illustrates the importance of slowly tapering dopaminergic medications and being aware of rare pharmacologic side effects.
INTRODUCTION
Amantadine hydrochloride, among the many happy accidents in medicine, was inadvertently discovered to alleviate the extrapyramidal symptoms of Parkinson’s disease (PD) in 1968. A woman with PD found her symptoms much improved while taking amantadine for flu prophylaxis. Later that year a large trial demonstrated both subjective and objective benefits when used to treat PD [1]. Since that time, amantadine has been used to treat PD alongside a number of other movement disorders.
Although its mechanism is not fully understood, amantadine is thought to achieve its effect via N-methyl-D-aspartate receptor antagonism, direct and indirect effects on dopamine neurons, and by decreasing anticholinergic tone [2]. Amantadine can cause dopamine toxicity: paranoia, hallucinations and tachycardia. For this reason, the medication is initiated progressively. Inversely, if it is rapidly discontinued, patients may develop amantadine withdrawal syndrome (AWS), a severe and persistent delirium often with concurrent extrapyramidal symptoms.
CASE REPORT
A 52-year-old female with a past medical history of spinocerebellar ataxia, hyperthyroidism and depression presented to the hospital with 2–3 weeks of hallucinations. Admission labs were remarkable for a new acute kidney injury with blood urea nitrogen (76 mg/dl) and creatinine (1.6 mg/dl from baseline of 0.8 mg/dl). Additionally, she was found to be coronavirus disease-2019 (COVID-19) positive. Complete blood count, urinalysis, thyroid stimulating hormone (TSH), serum ethanol level and head computed tomography were unremarkable. Vital signs were notable for a heart rate of 104. On arrival she was alert and answering questions appropriately. The patient had been prescribed amantadine for 2.5 years prior to admission and was taking 300 mg daily.
The neurology service suspected her hallucinations were related to amantadine toxicity and recommended a 3-day taper, shortened to 2 days by the primary service. Serum amantadine level was ordered on admission and found to be 1505 ng/dl (therapeutic range 200–1000 ng/ml and toxicity >2000 ng/ml). The patient continued to have hallucinations with concurrent agitation, prompting an electroencephalogram (EEG) and lumbar puncture. All lumbar puncture studies were normal. EEG showed background slowing consistent with encephalopathy with no epileptiform activity.
After 3 days, the patient was no longer having active hallucinations but became increasingly somnolent and disoriented. Five days into her course, she was no longer consistently speaking with providers. Two weeks into her hospitalization, she required assistance in feeding and was not reliably following commands. Given her persistent symptoms, the possibility of COVID-19 encephalopathy was raised and a repeat lumbar puncture considered for colony-stimulating factor polymerase chain reactiontesting. Prior to this, the patient was resumed on 200 mg of oral amantadine. Within 2 days she was alert, speaking in full sentences, and oriented to person, month and situation. Because the patient’s prolonged delirium resolved immediately after resuming amantadine, the diagnosis of AWS was made. The neurology service believed that the patient’s initial presentation was consistent with amantadine toxicity with the patient going into withdrawal in the subsequent days as the medication was tapered and held, thus explaining both her initial agitation and hallucinations and subsequent hypoactive delirium. She ultimately returned to her cognitive baseline and was discharged to subacute rehab.
DISCUSSION
Since 1987 there have been seven case reports describing instances of AWS including 15 patients. This is the first published since 2017 and is noteworthy in that it describes a patient without PD or underlying dementia. The first case series, published by Wilson in 1987, describes three older patients who experienced recrudescence of their PD motor symptoms after amantadine was held [3]. Only one of the three patients may have suffered from our more contemporary definition of AWS, an acute delirium following the discontinuation of the medication, whereas the other two patients experienced only movement symptoms.
In 1997 Factor published a case series describing three elderly patients who developed acute delirium with worsening motor function after amantadine was held [4]. All patients had underlying dementia and had been taking amantadine for more than 4 years. Symptoms quickly resolved after resuming the medication. Interestingly, all patients had their amantadine held due to hallucinations. Miyasaki republished a reply to the editor sharing two similar cases of patients with longstanding PD who developed AWS [5]. Factor responded with two further cases of elderly patients with characteristic PD and AWS. These cases were novel in that one patient did not have underlying dementia and both patients had been taking amantadine for less than 1 year. Again, symptoms entirely resolved with resumption of amantadine. Miyasaki hypothesized that pathogenesis of the delirium was related to the glutamatergic system. At this point some general risk factors for AWS were induced: old age, advanced PD, underlying dementia and duration of therapy. Factor agreed with Miyaski that AWS was unlikely related to dopaminergic pathways.
In 2009 Brantley published a case report of neuroleptic malignant syndrome (NMS) believed induced by amantadine withdrawal [6]. The authors hypothesized that more classic AWS exists on a spectrum which includes NMS. Marxreiter added an additional case of severe AWS in a patient with PD in 2017, helpfully noting the benefit of reintroducing amantadine early in instances of diagnostic uncertainty due to its rapid effects [7]. Finally, Fryml described three cases of AWS in a 2017 report which interestingly included the first patient without PD [8]. The authors noted the remarkable duration that AWS can persist: in one instance for weeks. Similar to Brantley, she describes AWS as a protean syndrome ranging from delirium to NMS, driven by dopaminergic derangements.
Our case illustrates both characteristic and unusual features of AWS. Characteristically, this case was prolonged and refractory, included motor symptoms, and entirely resolved with amantadine reintroduction. Atypically, this case involved a patient without PD who experienced a hypoactive delirium, although this has been also reported. Intriguingly, this case of AWS likely occurred after a period of amantadine toxicity, as the patient initially presented with hallucinations and elevated serum amantadine levels. We hope this report highlights the importance of prolonged amantadine tapers in the setting of toxicity as symptoms of overdose and withdrawal can overlap, creating diagnostic confusion. Further questions which remain to be answered include the exact pathophysiology of the syndrome and if it includes NMS as part of its spectrum.
ACKNOWLEDGMENTS
University of Chicago COVID-19 unit. No funding was received for this report.
CONFLICT OF INTEREST
None declared.
ETHICAL APPROVAL
Patient information was deidentified and informed consent obtained.
CONSENT
Written consent was obtained from the patient.
GUARANTOR
John P. Murray. | AMANTADINE HYDROCHLORIDE | DrugsGivenReaction | CC BY | 33614044 | 19,760,674 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Confusional state'. | Amantadine withdrawal syndrome masquerading as COVID-19 encephalopathy: a case report and review of the literature.
Amantadine withdrawal syndrome (AWS) is a rare but recognized cause of severe and persistent altered mental status sometimes with co-occurring extrapyramidal symptoms. First described in a case series from 1987, its clinical manifestations have been characterized along a spectrum ranging from profound hypoactive delirium to hyperactive delirium with hallucinations. Risk factors for withdrawal include abrupt medication discontinuation, prolonged use, older age and underlying dementia. Herein we describe a case of a 52-year-old woman who presented with confusion, hallucinations, and coronavirus disease-2019 infection. She subsequently developed a prolonged hypoactive delirium after her amantadine was tapered and held. Her hypoactive delirium entirely resolved with resumption of amantadine confirming the diagnosis of AWS. This case illustrates the importance of slowly tapering dopaminergic medications and being aware of rare pharmacologic side effects.
INTRODUCTION
Amantadine hydrochloride, among the many happy accidents in medicine, was inadvertently discovered to alleviate the extrapyramidal symptoms of Parkinson’s disease (PD) in 1968. A woman with PD found her symptoms much improved while taking amantadine for flu prophylaxis. Later that year a large trial demonstrated both subjective and objective benefits when used to treat PD [1]. Since that time, amantadine has been used to treat PD alongside a number of other movement disorders.
Although its mechanism is not fully understood, amantadine is thought to achieve its effect via N-methyl-D-aspartate receptor antagonism, direct and indirect effects on dopamine neurons, and by decreasing anticholinergic tone [2]. Amantadine can cause dopamine toxicity: paranoia, hallucinations and tachycardia. For this reason, the medication is initiated progressively. Inversely, if it is rapidly discontinued, patients may develop amantadine withdrawal syndrome (AWS), a severe and persistent delirium often with concurrent extrapyramidal symptoms.
CASE REPORT
A 52-year-old female with a past medical history of spinocerebellar ataxia, hyperthyroidism and depression presented to the hospital with 2–3 weeks of hallucinations. Admission labs were remarkable for a new acute kidney injury with blood urea nitrogen (76 mg/dl) and creatinine (1.6 mg/dl from baseline of 0.8 mg/dl). Additionally, she was found to be coronavirus disease-2019 (COVID-19) positive. Complete blood count, urinalysis, thyroid stimulating hormone (TSH), serum ethanol level and head computed tomography were unremarkable. Vital signs were notable for a heart rate of 104. On arrival she was alert and answering questions appropriately. The patient had been prescribed amantadine for 2.5 years prior to admission and was taking 300 mg daily.
The neurology service suspected her hallucinations were related to amantadine toxicity and recommended a 3-day taper, shortened to 2 days by the primary service. Serum amantadine level was ordered on admission and found to be 1505 ng/dl (therapeutic range 200–1000 ng/ml and toxicity >2000 ng/ml). The patient continued to have hallucinations with concurrent agitation, prompting an electroencephalogram (EEG) and lumbar puncture. All lumbar puncture studies were normal. EEG showed background slowing consistent with encephalopathy with no epileptiform activity.
After 3 days, the patient was no longer having active hallucinations but became increasingly somnolent and disoriented. Five days into her course, she was no longer consistently speaking with providers. Two weeks into her hospitalization, she required assistance in feeding and was not reliably following commands. Given her persistent symptoms, the possibility of COVID-19 encephalopathy was raised and a repeat lumbar puncture considered for colony-stimulating factor polymerase chain reactiontesting. Prior to this, the patient was resumed on 200 mg of oral amantadine. Within 2 days she was alert, speaking in full sentences, and oriented to person, month and situation. Because the patient’s prolonged delirium resolved immediately after resuming amantadine, the diagnosis of AWS was made. The neurology service believed that the patient’s initial presentation was consistent with amantadine toxicity with the patient going into withdrawal in the subsequent days as the medication was tapered and held, thus explaining both her initial agitation and hallucinations and subsequent hypoactive delirium. She ultimately returned to her cognitive baseline and was discharged to subacute rehab.
DISCUSSION
Since 1987 there have been seven case reports describing instances of AWS including 15 patients. This is the first published since 2017 and is noteworthy in that it describes a patient without PD or underlying dementia. The first case series, published by Wilson in 1987, describes three older patients who experienced recrudescence of their PD motor symptoms after amantadine was held [3]. Only one of the three patients may have suffered from our more contemporary definition of AWS, an acute delirium following the discontinuation of the medication, whereas the other two patients experienced only movement symptoms.
In 1997 Factor published a case series describing three elderly patients who developed acute delirium with worsening motor function after amantadine was held [4]. All patients had underlying dementia and had been taking amantadine for more than 4 years. Symptoms quickly resolved after resuming the medication. Interestingly, all patients had their amantadine held due to hallucinations. Miyasaki republished a reply to the editor sharing two similar cases of patients with longstanding PD who developed AWS [5]. Factor responded with two further cases of elderly patients with characteristic PD and AWS. These cases were novel in that one patient did not have underlying dementia and both patients had been taking amantadine for less than 1 year. Again, symptoms entirely resolved with resumption of amantadine. Miyasaki hypothesized that pathogenesis of the delirium was related to the glutamatergic system. At this point some general risk factors for AWS were induced: old age, advanced PD, underlying dementia and duration of therapy. Factor agreed with Miyaski that AWS was unlikely related to dopaminergic pathways.
In 2009 Brantley published a case report of neuroleptic malignant syndrome (NMS) believed induced by amantadine withdrawal [6]. The authors hypothesized that more classic AWS exists on a spectrum which includes NMS. Marxreiter added an additional case of severe AWS in a patient with PD in 2017, helpfully noting the benefit of reintroducing amantadine early in instances of diagnostic uncertainty due to its rapid effects [7]. Finally, Fryml described three cases of AWS in a 2017 report which interestingly included the first patient without PD [8]. The authors noted the remarkable duration that AWS can persist: in one instance for weeks. Similar to Brantley, she describes AWS as a protean syndrome ranging from delirium to NMS, driven by dopaminergic derangements.
Our case illustrates both characteristic and unusual features of AWS. Characteristically, this case was prolonged and refractory, included motor symptoms, and entirely resolved with amantadine reintroduction. Atypically, this case involved a patient without PD who experienced a hypoactive delirium, although this has been also reported. Intriguingly, this case of AWS likely occurred after a period of amantadine toxicity, as the patient initially presented with hallucinations and elevated serum amantadine levels. We hope this report highlights the importance of prolonged amantadine tapers in the setting of toxicity as symptoms of overdose and withdrawal can overlap, creating diagnostic confusion. Further questions which remain to be answered include the exact pathophysiology of the syndrome and if it includes NMS as part of its spectrum.
ACKNOWLEDGMENTS
University of Chicago COVID-19 unit. No funding was received for this report.
CONFLICT OF INTEREST
None declared.
ETHICAL APPROVAL
Patient information was deidentified and informed consent obtained.
CONSENT
Written consent was obtained from the patient.
GUARANTOR
John P. Murray. | AMANTADINE HYDROCHLORIDE | DrugsGivenReaction | CC BY | 33614044 | 19,760,674 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Coordination abnormal'. | Amantadine withdrawal syndrome masquerading as COVID-19 encephalopathy: a case report and review of the literature.
Amantadine withdrawal syndrome (AWS) is a rare but recognized cause of severe and persistent altered mental status sometimes with co-occurring extrapyramidal symptoms. First described in a case series from 1987, its clinical manifestations have been characterized along a spectrum ranging from profound hypoactive delirium to hyperactive delirium with hallucinations. Risk factors for withdrawal include abrupt medication discontinuation, prolonged use, older age and underlying dementia. Herein we describe a case of a 52-year-old woman who presented with confusion, hallucinations, and coronavirus disease-2019 infection. She subsequently developed a prolonged hypoactive delirium after her amantadine was tapered and held. Her hypoactive delirium entirely resolved with resumption of amantadine confirming the diagnosis of AWS. This case illustrates the importance of slowly tapering dopaminergic medications and being aware of rare pharmacologic side effects.
INTRODUCTION
Amantadine hydrochloride, among the many happy accidents in medicine, was inadvertently discovered to alleviate the extrapyramidal symptoms of Parkinson’s disease (PD) in 1968. A woman with PD found her symptoms much improved while taking amantadine for flu prophylaxis. Later that year a large trial demonstrated both subjective and objective benefits when used to treat PD [1]. Since that time, amantadine has been used to treat PD alongside a number of other movement disorders.
Although its mechanism is not fully understood, amantadine is thought to achieve its effect via N-methyl-D-aspartate receptor antagonism, direct and indirect effects on dopamine neurons, and by decreasing anticholinergic tone [2]. Amantadine can cause dopamine toxicity: paranoia, hallucinations and tachycardia. For this reason, the medication is initiated progressively. Inversely, if it is rapidly discontinued, patients may develop amantadine withdrawal syndrome (AWS), a severe and persistent delirium often with concurrent extrapyramidal symptoms.
CASE REPORT
A 52-year-old female with a past medical history of spinocerebellar ataxia, hyperthyroidism and depression presented to the hospital with 2–3 weeks of hallucinations. Admission labs were remarkable for a new acute kidney injury with blood urea nitrogen (76 mg/dl) and creatinine (1.6 mg/dl from baseline of 0.8 mg/dl). Additionally, she was found to be coronavirus disease-2019 (COVID-19) positive. Complete blood count, urinalysis, thyroid stimulating hormone (TSH), serum ethanol level and head computed tomography were unremarkable. Vital signs were notable for a heart rate of 104. On arrival she was alert and answering questions appropriately. The patient had been prescribed amantadine for 2.5 years prior to admission and was taking 300 mg daily.
The neurology service suspected her hallucinations were related to amantadine toxicity and recommended a 3-day taper, shortened to 2 days by the primary service. Serum amantadine level was ordered on admission and found to be 1505 ng/dl (therapeutic range 200–1000 ng/ml and toxicity >2000 ng/ml). The patient continued to have hallucinations with concurrent agitation, prompting an electroencephalogram (EEG) and lumbar puncture. All lumbar puncture studies were normal. EEG showed background slowing consistent with encephalopathy with no epileptiform activity.
After 3 days, the patient was no longer having active hallucinations but became increasingly somnolent and disoriented. Five days into her course, she was no longer consistently speaking with providers. Two weeks into her hospitalization, she required assistance in feeding and was not reliably following commands. Given her persistent symptoms, the possibility of COVID-19 encephalopathy was raised and a repeat lumbar puncture considered for colony-stimulating factor polymerase chain reactiontesting. Prior to this, the patient was resumed on 200 mg of oral amantadine. Within 2 days she was alert, speaking in full sentences, and oriented to person, month and situation. Because the patient’s prolonged delirium resolved immediately after resuming amantadine, the diagnosis of AWS was made. The neurology service believed that the patient’s initial presentation was consistent with amantadine toxicity with the patient going into withdrawal in the subsequent days as the medication was tapered and held, thus explaining both her initial agitation and hallucinations and subsequent hypoactive delirium. She ultimately returned to her cognitive baseline and was discharged to subacute rehab.
DISCUSSION
Since 1987 there have been seven case reports describing instances of AWS including 15 patients. This is the first published since 2017 and is noteworthy in that it describes a patient without PD or underlying dementia. The first case series, published by Wilson in 1987, describes three older patients who experienced recrudescence of their PD motor symptoms after amantadine was held [3]. Only one of the three patients may have suffered from our more contemporary definition of AWS, an acute delirium following the discontinuation of the medication, whereas the other two patients experienced only movement symptoms.
In 1997 Factor published a case series describing three elderly patients who developed acute delirium with worsening motor function after amantadine was held [4]. All patients had underlying dementia and had been taking amantadine for more than 4 years. Symptoms quickly resolved after resuming the medication. Interestingly, all patients had their amantadine held due to hallucinations. Miyasaki republished a reply to the editor sharing two similar cases of patients with longstanding PD who developed AWS [5]. Factor responded with two further cases of elderly patients with characteristic PD and AWS. These cases were novel in that one patient did not have underlying dementia and both patients had been taking amantadine for less than 1 year. Again, symptoms entirely resolved with resumption of amantadine. Miyasaki hypothesized that pathogenesis of the delirium was related to the glutamatergic system. At this point some general risk factors for AWS were induced: old age, advanced PD, underlying dementia and duration of therapy. Factor agreed with Miyaski that AWS was unlikely related to dopaminergic pathways.
In 2009 Brantley published a case report of neuroleptic malignant syndrome (NMS) believed induced by amantadine withdrawal [6]. The authors hypothesized that more classic AWS exists on a spectrum which includes NMS. Marxreiter added an additional case of severe AWS in a patient with PD in 2017, helpfully noting the benefit of reintroducing amantadine early in instances of diagnostic uncertainty due to its rapid effects [7]. Finally, Fryml described three cases of AWS in a 2017 report which interestingly included the first patient without PD [8]. The authors noted the remarkable duration that AWS can persist: in one instance for weeks. Similar to Brantley, she describes AWS as a protean syndrome ranging from delirium to NMS, driven by dopaminergic derangements.
Our case illustrates both characteristic and unusual features of AWS. Characteristically, this case was prolonged and refractory, included motor symptoms, and entirely resolved with amantadine reintroduction. Atypically, this case involved a patient without PD who experienced a hypoactive delirium, although this has been also reported. Intriguingly, this case of AWS likely occurred after a period of amantadine toxicity, as the patient initially presented with hallucinations and elevated serum amantadine levels. We hope this report highlights the importance of prolonged amantadine tapers in the setting of toxicity as symptoms of overdose and withdrawal can overlap, creating diagnostic confusion. Further questions which remain to be answered include the exact pathophysiology of the syndrome and if it includes NMS as part of its spectrum.
ACKNOWLEDGMENTS
University of Chicago COVID-19 unit. No funding was received for this report.
CONFLICT OF INTEREST
None declared.
ETHICAL APPROVAL
Patient information was deidentified and informed consent obtained.
CONSENT
Written consent was obtained from the patient.
GUARANTOR
John P. Murray. | AMANTADINE HYDROCHLORIDE | DrugsGivenReaction | CC BY | 33614044 | 19,760,674 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Delirium'. | Amantadine withdrawal syndrome masquerading as COVID-19 encephalopathy: a case report and review of the literature.
Amantadine withdrawal syndrome (AWS) is a rare but recognized cause of severe and persistent altered mental status sometimes with co-occurring extrapyramidal symptoms. First described in a case series from 1987, its clinical manifestations have been characterized along a spectrum ranging from profound hypoactive delirium to hyperactive delirium with hallucinations. Risk factors for withdrawal include abrupt medication discontinuation, prolonged use, older age and underlying dementia. Herein we describe a case of a 52-year-old woman who presented with confusion, hallucinations, and coronavirus disease-2019 infection. She subsequently developed a prolonged hypoactive delirium after her amantadine was tapered and held. Her hypoactive delirium entirely resolved with resumption of amantadine confirming the diagnosis of AWS. This case illustrates the importance of slowly tapering dopaminergic medications and being aware of rare pharmacologic side effects.
INTRODUCTION
Amantadine hydrochloride, among the many happy accidents in medicine, was inadvertently discovered to alleviate the extrapyramidal symptoms of Parkinson’s disease (PD) in 1968. A woman with PD found her symptoms much improved while taking amantadine for flu prophylaxis. Later that year a large trial demonstrated both subjective and objective benefits when used to treat PD [1]. Since that time, amantadine has been used to treat PD alongside a number of other movement disorders.
Although its mechanism is not fully understood, amantadine is thought to achieve its effect via N-methyl-D-aspartate receptor antagonism, direct and indirect effects on dopamine neurons, and by decreasing anticholinergic tone [2]. Amantadine can cause dopamine toxicity: paranoia, hallucinations and tachycardia. For this reason, the medication is initiated progressively. Inversely, if it is rapidly discontinued, patients may develop amantadine withdrawal syndrome (AWS), a severe and persistent delirium often with concurrent extrapyramidal symptoms.
CASE REPORT
A 52-year-old female with a past medical history of spinocerebellar ataxia, hyperthyroidism and depression presented to the hospital with 2–3 weeks of hallucinations. Admission labs were remarkable for a new acute kidney injury with blood urea nitrogen (76 mg/dl) and creatinine (1.6 mg/dl from baseline of 0.8 mg/dl). Additionally, she was found to be coronavirus disease-2019 (COVID-19) positive. Complete blood count, urinalysis, thyroid stimulating hormone (TSH), serum ethanol level and head computed tomography were unremarkable. Vital signs were notable for a heart rate of 104. On arrival she was alert and answering questions appropriately. The patient had been prescribed amantadine for 2.5 years prior to admission and was taking 300 mg daily.
The neurology service suspected her hallucinations were related to amantadine toxicity and recommended a 3-day taper, shortened to 2 days by the primary service. Serum amantadine level was ordered on admission and found to be 1505 ng/dl (therapeutic range 200–1000 ng/ml and toxicity >2000 ng/ml). The patient continued to have hallucinations with concurrent agitation, prompting an electroencephalogram (EEG) and lumbar puncture. All lumbar puncture studies were normal. EEG showed background slowing consistent with encephalopathy with no epileptiform activity.
After 3 days, the patient was no longer having active hallucinations but became increasingly somnolent and disoriented. Five days into her course, she was no longer consistently speaking with providers. Two weeks into her hospitalization, she required assistance in feeding and was not reliably following commands. Given her persistent symptoms, the possibility of COVID-19 encephalopathy was raised and a repeat lumbar puncture considered for colony-stimulating factor polymerase chain reactiontesting. Prior to this, the patient was resumed on 200 mg of oral amantadine. Within 2 days she was alert, speaking in full sentences, and oriented to person, month and situation. Because the patient’s prolonged delirium resolved immediately after resuming amantadine, the diagnosis of AWS was made. The neurology service believed that the patient’s initial presentation was consistent with amantadine toxicity with the patient going into withdrawal in the subsequent days as the medication was tapered and held, thus explaining both her initial agitation and hallucinations and subsequent hypoactive delirium. She ultimately returned to her cognitive baseline and was discharged to subacute rehab.
DISCUSSION
Since 1987 there have been seven case reports describing instances of AWS including 15 patients. This is the first published since 2017 and is noteworthy in that it describes a patient without PD or underlying dementia. The first case series, published by Wilson in 1987, describes three older patients who experienced recrudescence of their PD motor symptoms after amantadine was held [3]. Only one of the three patients may have suffered from our more contemporary definition of AWS, an acute delirium following the discontinuation of the medication, whereas the other two patients experienced only movement symptoms.
In 1997 Factor published a case series describing three elderly patients who developed acute delirium with worsening motor function after amantadine was held [4]. All patients had underlying dementia and had been taking amantadine for more than 4 years. Symptoms quickly resolved after resuming the medication. Interestingly, all patients had their amantadine held due to hallucinations. Miyasaki republished a reply to the editor sharing two similar cases of patients with longstanding PD who developed AWS [5]. Factor responded with two further cases of elderly patients with characteristic PD and AWS. These cases were novel in that one patient did not have underlying dementia and both patients had been taking amantadine for less than 1 year. Again, symptoms entirely resolved with resumption of amantadine. Miyasaki hypothesized that pathogenesis of the delirium was related to the glutamatergic system. At this point some general risk factors for AWS were induced: old age, advanced PD, underlying dementia and duration of therapy. Factor agreed with Miyaski that AWS was unlikely related to dopaminergic pathways.
In 2009 Brantley published a case report of neuroleptic malignant syndrome (NMS) believed induced by amantadine withdrawal [6]. The authors hypothesized that more classic AWS exists on a spectrum which includes NMS. Marxreiter added an additional case of severe AWS in a patient with PD in 2017, helpfully noting the benefit of reintroducing amantadine early in instances of diagnostic uncertainty due to its rapid effects [7]. Finally, Fryml described three cases of AWS in a 2017 report which interestingly included the first patient without PD [8]. The authors noted the remarkable duration that AWS can persist: in one instance for weeks. Similar to Brantley, she describes AWS as a protean syndrome ranging from delirium to NMS, driven by dopaminergic derangements.
Our case illustrates both characteristic and unusual features of AWS. Characteristically, this case was prolonged and refractory, included motor symptoms, and entirely resolved with amantadine reintroduction. Atypically, this case involved a patient without PD who experienced a hypoactive delirium, although this has been also reported. Intriguingly, this case of AWS likely occurred after a period of amantadine toxicity, as the patient initially presented with hallucinations and elevated serum amantadine levels. We hope this report highlights the importance of prolonged amantadine tapers in the setting of toxicity as symptoms of overdose and withdrawal can overlap, creating diagnostic confusion. Further questions which remain to be answered include the exact pathophysiology of the syndrome and if it includes NMS as part of its spectrum.
ACKNOWLEDGMENTS
University of Chicago COVID-19 unit. No funding was received for this report.
CONFLICT OF INTEREST
None declared.
ETHICAL APPROVAL
Patient information was deidentified and informed consent obtained.
CONSENT
Written consent was obtained from the patient.
GUARANTOR
John P. Murray. | AMANTADINE HYDROCHLORIDE | DrugsGivenReaction | CC BY | 33614044 | 19,760,674 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Disorientation'. | Amantadine withdrawal syndrome masquerading as COVID-19 encephalopathy: a case report and review of the literature.
Amantadine withdrawal syndrome (AWS) is a rare but recognized cause of severe and persistent altered mental status sometimes with co-occurring extrapyramidal symptoms. First described in a case series from 1987, its clinical manifestations have been characterized along a spectrum ranging from profound hypoactive delirium to hyperactive delirium with hallucinations. Risk factors for withdrawal include abrupt medication discontinuation, prolonged use, older age and underlying dementia. Herein we describe a case of a 52-year-old woman who presented with confusion, hallucinations, and coronavirus disease-2019 infection. She subsequently developed a prolonged hypoactive delirium after her amantadine was tapered and held. Her hypoactive delirium entirely resolved with resumption of amantadine confirming the diagnosis of AWS. This case illustrates the importance of slowly tapering dopaminergic medications and being aware of rare pharmacologic side effects.
INTRODUCTION
Amantadine hydrochloride, among the many happy accidents in medicine, was inadvertently discovered to alleviate the extrapyramidal symptoms of Parkinson’s disease (PD) in 1968. A woman with PD found her symptoms much improved while taking amantadine for flu prophylaxis. Later that year a large trial demonstrated both subjective and objective benefits when used to treat PD [1]. Since that time, amantadine has been used to treat PD alongside a number of other movement disorders.
Although its mechanism is not fully understood, amantadine is thought to achieve its effect via N-methyl-D-aspartate receptor antagonism, direct and indirect effects on dopamine neurons, and by decreasing anticholinergic tone [2]. Amantadine can cause dopamine toxicity: paranoia, hallucinations and tachycardia. For this reason, the medication is initiated progressively. Inversely, if it is rapidly discontinued, patients may develop amantadine withdrawal syndrome (AWS), a severe and persistent delirium often with concurrent extrapyramidal symptoms.
CASE REPORT
A 52-year-old female with a past medical history of spinocerebellar ataxia, hyperthyroidism and depression presented to the hospital with 2–3 weeks of hallucinations. Admission labs were remarkable for a new acute kidney injury with blood urea nitrogen (76 mg/dl) and creatinine (1.6 mg/dl from baseline of 0.8 mg/dl). Additionally, she was found to be coronavirus disease-2019 (COVID-19) positive. Complete blood count, urinalysis, thyroid stimulating hormone (TSH), serum ethanol level and head computed tomography were unremarkable. Vital signs were notable for a heart rate of 104. On arrival she was alert and answering questions appropriately. The patient had been prescribed amantadine for 2.5 years prior to admission and was taking 300 mg daily.
The neurology service suspected her hallucinations were related to amantadine toxicity and recommended a 3-day taper, shortened to 2 days by the primary service. Serum amantadine level was ordered on admission and found to be 1505 ng/dl (therapeutic range 200–1000 ng/ml and toxicity >2000 ng/ml). The patient continued to have hallucinations with concurrent agitation, prompting an electroencephalogram (EEG) and lumbar puncture. All lumbar puncture studies were normal. EEG showed background slowing consistent with encephalopathy with no epileptiform activity.
After 3 days, the patient was no longer having active hallucinations but became increasingly somnolent and disoriented. Five days into her course, she was no longer consistently speaking with providers. Two weeks into her hospitalization, she required assistance in feeding and was not reliably following commands. Given her persistent symptoms, the possibility of COVID-19 encephalopathy was raised and a repeat lumbar puncture considered for colony-stimulating factor polymerase chain reactiontesting. Prior to this, the patient was resumed on 200 mg of oral amantadine. Within 2 days she was alert, speaking in full sentences, and oriented to person, month and situation. Because the patient’s prolonged delirium resolved immediately after resuming amantadine, the diagnosis of AWS was made. The neurology service believed that the patient’s initial presentation was consistent with amantadine toxicity with the patient going into withdrawal in the subsequent days as the medication was tapered and held, thus explaining both her initial agitation and hallucinations and subsequent hypoactive delirium. She ultimately returned to her cognitive baseline and was discharged to subacute rehab.
DISCUSSION
Since 1987 there have been seven case reports describing instances of AWS including 15 patients. This is the first published since 2017 and is noteworthy in that it describes a patient without PD or underlying dementia. The first case series, published by Wilson in 1987, describes three older patients who experienced recrudescence of their PD motor symptoms after amantadine was held [3]. Only one of the three patients may have suffered from our more contemporary definition of AWS, an acute delirium following the discontinuation of the medication, whereas the other two patients experienced only movement symptoms.
In 1997 Factor published a case series describing three elderly patients who developed acute delirium with worsening motor function after amantadine was held [4]. All patients had underlying dementia and had been taking amantadine for more than 4 years. Symptoms quickly resolved after resuming the medication. Interestingly, all patients had their amantadine held due to hallucinations. Miyasaki republished a reply to the editor sharing two similar cases of patients with longstanding PD who developed AWS [5]. Factor responded with two further cases of elderly patients with characteristic PD and AWS. These cases were novel in that one patient did not have underlying dementia and both patients had been taking amantadine for less than 1 year. Again, symptoms entirely resolved with resumption of amantadine. Miyasaki hypothesized that pathogenesis of the delirium was related to the glutamatergic system. At this point some general risk factors for AWS were induced: old age, advanced PD, underlying dementia and duration of therapy. Factor agreed with Miyaski that AWS was unlikely related to dopaminergic pathways.
In 2009 Brantley published a case report of neuroleptic malignant syndrome (NMS) believed induced by amantadine withdrawal [6]. The authors hypothesized that more classic AWS exists on a spectrum which includes NMS. Marxreiter added an additional case of severe AWS in a patient with PD in 2017, helpfully noting the benefit of reintroducing amantadine early in instances of diagnostic uncertainty due to its rapid effects [7]. Finally, Fryml described three cases of AWS in a 2017 report which interestingly included the first patient without PD [8]. The authors noted the remarkable duration that AWS can persist: in one instance for weeks. Similar to Brantley, she describes AWS as a protean syndrome ranging from delirium to NMS, driven by dopaminergic derangements.
Our case illustrates both characteristic and unusual features of AWS. Characteristically, this case was prolonged and refractory, included motor symptoms, and entirely resolved with amantadine reintroduction. Atypically, this case involved a patient without PD who experienced a hypoactive delirium, although this has been also reported. Intriguingly, this case of AWS likely occurred after a period of amantadine toxicity, as the patient initially presented with hallucinations and elevated serum amantadine levels. We hope this report highlights the importance of prolonged amantadine tapers in the setting of toxicity as symptoms of overdose and withdrawal can overlap, creating diagnostic confusion. Further questions which remain to be answered include the exact pathophysiology of the syndrome and if it includes NMS as part of its spectrum.
ACKNOWLEDGMENTS
University of Chicago COVID-19 unit. No funding was received for this report.
CONFLICT OF INTEREST
None declared.
ETHICAL APPROVAL
Patient information was deidentified and informed consent obtained.
CONSENT
Written consent was obtained from the patient.
GUARANTOR
John P. Murray. | AMANTADINE HYDROCHLORIDE | DrugsGivenReaction | CC BY | 33614044 | 19,760,674 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Dysarthria'. | Amantadine withdrawal syndrome masquerading as COVID-19 encephalopathy: a case report and review of the literature.
Amantadine withdrawal syndrome (AWS) is a rare but recognized cause of severe and persistent altered mental status sometimes with co-occurring extrapyramidal symptoms. First described in a case series from 1987, its clinical manifestations have been characterized along a spectrum ranging from profound hypoactive delirium to hyperactive delirium with hallucinations. Risk factors for withdrawal include abrupt medication discontinuation, prolonged use, older age and underlying dementia. Herein we describe a case of a 52-year-old woman who presented with confusion, hallucinations, and coronavirus disease-2019 infection. She subsequently developed a prolonged hypoactive delirium after her amantadine was tapered and held. Her hypoactive delirium entirely resolved with resumption of amantadine confirming the diagnosis of AWS. This case illustrates the importance of slowly tapering dopaminergic medications and being aware of rare pharmacologic side effects.
INTRODUCTION
Amantadine hydrochloride, among the many happy accidents in medicine, was inadvertently discovered to alleviate the extrapyramidal symptoms of Parkinson’s disease (PD) in 1968. A woman with PD found her symptoms much improved while taking amantadine for flu prophylaxis. Later that year a large trial demonstrated both subjective and objective benefits when used to treat PD [1]. Since that time, amantadine has been used to treat PD alongside a number of other movement disorders.
Although its mechanism is not fully understood, amantadine is thought to achieve its effect via N-methyl-D-aspartate receptor antagonism, direct and indirect effects on dopamine neurons, and by decreasing anticholinergic tone [2]. Amantadine can cause dopamine toxicity: paranoia, hallucinations and tachycardia. For this reason, the medication is initiated progressively. Inversely, if it is rapidly discontinued, patients may develop amantadine withdrawal syndrome (AWS), a severe and persistent delirium often with concurrent extrapyramidal symptoms.
CASE REPORT
A 52-year-old female with a past medical history of spinocerebellar ataxia, hyperthyroidism and depression presented to the hospital with 2–3 weeks of hallucinations. Admission labs were remarkable for a new acute kidney injury with blood urea nitrogen (76 mg/dl) and creatinine (1.6 mg/dl from baseline of 0.8 mg/dl). Additionally, she was found to be coronavirus disease-2019 (COVID-19) positive. Complete blood count, urinalysis, thyroid stimulating hormone (TSH), serum ethanol level and head computed tomography were unremarkable. Vital signs were notable for a heart rate of 104. On arrival she was alert and answering questions appropriately. The patient had been prescribed amantadine for 2.5 years prior to admission and was taking 300 mg daily.
The neurology service suspected her hallucinations were related to amantadine toxicity and recommended a 3-day taper, shortened to 2 days by the primary service. Serum amantadine level was ordered on admission and found to be 1505 ng/dl (therapeutic range 200–1000 ng/ml and toxicity >2000 ng/ml). The patient continued to have hallucinations with concurrent agitation, prompting an electroencephalogram (EEG) and lumbar puncture. All lumbar puncture studies were normal. EEG showed background slowing consistent with encephalopathy with no epileptiform activity.
After 3 days, the patient was no longer having active hallucinations but became increasingly somnolent and disoriented. Five days into her course, she was no longer consistently speaking with providers. Two weeks into her hospitalization, she required assistance in feeding and was not reliably following commands. Given her persistent symptoms, the possibility of COVID-19 encephalopathy was raised and a repeat lumbar puncture considered for colony-stimulating factor polymerase chain reactiontesting. Prior to this, the patient was resumed on 200 mg of oral amantadine. Within 2 days she was alert, speaking in full sentences, and oriented to person, month and situation. Because the patient’s prolonged delirium resolved immediately after resuming amantadine, the diagnosis of AWS was made. The neurology service believed that the patient’s initial presentation was consistent with amantadine toxicity with the patient going into withdrawal in the subsequent days as the medication was tapered and held, thus explaining both her initial agitation and hallucinations and subsequent hypoactive delirium. She ultimately returned to her cognitive baseline and was discharged to subacute rehab.
DISCUSSION
Since 1987 there have been seven case reports describing instances of AWS including 15 patients. This is the first published since 2017 and is noteworthy in that it describes a patient without PD or underlying dementia. The first case series, published by Wilson in 1987, describes three older patients who experienced recrudescence of their PD motor symptoms after amantadine was held [3]. Only one of the three patients may have suffered from our more contemporary definition of AWS, an acute delirium following the discontinuation of the medication, whereas the other two patients experienced only movement symptoms.
In 1997 Factor published a case series describing three elderly patients who developed acute delirium with worsening motor function after amantadine was held [4]. All patients had underlying dementia and had been taking amantadine for more than 4 years. Symptoms quickly resolved after resuming the medication. Interestingly, all patients had their amantadine held due to hallucinations. Miyasaki republished a reply to the editor sharing two similar cases of patients with longstanding PD who developed AWS [5]. Factor responded with two further cases of elderly patients with characteristic PD and AWS. These cases were novel in that one patient did not have underlying dementia and both patients had been taking amantadine for less than 1 year. Again, symptoms entirely resolved with resumption of amantadine. Miyasaki hypothesized that pathogenesis of the delirium was related to the glutamatergic system. At this point some general risk factors for AWS were induced: old age, advanced PD, underlying dementia and duration of therapy. Factor agreed with Miyaski that AWS was unlikely related to dopaminergic pathways.
In 2009 Brantley published a case report of neuroleptic malignant syndrome (NMS) believed induced by amantadine withdrawal [6]. The authors hypothesized that more classic AWS exists on a spectrum which includes NMS. Marxreiter added an additional case of severe AWS in a patient with PD in 2017, helpfully noting the benefit of reintroducing amantadine early in instances of diagnostic uncertainty due to its rapid effects [7]. Finally, Fryml described three cases of AWS in a 2017 report which interestingly included the first patient without PD [8]. The authors noted the remarkable duration that AWS can persist: in one instance for weeks. Similar to Brantley, she describes AWS as a protean syndrome ranging from delirium to NMS, driven by dopaminergic derangements.
Our case illustrates both characteristic and unusual features of AWS. Characteristically, this case was prolonged and refractory, included motor symptoms, and entirely resolved with amantadine reintroduction. Atypically, this case involved a patient without PD who experienced a hypoactive delirium, although this has been also reported. Intriguingly, this case of AWS likely occurred after a period of amantadine toxicity, as the patient initially presented with hallucinations and elevated serum amantadine levels. We hope this report highlights the importance of prolonged amantadine tapers in the setting of toxicity as symptoms of overdose and withdrawal can overlap, creating diagnostic confusion. Further questions which remain to be answered include the exact pathophysiology of the syndrome and if it includes NMS as part of its spectrum.
ACKNOWLEDGMENTS
University of Chicago COVID-19 unit. No funding was received for this report.
CONFLICT OF INTEREST
None declared.
ETHICAL APPROVAL
Patient information was deidentified and informed consent obtained.
CONSENT
Written consent was obtained from the patient.
GUARANTOR
John P. Murray. | AMANTADINE HYDROCHLORIDE | DrugsGivenReaction | CC BY | 33614044 | 19,760,674 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Somnolence'. | Amantadine withdrawal syndrome masquerading as COVID-19 encephalopathy: a case report and review of the literature.
Amantadine withdrawal syndrome (AWS) is a rare but recognized cause of severe and persistent altered mental status sometimes with co-occurring extrapyramidal symptoms. First described in a case series from 1987, its clinical manifestations have been characterized along a spectrum ranging from profound hypoactive delirium to hyperactive delirium with hallucinations. Risk factors for withdrawal include abrupt medication discontinuation, prolonged use, older age and underlying dementia. Herein we describe a case of a 52-year-old woman who presented with confusion, hallucinations, and coronavirus disease-2019 infection. She subsequently developed a prolonged hypoactive delirium after her amantadine was tapered and held. Her hypoactive delirium entirely resolved with resumption of amantadine confirming the diagnosis of AWS. This case illustrates the importance of slowly tapering dopaminergic medications and being aware of rare pharmacologic side effects.
INTRODUCTION
Amantadine hydrochloride, among the many happy accidents in medicine, was inadvertently discovered to alleviate the extrapyramidal symptoms of Parkinson’s disease (PD) in 1968. A woman with PD found her symptoms much improved while taking amantadine for flu prophylaxis. Later that year a large trial demonstrated both subjective and objective benefits when used to treat PD [1]. Since that time, amantadine has been used to treat PD alongside a number of other movement disorders.
Although its mechanism is not fully understood, amantadine is thought to achieve its effect via N-methyl-D-aspartate receptor antagonism, direct and indirect effects on dopamine neurons, and by decreasing anticholinergic tone [2]. Amantadine can cause dopamine toxicity: paranoia, hallucinations and tachycardia. For this reason, the medication is initiated progressively. Inversely, if it is rapidly discontinued, patients may develop amantadine withdrawal syndrome (AWS), a severe and persistent delirium often with concurrent extrapyramidal symptoms.
CASE REPORT
A 52-year-old female with a past medical history of spinocerebellar ataxia, hyperthyroidism and depression presented to the hospital with 2–3 weeks of hallucinations. Admission labs were remarkable for a new acute kidney injury with blood urea nitrogen (76 mg/dl) and creatinine (1.6 mg/dl from baseline of 0.8 mg/dl). Additionally, she was found to be coronavirus disease-2019 (COVID-19) positive. Complete blood count, urinalysis, thyroid stimulating hormone (TSH), serum ethanol level and head computed tomography were unremarkable. Vital signs were notable for a heart rate of 104. On arrival she was alert and answering questions appropriately. The patient had been prescribed amantadine for 2.5 years prior to admission and was taking 300 mg daily.
The neurology service suspected her hallucinations were related to amantadine toxicity and recommended a 3-day taper, shortened to 2 days by the primary service. Serum amantadine level was ordered on admission and found to be 1505 ng/dl (therapeutic range 200–1000 ng/ml and toxicity >2000 ng/ml). The patient continued to have hallucinations with concurrent agitation, prompting an electroencephalogram (EEG) and lumbar puncture. All lumbar puncture studies were normal. EEG showed background slowing consistent with encephalopathy with no epileptiform activity.
After 3 days, the patient was no longer having active hallucinations but became increasingly somnolent and disoriented. Five days into her course, she was no longer consistently speaking with providers. Two weeks into her hospitalization, she required assistance in feeding and was not reliably following commands. Given her persistent symptoms, the possibility of COVID-19 encephalopathy was raised and a repeat lumbar puncture considered for colony-stimulating factor polymerase chain reactiontesting. Prior to this, the patient was resumed on 200 mg of oral amantadine. Within 2 days she was alert, speaking in full sentences, and oriented to person, month and situation. Because the patient’s prolonged delirium resolved immediately after resuming amantadine, the diagnosis of AWS was made. The neurology service believed that the patient’s initial presentation was consistent with amantadine toxicity with the patient going into withdrawal in the subsequent days as the medication was tapered and held, thus explaining both her initial agitation and hallucinations and subsequent hypoactive delirium. She ultimately returned to her cognitive baseline and was discharged to subacute rehab.
DISCUSSION
Since 1987 there have been seven case reports describing instances of AWS including 15 patients. This is the first published since 2017 and is noteworthy in that it describes a patient without PD or underlying dementia. The first case series, published by Wilson in 1987, describes three older patients who experienced recrudescence of their PD motor symptoms after amantadine was held [3]. Only one of the three patients may have suffered from our more contemporary definition of AWS, an acute delirium following the discontinuation of the medication, whereas the other two patients experienced only movement symptoms.
In 1997 Factor published a case series describing three elderly patients who developed acute delirium with worsening motor function after amantadine was held [4]. All patients had underlying dementia and had been taking amantadine for more than 4 years. Symptoms quickly resolved after resuming the medication. Interestingly, all patients had their amantadine held due to hallucinations. Miyasaki republished a reply to the editor sharing two similar cases of patients with longstanding PD who developed AWS [5]. Factor responded with two further cases of elderly patients with characteristic PD and AWS. These cases were novel in that one patient did not have underlying dementia and both patients had been taking amantadine for less than 1 year. Again, symptoms entirely resolved with resumption of amantadine. Miyasaki hypothesized that pathogenesis of the delirium was related to the glutamatergic system. At this point some general risk factors for AWS were induced: old age, advanced PD, underlying dementia and duration of therapy. Factor agreed with Miyaski that AWS was unlikely related to dopaminergic pathways.
In 2009 Brantley published a case report of neuroleptic malignant syndrome (NMS) believed induced by amantadine withdrawal [6]. The authors hypothesized that more classic AWS exists on a spectrum which includes NMS. Marxreiter added an additional case of severe AWS in a patient with PD in 2017, helpfully noting the benefit of reintroducing amantadine early in instances of diagnostic uncertainty due to its rapid effects [7]. Finally, Fryml described three cases of AWS in a 2017 report which interestingly included the first patient without PD [8]. The authors noted the remarkable duration that AWS can persist: in one instance for weeks. Similar to Brantley, she describes AWS as a protean syndrome ranging from delirium to NMS, driven by dopaminergic derangements.
Our case illustrates both characteristic and unusual features of AWS. Characteristically, this case was prolonged and refractory, included motor symptoms, and entirely resolved with amantadine reintroduction. Atypically, this case involved a patient without PD who experienced a hypoactive delirium, although this has been also reported. Intriguingly, this case of AWS likely occurred after a period of amantadine toxicity, as the patient initially presented with hallucinations and elevated serum amantadine levels. We hope this report highlights the importance of prolonged amantadine tapers in the setting of toxicity as symptoms of overdose and withdrawal can overlap, creating diagnostic confusion. Further questions which remain to be answered include the exact pathophysiology of the syndrome and if it includes NMS as part of its spectrum.
ACKNOWLEDGMENTS
University of Chicago COVID-19 unit. No funding was received for this report.
CONFLICT OF INTEREST
None declared.
ETHICAL APPROVAL
Patient information was deidentified and informed consent obtained.
CONSENT
Written consent was obtained from the patient.
GUARANTOR
John P. Murray. | AMANTADINE HYDROCHLORIDE | DrugsGivenReaction | CC BY | 33614044 | 19,760,674 | 2021-02 |
What was the administration route of drug 'AMANTADINE HYDROCHLORIDE'? | Amantadine withdrawal syndrome masquerading as COVID-19 encephalopathy: a case report and review of the literature.
Amantadine withdrawal syndrome (AWS) is a rare but recognized cause of severe and persistent altered mental status sometimes with co-occurring extrapyramidal symptoms. First described in a case series from 1987, its clinical manifestations have been characterized along a spectrum ranging from profound hypoactive delirium to hyperactive delirium with hallucinations. Risk factors for withdrawal include abrupt medication discontinuation, prolonged use, older age and underlying dementia. Herein we describe a case of a 52-year-old woman who presented with confusion, hallucinations, and coronavirus disease-2019 infection. She subsequently developed a prolonged hypoactive delirium after her amantadine was tapered and held. Her hypoactive delirium entirely resolved with resumption of amantadine confirming the diagnosis of AWS. This case illustrates the importance of slowly tapering dopaminergic medications and being aware of rare pharmacologic side effects.
INTRODUCTION
Amantadine hydrochloride, among the many happy accidents in medicine, was inadvertently discovered to alleviate the extrapyramidal symptoms of Parkinson’s disease (PD) in 1968. A woman with PD found her symptoms much improved while taking amantadine for flu prophylaxis. Later that year a large trial demonstrated both subjective and objective benefits when used to treat PD [1]. Since that time, amantadine has been used to treat PD alongside a number of other movement disorders.
Although its mechanism is not fully understood, amantadine is thought to achieve its effect via N-methyl-D-aspartate receptor antagonism, direct and indirect effects on dopamine neurons, and by decreasing anticholinergic tone [2]. Amantadine can cause dopamine toxicity: paranoia, hallucinations and tachycardia. For this reason, the medication is initiated progressively. Inversely, if it is rapidly discontinued, patients may develop amantadine withdrawal syndrome (AWS), a severe and persistent delirium often with concurrent extrapyramidal symptoms.
CASE REPORT
A 52-year-old female with a past medical history of spinocerebellar ataxia, hyperthyroidism and depression presented to the hospital with 2–3 weeks of hallucinations. Admission labs were remarkable for a new acute kidney injury with blood urea nitrogen (76 mg/dl) and creatinine (1.6 mg/dl from baseline of 0.8 mg/dl). Additionally, she was found to be coronavirus disease-2019 (COVID-19) positive. Complete blood count, urinalysis, thyroid stimulating hormone (TSH), serum ethanol level and head computed tomography were unremarkable. Vital signs were notable for a heart rate of 104. On arrival she was alert and answering questions appropriately. The patient had been prescribed amantadine for 2.5 years prior to admission and was taking 300 mg daily.
The neurology service suspected her hallucinations were related to amantadine toxicity and recommended a 3-day taper, shortened to 2 days by the primary service. Serum amantadine level was ordered on admission and found to be 1505 ng/dl (therapeutic range 200–1000 ng/ml and toxicity >2000 ng/ml). The patient continued to have hallucinations with concurrent agitation, prompting an electroencephalogram (EEG) and lumbar puncture. All lumbar puncture studies were normal. EEG showed background slowing consistent with encephalopathy with no epileptiform activity.
After 3 days, the patient was no longer having active hallucinations but became increasingly somnolent and disoriented. Five days into her course, she was no longer consistently speaking with providers. Two weeks into her hospitalization, she required assistance in feeding and was not reliably following commands. Given her persistent symptoms, the possibility of COVID-19 encephalopathy was raised and a repeat lumbar puncture considered for colony-stimulating factor polymerase chain reactiontesting. Prior to this, the patient was resumed on 200 mg of oral amantadine. Within 2 days she was alert, speaking in full sentences, and oriented to person, month and situation. Because the patient’s prolonged delirium resolved immediately after resuming amantadine, the diagnosis of AWS was made. The neurology service believed that the patient’s initial presentation was consistent with amantadine toxicity with the patient going into withdrawal in the subsequent days as the medication was tapered and held, thus explaining both her initial agitation and hallucinations and subsequent hypoactive delirium. She ultimately returned to her cognitive baseline and was discharged to subacute rehab.
DISCUSSION
Since 1987 there have been seven case reports describing instances of AWS including 15 patients. This is the first published since 2017 and is noteworthy in that it describes a patient without PD or underlying dementia. The first case series, published by Wilson in 1987, describes three older patients who experienced recrudescence of their PD motor symptoms after amantadine was held [3]. Only one of the three patients may have suffered from our more contemporary definition of AWS, an acute delirium following the discontinuation of the medication, whereas the other two patients experienced only movement symptoms.
In 1997 Factor published a case series describing three elderly patients who developed acute delirium with worsening motor function after amantadine was held [4]. All patients had underlying dementia and had been taking amantadine for more than 4 years. Symptoms quickly resolved after resuming the medication. Interestingly, all patients had their amantadine held due to hallucinations. Miyasaki republished a reply to the editor sharing two similar cases of patients with longstanding PD who developed AWS [5]. Factor responded with two further cases of elderly patients with characteristic PD and AWS. These cases were novel in that one patient did not have underlying dementia and both patients had been taking amantadine for less than 1 year. Again, symptoms entirely resolved with resumption of amantadine. Miyasaki hypothesized that pathogenesis of the delirium was related to the glutamatergic system. At this point some general risk factors for AWS were induced: old age, advanced PD, underlying dementia and duration of therapy. Factor agreed with Miyaski that AWS was unlikely related to dopaminergic pathways.
In 2009 Brantley published a case report of neuroleptic malignant syndrome (NMS) believed induced by amantadine withdrawal [6]. The authors hypothesized that more classic AWS exists on a spectrum which includes NMS. Marxreiter added an additional case of severe AWS in a patient with PD in 2017, helpfully noting the benefit of reintroducing amantadine early in instances of diagnostic uncertainty due to its rapid effects [7]. Finally, Fryml described three cases of AWS in a 2017 report which interestingly included the first patient without PD [8]. The authors noted the remarkable duration that AWS can persist: in one instance for weeks. Similar to Brantley, she describes AWS as a protean syndrome ranging from delirium to NMS, driven by dopaminergic derangements.
Our case illustrates both characteristic and unusual features of AWS. Characteristically, this case was prolonged and refractory, included motor symptoms, and entirely resolved with amantadine reintroduction. Atypically, this case involved a patient without PD who experienced a hypoactive delirium, although this has been also reported. Intriguingly, this case of AWS likely occurred after a period of amantadine toxicity, as the patient initially presented with hallucinations and elevated serum amantadine levels. We hope this report highlights the importance of prolonged amantadine tapers in the setting of toxicity as symptoms of overdose and withdrawal can overlap, creating diagnostic confusion. Further questions which remain to be answered include the exact pathophysiology of the syndrome and if it includes NMS as part of its spectrum.
ACKNOWLEDGMENTS
University of Chicago COVID-19 unit. No funding was received for this report.
CONFLICT OF INTEREST
None declared.
ETHICAL APPROVAL
Patient information was deidentified and informed consent obtained.
CONSENT
Written consent was obtained from the patient.
GUARANTOR
John P. Murray. | Oral | DrugAdministrationRoute | CC BY | 33614044 | 19,760,674 | 2021-02 |
What was the administration route of drug 'AMANTADINE'? | Amantadine withdrawal syndrome masquerading as COVID-19 encephalopathy: a case report and review of the literature.
Amantadine withdrawal syndrome (AWS) is a rare but recognized cause of severe and persistent altered mental status sometimes with co-occurring extrapyramidal symptoms. First described in a case series from 1987, its clinical manifestations have been characterized along a spectrum ranging from profound hypoactive delirium to hyperactive delirium with hallucinations. Risk factors for withdrawal include abrupt medication discontinuation, prolonged use, older age and underlying dementia. Herein we describe a case of a 52-year-old woman who presented with confusion, hallucinations, and coronavirus disease-2019 infection. She subsequently developed a prolonged hypoactive delirium after her amantadine was tapered and held. Her hypoactive delirium entirely resolved with resumption of amantadine confirming the diagnosis of AWS. This case illustrates the importance of slowly tapering dopaminergic medications and being aware of rare pharmacologic side effects.
INTRODUCTION
Amantadine hydrochloride, among the many happy accidents in medicine, was inadvertently discovered to alleviate the extrapyramidal symptoms of Parkinson’s disease (PD) in 1968. A woman with PD found her symptoms much improved while taking amantadine for flu prophylaxis. Later that year a large trial demonstrated both subjective and objective benefits when used to treat PD [1]. Since that time, amantadine has been used to treat PD alongside a number of other movement disorders.
Although its mechanism is not fully understood, amantadine is thought to achieve its effect via N-methyl-D-aspartate receptor antagonism, direct and indirect effects on dopamine neurons, and by decreasing anticholinergic tone [2]. Amantadine can cause dopamine toxicity: paranoia, hallucinations and tachycardia. For this reason, the medication is initiated progressively. Inversely, if it is rapidly discontinued, patients may develop amantadine withdrawal syndrome (AWS), a severe and persistent delirium often with concurrent extrapyramidal symptoms.
CASE REPORT
A 52-year-old female with a past medical history of spinocerebellar ataxia, hyperthyroidism and depression presented to the hospital with 2–3 weeks of hallucinations. Admission labs were remarkable for a new acute kidney injury with blood urea nitrogen (76 mg/dl) and creatinine (1.6 mg/dl from baseline of 0.8 mg/dl). Additionally, she was found to be coronavirus disease-2019 (COVID-19) positive. Complete blood count, urinalysis, thyroid stimulating hormone (TSH), serum ethanol level and head computed tomography were unremarkable. Vital signs were notable for a heart rate of 104. On arrival she was alert and answering questions appropriately. The patient had been prescribed amantadine for 2.5 years prior to admission and was taking 300 mg daily.
The neurology service suspected her hallucinations were related to amantadine toxicity and recommended a 3-day taper, shortened to 2 days by the primary service. Serum amantadine level was ordered on admission and found to be 1505 ng/dl (therapeutic range 200–1000 ng/ml and toxicity >2000 ng/ml). The patient continued to have hallucinations with concurrent agitation, prompting an electroencephalogram (EEG) and lumbar puncture. All lumbar puncture studies were normal. EEG showed background slowing consistent with encephalopathy with no epileptiform activity.
After 3 days, the patient was no longer having active hallucinations but became increasingly somnolent and disoriented. Five days into her course, she was no longer consistently speaking with providers. Two weeks into her hospitalization, she required assistance in feeding and was not reliably following commands. Given her persistent symptoms, the possibility of COVID-19 encephalopathy was raised and a repeat lumbar puncture considered for colony-stimulating factor polymerase chain reactiontesting. Prior to this, the patient was resumed on 200 mg of oral amantadine. Within 2 days she was alert, speaking in full sentences, and oriented to person, month and situation. Because the patient’s prolonged delirium resolved immediately after resuming amantadine, the diagnosis of AWS was made. The neurology service believed that the patient’s initial presentation was consistent with amantadine toxicity with the patient going into withdrawal in the subsequent days as the medication was tapered and held, thus explaining both her initial agitation and hallucinations and subsequent hypoactive delirium. She ultimately returned to her cognitive baseline and was discharged to subacute rehab.
DISCUSSION
Since 1987 there have been seven case reports describing instances of AWS including 15 patients. This is the first published since 2017 and is noteworthy in that it describes a patient without PD or underlying dementia. The first case series, published by Wilson in 1987, describes three older patients who experienced recrudescence of their PD motor symptoms after amantadine was held [3]. Only one of the three patients may have suffered from our more contemporary definition of AWS, an acute delirium following the discontinuation of the medication, whereas the other two patients experienced only movement symptoms.
In 1997 Factor published a case series describing three elderly patients who developed acute delirium with worsening motor function after amantadine was held [4]. All patients had underlying dementia and had been taking amantadine for more than 4 years. Symptoms quickly resolved after resuming the medication. Interestingly, all patients had their amantadine held due to hallucinations. Miyasaki republished a reply to the editor sharing two similar cases of patients with longstanding PD who developed AWS [5]. Factor responded with two further cases of elderly patients with characteristic PD and AWS. These cases were novel in that one patient did not have underlying dementia and both patients had been taking amantadine for less than 1 year. Again, symptoms entirely resolved with resumption of amantadine. Miyasaki hypothesized that pathogenesis of the delirium was related to the glutamatergic system. At this point some general risk factors for AWS were induced: old age, advanced PD, underlying dementia and duration of therapy. Factor agreed with Miyaski that AWS was unlikely related to dopaminergic pathways.
In 2009 Brantley published a case report of neuroleptic malignant syndrome (NMS) believed induced by amantadine withdrawal [6]. The authors hypothesized that more classic AWS exists on a spectrum which includes NMS. Marxreiter added an additional case of severe AWS in a patient with PD in 2017, helpfully noting the benefit of reintroducing amantadine early in instances of diagnostic uncertainty due to its rapid effects [7]. Finally, Fryml described three cases of AWS in a 2017 report which interestingly included the first patient without PD [8]. The authors noted the remarkable duration that AWS can persist: in one instance for weeks. Similar to Brantley, she describes AWS as a protean syndrome ranging from delirium to NMS, driven by dopaminergic derangements.
Our case illustrates both characteristic and unusual features of AWS. Characteristically, this case was prolonged and refractory, included motor symptoms, and entirely resolved with amantadine reintroduction. Atypically, this case involved a patient without PD who experienced a hypoactive delirium, although this has been also reported. Intriguingly, this case of AWS likely occurred after a period of amantadine toxicity, as the patient initially presented with hallucinations and elevated serum amantadine levels. We hope this report highlights the importance of prolonged amantadine tapers in the setting of toxicity as symptoms of overdose and withdrawal can overlap, creating diagnostic confusion. Further questions which remain to be answered include the exact pathophysiology of the syndrome and if it includes NMS as part of its spectrum.
ACKNOWLEDGMENTS
University of Chicago COVID-19 unit. No funding was received for this report.
CONFLICT OF INTEREST
None declared.
ETHICAL APPROVAL
Patient information was deidentified and informed consent obtained.
CONSENT
Written consent was obtained from the patient.
GUARANTOR
John P. Murray. | Oral | DrugAdministrationRoute | CC BY | 33614044 | 20,020,772 | 2021-02 |
What was the outcome of reaction 'Agitation'? | Amantadine withdrawal syndrome masquerading as COVID-19 encephalopathy: a case report and review of the literature.
Amantadine withdrawal syndrome (AWS) is a rare but recognized cause of severe and persistent altered mental status sometimes with co-occurring extrapyramidal symptoms. First described in a case series from 1987, its clinical manifestations have been characterized along a spectrum ranging from profound hypoactive delirium to hyperactive delirium with hallucinations. Risk factors for withdrawal include abrupt medication discontinuation, prolonged use, older age and underlying dementia. Herein we describe a case of a 52-year-old woman who presented with confusion, hallucinations, and coronavirus disease-2019 infection. She subsequently developed a prolonged hypoactive delirium after her amantadine was tapered and held. Her hypoactive delirium entirely resolved with resumption of amantadine confirming the diagnosis of AWS. This case illustrates the importance of slowly tapering dopaminergic medications and being aware of rare pharmacologic side effects.
INTRODUCTION
Amantadine hydrochloride, among the many happy accidents in medicine, was inadvertently discovered to alleviate the extrapyramidal symptoms of Parkinson’s disease (PD) in 1968. A woman with PD found her symptoms much improved while taking amantadine for flu prophylaxis. Later that year a large trial demonstrated both subjective and objective benefits when used to treat PD [1]. Since that time, amantadine has been used to treat PD alongside a number of other movement disorders.
Although its mechanism is not fully understood, amantadine is thought to achieve its effect via N-methyl-D-aspartate receptor antagonism, direct and indirect effects on dopamine neurons, and by decreasing anticholinergic tone [2]. Amantadine can cause dopamine toxicity: paranoia, hallucinations and tachycardia. For this reason, the medication is initiated progressively. Inversely, if it is rapidly discontinued, patients may develop amantadine withdrawal syndrome (AWS), a severe and persistent delirium often with concurrent extrapyramidal symptoms.
CASE REPORT
A 52-year-old female with a past medical history of spinocerebellar ataxia, hyperthyroidism and depression presented to the hospital with 2–3 weeks of hallucinations. Admission labs were remarkable for a new acute kidney injury with blood urea nitrogen (76 mg/dl) and creatinine (1.6 mg/dl from baseline of 0.8 mg/dl). Additionally, she was found to be coronavirus disease-2019 (COVID-19) positive. Complete blood count, urinalysis, thyroid stimulating hormone (TSH), serum ethanol level and head computed tomography were unremarkable. Vital signs were notable for a heart rate of 104. On arrival she was alert and answering questions appropriately. The patient had been prescribed amantadine for 2.5 years prior to admission and was taking 300 mg daily.
The neurology service suspected her hallucinations were related to amantadine toxicity and recommended a 3-day taper, shortened to 2 days by the primary service. Serum amantadine level was ordered on admission and found to be 1505 ng/dl (therapeutic range 200–1000 ng/ml and toxicity >2000 ng/ml). The patient continued to have hallucinations with concurrent agitation, prompting an electroencephalogram (EEG) and lumbar puncture. All lumbar puncture studies were normal. EEG showed background slowing consistent with encephalopathy with no epileptiform activity.
After 3 days, the patient was no longer having active hallucinations but became increasingly somnolent and disoriented. Five days into her course, she was no longer consistently speaking with providers. Two weeks into her hospitalization, she required assistance in feeding and was not reliably following commands. Given her persistent symptoms, the possibility of COVID-19 encephalopathy was raised and a repeat lumbar puncture considered for colony-stimulating factor polymerase chain reactiontesting. Prior to this, the patient was resumed on 200 mg of oral amantadine. Within 2 days she was alert, speaking in full sentences, and oriented to person, month and situation. Because the patient’s prolonged delirium resolved immediately after resuming amantadine, the diagnosis of AWS was made. The neurology service believed that the patient’s initial presentation was consistent with amantadine toxicity with the patient going into withdrawal in the subsequent days as the medication was tapered and held, thus explaining both her initial agitation and hallucinations and subsequent hypoactive delirium. She ultimately returned to her cognitive baseline and was discharged to subacute rehab.
DISCUSSION
Since 1987 there have been seven case reports describing instances of AWS including 15 patients. This is the first published since 2017 and is noteworthy in that it describes a patient without PD or underlying dementia. The first case series, published by Wilson in 1987, describes three older patients who experienced recrudescence of their PD motor symptoms after amantadine was held [3]. Only one of the three patients may have suffered from our more contemporary definition of AWS, an acute delirium following the discontinuation of the medication, whereas the other two patients experienced only movement symptoms.
In 1997 Factor published a case series describing three elderly patients who developed acute delirium with worsening motor function after amantadine was held [4]. All patients had underlying dementia and had been taking amantadine for more than 4 years. Symptoms quickly resolved after resuming the medication. Interestingly, all patients had their amantadine held due to hallucinations. Miyasaki republished a reply to the editor sharing two similar cases of patients with longstanding PD who developed AWS [5]. Factor responded with two further cases of elderly patients with characteristic PD and AWS. These cases were novel in that one patient did not have underlying dementia and both patients had been taking amantadine for less than 1 year. Again, symptoms entirely resolved with resumption of amantadine. Miyasaki hypothesized that pathogenesis of the delirium was related to the glutamatergic system. At this point some general risk factors for AWS were induced: old age, advanced PD, underlying dementia and duration of therapy. Factor agreed with Miyaski that AWS was unlikely related to dopaminergic pathways.
In 2009 Brantley published a case report of neuroleptic malignant syndrome (NMS) believed induced by amantadine withdrawal [6]. The authors hypothesized that more classic AWS exists on a spectrum which includes NMS. Marxreiter added an additional case of severe AWS in a patient with PD in 2017, helpfully noting the benefit of reintroducing amantadine early in instances of diagnostic uncertainty due to its rapid effects [7]. Finally, Fryml described three cases of AWS in a 2017 report which interestingly included the first patient without PD [8]. The authors noted the remarkable duration that AWS can persist: in one instance for weeks. Similar to Brantley, she describes AWS as a protean syndrome ranging from delirium to NMS, driven by dopaminergic derangements.
Our case illustrates both characteristic and unusual features of AWS. Characteristically, this case was prolonged and refractory, included motor symptoms, and entirely resolved with amantadine reintroduction. Atypically, this case involved a patient without PD who experienced a hypoactive delirium, although this has been also reported. Intriguingly, this case of AWS likely occurred after a period of amantadine toxicity, as the patient initially presented with hallucinations and elevated serum amantadine levels. We hope this report highlights the importance of prolonged amantadine tapers in the setting of toxicity as symptoms of overdose and withdrawal can overlap, creating diagnostic confusion. Further questions which remain to be answered include the exact pathophysiology of the syndrome and if it includes NMS as part of its spectrum.
ACKNOWLEDGMENTS
University of Chicago COVID-19 unit. No funding was received for this report.
CONFLICT OF INTEREST
None declared.
ETHICAL APPROVAL
Patient information was deidentified and informed consent obtained.
CONSENT
Written consent was obtained from the patient.
GUARANTOR
John P. Murray. | Recovered | ReactionOutcome | CC BY | 33614044 | 19,760,674 | 2021-02 |
What was the outcome of reaction 'Confusional state'? | Amantadine withdrawal syndrome masquerading as COVID-19 encephalopathy: a case report and review of the literature.
Amantadine withdrawal syndrome (AWS) is a rare but recognized cause of severe and persistent altered mental status sometimes with co-occurring extrapyramidal symptoms. First described in a case series from 1987, its clinical manifestations have been characterized along a spectrum ranging from profound hypoactive delirium to hyperactive delirium with hallucinations. Risk factors for withdrawal include abrupt medication discontinuation, prolonged use, older age and underlying dementia. Herein we describe a case of a 52-year-old woman who presented with confusion, hallucinations, and coronavirus disease-2019 infection. She subsequently developed a prolonged hypoactive delirium after her amantadine was tapered and held. Her hypoactive delirium entirely resolved with resumption of amantadine confirming the diagnosis of AWS. This case illustrates the importance of slowly tapering dopaminergic medications and being aware of rare pharmacologic side effects.
INTRODUCTION
Amantadine hydrochloride, among the many happy accidents in medicine, was inadvertently discovered to alleviate the extrapyramidal symptoms of Parkinson’s disease (PD) in 1968. A woman with PD found her symptoms much improved while taking amantadine for flu prophylaxis. Later that year a large trial demonstrated both subjective and objective benefits when used to treat PD [1]. Since that time, amantadine has been used to treat PD alongside a number of other movement disorders.
Although its mechanism is not fully understood, amantadine is thought to achieve its effect via N-methyl-D-aspartate receptor antagonism, direct and indirect effects on dopamine neurons, and by decreasing anticholinergic tone [2]. Amantadine can cause dopamine toxicity: paranoia, hallucinations and tachycardia. For this reason, the medication is initiated progressively. Inversely, if it is rapidly discontinued, patients may develop amantadine withdrawal syndrome (AWS), a severe and persistent delirium often with concurrent extrapyramidal symptoms.
CASE REPORT
A 52-year-old female with a past medical history of spinocerebellar ataxia, hyperthyroidism and depression presented to the hospital with 2–3 weeks of hallucinations. Admission labs were remarkable for a new acute kidney injury with blood urea nitrogen (76 mg/dl) and creatinine (1.6 mg/dl from baseline of 0.8 mg/dl). Additionally, she was found to be coronavirus disease-2019 (COVID-19) positive. Complete blood count, urinalysis, thyroid stimulating hormone (TSH), serum ethanol level and head computed tomography were unremarkable. Vital signs were notable for a heart rate of 104. On arrival she was alert and answering questions appropriately. The patient had been prescribed amantadine for 2.5 years prior to admission and was taking 300 mg daily.
The neurology service suspected her hallucinations were related to amantadine toxicity and recommended a 3-day taper, shortened to 2 days by the primary service. Serum amantadine level was ordered on admission and found to be 1505 ng/dl (therapeutic range 200–1000 ng/ml and toxicity >2000 ng/ml). The patient continued to have hallucinations with concurrent agitation, prompting an electroencephalogram (EEG) and lumbar puncture. All lumbar puncture studies were normal. EEG showed background slowing consistent with encephalopathy with no epileptiform activity.
After 3 days, the patient was no longer having active hallucinations but became increasingly somnolent and disoriented. Five days into her course, she was no longer consistently speaking with providers. Two weeks into her hospitalization, she required assistance in feeding and was not reliably following commands. Given her persistent symptoms, the possibility of COVID-19 encephalopathy was raised and a repeat lumbar puncture considered for colony-stimulating factor polymerase chain reactiontesting. Prior to this, the patient was resumed on 200 mg of oral amantadine. Within 2 days she was alert, speaking in full sentences, and oriented to person, month and situation. Because the patient’s prolonged delirium resolved immediately after resuming amantadine, the diagnosis of AWS was made. The neurology service believed that the patient’s initial presentation was consistent with amantadine toxicity with the patient going into withdrawal in the subsequent days as the medication was tapered and held, thus explaining both her initial agitation and hallucinations and subsequent hypoactive delirium. She ultimately returned to her cognitive baseline and was discharged to subacute rehab.
DISCUSSION
Since 1987 there have been seven case reports describing instances of AWS including 15 patients. This is the first published since 2017 and is noteworthy in that it describes a patient without PD or underlying dementia. The first case series, published by Wilson in 1987, describes three older patients who experienced recrudescence of their PD motor symptoms after amantadine was held [3]. Only one of the three patients may have suffered from our more contemporary definition of AWS, an acute delirium following the discontinuation of the medication, whereas the other two patients experienced only movement symptoms.
In 1997 Factor published a case series describing three elderly patients who developed acute delirium with worsening motor function after amantadine was held [4]. All patients had underlying dementia and had been taking amantadine for more than 4 years. Symptoms quickly resolved after resuming the medication. Interestingly, all patients had their amantadine held due to hallucinations. Miyasaki republished a reply to the editor sharing two similar cases of patients with longstanding PD who developed AWS [5]. Factor responded with two further cases of elderly patients with characteristic PD and AWS. These cases were novel in that one patient did not have underlying dementia and both patients had been taking amantadine for less than 1 year. Again, symptoms entirely resolved with resumption of amantadine. Miyasaki hypothesized that pathogenesis of the delirium was related to the glutamatergic system. At this point some general risk factors for AWS were induced: old age, advanced PD, underlying dementia and duration of therapy. Factor agreed with Miyaski that AWS was unlikely related to dopaminergic pathways.
In 2009 Brantley published a case report of neuroleptic malignant syndrome (NMS) believed induced by amantadine withdrawal [6]. The authors hypothesized that more classic AWS exists on a spectrum which includes NMS. Marxreiter added an additional case of severe AWS in a patient with PD in 2017, helpfully noting the benefit of reintroducing amantadine early in instances of diagnostic uncertainty due to its rapid effects [7]. Finally, Fryml described three cases of AWS in a 2017 report which interestingly included the first patient without PD [8]. The authors noted the remarkable duration that AWS can persist: in one instance for weeks. Similar to Brantley, she describes AWS as a protean syndrome ranging from delirium to NMS, driven by dopaminergic derangements.
Our case illustrates both characteristic and unusual features of AWS. Characteristically, this case was prolonged and refractory, included motor symptoms, and entirely resolved with amantadine reintroduction. Atypically, this case involved a patient without PD who experienced a hypoactive delirium, although this has been also reported. Intriguingly, this case of AWS likely occurred after a period of amantadine toxicity, as the patient initially presented with hallucinations and elevated serum amantadine levels. We hope this report highlights the importance of prolonged amantadine tapers in the setting of toxicity as symptoms of overdose and withdrawal can overlap, creating diagnostic confusion. Further questions which remain to be answered include the exact pathophysiology of the syndrome and if it includes NMS as part of its spectrum.
ACKNOWLEDGMENTS
University of Chicago COVID-19 unit. No funding was received for this report.
CONFLICT OF INTEREST
None declared.
ETHICAL APPROVAL
Patient information was deidentified and informed consent obtained.
CONSENT
Written consent was obtained from the patient.
GUARANTOR
John P. Murray. | Recovered | ReactionOutcome | CC BY | 33614044 | 19,760,674 | 2021-02 |
What was the outcome of reaction 'Coordination abnormal'? | Amantadine withdrawal syndrome masquerading as COVID-19 encephalopathy: a case report and review of the literature.
Amantadine withdrawal syndrome (AWS) is a rare but recognized cause of severe and persistent altered mental status sometimes with co-occurring extrapyramidal symptoms. First described in a case series from 1987, its clinical manifestations have been characterized along a spectrum ranging from profound hypoactive delirium to hyperactive delirium with hallucinations. Risk factors for withdrawal include abrupt medication discontinuation, prolonged use, older age and underlying dementia. Herein we describe a case of a 52-year-old woman who presented with confusion, hallucinations, and coronavirus disease-2019 infection. She subsequently developed a prolonged hypoactive delirium after her amantadine was tapered and held. Her hypoactive delirium entirely resolved with resumption of amantadine confirming the diagnosis of AWS. This case illustrates the importance of slowly tapering dopaminergic medications and being aware of rare pharmacologic side effects.
INTRODUCTION
Amantadine hydrochloride, among the many happy accidents in medicine, was inadvertently discovered to alleviate the extrapyramidal symptoms of Parkinson’s disease (PD) in 1968. A woman with PD found her symptoms much improved while taking amantadine for flu prophylaxis. Later that year a large trial demonstrated both subjective and objective benefits when used to treat PD [1]. Since that time, amantadine has been used to treat PD alongside a number of other movement disorders.
Although its mechanism is not fully understood, amantadine is thought to achieve its effect via N-methyl-D-aspartate receptor antagonism, direct and indirect effects on dopamine neurons, and by decreasing anticholinergic tone [2]. Amantadine can cause dopamine toxicity: paranoia, hallucinations and tachycardia. For this reason, the medication is initiated progressively. Inversely, if it is rapidly discontinued, patients may develop amantadine withdrawal syndrome (AWS), a severe and persistent delirium often with concurrent extrapyramidal symptoms.
CASE REPORT
A 52-year-old female with a past medical history of spinocerebellar ataxia, hyperthyroidism and depression presented to the hospital with 2–3 weeks of hallucinations. Admission labs were remarkable for a new acute kidney injury with blood urea nitrogen (76 mg/dl) and creatinine (1.6 mg/dl from baseline of 0.8 mg/dl). Additionally, she was found to be coronavirus disease-2019 (COVID-19) positive. Complete blood count, urinalysis, thyroid stimulating hormone (TSH), serum ethanol level and head computed tomography were unremarkable. Vital signs were notable for a heart rate of 104. On arrival she was alert and answering questions appropriately. The patient had been prescribed amantadine for 2.5 years prior to admission and was taking 300 mg daily.
The neurology service suspected her hallucinations were related to amantadine toxicity and recommended a 3-day taper, shortened to 2 days by the primary service. Serum amantadine level was ordered on admission and found to be 1505 ng/dl (therapeutic range 200–1000 ng/ml and toxicity >2000 ng/ml). The patient continued to have hallucinations with concurrent agitation, prompting an electroencephalogram (EEG) and lumbar puncture. All lumbar puncture studies were normal. EEG showed background slowing consistent with encephalopathy with no epileptiform activity.
After 3 days, the patient was no longer having active hallucinations but became increasingly somnolent and disoriented. Five days into her course, she was no longer consistently speaking with providers. Two weeks into her hospitalization, she required assistance in feeding and was not reliably following commands. Given her persistent symptoms, the possibility of COVID-19 encephalopathy was raised and a repeat lumbar puncture considered for colony-stimulating factor polymerase chain reactiontesting. Prior to this, the patient was resumed on 200 mg of oral amantadine. Within 2 days she was alert, speaking in full sentences, and oriented to person, month and situation. Because the patient’s prolonged delirium resolved immediately after resuming amantadine, the diagnosis of AWS was made. The neurology service believed that the patient’s initial presentation was consistent with amantadine toxicity with the patient going into withdrawal in the subsequent days as the medication was tapered and held, thus explaining both her initial agitation and hallucinations and subsequent hypoactive delirium. She ultimately returned to her cognitive baseline and was discharged to subacute rehab.
DISCUSSION
Since 1987 there have been seven case reports describing instances of AWS including 15 patients. This is the first published since 2017 and is noteworthy in that it describes a patient without PD or underlying dementia. The first case series, published by Wilson in 1987, describes three older patients who experienced recrudescence of their PD motor symptoms after amantadine was held [3]. Only one of the three patients may have suffered from our more contemporary definition of AWS, an acute delirium following the discontinuation of the medication, whereas the other two patients experienced only movement symptoms.
In 1997 Factor published a case series describing three elderly patients who developed acute delirium with worsening motor function after amantadine was held [4]. All patients had underlying dementia and had been taking amantadine for more than 4 years. Symptoms quickly resolved after resuming the medication. Interestingly, all patients had their amantadine held due to hallucinations. Miyasaki republished a reply to the editor sharing two similar cases of patients with longstanding PD who developed AWS [5]. Factor responded with two further cases of elderly patients with characteristic PD and AWS. These cases were novel in that one patient did not have underlying dementia and both patients had been taking amantadine for less than 1 year. Again, symptoms entirely resolved with resumption of amantadine. Miyasaki hypothesized that pathogenesis of the delirium was related to the glutamatergic system. At this point some general risk factors for AWS were induced: old age, advanced PD, underlying dementia and duration of therapy. Factor agreed with Miyaski that AWS was unlikely related to dopaminergic pathways.
In 2009 Brantley published a case report of neuroleptic malignant syndrome (NMS) believed induced by amantadine withdrawal [6]. The authors hypothesized that more classic AWS exists on a spectrum which includes NMS. Marxreiter added an additional case of severe AWS in a patient with PD in 2017, helpfully noting the benefit of reintroducing amantadine early in instances of diagnostic uncertainty due to its rapid effects [7]. Finally, Fryml described three cases of AWS in a 2017 report which interestingly included the first patient without PD [8]. The authors noted the remarkable duration that AWS can persist: in one instance for weeks. Similar to Brantley, she describes AWS as a protean syndrome ranging from delirium to NMS, driven by dopaminergic derangements.
Our case illustrates both characteristic and unusual features of AWS. Characteristically, this case was prolonged and refractory, included motor symptoms, and entirely resolved with amantadine reintroduction. Atypically, this case involved a patient without PD who experienced a hypoactive delirium, although this has been also reported. Intriguingly, this case of AWS likely occurred after a period of amantadine toxicity, as the patient initially presented with hallucinations and elevated serum amantadine levels. We hope this report highlights the importance of prolonged amantadine tapers in the setting of toxicity as symptoms of overdose and withdrawal can overlap, creating diagnostic confusion. Further questions which remain to be answered include the exact pathophysiology of the syndrome and if it includes NMS as part of its spectrum.
ACKNOWLEDGMENTS
University of Chicago COVID-19 unit. No funding was received for this report.
CONFLICT OF INTEREST
None declared.
ETHICAL APPROVAL
Patient information was deidentified and informed consent obtained.
CONSENT
Written consent was obtained from the patient.
GUARANTOR
John P. Murray. | Recovered | ReactionOutcome | CC BY | 33614044 | 19,760,674 | 2021-02 |
What was the outcome of reaction 'Delirium'? | Amantadine withdrawal syndrome masquerading as COVID-19 encephalopathy: a case report and review of the literature.
Amantadine withdrawal syndrome (AWS) is a rare but recognized cause of severe and persistent altered mental status sometimes with co-occurring extrapyramidal symptoms. First described in a case series from 1987, its clinical manifestations have been characterized along a spectrum ranging from profound hypoactive delirium to hyperactive delirium with hallucinations. Risk factors for withdrawal include abrupt medication discontinuation, prolonged use, older age and underlying dementia. Herein we describe a case of a 52-year-old woman who presented with confusion, hallucinations, and coronavirus disease-2019 infection. She subsequently developed a prolonged hypoactive delirium after her amantadine was tapered and held. Her hypoactive delirium entirely resolved with resumption of amantadine confirming the diagnosis of AWS. This case illustrates the importance of slowly tapering dopaminergic medications and being aware of rare pharmacologic side effects.
INTRODUCTION
Amantadine hydrochloride, among the many happy accidents in medicine, was inadvertently discovered to alleviate the extrapyramidal symptoms of Parkinson’s disease (PD) in 1968. A woman with PD found her symptoms much improved while taking amantadine for flu prophylaxis. Later that year a large trial demonstrated both subjective and objective benefits when used to treat PD [1]. Since that time, amantadine has been used to treat PD alongside a number of other movement disorders.
Although its mechanism is not fully understood, amantadine is thought to achieve its effect via N-methyl-D-aspartate receptor antagonism, direct and indirect effects on dopamine neurons, and by decreasing anticholinergic tone [2]. Amantadine can cause dopamine toxicity: paranoia, hallucinations and tachycardia. For this reason, the medication is initiated progressively. Inversely, if it is rapidly discontinued, patients may develop amantadine withdrawal syndrome (AWS), a severe and persistent delirium often with concurrent extrapyramidal symptoms.
CASE REPORT
A 52-year-old female with a past medical history of spinocerebellar ataxia, hyperthyroidism and depression presented to the hospital with 2–3 weeks of hallucinations. Admission labs were remarkable for a new acute kidney injury with blood urea nitrogen (76 mg/dl) and creatinine (1.6 mg/dl from baseline of 0.8 mg/dl). Additionally, she was found to be coronavirus disease-2019 (COVID-19) positive. Complete blood count, urinalysis, thyroid stimulating hormone (TSH), serum ethanol level and head computed tomography were unremarkable. Vital signs were notable for a heart rate of 104. On arrival she was alert and answering questions appropriately. The patient had been prescribed amantadine for 2.5 years prior to admission and was taking 300 mg daily.
The neurology service suspected her hallucinations were related to amantadine toxicity and recommended a 3-day taper, shortened to 2 days by the primary service. Serum amantadine level was ordered on admission and found to be 1505 ng/dl (therapeutic range 200–1000 ng/ml and toxicity >2000 ng/ml). The patient continued to have hallucinations with concurrent agitation, prompting an electroencephalogram (EEG) and lumbar puncture. All lumbar puncture studies were normal. EEG showed background slowing consistent with encephalopathy with no epileptiform activity.
After 3 days, the patient was no longer having active hallucinations but became increasingly somnolent and disoriented. Five days into her course, she was no longer consistently speaking with providers. Two weeks into her hospitalization, she required assistance in feeding and was not reliably following commands. Given her persistent symptoms, the possibility of COVID-19 encephalopathy was raised and a repeat lumbar puncture considered for colony-stimulating factor polymerase chain reactiontesting. Prior to this, the patient was resumed on 200 mg of oral amantadine. Within 2 days she was alert, speaking in full sentences, and oriented to person, month and situation. Because the patient’s prolonged delirium resolved immediately after resuming amantadine, the diagnosis of AWS was made. The neurology service believed that the patient’s initial presentation was consistent with amantadine toxicity with the patient going into withdrawal in the subsequent days as the medication was tapered and held, thus explaining both her initial agitation and hallucinations and subsequent hypoactive delirium. She ultimately returned to her cognitive baseline and was discharged to subacute rehab.
DISCUSSION
Since 1987 there have been seven case reports describing instances of AWS including 15 patients. This is the first published since 2017 and is noteworthy in that it describes a patient without PD or underlying dementia. The first case series, published by Wilson in 1987, describes three older patients who experienced recrudescence of their PD motor symptoms after amantadine was held [3]. Only one of the three patients may have suffered from our more contemporary definition of AWS, an acute delirium following the discontinuation of the medication, whereas the other two patients experienced only movement symptoms.
In 1997 Factor published a case series describing three elderly patients who developed acute delirium with worsening motor function after amantadine was held [4]. All patients had underlying dementia and had been taking amantadine for more than 4 years. Symptoms quickly resolved after resuming the medication. Interestingly, all patients had their amantadine held due to hallucinations. Miyasaki republished a reply to the editor sharing two similar cases of patients with longstanding PD who developed AWS [5]. Factor responded with two further cases of elderly patients with characteristic PD and AWS. These cases were novel in that one patient did not have underlying dementia and both patients had been taking amantadine for less than 1 year. Again, symptoms entirely resolved with resumption of amantadine. Miyasaki hypothesized that pathogenesis of the delirium was related to the glutamatergic system. At this point some general risk factors for AWS were induced: old age, advanced PD, underlying dementia and duration of therapy. Factor agreed with Miyaski that AWS was unlikely related to dopaminergic pathways.
In 2009 Brantley published a case report of neuroleptic malignant syndrome (NMS) believed induced by amantadine withdrawal [6]. The authors hypothesized that more classic AWS exists on a spectrum which includes NMS. Marxreiter added an additional case of severe AWS in a patient with PD in 2017, helpfully noting the benefit of reintroducing amantadine early in instances of diagnostic uncertainty due to its rapid effects [7]. Finally, Fryml described three cases of AWS in a 2017 report which interestingly included the first patient without PD [8]. The authors noted the remarkable duration that AWS can persist: in one instance for weeks. Similar to Brantley, she describes AWS as a protean syndrome ranging from delirium to NMS, driven by dopaminergic derangements.
Our case illustrates both characteristic and unusual features of AWS. Characteristically, this case was prolonged and refractory, included motor symptoms, and entirely resolved with amantadine reintroduction. Atypically, this case involved a patient without PD who experienced a hypoactive delirium, although this has been also reported. Intriguingly, this case of AWS likely occurred after a period of amantadine toxicity, as the patient initially presented with hallucinations and elevated serum amantadine levels. We hope this report highlights the importance of prolonged amantadine tapers in the setting of toxicity as symptoms of overdose and withdrawal can overlap, creating diagnostic confusion. Further questions which remain to be answered include the exact pathophysiology of the syndrome and if it includes NMS as part of its spectrum.
ACKNOWLEDGMENTS
University of Chicago COVID-19 unit. No funding was received for this report.
CONFLICT OF INTEREST
None declared.
ETHICAL APPROVAL
Patient information was deidentified and informed consent obtained.
CONSENT
Written consent was obtained from the patient.
GUARANTOR
John P. Murray. | Recovered | ReactionOutcome | CC BY | 33614044 | 19,760,674 | 2021-02 |
What was the outcome of reaction 'Disorientation'? | Amantadine withdrawal syndrome masquerading as COVID-19 encephalopathy: a case report and review of the literature.
Amantadine withdrawal syndrome (AWS) is a rare but recognized cause of severe and persistent altered mental status sometimes with co-occurring extrapyramidal symptoms. First described in a case series from 1987, its clinical manifestations have been characterized along a spectrum ranging from profound hypoactive delirium to hyperactive delirium with hallucinations. Risk factors for withdrawal include abrupt medication discontinuation, prolonged use, older age and underlying dementia. Herein we describe a case of a 52-year-old woman who presented with confusion, hallucinations, and coronavirus disease-2019 infection. She subsequently developed a prolonged hypoactive delirium after her amantadine was tapered and held. Her hypoactive delirium entirely resolved with resumption of amantadine confirming the diagnosis of AWS. This case illustrates the importance of slowly tapering dopaminergic medications and being aware of rare pharmacologic side effects.
INTRODUCTION
Amantadine hydrochloride, among the many happy accidents in medicine, was inadvertently discovered to alleviate the extrapyramidal symptoms of Parkinson’s disease (PD) in 1968. A woman with PD found her symptoms much improved while taking amantadine for flu prophylaxis. Later that year a large trial demonstrated both subjective and objective benefits when used to treat PD [1]. Since that time, amantadine has been used to treat PD alongside a number of other movement disorders.
Although its mechanism is not fully understood, amantadine is thought to achieve its effect via N-methyl-D-aspartate receptor antagonism, direct and indirect effects on dopamine neurons, and by decreasing anticholinergic tone [2]. Amantadine can cause dopamine toxicity: paranoia, hallucinations and tachycardia. For this reason, the medication is initiated progressively. Inversely, if it is rapidly discontinued, patients may develop amantadine withdrawal syndrome (AWS), a severe and persistent delirium often with concurrent extrapyramidal symptoms.
CASE REPORT
A 52-year-old female with a past medical history of spinocerebellar ataxia, hyperthyroidism and depression presented to the hospital with 2–3 weeks of hallucinations. Admission labs were remarkable for a new acute kidney injury with blood urea nitrogen (76 mg/dl) and creatinine (1.6 mg/dl from baseline of 0.8 mg/dl). Additionally, she was found to be coronavirus disease-2019 (COVID-19) positive. Complete blood count, urinalysis, thyroid stimulating hormone (TSH), serum ethanol level and head computed tomography were unremarkable. Vital signs were notable for a heart rate of 104. On arrival she was alert and answering questions appropriately. The patient had been prescribed amantadine for 2.5 years prior to admission and was taking 300 mg daily.
The neurology service suspected her hallucinations were related to amantadine toxicity and recommended a 3-day taper, shortened to 2 days by the primary service. Serum amantadine level was ordered on admission and found to be 1505 ng/dl (therapeutic range 200–1000 ng/ml and toxicity >2000 ng/ml). The patient continued to have hallucinations with concurrent agitation, prompting an electroencephalogram (EEG) and lumbar puncture. All lumbar puncture studies were normal. EEG showed background slowing consistent with encephalopathy with no epileptiform activity.
After 3 days, the patient was no longer having active hallucinations but became increasingly somnolent and disoriented. Five days into her course, she was no longer consistently speaking with providers. Two weeks into her hospitalization, she required assistance in feeding and was not reliably following commands. Given her persistent symptoms, the possibility of COVID-19 encephalopathy was raised and a repeat lumbar puncture considered for colony-stimulating factor polymerase chain reactiontesting. Prior to this, the patient was resumed on 200 mg of oral amantadine. Within 2 days she was alert, speaking in full sentences, and oriented to person, month and situation. Because the patient’s prolonged delirium resolved immediately after resuming amantadine, the diagnosis of AWS was made. The neurology service believed that the patient’s initial presentation was consistent with amantadine toxicity with the patient going into withdrawal in the subsequent days as the medication was tapered and held, thus explaining both her initial agitation and hallucinations and subsequent hypoactive delirium. She ultimately returned to her cognitive baseline and was discharged to subacute rehab.
DISCUSSION
Since 1987 there have been seven case reports describing instances of AWS including 15 patients. This is the first published since 2017 and is noteworthy in that it describes a patient without PD or underlying dementia. The first case series, published by Wilson in 1987, describes three older patients who experienced recrudescence of their PD motor symptoms after amantadine was held [3]. Only one of the three patients may have suffered from our more contemporary definition of AWS, an acute delirium following the discontinuation of the medication, whereas the other two patients experienced only movement symptoms.
In 1997 Factor published a case series describing three elderly patients who developed acute delirium with worsening motor function after amantadine was held [4]. All patients had underlying dementia and had been taking amantadine for more than 4 years. Symptoms quickly resolved after resuming the medication. Interestingly, all patients had their amantadine held due to hallucinations. Miyasaki republished a reply to the editor sharing two similar cases of patients with longstanding PD who developed AWS [5]. Factor responded with two further cases of elderly patients with characteristic PD and AWS. These cases were novel in that one patient did not have underlying dementia and both patients had been taking amantadine for less than 1 year. Again, symptoms entirely resolved with resumption of amantadine. Miyasaki hypothesized that pathogenesis of the delirium was related to the glutamatergic system. At this point some general risk factors for AWS were induced: old age, advanced PD, underlying dementia and duration of therapy. Factor agreed with Miyaski that AWS was unlikely related to dopaminergic pathways.
In 2009 Brantley published a case report of neuroleptic malignant syndrome (NMS) believed induced by amantadine withdrawal [6]. The authors hypothesized that more classic AWS exists on a spectrum which includes NMS. Marxreiter added an additional case of severe AWS in a patient with PD in 2017, helpfully noting the benefit of reintroducing amantadine early in instances of diagnostic uncertainty due to its rapid effects [7]. Finally, Fryml described three cases of AWS in a 2017 report which interestingly included the first patient without PD [8]. The authors noted the remarkable duration that AWS can persist: in one instance for weeks. Similar to Brantley, she describes AWS as a protean syndrome ranging from delirium to NMS, driven by dopaminergic derangements.
Our case illustrates both characteristic and unusual features of AWS. Characteristically, this case was prolonged and refractory, included motor symptoms, and entirely resolved with amantadine reintroduction. Atypically, this case involved a patient without PD who experienced a hypoactive delirium, although this has been also reported. Intriguingly, this case of AWS likely occurred after a period of amantadine toxicity, as the patient initially presented with hallucinations and elevated serum amantadine levels. We hope this report highlights the importance of prolonged amantadine tapers in the setting of toxicity as symptoms of overdose and withdrawal can overlap, creating diagnostic confusion. Further questions which remain to be answered include the exact pathophysiology of the syndrome and if it includes NMS as part of its spectrum.
ACKNOWLEDGMENTS
University of Chicago COVID-19 unit. No funding was received for this report.
CONFLICT OF INTEREST
None declared.
ETHICAL APPROVAL
Patient information was deidentified and informed consent obtained.
CONSENT
Written consent was obtained from the patient.
GUARANTOR
John P. Murray. | Recovered | ReactionOutcome | CC BY | 33614044 | 19,760,674 | 2021-02 |
What was the outcome of reaction 'Drug withdrawal syndrome'? | Amantadine withdrawal syndrome masquerading as COVID-19 encephalopathy: a case report and review of the literature.
Amantadine withdrawal syndrome (AWS) is a rare but recognized cause of severe and persistent altered mental status sometimes with co-occurring extrapyramidal symptoms. First described in a case series from 1987, its clinical manifestations have been characterized along a spectrum ranging from profound hypoactive delirium to hyperactive delirium with hallucinations. Risk factors for withdrawal include abrupt medication discontinuation, prolonged use, older age and underlying dementia. Herein we describe a case of a 52-year-old woman who presented with confusion, hallucinations, and coronavirus disease-2019 infection. She subsequently developed a prolonged hypoactive delirium after her amantadine was tapered and held. Her hypoactive delirium entirely resolved with resumption of amantadine confirming the diagnosis of AWS. This case illustrates the importance of slowly tapering dopaminergic medications and being aware of rare pharmacologic side effects.
INTRODUCTION
Amantadine hydrochloride, among the many happy accidents in medicine, was inadvertently discovered to alleviate the extrapyramidal symptoms of Parkinson’s disease (PD) in 1968. A woman with PD found her symptoms much improved while taking amantadine for flu prophylaxis. Later that year a large trial demonstrated both subjective and objective benefits when used to treat PD [1]. Since that time, amantadine has been used to treat PD alongside a number of other movement disorders.
Although its mechanism is not fully understood, amantadine is thought to achieve its effect via N-methyl-D-aspartate receptor antagonism, direct and indirect effects on dopamine neurons, and by decreasing anticholinergic tone [2]. Amantadine can cause dopamine toxicity: paranoia, hallucinations and tachycardia. For this reason, the medication is initiated progressively. Inversely, if it is rapidly discontinued, patients may develop amantadine withdrawal syndrome (AWS), a severe and persistent delirium often with concurrent extrapyramidal symptoms.
CASE REPORT
A 52-year-old female with a past medical history of spinocerebellar ataxia, hyperthyroidism and depression presented to the hospital with 2–3 weeks of hallucinations. Admission labs were remarkable for a new acute kidney injury with blood urea nitrogen (76 mg/dl) and creatinine (1.6 mg/dl from baseline of 0.8 mg/dl). Additionally, she was found to be coronavirus disease-2019 (COVID-19) positive. Complete blood count, urinalysis, thyroid stimulating hormone (TSH), serum ethanol level and head computed tomography were unremarkable. Vital signs were notable for a heart rate of 104. On arrival she was alert and answering questions appropriately. The patient had been prescribed amantadine for 2.5 years prior to admission and was taking 300 mg daily.
The neurology service suspected her hallucinations were related to amantadine toxicity and recommended a 3-day taper, shortened to 2 days by the primary service. Serum amantadine level was ordered on admission and found to be 1505 ng/dl (therapeutic range 200–1000 ng/ml and toxicity >2000 ng/ml). The patient continued to have hallucinations with concurrent agitation, prompting an electroencephalogram (EEG) and lumbar puncture. All lumbar puncture studies were normal. EEG showed background slowing consistent with encephalopathy with no epileptiform activity.
After 3 days, the patient was no longer having active hallucinations but became increasingly somnolent and disoriented. Five days into her course, she was no longer consistently speaking with providers. Two weeks into her hospitalization, she required assistance in feeding and was not reliably following commands. Given her persistent symptoms, the possibility of COVID-19 encephalopathy was raised and a repeat lumbar puncture considered for colony-stimulating factor polymerase chain reactiontesting. Prior to this, the patient was resumed on 200 mg of oral amantadine. Within 2 days she was alert, speaking in full sentences, and oriented to person, month and situation. Because the patient’s prolonged delirium resolved immediately after resuming amantadine, the diagnosis of AWS was made. The neurology service believed that the patient’s initial presentation was consistent with amantadine toxicity with the patient going into withdrawal in the subsequent days as the medication was tapered and held, thus explaining both her initial agitation and hallucinations and subsequent hypoactive delirium. She ultimately returned to her cognitive baseline and was discharged to subacute rehab.
DISCUSSION
Since 1987 there have been seven case reports describing instances of AWS including 15 patients. This is the first published since 2017 and is noteworthy in that it describes a patient without PD or underlying dementia. The first case series, published by Wilson in 1987, describes three older patients who experienced recrudescence of their PD motor symptoms after amantadine was held [3]. Only one of the three patients may have suffered from our more contemporary definition of AWS, an acute delirium following the discontinuation of the medication, whereas the other two patients experienced only movement symptoms.
In 1997 Factor published a case series describing three elderly patients who developed acute delirium with worsening motor function after amantadine was held [4]. All patients had underlying dementia and had been taking amantadine for more than 4 years. Symptoms quickly resolved after resuming the medication. Interestingly, all patients had their amantadine held due to hallucinations. Miyasaki republished a reply to the editor sharing two similar cases of patients with longstanding PD who developed AWS [5]. Factor responded with two further cases of elderly patients with characteristic PD and AWS. These cases were novel in that one patient did not have underlying dementia and both patients had been taking amantadine for less than 1 year. Again, symptoms entirely resolved with resumption of amantadine. Miyasaki hypothesized that pathogenesis of the delirium was related to the glutamatergic system. At this point some general risk factors for AWS were induced: old age, advanced PD, underlying dementia and duration of therapy. Factor agreed with Miyaski that AWS was unlikely related to dopaminergic pathways.
In 2009 Brantley published a case report of neuroleptic malignant syndrome (NMS) believed induced by amantadine withdrawal [6]. The authors hypothesized that more classic AWS exists on a spectrum which includes NMS. Marxreiter added an additional case of severe AWS in a patient with PD in 2017, helpfully noting the benefit of reintroducing amantadine early in instances of diagnostic uncertainty due to its rapid effects [7]. Finally, Fryml described three cases of AWS in a 2017 report which interestingly included the first patient without PD [8]. The authors noted the remarkable duration that AWS can persist: in one instance for weeks. Similar to Brantley, she describes AWS as a protean syndrome ranging from delirium to NMS, driven by dopaminergic derangements.
Our case illustrates both characteristic and unusual features of AWS. Characteristically, this case was prolonged and refractory, included motor symptoms, and entirely resolved with amantadine reintroduction. Atypically, this case involved a patient without PD who experienced a hypoactive delirium, although this has been also reported. Intriguingly, this case of AWS likely occurred after a period of amantadine toxicity, as the patient initially presented with hallucinations and elevated serum amantadine levels. We hope this report highlights the importance of prolonged amantadine tapers in the setting of toxicity as symptoms of overdose and withdrawal can overlap, creating diagnostic confusion. Further questions which remain to be answered include the exact pathophysiology of the syndrome and if it includes NMS as part of its spectrum.
ACKNOWLEDGMENTS
University of Chicago COVID-19 unit. No funding was received for this report.
CONFLICT OF INTEREST
None declared.
ETHICAL APPROVAL
Patient information was deidentified and informed consent obtained.
CONSENT
Written consent was obtained from the patient.
GUARANTOR
John P. Murray. | Recovered | ReactionOutcome | CC BY | 33614044 | 19,760,674 | 2021-02 |
What was the outcome of reaction 'Dysarthria'? | Amantadine withdrawal syndrome masquerading as COVID-19 encephalopathy: a case report and review of the literature.
Amantadine withdrawal syndrome (AWS) is a rare but recognized cause of severe and persistent altered mental status sometimes with co-occurring extrapyramidal symptoms. First described in a case series from 1987, its clinical manifestations have been characterized along a spectrum ranging from profound hypoactive delirium to hyperactive delirium with hallucinations. Risk factors for withdrawal include abrupt medication discontinuation, prolonged use, older age and underlying dementia. Herein we describe a case of a 52-year-old woman who presented with confusion, hallucinations, and coronavirus disease-2019 infection. She subsequently developed a prolonged hypoactive delirium after her amantadine was tapered and held. Her hypoactive delirium entirely resolved with resumption of amantadine confirming the diagnosis of AWS. This case illustrates the importance of slowly tapering dopaminergic medications and being aware of rare pharmacologic side effects.
INTRODUCTION
Amantadine hydrochloride, among the many happy accidents in medicine, was inadvertently discovered to alleviate the extrapyramidal symptoms of Parkinson’s disease (PD) in 1968. A woman with PD found her symptoms much improved while taking amantadine for flu prophylaxis. Later that year a large trial demonstrated both subjective and objective benefits when used to treat PD [1]. Since that time, amantadine has been used to treat PD alongside a number of other movement disorders.
Although its mechanism is not fully understood, amantadine is thought to achieve its effect via N-methyl-D-aspartate receptor antagonism, direct and indirect effects on dopamine neurons, and by decreasing anticholinergic tone [2]. Amantadine can cause dopamine toxicity: paranoia, hallucinations and tachycardia. For this reason, the medication is initiated progressively. Inversely, if it is rapidly discontinued, patients may develop amantadine withdrawal syndrome (AWS), a severe and persistent delirium often with concurrent extrapyramidal symptoms.
CASE REPORT
A 52-year-old female with a past medical history of spinocerebellar ataxia, hyperthyroidism and depression presented to the hospital with 2–3 weeks of hallucinations. Admission labs were remarkable for a new acute kidney injury with blood urea nitrogen (76 mg/dl) and creatinine (1.6 mg/dl from baseline of 0.8 mg/dl). Additionally, she was found to be coronavirus disease-2019 (COVID-19) positive. Complete blood count, urinalysis, thyroid stimulating hormone (TSH), serum ethanol level and head computed tomography were unremarkable. Vital signs were notable for a heart rate of 104. On arrival she was alert and answering questions appropriately. The patient had been prescribed amantadine for 2.5 years prior to admission and was taking 300 mg daily.
The neurology service suspected her hallucinations were related to amantadine toxicity and recommended a 3-day taper, shortened to 2 days by the primary service. Serum amantadine level was ordered on admission and found to be 1505 ng/dl (therapeutic range 200–1000 ng/ml and toxicity >2000 ng/ml). The patient continued to have hallucinations with concurrent agitation, prompting an electroencephalogram (EEG) and lumbar puncture. All lumbar puncture studies were normal. EEG showed background slowing consistent with encephalopathy with no epileptiform activity.
After 3 days, the patient was no longer having active hallucinations but became increasingly somnolent and disoriented. Five days into her course, she was no longer consistently speaking with providers. Two weeks into her hospitalization, she required assistance in feeding and was not reliably following commands. Given her persistent symptoms, the possibility of COVID-19 encephalopathy was raised and a repeat lumbar puncture considered for colony-stimulating factor polymerase chain reactiontesting. Prior to this, the patient was resumed on 200 mg of oral amantadine. Within 2 days she was alert, speaking in full sentences, and oriented to person, month and situation. Because the patient’s prolonged delirium resolved immediately after resuming amantadine, the diagnosis of AWS was made. The neurology service believed that the patient’s initial presentation was consistent with amantadine toxicity with the patient going into withdrawal in the subsequent days as the medication was tapered and held, thus explaining both her initial agitation and hallucinations and subsequent hypoactive delirium. She ultimately returned to her cognitive baseline and was discharged to subacute rehab.
DISCUSSION
Since 1987 there have been seven case reports describing instances of AWS including 15 patients. This is the first published since 2017 and is noteworthy in that it describes a patient without PD or underlying dementia. The first case series, published by Wilson in 1987, describes three older patients who experienced recrudescence of their PD motor symptoms after amantadine was held [3]. Only one of the three patients may have suffered from our more contemporary definition of AWS, an acute delirium following the discontinuation of the medication, whereas the other two patients experienced only movement symptoms.
In 1997 Factor published a case series describing three elderly patients who developed acute delirium with worsening motor function after amantadine was held [4]. All patients had underlying dementia and had been taking amantadine for more than 4 years. Symptoms quickly resolved after resuming the medication. Interestingly, all patients had their amantadine held due to hallucinations. Miyasaki republished a reply to the editor sharing two similar cases of patients with longstanding PD who developed AWS [5]. Factor responded with two further cases of elderly patients with characteristic PD and AWS. These cases were novel in that one patient did not have underlying dementia and both patients had been taking amantadine for less than 1 year. Again, symptoms entirely resolved with resumption of amantadine. Miyasaki hypothesized that pathogenesis of the delirium was related to the glutamatergic system. At this point some general risk factors for AWS were induced: old age, advanced PD, underlying dementia and duration of therapy. Factor agreed with Miyaski that AWS was unlikely related to dopaminergic pathways.
In 2009 Brantley published a case report of neuroleptic malignant syndrome (NMS) believed induced by amantadine withdrawal [6]. The authors hypothesized that more classic AWS exists on a spectrum which includes NMS. Marxreiter added an additional case of severe AWS in a patient with PD in 2017, helpfully noting the benefit of reintroducing amantadine early in instances of diagnostic uncertainty due to its rapid effects [7]. Finally, Fryml described three cases of AWS in a 2017 report which interestingly included the first patient without PD [8]. The authors noted the remarkable duration that AWS can persist: in one instance for weeks. Similar to Brantley, she describes AWS as a protean syndrome ranging from delirium to NMS, driven by dopaminergic derangements.
Our case illustrates both characteristic and unusual features of AWS. Characteristically, this case was prolonged and refractory, included motor symptoms, and entirely resolved with amantadine reintroduction. Atypically, this case involved a patient without PD who experienced a hypoactive delirium, although this has been also reported. Intriguingly, this case of AWS likely occurred after a period of amantadine toxicity, as the patient initially presented with hallucinations and elevated serum amantadine levels. We hope this report highlights the importance of prolonged amantadine tapers in the setting of toxicity as symptoms of overdose and withdrawal can overlap, creating diagnostic confusion. Further questions which remain to be answered include the exact pathophysiology of the syndrome and if it includes NMS as part of its spectrum.
ACKNOWLEDGMENTS
University of Chicago COVID-19 unit. No funding was received for this report.
CONFLICT OF INTEREST
None declared.
ETHICAL APPROVAL
Patient information was deidentified and informed consent obtained.
CONSENT
Written consent was obtained from the patient.
GUARANTOR
John P. Murray. | Recovered | ReactionOutcome | CC BY | 33614044 | 19,760,674 | 2021-02 |
What was the outcome of reaction 'Hallucination'? | Amantadine withdrawal syndrome masquerading as COVID-19 encephalopathy: a case report and review of the literature.
Amantadine withdrawal syndrome (AWS) is a rare but recognized cause of severe and persistent altered mental status sometimes with co-occurring extrapyramidal symptoms. First described in a case series from 1987, its clinical manifestations have been characterized along a spectrum ranging from profound hypoactive delirium to hyperactive delirium with hallucinations. Risk factors for withdrawal include abrupt medication discontinuation, prolonged use, older age and underlying dementia. Herein we describe a case of a 52-year-old woman who presented with confusion, hallucinations, and coronavirus disease-2019 infection. She subsequently developed a prolonged hypoactive delirium after her amantadine was tapered and held. Her hypoactive delirium entirely resolved with resumption of amantadine confirming the diagnosis of AWS. This case illustrates the importance of slowly tapering dopaminergic medications and being aware of rare pharmacologic side effects.
INTRODUCTION
Amantadine hydrochloride, among the many happy accidents in medicine, was inadvertently discovered to alleviate the extrapyramidal symptoms of Parkinson’s disease (PD) in 1968. A woman with PD found her symptoms much improved while taking amantadine for flu prophylaxis. Later that year a large trial demonstrated both subjective and objective benefits when used to treat PD [1]. Since that time, amantadine has been used to treat PD alongside a number of other movement disorders.
Although its mechanism is not fully understood, amantadine is thought to achieve its effect via N-methyl-D-aspartate receptor antagonism, direct and indirect effects on dopamine neurons, and by decreasing anticholinergic tone [2]. Amantadine can cause dopamine toxicity: paranoia, hallucinations and tachycardia. For this reason, the medication is initiated progressively. Inversely, if it is rapidly discontinued, patients may develop amantadine withdrawal syndrome (AWS), a severe and persistent delirium often with concurrent extrapyramidal symptoms.
CASE REPORT
A 52-year-old female with a past medical history of spinocerebellar ataxia, hyperthyroidism and depression presented to the hospital with 2–3 weeks of hallucinations. Admission labs were remarkable for a new acute kidney injury with blood urea nitrogen (76 mg/dl) and creatinine (1.6 mg/dl from baseline of 0.8 mg/dl). Additionally, she was found to be coronavirus disease-2019 (COVID-19) positive. Complete blood count, urinalysis, thyroid stimulating hormone (TSH), serum ethanol level and head computed tomography were unremarkable. Vital signs were notable for a heart rate of 104. On arrival she was alert and answering questions appropriately. The patient had been prescribed amantadine for 2.5 years prior to admission and was taking 300 mg daily.
The neurology service suspected her hallucinations were related to amantadine toxicity and recommended a 3-day taper, shortened to 2 days by the primary service. Serum amantadine level was ordered on admission and found to be 1505 ng/dl (therapeutic range 200–1000 ng/ml and toxicity >2000 ng/ml). The patient continued to have hallucinations with concurrent agitation, prompting an electroencephalogram (EEG) and lumbar puncture. All lumbar puncture studies were normal. EEG showed background slowing consistent with encephalopathy with no epileptiform activity.
After 3 days, the patient was no longer having active hallucinations but became increasingly somnolent and disoriented. Five days into her course, she was no longer consistently speaking with providers. Two weeks into her hospitalization, she required assistance in feeding and was not reliably following commands. Given her persistent symptoms, the possibility of COVID-19 encephalopathy was raised and a repeat lumbar puncture considered for colony-stimulating factor polymerase chain reactiontesting. Prior to this, the patient was resumed on 200 mg of oral amantadine. Within 2 days she was alert, speaking in full sentences, and oriented to person, month and situation. Because the patient’s prolonged delirium resolved immediately after resuming amantadine, the diagnosis of AWS was made. The neurology service believed that the patient’s initial presentation was consistent with amantadine toxicity with the patient going into withdrawal in the subsequent days as the medication was tapered and held, thus explaining both her initial agitation and hallucinations and subsequent hypoactive delirium. She ultimately returned to her cognitive baseline and was discharged to subacute rehab.
DISCUSSION
Since 1987 there have been seven case reports describing instances of AWS including 15 patients. This is the first published since 2017 and is noteworthy in that it describes a patient without PD or underlying dementia. The first case series, published by Wilson in 1987, describes three older patients who experienced recrudescence of their PD motor symptoms after amantadine was held [3]. Only one of the three patients may have suffered from our more contemporary definition of AWS, an acute delirium following the discontinuation of the medication, whereas the other two patients experienced only movement symptoms.
In 1997 Factor published a case series describing three elderly patients who developed acute delirium with worsening motor function after amantadine was held [4]. All patients had underlying dementia and had been taking amantadine for more than 4 years. Symptoms quickly resolved after resuming the medication. Interestingly, all patients had their amantadine held due to hallucinations. Miyasaki republished a reply to the editor sharing two similar cases of patients with longstanding PD who developed AWS [5]. Factor responded with two further cases of elderly patients with characteristic PD and AWS. These cases were novel in that one patient did not have underlying dementia and both patients had been taking amantadine for less than 1 year. Again, symptoms entirely resolved with resumption of amantadine. Miyasaki hypothesized that pathogenesis of the delirium was related to the glutamatergic system. At this point some general risk factors for AWS were induced: old age, advanced PD, underlying dementia and duration of therapy. Factor agreed with Miyaski that AWS was unlikely related to dopaminergic pathways.
In 2009 Brantley published a case report of neuroleptic malignant syndrome (NMS) believed induced by amantadine withdrawal [6]. The authors hypothesized that more classic AWS exists on a spectrum which includes NMS. Marxreiter added an additional case of severe AWS in a patient with PD in 2017, helpfully noting the benefit of reintroducing amantadine early in instances of diagnostic uncertainty due to its rapid effects [7]. Finally, Fryml described three cases of AWS in a 2017 report which interestingly included the first patient without PD [8]. The authors noted the remarkable duration that AWS can persist: in one instance for weeks. Similar to Brantley, she describes AWS as a protean syndrome ranging from delirium to NMS, driven by dopaminergic derangements.
Our case illustrates both characteristic and unusual features of AWS. Characteristically, this case was prolonged and refractory, included motor symptoms, and entirely resolved with amantadine reintroduction. Atypically, this case involved a patient without PD who experienced a hypoactive delirium, although this has been also reported. Intriguingly, this case of AWS likely occurred after a period of amantadine toxicity, as the patient initially presented with hallucinations and elevated serum amantadine levels. We hope this report highlights the importance of prolonged amantadine tapers in the setting of toxicity as symptoms of overdose and withdrawal can overlap, creating diagnostic confusion. Further questions which remain to be answered include the exact pathophysiology of the syndrome and if it includes NMS as part of its spectrum.
ACKNOWLEDGMENTS
University of Chicago COVID-19 unit. No funding was received for this report.
CONFLICT OF INTEREST
None declared.
ETHICAL APPROVAL
Patient information was deidentified and informed consent obtained.
CONSENT
Written consent was obtained from the patient.
GUARANTOR
John P. Murray. | Recovered | ReactionOutcome | CC BY | 33614044 | 19,760,674 | 2021-02 |
What was the outcome of reaction 'Somnolence'? | Amantadine withdrawal syndrome masquerading as COVID-19 encephalopathy: a case report and review of the literature.
Amantadine withdrawal syndrome (AWS) is a rare but recognized cause of severe and persistent altered mental status sometimes with co-occurring extrapyramidal symptoms. First described in a case series from 1987, its clinical manifestations have been characterized along a spectrum ranging from profound hypoactive delirium to hyperactive delirium with hallucinations. Risk factors for withdrawal include abrupt medication discontinuation, prolonged use, older age and underlying dementia. Herein we describe a case of a 52-year-old woman who presented with confusion, hallucinations, and coronavirus disease-2019 infection. She subsequently developed a prolonged hypoactive delirium after her amantadine was tapered and held. Her hypoactive delirium entirely resolved with resumption of amantadine confirming the diagnosis of AWS. This case illustrates the importance of slowly tapering dopaminergic medications and being aware of rare pharmacologic side effects.
INTRODUCTION
Amantadine hydrochloride, among the many happy accidents in medicine, was inadvertently discovered to alleviate the extrapyramidal symptoms of Parkinson’s disease (PD) in 1968. A woman with PD found her symptoms much improved while taking amantadine for flu prophylaxis. Later that year a large trial demonstrated both subjective and objective benefits when used to treat PD [1]. Since that time, amantadine has been used to treat PD alongside a number of other movement disorders.
Although its mechanism is not fully understood, amantadine is thought to achieve its effect via N-methyl-D-aspartate receptor antagonism, direct and indirect effects on dopamine neurons, and by decreasing anticholinergic tone [2]. Amantadine can cause dopamine toxicity: paranoia, hallucinations and tachycardia. For this reason, the medication is initiated progressively. Inversely, if it is rapidly discontinued, patients may develop amantadine withdrawal syndrome (AWS), a severe and persistent delirium often with concurrent extrapyramidal symptoms.
CASE REPORT
A 52-year-old female with a past medical history of spinocerebellar ataxia, hyperthyroidism and depression presented to the hospital with 2–3 weeks of hallucinations. Admission labs were remarkable for a new acute kidney injury with blood urea nitrogen (76 mg/dl) and creatinine (1.6 mg/dl from baseline of 0.8 mg/dl). Additionally, she was found to be coronavirus disease-2019 (COVID-19) positive. Complete blood count, urinalysis, thyroid stimulating hormone (TSH), serum ethanol level and head computed tomography were unremarkable. Vital signs were notable for a heart rate of 104. On arrival she was alert and answering questions appropriately. The patient had been prescribed amantadine for 2.5 years prior to admission and was taking 300 mg daily.
The neurology service suspected her hallucinations were related to amantadine toxicity and recommended a 3-day taper, shortened to 2 days by the primary service. Serum amantadine level was ordered on admission and found to be 1505 ng/dl (therapeutic range 200–1000 ng/ml and toxicity >2000 ng/ml). The patient continued to have hallucinations with concurrent agitation, prompting an electroencephalogram (EEG) and lumbar puncture. All lumbar puncture studies were normal. EEG showed background slowing consistent with encephalopathy with no epileptiform activity.
After 3 days, the patient was no longer having active hallucinations but became increasingly somnolent and disoriented. Five days into her course, she was no longer consistently speaking with providers. Two weeks into her hospitalization, she required assistance in feeding and was not reliably following commands. Given her persistent symptoms, the possibility of COVID-19 encephalopathy was raised and a repeat lumbar puncture considered for colony-stimulating factor polymerase chain reactiontesting. Prior to this, the patient was resumed on 200 mg of oral amantadine. Within 2 days she was alert, speaking in full sentences, and oriented to person, month and situation. Because the patient’s prolonged delirium resolved immediately after resuming amantadine, the diagnosis of AWS was made. The neurology service believed that the patient’s initial presentation was consistent with amantadine toxicity with the patient going into withdrawal in the subsequent days as the medication was tapered and held, thus explaining both her initial agitation and hallucinations and subsequent hypoactive delirium. She ultimately returned to her cognitive baseline and was discharged to subacute rehab.
DISCUSSION
Since 1987 there have been seven case reports describing instances of AWS including 15 patients. This is the first published since 2017 and is noteworthy in that it describes a patient without PD or underlying dementia. The first case series, published by Wilson in 1987, describes three older patients who experienced recrudescence of their PD motor symptoms after amantadine was held [3]. Only one of the three patients may have suffered from our more contemporary definition of AWS, an acute delirium following the discontinuation of the medication, whereas the other two patients experienced only movement symptoms.
In 1997 Factor published a case series describing three elderly patients who developed acute delirium with worsening motor function after amantadine was held [4]. All patients had underlying dementia and had been taking amantadine for more than 4 years. Symptoms quickly resolved after resuming the medication. Interestingly, all patients had their amantadine held due to hallucinations. Miyasaki republished a reply to the editor sharing two similar cases of patients with longstanding PD who developed AWS [5]. Factor responded with two further cases of elderly patients with characteristic PD and AWS. These cases were novel in that one patient did not have underlying dementia and both patients had been taking amantadine for less than 1 year. Again, symptoms entirely resolved with resumption of amantadine. Miyasaki hypothesized that pathogenesis of the delirium was related to the glutamatergic system. At this point some general risk factors for AWS were induced: old age, advanced PD, underlying dementia and duration of therapy. Factor agreed with Miyaski that AWS was unlikely related to dopaminergic pathways.
In 2009 Brantley published a case report of neuroleptic malignant syndrome (NMS) believed induced by amantadine withdrawal [6]. The authors hypothesized that more classic AWS exists on a spectrum which includes NMS. Marxreiter added an additional case of severe AWS in a patient with PD in 2017, helpfully noting the benefit of reintroducing amantadine early in instances of diagnostic uncertainty due to its rapid effects [7]. Finally, Fryml described three cases of AWS in a 2017 report which interestingly included the first patient without PD [8]. The authors noted the remarkable duration that AWS can persist: in one instance for weeks. Similar to Brantley, she describes AWS as a protean syndrome ranging from delirium to NMS, driven by dopaminergic derangements.
Our case illustrates both characteristic and unusual features of AWS. Characteristically, this case was prolonged and refractory, included motor symptoms, and entirely resolved with amantadine reintroduction. Atypically, this case involved a patient without PD who experienced a hypoactive delirium, although this has been also reported. Intriguingly, this case of AWS likely occurred after a period of amantadine toxicity, as the patient initially presented with hallucinations and elevated serum amantadine levels. We hope this report highlights the importance of prolonged amantadine tapers in the setting of toxicity as symptoms of overdose and withdrawal can overlap, creating diagnostic confusion. Further questions which remain to be answered include the exact pathophysiology of the syndrome and if it includes NMS as part of its spectrum.
ACKNOWLEDGMENTS
University of Chicago COVID-19 unit. No funding was received for this report.
CONFLICT OF INTEREST
None declared.
ETHICAL APPROVAL
Patient information was deidentified and informed consent obtained.
CONSENT
Written consent was obtained from the patient.
GUARANTOR
John P. Murray. | Recovered | ReactionOutcome | CC BY | 33614044 | 19,760,674 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Haemorrhagic infarction'. | One clot after another in COVID-19 patient: diagnostic utility of handheld echocardiogram.
A 63-year-old woman was admitted with severe respiratory distress requiring mechanical ventilation and shock requiring vasopressor support. She was found to have COVID-19 pneumonia. Focused cardiac ultrasound performed for evaluation of shock was significant for right ventricular dilation and dysfunction with signs of right ventricular pressure overload. Given worsening shock and hypoxemia systemic thrombolysis was administered for presumed massive pulmonary embolism with remarkable improvement of hemodynamics and respiratory failure. In next 24 h patient's neurologic status deteriorated to the point of unresponsiveness. Emergent computed tomography showed multiple ischemic infarcts concerning for embolic etiology. Focused cardiac ultrasound with agitated saline showed large right to left shunt due to a patent foramen ovale. This was confirmed by transesophageal echocardiogram, 5 months later. This case highlights strengths of focused cardiac ultrasound in critical care setting and in patients with COVID-19 when access to other imaging modalities can be limited.
INTRODUCTION
We present a patient with COVID-19 infection presenting with respiratory failure and shock. Our case report highlights the strengths of focused cardiac ultrasound in differential diagnosis of shock and paradoxical embolism, especially valuable in patients with COVID-19 when access to other imaging modalities can be limited.
CASE REPORT
A 63-year-old woman with the history of hypertension presented to the emergency department during COVID-19 pandemic with significant shortness of breath on minimal exertion and fatigue for 3 weeks. Patient was hypoxic to 74% and tachypneic to 30 breaths/min and required endotracheal intubation. Physical exam was unremarkable. Shortly, thereafter, she became persistently hypotensive requiring vasopressor support. Electrocardiogram revealed sinus rhythm with rate of 70 bpm, tall R wave in V2 and symmetric T wave inversions in precordial leads (Fig. 1). Chest radiograph post intubation showed bilateral patchy infiltrates. Initial severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) PCR test was negative while the second PCR for SARS-CoV-2 done 24 h later returned positive.
Figure 1 Initial electrocardiogram showing sinus rhythm with rate of 70 bpm, tall R wave in V2 and symmetric T wave inversions in precordial leads.
Initial troponin T was 0.07 ng/ml with maximum at 0.22 ng/ml (reference range < 0.01 ng/ml) and NT-proBNP was 12 945 pg/ml. Elevated white blood cell count (21.1 × 103/μl), creatinine (1.45 mg/dl), C-reactive protein (25.9 mg/dl) and ferritin (546 ng/ml) and D- Dimer 4.34 (ref range ≤ 0.63 mg/l) was noted. Serial ECGs remained stable.
Patient remained persistently hypoxic with PaO2/FiO2 ratio of 85 which along with CXR findings is suggestive of severe acute respiratory distress syndrome (ARDS). Central venous oxygen saturation of 62% suggested the possibility of mixed shock.
Computed tomography angiogram of chest was deferred due to hemodynamic instability and refractory hypoxemia. Systemic anticoagulation with heparin and broad-spectrum antibiotics was initiated. Due to institutional COVID-19 policy for transthoracic echocardiography to minimize personnel exposure, focused cardiac ultrasound (FoCUS) was performed, which revealed mildly increased right ventricular cavity size with flattened septum in systole and diastole along with bowing of interatrial septum toward the left supporting ECG findings of right ventricular strain (Fig. 2, Supplementary video 1). Due to suspected massive pulmonary embolism (PE) alteplase 50 mg was given intravenously over 120 min. This resulted in significant improvement of hemodynamics, perfusion indices and oxygenation within next 12 h to the extent that hypotension resolved despite being on high PEEP protocol for ARDS.
Figure 2 Parasternal short-axis view demonstrating dilated right ventricle (star) with flattened septum (arrow).
After 24 h, patient was noted to be unresponsive despite being off sedation. Urgent computed tomography (CT) of head revealed multifocal infarcts of both cerebral and cerebellar hemispheres with associated mass effects concerning for acute ischemic infarcts. Follow-up CT in 12 h revealed hemorrhagic transformation and anticoagulation with heparin was held. Due to concern for cardioembolic phenomenon, FoCUS with agitated saline was done that showed early right to left shunt consistent with patent foramen ovale (PFO) (Fig. 3, Supplementary video 2). Doppler ultrasound of legs did not reveal deep venous thrombosis (DVT). No evidence of atrial fibrillation was noted on prolonged cardiac monitoring. Antiphospholipid antibody syndrome workup was negative.
Figure 3 Apical four chamber view with early right to left shunt by agitated saline study.
Patient remained intubated for 20 days due to poor mental status but was eventually successfully liberated from mechanical ventilation. She was discharged on apixaban 5 mg BID for PE. After 5 months of continuous physical, neurological and nutritional improvement, TEE was done which confirmed the PFO (Figs. 4 and 5). She was referred for PFO closure.
Figure 4 Three-dimensional transesophageal echocardiography with PFO in interatrial septum.
Figure 5 Transesophageal echocardiography. Agitated saline study with bubbles crossing from right atrium to left atrium through PFO.
DISCUSSION
Shock in COVID-19 patients requires careful assessment. Distributive shock from inflammatory response to SARS-CoV-2 is common, but other types of shock including cardiogenic, obstructive (including tamponade and tension pneumothorax), as well as mixed shock should be considered. Myopericarditis, stress cardiomyopathy, and myocardial infraction (MI) should be in the differential for cardiogenic shock in such patients. A high degree of clinical suspicion is required to diagnose obstructive shock from PE given significant hypoxemia in severe COVID-19 cases due to ARDS [1]. Classic ECG changes of right ventricular strain S1Q3T3 are insensitive. On the other hand, simultaneous T wave inversions in inferior and precordial leads with maximum amplitude of T wave in V1–V2 was previously reported, as sign of PE [2].
Hypercoagulability, both in macro and microvascular circulation, is important contributor to morbidity and mortality in COVID-19 infection, and our understanding of the disease is evolving rapidly. Macro-thrombotic events including acute MI, acute limb ischemia, stoke, DVT, PE as well as pulmonary intravascular coagulopathy with micro-thrombotic complications are described in [3]. Early diagnosis of these grave thrombotic complications in COVID-19 patients may improve outcomes substantially.
COVID-19 pandemic created a situation wherein healthcare workers safety and highest care to patients must be in delicate balance. Multiple institutions including American Society of Echocardiography implemented new policies to change use criteria and protocols for different imaging modalities to limit exposure of healthcare workers [4, 5]. FoCUS is valuable bedside tool and able to provide information on left and right ventricular systolic function, valvular abnormalities, pericardial effusion and volume status [6]. There are only limited reports on echocardiography and FoCUS use in COVID-19 patients [7]. Study by European Association of cardiovascular imaging showed 55% of patients with presumed or confirmed COVID-19 had abnormal echocardiography results which changed the management in one-third of the patients [8]. In a smaller study of 91 suspected or known COVID-19 patients, sonographers spent significantly less time using handheld ultrasound but still provided sufficient information for clinical team [9]. The major limitation of FOCUS is the diagnostic accuracy is dependent on the operator’s skills.
In our case, FoCUS was not only used for diagnosis of massive PE but also to diagnose the large interatrial shunt. Prompt diagnosis of massive PE and appropriate thrombolysis dramatically improved hemodynamics and oxygenation. Although stroke can be explained by prothrombotic state in COVID-19, embolic origin, particularly paradoxical embolism, needs to be ruled out [10]. FoCUS with agitated saline confirmed the diagnosis of interatrial right to left shunting as route for paradoxical embolism.
To conclude, FoCUS facilitated diagnosis of massive pulmonary thromboembolism and interatrial shunt that guided clinical management. High clinical suspicion for thrombotic complications in COVID-19 patients is required for prompt diagnosis. FoCUS is a helpful tool readily available at bedside with advantage of limiting exposure of healthcare workers.
CONFLICT OF INTEREST STATEMENT
No conflicts of interest.
FUNDING
Not applicable.
ETHICAL APPROVAL
None required.
CONSENT
We obtained written informed consent from the patient for the publication of this case report and the accompanying images.
GUARANTOR
Stuart Zarich MD.
Supplementary Material
Figure_2_Online_video_1_omaa141 Click here for additional data file.
Figure_3_online_video_2_omaa141 Click here for additional data file. | ALTEPLASE, HEPARIN SODIUM | DrugsGivenReaction | CC BY | 33614051 | 20,017,769 | 2021-02 |
What was the administration route of drug 'ALTEPLASE'? | One clot after another in COVID-19 patient: diagnostic utility of handheld echocardiogram.
A 63-year-old woman was admitted with severe respiratory distress requiring mechanical ventilation and shock requiring vasopressor support. She was found to have COVID-19 pneumonia. Focused cardiac ultrasound performed for evaluation of shock was significant for right ventricular dilation and dysfunction with signs of right ventricular pressure overload. Given worsening shock and hypoxemia systemic thrombolysis was administered for presumed massive pulmonary embolism with remarkable improvement of hemodynamics and respiratory failure. In next 24 h patient's neurologic status deteriorated to the point of unresponsiveness. Emergent computed tomography showed multiple ischemic infarcts concerning for embolic etiology. Focused cardiac ultrasound with agitated saline showed large right to left shunt due to a patent foramen ovale. This was confirmed by transesophageal echocardiogram, 5 months later. This case highlights strengths of focused cardiac ultrasound in critical care setting and in patients with COVID-19 when access to other imaging modalities can be limited.
INTRODUCTION
We present a patient with COVID-19 infection presenting with respiratory failure and shock. Our case report highlights the strengths of focused cardiac ultrasound in differential diagnosis of shock and paradoxical embolism, especially valuable in patients with COVID-19 when access to other imaging modalities can be limited.
CASE REPORT
A 63-year-old woman with the history of hypertension presented to the emergency department during COVID-19 pandemic with significant shortness of breath on minimal exertion and fatigue for 3 weeks. Patient was hypoxic to 74% and tachypneic to 30 breaths/min and required endotracheal intubation. Physical exam was unremarkable. Shortly, thereafter, she became persistently hypotensive requiring vasopressor support. Electrocardiogram revealed sinus rhythm with rate of 70 bpm, tall R wave in V2 and symmetric T wave inversions in precordial leads (Fig. 1). Chest radiograph post intubation showed bilateral patchy infiltrates. Initial severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) PCR test was negative while the second PCR for SARS-CoV-2 done 24 h later returned positive.
Figure 1 Initial electrocardiogram showing sinus rhythm with rate of 70 bpm, tall R wave in V2 and symmetric T wave inversions in precordial leads.
Initial troponin T was 0.07 ng/ml with maximum at 0.22 ng/ml (reference range < 0.01 ng/ml) and NT-proBNP was 12 945 pg/ml. Elevated white blood cell count (21.1 × 103/μl), creatinine (1.45 mg/dl), C-reactive protein (25.9 mg/dl) and ferritin (546 ng/ml) and D- Dimer 4.34 (ref range ≤ 0.63 mg/l) was noted. Serial ECGs remained stable.
Patient remained persistently hypoxic with PaO2/FiO2 ratio of 85 which along with CXR findings is suggestive of severe acute respiratory distress syndrome (ARDS). Central venous oxygen saturation of 62% suggested the possibility of mixed shock.
Computed tomography angiogram of chest was deferred due to hemodynamic instability and refractory hypoxemia. Systemic anticoagulation with heparin and broad-spectrum antibiotics was initiated. Due to institutional COVID-19 policy for transthoracic echocardiography to minimize personnel exposure, focused cardiac ultrasound (FoCUS) was performed, which revealed mildly increased right ventricular cavity size with flattened septum in systole and diastole along with bowing of interatrial septum toward the left supporting ECG findings of right ventricular strain (Fig. 2, Supplementary video 1). Due to suspected massive pulmonary embolism (PE) alteplase 50 mg was given intravenously over 120 min. This resulted in significant improvement of hemodynamics, perfusion indices and oxygenation within next 12 h to the extent that hypotension resolved despite being on high PEEP protocol for ARDS.
Figure 2 Parasternal short-axis view demonstrating dilated right ventricle (star) with flattened septum (arrow).
After 24 h, patient was noted to be unresponsive despite being off sedation. Urgent computed tomography (CT) of head revealed multifocal infarcts of both cerebral and cerebellar hemispheres with associated mass effects concerning for acute ischemic infarcts. Follow-up CT in 12 h revealed hemorrhagic transformation and anticoagulation with heparin was held. Due to concern for cardioembolic phenomenon, FoCUS with agitated saline was done that showed early right to left shunt consistent with patent foramen ovale (PFO) (Fig. 3, Supplementary video 2). Doppler ultrasound of legs did not reveal deep venous thrombosis (DVT). No evidence of atrial fibrillation was noted on prolonged cardiac monitoring. Antiphospholipid antibody syndrome workup was negative.
Figure 3 Apical four chamber view with early right to left shunt by agitated saline study.
Patient remained intubated for 20 days due to poor mental status but was eventually successfully liberated from mechanical ventilation. She was discharged on apixaban 5 mg BID for PE. After 5 months of continuous physical, neurological and nutritional improvement, TEE was done which confirmed the PFO (Figs. 4 and 5). She was referred for PFO closure.
Figure 4 Three-dimensional transesophageal echocardiography with PFO in interatrial septum.
Figure 5 Transesophageal echocardiography. Agitated saline study with bubbles crossing from right atrium to left atrium through PFO.
DISCUSSION
Shock in COVID-19 patients requires careful assessment. Distributive shock from inflammatory response to SARS-CoV-2 is common, but other types of shock including cardiogenic, obstructive (including tamponade and tension pneumothorax), as well as mixed shock should be considered. Myopericarditis, stress cardiomyopathy, and myocardial infraction (MI) should be in the differential for cardiogenic shock in such patients. A high degree of clinical suspicion is required to diagnose obstructive shock from PE given significant hypoxemia in severe COVID-19 cases due to ARDS [1]. Classic ECG changes of right ventricular strain S1Q3T3 are insensitive. On the other hand, simultaneous T wave inversions in inferior and precordial leads with maximum amplitude of T wave in V1–V2 was previously reported, as sign of PE [2].
Hypercoagulability, both in macro and microvascular circulation, is important contributor to morbidity and mortality in COVID-19 infection, and our understanding of the disease is evolving rapidly. Macro-thrombotic events including acute MI, acute limb ischemia, stoke, DVT, PE as well as pulmonary intravascular coagulopathy with micro-thrombotic complications are described in [3]. Early diagnosis of these grave thrombotic complications in COVID-19 patients may improve outcomes substantially.
COVID-19 pandemic created a situation wherein healthcare workers safety and highest care to patients must be in delicate balance. Multiple institutions including American Society of Echocardiography implemented new policies to change use criteria and protocols for different imaging modalities to limit exposure of healthcare workers [4, 5]. FoCUS is valuable bedside tool and able to provide information on left and right ventricular systolic function, valvular abnormalities, pericardial effusion and volume status [6]. There are only limited reports on echocardiography and FoCUS use in COVID-19 patients [7]. Study by European Association of cardiovascular imaging showed 55% of patients with presumed or confirmed COVID-19 had abnormal echocardiography results which changed the management in one-third of the patients [8]. In a smaller study of 91 suspected or known COVID-19 patients, sonographers spent significantly less time using handheld ultrasound but still provided sufficient information for clinical team [9]. The major limitation of FOCUS is the diagnostic accuracy is dependent on the operator’s skills.
In our case, FoCUS was not only used for diagnosis of massive PE but also to diagnose the large interatrial shunt. Prompt diagnosis of massive PE and appropriate thrombolysis dramatically improved hemodynamics and oxygenation. Although stroke can be explained by prothrombotic state in COVID-19, embolic origin, particularly paradoxical embolism, needs to be ruled out [10]. FoCUS with agitated saline confirmed the diagnosis of interatrial right to left shunting as route for paradoxical embolism.
To conclude, FoCUS facilitated diagnosis of massive pulmonary thromboembolism and interatrial shunt that guided clinical management. High clinical suspicion for thrombotic complications in COVID-19 patients is required for prompt diagnosis. FoCUS is a helpful tool readily available at bedside with advantage of limiting exposure of healthcare workers.
CONFLICT OF INTEREST STATEMENT
No conflicts of interest.
FUNDING
Not applicable.
ETHICAL APPROVAL
None required.
CONSENT
We obtained written informed consent from the patient for the publication of this case report and the accompanying images.
GUARANTOR
Stuart Zarich MD.
Supplementary Material
Figure_2_Online_video_1_omaa141 Click here for additional data file.
Figure_3_online_video_2_omaa141 Click here for additional data file. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY | 33614051 | 20,017,769 | 2021-02 |
What was the outcome of reaction 'Haemorrhagic infarction'? | One clot after another in COVID-19 patient: diagnostic utility of handheld echocardiogram.
A 63-year-old woman was admitted with severe respiratory distress requiring mechanical ventilation and shock requiring vasopressor support. She was found to have COVID-19 pneumonia. Focused cardiac ultrasound performed for evaluation of shock was significant for right ventricular dilation and dysfunction with signs of right ventricular pressure overload. Given worsening shock and hypoxemia systemic thrombolysis was administered for presumed massive pulmonary embolism with remarkable improvement of hemodynamics and respiratory failure. In next 24 h patient's neurologic status deteriorated to the point of unresponsiveness. Emergent computed tomography showed multiple ischemic infarcts concerning for embolic etiology. Focused cardiac ultrasound with agitated saline showed large right to left shunt due to a patent foramen ovale. This was confirmed by transesophageal echocardiogram, 5 months later. This case highlights strengths of focused cardiac ultrasound in critical care setting and in patients with COVID-19 when access to other imaging modalities can be limited.
INTRODUCTION
We present a patient with COVID-19 infection presenting with respiratory failure and shock. Our case report highlights the strengths of focused cardiac ultrasound in differential diagnosis of shock and paradoxical embolism, especially valuable in patients with COVID-19 when access to other imaging modalities can be limited.
CASE REPORT
A 63-year-old woman with the history of hypertension presented to the emergency department during COVID-19 pandemic with significant shortness of breath on minimal exertion and fatigue for 3 weeks. Patient was hypoxic to 74% and tachypneic to 30 breaths/min and required endotracheal intubation. Physical exam was unremarkable. Shortly, thereafter, she became persistently hypotensive requiring vasopressor support. Electrocardiogram revealed sinus rhythm with rate of 70 bpm, tall R wave in V2 and symmetric T wave inversions in precordial leads (Fig. 1). Chest radiograph post intubation showed bilateral patchy infiltrates. Initial severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) PCR test was negative while the second PCR for SARS-CoV-2 done 24 h later returned positive.
Figure 1 Initial electrocardiogram showing sinus rhythm with rate of 70 bpm, tall R wave in V2 and symmetric T wave inversions in precordial leads.
Initial troponin T was 0.07 ng/ml with maximum at 0.22 ng/ml (reference range < 0.01 ng/ml) and NT-proBNP was 12 945 pg/ml. Elevated white blood cell count (21.1 × 103/μl), creatinine (1.45 mg/dl), C-reactive protein (25.9 mg/dl) and ferritin (546 ng/ml) and D- Dimer 4.34 (ref range ≤ 0.63 mg/l) was noted. Serial ECGs remained stable.
Patient remained persistently hypoxic with PaO2/FiO2 ratio of 85 which along with CXR findings is suggestive of severe acute respiratory distress syndrome (ARDS). Central venous oxygen saturation of 62% suggested the possibility of mixed shock.
Computed tomography angiogram of chest was deferred due to hemodynamic instability and refractory hypoxemia. Systemic anticoagulation with heparin and broad-spectrum antibiotics was initiated. Due to institutional COVID-19 policy for transthoracic echocardiography to minimize personnel exposure, focused cardiac ultrasound (FoCUS) was performed, which revealed mildly increased right ventricular cavity size with flattened septum in systole and diastole along with bowing of interatrial septum toward the left supporting ECG findings of right ventricular strain (Fig. 2, Supplementary video 1). Due to suspected massive pulmonary embolism (PE) alteplase 50 mg was given intravenously over 120 min. This resulted in significant improvement of hemodynamics, perfusion indices and oxygenation within next 12 h to the extent that hypotension resolved despite being on high PEEP protocol for ARDS.
Figure 2 Parasternal short-axis view demonstrating dilated right ventricle (star) with flattened septum (arrow).
After 24 h, patient was noted to be unresponsive despite being off sedation. Urgent computed tomography (CT) of head revealed multifocal infarcts of both cerebral and cerebellar hemispheres with associated mass effects concerning for acute ischemic infarcts. Follow-up CT in 12 h revealed hemorrhagic transformation and anticoagulation with heparin was held. Due to concern for cardioembolic phenomenon, FoCUS with agitated saline was done that showed early right to left shunt consistent with patent foramen ovale (PFO) (Fig. 3, Supplementary video 2). Doppler ultrasound of legs did not reveal deep venous thrombosis (DVT). No evidence of atrial fibrillation was noted on prolonged cardiac monitoring. Antiphospholipid antibody syndrome workup was negative.
Figure 3 Apical four chamber view with early right to left shunt by agitated saline study.
Patient remained intubated for 20 days due to poor mental status but was eventually successfully liberated from mechanical ventilation. She was discharged on apixaban 5 mg BID for PE. After 5 months of continuous physical, neurological and nutritional improvement, TEE was done which confirmed the PFO (Figs. 4 and 5). She was referred for PFO closure.
Figure 4 Three-dimensional transesophageal echocardiography with PFO in interatrial septum.
Figure 5 Transesophageal echocardiography. Agitated saline study with bubbles crossing from right atrium to left atrium through PFO.
DISCUSSION
Shock in COVID-19 patients requires careful assessment. Distributive shock from inflammatory response to SARS-CoV-2 is common, but other types of shock including cardiogenic, obstructive (including tamponade and tension pneumothorax), as well as mixed shock should be considered. Myopericarditis, stress cardiomyopathy, and myocardial infraction (MI) should be in the differential for cardiogenic shock in such patients. A high degree of clinical suspicion is required to diagnose obstructive shock from PE given significant hypoxemia in severe COVID-19 cases due to ARDS [1]. Classic ECG changes of right ventricular strain S1Q3T3 are insensitive. On the other hand, simultaneous T wave inversions in inferior and precordial leads with maximum amplitude of T wave in V1–V2 was previously reported, as sign of PE [2].
Hypercoagulability, both in macro and microvascular circulation, is important contributor to morbidity and mortality in COVID-19 infection, and our understanding of the disease is evolving rapidly. Macro-thrombotic events including acute MI, acute limb ischemia, stoke, DVT, PE as well as pulmonary intravascular coagulopathy with micro-thrombotic complications are described in [3]. Early diagnosis of these grave thrombotic complications in COVID-19 patients may improve outcomes substantially.
COVID-19 pandemic created a situation wherein healthcare workers safety and highest care to patients must be in delicate balance. Multiple institutions including American Society of Echocardiography implemented new policies to change use criteria and protocols for different imaging modalities to limit exposure of healthcare workers [4, 5]. FoCUS is valuable bedside tool and able to provide information on left and right ventricular systolic function, valvular abnormalities, pericardial effusion and volume status [6]. There are only limited reports on echocardiography and FoCUS use in COVID-19 patients [7]. Study by European Association of cardiovascular imaging showed 55% of patients with presumed or confirmed COVID-19 had abnormal echocardiography results which changed the management in one-third of the patients [8]. In a smaller study of 91 suspected or known COVID-19 patients, sonographers spent significantly less time using handheld ultrasound but still provided sufficient information for clinical team [9]. The major limitation of FOCUS is the diagnostic accuracy is dependent on the operator’s skills.
In our case, FoCUS was not only used for diagnosis of massive PE but also to diagnose the large interatrial shunt. Prompt diagnosis of massive PE and appropriate thrombolysis dramatically improved hemodynamics and oxygenation. Although stroke can be explained by prothrombotic state in COVID-19, embolic origin, particularly paradoxical embolism, needs to be ruled out [10]. FoCUS with agitated saline confirmed the diagnosis of interatrial right to left shunting as route for paradoxical embolism.
To conclude, FoCUS facilitated diagnosis of massive pulmonary thromboembolism and interatrial shunt that guided clinical management. High clinical suspicion for thrombotic complications in COVID-19 patients is required for prompt diagnosis. FoCUS is a helpful tool readily available at bedside with advantage of limiting exposure of healthcare workers.
CONFLICT OF INTEREST STATEMENT
No conflicts of interest.
FUNDING
Not applicable.
ETHICAL APPROVAL
None required.
CONSENT
We obtained written informed consent from the patient for the publication of this case report and the accompanying images.
GUARANTOR
Stuart Zarich MD.
Supplementary Material
Figure_2_Online_video_1_omaa141 Click here for additional data file.
Figure_3_online_video_2_omaa141 Click here for additional data file. | Recovered | ReactionOutcome | CC BY | 33614051 | 20,017,769 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Drug ineffective'. | Marked Rebound of Platelet Count in the Early Postpartum Period in a Patient with Essential Thrombocythemia.
Essential thrombocythemia (ET) occurs predominantly in the elderly, but approximately 20% of patients are <40 years old. Unlike other myeloproliferative neoplasms, ET occurs more commonly in women. We encountered a 38-year-old women diagnosed with ET who exhibited elevated platelet count in early pregnancy. Her platelet count exceeded 1500 × 109/L by late pregnancy; interferon α was administered but failed to induce an adequate response. She underwent emergency cesarean delivery at 37 weeks of gestation. Although her platelet count was 1000 × 109/L immediately after delivery, it markedly increased to 3271 × 109/L approximately 2 weeks later. Cytoreductive therapy was resumed; the subsequent course was free from complications. Several review articles have indicated that because platelet counts of patients may again increase to the pregnancy level or rebound after delivery, cytoreductive therapy should be administered if necessary. However, there is insufficient information on when therapeutic interventions are necessary and how they should be performed. It remains unknown whether the platelet count will decrease after some time without treatment if it rebounds. We hope management guidelines will be established by collecting detailed data on the postpartum course as well as during pregnancy.
1. Introduction
Essential thrombocythemia (ET) occurs predominantly in the elderly, but approximately 20% of patients are <40 years old [1]. Unlike other myeloproliferative neoplasms (MPNs), ET occurs more commonly in women. Consequently, encountering ET in women of reproductive age is not a rare occurrence. Pregnancy and delivery may promote thromboembolism; thus, the perinatal management of patients with ET is becoming an important issue. Although expert consensus and several guidelines describing the management of these patients have been reported [2–6], there are currently no clear guidelines in Japan [7]. Some of the aforementioned guidelines recommend interferon (IFN) therapy for pregnant women with ET who are at a high risk of pregnancy loss. However, IFN is not approved for patients with ET in Japan. Furthermore, because ET is likely to cause thrombotic events, particularly in the postpartum period, low-molecular-weight heparin is commonly administered for 6 weeks after delivery in Europe and the United States. However, it is not indicated for such use in Japan, either. According to aforementioned and other guidelines, the platelet counts of patients with ET increase after delivery [3–6], but many aspects regarding the timing and degree of rebound remain unknown. Few guidelines, including Japanese guidelines [7], mention the optimal blood test interval and therapeutic strategies.
We present a case in which IFN therapy was administered when the platelet count exceeded 1500 × 109/L during late pregnancy. In the present case, the platelet count decreased to approximately 1000 × 109/L immediately after delivery, and cytoreductive therapy was discontinued. However, approximately 2 weeks later, the platelet count markedly rebounded.
2. Case Presentation
The patient was a 38-year-old woman who was referred to our hospital at approximately 7 weeks of gestation for an elevated platelet count detected during a prenatal checkup. She had vaginally delivered her first child at 40 weeks of gestation 8 years earlier and her second child at 39 weeks of gestation 5 years earlier. No abnormalities were observed during the perinatal periods of both pregnancies, and both the patient and her infants were healthy. She had no history of thrombosis or cardiovascular risk factors, such as diabetes mellitus, hypertension, or dyslipidemia, and was a nonsmoker. At her visit, the physical examination failed to identify any abnormal findings or splenomegaly. Blood tests indicated a white blood cell count of 11.4 × 109/L, a hemoglobin level of 14.0 g/dL, a hematocrit level of 40.3%, a platelet count of 1074 × 109/L, and a von Willebrand factor ristocetin cofactor activity (vWFRCo) of 49% (Table 1). At 9 weeks of gestation, a bone marrow biopsy was performed that revealed normocellular bone marrow with an increased number of large to giant megakaryocytes and absence of evidence of reactive thrombocytosis; a diagnosis of ET was made. The presence of driver gene mutations was evaluated, and the patient was negative for all Janus kinase 2 (JAK2V617F), calreticulin (CALR), and myeloproliferative leukemia (MPL) mutations, which suggested that she had the so-called triple-negative ET.
Low-dose aspirin was initiated. Her platelet count decreased as the pregnancy progressed. At 30 weeks of gestation, her platelet count had decreased to 432 × 109/L. Subsequently, her platelet count rapidly rebounded. At 34 weeks of gestation, it exceeded 1500 × 109/L, which suggested that she was at a high risk (Figure 1). We provided sufficient explanation to the patient and obtained informed consent from her. After the approval of the ethics committee of our hospital, IFNα (Sumiferon® Dainippon Sumitomo, Osaka, Japan) was administered at 34 weeks and 2 days of gestation. IFNα was administered at a dose of 3 million units 3 times/week at 34 weeks of gestation and at a dose of 6 million units 3 times/week at 35 weeks. The decrease in the platelet count was insufficient; thus, IFNα was administered at a dose of 6 million units daily beginning at 36 weeks, and the daily dose was subsequently increased to 9 million units. Although no adverse events associated with IFNα were observed, her platelet count decreased to only 1229 × 109/L. Ultimately, the patient underwent emergency cesarean delivery at 37 weeks and 1 day of gestation (low-dose aspirin was switched to unfractionated heparin at 36 weeks of gestation).
The infant weighed 2581 g and had Apgar scores of 7 points at 1 min and 8 points at 5 min. Although the infant exhibited transient tachypnea and was temporarily admitted to the neonatal intensive care unit, there were no apparent complications, and the infant was discharged from our hospital. The platelet count of the infant at birth was 317 × 109/L. After delivery, low-molecular-weight heparin was initiated for the mother, and low-dose aspirin was also resumed. Her platelet count was approximately 1000 × 109/L. Cytoreductive therapy was discontinued temporarily, and we allowed her to breastfeed as per her request. At 18 days after delivery, her platelet count had markedly increased to 3271 × 109/L, and her vWFRCo decreased to 31%. She appeared to have acquired von Willebrand syndrome; thus, we determined that she was at a high risk of bleeding. Administration of low-molecular-weight heparin and low-dose aspirin and breastfeeding were discontinued, and hydroxyurea was initiated as a cytoreductive therapy. Approximately 2 months after delivery when her platelet count reached controllable levels, anagrelide was added. Her platelet count was well controlled; thus, hydroxyurea was discontinued after approximately 3 months of use. At present, her platelet count is controlled at approximately 400 × 109/L with 1.0 mg/day of anagrelide. The results of the gene mutation test after cytoreductive therapy were negative for TET oncogene family number 2 (TET2), additional sex combs like 1 (ASXL1), isocitrate dehydrogenase ½ (IDH1/2), and tumor protein p53 (TP53) mutations.
3. Discussion
Both pregnancy and ET contribute to the risk of thrombosis; thus, pregnant women with ET may be at a higher risk of thrombosis. Additionally, various complications, such as placental infarction, fetal growth restriction, and fetal wastage, can affect not only the mother but also the fetus. Greiesshammer et al. identified case reports of ≥9 pregnancies in ≥4 patients with ET that were published in and after 2000 and analyzed 10 case reports describing pregnancy outcomes [4]. According to their analysis, the live birth rate in pregnant women with ET was almost 70%; the full-term normal delivery rate was lower in pregnant women with ET than in healthy pregnant women, and the rates of spontaneous abortion and stillbirth were higher. These findings cannot be disregarded. High-risk pregnancies in patients with MPN are often defined based on the definitions developed by Greiesshammer et al. [4] and the European LeukemiaNet [2]. Additionally, expert consensus and several guidelines recommend the use of IFNα for high-risk pregnancy [2–6], and the Japanese guidelines also indicate that the use of IFNα should be considered although it is not covered by the National Health Insurance [7]. A previous retrospective study reported that the use of IFNα is an independent factor affecting the live birth rate [8], and a recent systematic review and meta-analysis of pregnant women with MPN also showed that the use of IFN is associated with a high live birth rate [9].
Based on the above discussion, IFNα was used in our patient with due ethical considerations; unfortunately, its effect was insufficient. Her platelet count rapidly increased around 34 weeks of gestation despite increasing the IFNα dose; hence, the IFNα administration period might have been insufficient. Edahiro et al. reported that the median platelet count decreased by approximately 37% from 910 × 109 to 573 × 109/L in seven patients after 2 months of IFNα therapy that was started after the discovery of pregnancy [10]. As our patient received the drug for approximately 1 month, its effect might have been insufficient. Generally, IFNα is thought to exert favorable molecular genetic effects because it can target cells positive for not only JAK2V617F mutations but also CALR and other mutations [11]. However, a report of the use of pegylated IFNα in patients positive for CALR mutations showed that its molecular genetic effects were lower in patients with CALR mutations and in those with mutations of additional genes such as TET2, ASXL1, IDH2, and TP53 [12]. In other words, the sensitivity of IFNα may differ among mutated clones. Moreover, a small-scale study suggests that patients with triple-negative ET may be more resistant to IFNα than patients with JAK2V617F or CALR mutations [10]. According to our tests, our patient did not have any abnormalities of the aforementioned additional genes, but she did have triple-negative ET. Consequently, the effects of IFNα might have been limited.
Finally, we would like to discuss the postpartum rebound of platelet count in our patient. Several review articles have indicated that because platelet counts of patients may again increase to the prepregnancy level [13] or rebound after delivery, cytoreductive therapy should be administered if necessary [3–6]. However, there is insufficient information on when therapeutic interventions are necessary and how they should be performed. It remains unknown whether the platelet count will decrease after some time without treatment if it rebounds. According to our searches in the English literature, some reports indicate that no particular cytoreductive therapy was required after delivery, whereas other reports describe cases in which patients were treated for a rebound of platelet count [14–18]. Sakai et al. reported a case in which the platelet count increased to ≥1000 × 109/L within 3 months after delivery and another case in which the platelet count increased to ≥800 × 109/L within 2 months after delivery. Cytoreductive therapy was resumed in the former case [14]. Iwashita et al. reported a case of a woman, para 2, whose platelet count increased to ≥2000 × 109/L within 1-2 months after delivery in both pregnancies but decreased to approximately 800 × 109 to 900 × 109/L several months later [15]. Although the prepregnancy platelet count affects the postpartum count, one report cited a platelet count increase to a maximum of 3000 × 109/L after delivery [19]. However, we did not identify any patients in the literature with a postpartum platelet count increasing as high as that of our patient. After pregnancy, cytoreductive therapy is rarely required because young women are often at a low risk based on the conventional risk classification for thrombosis [20]. Furthermore, the decision to perform cytoreductive therapy is expected to differ depending on whether the patient will breastfeed their infant after delivery. Thus, individualized treatment should be considered. While we assume that treatment varies depending on the postpartum status of the patients, a certain expert consensus indicates that blood tests should be counted at 6 weeks after delivery [3]. However, caution should be exercised because some women exhibit a rebound of platelet count within 2–4 weeks after delivery, as with our patient and the aforementioned cases [16, 17].
In conclusion, we encountered a patient who exhibited a marked rebound of platelet count soon after delivery. She resumed cytoreductive therapy; the subsequent course was uneventful without any complications. The evidence for the treatment of pregnant women with ET is limited. We hope that management guidelines will be established through the collection of data both during pregnancy and detailed data on the postpartum course.
Data Availability
No data were used in this study.
Conflicts of Interest
Yoshinori Hashimoto reports receiving honoraria from Takeda Pharmaceutical Co., Ltd. The other authors declare that they have no conflicts of interest.
Figure 1 Clinical course and serial changes in the platelet count. MU, million units; VWFRCo, von Willebrand factor ristocetin cofactor activity.
Table 1 Laboratory findings on admission.
Peripheral blood
WBC 11.4 × 109/L
Neu 76.5%
Lym 17.1%
Mon 4.9%
Eos 1.4%
Bas 1.0%
RBC 4.6 × 1012/L
Hb 14.0 g/dL
Hct 40.3%
MCV 86.9 fL
Ret 1.8 × 1012/L
Plt 1074 × 109/L
Chemistry
TP 7.5 g/dL
Alb 4.8 g/dL
T-bil 0.6 mg/dL
AST 18 U/lL
ALT 25 U/L
ALP 117 U/L
LDH 163 U/L
BUN 7.2 mg/dL
Cr 0.4 mg/dL
UA 3.2 mg/dL
Na 135 mEq/L
K 4.3 mEq/L
Coagulation
PT-INR 0.95
APTT 30.2 sec
vWFRCo 49%
Serology
CRP 0.04 mg/dL
Other findings
JAK2V617F <1.0%
MPLW515L (−)
MPLW515K (−)
CALR type1 <1.0%
CALR type2 <1.0%
ABO/Rh A/+
Ret, reticulocyte; VWFRCo, von Willebrand factor ristocetin cofactor activity; JAK2, Janus kinase 2; MPL, myeloproliferative leukemia protein; CALR, calreticulin, ABO/Rh, ABO blood group/Rhesus blood group. | ASPIRIN, UNSPECIFIED INGREDIENT | DrugsGivenReaction | CC BY | 33614173 | 19,456,283 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Exposure during pregnancy'. | Marked Rebound of Platelet Count in the Early Postpartum Period in a Patient with Essential Thrombocythemia.
Essential thrombocythemia (ET) occurs predominantly in the elderly, but approximately 20% of patients are <40 years old. Unlike other myeloproliferative neoplasms, ET occurs more commonly in women. We encountered a 38-year-old women diagnosed with ET who exhibited elevated platelet count in early pregnancy. Her platelet count exceeded 1500 × 109/L by late pregnancy; interferon α was administered but failed to induce an adequate response. She underwent emergency cesarean delivery at 37 weeks of gestation. Although her platelet count was 1000 × 109/L immediately after delivery, it markedly increased to 3271 × 109/L approximately 2 weeks later. Cytoreductive therapy was resumed; the subsequent course was free from complications. Several review articles have indicated that because platelet counts of patients may again increase to the pregnancy level or rebound after delivery, cytoreductive therapy should be administered if necessary. However, there is insufficient information on when therapeutic interventions are necessary and how they should be performed. It remains unknown whether the platelet count will decrease after some time without treatment if it rebounds. We hope management guidelines will be established by collecting detailed data on the postpartum course as well as during pregnancy.
1. Introduction
Essential thrombocythemia (ET) occurs predominantly in the elderly, but approximately 20% of patients are <40 years old [1]. Unlike other myeloproliferative neoplasms (MPNs), ET occurs more commonly in women. Consequently, encountering ET in women of reproductive age is not a rare occurrence. Pregnancy and delivery may promote thromboembolism; thus, the perinatal management of patients with ET is becoming an important issue. Although expert consensus and several guidelines describing the management of these patients have been reported [2–6], there are currently no clear guidelines in Japan [7]. Some of the aforementioned guidelines recommend interferon (IFN) therapy for pregnant women with ET who are at a high risk of pregnancy loss. However, IFN is not approved for patients with ET in Japan. Furthermore, because ET is likely to cause thrombotic events, particularly in the postpartum period, low-molecular-weight heparin is commonly administered for 6 weeks after delivery in Europe and the United States. However, it is not indicated for such use in Japan, either. According to aforementioned and other guidelines, the platelet counts of patients with ET increase after delivery [3–6], but many aspects regarding the timing and degree of rebound remain unknown. Few guidelines, including Japanese guidelines [7], mention the optimal blood test interval and therapeutic strategies.
We present a case in which IFN therapy was administered when the platelet count exceeded 1500 × 109/L during late pregnancy. In the present case, the platelet count decreased to approximately 1000 × 109/L immediately after delivery, and cytoreductive therapy was discontinued. However, approximately 2 weeks later, the platelet count markedly rebounded.
2. Case Presentation
The patient was a 38-year-old woman who was referred to our hospital at approximately 7 weeks of gestation for an elevated platelet count detected during a prenatal checkup. She had vaginally delivered her first child at 40 weeks of gestation 8 years earlier and her second child at 39 weeks of gestation 5 years earlier. No abnormalities were observed during the perinatal periods of both pregnancies, and both the patient and her infants were healthy. She had no history of thrombosis or cardiovascular risk factors, such as diabetes mellitus, hypertension, or dyslipidemia, and was a nonsmoker. At her visit, the physical examination failed to identify any abnormal findings or splenomegaly. Blood tests indicated a white blood cell count of 11.4 × 109/L, a hemoglobin level of 14.0 g/dL, a hematocrit level of 40.3%, a platelet count of 1074 × 109/L, and a von Willebrand factor ristocetin cofactor activity (vWFRCo) of 49% (Table 1). At 9 weeks of gestation, a bone marrow biopsy was performed that revealed normocellular bone marrow with an increased number of large to giant megakaryocytes and absence of evidence of reactive thrombocytosis; a diagnosis of ET was made. The presence of driver gene mutations was evaluated, and the patient was negative for all Janus kinase 2 (JAK2V617F), calreticulin (CALR), and myeloproliferative leukemia (MPL) mutations, which suggested that she had the so-called triple-negative ET.
Low-dose aspirin was initiated. Her platelet count decreased as the pregnancy progressed. At 30 weeks of gestation, her platelet count had decreased to 432 × 109/L. Subsequently, her platelet count rapidly rebounded. At 34 weeks of gestation, it exceeded 1500 × 109/L, which suggested that she was at a high risk (Figure 1). We provided sufficient explanation to the patient and obtained informed consent from her. After the approval of the ethics committee of our hospital, IFNα (Sumiferon® Dainippon Sumitomo, Osaka, Japan) was administered at 34 weeks and 2 days of gestation. IFNα was administered at a dose of 3 million units 3 times/week at 34 weeks of gestation and at a dose of 6 million units 3 times/week at 35 weeks. The decrease in the platelet count was insufficient; thus, IFNα was administered at a dose of 6 million units daily beginning at 36 weeks, and the daily dose was subsequently increased to 9 million units. Although no adverse events associated with IFNα were observed, her platelet count decreased to only 1229 × 109/L. Ultimately, the patient underwent emergency cesarean delivery at 37 weeks and 1 day of gestation (low-dose aspirin was switched to unfractionated heparin at 36 weeks of gestation).
The infant weighed 2581 g and had Apgar scores of 7 points at 1 min and 8 points at 5 min. Although the infant exhibited transient tachypnea and was temporarily admitted to the neonatal intensive care unit, there were no apparent complications, and the infant was discharged from our hospital. The platelet count of the infant at birth was 317 × 109/L. After delivery, low-molecular-weight heparin was initiated for the mother, and low-dose aspirin was also resumed. Her platelet count was approximately 1000 × 109/L. Cytoreductive therapy was discontinued temporarily, and we allowed her to breastfeed as per her request. At 18 days after delivery, her platelet count had markedly increased to 3271 × 109/L, and her vWFRCo decreased to 31%. She appeared to have acquired von Willebrand syndrome; thus, we determined that she was at a high risk of bleeding. Administration of low-molecular-weight heparin and low-dose aspirin and breastfeeding were discontinued, and hydroxyurea was initiated as a cytoreductive therapy. Approximately 2 months after delivery when her platelet count reached controllable levels, anagrelide was added. Her platelet count was well controlled; thus, hydroxyurea was discontinued after approximately 3 months of use. At present, her platelet count is controlled at approximately 400 × 109/L with 1.0 mg/day of anagrelide. The results of the gene mutation test after cytoreductive therapy were negative for TET oncogene family number 2 (TET2), additional sex combs like 1 (ASXL1), isocitrate dehydrogenase ½ (IDH1/2), and tumor protein p53 (TP53) mutations.
3. Discussion
Both pregnancy and ET contribute to the risk of thrombosis; thus, pregnant women with ET may be at a higher risk of thrombosis. Additionally, various complications, such as placental infarction, fetal growth restriction, and fetal wastage, can affect not only the mother but also the fetus. Greiesshammer et al. identified case reports of ≥9 pregnancies in ≥4 patients with ET that were published in and after 2000 and analyzed 10 case reports describing pregnancy outcomes [4]. According to their analysis, the live birth rate in pregnant women with ET was almost 70%; the full-term normal delivery rate was lower in pregnant women with ET than in healthy pregnant women, and the rates of spontaneous abortion and stillbirth were higher. These findings cannot be disregarded. High-risk pregnancies in patients with MPN are often defined based on the definitions developed by Greiesshammer et al. [4] and the European LeukemiaNet [2]. Additionally, expert consensus and several guidelines recommend the use of IFNα for high-risk pregnancy [2–6], and the Japanese guidelines also indicate that the use of IFNα should be considered although it is not covered by the National Health Insurance [7]. A previous retrospective study reported that the use of IFNα is an independent factor affecting the live birth rate [8], and a recent systematic review and meta-analysis of pregnant women with MPN also showed that the use of IFN is associated with a high live birth rate [9].
Based on the above discussion, IFNα was used in our patient with due ethical considerations; unfortunately, its effect was insufficient. Her platelet count rapidly increased around 34 weeks of gestation despite increasing the IFNα dose; hence, the IFNα administration period might have been insufficient. Edahiro et al. reported that the median platelet count decreased by approximately 37% from 910 × 109 to 573 × 109/L in seven patients after 2 months of IFNα therapy that was started after the discovery of pregnancy [10]. As our patient received the drug for approximately 1 month, its effect might have been insufficient. Generally, IFNα is thought to exert favorable molecular genetic effects because it can target cells positive for not only JAK2V617F mutations but also CALR and other mutations [11]. However, a report of the use of pegylated IFNα in patients positive for CALR mutations showed that its molecular genetic effects were lower in patients with CALR mutations and in those with mutations of additional genes such as TET2, ASXL1, IDH2, and TP53 [12]. In other words, the sensitivity of IFNα may differ among mutated clones. Moreover, a small-scale study suggests that patients with triple-negative ET may be more resistant to IFNα than patients with JAK2V617F or CALR mutations [10]. According to our tests, our patient did not have any abnormalities of the aforementioned additional genes, but she did have triple-negative ET. Consequently, the effects of IFNα might have been limited.
Finally, we would like to discuss the postpartum rebound of platelet count in our patient. Several review articles have indicated that because platelet counts of patients may again increase to the prepregnancy level [13] or rebound after delivery, cytoreductive therapy should be administered if necessary [3–6]. However, there is insufficient information on when therapeutic interventions are necessary and how they should be performed. It remains unknown whether the platelet count will decrease after some time without treatment if it rebounds. According to our searches in the English literature, some reports indicate that no particular cytoreductive therapy was required after delivery, whereas other reports describe cases in which patients were treated for a rebound of platelet count [14–18]. Sakai et al. reported a case in which the platelet count increased to ≥1000 × 109/L within 3 months after delivery and another case in which the platelet count increased to ≥800 × 109/L within 2 months after delivery. Cytoreductive therapy was resumed in the former case [14]. Iwashita et al. reported a case of a woman, para 2, whose platelet count increased to ≥2000 × 109/L within 1-2 months after delivery in both pregnancies but decreased to approximately 800 × 109 to 900 × 109/L several months later [15]. Although the prepregnancy platelet count affects the postpartum count, one report cited a platelet count increase to a maximum of 3000 × 109/L after delivery [19]. However, we did not identify any patients in the literature with a postpartum platelet count increasing as high as that of our patient. After pregnancy, cytoreductive therapy is rarely required because young women are often at a low risk based on the conventional risk classification for thrombosis [20]. Furthermore, the decision to perform cytoreductive therapy is expected to differ depending on whether the patient will breastfeed their infant after delivery. Thus, individualized treatment should be considered. While we assume that treatment varies depending on the postpartum status of the patients, a certain expert consensus indicates that blood tests should be counted at 6 weeks after delivery [3]. However, caution should be exercised because some women exhibit a rebound of platelet count within 2–4 weeks after delivery, as with our patient and the aforementioned cases [16, 17].
In conclusion, we encountered a patient who exhibited a marked rebound of platelet count soon after delivery. She resumed cytoreductive therapy; the subsequent course was uneventful without any complications. The evidence for the treatment of pregnant women with ET is limited. We hope that management guidelines will be established through the collection of data both during pregnancy and detailed data on the postpartum course.
Data Availability
No data were used in this study.
Conflicts of Interest
Yoshinori Hashimoto reports receiving honoraria from Takeda Pharmaceutical Co., Ltd. The other authors declare that they have no conflicts of interest.
Figure 1 Clinical course and serial changes in the platelet count. MU, million units; VWFRCo, von Willebrand factor ristocetin cofactor activity.
Table 1 Laboratory findings on admission.
Peripheral blood
WBC 11.4 × 109/L
Neu 76.5%
Lym 17.1%
Mon 4.9%
Eos 1.4%
Bas 1.0%
RBC 4.6 × 1012/L
Hb 14.0 g/dL
Hct 40.3%
MCV 86.9 fL
Ret 1.8 × 1012/L
Plt 1074 × 109/L
Chemistry
TP 7.5 g/dL
Alb 4.8 g/dL
T-bil 0.6 mg/dL
AST 18 U/lL
ALT 25 U/L
ALP 117 U/L
LDH 163 U/L
BUN 7.2 mg/dL
Cr 0.4 mg/dL
UA 3.2 mg/dL
Na 135 mEq/L
K 4.3 mEq/L
Coagulation
PT-INR 0.95
APTT 30.2 sec
vWFRCo 49%
Serology
CRP 0.04 mg/dL
Other findings
JAK2V617F <1.0%
MPLW515L (−)
MPLW515K (−)
CALR type1 <1.0%
CALR type2 <1.0%
ABO/Rh A/+
Ret, reticulocyte; VWFRCo, von Willebrand factor ristocetin cofactor activity; JAK2, Janus kinase 2; MPL, myeloproliferative leukemia protein; CALR, calreticulin, ABO/Rh, ABO blood group/Rhesus blood group. | ASPIRIN, UNSPECIFIED INGREDIENT | DrugsGivenReaction | CC BY | 33614173 | 19,456,283 | 2021 |
What was the dosage of drug 'ASPIRIN'? | Marked Rebound of Platelet Count in the Early Postpartum Period in a Patient with Essential Thrombocythemia.
Essential thrombocythemia (ET) occurs predominantly in the elderly, but approximately 20% of patients are <40 years old. Unlike other myeloproliferative neoplasms, ET occurs more commonly in women. We encountered a 38-year-old women diagnosed with ET who exhibited elevated platelet count in early pregnancy. Her platelet count exceeded 1500 × 109/L by late pregnancy; interferon α was administered but failed to induce an adequate response. She underwent emergency cesarean delivery at 37 weeks of gestation. Although her platelet count was 1000 × 109/L immediately after delivery, it markedly increased to 3271 × 109/L approximately 2 weeks later. Cytoreductive therapy was resumed; the subsequent course was free from complications. Several review articles have indicated that because platelet counts of patients may again increase to the pregnancy level or rebound after delivery, cytoreductive therapy should be administered if necessary. However, there is insufficient information on when therapeutic interventions are necessary and how they should be performed. It remains unknown whether the platelet count will decrease after some time without treatment if it rebounds. We hope management guidelines will be established by collecting detailed data on the postpartum course as well as during pregnancy.
1. Introduction
Essential thrombocythemia (ET) occurs predominantly in the elderly, but approximately 20% of patients are <40 years old [1]. Unlike other myeloproliferative neoplasms (MPNs), ET occurs more commonly in women. Consequently, encountering ET in women of reproductive age is not a rare occurrence. Pregnancy and delivery may promote thromboembolism; thus, the perinatal management of patients with ET is becoming an important issue. Although expert consensus and several guidelines describing the management of these patients have been reported [2–6], there are currently no clear guidelines in Japan [7]. Some of the aforementioned guidelines recommend interferon (IFN) therapy for pregnant women with ET who are at a high risk of pregnancy loss. However, IFN is not approved for patients with ET in Japan. Furthermore, because ET is likely to cause thrombotic events, particularly in the postpartum period, low-molecular-weight heparin is commonly administered for 6 weeks after delivery in Europe and the United States. However, it is not indicated for such use in Japan, either. According to aforementioned and other guidelines, the platelet counts of patients with ET increase after delivery [3–6], but many aspects regarding the timing and degree of rebound remain unknown. Few guidelines, including Japanese guidelines [7], mention the optimal blood test interval and therapeutic strategies.
We present a case in which IFN therapy was administered when the platelet count exceeded 1500 × 109/L during late pregnancy. In the present case, the platelet count decreased to approximately 1000 × 109/L immediately after delivery, and cytoreductive therapy was discontinued. However, approximately 2 weeks later, the platelet count markedly rebounded.
2. Case Presentation
The patient was a 38-year-old woman who was referred to our hospital at approximately 7 weeks of gestation for an elevated platelet count detected during a prenatal checkup. She had vaginally delivered her first child at 40 weeks of gestation 8 years earlier and her second child at 39 weeks of gestation 5 years earlier. No abnormalities were observed during the perinatal periods of both pregnancies, and both the patient and her infants were healthy. She had no history of thrombosis or cardiovascular risk factors, such as diabetes mellitus, hypertension, or dyslipidemia, and was a nonsmoker. At her visit, the physical examination failed to identify any abnormal findings or splenomegaly. Blood tests indicated a white blood cell count of 11.4 × 109/L, a hemoglobin level of 14.0 g/dL, a hematocrit level of 40.3%, a platelet count of 1074 × 109/L, and a von Willebrand factor ristocetin cofactor activity (vWFRCo) of 49% (Table 1). At 9 weeks of gestation, a bone marrow biopsy was performed that revealed normocellular bone marrow with an increased number of large to giant megakaryocytes and absence of evidence of reactive thrombocytosis; a diagnosis of ET was made. The presence of driver gene mutations was evaluated, and the patient was negative for all Janus kinase 2 (JAK2V617F), calreticulin (CALR), and myeloproliferative leukemia (MPL) mutations, which suggested that she had the so-called triple-negative ET.
Low-dose aspirin was initiated. Her platelet count decreased as the pregnancy progressed. At 30 weeks of gestation, her platelet count had decreased to 432 × 109/L. Subsequently, her platelet count rapidly rebounded. At 34 weeks of gestation, it exceeded 1500 × 109/L, which suggested that she was at a high risk (Figure 1). We provided sufficient explanation to the patient and obtained informed consent from her. After the approval of the ethics committee of our hospital, IFNα (Sumiferon® Dainippon Sumitomo, Osaka, Japan) was administered at 34 weeks and 2 days of gestation. IFNα was administered at a dose of 3 million units 3 times/week at 34 weeks of gestation and at a dose of 6 million units 3 times/week at 35 weeks. The decrease in the platelet count was insufficient; thus, IFNα was administered at a dose of 6 million units daily beginning at 36 weeks, and the daily dose was subsequently increased to 9 million units. Although no adverse events associated with IFNα were observed, her platelet count decreased to only 1229 × 109/L. Ultimately, the patient underwent emergency cesarean delivery at 37 weeks and 1 day of gestation (low-dose aspirin was switched to unfractionated heparin at 36 weeks of gestation).
The infant weighed 2581 g and had Apgar scores of 7 points at 1 min and 8 points at 5 min. Although the infant exhibited transient tachypnea and was temporarily admitted to the neonatal intensive care unit, there were no apparent complications, and the infant was discharged from our hospital. The platelet count of the infant at birth was 317 × 109/L. After delivery, low-molecular-weight heparin was initiated for the mother, and low-dose aspirin was also resumed. Her platelet count was approximately 1000 × 109/L. Cytoreductive therapy was discontinued temporarily, and we allowed her to breastfeed as per her request. At 18 days after delivery, her platelet count had markedly increased to 3271 × 109/L, and her vWFRCo decreased to 31%. She appeared to have acquired von Willebrand syndrome; thus, we determined that she was at a high risk of bleeding. Administration of low-molecular-weight heparin and low-dose aspirin and breastfeeding were discontinued, and hydroxyurea was initiated as a cytoreductive therapy. Approximately 2 months after delivery when her platelet count reached controllable levels, anagrelide was added. Her platelet count was well controlled; thus, hydroxyurea was discontinued after approximately 3 months of use. At present, her platelet count is controlled at approximately 400 × 109/L with 1.0 mg/day of anagrelide. The results of the gene mutation test after cytoreductive therapy were negative for TET oncogene family number 2 (TET2), additional sex combs like 1 (ASXL1), isocitrate dehydrogenase ½ (IDH1/2), and tumor protein p53 (TP53) mutations.
3. Discussion
Both pregnancy and ET contribute to the risk of thrombosis; thus, pregnant women with ET may be at a higher risk of thrombosis. Additionally, various complications, such as placental infarction, fetal growth restriction, and fetal wastage, can affect not only the mother but also the fetus. Greiesshammer et al. identified case reports of ≥9 pregnancies in ≥4 patients with ET that were published in and after 2000 and analyzed 10 case reports describing pregnancy outcomes [4]. According to their analysis, the live birth rate in pregnant women with ET was almost 70%; the full-term normal delivery rate was lower in pregnant women with ET than in healthy pregnant women, and the rates of spontaneous abortion and stillbirth were higher. These findings cannot be disregarded. High-risk pregnancies in patients with MPN are often defined based on the definitions developed by Greiesshammer et al. [4] and the European LeukemiaNet [2]. Additionally, expert consensus and several guidelines recommend the use of IFNα for high-risk pregnancy [2–6], and the Japanese guidelines also indicate that the use of IFNα should be considered although it is not covered by the National Health Insurance [7]. A previous retrospective study reported that the use of IFNα is an independent factor affecting the live birth rate [8], and a recent systematic review and meta-analysis of pregnant women with MPN also showed that the use of IFN is associated with a high live birth rate [9].
Based on the above discussion, IFNα was used in our patient with due ethical considerations; unfortunately, its effect was insufficient. Her platelet count rapidly increased around 34 weeks of gestation despite increasing the IFNα dose; hence, the IFNα administration period might have been insufficient. Edahiro et al. reported that the median platelet count decreased by approximately 37% from 910 × 109 to 573 × 109/L in seven patients after 2 months of IFNα therapy that was started after the discovery of pregnancy [10]. As our patient received the drug for approximately 1 month, its effect might have been insufficient. Generally, IFNα is thought to exert favorable molecular genetic effects because it can target cells positive for not only JAK2V617F mutations but also CALR and other mutations [11]. However, a report of the use of pegylated IFNα in patients positive for CALR mutations showed that its molecular genetic effects were lower in patients with CALR mutations and in those with mutations of additional genes such as TET2, ASXL1, IDH2, and TP53 [12]. In other words, the sensitivity of IFNα may differ among mutated clones. Moreover, a small-scale study suggests that patients with triple-negative ET may be more resistant to IFNα than patients with JAK2V617F or CALR mutations [10]. According to our tests, our patient did not have any abnormalities of the aforementioned additional genes, but she did have triple-negative ET. Consequently, the effects of IFNα might have been limited.
Finally, we would like to discuss the postpartum rebound of platelet count in our patient. Several review articles have indicated that because platelet counts of patients may again increase to the prepregnancy level [13] or rebound after delivery, cytoreductive therapy should be administered if necessary [3–6]. However, there is insufficient information on when therapeutic interventions are necessary and how they should be performed. It remains unknown whether the platelet count will decrease after some time without treatment if it rebounds. According to our searches in the English literature, some reports indicate that no particular cytoreductive therapy was required after delivery, whereas other reports describe cases in which patients were treated for a rebound of platelet count [14–18]. Sakai et al. reported a case in which the platelet count increased to ≥1000 × 109/L within 3 months after delivery and another case in which the platelet count increased to ≥800 × 109/L within 2 months after delivery. Cytoreductive therapy was resumed in the former case [14]. Iwashita et al. reported a case of a woman, para 2, whose platelet count increased to ≥2000 × 109/L within 1-2 months after delivery in both pregnancies but decreased to approximately 800 × 109 to 900 × 109/L several months later [15]. Although the prepregnancy platelet count affects the postpartum count, one report cited a platelet count increase to a maximum of 3000 × 109/L after delivery [19]. However, we did not identify any patients in the literature with a postpartum platelet count increasing as high as that of our patient. After pregnancy, cytoreductive therapy is rarely required because young women are often at a low risk based on the conventional risk classification for thrombosis [20]. Furthermore, the decision to perform cytoreductive therapy is expected to differ depending on whether the patient will breastfeed their infant after delivery. Thus, individualized treatment should be considered. While we assume that treatment varies depending on the postpartum status of the patients, a certain expert consensus indicates that blood tests should be counted at 6 weeks after delivery [3]. However, caution should be exercised because some women exhibit a rebound of platelet count within 2–4 weeks after delivery, as with our patient and the aforementioned cases [16, 17].
In conclusion, we encountered a patient who exhibited a marked rebound of platelet count soon after delivery. She resumed cytoreductive therapy; the subsequent course was uneventful without any complications. The evidence for the treatment of pregnant women with ET is limited. We hope that management guidelines will be established through the collection of data both during pregnancy and detailed data on the postpartum course.
Data Availability
No data were used in this study.
Conflicts of Interest
Yoshinori Hashimoto reports receiving honoraria from Takeda Pharmaceutical Co., Ltd. The other authors declare that they have no conflicts of interest.
Figure 1 Clinical course and serial changes in the platelet count. MU, million units; VWFRCo, von Willebrand factor ristocetin cofactor activity.
Table 1 Laboratory findings on admission.
Peripheral blood
WBC 11.4 × 109/L
Neu 76.5%
Lym 17.1%
Mon 4.9%
Eos 1.4%
Bas 1.0%
RBC 4.6 × 1012/L
Hb 14.0 g/dL
Hct 40.3%
MCV 86.9 fL
Ret 1.8 × 1012/L
Plt 1074 × 109/L
Chemistry
TP 7.5 g/dL
Alb 4.8 g/dL
T-bil 0.6 mg/dL
AST 18 U/lL
ALT 25 U/L
ALP 117 U/L
LDH 163 U/L
BUN 7.2 mg/dL
Cr 0.4 mg/dL
UA 3.2 mg/dL
Na 135 mEq/L
K 4.3 mEq/L
Coagulation
PT-INR 0.95
APTT 30.2 sec
vWFRCo 49%
Serology
CRP 0.04 mg/dL
Other findings
JAK2V617F <1.0%
MPLW515L (−)
MPLW515K (−)
CALR type1 <1.0%
CALR type2 <1.0%
ABO/Rh A/+
Ret, reticulocyte; VWFRCo, von Willebrand factor ristocetin cofactor activity; JAK2, Janus kinase 2; MPL, myeloproliferative leukemia protein; CALR, calreticulin, ABO/Rh, ABO blood group/Rhesus blood group. | LOW DOSE | DrugDosageText | CC BY | 33614173 | 19,456,283 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Condition aggravated'. | Spontaneous Broad Ligament Hematoma after Vaginal Delivery Requiring Hysterectomy.
Background Broad ligament hematomas are rare in the setting of vaginal delivery. When they do occur, patients typically present with acute hemodynamic instability. No cases of infected broad ligament hematomas have been reported. Case A 22-year-old G2 P1011 status post vaginal delivery complicated by chorioamnionitis and pre-eclampsia presented 5 days postpartum with subjective complaints of fever, vomiting, and increased vaginal bleeding. She was treated with antibiotics and uterine evacuation was planned for presumed retained products. After dilation and curettage, the patient was transferred to our facility, as her clinical status did not improve, and was later found to have an infected broad ligament hematoma requiring hysterectomy. Conclusion Though uncommon, broad ligament hematomas should be considered in postpartum women presenting with anemia and vaginal bleeding, even without hemodynamic instability. Recent intrauterine infections may predispose to hematoma infection.
Teaching Objectives
Describe the clinical presentation for spontaneous broad ligament hematoma after labor.
Describe the recommended medical therapy for spontaneous broad ligament hematoma.
Spontaneous broad ligament hematoma formation occurring during labor is exceedingly rare. Broad ligament hematomas are a known complication during cesarean delivery but spontaneous hematomas during labor or vaginal delivery are uncommon. Spontaneous broad ligament hematomas may result from spontaneous rupture of either branches of the uterine artery or uterine veins and are considered obstetric emergencies resulting in maternal mortality rates as high as 40% when associated with labor.
1
While broad ligament hematomas are a documented consequence of uterine artery or vein rupture, this report is unique because our patient's hematoma was complicated by delayed sepsis and anemia instead of acute hemodynamic changes. This case emphasizes the importance of early recognition and evacuation of infected hematomas to ensure the highest possibility of uterine preservation.
Case Report
We report a case of a 22-year-old G2 P1011 woman who underwent an uncomplicated spontaneous vaginal delivery at 41 weeks and 2 days who subsequently developed sepsis in the setting of a spontaneous broad ligament hematoma. She was admitted to an outside hospital for an induction of labor at term. Her medical history was significant for class 1 obesity, and she had no history of prior uterine or pelvic surgery. Her cervix was unfavorable and she received a combination of misoprostol and Foley balloon catheter for cervical ripening and intravenous oxytocin for labor induction. The intrapartum course was complicated by chorioamnionitis and pre-eclampsia without severe features. The patient received an epidural for anesthesia and antibiotic therapy for chorioamnionitis was initiated. During the delivery admission, her hemoglobin was noted to be 11.7 g/dL at the start of her induction, and there was no objective evidence of hemodynamic instability or abdominal pain during or following the delivery. Her labor lasted ∼40 hours and resulted in a spontaneous vaginal delivery of a 3,870 g infant with a quantitative blood loss of 730 mL. Her postpartum course was uneventful. She remained afebrile and hemodynamically stable and was discharged on the second postpartum day.
The patient then presented to the emergency room 5 days after delivery reporting a 1-day history of fever, nausea, and vomiting, and increased vaginal bleeding. Her initial vital signs were significant for a temperature of 39.5°C, pulse of 144 beats per minute (bpm), and blood pressure of 144/89 mm Hg. Her abdominal exam was significant for exquisite fundal tenderness at the umbilicus, and her pelvic exam revealed a 20-week size uterus and a small amount of clotted blood in the vaginal vault consistent with normal postpartum lochia. The patient's complete blood count was notable for leukocytosis with a white blood count of 17.7 × 10
9
/L, anemia with a hemoglobin of 8.4 g/dL, and a venous lactate of 0.9 mmol/L. Urine analysis results suggested probable contamination, and urine culture showed mixed flora.
An abdominal ultrasound demonstrated a thickened endometrial stripe with some flow signal (
Fig. 1A
) and a heterogenous mass in the left pelvis inseparable from left uterus, favoring an exophytic uterine mass such as fibroid (
Fig. 1B
). The working diagnosis at the time was concerning for endometritis and possible retained products of conception, and she was started on ertapenem and admitted for further monitoring.
Fig. 1
(
A
) Heterogeneous mass measuring 16 × 18.7 × 10.7 cm, with poorly defined cavity and thickened endometrial stripe, concerning for retained products and/or superimposed infection. (
B
) Heterogeneous mass in left pelvis inseparable from presumed uterus that was initially thought to represent an exophytic uterine mass such as fibroid. (
C
) Computed tomography abdomen and pelvis with large hemorrhagic collection in the right pelvis abutting an enlarged and irregularly shaped uterus on the left, concerning for uterine rupture.
After initiation of intravenous antibiotics, the patient became afebrile during the first 24 hours of that admission. However, on hospital day 2, she developed a fever again to 39.5°C, so she was transitioned to meropenem. On hospital day 3, she was noted to have persistent fever, moderate lochia, worsening tachycardia, leukocytosis, and anemia with a decrease in her hemoglobin to 7.0 g/dL, respectively. Hemolysis workup revealed normal haptoglobin and mildly elevated reticulocytes. At that point, blood cultures were ordered and clindamycin was added for group A streptococcus coverage.
Due to concern for retained products possibly being the cause of infection and fall in her hemoglobin levels, the decision was made to proceed to the operating room for an ultrasound-guided dilation and curettage (D&C). During the D&C, scant filmy tissue and a small blood clot were aspirated from the uterine cavity. Despite multiple attempts with sharp curettage, further material was unable to be evacuated. Given the patient's worsening clinical status, inconsistent imaging and difficult D&C revealing minimal to no obvious retained products of conception, the patient was transferred to our tertiary care center for higher level of care.
Upon arrival to our facility, the patient's vitals were concerning for sepsis with a fever to 39.2°C, tachycardia with pulse of 114 bpm, and new oxygen desaturations measured by pulse oximetry that required 8 L/minute oxygen supplementation by nasal canula. Abdominal exam at that time noted significant tenderness to palpation in the right lower quadrant. Pelvic exam revealed no active bleeding. Laboratory findings were significant for persistent leukocytosis and anemia, with lactate and a comprehensive metabolic panel was within normal limits. Chest X-ray demonstrated mild pulmonary edema and trace pleural effusions.
Repeat bedside ultrasonographic assessment revealed that the large heterogeneous mass in the patient's right adnexa was most consistent with a hematoma. Conversely, the mass in the patient's left pelvis was identified to be the uterus, displaced to the left by the hematoma. The contrasted computed tomography demonstrated a large hemorrhagic collection in the pelvis abutting the uterus concerning for potential uterine rupture with a large pelvic hematoma. In addition, significant right sided hydronephrosis was also present. (
Fig. 1C
). Definitive extravasation of blood was not identified.
The patient was consented and scheduled for an emergent exploratory laparotomy for evacuation of hematoma, possible repair of ruptured uterus, and possible hysterectomy.
The patient received meropenem and cefazolin preoperatively. Initial abdominal survey demonstrated an enlarged discolored uterus with a 15 × 15cm right broad ligament hematoma extending into the retroperitoneum to the level of the pelvic brim (
Fig. 2
). The uterine wall in the right lateral uterine segment was friable with weakened tissue integrity upon handling. There was noted to be a large defect in the broad ligament adjacent to where the cervical branch of the right uterine artery would have been. It was suspected that the hematoma was due to spontaneous rupture of the uterine artery in this region that subsequently bled into the broad ligament and retroperitoneal space. The remainder of the abdominal survey did not reveal any other abnormalities.
Fig. 2
Intraoperative broad ligament hematoma (15 × 15 cm).
The blood and clot were evacuated from the hematoma, and no obvious actively bleeding vessel or uterine wall defect was noted. Given the patient's clinical status that suggested a systemic infection and the dusky appearance and friability of the uterus, the decision was made to proceed with a supracervical hysterectomy. In addition, a right ureteral stent was placed by urology intraoperatively for the severe hydroureteronephrosis. Estimated intraoperative blood loss was 550 mL including evacuated blood from the hematoma. She received three units of packed red blood cells during the operation.
After the procedure, the patient was started on vancomycin and piperacillin–tazobactam. She remained afebrile with down-trending white blood cell count and stable hemoglobin for the remainder of the hospitalization. She was discharged on postoperative day 3 with a 7-day course of trimethoprim–sulfamethoxazole, metronidazole, and prophylactic enoxaparin.
Final pathology demonstrated a large organizing hematoma involving the full thickness of the myometrium with acute and chronic inflammation without an identifiable uterine rupture and extensive myometrial necrosis. The patient was followed up in the obstetrics clinic for staple removal and was found to be doing well. Her right ureteral stent was removed in urology clinic 6 weeks following the procedure and repeat imaging demonstrated resolution of the hydronephrosis.
Comment
Broad ligament hematomas are rare in obstetrics, with an incidence of ∼1:20,000,
2
and may occur as a result of operative vaginal or cesarean deliveries or spontaneously due to uterine artery or varices rupture. These hematomas typically form due to vaginal, cervical, or uterine tears extending to the uterine or vaginal arteries. It has been suggested that rapid labor, cesarean section, instrumental deliveries, and trauma may predispose patients to developing these lacerations.
3
When broad ligament hematomas occur spontaneously, they are usually due to vessel rupture, most commonly the uterine artery. Spontaneous uterine artery rupture has been found to cause 40% maternal mortality when associated with labor and may be a result of pronounced blood pressure fluctuations during labor.
1
Hormonal changes during pregnancy may also play a role as well—previous studies have shown that pregnancy-level estrogen, and to a lesser extent progesterone, suppresses intimal proliferation in response to vascular injury,
4
putting vessels at greater risk of rupture. In the majority of cases, patients who developed broad ligament hematomas during labor present with acute hemodynamic instability within hours of delivery.
2
5
6
There have not been any cases reported of broad ligament hematomas complicated by infection.
This case is unique because of our patient's delayed presentation as well the development of an infection progressing to sepsis. Our patient's relatively uneventful vaginal delivery without the need for instrumental assistance along with the intra-operative findings suggests that the cause of her hematoma was due to a spontaneous vessel rupture, likely the uterine artery, which probably occurred during labor or delivery. Her lack of hemodynamic instability suggests that the broad ligament was able to sufficiently contain the resulting hemorrhage and minimize the rate of extravasation, resulting in a delayed presentation. Because red blood cell levels may take up to days to reflect blood loss, diagnosing occult bleeds such as this becomes difficult without suggestive vital sign abnormalities. Though our patient became anemic after her delivery, her hemoglobin drop was appropriate for her quantitative blood loss. Nonetheless, anemia in the postpartum period should carefully evaluated for possible signs of intra-abdominal bleed.
By the time, the patient presented on postpartum day 5, the hematoma had developed to a significant size and had also become infected. It is possible that her peripartum diagnosis of chorioamnionitis increased her risk for developing this infection, as previous studies have shown chorioamnionitis to be associated with increased risk of endomyometritis and pelvic abscesses despite appropriate treatment.
7
Her initial ultrasound findings also noted a flow signal in what was later identified as the hematoma, suggesting a potential for active bleeding.
By the time the patient presented to the tertiary care center, the patient's status worsened and she had developed signs of sepsis. Due to her worsening clinical status and uncertain source of bleeding, she required laparotomy for removal of the source of infection. It is conceivable that if the infected hematoma had been identified earlier prior to her development of sepsis, it may have been possible for the patient to undergo only surgical evacuation of the hematoma, sparing the uterus. Early recognition and hematoma evacuation may have provided greater possibility of uterine preservation in this patient. If the hematoma had been recognized prior to the onset of infection, the patient may have also qualified for more conservative treatments such as uterine arterial embolization.
3
However, because the patient was septic by the time the hematoma was discovered, a laparotomy with hematoma evacuation and hysterectomy was necessary to ensure that the source of infection was adequately removed.
Overall, this case emphasizes the management of a broad ligament hematoma, an obstetric emergency, on the differential for anemia and vaginal bleeding among intra- and postpartum patients. While these cases typically present with hemodynamic instability within hours after delivery, it is also possible for these bleeding episodes to occur at a slower rate without suggestive vital sign abnormalities. Slow changes in red blood cell counts can make this a difficult diagnosis, so any decrease in red blood counts after delivery should be carefully considered. Further, collections of blood in the setting of a recent intrauterine infection may predispose patients to developing a superimposed infection of the blood collection. While it is uncertain whether the uterus can be preserved in these cases, earlier diagnosis and drainage would likely increase the possibility.
Conflict of Interest None. | CLINDAMYCIN, MEROPENEM | DrugsGivenReaction | CC BY-NC-ND | 33614197 | 19,490,006 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Sepsis'. | Spontaneous Broad Ligament Hematoma after Vaginal Delivery Requiring Hysterectomy.
Background Broad ligament hematomas are rare in the setting of vaginal delivery. When they do occur, patients typically present with acute hemodynamic instability. No cases of infected broad ligament hematomas have been reported. Case A 22-year-old G2 P1011 status post vaginal delivery complicated by chorioamnionitis and pre-eclampsia presented 5 days postpartum with subjective complaints of fever, vomiting, and increased vaginal bleeding. She was treated with antibiotics and uterine evacuation was planned for presumed retained products. After dilation and curettage, the patient was transferred to our facility, as her clinical status did not improve, and was later found to have an infected broad ligament hematoma requiring hysterectomy. Conclusion Though uncommon, broad ligament hematomas should be considered in postpartum women presenting with anemia and vaginal bleeding, even without hemodynamic instability. Recent intrauterine infections may predispose to hematoma infection.
Teaching Objectives
Describe the clinical presentation for spontaneous broad ligament hematoma after labor.
Describe the recommended medical therapy for spontaneous broad ligament hematoma.
Spontaneous broad ligament hematoma formation occurring during labor is exceedingly rare. Broad ligament hematomas are a known complication during cesarean delivery but spontaneous hematomas during labor or vaginal delivery are uncommon. Spontaneous broad ligament hematomas may result from spontaneous rupture of either branches of the uterine artery or uterine veins and are considered obstetric emergencies resulting in maternal mortality rates as high as 40% when associated with labor.
1
While broad ligament hematomas are a documented consequence of uterine artery or vein rupture, this report is unique because our patient's hematoma was complicated by delayed sepsis and anemia instead of acute hemodynamic changes. This case emphasizes the importance of early recognition and evacuation of infected hematomas to ensure the highest possibility of uterine preservation.
Case Report
We report a case of a 22-year-old G2 P1011 woman who underwent an uncomplicated spontaneous vaginal delivery at 41 weeks and 2 days who subsequently developed sepsis in the setting of a spontaneous broad ligament hematoma. She was admitted to an outside hospital for an induction of labor at term. Her medical history was significant for class 1 obesity, and she had no history of prior uterine or pelvic surgery. Her cervix was unfavorable and she received a combination of misoprostol and Foley balloon catheter for cervical ripening and intravenous oxytocin for labor induction. The intrapartum course was complicated by chorioamnionitis and pre-eclampsia without severe features. The patient received an epidural for anesthesia and antibiotic therapy for chorioamnionitis was initiated. During the delivery admission, her hemoglobin was noted to be 11.7 g/dL at the start of her induction, and there was no objective evidence of hemodynamic instability or abdominal pain during or following the delivery. Her labor lasted ∼40 hours and resulted in a spontaneous vaginal delivery of a 3,870 g infant with a quantitative blood loss of 730 mL. Her postpartum course was uneventful. She remained afebrile and hemodynamically stable and was discharged on the second postpartum day.
The patient then presented to the emergency room 5 days after delivery reporting a 1-day history of fever, nausea, and vomiting, and increased vaginal bleeding. Her initial vital signs were significant for a temperature of 39.5°C, pulse of 144 beats per minute (bpm), and blood pressure of 144/89 mm Hg. Her abdominal exam was significant for exquisite fundal tenderness at the umbilicus, and her pelvic exam revealed a 20-week size uterus and a small amount of clotted blood in the vaginal vault consistent with normal postpartum lochia. The patient's complete blood count was notable for leukocytosis with a white blood count of 17.7 × 10
9
/L, anemia with a hemoglobin of 8.4 g/dL, and a venous lactate of 0.9 mmol/L. Urine analysis results suggested probable contamination, and urine culture showed mixed flora.
An abdominal ultrasound demonstrated a thickened endometrial stripe with some flow signal (
Fig. 1A
) and a heterogenous mass in the left pelvis inseparable from left uterus, favoring an exophytic uterine mass such as fibroid (
Fig. 1B
). The working diagnosis at the time was concerning for endometritis and possible retained products of conception, and she was started on ertapenem and admitted for further monitoring.
Fig. 1
(
A
) Heterogeneous mass measuring 16 × 18.7 × 10.7 cm, with poorly defined cavity and thickened endometrial stripe, concerning for retained products and/or superimposed infection. (
B
) Heterogeneous mass in left pelvis inseparable from presumed uterus that was initially thought to represent an exophytic uterine mass such as fibroid. (
C
) Computed tomography abdomen and pelvis with large hemorrhagic collection in the right pelvis abutting an enlarged and irregularly shaped uterus on the left, concerning for uterine rupture.
After initiation of intravenous antibiotics, the patient became afebrile during the first 24 hours of that admission. However, on hospital day 2, she developed a fever again to 39.5°C, so she was transitioned to meropenem. On hospital day 3, she was noted to have persistent fever, moderate lochia, worsening tachycardia, leukocytosis, and anemia with a decrease in her hemoglobin to 7.0 g/dL, respectively. Hemolysis workup revealed normal haptoglobin and mildly elevated reticulocytes. At that point, blood cultures were ordered and clindamycin was added for group A streptococcus coverage.
Due to concern for retained products possibly being the cause of infection and fall in her hemoglobin levels, the decision was made to proceed to the operating room for an ultrasound-guided dilation and curettage (D&C). During the D&C, scant filmy tissue and a small blood clot were aspirated from the uterine cavity. Despite multiple attempts with sharp curettage, further material was unable to be evacuated. Given the patient's worsening clinical status, inconsistent imaging and difficult D&C revealing minimal to no obvious retained products of conception, the patient was transferred to our tertiary care center for higher level of care.
Upon arrival to our facility, the patient's vitals were concerning for sepsis with a fever to 39.2°C, tachycardia with pulse of 114 bpm, and new oxygen desaturations measured by pulse oximetry that required 8 L/minute oxygen supplementation by nasal canula. Abdominal exam at that time noted significant tenderness to palpation in the right lower quadrant. Pelvic exam revealed no active bleeding. Laboratory findings were significant for persistent leukocytosis and anemia, with lactate and a comprehensive metabolic panel was within normal limits. Chest X-ray demonstrated mild pulmonary edema and trace pleural effusions.
Repeat bedside ultrasonographic assessment revealed that the large heterogeneous mass in the patient's right adnexa was most consistent with a hematoma. Conversely, the mass in the patient's left pelvis was identified to be the uterus, displaced to the left by the hematoma. The contrasted computed tomography demonstrated a large hemorrhagic collection in the pelvis abutting the uterus concerning for potential uterine rupture with a large pelvic hematoma. In addition, significant right sided hydronephrosis was also present. (
Fig. 1C
). Definitive extravasation of blood was not identified.
The patient was consented and scheduled for an emergent exploratory laparotomy for evacuation of hematoma, possible repair of ruptured uterus, and possible hysterectomy.
The patient received meropenem and cefazolin preoperatively. Initial abdominal survey demonstrated an enlarged discolored uterus with a 15 × 15cm right broad ligament hematoma extending into the retroperitoneum to the level of the pelvic brim (
Fig. 2
). The uterine wall in the right lateral uterine segment was friable with weakened tissue integrity upon handling. There was noted to be a large defect in the broad ligament adjacent to where the cervical branch of the right uterine artery would have been. It was suspected that the hematoma was due to spontaneous rupture of the uterine artery in this region that subsequently bled into the broad ligament and retroperitoneal space. The remainder of the abdominal survey did not reveal any other abnormalities.
Fig. 2
Intraoperative broad ligament hematoma (15 × 15 cm).
The blood and clot were evacuated from the hematoma, and no obvious actively bleeding vessel or uterine wall defect was noted. Given the patient's clinical status that suggested a systemic infection and the dusky appearance and friability of the uterus, the decision was made to proceed with a supracervical hysterectomy. In addition, a right ureteral stent was placed by urology intraoperatively for the severe hydroureteronephrosis. Estimated intraoperative blood loss was 550 mL including evacuated blood from the hematoma. She received three units of packed red blood cells during the operation.
After the procedure, the patient was started on vancomycin and piperacillin–tazobactam. She remained afebrile with down-trending white blood cell count and stable hemoglobin for the remainder of the hospitalization. She was discharged on postoperative day 3 with a 7-day course of trimethoprim–sulfamethoxazole, metronidazole, and prophylactic enoxaparin.
Final pathology demonstrated a large organizing hematoma involving the full thickness of the myometrium with acute and chronic inflammation without an identifiable uterine rupture and extensive myometrial necrosis. The patient was followed up in the obstetrics clinic for staple removal and was found to be doing well. Her right ureteral stent was removed in urology clinic 6 weeks following the procedure and repeat imaging demonstrated resolution of the hydronephrosis.
Comment
Broad ligament hematomas are rare in obstetrics, with an incidence of ∼1:20,000,
2
and may occur as a result of operative vaginal or cesarean deliveries or spontaneously due to uterine artery or varices rupture. These hematomas typically form due to vaginal, cervical, or uterine tears extending to the uterine or vaginal arteries. It has been suggested that rapid labor, cesarean section, instrumental deliveries, and trauma may predispose patients to developing these lacerations.
3
When broad ligament hematomas occur spontaneously, they are usually due to vessel rupture, most commonly the uterine artery. Spontaneous uterine artery rupture has been found to cause 40% maternal mortality when associated with labor and may be a result of pronounced blood pressure fluctuations during labor.
1
Hormonal changes during pregnancy may also play a role as well—previous studies have shown that pregnancy-level estrogen, and to a lesser extent progesterone, suppresses intimal proliferation in response to vascular injury,
4
putting vessels at greater risk of rupture. In the majority of cases, patients who developed broad ligament hematomas during labor present with acute hemodynamic instability within hours of delivery.
2
5
6
There have not been any cases reported of broad ligament hematomas complicated by infection.
This case is unique because of our patient's delayed presentation as well the development of an infection progressing to sepsis. Our patient's relatively uneventful vaginal delivery without the need for instrumental assistance along with the intra-operative findings suggests that the cause of her hematoma was due to a spontaneous vessel rupture, likely the uterine artery, which probably occurred during labor or delivery. Her lack of hemodynamic instability suggests that the broad ligament was able to sufficiently contain the resulting hemorrhage and minimize the rate of extravasation, resulting in a delayed presentation. Because red blood cell levels may take up to days to reflect blood loss, diagnosing occult bleeds such as this becomes difficult without suggestive vital sign abnormalities. Though our patient became anemic after her delivery, her hemoglobin drop was appropriate for her quantitative blood loss. Nonetheless, anemia in the postpartum period should carefully evaluated for possible signs of intra-abdominal bleed.
By the time, the patient presented on postpartum day 5, the hematoma had developed to a significant size and had also become infected. It is possible that her peripartum diagnosis of chorioamnionitis increased her risk for developing this infection, as previous studies have shown chorioamnionitis to be associated with increased risk of endomyometritis and pelvic abscesses despite appropriate treatment.
7
Her initial ultrasound findings also noted a flow signal in what was later identified as the hematoma, suggesting a potential for active bleeding.
By the time the patient presented to the tertiary care center, the patient's status worsened and she had developed signs of sepsis. Due to her worsening clinical status and uncertain source of bleeding, she required laparotomy for removal of the source of infection. It is conceivable that if the infected hematoma had been identified earlier prior to her development of sepsis, it may have been possible for the patient to undergo only surgical evacuation of the hematoma, sparing the uterus. Early recognition and hematoma evacuation may have provided greater possibility of uterine preservation in this patient. If the hematoma had been recognized prior to the onset of infection, the patient may have also qualified for more conservative treatments such as uterine arterial embolization.
3
However, because the patient was septic by the time the hematoma was discovered, a laparotomy with hematoma evacuation and hysterectomy was necessary to ensure that the source of infection was adequately removed.
Overall, this case emphasizes the management of a broad ligament hematoma, an obstetric emergency, on the differential for anemia and vaginal bleeding among intra- and postpartum patients. While these cases typically present with hemodynamic instability within hours after delivery, it is also possible for these bleeding episodes to occur at a slower rate without suggestive vital sign abnormalities. Slow changes in red blood cell counts can make this a difficult diagnosis, so any decrease in red blood counts after delivery should be carefully considered. Further, collections of blood in the setting of a recent intrauterine infection may predispose patients to developing a superimposed infection of the blood collection. While it is uncertain whether the uterus can be preserved in these cases, earlier diagnosis and drainage would likely increase the possibility.
Conflict of Interest None. | CLINDAMYCIN, MEROPENEM | DrugsGivenReaction | CC BY-NC-ND | 33614197 | 19,490,006 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Exposure during pregnancy'. | CT Angiography or Cardiac MRI for Detection of Coronary Artery Aneurysms in Kawasaki Disease.
Background: Kawasaki disease (KD) is an acute vasculitis that mainly affects the coronary arteries. This inflammation can cause coronary artery aneurysms (CAAs). Patients with KD need cardiac assessment for risk stratification for the development of myocardial ischemia, based on Z-score (luminal diameter of the coronary artery corrected for body surface area). Echocardiography is the primary imaging modality in KD but has several important limitations. Coronary computed tomographic angiography (cCTA) and Cardiac MRI (CMR) are non-invasive imaging modalities and of additional value for assessment of CAAs with a high diagnostic yield. The objective of this single center, retrospective study is to explore the diagnostic potential of coronary artery assessment of cCTA vs. CMR in children with KD. Methods and Results: Out of 965 KD patients from our database, a total of 111 cCTAs (104 patients) and 311 CMR (225 patients) have been performed since 2010. For comparison, we identified 54 KD patients who had undergone both cCTA and CMR. CMR only identified eight patients with CAAs compared to 14 patients by cCTA. CMR missed 50% of the CAAs identified by cCTA. Conclusions: Our single center study demonstrates that cCTA may be a more sensitive diagnostic tool to detect CAAs in KD patients, compared to CMR.
Introduction
Kawasaki disease (KD) is an acute vasculitis of the medium-and-small-sized arteries of unknown etiology. To date, KD is the most common acquired pediatric heart disease in Western society (1). The vasculitis mainly affects the coronary arteries and the inflammation can cause coronary artery aneurysms (CAAs). Due to the formation of CAAs, CAA-related secondary complications can occur such as thrombosis, calcification, and stenosis/occlusion which can lead to myocardial ischemia. The occurrence of stenosis and thrombosis may well be inherent to the size of the CAA (2). Currently, echocardiography is used as the primary imaging modality in KD, and is a good first, rapid, and non-invasive screening tool in the acute phase. According to the American Heart Association (AHA) guidelines of 2017, additional imaging should be considered during follow-up after the patient has been categorized (by echocardiography) with a CAA (Z-score ≥ 2.5) (3), due to an associated increased risk for myocardial ischemia. This is where the Japanese Circulation Society (JCS) differs in their recommendations from the AHA. Low diagnostic accuracy of echocardiography due to limited visualization of distal coronary segments may result in underestimation of the CAA burden and may increase the risk for secondary complications (4). Therefore, the JCS suggests performing additional imaging in the convalescent phase (5) for a more accurate categorization of CAA severity.
Invasive Coronary Angiography (CAG), coronary computed tomographic angiography (cCTA) and Cardiac MRI (CMR) have been suggested as alternatives complementary to echocardiography by the AHA guidelines of 2017. Invasive CAG is not routinely used because of its invasive nature and risk of complications. In a recent overview, the need for guidance for the long-term management of KD patients was emphasized, suggesting non-invasive modalities such as echocardiography and CMR, and only when other modalities cannot be used, to consider low radiation dose computed tomography (CT) (6). As the limitations of echocardiography are known, we have been performing additional imaging such as cCTA and CMR, in selected patients in our national referral center (7). In our previous study we have demonstrated the relevance of routine additional imaging for coronary artery assessment by evaluating echocardiography and cCTA for the detection of CAAs, secondary coronary artery pathology, and radiation exposure (4). In the current study, we took the approach to investigate CAA detection with cCTA and CMR, if imaging results were both available in the same patient during follow-up. The aim of this retrospective single-center study is to compare the diagnostic yield of cCTA and CMR in clinical practice for the detection of CAAs in KD patients.
Methods
Study Population
Patients that met the AHA diagnostic criteria for KD, and presented to the follow-up of the national referral center for KD in the Netherlands and underwent CMR and cCTA between the year 2008 and 2020, were retrospectively included in this study. The AHA diagnostic criteria for KD are: persistent fever for ≥5 days and ≥4 of the five clinical features (rash, conjunctivitis, cervical lymphadenopathy, oral changes, and extremity changes) in the case of complete KD and, for incomplete KD, if fewer than 4 of the clinical features with prolonged unexplained fever and compatible echocardiography and/or laboratory findings are present. As cCTA and CMR are not part of the routine cardiac assessment in patients with KD, these patients are a selected subset of the KD population. The majority of these patients had been previously diagnosed with CAA upon echocardiography. It is exactly this group of patients (with proximal coronary artery pathology upon echocardiography) that has the risk for potentially missed distal coronary artery involvement upon echocardiography, since the patients with no proximal involvement have no reports on having distal involvement (4). The primary objectives for additional imaging in these patients were: i.e., to verify whether CAAs could be missed in the distal parts of the coronary arteries, beyond the window of inspection by echocardiography, and—at the same time—to look for secondary coronary artery pathology (such as stenosis, occlusion, calcification, or thrombus formation). Beta-blockers were used if patients were older than the age of 12 and had a heart rate above 70–75 beats per minute (BPM) prior to the imaging. Clinical information about the acute phase and of the follow-up was extracted from medical records. Institutional Review Board approval was obtained.
CMR
Magnetic resonance imaging (MRI) images were acquired using a 1.5-T whole body MRI scanner with cardiac software (Siemens, Magnetom, Avanto; Siemens, Erlangen, and Germany). The imaging protocol included a navigator gated, ECG-triggered, non-contrast enhanced magnetic resonance coronary angiography (MRA) series, using a 3D echo time (TE)/repetition time (TR) optimized steady state free precession sequence with a fat saturated prepulse and T2 preparation (FOV 340–400 mm, base resolution 288 pixels. This resulted in a 3D image with a resolution of ~0.6 × 0.6 × 1.0 mm/pixel, encompassing the entire coronary tree. Acceptance window of the navigator was set to 2 mm. ECG triggering was set to the period of diastasis in the heart cycle. Imaging results were discussed in a multi-disciplinary team, consisting of a radiologist, cardiologist, pediatric cardiologist, and pediatric immunologist (all with expertise in KD).
cCTA
For cCTA a dual-source 2 × 192-slice multidetector CT scanner (Siemens Somatom Force, Erlangen, Germany) was used from November 2015. Before 2015, the cCTA images were acquired using a 64-slice CT scanner (Philips, Brilliance64). For both scanners a prospective ECG-triggered step-and-shoot protocol was used and images were reconstructed with a slice-thickness of 0.6 and 0.9 mm, respectively. Contrast medium (Ultravist 300 mg/ml, Bayer Healthcare Pharmaceuticals) was administered intravenously. The total iodine dose and iodine delivery rate were adjusted for body weight. The scan delay was determined using a test bolus, after which 4 s were added for the scan delay of the main bolus. A multidisciplinary team including a radiologist, cardiologist, pediatric cardiologist, and pediatric immunologist (with expertise in KD) discussed the results, as reported previously (4).
Measurements
Coronary artery diameters were measured and the CAAs Z-score was calculated according to the McCrindle/Boston model (8). There is no current alternative to the standardized measures of CAA obtained by echocardiography (9). Hence, we have used these values as the best available substrate, recognizing that they are obtained by measuring different components of the coronary arteries (internal appearance of wall to wall on echocardiography, rather than luminal diameter of contract on cCTA/CMR). A Z-score ≥ 3 was considered to be an aneurysm (as compared to a Z-score ≥ 2.5, which is normally used). By using a cut-off of a Z-score ≥ 3 instead of a Z-score ≥ 2.5 we aimed to increase specificity because a Z-score ≥ 2.5 in 1 coronary artery branch occurs in 0.6% of afebrile children and a Z-score ≥ 3.0 occurs in 0.1% (3). Also a study found that coronary artery dimensions in febrile children (non-KD) are larger than those in afebrile children, but smaller than in febrile KD patients (9). Even though not performed at the same age, majority of the imaging took place in the stable phase of the disease (i.e., more than 2 years after onset of disease) when remodeling is not expected anymore. Thereafter, discrepancies in outcome (number of detected CAAs) were considered the result of a lack of diagnostic accuracy. The left main coronary artery (LMCA), left anterior descending artery (LAD), right coronary artery (RCA), and circumflex (Cx) were evaluated. A CAA in the Cx was defined as luminal diameter ≥ 4.0 mm (10). Not only luminal dimensions were visualized, also myocardial ischemia, vascular stenosis, occlusion, vessel wall calcification and intravascular thrombosis were reported. Stenosis was defined as a narrowed lumen which influences the blood flow while an occlusion is a complete blockage of the lumen with no reserve flow. When on CMR, the coronary arteries were not visualized distinctly enough to make accurate and reliable measurements, coronary arteries were classified as NORMAL/ABNORMAL by two independent radiologists, blinded for the initial echocardiography and any additional imaging.
Statistics
We generated demographic characteristics of KD patients who underwent both cCTA and CMR, presented as numbers with percentages and, where appropriate, with their mean or median and ranges (Table 1).
Table 1 Demographics and characteristics of 54 KD patients with imaging performed both by cCTA and CMR.
Demographics n = 54 Remarks
Male n = 43
Female n = 11
Age in years at onset KD (median, range) 3.1 (0.12–11.15) Age-at-onset was unknown in two patients.
Missed diagnosis, no treatment n = 7 No treatment (IVIG/prednisone) received in seven cases, of which two did receive ASA.
Day of treatment after onset of fever (median, range) 8 (4–26) In 2 patients the day of treatment was unclear.
Treatment > 10 days after fever onset n = 11
Non-responder to 1st IVIG n = 11 Persistent fever > 48 h after IVIG treatment.
ΔTime in years (time between CMR and cCTA) (median, range) 3 (0–7) In 3 patients the cCTA was performed after the CMR. ΔTime in years (time between cCTA and CMR) for these patients was 1, 1, and 4 years.
CAA Z-score acute stage
• Z-score > 10* (giant) n = 12
• Z-score 3–10* (small- to medium-sized aneurysms) n = 13
• Z-score <3* (no aneurysm) n = 23
• Unknown n = 6
* CAA status is based on prior echocardiography results in the acute phase of KD.
Results
Study Population
We collected the cCTA and CMR results from 54 pediatric KD patients who had undergone both imaging techniques during the follow-up and we compared the imaging results retrospectively, of which nine were performed before 2015. All of the CMRs were executed prior to cCTA, except for three cases. The majority of the study population in which both cCTA and CMR scanning has been performed, was male (80%). The median age at onset of disease was 3.1 years (range 0.12–11.15). A total of 12 patients (22%) had giant aneurysms (Z-score ≥ 10) following the acute presentation with clinical KD (Table 1). Classic KD diagnosis presenting with ≥4 of the 5 principal clinical features was present in the majority of cases (74%), incomplete KD was present in a minority (20%), and in the remaining three patients (6%) the clinical features at the acute stage of the disease were unknown. Most patients had been treated adequately with oral acetylsalicylic acid (ASA) and high-dose intravenous immunoglobulin (IVIG) [once (67%), or twice (20%)], whereas a minority of cases (13%) was initially missed and did not receive any treatment. The difference in median age for cCTA when compared to CMR [16.5 years (1–59) vs. 12 years (0–57)], medians, and ranges), is in part explained by the earlier availability of the non-invasive CMR modality whereas the third generation dual-source cCTA only became available in 2015. Anesthesia was used in two patients for CMR as well as for cCTA because of their young age. The remaining patients were scanned while conscious and alert, medication to manage heart rhythm (i.e., beta-blockers) were not routinely used, only when the heart rate exceeded 70–75 beats per minute. The two patients with a history of coronary artery bypass grafting (CABG) were excluded from analysis.
CAA Detection
With respect to the accuracy of coronary abnormalities we identified a total of 30 CAAs in 14 patients upon cCTA against 15 CAAs upon CMR in eight patients (Table 2). When the CAAs, visualized by cCTA were considered valid and true, the distribution of CAAs missed by CMR was as followed: four CAAs in the LMCA, three CAAs in the RCA, seven CAAs in the LAD, and one CAA in the Cx. There was no clear cut-off in diameter above which the CMR was able to detect the CAAs (Table 3), but predominantly determined by imaging quality overall instead.
Table 2 Total CAAs detected by cCTA vs CMR.
Coronary artery CAA on cCTA CAA on CMR
LMCA 7 3
RCA 12 7
LAD 10 3
Cx 1 0
Table 3 CAAs missed by CMR, with accompanying Z-scores calculated from the luminal diameters acquired by cCTA.
LMCA in mm (Z score) RCA in mm (Z-score) LAD in mm (Z-score) Cx in mm
5 (1.25)a 4 (3.3) 4 (3.0) 7
6 (4.26) 7.4 (9.15) 4 (2.52)b
6 (3.88) 6.4 (7.69)
9 (29.92)
7 (6.52)
5 (3.07)
a Patient was overweight (BMI 35.1) which strongly affected the calculation of his Z-score.
b Borderline Z-score of 2.52, but with an irregular wall and an internal diameter of >1.5 times that of the adjacent segment, hence counted as CAA.
In one patient, the CMR detected four CAAs in the RCA and one CAA in the Cx, while the cCTA detected only three CAAs in the RCA and a normal Cx. The delay between CMR and cCTA was 10 months. A month prior to the cCTA a CAG was performed, the results of the CAG were in concordance with the cCTA. Imaging in this patient was performed in the 1st year after onset of disease [also referred to as the dynamic phase (4, 11)] therefore, this discrepancy is most likely due to remodeling.
The CMR detected CAAs in three patients which actually had no CAAs in the coronary artery tree upon cCTA (neither in echocardiography) whereas the CMR detected a CAA in the LAD (1 patient) and in the Cx (2 patients). The delay between CMR and cCTA was 61, 67, and 59 months. However, imaging in these patients was performed long after onset of disease (>2 years), also referred to as the static phase (4), making the contribution of remodeling or normalization much less likely as the explanation for these discrepancies.
cCTA and CMR; Logistics and Failure Rates
Diagnostic failure rates to accurately assess the presence of vascular lesions in these patients by either cCTA or CMR were 9.6% (a total of nine coronary arteries were failed to visualize in five patients) and 59.6% (a total of 108 coronary arteries were failed to visualize in 31 patients), respectively, when both modalities were compared with each other. The main reason that CMR data acquisition failed to accurately assess the presence of a vascular lesion and therefore 1 or more coronary arteries could not be interpreted, more often than in cCTA, was due to motion artifacts caused by (i.e.,) irregular breathing and insufficient image quality; all but two patients were subsequently assessed successfully by cCTA. The cCTA gave insufficient results in five cases (without anesthesia) because of motion artifact (4) and so-called “streaking” due to beam hardening and scatter (1). In three patients the coronary artery segments which were visualized insufficiently by cCTA could be assessed by CMR or echocardiography and were unaffected. In the other two patients the Cx was not visualized well-enough either by cCTA, CMR and echocardiography. These latter two patients had no history of CAAs in any of the other coronary branches though.
CAA-Related Secondary Complications
Imaging by cCTA was able to detect additional vascular pathology in nine patients with coronary features such as calcification (n = 8), stenosis (n = 4), occlusion (n = 1) which were not observed by routine CMR. Coronary artery thrombosis (n = 3) was detected only once by CMR. In three patients CMR enabled us to identify myocardial infarction, cCTA revealed signs of myocardial infarction in two of these patients but with much less accuracy.
Clinical Repercussions
As a consequence of the insufficient performance of CMR, of the eight patients diagnosed with CAA upon CMR, four patients had a second or third CAA that were identified by cCTA and not by CMR. This did not lead to a change of CAA classification, in other words, the missed CAA did not exceed the other visible CAA in Z-score and therefore did not have clinical repercussions. CMR missed CAAs in three additional patients because of diagnostic failure (mainly due to motion artifact as mentioned before) which led to subsequent imaging by cCTA. Of these, one patient needed to start acetylsalicylic acid based on the new results of the cCTA. Finally, in the last three patients redefinition by cCTA of initially missed CAAs led to a different classification, i.e., from “no CAA” to “small CAA” in two patients and near giant CAA (Z-score 9.15) in one patient (Figure 1, Table 3). This last patient needed to start acetylsalicylic acid and also underwent subsequent CMR cardiac stress testing to detect possible myocardial damage, as she was pregnant at the moment of redefinition by cCTA, which showed no myocardial ischemia.
Figure 1 cCTA imaging (a) and CMR imaging (b) of KD patient with near giant CAA (*) in RCA. Calcification and partial coronary artery thrombus are only visible upon cCTA.
Discussion
Our study in KD indicates that cCTA is the better modality to assess the coronary artery lesions in clinical practice when compared to CMR, and can be used for a more precise risk stratification and monitoring during follow-up of patients.
Third generation dual-source cCTA has proven to be of great value for the evaluation of the luminal diameter of the coronary artery compared to invasive coronary angiography in adults (12, 13) and in KD patients (14) as well as the detection of CAAs and CAA-related secondary complications in KD (4, 15–17). The strength of cCTA lies predominantly in visualizing the anatomy and therefore to detect aneurysms, stenosis, calcification, and thrombosis. Other benefits of the third dual-source cCTA are the low radiation exposure and fast acquisition time leading to a lower burden on the pediatric population. Therefore, third generation dual-source cCTA appears to be a good candidate for coronary artery assessment in KD, i.e., risk stratification for the development of myocardial ischemia. However, CMR does not expose patients to radiation, unlike CT imaging and CAG. There is consensus that radiation exposure (due to imaging), is associated with an increase in lifetime cancer risk, especially in children and should be kept to a minimum (18, 19). Recent guidelines consider this radiation exposure and therefore mention CMR as a good imaging technique in KD (6), however, our data suggest cCTA is the more preferred modality for the visualization vascular morphology, thrombus formation and calcified lesions. CMR is valuable to visualize tissue characteristics and physiology, and has been used to demonstrate and in particular ischemia and tissue damage following myocardial infarction in KD (20, 21). Other imaging methods to evaluate cardiac function are being investigated as well (22). Current development in CT scanning techniques may enable cardiac function assessment in the future at low-dose radiation exposure (23, 24), but to date however, CMR remains the most suitable and best imaging modality for the evaluation of cardiac function and for detection of ischemia and infarction.
Differences in applicability and accuracy between CMR and cCTA have been described in the past in adults with coronary artery disease (CAD) (25). These patients mainly presented with obstructive CAD due to plaque formation and may not be comparable with our pediatric population with KD. Previous studies have attempted to determine the clinical applicability of either CT or CMR for the risk stratification (4, 12–17, 21, 26–29), but there are no comparative imaging studies available for KD to date.
Upon comparison of both modalities in daily practice, our data shows that cCTA outperforms CMR in the detection of CAAs. CMR showed a higher diagnostic failure rate for coronary artery assessment mainly due to motion artifacts caused by protracted acquisition time, compared to cCTA (respectively, 59.6 vs. 9.6%). To note, suboptimal images were rated as “diagnostic failure,” as these suboptimal images led to the under-reporting of CAAs. The CAAs missed by CMR were more frequently localized in the LAD, followed by the LCA and RCA; of which three were missed because of inadequate performance.
Because echocardiography also had not been able to detect these CAAs, two patients went undertreated for 5 and 2 years, until their medium-sized CAAs were detected and oral medication was (re)started. In four patients, the CAA classification changed from normal to “small CAA,” which needed no further medication. The four patients in whom additional CAAs were detected that had been missed upon CMR, were already taking oral aspirin, but will be monitored by repeated cCTA during follow-up as a consequence. Important factors that contribute in the higher CAA detection rate by cCTA are high spatial resolution of the cCTA (0.6 mm/pixel vs. 0.6 × 0.6 × 1 mm/pixel in MRI), and high temporal resolution. This higher spatial resolution also contributes to the detection of additional coronary artery pathology (i.e., calcification, stenosis, and thrombosis), while CMR was inaccurate or unable to do so. These CAA-related secondary complications are relevant to be properly diagnosed for treatment considerations during follow-up. Another important factor for accurate coronary artery assessment is heart rate. A higher heart rate is a disadvantage for accurate coronary artery assessment. In our study, the average age of the children undergoing cCTA, and as a consequence their heart rate (since younger children on average have a higher heart rate than older children), was higher than in those that were imaged by CMR. Instead of the heart rate at start, longer acquisition time, and variability in heart rate upon CMR is probably the reason for a higher failure rate and lack of sufficient accuracy in CAA detection in KD. Stricter regulation of heart rate, managed by beta-blockers, could improve the diagnostic accuracy of CMR.
Limitations
Retrospective analysis introduces variation of the data, having not been systematically collected in a predefined prospective manner. In our case, patients have been selected based on the prerequisite of having complementary imaging with both CMR and cCTA data available in the same patients. Most often these patients were known to have CAAs as previously visualized in the (sub)acute stage upon echocardiography. Thus, our patient cohort does not represent a normal unselected KD population. This, however, may not be a disadvantage because it is exactly this subgroup of patients that should be routinely monitored more closely. Despite the fact that most imaging was performed in the stable phase in which remodeling of coronary artery lesions is not expected anymore, the delay between both imaging techniques may have been of influence on our results. Since there were no luminal diameters available for some of the coronary arteries on CMR, the arteries were scored as “normal” or “abnormal” based on the experienced eye. This approach was considered the most realistic for subsequent comparisons between the two imaging groups (i.e., cCTA and CMR). The inability to measure the exact coronary artery diameter on CMR supports our first suspicion that CMR could have a lower diagnostic accuracy compared to cCTA.
Finally, we calculated the Z-scores using the McCrindle/Boston model, although not formally validated for being used for imaging by cCTA and CMR.
Conclusion
Our study in KD shows that cCTA is an excellent imaging modality to assess the coronary artery tree at great resolution. cCTA detects CAAs more frequent and with greater detail when compared to CMR. Therefore, we recommend to perform cCTA in addition to echocardiography in CAA positive KD patients to detect and classify CAAs.
Data Availability Statement
The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.
Ethics Statement
Ethical review and approval was not required for the study on human participants in accordance with the local legislation and institutional requirements. Written informed consent to participate in this study was provided by the participants' legal guardian/next of kin.
Author Contributions
DS-BD conceptualized the study, collected data, and drafted the initial manuscript. IK and TK contributed equally as co-senior authors and conceptualized the study, coordinated, and supervised data collection and reviewed the manuscript for important intellectual content and revised the manuscript. NP conceptualized the study and reviewed for important intellectual content and revised the manuscript. All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
We are grateful to Dr. M. van den Hof for statistical advice.
Abbreviations
AHA American Heart Association
ASA acetylsalicylic acid
BPM beats per minute
CAAs Coronary artery aneurysms
CABG coronary artery bypass grafting
CAD coronary artery disease
CAG coronary angiography
cCTA coronary computed tomographic angiography
CMR cardiac magnetic resonance imaging
CT computed tomography
Cx circumflex
IVIG intravenous immunoglobulin
JCS Japanese Circulation Society
KD Kawasaki disease
LAD left anterior descending artery
LMCA left main coronary artery
MRA magnetic resonance coronary angiography
MRI magnetic resonance imaging
RCA right coronary artery
TE echo time
TR repetition time.
Funding. The funding was made available by the foundation Kind en Handicap and an anonymous donor through the AMC foundation. | ASPIRIN, IOPROMIDE | DrugsGivenReaction | CC BY | 33614558 | 19,727,701 | 2021 |
What was the dosage of drug 'IOPROMIDE'? | CT Angiography or Cardiac MRI for Detection of Coronary Artery Aneurysms in Kawasaki Disease.
Background: Kawasaki disease (KD) is an acute vasculitis that mainly affects the coronary arteries. This inflammation can cause coronary artery aneurysms (CAAs). Patients with KD need cardiac assessment for risk stratification for the development of myocardial ischemia, based on Z-score (luminal diameter of the coronary artery corrected for body surface area). Echocardiography is the primary imaging modality in KD but has several important limitations. Coronary computed tomographic angiography (cCTA) and Cardiac MRI (CMR) are non-invasive imaging modalities and of additional value for assessment of CAAs with a high diagnostic yield. The objective of this single center, retrospective study is to explore the diagnostic potential of coronary artery assessment of cCTA vs. CMR in children with KD. Methods and Results: Out of 965 KD patients from our database, a total of 111 cCTAs (104 patients) and 311 CMR (225 patients) have been performed since 2010. For comparison, we identified 54 KD patients who had undergone both cCTA and CMR. CMR only identified eight patients with CAAs compared to 14 patients by cCTA. CMR missed 50% of the CAAs identified by cCTA. Conclusions: Our single center study demonstrates that cCTA may be a more sensitive diagnostic tool to detect CAAs in KD patients, compared to CMR.
Introduction
Kawasaki disease (KD) is an acute vasculitis of the medium-and-small-sized arteries of unknown etiology. To date, KD is the most common acquired pediatric heart disease in Western society (1). The vasculitis mainly affects the coronary arteries and the inflammation can cause coronary artery aneurysms (CAAs). Due to the formation of CAAs, CAA-related secondary complications can occur such as thrombosis, calcification, and stenosis/occlusion which can lead to myocardial ischemia. The occurrence of stenosis and thrombosis may well be inherent to the size of the CAA (2). Currently, echocardiography is used as the primary imaging modality in KD, and is a good first, rapid, and non-invasive screening tool in the acute phase. According to the American Heart Association (AHA) guidelines of 2017, additional imaging should be considered during follow-up after the patient has been categorized (by echocardiography) with a CAA (Z-score ≥ 2.5) (3), due to an associated increased risk for myocardial ischemia. This is where the Japanese Circulation Society (JCS) differs in their recommendations from the AHA. Low diagnostic accuracy of echocardiography due to limited visualization of distal coronary segments may result in underestimation of the CAA burden and may increase the risk for secondary complications (4). Therefore, the JCS suggests performing additional imaging in the convalescent phase (5) for a more accurate categorization of CAA severity.
Invasive Coronary Angiography (CAG), coronary computed tomographic angiography (cCTA) and Cardiac MRI (CMR) have been suggested as alternatives complementary to echocardiography by the AHA guidelines of 2017. Invasive CAG is not routinely used because of its invasive nature and risk of complications. In a recent overview, the need for guidance for the long-term management of KD patients was emphasized, suggesting non-invasive modalities such as echocardiography and CMR, and only when other modalities cannot be used, to consider low radiation dose computed tomography (CT) (6). As the limitations of echocardiography are known, we have been performing additional imaging such as cCTA and CMR, in selected patients in our national referral center (7). In our previous study we have demonstrated the relevance of routine additional imaging for coronary artery assessment by evaluating echocardiography and cCTA for the detection of CAAs, secondary coronary artery pathology, and radiation exposure (4). In the current study, we took the approach to investigate CAA detection with cCTA and CMR, if imaging results were both available in the same patient during follow-up. The aim of this retrospective single-center study is to compare the diagnostic yield of cCTA and CMR in clinical practice for the detection of CAAs in KD patients.
Methods
Study Population
Patients that met the AHA diagnostic criteria for KD, and presented to the follow-up of the national referral center for KD in the Netherlands and underwent CMR and cCTA between the year 2008 and 2020, were retrospectively included in this study. The AHA diagnostic criteria for KD are: persistent fever for ≥5 days and ≥4 of the five clinical features (rash, conjunctivitis, cervical lymphadenopathy, oral changes, and extremity changes) in the case of complete KD and, for incomplete KD, if fewer than 4 of the clinical features with prolonged unexplained fever and compatible echocardiography and/or laboratory findings are present. As cCTA and CMR are not part of the routine cardiac assessment in patients with KD, these patients are a selected subset of the KD population. The majority of these patients had been previously diagnosed with CAA upon echocardiography. It is exactly this group of patients (with proximal coronary artery pathology upon echocardiography) that has the risk for potentially missed distal coronary artery involvement upon echocardiography, since the patients with no proximal involvement have no reports on having distal involvement (4). The primary objectives for additional imaging in these patients were: i.e., to verify whether CAAs could be missed in the distal parts of the coronary arteries, beyond the window of inspection by echocardiography, and—at the same time—to look for secondary coronary artery pathology (such as stenosis, occlusion, calcification, or thrombus formation). Beta-blockers were used if patients were older than the age of 12 and had a heart rate above 70–75 beats per minute (BPM) prior to the imaging. Clinical information about the acute phase and of the follow-up was extracted from medical records. Institutional Review Board approval was obtained.
CMR
Magnetic resonance imaging (MRI) images were acquired using a 1.5-T whole body MRI scanner with cardiac software (Siemens, Magnetom, Avanto; Siemens, Erlangen, and Germany). The imaging protocol included a navigator gated, ECG-triggered, non-contrast enhanced magnetic resonance coronary angiography (MRA) series, using a 3D echo time (TE)/repetition time (TR) optimized steady state free precession sequence with a fat saturated prepulse and T2 preparation (FOV 340–400 mm, base resolution 288 pixels. This resulted in a 3D image with a resolution of ~0.6 × 0.6 × 1.0 mm/pixel, encompassing the entire coronary tree. Acceptance window of the navigator was set to 2 mm. ECG triggering was set to the period of diastasis in the heart cycle. Imaging results were discussed in a multi-disciplinary team, consisting of a radiologist, cardiologist, pediatric cardiologist, and pediatric immunologist (all with expertise in KD).
cCTA
For cCTA a dual-source 2 × 192-slice multidetector CT scanner (Siemens Somatom Force, Erlangen, Germany) was used from November 2015. Before 2015, the cCTA images were acquired using a 64-slice CT scanner (Philips, Brilliance64). For both scanners a prospective ECG-triggered step-and-shoot protocol was used and images were reconstructed with a slice-thickness of 0.6 and 0.9 mm, respectively. Contrast medium (Ultravist 300 mg/ml, Bayer Healthcare Pharmaceuticals) was administered intravenously. The total iodine dose and iodine delivery rate were adjusted for body weight. The scan delay was determined using a test bolus, after which 4 s were added for the scan delay of the main bolus. A multidisciplinary team including a radiologist, cardiologist, pediatric cardiologist, and pediatric immunologist (with expertise in KD) discussed the results, as reported previously (4).
Measurements
Coronary artery diameters were measured and the CAAs Z-score was calculated according to the McCrindle/Boston model (8). There is no current alternative to the standardized measures of CAA obtained by echocardiography (9). Hence, we have used these values as the best available substrate, recognizing that they are obtained by measuring different components of the coronary arteries (internal appearance of wall to wall on echocardiography, rather than luminal diameter of contract on cCTA/CMR). A Z-score ≥ 3 was considered to be an aneurysm (as compared to a Z-score ≥ 2.5, which is normally used). By using a cut-off of a Z-score ≥ 3 instead of a Z-score ≥ 2.5 we aimed to increase specificity because a Z-score ≥ 2.5 in 1 coronary artery branch occurs in 0.6% of afebrile children and a Z-score ≥ 3.0 occurs in 0.1% (3). Also a study found that coronary artery dimensions in febrile children (non-KD) are larger than those in afebrile children, but smaller than in febrile KD patients (9). Even though not performed at the same age, majority of the imaging took place in the stable phase of the disease (i.e., more than 2 years after onset of disease) when remodeling is not expected anymore. Thereafter, discrepancies in outcome (number of detected CAAs) were considered the result of a lack of diagnostic accuracy. The left main coronary artery (LMCA), left anterior descending artery (LAD), right coronary artery (RCA), and circumflex (Cx) were evaluated. A CAA in the Cx was defined as luminal diameter ≥ 4.0 mm (10). Not only luminal dimensions were visualized, also myocardial ischemia, vascular stenosis, occlusion, vessel wall calcification and intravascular thrombosis were reported. Stenosis was defined as a narrowed lumen which influences the blood flow while an occlusion is a complete blockage of the lumen with no reserve flow. When on CMR, the coronary arteries were not visualized distinctly enough to make accurate and reliable measurements, coronary arteries were classified as NORMAL/ABNORMAL by two independent radiologists, blinded for the initial echocardiography and any additional imaging.
Statistics
We generated demographic characteristics of KD patients who underwent both cCTA and CMR, presented as numbers with percentages and, where appropriate, with their mean or median and ranges (Table 1).
Table 1 Demographics and characteristics of 54 KD patients with imaging performed both by cCTA and CMR.
Demographics n = 54 Remarks
Male n = 43
Female n = 11
Age in years at onset KD (median, range) 3.1 (0.12–11.15) Age-at-onset was unknown in two patients.
Missed diagnosis, no treatment n = 7 No treatment (IVIG/prednisone) received in seven cases, of which two did receive ASA.
Day of treatment after onset of fever (median, range) 8 (4–26) In 2 patients the day of treatment was unclear.
Treatment > 10 days after fever onset n = 11
Non-responder to 1st IVIG n = 11 Persistent fever > 48 h after IVIG treatment.
ΔTime in years (time between CMR and cCTA) (median, range) 3 (0–7) In 3 patients the cCTA was performed after the CMR. ΔTime in years (time between cCTA and CMR) for these patients was 1, 1, and 4 years.
CAA Z-score acute stage
• Z-score > 10* (giant) n = 12
• Z-score 3–10* (small- to medium-sized aneurysms) n = 13
• Z-score <3* (no aneurysm) n = 23
• Unknown n = 6
* CAA status is based on prior echocardiography results in the acute phase of KD.
Results
Study Population
We collected the cCTA and CMR results from 54 pediatric KD patients who had undergone both imaging techniques during the follow-up and we compared the imaging results retrospectively, of which nine were performed before 2015. All of the CMRs were executed prior to cCTA, except for three cases. The majority of the study population in which both cCTA and CMR scanning has been performed, was male (80%). The median age at onset of disease was 3.1 years (range 0.12–11.15). A total of 12 patients (22%) had giant aneurysms (Z-score ≥ 10) following the acute presentation with clinical KD (Table 1). Classic KD diagnosis presenting with ≥4 of the 5 principal clinical features was present in the majority of cases (74%), incomplete KD was present in a minority (20%), and in the remaining three patients (6%) the clinical features at the acute stage of the disease were unknown. Most patients had been treated adequately with oral acetylsalicylic acid (ASA) and high-dose intravenous immunoglobulin (IVIG) [once (67%), or twice (20%)], whereas a minority of cases (13%) was initially missed and did not receive any treatment. The difference in median age for cCTA when compared to CMR [16.5 years (1–59) vs. 12 years (0–57)], medians, and ranges), is in part explained by the earlier availability of the non-invasive CMR modality whereas the third generation dual-source cCTA only became available in 2015. Anesthesia was used in two patients for CMR as well as for cCTA because of their young age. The remaining patients were scanned while conscious and alert, medication to manage heart rhythm (i.e., beta-blockers) were not routinely used, only when the heart rate exceeded 70–75 beats per minute. The two patients with a history of coronary artery bypass grafting (CABG) were excluded from analysis.
CAA Detection
With respect to the accuracy of coronary abnormalities we identified a total of 30 CAAs in 14 patients upon cCTA against 15 CAAs upon CMR in eight patients (Table 2). When the CAAs, visualized by cCTA were considered valid and true, the distribution of CAAs missed by CMR was as followed: four CAAs in the LMCA, three CAAs in the RCA, seven CAAs in the LAD, and one CAA in the Cx. There was no clear cut-off in diameter above which the CMR was able to detect the CAAs (Table 3), but predominantly determined by imaging quality overall instead.
Table 2 Total CAAs detected by cCTA vs CMR.
Coronary artery CAA on cCTA CAA on CMR
LMCA 7 3
RCA 12 7
LAD 10 3
Cx 1 0
Table 3 CAAs missed by CMR, with accompanying Z-scores calculated from the luminal diameters acquired by cCTA.
LMCA in mm (Z score) RCA in mm (Z-score) LAD in mm (Z-score) Cx in mm
5 (1.25)a 4 (3.3) 4 (3.0) 7
6 (4.26) 7.4 (9.15) 4 (2.52)b
6 (3.88) 6.4 (7.69)
9 (29.92)
7 (6.52)
5 (3.07)
a Patient was overweight (BMI 35.1) which strongly affected the calculation of his Z-score.
b Borderline Z-score of 2.52, but with an irregular wall and an internal diameter of >1.5 times that of the adjacent segment, hence counted as CAA.
In one patient, the CMR detected four CAAs in the RCA and one CAA in the Cx, while the cCTA detected only three CAAs in the RCA and a normal Cx. The delay between CMR and cCTA was 10 months. A month prior to the cCTA a CAG was performed, the results of the CAG were in concordance with the cCTA. Imaging in this patient was performed in the 1st year after onset of disease [also referred to as the dynamic phase (4, 11)] therefore, this discrepancy is most likely due to remodeling.
The CMR detected CAAs in three patients which actually had no CAAs in the coronary artery tree upon cCTA (neither in echocardiography) whereas the CMR detected a CAA in the LAD (1 patient) and in the Cx (2 patients). The delay between CMR and cCTA was 61, 67, and 59 months. However, imaging in these patients was performed long after onset of disease (>2 years), also referred to as the static phase (4), making the contribution of remodeling or normalization much less likely as the explanation for these discrepancies.
cCTA and CMR; Logistics and Failure Rates
Diagnostic failure rates to accurately assess the presence of vascular lesions in these patients by either cCTA or CMR were 9.6% (a total of nine coronary arteries were failed to visualize in five patients) and 59.6% (a total of 108 coronary arteries were failed to visualize in 31 patients), respectively, when both modalities were compared with each other. The main reason that CMR data acquisition failed to accurately assess the presence of a vascular lesion and therefore 1 or more coronary arteries could not be interpreted, more often than in cCTA, was due to motion artifacts caused by (i.e.,) irregular breathing and insufficient image quality; all but two patients were subsequently assessed successfully by cCTA. The cCTA gave insufficient results in five cases (without anesthesia) because of motion artifact (4) and so-called “streaking” due to beam hardening and scatter (1). In three patients the coronary artery segments which were visualized insufficiently by cCTA could be assessed by CMR or echocardiography and were unaffected. In the other two patients the Cx was not visualized well-enough either by cCTA, CMR and echocardiography. These latter two patients had no history of CAAs in any of the other coronary branches though.
CAA-Related Secondary Complications
Imaging by cCTA was able to detect additional vascular pathology in nine patients with coronary features such as calcification (n = 8), stenosis (n = 4), occlusion (n = 1) which were not observed by routine CMR. Coronary artery thrombosis (n = 3) was detected only once by CMR. In three patients CMR enabled us to identify myocardial infarction, cCTA revealed signs of myocardial infarction in two of these patients but with much less accuracy.
Clinical Repercussions
As a consequence of the insufficient performance of CMR, of the eight patients diagnosed with CAA upon CMR, four patients had a second or third CAA that were identified by cCTA and not by CMR. This did not lead to a change of CAA classification, in other words, the missed CAA did not exceed the other visible CAA in Z-score and therefore did not have clinical repercussions. CMR missed CAAs in three additional patients because of diagnostic failure (mainly due to motion artifact as mentioned before) which led to subsequent imaging by cCTA. Of these, one patient needed to start acetylsalicylic acid based on the new results of the cCTA. Finally, in the last three patients redefinition by cCTA of initially missed CAAs led to a different classification, i.e., from “no CAA” to “small CAA” in two patients and near giant CAA (Z-score 9.15) in one patient (Figure 1, Table 3). This last patient needed to start acetylsalicylic acid and also underwent subsequent CMR cardiac stress testing to detect possible myocardial damage, as she was pregnant at the moment of redefinition by cCTA, which showed no myocardial ischemia.
Figure 1 cCTA imaging (a) and CMR imaging (b) of KD patient with near giant CAA (*) in RCA. Calcification and partial coronary artery thrombus are only visible upon cCTA.
Discussion
Our study in KD indicates that cCTA is the better modality to assess the coronary artery lesions in clinical practice when compared to CMR, and can be used for a more precise risk stratification and monitoring during follow-up of patients.
Third generation dual-source cCTA has proven to be of great value for the evaluation of the luminal diameter of the coronary artery compared to invasive coronary angiography in adults (12, 13) and in KD patients (14) as well as the detection of CAAs and CAA-related secondary complications in KD (4, 15–17). The strength of cCTA lies predominantly in visualizing the anatomy and therefore to detect aneurysms, stenosis, calcification, and thrombosis. Other benefits of the third dual-source cCTA are the low radiation exposure and fast acquisition time leading to a lower burden on the pediatric population. Therefore, third generation dual-source cCTA appears to be a good candidate for coronary artery assessment in KD, i.e., risk stratification for the development of myocardial ischemia. However, CMR does not expose patients to radiation, unlike CT imaging and CAG. There is consensus that radiation exposure (due to imaging), is associated with an increase in lifetime cancer risk, especially in children and should be kept to a minimum (18, 19). Recent guidelines consider this radiation exposure and therefore mention CMR as a good imaging technique in KD (6), however, our data suggest cCTA is the more preferred modality for the visualization vascular morphology, thrombus formation and calcified lesions. CMR is valuable to visualize tissue characteristics and physiology, and has been used to demonstrate and in particular ischemia and tissue damage following myocardial infarction in KD (20, 21). Other imaging methods to evaluate cardiac function are being investigated as well (22). Current development in CT scanning techniques may enable cardiac function assessment in the future at low-dose radiation exposure (23, 24), but to date however, CMR remains the most suitable and best imaging modality for the evaluation of cardiac function and for detection of ischemia and infarction.
Differences in applicability and accuracy between CMR and cCTA have been described in the past in adults with coronary artery disease (CAD) (25). These patients mainly presented with obstructive CAD due to plaque formation and may not be comparable with our pediatric population with KD. Previous studies have attempted to determine the clinical applicability of either CT or CMR for the risk stratification (4, 12–17, 21, 26–29), but there are no comparative imaging studies available for KD to date.
Upon comparison of both modalities in daily practice, our data shows that cCTA outperforms CMR in the detection of CAAs. CMR showed a higher diagnostic failure rate for coronary artery assessment mainly due to motion artifacts caused by protracted acquisition time, compared to cCTA (respectively, 59.6 vs. 9.6%). To note, suboptimal images were rated as “diagnostic failure,” as these suboptimal images led to the under-reporting of CAAs. The CAAs missed by CMR were more frequently localized in the LAD, followed by the LCA and RCA; of which three were missed because of inadequate performance.
Because echocardiography also had not been able to detect these CAAs, two patients went undertreated for 5 and 2 years, until their medium-sized CAAs were detected and oral medication was (re)started. In four patients, the CAA classification changed from normal to “small CAA,” which needed no further medication. The four patients in whom additional CAAs were detected that had been missed upon CMR, were already taking oral aspirin, but will be monitored by repeated cCTA during follow-up as a consequence. Important factors that contribute in the higher CAA detection rate by cCTA are high spatial resolution of the cCTA (0.6 mm/pixel vs. 0.6 × 0.6 × 1 mm/pixel in MRI), and high temporal resolution. This higher spatial resolution also contributes to the detection of additional coronary artery pathology (i.e., calcification, stenosis, and thrombosis), while CMR was inaccurate or unable to do so. These CAA-related secondary complications are relevant to be properly diagnosed for treatment considerations during follow-up. Another important factor for accurate coronary artery assessment is heart rate. A higher heart rate is a disadvantage for accurate coronary artery assessment. In our study, the average age of the children undergoing cCTA, and as a consequence their heart rate (since younger children on average have a higher heart rate than older children), was higher than in those that were imaged by CMR. Instead of the heart rate at start, longer acquisition time, and variability in heart rate upon CMR is probably the reason for a higher failure rate and lack of sufficient accuracy in CAA detection in KD. Stricter regulation of heart rate, managed by beta-blockers, could improve the diagnostic accuracy of CMR.
Limitations
Retrospective analysis introduces variation of the data, having not been systematically collected in a predefined prospective manner. In our case, patients have been selected based on the prerequisite of having complementary imaging with both CMR and cCTA data available in the same patients. Most often these patients were known to have CAAs as previously visualized in the (sub)acute stage upon echocardiography. Thus, our patient cohort does not represent a normal unselected KD population. This, however, may not be a disadvantage because it is exactly this subgroup of patients that should be routinely monitored more closely. Despite the fact that most imaging was performed in the stable phase in which remodeling of coronary artery lesions is not expected anymore, the delay between both imaging techniques may have been of influence on our results. Since there were no luminal diameters available for some of the coronary arteries on CMR, the arteries were scored as “normal” or “abnormal” based on the experienced eye. This approach was considered the most realistic for subsequent comparisons between the two imaging groups (i.e., cCTA and CMR). The inability to measure the exact coronary artery diameter on CMR supports our first suspicion that CMR could have a lower diagnostic accuracy compared to cCTA.
Finally, we calculated the Z-scores using the McCrindle/Boston model, although not formally validated for being used for imaging by cCTA and CMR.
Conclusion
Our study in KD shows that cCTA is an excellent imaging modality to assess the coronary artery tree at great resolution. cCTA detects CAAs more frequent and with greater detail when compared to CMR. Therefore, we recommend to perform cCTA in addition to echocardiography in CAA positive KD patients to detect and classify CAAs.
Data Availability Statement
The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.
Ethics Statement
Ethical review and approval was not required for the study on human participants in accordance with the local legislation and institutional requirements. Written informed consent to participate in this study was provided by the participants' legal guardian/next of kin.
Author Contributions
DS-BD conceptualized the study, collected data, and drafted the initial manuscript. IK and TK contributed equally as co-senior authors and conceptualized the study, coordinated, and supervised data collection and reviewed the manuscript for important intellectual content and revised the manuscript. NP conceptualized the study and reviewed for important intellectual content and revised the manuscript. All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
We are grateful to Dr. M. van den Hof for statistical advice.
Abbreviations
AHA American Heart Association
ASA acetylsalicylic acid
BPM beats per minute
CAAs Coronary artery aneurysms
CABG coronary artery bypass grafting
CAD coronary artery disease
CAG coronary angiography
cCTA coronary computed tomographic angiography
CMR cardiac magnetic resonance imaging
CT computed tomography
Cx circumflex
IVIG intravenous immunoglobulin
JCS Japanese Circulation Society
KD Kawasaki disease
LAD left anterior descending artery
LMCA left main coronary artery
MRA magnetic resonance coronary angiography
MRI magnetic resonance imaging
RCA right coronary artery
TE echo time
TR repetition time.
Funding. The funding was made available by the foundation Kind en Handicap and an anonymous donor through the AMC foundation. | UNK UNK, ONCE | DrugDosageText | CC BY | 33614558 | 19,727,701 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Hypogammaglobulinaemia'. | Respiratory subtype of relapsing polychondritis frequently presents as difficult asthma: a descriptive study of respiratory involvement in relapsing polychondritis with 13 patients from a single UK centre.
Relapsing polychondritis is a rare multisystem vasculitis characterised by recurrent cartilage inflammation. Respiratory involvement, of which tracheobronchomalacia (TBM) is the commonest form, is difficult to treat and is linked to increased mortality. We describe 13 patients with respiratory involvement.
This is a retrospective study of all the patients with relapsing polychondritis at University Hospitals Coventry and Warwickshire NHS Trust (UHCW), a secondary care provider for ∼500 000. Only patients with respiratory involvement were included in this study.
We identified 13 patients who fulfilled the inclusion criteria. Most patients were identified from the "difficult asthma" clinic. TBM was seen in 11 patients, whilst two patients had pleural effusions which resolved with immunosuppression and one patient had small airways disease. Computed tomography scans (inspiratory and expiratory) and bronchoscopy findings were useful in diagnosing TBM. Pulmonary function testing revealed significant expiratory flow abnormalities. All patients were treated with corticosteroids/disease-modifying anti-rheumatic drugs (DMARDs) and some were given cyclophosphamide or biological agents, although the response to cyclophosphamide (1 out of 4) or biologicals (2 out of 4) was modest in this cohort. Ambulatory continuous positive airway pressure ventilation was successful in four patients.
Relapsing polychondritis may be overlooked in "difficult asthma" clinics with patients having TBM (not asthma) and other features of relapsing polychondritis. Awareness of this condition is crucial to enable early diagnosis and interventions to reduce the risk of life-threatening airway collapse. A number of patients respond well to DMARDs and are able to minimise corticosteroid use.
Introduction
Relapsing polychondritis was described by Pearson
et al. [1] in 1960 as a rare multisystem disease characterised by recurrent episodes of inflammation and subsequent degeneration of cartilage and connective tissue throughout the body. Relapsing polychondritis most commonly affects the respiratory tract, nose, ears and joints [1–4]. McAdam
et al. [3] described six classical features of relapsing polychondritis, namely bilateral auricular chondritis, nasal chondritis, respiratory tract chondritis, seronegative inflammatory arthritis, ocular inflammation and audiovestibular damage. McAdam's diagnostic criteria needed three out of six of the aforementioned clinical features for confirmation of diagnosis. Additional diagnostic criteria were developed by Damiani
et al. [5] and Michet
et al. [2]. Both of these groups have developed A and B criteria with Damiani criteria keeping all six primary clinical features as A criteria and additionally including histological confirmation as a B criterion and response to corticosteroids or dapsone as a C criterion. Three A criteria or one A and B, or two A with C are needed for diagnosis. Michet criteria include nasal, auricular and laryngotracheal cartilage inflammation as A criteria with the rest as B criteria, and two A or one A and two B criteria are needed for diagnosis.
Respiratory tract chondritis is thought to affect up to 50% of patients during the course of their disease [2, 3, 6] and remains the primary cause of mortality in relapsing polychondritis [3]. Patients often experience airway symptoms such as dyspnoea, cough, chest discomfort, hoarseness, stridor [7] and even complete aphonia in some cases [4] due to inflammatory oedema of the larynx, trachea and bronchi. The underlying chronic cartilage inflammation in the tracheobronchial tree leads to tracheomalacia [8]; or tracheobronchomalacia (TBM) when this extends to one or both primary bronchi. Both phenomena can result in exaggerated airway narrowing during expiration and widening during inspiration [9–11], demonstrable in pulmonary function tests and computed tomography (CT) scans of the chest. Unless early diagnosis and appropriate medical or surgical interventions are in place, the progressive cartilage destruction in the airways due to recurrent cartilaginous inflammation may ultimately result in life-threatening airway obstruction and dynamic airway collapse [12]. Relapsing polychondritis can involve the eyes, neurological system, heart and blood vessels, and there is an association with the HLA DR4 allele [13]. Respiratory problems can be particularly difficult to treat, and very little data exist to guide us with regards to optimal screening and assessment modalities for tracheomalacia or TBM. Management of these patients continues to remain a challenge, and the diagnostic delay can often result in significant damage, which necessitates long-term mechanical support through stents or pneumatic support through continuous positive airway pressure (CPAP) [14, 15]. Despite best treatment, patients are often left with substantial life-changing disability.
We describe a series of patients with relapsing polychondritis all of whom had respiratory involvement. Most had presented to respiratory clinics or had been admitted to hospital with severe shortness of breath. All patients attended University Hospital Coventry and Warwickshire NHS Trust, which is based in Coventry in the West Midlands in the UK and is a secondary care provider for a population of around 500 000. This case series describes the respiratory manifestations and aims to increase the awareness of relapsing polychondritis in patients presenting with respiratory symptoms, particularly in individuals who appear to have oral corticosteroid-dependent asthma.
Materials and methods
We reviewed the medical records of 13 patients with relapsing polychondritis, all of whom had respiratory involvement. Patients were identified through the respiratory and rheumatology clinics at a single centre between 2013 and 2018, and patients were often seen together in a combined clinic. The diagnosis of relapsing polychondritis was made clinically using the clinical diagnostic criteria [2, 3, 5]. Disease activity was assessed using the Relapsing Polychondritis Disease Activity Index (RPDAI) which includes scoring on each organ that can be affected by relapsing polychondritis as well as C-reactive protein (CRP) [16]. There are 28 different items with scores ranging from 1 to 24. Respiratory chondritis scores 14 without and 24 with respiratory failure and is the highest scoring item in RPDAI. Patients’ demographic characteristics, clinical features, diagnostic test results and therapeutic interventions were noted. The database was set up in 2016 and details of patients were updated regularly. Ethical approval was obtained from the Research and Development office within our Trust (approval number – GF 0267). Statistics are predominantly descriptive, and the Microsoft Excel program was used to assimilate the data.
Results
We identified 13 patients with relapsing polychondritis; all of these patients had respiratory involvement. We did not need to exclude any patients due to lack of respiratory involvement. Most of these patients (10 out of 13) were identified in “difficult asthma” clinics with two being diagnosed following an inpatient admission with acute shortness of breath and one diagnosed from a rheumatology clinic. The demographics are described in table 1. Male to female ratio was 1:3 with three males and nine females. The median age of the patients was 65 (range 28 to 76) years. Most patients had other comorbidities with diabetes being the commonest (five patients) and hypertension seen in four patients. Other autoimmune disorders were diagnosed in seven of these patients. Psoriasis and hypothyroidism were noted in two patients each. One patient had overlap with Behcet's disease (mouth and genital ulcers with inflamed cartilage – MAGIC syndrome), and another had ankylosing spondylitis (table 1, figures 1–5).
TABLE 1 Clinical features of patients with relapsing polychondritis
Patient Sex Age years Comorbidities BAC NC RTC SP OI AD Response to corticosteroids TBM proven
1 M 65 T2DM, hypothyroid, psoriasis Y Y Y N Y N Y Y
2 F 70 Memory loss N Y Y Y N N Y Y
3 F 50 T2DM Y Y Y Y N Y Y Y
4 F 53 Hypothyroid, fibromyalgia, HTN, Behçet's, obesity Y Y Y Y N N Y Y
5 F 76 Previous TB, immunodeficiency, HTN, T2DM, OA N N Y Y N Y Y Y
6 F 74 HTN, angina, AF, T2DM, antiphospholipid antibodies Y Y Y Y N N Y Y
7 F 76 Emphysema N N Y N N N Y Y
8 F 70 HTN, obesity, acoustic neuroma, hyperlipidaemia N N Y Y N N Y Y
9 F 78 T2DM, obesity, MI, AF, CKD, dementia, asthma Y Y Y Y N Y Y Y
10 M 31 Hypoadrenalism, bronchiectasis Y Y Y Y N N Y Y
11 F 52 Obesity, COPD, ankylosing spondylitis, psoriasis Y Y N Y N Y Y N
12 M 79 Myelodysplasia, follicular lymphoma, osteoporosis Y N Y N Y N Y N
13 M 78 T2DM, IHD, CKD, myositis N N Y Y N Y Y Y
BAC: bilateral auricular chondritis; NC: nasal chondritis; RTC: respiratory tract chondritis; SP: seronegative polyarthritis; OI: ocular inflammation; AD: audiovestibular damage; TBM: tracheobronchomalacia; T2DM: type 2 diabetes mellitus; HTN: hypertension; TB: tuberculosis; OA: osteoarthritis; AF: atrial fibrillation; MI: myocardial infarction; CKD: chronic kidney disease; IHD: ischaemic heart disease.
FIGURE 1 a) Admission computed tomography (CT) scan showing near complete collapse of trachea in a patient that was subsequently diagnosed with relapsing polychondritis. b) Repeat CT after intravenous corticosteroids with inspiratory and expiratory films showing significant improvement of tracheal narrowing (expiratory phase CT).
FIGURE 2 a) Patient with admission computed tomography (CT) chest showing near complete collapse of trachea and pleural effusions. b) Repeat CT after treatment with high-dose corticosteroids with improvement in trachea and resolution of pleural effusions.
FIGURE 3 Patient with collapse of trachea.
FIGURE 4 a) Patient with presentation computed tomography showing significant narrowing of trachea. b) Post-treatment imaging showing improvement in dimensions of trachea.
FIGURE 5 Pre-treatment tracheal collapse in a patient.
We found that eight patients (62%) had bilateral auricular chondritis and nasal chondritis, whilst 10 patients (77%) had seronegative polyarthropathy with two patients (15%) having ocular inflammation and five patients (38%) had audiovestibular damage (figure 6). All patients had good response to oral prednisolone and fulfilled criteria for diagnosis of relapsing polychondritis (Damiani). Most patients (10 out of 13) were picked up from the difficult asthma clinics. All patients had wheeze and persistent cough and hence a diagnostic label of asthma, but it was the presence of monophonic wheeze, presence of inspiratory stridor in two patients, barking nature of cough in two patients and lack of classical reversibility and response to steroids that led to the suspicion of underlying more complex airway issues and possible expiratory airway collapsibility. Patients with good response to oral prednisolone demonstrated return of their signs and worsening of other symptoms with dosage reduction below 20 mg daily leading to further suspicion about the underlying diagnosis. Dynamic CT (inspiratory and expiratory) images were obtained along with flexible bronchoscopy. Bronchoscopy was performed in four patients. Mild sedation using intravenous midazolam and local analgesia with 2% lignocaine were instilled. Patients were able to cooperate and forcibly exhale. Views were taken from the proximal and distal trachea, right and left main bronchi and segmental bronchi during inspiration and forced expiration. Fifty per cent or more reduction in the cross-sectional area of the airway during the dynamic bronchoscopy and CT were used as the diagnostic cut-off for the diagnosis of TBM. Two of our patients demonstrated smooth thickening of the airway wall and luminal narrowing of the distal trachea and main bronchi, and one demonstrated symmetrical stenosis of the large airways, whereas the remaining patients had >50% reduction of the airway luminal area with crescentic appearance of the airway due to flattening of airway walls during expiration.
FIGURE 6 Patient images demonstrating auricular chondritis with inflammation of the external ear with sparing of non-cartilaginous part.
Although other features such as bilateral auricular chondritis or nasal chondritis had been present in eight patients, they had rarely complained about these symptoms to their clinicians as other symptoms, particularly severe breathlessness, were their primary concern. Eliciting these symptoms required direct questioning. One patient had classical nasal bridge collapse which they previously told several clinicians (via interpreters) was the result of childhood trauma, although on detailed questioning there was in fact no history of trauma. Seronegative inflammatory arthritis was a presenting feature in two patients (predominantly large joints) and had been noted in 10 patients.
Laboratory testing showed anaemia in seven patients and raised inflammatory markers including CRP or erythrocyte sedimentation rate in six patients. As a number of patients were on long-term corticosteroids for “difficult asthma”, it was difficult to get accurate trends of inflammatory markers prior to treatment. None of the patients had evidence of eosinophilia at any point. Rheumatoid factor, anti-cyclic citrullinated antibodies, antinuclear antibodies, anti-double-stranded DNA antibodies and neutrophil cytoplasmic antibodies were all negative, although one patient had antiphospholipid antibodies. Chest radiographs were normal in 11 patients; two had shown features of pleural effusions and these were confirmed on CT scans later. None of the patients had any other features to suggest antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis.
In 12 out of 13 patients, flow-volume loops demonstrated flattening of either inspiratory or expiratory curves, or both. Flattening of the expiratory limbs in flow-volume loops was prevalent in most, suggesting large airway collapsibility during expiration (figures 7 and 8). There was no evidence of reversibility with β2 agonists in 11 patients, whilst one patient with small airway disease showed reversibility with likely coexistent asthma.
FIGURE 7 Flow–volume loop of patient 4 showing flattening of the expiratory limb and inspiratory limb to a lesser extent.
FIGURE 8 Flow–volume curve of patient 6 showing flattening of the expiratory limb and inspiratory limb to a lesser extent.
Treatment
Corticosteroids and conventional disease modifying agents
Corticosteroids were used in all patients, and disease-modifying anti-rheumatic drugs (DMARDs) such as methotrexate 15 to 25 mg weekly (6 patients), azathioprine 1–2.5 mg·kg·day−1 (2 patients) and mycophenolate mofetil 1–2 g daily (2 patients) were successful in reducing disease activity (table 2). One patient developed hypogammaglobulinaemia, which was thought to be secondary to immunosuppression and was treated with replacement intravenous immunoglobulin (IVIG) as she was having recurrent infections (predominantly chest infections). Prednisolone was usually started at 1 mg·kg·day−1 orally in patients with respiratory failure and 0.5 mg·kg·day−1 in patients without respiratory failure with gradual tapering every 2–4 weeks initially. Dose reduction was achieved in all cases, but four patients struggled to wean prednisolone dose down below 10 mg. In two patients, we used <20 mg prednisolone, as higher doses were not needed. Intravenous cyclophosphamide was used in four cases but was thought to be unsuccessful in three of these on the basis of lack of symptomatic benefit. Cyclophosphamide was only used after failure of conventional DMARDs and was used primarily for TBM.
TABLE 2 Pharmacological and non-pharmacological treatment for patients with relapsing polychondritis
Patient Sex Age years CPAP Stent IS drugs Corticosteroid dose Previous drugs Baseline RPDAI
1 M 65 N N MTX Pred 37
2 F 70 N N MMF, infliximab Pred 5 mg SSZ 27
3 F 50 DNT N MTX Pred 45
4 F 53 Y Y MMF, MTX Pred 10 mg AZA, cyclophosphamide, ADA and ETN 47
5 F 76 Y N SSZ, HCQ, ABT, IVIG Pred 7.5 mg MTX, ETN, leflunomide, AZA 44
6 F 74 Y Y MTX, AZA Pred 10 mg Cyclophosphamide 43
7 F 76 Y N Cyclophosphamide Pred 10 mg MTX 27
8 F 70 N N AZA Pred 5 mg 15
9 F 78 DNT N Pred 5 mg MTX, AZA, HCQ 24
10 M 31 N N HCT 20/10/10 33
11 F 52 N N Secukinumab Pred 10 mg MTX, ETN, HCQ, cyclophosphamide, ADA 38
12 M 79 N N Pred 5 mg 35
13 M 78 Y Y MTX Pred 5 mg AZA 40
CPAP: continuous positive airway pressure; IS: immunosuppressant; RPDAI: Relapsing Polychondritis Activity Index; MTX: methotrexate; Pred: prednisolone; MMF: mycophenolate mofetil; SSZ: sulfasalazine; DNT: did not tolerate; AZA: azathioprine; ETN: etanercept; HCQ: hydroxychloroquine; ABT: abatacept; IVIG: intravenous immunoglobulin; HCT: hydrocortisone; ADA: adalimumab.
Airway support
Patients with severe airway collapse >90% of airway area with disabling symptoms were considered for large airway stenting alongside medical therapies. Successful stenting was performed in three patients; in one other patient the stent had to be removed as it was exacerbating infections and in another due to continuous coughing. Six patients with moderately severe airway compromise (75–90%) and significant breathlessness on exertion were receiving intermittent ambulatory CPAP; two discontinued due to lack of tolerance. Noninvasive ventilation (NIV) was used with maximum inspiratory pressure (IPAP) of 24 and expiratory pressures (EPAP) of 10 cmH2O whilst CPAP pressures were between 10 and 13 cmH2O. Overnight sleep studies excluded significant sleep disordered breathing in these patients. Within this cohort, seven patients have had recurrent admissions for “flare of asthma” prior to the diagnosis with three of these not requiring further inpatient admissions once immunosuppression was instituted.
Biological DMARDs
Biological DMARDs were tried in four patients with anti-tumour necrosis factor (TNF) therapies being successful in one and unsuccessful in three patients (two due to inefficacy, another due to allergic reactions to both etanercept and adalimumab). Of the three patients who failed anti-TNF therapy, two were tried on other agents, with one patient responding well to abatacept whilst another patient was started on secukinumab for ankylosing spondylitis and had good response for spinal disease, but no change in RPDAI.
Eight patients are still under regular follow-up and have been under follow-up for >5 years since diagnosis, one has been lost to follow-up and four patients have died. In two of these cases, primary cause of death was chest infection; in the other two, it was unrelated causes, one from complications of myelodysplasia.
Discussion
A number of studies have described small numbers of patients with respiratory features and some have shown airway involvement to be the leading cause of death in relapsing polychondritis [1, 3, 6, 15, 17]. TBM has been reported in the literature in up to 50% of patients with relapsing polychondritis. Our series saw TBM as the commonest presentation of relapsing polychondritis, although it is quite likely that a number of patients with less serious problems might not have been appropriately diagnosed given the rarity of this condition. A French series reported 142 patients with relapsing polychondritis who formed three distinct patterns – haematological, respiratory and “mild” phenotypes [18]. Within the respiratory phenotype, which formed 22.5% of their series, auricular involvement was less common, something we have seen as well. Similar to our series, they found that these patients received more intensive treatment, were prone to infections and were frequently admitted to the intensive care unit. Our series provides more detail about the respiratory subtype of relapsing polychondritis with specific focus on presentation and management. We did not need to exclude any patients with relapsing polychondritis due to lack of respiratory involvement. Given its rarity, it is likely that there are other patients with less serious manifestations that have not reached rheumatology or respiratory clinics and have not been given the diagnosis yet. The majority of these patients were originally thought to have oral corticosteroid-dependent asthma, and once TBM was suspected or diagnosed, physicians started searching for and finding other features of relapsing polychondritis. Patients had not complained about the other manifestations such as chronic auricular chondritis or nasal chondritis as the symptom of breathlessness predominated.
Physical treatments of TBM with stenting and CPAP are well recognised [6–9, 17, 19]; however, there is very little information in the literature about pharmacological treatment of TBM through immunosuppression. This is important as TBM can be the only manifestation of relapsing polychondritis [20]. In our series, most patients had responded well to pharmacological therapy, although some needed stent insertion to support the bronchial tree. Stenting also had mixed results, and it is unclear as to whether there are specific features that would indicate use of stents in preference to drug therapy. Stenting is most likely to be useful after optimal control of active disease (to stabilise the damaged section of the tracheobronchial tree once medical treatment has controlled active inflammation). Complications following stenting are relatively common with one study showing 49 out of 58 patients having a complication, the commonest of which are stent migration, infection and partial obstruction [21]. Aggressive early management can be difficult to achieve when the patient has been symptomatic for so many years and airway damage has accumulated before the diagnosis is made. Intermittent ambulatory CPAP has been described previously with variable results [22–24]; our group has previously described successful use of CPAP in TBM. Such long-term use of portable NIV combined with overnight CPAP has not been reported to our knowledge. We have seen good symptomatic improvement and long-term stability with CPAP used in this fashion together with medical treatments.
Clinical and symptomatic evaluation, dynamic (inspiratory and expiratory) CT scans and flexible bronchoscopy were critical in establishing the diagnosis of TBM, which is consistent with reports from the literature [8–10]. Other features of relapsing polychondritis were identified clinically, although recent reports suggest positron emission tomography CT (PET CT) might be an additional resource for defining the severity and extent of disease [25]. PET CT has other potential advantages as it can: a) differentiate damage from active inflammation, and b) provide information about large vessel vasculitis and other organs that are not easy to assess clinically. We have not used this modality in our patients, and this could be evaluated in future studies.
The prevalence of relapsing polychondritis in Coventry appears to be at least 26 per million on the basis that we have 13 patients locally within our catchment area of around 500 000. If these prevalence data were true for the rest of the UK as well, one would expect roughly 1500 additional patients! It is difficult to estimate the true prevalence for a rare condition, and the literature has offered very wide estimates ranging between 3.5 per million to 23 per million. Hungarian data suggest similar numbers (23 per million) to the numbers estimated here based on 233 cases from a population of 10 million [26]. Incidence in that study was around 3.5 per million patient years. Incidence of relapsing polychondritis in a UK study was 0.71 per million patient years and prevalence was estimated at 9 per million [27]. In Rochester (Minnesota, USA), the incidence of relapsing polychondritis was estimated at 3.5 per million [4]. Given the rarity of the condition and difficulty in diagnosis, it is not a surprise that there is such wide variation. This study provides new impetus to look for specific features of relapsing polychondritis that may have a major influence on incidence and prevalence estimates.
There are no controlled clinical trials in this area (as is the case for a number of rare diseases), and it may be possible to set up trials in this area if the prevalence is significantly higher than was previously thought. There is a need to increase awareness of this disease amongst all the specialties that are likely to come across these patients. Optimal management of these patients continues to remain a challenge. The exact pathogenesis is not clearly understood. Various immune processes that have been described include reduction of immunoregulatory cells, antibodies attacking cartilage tissue elements like type-II, type-IX and type-XI collagen and matrilin1, changes in cytokine profiles, deposition of immune complexes and insufficient tissue regeneration [28–34]. This makes it quite challenging when choosing drugs for refractory patients. Within our cohort, we observed some responses to DMARDs with methotrexate, azathioprine and mycophenolate being successful. In fact, in one patient we were able to completely stop corticosteroids and have not needed to go back to corticosteroids for >2 years. Responses to biological agents and i.v. cyclophosphamide have been modest in this cohort – this may be due to delay in diagnosis, which can sometimes be a number of years. Also, we have not routinely used i.v. cyclophosphamide for induction but tended to use it when other agents have failed. Disease activity and damage scores have been developed [16, 35] and are of use in documenting response to treatment; and also serve as a reminder of the various manifestations of this rare illness. Multiple biological agents have been tried, but due to the rarity of the condition, there are no randomised controlled trials in this field. A French national study looking at biologicals in relapsing polychondritis did not demonstrate any clear trends that would help guide use of biological agents [36].
Limitations
This is a retrospective review and studies of this sort are subject to systemic biases, which are applicable to this study. Prevalence data are affected by referral pathways and other biases which would be applicable to this study. Also, patients presenting with respiratory symptoms were selected, so this is a referral bias. There is also likely to be left censorship bias as some patients who may have died or were lost to follow-up would not have been included.
Conclusions
Relapsing polychondritis, although rare, with prevalent respiratory involvement may be the cause of significant morbidity and mortality. Patients might be misdiagnosed with other respiratory diseases in particular being labelled as “difficult asthma”. There is an important need to recognise and diagnose relapsing polychondritis, as there are specific treatment options including DMARDs that these patients are likely to benefit from. Awareness of this condition is crucial to enable early diagnosis and clinical interventions to reduce the risk of life-threatening airway collapse.
Author contributions: All authors have contributed to the study design and write up. SD, CG, GP, AA, JS, ST have helped with data collection and analysis.
Data availability: Data collected as part of their standard care were used for this study. There were no additional interventions performed.
Conflict of interest: S. Dubey has nothing to disclose.
Conflict of interest: C. Gelder has nothing to disclose.
Conflict of interest: G. Pink has nothing to disclose.
Conflict of interest: A. Ali has nothing to disclose.
Conflict of interest: C. Taylor has nothing to disclose.
Conflict of interest: J. Shakespeare has nothing to disclose.
Conflict of interest: S. Townsend has nothing to disclose.
Conflict of interest: P. Murphy reports grants paid to his institution and personal fees for CPD approved activity from Philips, ResMed, F&P and B&D Electromedical, advisory board fees from Santhera, and grants paid to his institution from GSK, outside the submitted work.
Conflict of interest: N. Hart reports an unrestricted research grant for the OPIP Trial from Philips-Respironics, personal fees for a lecture at TOP Forum China from Philips-Respironics Lecture, and unrestricted research grants for the HoT-HMV Trial from RESMED and Philips-Respironics, outside the submitted work; in addition, he has a European patent issued and a US patent pending for MYOTRACE. His research group has received unrestricted grants (managed by Guy's & St Thomas’ Foundation Trust) from Philips and Resmed. Philips are contributing to the development of the MYOTRACE technology.
Conflict of interest: D. D'Cruz has nothing to disclose. | ABATACEPT, HYDROXYCHLOROQUINE, PREDNISOLONE, SULFASALAZINE | DrugsGivenReaction | CC BY-NC | 33614776 | 20,321,562 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Drug ineffective'. | Chlorambucil combination therapy in refractory serpiginous choroiditis: A cure?
To find a remedy for serpiginous choroiditis refractory to oral prednisone and chlorambucil treatment.
Eight eyes of four patients (all female) with advanced macular involvement secondary to serpiginous choroiditis were included in the study. The average age of the patients was 45.2 years. One eye of each patient was legally blind and the lesion was close to the fovea in the other eye. All four patients failed oral prednisone and chlorambucil therapy. However, case 1 responded to chlorambucil treatment after intravitreal dexamethasone implant implantation and discontinuation of oral prednisone. Case 2 responded to chlorambucil therapy when oral prednisone was stopped in combination with infliximab therapy. Due to long follow-up period of more than four years, these two cases are considered to be cured. Case 3 and case 4 were not able to achieve remission with chlorambucil and immunomodulatory therapy. They refused intravitreal steroid implant due to side effects profile.
The stability of WBC counts within toxic levels close to normal or lower limits of normal (3000-4500 cells/μl) during treatment with chlorambucil is an essential factor for the success of this therapy. A combination of dexamethasone intravitreal implant with chlorambucil therapy can be an effective and promising regimen in inducing and maintaining remission in refractory serpiginous choroiditis patients who fail a combination of systemic corticosteroid and chlorambucil therapy.
1 Introduction
Serpiginous choroiditis (SC) is a rare, chronic, asymmetrically bilateral posterior uveitis with a recurrent course. The exact prevalence of SC is unknown; however, it is estimated between 1.6% and 5.3% of posterior uveitis cases in non-endemic areas for tuberculosis.1 Major features of SC include choriocapillaris occlusive vasculitis, secondary endothelial cell injury, and subsequent atrophy of the retinal pigment epithelium, outer retina, and choroid.2,3 Histopathology studies reveal lymphocytic infiltration in the choroid and, less commonly, around vessels.4 The peripapillary area is classically involved in SC and accounts for 80% of the cases.5 The prognosis of vision is poor when it involves the macula, especially in the macular variant of SC. Moreover, the macular variant has a higher risk of developing choroidal neovascularization in nearly half of the affected patients.6,7 Fluorescein angiography (FA), indocyanine green angiography (ICG), optical coherence tomography (OCT), fundus autofluorescence (FAF), and microperimetry are the ancillary diagnostic tools and tests which help in the diagnosis, follow-up, and monitoring for secondary complications.1
Historically, the administration of high doses of oral or intravenous steroids was considered as the standard of care for patients with SC.8 However, immunosuppressive agents such as azathioprine, cyclosporine, chlorambucil, and cyclophosphamide emerged as treatment options for steroid-free remission.4,9, 10, 11, 12 Of these, the alkylating agents cyclophosphamide and chlorambucil have been noted to have a high success rate in the treatment of SC.4,10,12 Chlorambucil, being a potent alkylating agent, can interfere with DNA replication and cell division.13 This medication can induce remission, maintain remission, and even cure this disease.12
Despite successful treatment of SC with alkylating agents, in some patients the disease can recur frequently and progress to affect the central vision. This becomes more important in patients with poor vision in the other eye secondary to SC or advanced SC encroaching the fovea in the affected eye. In this case series, we decided to evaluate possible remedies for refractory and recurrent SC in patients who have been treated with chlorambucil and oral or intravenous corticosteroids.
2 4 Cases
Case 1. A sixty-year-old female was referred to us for the evaluation of macular SC OU. She had noticed blurry vision OS one month before her first visit with us. A geographic lesion with indistinct and irregular borders was observed in both eyes. The lesion was uni-centric OU, temporal to fovea OD and peripapillary with extension to fovea OS. FA and ICG showed the activity of the lesions in both eyes (Fig. 1A). Her best-corrected visual acuity (BCVA) was 20/20 OD and decreased OS to 20/100. Complete blood work-up for uveitis ruled out non-infectious and infectious posterior uveitis, including syphilis and tuberculosis. Based on these findings, she was diagnosed with autoimmune SC OU and was started on a combination of chlorambucil and daily oral prednisone. Chlorambucil was titrated based on her white blood cell (WBC) count. She had another flare-up while she was on 2 mg/day prednisone and had already stopped chlorambucil for three weeks due to WBC 3200 cells/μl. BCVA OS decreased to 20/125, and ICGA confirmed enlargement of the lesion. Chlorambucil was restarted to 2 mg every other day, and oral prednisone was increased to 5 mg/day. With this change in her regimen, the vision increased to the baseline before her last flare, to 20/40. Treatment with chlorambucil was stopped after one year. Her follow-up visit increased to every three months from monthly. Then, six months later, she was started on oral methotrexate 7.5 mg weekly by her rheumatologist because of her joint issues. She was followed every three months for seven months until she noticed a change in OS again. At that time, she was on oral methotrexate 15 mg weekly. BCVA OS decreased to 20/125, and ancillary tests showed activity at the border of the lesions on the foveal side (Fig. 1B). She received one dose of 1 g intravenous methylprednisolone, intravitreal injection of triamcinolone and bevacizumab, and was restarted on oral prednisone 80 mg/day. A week later, her methotrexate dose was boosted to methotrexate 25 mg weekly subcutaneous injections, and we tapered prednisone 10 mg weekly. In three months, oral prednisone was tapered and stopped. Three months later, her lesion became active and she developed choroidal neovascularization (CNV) for which she received a bevacizumab injection. She was restarted on chlorambucil and oral prednisone. The decision for local therapy with dexamethasone implant was made at this point, and she was put back on chlorambucil 2 mg every three days. She was on chlorambucil without oral prednisone, titrating the dose based on WBC for seventeen months, after which she was considered cured (Fig. 1C). In her last visit with us, her BCVA OD and OS were 20/20 and 20/50, respectively. The patient's average WBC count while on chlorambucil with prednisone, chlorambucil without prednisone, and chlorambucil after dexamethasone intravitreal implant were 5500 ± 2900, 4700 ± 1100 and 4100 ± 500 cells/μl, respectively. The total duration of treatment before dexamethasone intravitreal implant was 60 months and 17 months after dexamethasone intravitreal implant. The total length of follow-up is 132 months, and the total duration of remission off medication is 48 months (Table 1).Fig. 1 A patient with bilateral serpiginous choroidopathy. (A) Serpiginous lesions in both eyes, encroaching the fovea in right eye and with foveal involvement in left eye. Fluoresecein angiography shows activity in both eyes. (B) The middle row shows progression towards the fovea with leakage pointing toward the fovea in the right eye. (C) Shows the stability of fundus photos and fluorescein angiography in both eyes at one year after intravitreal dexamethasone implant and chlorambucil treatment.
Fig. 1Table 1 Demographics and clinical characteristics of patients with resistant serpiginous choroiditis.
Table 1 Age years Sex Laterality BCVA first visit WBC (C + P) cells/μl
(x 10c) WBC (C) cells/μl
(x 10c) WBC (C + IMTor implan cells/μl (*10c) Duration of treatment before IMT Duration of treatment after IMT Duration of follow-up on chlorambucil Duration of follow-up off chlorambucil BCVA last visit
Patient 1 60 F Bilat 20/20 20/100 5.5 ± 2.9 4.7 ± 1.1 4.1 ± 0.5 60a months 17b months 60 months 83 months 20/20 20/50
OD
OS
Patient 2 42 F Bilat 1 mcf 20/20 5.7 ± 2.2 N/A 3.8 ± 0.5 40c months 19d months 49 months 60 months 1mcf
20/15
OD
OS
Patient 3 32 F Bilat HM 20/20 8.8 ± 3.4 N/A N/A 5 + 10 e months N/A 5 months N/A HM 20/50
OD
OS
Patient 4 47 F Bilat 20/30 1mcf 6.2 ± 3.3 N/A N/A N/A N/A 12 months N/A 20/50 1mcf
OD
OS
BCVA:best corrected visual acuity; Bilat:bilateral; C:chlorambucil; CF:counting fingers; HM:hand motion; IMT:immunomodulatory therapy; P:prednisone; N/A:not applicable.
a Before intravitreal dexamethasone implant.
b After intravitreal dexamethasone implant.
c Before starting infliximab.
d After starting infliximab.
e 5 months chlorambucil and 10 months cyclophosphamide.
Case 2. A 42-year-old female was referred to us with blurry vision and field distortion OD for ten years and OS for eight years. Her vision was counting fingers at 1 m OD and 20/20 OS. At the time of presentation, the patient had already received multiple intravitreal anti-VEGF (bevacizumab) and triamcinolone injections OD. The geographic lesions were peripapillary OU, with foveal involvement OD. Initial FA revealed chorioretinal scarring with window defects OU and leakage on borders OD (Fig. 2A). On ICG, the area of hypolucency OS extended further into the macula, which was not seen on FA (Fig. 2B). Complete blood work-up for uveitis ruled out non-infectious and infectious posterior uveitis, including syphilis and tuberculosis. Based on these findings, she was diagnosed with autoimmune SC OU and we recommended therapy with chlorambucil. She sought a second opinion elsewhere, where she was started on mycophenolate mofetil (MMF) 1 g daily with infliximab 300 mg IV every four weeks and oral prednisone 80 mg/day with taper. MMF and infliximab were eventually discontinued due to elevated LFTs. On follow up at our clinic eighteen months after the initial consult, chlorambucil was finally started with dose adjustment based on weekly monitoring of WBC count to reach the endpoint of WBC count 3000–4500 cells/μl. While on chlorambucil 20mg and prednisone 40mg daily, the patient became symptomatic OS with new changes and leakage on FA OS, prompting boosting of oral prednisone to 80 mg; she also received one ranibizumab injection OS locally. Six weeks after starting treatment with chlorambucil (20mg at this time) and oral prednisone 80 mg daily, WBC count dropped down to 4900 cells/μl, so we started tapering prednisone. Two months after initiation of chlorambucil therapy, chlorambucil was stopped while tapering prednisone at 30 mg/day with a WBC count of 3300 cells/μl. At this point, FA, FAF, and OCT showed stability and quiescence. On a subsequent visit with her local ophthalmologist, infliximab 600 mg infusions every four weeks was started for activity OS, and eventually increased to 900 mg every four weeks in combination with chlorambucil. WBC count increased to 7900 cells/μl while on prednisone 10 mg with taper, and chlorambucil was restarted at 4 mg daily, eventually going up to 6 mg daily (Fig. 2B). Chlorambucil dose adjustment with weekly WBC count was continued. Meanwhile, she received a bevacizumab injection with her local ophthalmologist due to central vision distortion OD. On her eight-month of treatment, WBC count dipped to 2000 cells/μl, and chlorambucil was stopped. After one week, with WBC count creeping back up to 4800 cells/μl, chlorambucil was restarted at 2 mg/day. Disease activity was then noted at ten months from treatment initiation with no interventions at that time. On follow up at our clinic fourteen months after starting chlorambucil, the activity noted at ten months prompted treatment extension, and the patient was educated on the risks vs. benefits of this decision. Chlorambucil treatment was continued for a total duration of twenty-one months. FA and OCT macula findings were stable and the patient was asymptomatic (Fig. 2C,D). Subsequent consults established disease stability with no new symptoms or activity. Infliximab was eventually tapered by 100 mg every four weeks. On her last consult at our clinic, she was on infliximab 100 mg infusions every four weeks with a final VA of 20/400 OD and 20/15 OS and stable findings on FA and macula OCT. Her average WBC count was 5700 ± 2200 cells/μl while on chlorambucil with prednisone, and 3800 ± 500 cells/μl when she was on chlorambucil after starting infliximab infusions without prednisone. The total duration of treatment before and after beginning infliximab infusions was 40 and 19 months, respectively. The total length of follow-up is 108 months. The total period of remission off chlorambucil is 60 months (Table 1).Fig. 2 (A) Fundus photo and fluorescein angiography of a patient with bilateral serpiginous choroiditis at the primary visit at our clinic. (B) The same patient during a recurrence in the left eye close to the fovea. (C,D) Stability of year after stopping chlorambucil while on infliximab tapering. (E) Macular optical coherence tomography at the first visit (left), during a recurrence (middle), and the last visit (right).
Fig. 2
Case 3. A 32-year-old female presented with decreased vision, floaters, and photophobia OS. Vision OD was poor due to retinal detachment after a motor vehicle accident. Before presenting to her initial consultation at our clinic, complete blood work-up for uveitis had ruled out non-infectious and infectious posterior uveitis, including syphilis and tuberculosis and she had already been diagnosed with idiopathic SC. She had been on MMF 2 g daily, cyclosporin 25 mg and prednisone 30 mg daily for fourteen months. Her vision was hand-motion OD and 20/20 OS at presentation. A fundus examination revealed optic atrophy and a horizontal scar OD in addition to diffuse chorioretinal (CR) scarring in both eyes. Given the possibility of the activity of the lesion potentially affecting the fovea OS and her monocular status, chlorambucil and cyclophosphamide were discussed as treatment options.
The patient was started on chlorambucil 4 mg daily and continued on 25 mg of prednisone daily. A month later, her WBC count dropped from 14,800 to 12,100 cells/μl. However, she felt her vision had decreased once again after two weeks on chlorambucil. She was advised to increase chlorambucil to 6 mg/day from 4 mg/day, as well as increase prednisone to 40 mg daily. After one week at this dose, she reported stable vision OD. Chlorambucil dose adjustment with weekly WBC count and oral prednisone were continued until she reported stable vision and no other symptoms. At this time, she was advised to increase chlorambucil to 12 mg daily.
Approximately four months after her initial visit, the patient presented to our clinic with worsening scotoma and floaters OS. At this point, she was on prednisone 5 mg daily and chlorambucil 10 mg daily. She had stopped chlorambucil for a week due to fever, and the WBC count was at 11,200 cells/μl. FA and ICG showed active choroidal inflammation at the lesion border, especially OS. Later on, she developed a diffuse, itchy rash, and because of this side effect, she was started on bi-weekly cyclophosphamide pulse therapy. She had five doses of cyclophosphamide pulse therapy, and her WBC count was between 4500 and 6300 cells/μl. However, a few days later, she complained of decreased vision OS with more central involvement. Her local ophthalmologist increased her prednisone to 60 mg, and she received her next cyclophosphamide infusion four days later with WBC count at 4000 cells/μl. Cyclophosphamide therapy was finally stopped due to persistent skin rash.
In the interim, she followed up with her local ophthalmologist while on oral prednisone with different doses based on disease activity. Her next visit with us was seven years later, and vision OS had deteriorated to 20/50. FA showed active inflammation OS in the form of enlarged CR lesions approaching the fovea with multifocal areas of leakage at the margins of the lesions (Fig. 3B). Up to that point, the patient had been off all immunomodulatory therapy (IMT) for seven years, yet only cyclophosphamide appeared to halt the progression of her disease. Monthly cyclophosphamide pulse therapy was resumed but was later stopped after eight months due to low WBC count. After this, she continued with oral prednisone 20 mg daily. At her last follow-up visit, chlorambucil was restarted due to the persistence of symptoms, worsening of vision OS, and the progression of lesion activity on imaging (Fig. 3C). Intravitreal steroid implants were also discussed. The patient was never able to taper off oral prednisone during treatment, and the average WBC count during her course of treatment was 8800 ± 3400 cells/μl. The total duration of treatment with chlorambucil was 5 months, cyclophosphamide was 10 months, and MMF plus cyclosporine was 14 months. The total duration of follow-up is 148 months. She has never been in remission for an extended period off medication (Table 1).Fig. 3 (A) Fundus photo of both eyes of a patient with bilateral serpiginous choroiditis. History of traumatic retinal detachment surgery with legal blindness in the right eye and active serpiginous choroiditis in the left eye. Fluorescein angiography shows an active lesion in the left eye. (B) Optical coherence tomography, fundus autofluorescence, and fluorescein angiography during a recurrence where the patient was started on cyclophosphamide pulse therapy. (C) Progression of the lesion in the left eye with an active lesion in fluorescein angiography at her last visit. Intravitreal dexamethasone and triamcinolone implants were discussed at this visit.
Fig. 3
Case 4. A 47-year-old female was referred to our center with decreased vision OU for one month and had been started on prednisone 50 mg daily before her first visit with us. Her vision OD and OS were 20/30 and counting fingers at 1 m, respectively, at presentation. Dilated fundoscopy showed bilateral geographic lesions nasal to the fovea OD and involving the fovea OS (Fig. 4A). Complete blood work-up for uveitis ruled out non-infectious and infectious posterior uveitis, including syphilis and tuberculosis. Based on these findings, and she was diagnosed with autoimmune SC OU. Oral prednisone was increased to 60 mg daily, and due to significant vision loss OS, she was started on chlorambucil 6 mg daily. Chlorambucil treatment with WBC count monitoring and tapering of oral prednisone was continued for a year. Once the oral prednisone taper was completed, she continued with chlorambucil monotherapy for five more months, at which time she had achieved remission. After four months; however, she had a flare-up OD, which was first treated with 1 g IV methylprednisolone infusion and intravenous methotrexate 200 mg/day. Subsequently, she was continued on subcutaneous methotrexate 15 mg weekly along with folic acid 1 mg/day for two years. She developed another flare-up when tapering methotrexate; hence methotrexate dose was boosted, and a combination of chlorambucil and oral prednisone was restarted. The patient was on chlorambucil and oral prednisone for one year, with an average WBC count of 6200 ± 3300 cells/μl. The patient was then on chlorambucil alone for another two months. She had been flare-free for twenty months when she had another episode. This time she was treated with intravenous and subcutaneous methotrexate. She had another flare during tapering of methotrexate and she is currently on a combination of chlorambucil, prednisone, and subcutaneous methotrexate therapy. The total duration of follow-up has been 116 months. She has never been in remission for an extended period (Table 1).Fig. 4 A serpiginous choroiditis patient with multiple recurrences despite treatment with a combination of oral prednisone and chlorambucil therapy. (A) Color fundus photos and fluorescein angiography of both eyes at the first visit, which showed activity around the lesion in both eyes. (B) The second row shows the progression of lesions in both eyes during a recurrence on fundus photos and fundus autofluorescence. (C) Fundus autofluorescence and fluorescein angiography showed reactivation of the supratemporal area of the lesion in the right eye. (D) Optical coherence tomography shows the lesion, edema, and destruction of the supratemporal part of the lesion, compatible with fundus autofluorescence and fluorescein angiography. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)
Fig. 4
3 Discussion
The pathogenesis of serpiginous choroiditis (SC) is unknown. The course of the disease is indolent and can be asymptomatic until it involves the macula and the central vision. Many patients can have old scars even at the first visit when they are diagnosed with SC.14 Laatikainen and Erkkila et al. reported that new lesions may appear at an interval of 3 months–4 years. They also demonstrated that active lesions resolve in a few weeks; however, signs of activity may last between 1 and 9 months.14 Central vision is involved in 20%–50% of cases, with the likelihood increasing with longer duration of follow-up and disease activity.8,14 Recurrences that affect the macula can cause severe visual loss of less than 20/200, which is typically irreversible and may induce CNV in the macula or around the optic disc.15
There are no controlled trials for the treatment of SC due to the rarity of the disease. Cytosine arabinoside, azathioprine, and oral prednisone were used with reported improved visual acuity in one month.16 Employment of a combination of cyclosporine and oral prednisone as a treatment of active SC had conflicting results. Hopper and Kaplan reported a triple-agent regimen of azathioprine, cyclosporine, and oral prednisone that resulted in rapid control of the active SC and vision recovery; however, disease recurrence was the study's main problem.9 Akpek et al. employed the same regimen in a more extended study and found that this regimen helped keep the inflammation quiet during treatment; however, it did not maintain remission off medication.17
Alkylating agents can bind to DNA, interfere with DNA replication, and subsequently interfere with cell division. Cyclophosphamide is commonly used because of its predictable, dose-dependent, and reversible adverse effects on WBC count18; nonetheless, it can result in serious side effects, some of which are life-threatening. These side effects include reversible hematuria, hemorrhagic cystitis, reversible alopecia, sterility, bladder cancer, lymphoma, and leukemia. Chlorambucil is another alkylating agent primarily used for the treatment of several lymphoproliferative diseases. It is a stable derivative of the nitrogen mustard.19 Based on its ability to reduce circulating lymphocytes, chlorambucil is effective in the treatment of rheumatologic diseases, including juvenile rheumatoid arthritis, systemic lupus erythematosus, and nephrotic syndrome.20, 21, 22, 23 Given the availability of other conventional immunomodulatory agents and biologic response modifiers that yield better results with fewer unpredictable side effects, ophthalmologists are reluctant to use chlorambucil. Our knowledge about biologic response modifier agents is limited to a few case reports and some of our patients had already failed infliximab, mycophenolate mofetil, methotreaxte before their first presentation to us or during follow-up with us. Palmer et al. studied the side effects of chlorambucil and found that these side effects are related to the total dose and duration of treatment.24 However, Tessler et al. found chlorambucil to be a successful treatment for different types of uveitis with no severe complications during 12 years of follow-up. They also reported complete remission in all patients. Although chlorambucil dose in their study was administered regardless of body weight, it did not exceed 2.2 g per patient during the entire treatment.25 Based on these findings, recent studies still rely on alkylating agents including cyclophosphamide and chlorambucil for classical and macular SC.5,12,32
It may take more time for chlorambucil to show its therapeutic and toxic effects. Patients on this medication should be monitored with weekly blood counts, specifically WBC and platelet counts, since its side effects are not always dose-related.25 Chlorambucil is administered orally because it has excellent gastrointestinal absorption, and its superiority over cyclophosphamide is related to the absence of associated side effects such as hair loss, hemorrhagic cystitis, and bladder cancer.26
The recommendation for the daily and total dose of chlorambucil is equal to or less than 0.2 mg/kg and 2.2 g, respectively. These recommendations help avoid late complications such as lymphoma and leukemia.27 Various doses of chlorambucil have been employed in the past in the field of ophthalmology. The use of lower doses of chlorambucil over an extended period, such as more than one year, without provoking bone marrow toxicity is one approach.28, 29, 30, 31 However, it has been demonstrated that sustained remission of the disease is achievable when the WBC count remained depressed for at least six weeks. This finding suggests that effective treatment with chlorambucil requires the induction of a toxic hematologic response.25
The recent literature shows that alkylating agents are still the most potent and effective treatment in patients with SC.4,12,32 Venkatesh and colleagues showed that intravenous cyclophosphamide pulse therapy provided a rapid resolution of active lesions and helped maintain good functional visual acuity.4 However, they admitted that this treatment might not prevent recurrences in patients with SC.4 Venkatesh et al. also studied intravenous methylprednisolone and cyclophosphamide in macular SC; they, again demonstrated it could be effective in acute macular SC, yet admitted that this treatment had no effects on disease relapses in the long-term.32 Ebrahimiadib et al. retrospectively studied 17 patients on chlorambucil with dose escalation based on weekly WBC count, with the target of 3000–4500 white blood cells/μl. They concluded that chlorambucil was well tolerated by the patients and was effective in preventing recurrences.12 Although all these recent studies provided important facts regarding SC treatment, they did not discuss the next step for the patients who failed these treatments. In the current study, we decided to evaluate the possible causes of chlorambucil treatment failure in patients with resistant SC and to examine possible successful regimens in these patients. To the best of our knowledge, this study is the first one which evaluates the possible remedy for resistance to chlorambucil as one of the most commonly employed medications in SC patients.
Histopathological studies in SC have demonstrated that lymphocytes infiltrate the choroid, and less commonly, vessels, leading to subsequent choriocapillaris occlusive vasculitis. This finding may indicate the important roles of lymphocytes in the pathogenesis of the disease.5 The histopathology in SC is very similar to birdshot chorioretinopathy.33,34 On the other hand, multiple studies have discussed the effects of long-term systemic corticosteroids on lymphocyte proliferation and T-cell population.35,36 Ferrari et al. reported increased lymphocytes, including increased absolute numbers of T cells, CD4+ and CD8+ cells, after four weeks of corticosteroid therapy in idiopathic thrombocytopenic purpura (ITP).35 Moreover, lymphocyte redistribution has been discussed in long-term steroid therapy.36 These changes associated with long-term corticosteroid use may interfere with the aim of chlorambucil treatment, since cells with higher proliferation rates are the target of this therapy. The negative effect of long-term systemic corticosteroids on birdshot chorioretinopathy has been studied in the past.37,38 Due to similarities between birdshot chorioretinopathy and SC in terms of histopathology, these facts can be applied to SC patients as well.
The target WBC count for chlorambucil therapy for SC is between 3000 and 4500 cells/μl. Chlorambucil dose adjustment is based on a weekly WBC count. In our experience, patients might be considered cured if there is no recurrence during the treatment period, which is around one year. Our observation in this case series showed that patients on high doses of systemic corticosteroids have unstable WBC count during chlorambucil therapy. Keeping this count in the satisfactory range for a reasonable period of at least six weeks can be challenging since it has been shown that induced toxic hematologic response is required for effective treatment with chlorambucil.25 The first two patients in this case series achieved durable remission and were likely cured after employing local corticosteroids or systemic immunomodulatory therapy, which allowed us to stop systemic corticosteroid use during chlorambucil therapy. However, the third and fourth patients are still experiencing recurrences since all systemic immunomodulatory therapies were unable to induce steroid-free remission. Local corticosteroid therapy was also recommended for both of the patients, but its potential side effects and the patients’ monocular statuses made this option unappealing.
We might be criticized for not employing local corticosteroid monotherapy without any systemic therapy. We believe that, although corticosteroids are the best option for controlling of acute ocular inflammation of any type, they are not potent enough to prime or re-program the immune system12 and not to respond to self-antigens as we expect with immunomodulatory therapy. This is similar to what occurs to pathologic cancer cells especially in blood cancers (lymphoma and leukemia) in patients who achieve remission with chemotherapy which is an advanced and more aggressive form of immunomodulatory therapy. Based on the above mentioned theory, corticosteroids as monotherapy cannot halt the inflammation thoroughly, so the ongoing inflammation can cause more cells destruction and epitopes exposures which might result in more resistant ocular inflammation which is believed to happen in patients with resistant autoimmune SC. we assume that the employment of systemic corticosteroid therapy, along with chlorambucil, is the main obstacle in achieving remission in patients with SC. This combination therapy is mostly seen in monocular patients or in vision-threatening SC where there is a lower threshold for aggressive systemic corticosteroid therapy in these patients.
We might also be criticized for using different therapies in one patient; however, we follow the strategy of “one change at a time” and this means that any time a conventional IMT is tried, we wait for three months with no changes to assess its effectiveness. For biologic response modifier agents, we wait for two months. This strategy makes interaction between medications unlikely. Moreover, since our mission is systemic steroid free remission, we only consider a medication to be effective if the inflammation stays in remission even after the effects of steroids are gone. Furthermore, none of these therapies induced long term remission in our patients.
Dexamethasone intravitreal implants have been employed in the treatment of active SC and serpiginous-like choroiditis.39,40 In these studies, the authors showed the success of this implant in controlling active SC. Based on these studies, dexamethasone can be an alternative to high dose oral or intravenous corticosteroid without systemic side effects including its effects on bone marrow, secondary lymphoid tissues, and peripheral blood regarding WBC counts, especially lymphocytes.
One common fact between all patients in this case series is the instability of WBC count during chlorambucil therapy plus systemic corticosteroids. This issue was addressed in one patient with dexamethasone intravitreal implant and in another patient with infliximab therapy. Both patients allowed us to taper and stop oral prednisone during chlorambucil therapy. The latter patient has been in remission for four years, which is the time frame during which one would expect a new lesion based on the Laatikainen and Erkkila et al. study.14 Despite this, this patient continues to take infliximab at a dose of 300 mg every four weeks since there is a fear of SC recurrence once infliximab therapy is terminated. However, this concept and hypothesis need further, more sophisticated examination.
This study had inherent limitations given its retrospective study design with a small sample size due to the rarity of cases of SC. It was even more challenging to find refractory cases with a reasonable follow-up period to expect a recurrence as all of these patients have at least 8 years of follow-up at our center without any serious side effects. Furthermore, all confounding factors cannot be controlled in a retrospective study. Regardless, we believe that confounding factors related to WBC might not interfere in this study since chlorambucil dose is adjusted based on WBC count and in clinical practice, changes in WBC count are typically more related to changes in corticosteroid dosage. Based on all these limitations, the results of this case series should be interpreted with caution and justifies the need for more potent studies.
4 Conclusion
The stability of WBC counts within toxic levels close to normal or lower limits of normal (3000–4500 cells/μl) during treatment with chlorambucil is an essential factor for the success of this therapy. A combination of dexamethasone intravitreal implant with chlorambucil therapy can be an effective and promising regimen in inducing and maintaining remission in refractory SC patients who fail a combination of systemic corticosteroid and chlorambucil therapy as the first line therapy. However, this primitive hypothesis should be investigated with more potent studies and larger sample sizes.
Patient consent
Consent to publish the personal information and cases details was obtained from all the patients.
Financial supports
None.
All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.
Disclosures
Dr. C Stephen Foster declares the following: Consultancies with Aldeyra Therapeutics (Lexington, MA), Allakos (Redwood City, CA), Bausch & Lomb Surgical, Inc (Rancho Cucamonga, CA), Eyegate Pharma (Waltham, MA), Genentech (South San Francisco, CA), Novartis (Cambridge, MA), pSivida (Watertown, MA) Grants or grants pending with Aciont (Salt Lake City, UT), Alcon (Aliso Viejo, CA), Aldeyra Therapeutics (Lexington, MA), Bausch & Lomb (Rochester, NY), Clearside Biomedical (Alpharetta, GA), Dompé pharmaceutical (Milan, Italy), Eyegate Pharma (Waltham, MA), Mallinckrodt pharmaceuticals (Staines-upon-Thames, UK), Novartis Pharmaceuticals (Cambridge, MA), pSivida (Watertown, MA), Santen (Osaka, Japan). Payment for lectures including service on speaking bureaus: Alcon (Aliso Viejo, CA), Allergan (Dublin, Ireland), Mallinckrodt pharmaceuticals (Staines-upon-Thames, UK). Stock or Stock Options: Eyegate Pharma (Waltham, MA).
The other authors have nothing to declare.
Compliance with ethics guidelines
This study was approved by the New England Institutional Review Board, which has issued a waiver of informed consent for the retrospective chart review analysis. This study was performed in accordance with the Helsinki Declaration of 1964, and its later amendments. All participants provided consent for publication if any identifying information is included in the manuscript.
Data availability
The data that support the findings of this study are available from the corresponding author, upon reasonable request.
Declaration of competing interest
No conflicting relationship exists for any author. | CHLORAMBUCIL, PREDNISONE | DrugsGivenReaction | CC BY-NC-ND | 33615036 | 19,163,199 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Metamorphopsia'. | Chlorambucil combination therapy in refractory serpiginous choroiditis: A cure?
To find a remedy for serpiginous choroiditis refractory to oral prednisone and chlorambucil treatment.
Eight eyes of four patients (all female) with advanced macular involvement secondary to serpiginous choroiditis were included in the study. The average age of the patients was 45.2 years. One eye of each patient was legally blind and the lesion was close to the fovea in the other eye. All four patients failed oral prednisone and chlorambucil therapy. However, case 1 responded to chlorambucil treatment after intravitreal dexamethasone implant implantation and discontinuation of oral prednisone. Case 2 responded to chlorambucil therapy when oral prednisone was stopped in combination with infliximab therapy. Due to long follow-up period of more than four years, these two cases are considered to be cured. Case 3 and case 4 were not able to achieve remission with chlorambucil and immunomodulatory therapy. They refused intravitreal steroid implant due to side effects profile.
The stability of WBC counts within toxic levels close to normal or lower limits of normal (3000-4500 cells/μl) during treatment with chlorambucil is an essential factor for the success of this therapy. A combination of dexamethasone intravitreal implant with chlorambucil therapy can be an effective and promising regimen in inducing and maintaining remission in refractory serpiginous choroiditis patients who fail a combination of systemic corticosteroid and chlorambucil therapy.
1 Introduction
Serpiginous choroiditis (SC) is a rare, chronic, asymmetrically bilateral posterior uveitis with a recurrent course. The exact prevalence of SC is unknown; however, it is estimated between 1.6% and 5.3% of posterior uveitis cases in non-endemic areas for tuberculosis.1 Major features of SC include choriocapillaris occlusive vasculitis, secondary endothelial cell injury, and subsequent atrophy of the retinal pigment epithelium, outer retina, and choroid.2,3 Histopathology studies reveal lymphocytic infiltration in the choroid and, less commonly, around vessels.4 The peripapillary area is classically involved in SC and accounts for 80% of the cases.5 The prognosis of vision is poor when it involves the macula, especially in the macular variant of SC. Moreover, the macular variant has a higher risk of developing choroidal neovascularization in nearly half of the affected patients.6,7 Fluorescein angiography (FA), indocyanine green angiography (ICG), optical coherence tomography (OCT), fundus autofluorescence (FAF), and microperimetry are the ancillary diagnostic tools and tests which help in the diagnosis, follow-up, and monitoring for secondary complications.1
Historically, the administration of high doses of oral or intravenous steroids was considered as the standard of care for patients with SC.8 However, immunosuppressive agents such as azathioprine, cyclosporine, chlorambucil, and cyclophosphamide emerged as treatment options for steroid-free remission.4,9, 10, 11, 12 Of these, the alkylating agents cyclophosphamide and chlorambucil have been noted to have a high success rate in the treatment of SC.4,10,12 Chlorambucil, being a potent alkylating agent, can interfere with DNA replication and cell division.13 This medication can induce remission, maintain remission, and even cure this disease.12
Despite successful treatment of SC with alkylating agents, in some patients the disease can recur frequently and progress to affect the central vision. This becomes more important in patients with poor vision in the other eye secondary to SC or advanced SC encroaching the fovea in the affected eye. In this case series, we decided to evaluate possible remedies for refractory and recurrent SC in patients who have been treated with chlorambucil and oral or intravenous corticosteroids.
2 4 Cases
Case 1. A sixty-year-old female was referred to us for the evaluation of macular SC OU. She had noticed blurry vision OS one month before her first visit with us. A geographic lesion with indistinct and irregular borders was observed in both eyes. The lesion was uni-centric OU, temporal to fovea OD and peripapillary with extension to fovea OS. FA and ICG showed the activity of the lesions in both eyes (Fig. 1A). Her best-corrected visual acuity (BCVA) was 20/20 OD and decreased OS to 20/100. Complete blood work-up for uveitis ruled out non-infectious and infectious posterior uveitis, including syphilis and tuberculosis. Based on these findings, she was diagnosed with autoimmune SC OU and was started on a combination of chlorambucil and daily oral prednisone. Chlorambucil was titrated based on her white blood cell (WBC) count. She had another flare-up while she was on 2 mg/day prednisone and had already stopped chlorambucil for three weeks due to WBC 3200 cells/μl. BCVA OS decreased to 20/125, and ICGA confirmed enlargement of the lesion. Chlorambucil was restarted to 2 mg every other day, and oral prednisone was increased to 5 mg/day. With this change in her regimen, the vision increased to the baseline before her last flare, to 20/40. Treatment with chlorambucil was stopped after one year. Her follow-up visit increased to every three months from monthly. Then, six months later, she was started on oral methotrexate 7.5 mg weekly by her rheumatologist because of her joint issues. She was followed every three months for seven months until she noticed a change in OS again. At that time, she was on oral methotrexate 15 mg weekly. BCVA OS decreased to 20/125, and ancillary tests showed activity at the border of the lesions on the foveal side (Fig. 1B). She received one dose of 1 g intravenous methylprednisolone, intravitreal injection of triamcinolone and bevacizumab, and was restarted on oral prednisone 80 mg/day. A week later, her methotrexate dose was boosted to methotrexate 25 mg weekly subcutaneous injections, and we tapered prednisone 10 mg weekly. In three months, oral prednisone was tapered and stopped. Three months later, her lesion became active and she developed choroidal neovascularization (CNV) for which she received a bevacizumab injection. She was restarted on chlorambucil and oral prednisone. The decision for local therapy with dexamethasone implant was made at this point, and she was put back on chlorambucil 2 mg every three days. She was on chlorambucil without oral prednisone, titrating the dose based on WBC for seventeen months, after which she was considered cured (Fig. 1C). In her last visit with us, her BCVA OD and OS were 20/20 and 20/50, respectively. The patient's average WBC count while on chlorambucil with prednisone, chlorambucil without prednisone, and chlorambucil after dexamethasone intravitreal implant were 5500 ± 2900, 4700 ± 1100 and 4100 ± 500 cells/μl, respectively. The total duration of treatment before dexamethasone intravitreal implant was 60 months and 17 months after dexamethasone intravitreal implant. The total length of follow-up is 132 months, and the total duration of remission off medication is 48 months (Table 1).Fig. 1 A patient with bilateral serpiginous choroidopathy. (A) Serpiginous lesions in both eyes, encroaching the fovea in right eye and with foveal involvement in left eye. Fluoresecein angiography shows activity in both eyes. (B) The middle row shows progression towards the fovea with leakage pointing toward the fovea in the right eye. (C) Shows the stability of fundus photos and fluorescein angiography in both eyes at one year after intravitreal dexamethasone implant and chlorambucil treatment.
Fig. 1Table 1 Demographics and clinical characteristics of patients with resistant serpiginous choroiditis.
Table 1 Age years Sex Laterality BCVA first visit WBC (C + P) cells/μl
(x 10c) WBC (C) cells/μl
(x 10c) WBC (C + IMTor implan cells/μl (*10c) Duration of treatment before IMT Duration of treatment after IMT Duration of follow-up on chlorambucil Duration of follow-up off chlorambucil BCVA last visit
Patient 1 60 F Bilat 20/20 20/100 5.5 ± 2.9 4.7 ± 1.1 4.1 ± 0.5 60a months 17b months 60 months 83 months 20/20 20/50
OD
OS
Patient 2 42 F Bilat 1 mcf 20/20 5.7 ± 2.2 N/A 3.8 ± 0.5 40c months 19d months 49 months 60 months 1mcf
20/15
OD
OS
Patient 3 32 F Bilat HM 20/20 8.8 ± 3.4 N/A N/A 5 + 10 e months N/A 5 months N/A HM 20/50
OD
OS
Patient 4 47 F Bilat 20/30 1mcf 6.2 ± 3.3 N/A N/A N/A N/A 12 months N/A 20/50 1mcf
OD
OS
BCVA:best corrected visual acuity; Bilat:bilateral; C:chlorambucil; CF:counting fingers; HM:hand motion; IMT:immunomodulatory therapy; P:prednisone; N/A:not applicable.
a Before intravitreal dexamethasone implant.
b After intravitreal dexamethasone implant.
c Before starting infliximab.
d After starting infliximab.
e 5 months chlorambucil and 10 months cyclophosphamide.
Case 2. A 42-year-old female was referred to us with blurry vision and field distortion OD for ten years and OS for eight years. Her vision was counting fingers at 1 m OD and 20/20 OS. At the time of presentation, the patient had already received multiple intravitreal anti-VEGF (bevacizumab) and triamcinolone injections OD. The geographic lesions were peripapillary OU, with foveal involvement OD. Initial FA revealed chorioretinal scarring with window defects OU and leakage on borders OD (Fig. 2A). On ICG, the area of hypolucency OS extended further into the macula, which was not seen on FA (Fig. 2B). Complete blood work-up for uveitis ruled out non-infectious and infectious posterior uveitis, including syphilis and tuberculosis. Based on these findings, she was diagnosed with autoimmune SC OU and we recommended therapy with chlorambucil. She sought a second opinion elsewhere, where she was started on mycophenolate mofetil (MMF) 1 g daily with infliximab 300 mg IV every four weeks and oral prednisone 80 mg/day with taper. MMF and infliximab were eventually discontinued due to elevated LFTs. On follow up at our clinic eighteen months after the initial consult, chlorambucil was finally started with dose adjustment based on weekly monitoring of WBC count to reach the endpoint of WBC count 3000–4500 cells/μl. While on chlorambucil 20mg and prednisone 40mg daily, the patient became symptomatic OS with new changes and leakage on FA OS, prompting boosting of oral prednisone to 80 mg; she also received one ranibizumab injection OS locally. Six weeks after starting treatment with chlorambucil (20mg at this time) and oral prednisone 80 mg daily, WBC count dropped down to 4900 cells/μl, so we started tapering prednisone. Two months after initiation of chlorambucil therapy, chlorambucil was stopped while tapering prednisone at 30 mg/day with a WBC count of 3300 cells/μl. At this point, FA, FAF, and OCT showed stability and quiescence. On a subsequent visit with her local ophthalmologist, infliximab 600 mg infusions every four weeks was started for activity OS, and eventually increased to 900 mg every four weeks in combination with chlorambucil. WBC count increased to 7900 cells/μl while on prednisone 10 mg with taper, and chlorambucil was restarted at 4 mg daily, eventually going up to 6 mg daily (Fig. 2B). Chlorambucil dose adjustment with weekly WBC count was continued. Meanwhile, she received a bevacizumab injection with her local ophthalmologist due to central vision distortion OD. On her eight-month of treatment, WBC count dipped to 2000 cells/μl, and chlorambucil was stopped. After one week, with WBC count creeping back up to 4800 cells/μl, chlorambucil was restarted at 2 mg/day. Disease activity was then noted at ten months from treatment initiation with no interventions at that time. On follow up at our clinic fourteen months after starting chlorambucil, the activity noted at ten months prompted treatment extension, and the patient was educated on the risks vs. benefits of this decision. Chlorambucil treatment was continued for a total duration of twenty-one months. FA and OCT macula findings were stable and the patient was asymptomatic (Fig. 2C,D). Subsequent consults established disease stability with no new symptoms or activity. Infliximab was eventually tapered by 100 mg every four weeks. On her last consult at our clinic, she was on infliximab 100 mg infusions every four weeks with a final VA of 20/400 OD and 20/15 OS and stable findings on FA and macula OCT. Her average WBC count was 5700 ± 2200 cells/μl while on chlorambucil with prednisone, and 3800 ± 500 cells/μl when she was on chlorambucil after starting infliximab infusions without prednisone. The total duration of treatment before and after beginning infliximab infusions was 40 and 19 months, respectively. The total length of follow-up is 108 months. The total period of remission off chlorambucil is 60 months (Table 1).Fig. 2 (A) Fundus photo and fluorescein angiography of a patient with bilateral serpiginous choroiditis at the primary visit at our clinic. (B) The same patient during a recurrence in the left eye close to the fovea. (C,D) Stability of year after stopping chlorambucil while on infliximab tapering. (E) Macular optical coherence tomography at the first visit (left), during a recurrence (middle), and the last visit (right).
Fig. 2
Case 3. A 32-year-old female presented with decreased vision, floaters, and photophobia OS. Vision OD was poor due to retinal detachment after a motor vehicle accident. Before presenting to her initial consultation at our clinic, complete blood work-up for uveitis had ruled out non-infectious and infectious posterior uveitis, including syphilis and tuberculosis and she had already been diagnosed with idiopathic SC. She had been on MMF 2 g daily, cyclosporin 25 mg and prednisone 30 mg daily for fourteen months. Her vision was hand-motion OD and 20/20 OS at presentation. A fundus examination revealed optic atrophy and a horizontal scar OD in addition to diffuse chorioretinal (CR) scarring in both eyes. Given the possibility of the activity of the lesion potentially affecting the fovea OS and her monocular status, chlorambucil and cyclophosphamide were discussed as treatment options.
The patient was started on chlorambucil 4 mg daily and continued on 25 mg of prednisone daily. A month later, her WBC count dropped from 14,800 to 12,100 cells/μl. However, she felt her vision had decreased once again after two weeks on chlorambucil. She was advised to increase chlorambucil to 6 mg/day from 4 mg/day, as well as increase prednisone to 40 mg daily. After one week at this dose, she reported stable vision OD. Chlorambucil dose adjustment with weekly WBC count and oral prednisone were continued until she reported stable vision and no other symptoms. At this time, she was advised to increase chlorambucil to 12 mg daily.
Approximately four months after her initial visit, the patient presented to our clinic with worsening scotoma and floaters OS. At this point, she was on prednisone 5 mg daily and chlorambucil 10 mg daily. She had stopped chlorambucil for a week due to fever, and the WBC count was at 11,200 cells/μl. FA and ICG showed active choroidal inflammation at the lesion border, especially OS. Later on, she developed a diffuse, itchy rash, and because of this side effect, she was started on bi-weekly cyclophosphamide pulse therapy. She had five doses of cyclophosphamide pulse therapy, and her WBC count was between 4500 and 6300 cells/μl. However, a few days later, she complained of decreased vision OS with more central involvement. Her local ophthalmologist increased her prednisone to 60 mg, and she received her next cyclophosphamide infusion four days later with WBC count at 4000 cells/μl. Cyclophosphamide therapy was finally stopped due to persistent skin rash.
In the interim, she followed up with her local ophthalmologist while on oral prednisone with different doses based on disease activity. Her next visit with us was seven years later, and vision OS had deteriorated to 20/50. FA showed active inflammation OS in the form of enlarged CR lesions approaching the fovea with multifocal areas of leakage at the margins of the lesions (Fig. 3B). Up to that point, the patient had been off all immunomodulatory therapy (IMT) for seven years, yet only cyclophosphamide appeared to halt the progression of her disease. Monthly cyclophosphamide pulse therapy was resumed but was later stopped after eight months due to low WBC count. After this, she continued with oral prednisone 20 mg daily. At her last follow-up visit, chlorambucil was restarted due to the persistence of symptoms, worsening of vision OS, and the progression of lesion activity on imaging (Fig. 3C). Intravitreal steroid implants were also discussed. The patient was never able to taper off oral prednisone during treatment, and the average WBC count during her course of treatment was 8800 ± 3400 cells/μl. The total duration of treatment with chlorambucil was 5 months, cyclophosphamide was 10 months, and MMF plus cyclosporine was 14 months. The total duration of follow-up is 148 months. She has never been in remission for an extended period off medication (Table 1).Fig. 3 (A) Fundus photo of both eyes of a patient with bilateral serpiginous choroiditis. History of traumatic retinal detachment surgery with legal blindness in the right eye and active serpiginous choroiditis in the left eye. Fluorescein angiography shows an active lesion in the left eye. (B) Optical coherence tomography, fundus autofluorescence, and fluorescein angiography during a recurrence where the patient was started on cyclophosphamide pulse therapy. (C) Progression of the lesion in the left eye with an active lesion in fluorescein angiography at her last visit. Intravitreal dexamethasone and triamcinolone implants were discussed at this visit.
Fig. 3
Case 4. A 47-year-old female was referred to our center with decreased vision OU for one month and had been started on prednisone 50 mg daily before her first visit with us. Her vision OD and OS were 20/30 and counting fingers at 1 m, respectively, at presentation. Dilated fundoscopy showed bilateral geographic lesions nasal to the fovea OD and involving the fovea OS (Fig. 4A). Complete blood work-up for uveitis ruled out non-infectious and infectious posterior uveitis, including syphilis and tuberculosis. Based on these findings, and she was diagnosed with autoimmune SC OU. Oral prednisone was increased to 60 mg daily, and due to significant vision loss OS, she was started on chlorambucil 6 mg daily. Chlorambucil treatment with WBC count monitoring and tapering of oral prednisone was continued for a year. Once the oral prednisone taper was completed, she continued with chlorambucil monotherapy for five more months, at which time she had achieved remission. After four months; however, she had a flare-up OD, which was first treated with 1 g IV methylprednisolone infusion and intravenous methotrexate 200 mg/day. Subsequently, she was continued on subcutaneous methotrexate 15 mg weekly along with folic acid 1 mg/day for two years. She developed another flare-up when tapering methotrexate; hence methotrexate dose was boosted, and a combination of chlorambucil and oral prednisone was restarted. The patient was on chlorambucil and oral prednisone for one year, with an average WBC count of 6200 ± 3300 cells/μl. The patient was then on chlorambucil alone for another two months. She had been flare-free for twenty months when she had another episode. This time she was treated with intravenous and subcutaneous methotrexate. She had another flare during tapering of methotrexate and she is currently on a combination of chlorambucil, prednisone, and subcutaneous methotrexate therapy. The total duration of follow-up has been 116 months. She has never been in remission for an extended period (Table 1).Fig. 4 A serpiginous choroiditis patient with multiple recurrences despite treatment with a combination of oral prednisone and chlorambucil therapy. (A) Color fundus photos and fluorescein angiography of both eyes at the first visit, which showed activity around the lesion in both eyes. (B) The second row shows the progression of lesions in both eyes during a recurrence on fundus photos and fundus autofluorescence. (C) Fundus autofluorescence and fluorescein angiography showed reactivation of the supratemporal area of the lesion in the right eye. (D) Optical coherence tomography shows the lesion, edema, and destruction of the supratemporal part of the lesion, compatible with fundus autofluorescence and fluorescein angiography. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)
Fig. 4
3 Discussion
The pathogenesis of serpiginous choroiditis (SC) is unknown. The course of the disease is indolent and can be asymptomatic until it involves the macula and the central vision. Many patients can have old scars even at the first visit when they are diagnosed with SC.14 Laatikainen and Erkkila et al. reported that new lesions may appear at an interval of 3 months–4 years. They also demonstrated that active lesions resolve in a few weeks; however, signs of activity may last between 1 and 9 months.14 Central vision is involved in 20%–50% of cases, with the likelihood increasing with longer duration of follow-up and disease activity.8,14 Recurrences that affect the macula can cause severe visual loss of less than 20/200, which is typically irreversible and may induce CNV in the macula or around the optic disc.15
There are no controlled trials for the treatment of SC due to the rarity of the disease. Cytosine arabinoside, azathioprine, and oral prednisone were used with reported improved visual acuity in one month.16 Employment of a combination of cyclosporine and oral prednisone as a treatment of active SC had conflicting results. Hopper and Kaplan reported a triple-agent regimen of azathioprine, cyclosporine, and oral prednisone that resulted in rapid control of the active SC and vision recovery; however, disease recurrence was the study's main problem.9 Akpek et al. employed the same regimen in a more extended study and found that this regimen helped keep the inflammation quiet during treatment; however, it did not maintain remission off medication.17
Alkylating agents can bind to DNA, interfere with DNA replication, and subsequently interfere with cell division. Cyclophosphamide is commonly used because of its predictable, dose-dependent, and reversible adverse effects on WBC count18; nonetheless, it can result in serious side effects, some of which are life-threatening. These side effects include reversible hematuria, hemorrhagic cystitis, reversible alopecia, sterility, bladder cancer, lymphoma, and leukemia. Chlorambucil is another alkylating agent primarily used for the treatment of several lymphoproliferative diseases. It is a stable derivative of the nitrogen mustard.19 Based on its ability to reduce circulating lymphocytes, chlorambucil is effective in the treatment of rheumatologic diseases, including juvenile rheumatoid arthritis, systemic lupus erythematosus, and nephrotic syndrome.20, 21, 22, 23 Given the availability of other conventional immunomodulatory agents and biologic response modifiers that yield better results with fewer unpredictable side effects, ophthalmologists are reluctant to use chlorambucil. Our knowledge about biologic response modifier agents is limited to a few case reports and some of our patients had already failed infliximab, mycophenolate mofetil, methotreaxte before their first presentation to us or during follow-up with us. Palmer et al. studied the side effects of chlorambucil and found that these side effects are related to the total dose and duration of treatment.24 However, Tessler et al. found chlorambucil to be a successful treatment for different types of uveitis with no severe complications during 12 years of follow-up. They also reported complete remission in all patients. Although chlorambucil dose in their study was administered regardless of body weight, it did not exceed 2.2 g per patient during the entire treatment.25 Based on these findings, recent studies still rely on alkylating agents including cyclophosphamide and chlorambucil for classical and macular SC.5,12,32
It may take more time for chlorambucil to show its therapeutic and toxic effects. Patients on this medication should be monitored with weekly blood counts, specifically WBC and platelet counts, since its side effects are not always dose-related.25 Chlorambucil is administered orally because it has excellent gastrointestinal absorption, and its superiority over cyclophosphamide is related to the absence of associated side effects such as hair loss, hemorrhagic cystitis, and bladder cancer.26
The recommendation for the daily and total dose of chlorambucil is equal to or less than 0.2 mg/kg and 2.2 g, respectively. These recommendations help avoid late complications such as lymphoma and leukemia.27 Various doses of chlorambucil have been employed in the past in the field of ophthalmology. The use of lower doses of chlorambucil over an extended period, such as more than one year, without provoking bone marrow toxicity is one approach.28, 29, 30, 31 However, it has been demonstrated that sustained remission of the disease is achievable when the WBC count remained depressed for at least six weeks. This finding suggests that effective treatment with chlorambucil requires the induction of a toxic hematologic response.25
The recent literature shows that alkylating agents are still the most potent and effective treatment in patients with SC.4,12,32 Venkatesh and colleagues showed that intravenous cyclophosphamide pulse therapy provided a rapid resolution of active lesions and helped maintain good functional visual acuity.4 However, they admitted that this treatment might not prevent recurrences in patients with SC.4 Venkatesh et al. also studied intravenous methylprednisolone and cyclophosphamide in macular SC; they, again demonstrated it could be effective in acute macular SC, yet admitted that this treatment had no effects on disease relapses in the long-term.32 Ebrahimiadib et al. retrospectively studied 17 patients on chlorambucil with dose escalation based on weekly WBC count, with the target of 3000–4500 white blood cells/μl. They concluded that chlorambucil was well tolerated by the patients and was effective in preventing recurrences.12 Although all these recent studies provided important facts regarding SC treatment, they did not discuss the next step for the patients who failed these treatments. In the current study, we decided to evaluate the possible causes of chlorambucil treatment failure in patients with resistant SC and to examine possible successful regimens in these patients. To the best of our knowledge, this study is the first one which evaluates the possible remedy for resistance to chlorambucil as one of the most commonly employed medications in SC patients.
Histopathological studies in SC have demonstrated that lymphocytes infiltrate the choroid, and less commonly, vessels, leading to subsequent choriocapillaris occlusive vasculitis. This finding may indicate the important roles of lymphocytes in the pathogenesis of the disease.5 The histopathology in SC is very similar to birdshot chorioretinopathy.33,34 On the other hand, multiple studies have discussed the effects of long-term systemic corticosteroids on lymphocyte proliferation and T-cell population.35,36 Ferrari et al. reported increased lymphocytes, including increased absolute numbers of T cells, CD4+ and CD8+ cells, after four weeks of corticosteroid therapy in idiopathic thrombocytopenic purpura (ITP).35 Moreover, lymphocyte redistribution has been discussed in long-term steroid therapy.36 These changes associated with long-term corticosteroid use may interfere with the aim of chlorambucil treatment, since cells with higher proliferation rates are the target of this therapy. The negative effect of long-term systemic corticosteroids on birdshot chorioretinopathy has been studied in the past.37,38 Due to similarities between birdshot chorioretinopathy and SC in terms of histopathology, these facts can be applied to SC patients as well.
The target WBC count for chlorambucil therapy for SC is between 3000 and 4500 cells/μl. Chlorambucil dose adjustment is based on a weekly WBC count. In our experience, patients might be considered cured if there is no recurrence during the treatment period, which is around one year. Our observation in this case series showed that patients on high doses of systemic corticosteroids have unstable WBC count during chlorambucil therapy. Keeping this count in the satisfactory range for a reasonable period of at least six weeks can be challenging since it has been shown that induced toxic hematologic response is required for effective treatment with chlorambucil.25 The first two patients in this case series achieved durable remission and were likely cured after employing local corticosteroids or systemic immunomodulatory therapy, which allowed us to stop systemic corticosteroid use during chlorambucil therapy. However, the third and fourth patients are still experiencing recurrences since all systemic immunomodulatory therapies were unable to induce steroid-free remission. Local corticosteroid therapy was also recommended for both of the patients, but its potential side effects and the patients’ monocular statuses made this option unappealing.
We might be criticized for not employing local corticosteroid monotherapy without any systemic therapy. We believe that, although corticosteroids are the best option for controlling of acute ocular inflammation of any type, they are not potent enough to prime or re-program the immune system12 and not to respond to self-antigens as we expect with immunomodulatory therapy. This is similar to what occurs to pathologic cancer cells especially in blood cancers (lymphoma and leukemia) in patients who achieve remission with chemotherapy which is an advanced and more aggressive form of immunomodulatory therapy. Based on the above mentioned theory, corticosteroids as monotherapy cannot halt the inflammation thoroughly, so the ongoing inflammation can cause more cells destruction and epitopes exposures which might result in more resistant ocular inflammation which is believed to happen in patients with resistant autoimmune SC. we assume that the employment of systemic corticosteroid therapy, along with chlorambucil, is the main obstacle in achieving remission in patients with SC. This combination therapy is mostly seen in monocular patients or in vision-threatening SC where there is a lower threshold for aggressive systemic corticosteroid therapy in these patients.
We might also be criticized for using different therapies in one patient; however, we follow the strategy of “one change at a time” and this means that any time a conventional IMT is tried, we wait for three months with no changes to assess its effectiveness. For biologic response modifier agents, we wait for two months. This strategy makes interaction between medications unlikely. Moreover, since our mission is systemic steroid free remission, we only consider a medication to be effective if the inflammation stays in remission even after the effects of steroids are gone. Furthermore, none of these therapies induced long term remission in our patients.
Dexamethasone intravitreal implants have been employed in the treatment of active SC and serpiginous-like choroiditis.39,40 In these studies, the authors showed the success of this implant in controlling active SC. Based on these studies, dexamethasone can be an alternative to high dose oral or intravenous corticosteroid without systemic side effects including its effects on bone marrow, secondary lymphoid tissues, and peripheral blood regarding WBC counts, especially lymphocytes.
One common fact between all patients in this case series is the instability of WBC count during chlorambucil therapy plus systemic corticosteroids. This issue was addressed in one patient with dexamethasone intravitreal implant and in another patient with infliximab therapy. Both patients allowed us to taper and stop oral prednisone during chlorambucil therapy. The latter patient has been in remission for four years, which is the time frame during which one would expect a new lesion based on the Laatikainen and Erkkila et al. study.14 Despite this, this patient continues to take infliximab at a dose of 300 mg every four weeks since there is a fear of SC recurrence once infliximab therapy is terminated. However, this concept and hypothesis need further, more sophisticated examination.
This study had inherent limitations given its retrospective study design with a small sample size due to the rarity of cases of SC. It was even more challenging to find refractory cases with a reasonable follow-up period to expect a recurrence as all of these patients have at least 8 years of follow-up at our center without any serious side effects. Furthermore, all confounding factors cannot be controlled in a retrospective study. Regardless, we believe that confounding factors related to WBC might not interfere in this study since chlorambucil dose is adjusted based on WBC count and in clinical practice, changes in WBC count are typically more related to changes in corticosteroid dosage. Based on all these limitations, the results of this case series should be interpreted with caution and justifies the need for more potent studies.
4 Conclusion
The stability of WBC counts within toxic levels close to normal or lower limits of normal (3000–4500 cells/μl) during treatment with chlorambucil is an essential factor for the success of this therapy. A combination of dexamethasone intravitreal implant with chlorambucil therapy can be an effective and promising regimen in inducing and maintaining remission in refractory SC patients who fail a combination of systemic corticosteroid and chlorambucil therapy as the first line therapy. However, this primitive hypothesis should be investigated with more potent studies and larger sample sizes.
Patient consent
Consent to publish the personal information and cases details was obtained from all the patients.
Financial supports
None.
All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.
Disclosures
Dr. C Stephen Foster declares the following: Consultancies with Aldeyra Therapeutics (Lexington, MA), Allakos (Redwood City, CA), Bausch & Lomb Surgical, Inc (Rancho Cucamonga, CA), Eyegate Pharma (Waltham, MA), Genentech (South San Francisco, CA), Novartis (Cambridge, MA), pSivida (Watertown, MA) Grants or grants pending with Aciont (Salt Lake City, UT), Alcon (Aliso Viejo, CA), Aldeyra Therapeutics (Lexington, MA), Bausch & Lomb (Rochester, NY), Clearside Biomedical (Alpharetta, GA), Dompé pharmaceutical (Milan, Italy), Eyegate Pharma (Waltham, MA), Mallinckrodt pharmaceuticals (Staines-upon-Thames, UK), Novartis Pharmaceuticals (Cambridge, MA), pSivida (Watertown, MA), Santen (Osaka, Japan). Payment for lectures including service on speaking bureaus: Alcon (Aliso Viejo, CA), Allergan (Dublin, Ireland), Mallinckrodt pharmaceuticals (Staines-upon-Thames, UK). Stock or Stock Options: Eyegate Pharma (Waltham, MA).
The other authors have nothing to declare.
Compliance with ethics guidelines
This study was approved by the New England Institutional Review Board, which has issued a waiver of informed consent for the retrospective chart review analysis. This study was performed in accordance with the Helsinki Declaration of 1964, and its later amendments. All participants provided consent for publication if any identifying information is included in the manuscript.
Data availability
The data that support the findings of this study are available from the corresponding author, upon reasonable request.
Declaration of competing interest
No conflicting relationship exists for any author. | BEVACIZUMAB, CHLORAMBUCIL, INFLIXIMAB, MYCOPHENOLATE MOFETIL, PREDNISONE, RANIBIZUMAB, TRIAMCINOLONE | DrugsGivenReaction | CC BY-NC-ND | 33615036 | 19,000,865 | 2021-03 |
What was the administration route of drug 'INFLIXIMAB'? | Chlorambucil combination therapy in refractory serpiginous choroiditis: A cure?
To find a remedy for serpiginous choroiditis refractory to oral prednisone and chlorambucil treatment.
Eight eyes of four patients (all female) with advanced macular involvement secondary to serpiginous choroiditis were included in the study. The average age of the patients was 45.2 years. One eye of each patient was legally blind and the lesion was close to the fovea in the other eye. All four patients failed oral prednisone and chlorambucil therapy. However, case 1 responded to chlorambucil treatment after intravitreal dexamethasone implant implantation and discontinuation of oral prednisone. Case 2 responded to chlorambucil therapy when oral prednisone was stopped in combination with infliximab therapy. Due to long follow-up period of more than four years, these two cases are considered to be cured. Case 3 and case 4 were not able to achieve remission with chlorambucil and immunomodulatory therapy. They refused intravitreal steroid implant due to side effects profile.
The stability of WBC counts within toxic levels close to normal or lower limits of normal (3000-4500 cells/μl) during treatment with chlorambucil is an essential factor for the success of this therapy. A combination of dexamethasone intravitreal implant with chlorambucil therapy can be an effective and promising regimen in inducing and maintaining remission in refractory serpiginous choroiditis patients who fail a combination of systemic corticosteroid and chlorambucil therapy.
1 Introduction
Serpiginous choroiditis (SC) is a rare, chronic, asymmetrically bilateral posterior uveitis with a recurrent course. The exact prevalence of SC is unknown; however, it is estimated between 1.6% and 5.3% of posterior uveitis cases in non-endemic areas for tuberculosis.1 Major features of SC include choriocapillaris occlusive vasculitis, secondary endothelial cell injury, and subsequent atrophy of the retinal pigment epithelium, outer retina, and choroid.2,3 Histopathology studies reveal lymphocytic infiltration in the choroid and, less commonly, around vessels.4 The peripapillary area is classically involved in SC and accounts for 80% of the cases.5 The prognosis of vision is poor when it involves the macula, especially in the macular variant of SC. Moreover, the macular variant has a higher risk of developing choroidal neovascularization in nearly half of the affected patients.6,7 Fluorescein angiography (FA), indocyanine green angiography (ICG), optical coherence tomography (OCT), fundus autofluorescence (FAF), and microperimetry are the ancillary diagnostic tools and tests which help in the diagnosis, follow-up, and monitoring for secondary complications.1
Historically, the administration of high doses of oral or intravenous steroids was considered as the standard of care for patients with SC.8 However, immunosuppressive agents such as azathioprine, cyclosporine, chlorambucil, and cyclophosphamide emerged as treatment options for steroid-free remission.4,9, 10, 11, 12 Of these, the alkylating agents cyclophosphamide and chlorambucil have been noted to have a high success rate in the treatment of SC.4,10,12 Chlorambucil, being a potent alkylating agent, can interfere with DNA replication and cell division.13 This medication can induce remission, maintain remission, and even cure this disease.12
Despite successful treatment of SC with alkylating agents, in some patients the disease can recur frequently and progress to affect the central vision. This becomes more important in patients with poor vision in the other eye secondary to SC or advanced SC encroaching the fovea in the affected eye. In this case series, we decided to evaluate possible remedies for refractory and recurrent SC in patients who have been treated with chlorambucil and oral or intravenous corticosteroids.
2 4 Cases
Case 1. A sixty-year-old female was referred to us for the evaluation of macular SC OU. She had noticed blurry vision OS one month before her first visit with us. A geographic lesion with indistinct and irregular borders was observed in both eyes. The lesion was uni-centric OU, temporal to fovea OD and peripapillary with extension to fovea OS. FA and ICG showed the activity of the lesions in both eyes (Fig. 1A). Her best-corrected visual acuity (BCVA) was 20/20 OD and decreased OS to 20/100. Complete blood work-up for uveitis ruled out non-infectious and infectious posterior uveitis, including syphilis and tuberculosis. Based on these findings, she was diagnosed with autoimmune SC OU and was started on a combination of chlorambucil and daily oral prednisone. Chlorambucil was titrated based on her white blood cell (WBC) count. She had another flare-up while she was on 2 mg/day prednisone and had already stopped chlorambucil for three weeks due to WBC 3200 cells/μl. BCVA OS decreased to 20/125, and ICGA confirmed enlargement of the lesion. Chlorambucil was restarted to 2 mg every other day, and oral prednisone was increased to 5 mg/day. With this change in her regimen, the vision increased to the baseline before her last flare, to 20/40. Treatment with chlorambucil was stopped after one year. Her follow-up visit increased to every three months from monthly. Then, six months later, she was started on oral methotrexate 7.5 mg weekly by her rheumatologist because of her joint issues. She was followed every three months for seven months until she noticed a change in OS again. At that time, she was on oral methotrexate 15 mg weekly. BCVA OS decreased to 20/125, and ancillary tests showed activity at the border of the lesions on the foveal side (Fig. 1B). She received one dose of 1 g intravenous methylprednisolone, intravitreal injection of triamcinolone and bevacizumab, and was restarted on oral prednisone 80 mg/day. A week later, her methotrexate dose was boosted to methotrexate 25 mg weekly subcutaneous injections, and we tapered prednisone 10 mg weekly. In three months, oral prednisone was tapered and stopped. Three months later, her lesion became active and she developed choroidal neovascularization (CNV) for which she received a bevacizumab injection. She was restarted on chlorambucil and oral prednisone. The decision for local therapy with dexamethasone implant was made at this point, and she was put back on chlorambucil 2 mg every three days. She was on chlorambucil without oral prednisone, titrating the dose based on WBC for seventeen months, after which she was considered cured (Fig. 1C). In her last visit with us, her BCVA OD and OS were 20/20 and 20/50, respectively. The patient's average WBC count while on chlorambucil with prednisone, chlorambucil without prednisone, and chlorambucil after dexamethasone intravitreal implant were 5500 ± 2900, 4700 ± 1100 and 4100 ± 500 cells/μl, respectively. The total duration of treatment before dexamethasone intravitreal implant was 60 months and 17 months after dexamethasone intravitreal implant. The total length of follow-up is 132 months, and the total duration of remission off medication is 48 months (Table 1).Fig. 1 A patient with bilateral serpiginous choroidopathy. (A) Serpiginous lesions in both eyes, encroaching the fovea in right eye and with foveal involvement in left eye. Fluoresecein angiography shows activity in both eyes. (B) The middle row shows progression towards the fovea with leakage pointing toward the fovea in the right eye. (C) Shows the stability of fundus photos and fluorescein angiography in both eyes at one year after intravitreal dexamethasone implant and chlorambucil treatment.
Fig. 1Table 1 Demographics and clinical characteristics of patients with resistant serpiginous choroiditis.
Table 1 Age years Sex Laterality BCVA first visit WBC (C + P) cells/μl
(x 10c) WBC (C) cells/μl
(x 10c) WBC (C + IMTor implan cells/μl (*10c) Duration of treatment before IMT Duration of treatment after IMT Duration of follow-up on chlorambucil Duration of follow-up off chlorambucil BCVA last visit
Patient 1 60 F Bilat 20/20 20/100 5.5 ± 2.9 4.7 ± 1.1 4.1 ± 0.5 60a months 17b months 60 months 83 months 20/20 20/50
OD
OS
Patient 2 42 F Bilat 1 mcf 20/20 5.7 ± 2.2 N/A 3.8 ± 0.5 40c months 19d months 49 months 60 months 1mcf
20/15
OD
OS
Patient 3 32 F Bilat HM 20/20 8.8 ± 3.4 N/A N/A 5 + 10 e months N/A 5 months N/A HM 20/50
OD
OS
Patient 4 47 F Bilat 20/30 1mcf 6.2 ± 3.3 N/A N/A N/A N/A 12 months N/A 20/50 1mcf
OD
OS
BCVA:best corrected visual acuity; Bilat:bilateral; C:chlorambucil; CF:counting fingers; HM:hand motion; IMT:immunomodulatory therapy; P:prednisone; N/A:not applicable.
a Before intravitreal dexamethasone implant.
b After intravitreal dexamethasone implant.
c Before starting infliximab.
d After starting infliximab.
e 5 months chlorambucil and 10 months cyclophosphamide.
Case 2. A 42-year-old female was referred to us with blurry vision and field distortion OD for ten years and OS for eight years. Her vision was counting fingers at 1 m OD and 20/20 OS. At the time of presentation, the patient had already received multiple intravitreal anti-VEGF (bevacizumab) and triamcinolone injections OD. The geographic lesions were peripapillary OU, with foveal involvement OD. Initial FA revealed chorioretinal scarring with window defects OU and leakage on borders OD (Fig. 2A). On ICG, the area of hypolucency OS extended further into the macula, which was not seen on FA (Fig. 2B). Complete blood work-up for uveitis ruled out non-infectious and infectious posterior uveitis, including syphilis and tuberculosis. Based on these findings, she was diagnosed with autoimmune SC OU and we recommended therapy with chlorambucil. She sought a second opinion elsewhere, where she was started on mycophenolate mofetil (MMF) 1 g daily with infliximab 300 mg IV every four weeks and oral prednisone 80 mg/day with taper. MMF and infliximab were eventually discontinued due to elevated LFTs. On follow up at our clinic eighteen months after the initial consult, chlorambucil was finally started with dose adjustment based on weekly monitoring of WBC count to reach the endpoint of WBC count 3000–4500 cells/μl. While on chlorambucil 20mg and prednisone 40mg daily, the patient became symptomatic OS with new changes and leakage on FA OS, prompting boosting of oral prednisone to 80 mg; she also received one ranibizumab injection OS locally. Six weeks after starting treatment with chlorambucil (20mg at this time) and oral prednisone 80 mg daily, WBC count dropped down to 4900 cells/μl, so we started tapering prednisone. Two months after initiation of chlorambucil therapy, chlorambucil was stopped while tapering prednisone at 30 mg/day with a WBC count of 3300 cells/μl. At this point, FA, FAF, and OCT showed stability and quiescence. On a subsequent visit with her local ophthalmologist, infliximab 600 mg infusions every four weeks was started for activity OS, and eventually increased to 900 mg every four weeks in combination with chlorambucil. WBC count increased to 7900 cells/μl while on prednisone 10 mg with taper, and chlorambucil was restarted at 4 mg daily, eventually going up to 6 mg daily (Fig. 2B). Chlorambucil dose adjustment with weekly WBC count was continued. Meanwhile, she received a bevacizumab injection with her local ophthalmologist due to central vision distortion OD. On her eight-month of treatment, WBC count dipped to 2000 cells/μl, and chlorambucil was stopped. After one week, with WBC count creeping back up to 4800 cells/μl, chlorambucil was restarted at 2 mg/day. Disease activity was then noted at ten months from treatment initiation with no interventions at that time. On follow up at our clinic fourteen months after starting chlorambucil, the activity noted at ten months prompted treatment extension, and the patient was educated on the risks vs. benefits of this decision. Chlorambucil treatment was continued for a total duration of twenty-one months. FA and OCT macula findings were stable and the patient was asymptomatic (Fig. 2C,D). Subsequent consults established disease stability with no new symptoms or activity. Infliximab was eventually tapered by 100 mg every four weeks. On her last consult at our clinic, she was on infliximab 100 mg infusions every four weeks with a final VA of 20/400 OD and 20/15 OS and stable findings on FA and macula OCT. Her average WBC count was 5700 ± 2200 cells/μl while on chlorambucil with prednisone, and 3800 ± 500 cells/μl when she was on chlorambucil after starting infliximab infusions without prednisone. The total duration of treatment before and after beginning infliximab infusions was 40 and 19 months, respectively. The total length of follow-up is 108 months. The total period of remission off chlorambucil is 60 months (Table 1).Fig. 2 (A) Fundus photo and fluorescein angiography of a patient with bilateral serpiginous choroiditis at the primary visit at our clinic. (B) The same patient during a recurrence in the left eye close to the fovea. (C,D) Stability of year after stopping chlorambucil while on infliximab tapering. (E) Macular optical coherence tomography at the first visit (left), during a recurrence (middle), and the last visit (right).
Fig. 2
Case 3. A 32-year-old female presented with decreased vision, floaters, and photophobia OS. Vision OD was poor due to retinal detachment after a motor vehicle accident. Before presenting to her initial consultation at our clinic, complete blood work-up for uveitis had ruled out non-infectious and infectious posterior uveitis, including syphilis and tuberculosis and she had already been diagnosed with idiopathic SC. She had been on MMF 2 g daily, cyclosporin 25 mg and prednisone 30 mg daily for fourteen months. Her vision was hand-motion OD and 20/20 OS at presentation. A fundus examination revealed optic atrophy and a horizontal scar OD in addition to diffuse chorioretinal (CR) scarring in both eyes. Given the possibility of the activity of the lesion potentially affecting the fovea OS and her monocular status, chlorambucil and cyclophosphamide were discussed as treatment options.
The patient was started on chlorambucil 4 mg daily and continued on 25 mg of prednisone daily. A month later, her WBC count dropped from 14,800 to 12,100 cells/μl. However, she felt her vision had decreased once again after two weeks on chlorambucil. She was advised to increase chlorambucil to 6 mg/day from 4 mg/day, as well as increase prednisone to 40 mg daily. After one week at this dose, she reported stable vision OD. Chlorambucil dose adjustment with weekly WBC count and oral prednisone were continued until she reported stable vision and no other symptoms. At this time, she was advised to increase chlorambucil to 12 mg daily.
Approximately four months after her initial visit, the patient presented to our clinic with worsening scotoma and floaters OS. At this point, she was on prednisone 5 mg daily and chlorambucil 10 mg daily. She had stopped chlorambucil for a week due to fever, and the WBC count was at 11,200 cells/μl. FA and ICG showed active choroidal inflammation at the lesion border, especially OS. Later on, she developed a diffuse, itchy rash, and because of this side effect, she was started on bi-weekly cyclophosphamide pulse therapy. She had five doses of cyclophosphamide pulse therapy, and her WBC count was between 4500 and 6300 cells/μl. However, a few days later, she complained of decreased vision OS with more central involvement. Her local ophthalmologist increased her prednisone to 60 mg, and she received her next cyclophosphamide infusion four days later with WBC count at 4000 cells/μl. Cyclophosphamide therapy was finally stopped due to persistent skin rash.
In the interim, she followed up with her local ophthalmologist while on oral prednisone with different doses based on disease activity. Her next visit with us was seven years later, and vision OS had deteriorated to 20/50. FA showed active inflammation OS in the form of enlarged CR lesions approaching the fovea with multifocal areas of leakage at the margins of the lesions (Fig. 3B). Up to that point, the patient had been off all immunomodulatory therapy (IMT) for seven years, yet only cyclophosphamide appeared to halt the progression of her disease. Monthly cyclophosphamide pulse therapy was resumed but was later stopped after eight months due to low WBC count. After this, she continued with oral prednisone 20 mg daily. At her last follow-up visit, chlorambucil was restarted due to the persistence of symptoms, worsening of vision OS, and the progression of lesion activity on imaging (Fig. 3C). Intravitreal steroid implants were also discussed. The patient was never able to taper off oral prednisone during treatment, and the average WBC count during her course of treatment was 8800 ± 3400 cells/μl. The total duration of treatment with chlorambucil was 5 months, cyclophosphamide was 10 months, and MMF plus cyclosporine was 14 months. The total duration of follow-up is 148 months. She has never been in remission for an extended period off medication (Table 1).Fig. 3 (A) Fundus photo of both eyes of a patient with bilateral serpiginous choroiditis. History of traumatic retinal detachment surgery with legal blindness in the right eye and active serpiginous choroiditis in the left eye. Fluorescein angiography shows an active lesion in the left eye. (B) Optical coherence tomography, fundus autofluorescence, and fluorescein angiography during a recurrence where the patient was started on cyclophosphamide pulse therapy. (C) Progression of the lesion in the left eye with an active lesion in fluorescein angiography at her last visit. Intravitreal dexamethasone and triamcinolone implants were discussed at this visit.
Fig. 3
Case 4. A 47-year-old female was referred to our center with decreased vision OU for one month and had been started on prednisone 50 mg daily before her first visit with us. Her vision OD and OS were 20/30 and counting fingers at 1 m, respectively, at presentation. Dilated fundoscopy showed bilateral geographic lesions nasal to the fovea OD and involving the fovea OS (Fig. 4A). Complete blood work-up for uveitis ruled out non-infectious and infectious posterior uveitis, including syphilis and tuberculosis. Based on these findings, and she was diagnosed with autoimmune SC OU. Oral prednisone was increased to 60 mg daily, and due to significant vision loss OS, she was started on chlorambucil 6 mg daily. Chlorambucil treatment with WBC count monitoring and tapering of oral prednisone was continued for a year. Once the oral prednisone taper was completed, she continued with chlorambucil monotherapy for five more months, at which time she had achieved remission. After four months; however, she had a flare-up OD, which was first treated with 1 g IV methylprednisolone infusion and intravenous methotrexate 200 mg/day. Subsequently, she was continued on subcutaneous methotrexate 15 mg weekly along with folic acid 1 mg/day for two years. She developed another flare-up when tapering methotrexate; hence methotrexate dose was boosted, and a combination of chlorambucil and oral prednisone was restarted. The patient was on chlorambucil and oral prednisone for one year, with an average WBC count of 6200 ± 3300 cells/μl. The patient was then on chlorambucil alone for another two months. She had been flare-free for twenty months when she had another episode. This time she was treated with intravenous and subcutaneous methotrexate. She had another flare during tapering of methotrexate and she is currently on a combination of chlorambucil, prednisone, and subcutaneous methotrexate therapy. The total duration of follow-up has been 116 months. She has never been in remission for an extended period (Table 1).Fig. 4 A serpiginous choroiditis patient with multiple recurrences despite treatment with a combination of oral prednisone and chlorambucil therapy. (A) Color fundus photos and fluorescein angiography of both eyes at the first visit, which showed activity around the lesion in both eyes. (B) The second row shows the progression of lesions in both eyes during a recurrence on fundus photos and fundus autofluorescence. (C) Fundus autofluorescence and fluorescein angiography showed reactivation of the supratemporal area of the lesion in the right eye. (D) Optical coherence tomography shows the lesion, edema, and destruction of the supratemporal part of the lesion, compatible with fundus autofluorescence and fluorescein angiography. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)
Fig. 4
3 Discussion
The pathogenesis of serpiginous choroiditis (SC) is unknown. The course of the disease is indolent and can be asymptomatic until it involves the macula and the central vision. Many patients can have old scars even at the first visit when they are diagnosed with SC.14 Laatikainen and Erkkila et al. reported that new lesions may appear at an interval of 3 months–4 years. They also demonstrated that active lesions resolve in a few weeks; however, signs of activity may last between 1 and 9 months.14 Central vision is involved in 20%–50% of cases, with the likelihood increasing with longer duration of follow-up and disease activity.8,14 Recurrences that affect the macula can cause severe visual loss of less than 20/200, which is typically irreversible and may induce CNV in the macula or around the optic disc.15
There are no controlled trials for the treatment of SC due to the rarity of the disease. Cytosine arabinoside, azathioprine, and oral prednisone were used with reported improved visual acuity in one month.16 Employment of a combination of cyclosporine and oral prednisone as a treatment of active SC had conflicting results. Hopper and Kaplan reported a triple-agent regimen of azathioprine, cyclosporine, and oral prednisone that resulted in rapid control of the active SC and vision recovery; however, disease recurrence was the study's main problem.9 Akpek et al. employed the same regimen in a more extended study and found that this regimen helped keep the inflammation quiet during treatment; however, it did not maintain remission off medication.17
Alkylating agents can bind to DNA, interfere with DNA replication, and subsequently interfere with cell division. Cyclophosphamide is commonly used because of its predictable, dose-dependent, and reversible adverse effects on WBC count18; nonetheless, it can result in serious side effects, some of which are life-threatening. These side effects include reversible hematuria, hemorrhagic cystitis, reversible alopecia, sterility, bladder cancer, lymphoma, and leukemia. Chlorambucil is another alkylating agent primarily used for the treatment of several lymphoproliferative diseases. It is a stable derivative of the nitrogen mustard.19 Based on its ability to reduce circulating lymphocytes, chlorambucil is effective in the treatment of rheumatologic diseases, including juvenile rheumatoid arthritis, systemic lupus erythematosus, and nephrotic syndrome.20, 21, 22, 23 Given the availability of other conventional immunomodulatory agents and biologic response modifiers that yield better results with fewer unpredictable side effects, ophthalmologists are reluctant to use chlorambucil. Our knowledge about biologic response modifier agents is limited to a few case reports and some of our patients had already failed infliximab, mycophenolate mofetil, methotreaxte before their first presentation to us or during follow-up with us. Palmer et al. studied the side effects of chlorambucil and found that these side effects are related to the total dose and duration of treatment.24 However, Tessler et al. found chlorambucil to be a successful treatment for different types of uveitis with no severe complications during 12 years of follow-up. They also reported complete remission in all patients. Although chlorambucil dose in their study was administered regardless of body weight, it did not exceed 2.2 g per patient during the entire treatment.25 Based on these findings, recent studies still rely on alkylating agents including cyclophosphamide and chlorambucil for classical and macular SC.5,12,32
It may take more time for chlorambucil to show its therapeutic and toxic effects. Patients on this medication should be monitored with weekly blood counts, specifically WBC and platelet counts, since its side effects are not always dose-related.25 Chlorambucil is administered orally because it has excellent gastrointestinal absorption, and its superiority over cyclophosphamide is related to the absence of associated side effects such as hair loss, hemorrhagic cystitis, and bladder cancer.26
The recommendation for the daily and total dose of chlorambucil is equal to or less than 0.2 mg/kg and 2.2 g, respectively. These recommendations help avoid late complications such as lymphoma and leukemia.27 Various doses of chlorambucil have been employed in the past in the field of ophthalmology. The use of lower doses of chlorambucil over an extended period, such as more than one year, without provoking bone marrow toxicity is one approach.28, 29, 30, 31 However, it has been demonstrated that sustained remission of the disease is achievable when the WBC count remained depressed for at least six weeks. This finding suggests that effective treatment with chlorambucil requires the induction of a toxic hematologic response.25
The recent literature shows that alkylating agents are still the most potent and effective treatment in patients with SC.4,12,32 Venkatesh and colleagues showed that intravenous cyclophosphamide pulse therapy provided a rapid resolution of active lesions and helped maintain good functional visual acuity.4 However, they admitted that this treatment might not prevent recurrences in patients with SC.4 Venkatesh et al. also studied intravenous methylprednisolone and cyclophosphamide in macular SC; they, again demonstrated it could be effective in acute macular SC, yet admitted that this treatment had no effects on disease relapses in the long-term.32 Ebrahimiadib et al. retrospectively studied 17 patients on chlorambucil with dose escalation based on weekly WBC count, with the target of 3000–4500 white blood cells/μl. They concluded that chlorambucil was well tolerated by the patients and was effective in preventing recurrences.12 Although all these recent studies provided important facts regarding SC treatment, they did not discuss the next step for the patients who failed these treatments. In the current study, we decided to evaluate the possible causes of chlorambucil treatment failure in patients with resistant SC and to examine possible successful regimens in these patients. To the best of our knowledge, this study is the first one which evaluates the possible remedy for resistance to chlorambucil as one of the most commonly employed medications in SC patients.
Histopathological studies in SC have demonstrated that lymphocytes infiltrate the choroid, and less commonly, vessels, leading to subsequent choriocapillaris occlusive vasculitis. This finding may indicate the important roles of lymphocytes in the pathogenesis of the disease.5 The histopathology in SC is very similar to birdshot chorioretinopathy.33,34 On the other hand, multiple studies have discussed the effects of long-term systemic corticosteroids on lymphocyte proliferation and T-cell population.35,36 Ferrari et al. reported increased lymphocytes, including increased absolute numbers of T cells, CD4+ and CD8+ cells, after four weeks of corticosteroid therapy in idiopathic thrombocytopenic purpura (ITP).35 Moreover, lymphocyte redistribution has been discussed in long-term steroid therapy.36 These changes associated with long-term corticosteroid use may interfere with the aim of chlorambucil treatment, since cells with higher proliferation rates are the target of this therapy. The negative effect of long-term systemic corticosteroids on birdshot chorioretinopathy has been studied in the past.37,38 Due to similarities between birdshot chorioretinopathy and SC in terms of histopathology, these facts can be applied to SC patients as well.
The target WBC count for chlorambucil therapy for SC is between 3000 and 4500 cells/μl. Chlorambucil dose adjustment is based on a weekly WBC count. In our experience, patients might be considered cured if there is no recurrence during the treatment period, which is around one year. Our observation in this case series showed that patients on high doses of systemic corticosteroids have unstable WBC count during chlorambucil therapy. Keeping this count in the satisfactory range for a reasonable period of at least six weeks can be challenging since it has been shown that induced toxic hematologic response is required for effective treatment with chlorambucil.25 The first two patients in this case series achieved durable remission and were likely cured after employing local corticosteroids or systemic immunomodulatory therapy, which allowed us to stop systemic corticosteroid use during chlorambucil therapy. However, the third and fourth patients are still experiencing recurrences since all systemic immunomodulatory therapies were unable to induce steroid-free remission. Local corticosteroid therapy was also recommended for both of the patients, but its potential side effects and the patients’ monocular statuses made this option unappealing.
We might be criticized for not employing local corticosteroid monotherapy without any systemic therapy. We believe that, although corticosteroids are the best option for controlling of acute ocular inflammation of any type, they are not potent enough to prime or re-program the immune system12 and not to respond to self-antigens as we expect with immunomodulatory therapy. This is similar to what occurs to pathologic cancer cells especially in blood cancers (lymphoma and leukemia) in patients who achieve remission with chemotherapy which is an advanced and more aggressive form of immunomodulatory therapy. Based on the above mentioned theory, corticosteroids as monotherapy cannot halt the inflammation thoroughly, so the ongoing inflammation can cause more cells destruction and epitopes exposures which might result in more resistant ocular inflammation which is believed to happen in patients with resistant autoimmune SC. we assume that the employment of systemic corticosteroid therapy, along with chlorambucil, is the main obstacle in achieving remission in patients with SC. This combination therapy is mostly seen in monocular patients or in vision-threatening SC where there is a lower threshold for aggressive systemic corticosteroid therapy in these patients.
We might also be criticized for using different therapies in one patient; however, we follow the strategy of “one change at a time” and this means that any time a conventional IMT is tried, we wait for three months with no changes to assess its effectiveness. For biologic response modifier agents, we wait for two months. This strategy makes interaction between medications unlikely. Moreover, since our mission is systemic steroid free remission, we only consider a medication to be effective if the inflammation stays in remission even after the effects of steroids are gone. Furthermore, none of these therapies induced long term remission in our patients.
Dexamethasone intravitreal implants have been employed in the treatment of active SC and serpiginous-like choroiditis.39,40 In these studies, the authors showed the success of this implant in controlling active SC. Based on these studies, dexamethasone can be an alternative to high dose oral or intravenous corticosteroid without systemic side effects including its effects on bone marrow, secondary lymphoid tissues, and peripheral blood regarding WBC counts, especially lymphocytes.
One common fact between all patients in this case series is the instability of WBC count during chlorambucil therapy plus systemic corticosteroids. This issue was addressed in one patient with dexamethasone intravitreal implant and in another patient with infliximab therapy. Both patients allowed us to taper and stop oral prednisone during chlorambucil therapy. The latter patient has been in remission for four years, which is the time frame during which one would expect a new lesion based on the Laatikainen and Erkkila et al. study.14 Despite this, this patient continues to take infliximab at a dose of 300 mg every four weeks since there is a fear of SC recurrence once infliximab therapy is terminated. However, this concept and hypothesis need further, more sophisticated examination.
This study had inherent limitations given its retrospective study design with a small sample size due to the rarity of cases of SC. It was even more challenging to find refractory cases with a reasonable follow-up period to expect a recurrence as all of these patients have at least 8 years of follow-up at our center without any serious side effects. Furthermore, all confounding factors cannot be controlled in a retrospective study. Regardless, we believe that confounding factors related to WBC might not interfere in this study since chlorambucil dose is adjusted based on WBC count and in clinical practice, changes in WBC count are typically more related to changes in corticosteroid dosage. Based on all these limitations, the results of this case series should be interpreted with caution and justifies the need for more potent studies.
4 Conclusion
The stability of WBC counts within toxic levels close to normal or lower limits of normal (3000–4500 cells/μl) during treatment with chlorambucil is an essential factor for the success of this therapy. A combination of dexamethasone intravitreal implant with chlorambucil therapy can be an effective and promising regimen in inducing and maintaining remission in refractory SC patients who fail a combination of systemic corticosteroid and chlorambucil therapy as the first line therapy. However, this primitive hypothesis should be investigated with more potent studies and larger sample sizes.
Patient consent
Consent to publish the personal information and cases details was obtained from all the patients.
Financial supports
None.
All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.
Disclosures
Dr. C Stephen Foster declares the following: Consultancies with Aldeyra Therapeutics (Lexington, MA), Allakos (Redwood City, CA), Bausch & Lomb Surgical, Inc (Rancho Cucamonga, CA), Eyegate Pharma (Waltham, MA), Genentech (South San Francisco, CA), Novartis (Cambridge, MA), pSivida (Watertown, MA) Grants or grants pending with Aciont (Salt Lake City, UT), Alcon (Aliso Viejo, CA), Aldeyra Therapeutics (Lexington, MA), Bausch & Lomb (Rochester, NY), Clearside Biomedical (Alpharetta, GA), Dompé pharmaceutical (Milan, Italy), Eyegate Pharma (Waltham, MA), Mallinckrodt pharmaceuticals (Staines-upon-Thames, UK), Novartis Pharmaceuticals (Cambridge, MA), pSivida (Watertown, MA), Santen (Osaka, Japan). Payment for lectures including service on speaking bureaus: Alcon (Aliso Viejo, CA), Allergan (Dublin, Ireland), Mallinckrodt pharmaceuticals (Staines-upon-Thames, UK). Stock or Stock Options: Eyegate Pharma (Waltham, MA).
The other authors have nothing to declare.
Compliance with ethics guidelines
This study was approved by the New England Institutional Review Board, which has issued a waiver of informed consent for the retrospective chart review analysis. This study was performed in accordance with the Helsinki Declaration of 1964, and its later amendments. All participants provided consent for publication if any identifying information is included in the manuscript.
Data availability
The data that support the findings of this study are available from the corresponding author, upon reasonable request.
Declaration of competing interest
No conflicting relationship exists for any author. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY-NC-ND | 33615036 | 19,884,508 | 2021-03 |
What was the administration route of drug 'PREDNISONE'? | Chlorambucil combination therapy in refractory serpiginous choroiditis: A cure?
To find a remedy for serpiginous choroiditis refractory to oral prednisone and chlorambucil treatment.
Eight eyes of four patients (all female) with advanced macular involvement secondary to serpiginous choroiditis were included in the study. The average age of the patients was 45.2 years. One eye of each patient was legally blind and the lesion was close to the fovea in the other eye. All four patients failed oral prednisone and chlorambucil therapy. However, case 1 responded to chlorambucil treatment after intravitreal dexamethasone implant implantation and discontinuation of oral prednisone. Case 2 responded to chlorambucil therapy when oral prednisone was stopped in combination with infliximab therapy. Due to long follow-up period of more than four years, these two cases are considered to be cured. Case 3 and case 4 were not able to achieve remission with chlorambucil and immunomodulatory therapy. They refused intravitreal steroid implant due to side effects profile.
The stability of WBC counts within toxic levels close to normal or lower limits of normal (3000-4500 cells/μl) during treatment with chlorambucil is an essential factor for the success of this therapy. A combination of dexamethasone intravitreal implant with chlorambucil therapy can be an effective and promising regimen in inducing and maintaining remission in refractory serpiginous choroiditis patients who fail a combination of systemic corticosteroid and chlorambucil therapy.
1 Introduction
Serpiginous choroiditis (SC) is a rare, chronic, asymmetrically bilateral posterior uveitis with a recurrent course. The exact prevalence of SC is unknown; however, it is estimated between 1.6% and 5.3% of posterior uveitis cases in non-endemic areas for tuberculosis.1 Major features of SC include choriocapillaris occlusive vasculitis, secondary endothelial cell injury, and subsequent atrophy of the retinal pigment epithelium, outer retina, and choroid.2,3 Histopathology studies reveal lymphocytic infiltration in the choroid and, less commonly, around vessels.4 The peripapillary area is classically involved in SC and accounts for 80% of the cases.5 The prognosis of vision is poor when it involves the macula, especially in the macular variant of SC. Moreover, the macular variant has a higher risk of developing choroidal neovascularization in nearly half of the affected patients.6,7 Fluorescein angiography (FA), indocyanine green angiography (ICG), optical coherence tomography (OCT), fundus autofluorescence (FAF), and microperimetry are the ancillary diagnostic tools and tests which help in the diagnosis, follow-up, and monitoring for secondary complications.1
Historically, the administration of high doses of oral or intravenous steroids was considered as the standard of care for patients with SC.8 However, immunosuppressive agents such as azathioprine, cyclosporine, chlorambucil, and cyclophosphamide emerged as treatment options for steroid-free remission.4,9, 10, 11, 12 Of these, the alkylating agents cyclophosphamide and chlorambucil have been noted to have a high success rate in the treatment of SC.4,10,12 Chlorambucil, being a potent alkylating agent, can interfere with DNA replication and cell division.13 This medication can induce remission, maintain remission, and even cure this disease.12
Despite successful treatment of SC with alkylating agents, in some patients the disease can recur frequently and progress to affect the central vision. This becomes more important in patients with poor vision in the other eye secondary to SC or advanced SC encroaching the fovea in the affected eye. In this case series, we decided to evaluate possible remedies for refractory and recurrent SC in patients who have been treated with chlorambucil and oral or intravenous corticosteroids.
2 4 Cases
Case 1. A sixty-year-old female was referred to us for the evaluation of macular SC OU. She had noticed blurry vision OS one month before her first visit with us. A geographic lesion with indistinct and irregular borders was observed in both eyes. The lesion was uni-centric OU, temporal to fovea OD and peripapillary with extension to fovea OS. FA and ICG showed the activity of the lesions in both eyes (Fig. 1A). Her best-corrected visual acuity (BCVA) was 20/20 OD and decreased OS to 20/100. Complete blood work-up for uveitis ruled out non-infectious and infectious posterior uveitis, including syphilis and tuberculosis. Based on these findings, she was diagnosed with autoimmune SC OU and was started on a combination of chlorambucil and daily oral prednisone. Chlorambucil was titrated based on her white blood cell (WBC) count. She had another flare-up while she was on 2 mg/day prednisone and had already stopped chlorambucil for three weeks due to WBC 3200 cells/μl. BCVA OS decreased to 20/125, and ICGA confirmed enlargement of the lesion. Chlorambucil was restarted to 2 mg every other day, and oral prednisone was increased to 5 mg/day. With this change in her regimen, the vision increased to the baseline before her last flare, to 20/40. Treatment with chlorambucil was stopped after one year. Her follow-up visit increased to every three months from monthly. Then, six months later, she was started on oral methotrexate 7.5 mg weekly by her rheumatologist because of her joint issues. She was followed every three months for seven months until she noticed a change in OS again. At that time, she was on oral methotrexate 15 mg weekly. BCVA OS decreased to 20/125, and ancillary tests showed activity at the border of the lesions on the foveal side (Fig. 1B). She received one dose of 1 g intravenous methylprednisolone, intravitreal injection of triamcinolone and bevacizumab, and was restarted on oral prednisone 80 mg/day. A week later, her methotrexate dose was boosted to methotrexate 25 mg weekly subcutaneous injections, and we tapered prednisone 10 mg weekly. In three months, oral prednisone was tapered and stopped. Three months later, her lesion became active and she developed choroidal neovascularization (CNV) for which she received a bevacizumab injection. She was restarted on chlorambucil and oral prednisone. The decision for local therapy with dexamethasone implant was made at this point, and she was put back on chlorambucil 2 mg every three days. She was on chlorambucil without oral prednisone, titrating the dose based on WBC for seventeen months, after which she was considered cured (Fig. 1C). In her last visit with us, her BCVA OD and OS were 20/20 and 20/50, respectively. The patient's average WBC count while on chlorambucil with prednisone, chlorambucil without prednisone, and chlorambucil after dexamethasone intravitreal implant were 5500 ± 2900, 4700 ± 1100 and 4100 ± 500 cells/μl, respectively. The total duration of treatment before dexamethasone intravitreal implant was 60 months and 17 months after dexamethasone intravitreal implant. The total length of follow-up is 132 months, and the total duration of remission off medication is 48 months (Table 1).Fig. 1 A patient with bilateral serpiginous choroidopathy. (A) Serpiginous lesions in both eyes, encroaching the fovea in right eye and with foveal involvement in left eye. Fluoresecein angiography shows activity in both eyes. (B) The middle row shows progression towards the fovea with leakage pointing toward the fovea in the right eye. (C) Shows the stability of fundus photos and fluorescein angiography in both eyes at one year after intravitreal dexamethasone implant and chlorambucil treatment.
Fig. 1Table 1 Demographics and clinical characteristics of patients with resistant serpiginous choroiditis.
Table 1 Age years Sex Laterality BCVA first visit WBC (C + P) cells/μl
(x 10c) WBC (C) cells/μl
(x 10c) WBC (C + IMTor implan cells/μl (*10c) Duration of treatment before IMT Duration of treatment after IMT Duration of follow-up on chlorambucil Duration of follow-up off chlorambucil BCVA last visit
Patient 1 60 F Bilat 20/20 20/100 5.5 ± 2.9 4.7 ± 1.1 4.1 ± 0.5 60a months 17b months 60 months 83 months 20/20 20/50
OD
OS
Patient 2 42 F Bilat 1 mcf 20/20 5.7 ± 2.2 N/A 3.8 ± 0.5 40c months 19d months 49 months 60 months 1mcf
20/15
OD
OS
Patient 3 32 F Bilat HM 20/20 8.8 ± 3.4 N/A N/A 5 + 10 e months N/A 5 months N/A HM 20/50
OD
OS
Patient 4 47 F Bilat 20/30 1mcf 6.2 ± 3.3 N/A N/A N/A N/A 12 months N/A 20/50 1mcf
OD
OS
BCVA:best corrected visual acuity; Bilat:bilateral; C:chlorambucil; CF:counting fingers; HM:hand motion; IMT:immunomodulatory therapy; P:prednisone; N/A:not applicable.
a Before intravitreal dexamethasone implant.
b After intravitreal dexamethasone implant.
c Before starting infliximab.
d After starting infliximab.
e 5 months chlorambucil and 10 months cyclophosphamide.
Case 2. A 42-year-old female was referred to us with blurry vision and field distortion OD for ten years and OS for eight years. Her vision was counting fingers at 1 m OD and 20/20 OS. At the time of presentation, the patient had already received multiple intravitreal anti-VEGF (bevacizumab) and triamcinolone injections OD. The geographic lesions were peripapillary OU, with foveal involvement OD. Initial FA revealed chorioretinal scarring with window defects OU and leakage on borders OD (Fig. 2A). On ICG, the area of hypolucency OS extended further into the macula, which was not seen on FA (Fig. 2B). Complete blood work-up for uveitis ruled out non-infectious and infectious posterior uveitis, including syphilis and tuberculosis. Based on these findings, she was diagnosed with autoimmune SC OU and we recommended therapy with chlorambucil. She sought a second opinion elsewhere, where she was started on mycophenolate mofetil (MMF) 1 g daily with infliximab 300 mg IV every four weeks and oral prednisone 80 mg/day with taper. MMF and infliximab were eventually discontinued due to elevated LFTs. On follow up at our clinic eighteen months after the initial consult, chlorambucil was finally started with dose adjustment based on weekly monitoring of WBC count to reach the endpoint of WBC count 3000–4500 cells/μl. While on chlorambucil 20mg and prednisone 40mg daily, the patient became symptomatic OS with new changes and leakage on FA OS, prompting boosting of oral prednisone to 80 mg; she also received one ranibizumab injection OS locally. Six weeks after starting treatment with chlorambucil (20mg at this time) and oral prednisone 80 mg daily, WBC count dropped down to 4900 cells/μl, so we started tapering prednisone. Two months after initiation of chlorambucil therapy, chlorambucil was stopped while tapering prednisone at 30 mg/day with a WBC count of 3300 cells/μl. At this point, FA, FAF, and OCT showed stability and quiescence. On a subsequent visit with her local ophthalmologist, infliximab 600 mg infusions every four weeks was started for activity OS, and eventually increased to 900 mg every four weeks in combination with chlorambucil. WBC count increased to 7900 cells/μl while on prednisone 10 mg with taper, and chlorambucil was restarted at 4 mg daily, eventually going up to 6 mg daily (Fig. 2B). Chlorambucil dose adjustment with weekly WBC count was continued. Meanwhile, she received a bevacizumab injection with her local ophthalmologist due to central vision distortion OD. On her eight-month of treatment, WBC count dipped to 2000 cells/μl, and chlorambucil was stopped. After one week, with WBC count creeping back up to 4800 cells/μl, chlorambucil was restarted at 2 mg/day. Disease activity was then noted at ten months from treatment initiation with no interventions at that time. On follow up at our clinic fourteen months after starting chlorambucil, the activity noted at ten months prompted treatment extension, and the patient was educated on the risks vs. benefits of this decision. Chlorambucil treatment was continued for a total duration of twenty-one months. FA and OCT macula findings were stable and the patient was asymptomatic (Fig. 2C,D). Subsequent consults established disease stability with no new symptoms or activity. Infliximab was eventually tapered by 100 mg every four weeks. On her last consult at our clinic, she was on infliximab 100 mg infusions every four weeks with a final VA of 20/400 OD and 20/15 OS and stable findings on FA and macula OCT. Her average WBC count was 5700 ± 2200 cells/μl while on chlorambucil with prednisone, and 3800 ± 500 cells/μl when she was on chlorambucil after starting infliximab infusions without prednisone. The total duration of treatment before and after beginning infliximab infusions was 40 and 19 months, respectively. The total length of follow-up is 108 months. The total period of remission off chlorambucil is 60 months (Table 1).Fig. 2 (A) Fundus photo and fluorescein angiography of a patient with bilateral serpiginous choroiditis at the primary visit at our clinic. (B) The same patient during a recurrence in the left eye close to the fovea. (C,D) Stability of year after stopping chlorambucil while on infliximab tapering. (E) Macular optical coherence tomography at the first visit (left), during a recurrence (middle), and the last visit (right).
Fig. 2
Case 3. A 32-year-old female presented with decreased vision, floaters, and photophobia OS. Vision OD was poor due to retinal detachment after a motor vehicle accident. Before presenting to her initial consultation at our clinic, complete blood work-up for uveitis had ruled out non-infectious and infectious posterior uveitis, including syphilis and tuberculosis and she had already been diagnosed with idiopathic SC. She had been on MMF 2 g daily, cyclosporin 25 mg and prednisone 30 mg daily for fourteen months. Her vision was hand-motion OD and 20/20 OS at presentation. A fundus examination revealed optic atrophy and a horizontal scar OD in addition to diffuse chorioretinal (CR) scarring in both eyes. Given the possibility of the activity of the lesion potentially affecting the fovea OS and her monocular status, chlorambucil and cyclophosphamide were discussed as treatment options.
The patient was started on chlorambucil 4 mg daily and continued on 25 mg of prednisone daily. A month later, her WBC count dropped from 14,800 to 12,100 cells/μl. However, she felt her vision had decreased once again after two weeks on chlorambucil. She was advised to increase chlorambucil to 6 mg/day from 4 mg/day, as well as increase prednisone to 40 mg daily. After one week at this dose, she reported stable vision OD. Chlorambucil dose adjustment with weekly WBC count and oral prednisone were continued until she reported stable vision and no other symptoms. At this time, she was advised to increase chlorambucil to 12 mg daily.
Approximately four months after her initial visit, the patient presented to our clinic with worsening scotoma and floaters OS. At this point, she was on prednisone 5 mg daily and chlorambucil 10 mg daily. She had stopped chlorambucil for a week due to fever, and the WBC count was at 11,200 cells/μl. FA and ICG showed active choroidal inflammation at the lesion border, especially OS. Later on, she developed a diffuse, itchy rash, and because of this side effect, she was started on bi-weekly cyclophosphamide pulse therapy. She had five doses of cyclophosphamide pulse therapy, and her WBC count was between 4500 and 6300 cells/μl. However, a few days later, she complained of decreased vision OS with more central involvement. Her local ophthalmologist increased her prednisone to 60 mg, and she received her next cyclophosphamide infusion four days later with WBC count at 4000 cells/μl. Cyclophosphamide therapy was finally stopped due to persistent skin rash.
In the interim, she followed up with her local ophthalmologist while on oral prednisone with different doses based on disease activity. Her next visit with us was seven years later, and vision OS had deteriorated to 20/50. FA showed active inflammation OS in the form of enlarged CR lesions approaching the fovea with multifocal areas of leakage at the margins of the lesions (Fig. 3B). Up to that point, the patient had been off all immunomodulatory therapy (IMT) for seven years, yet only cyclophosphamide appeared to halt the progression of her disease. Monthly cyclophosphamide pulse therapy was resumed but was later stopped after eight months due to low WBC count. After this, she continued with oral prednisone 20 mg daily. At her last follow-up visit, chlorambucil was restarted due to the persistence of symptoms, worsening of vision OS, and the progression of lesion activity on imaging (Fig. 3C). Intravitreal steroid implants were also discussed. The patient was never able to taper off oral prednisone during treatment, and the average WBC count during her course of treatment was 8800 ± 3400 cells/μl. The total duration of treatment with chlorambucil was 5 months, cyclophosphamide was 10 months, and MMF plus cyclosporine was 14 months. The total duration of follow-up is 148 months. She has never been in remission for an extended period off medication (Table 1).Fig. 3 (A) Fundus photo of both eyes of a patient with bilateral serpiginous choroiditis. History of traumatic retinal detachment surgery with legal blindness in the right eye and active serpiginous choroiditis in the left eye. Fluorescein angiography shows an active lesion in the left eye. (B) Optical coherence tomography, fundus autofluorescence, and fluorescein angiography during a recurrence where the patient was started on cyclophosphamide pulse therapy. (C) Progression of the lesion in the left eye with an active lesion in fluorescein angiography at her last visit. Intravitreal dexamethasone and triamcinolone implants were discussed at this visit.
Fig. 3
Case 4. A 47-year-old female was referred to our center with decreased vision OU for one month and had been started on prednisone 50 mg daily before her first visit with us. Her vision OD and OS were 20/30 and counting fingers at 1 m, respectively, at presentation. Dilated fundoscopy showed bilateral geographic lesions nasal to the fovea OD and involving the fovea OS (Fig. 4A). Complete blood work-up for uveitis ruled out non-infectious and infectious posterior uveitis, including syphilis and tuberculosis. Based on these findings, and she was diagnosed with autoimmune SC OU. Oral prednisone was increased to 60 mg daily, and due to significant vision loss OS, she was started on chlorambucil 6 mg daily. Chlorambucil treatment with WBC count monitoring and tapering of oral prednisone was continued for a year. Once the oral prednisone taper was completed, she continued with chlorambucil monotherapy for five more months, at which time she had achieved remission. After four months; however, she had a flare-up OD, which was first treated with 1 g IV methylprednisolone infusion and intravenous methotrexate 200 mg/day. Subsequently, she was continued on subcutaneous methotrexate 15 mg weekly along with folic acid 1 mg/day for two years. She developed another flare-up when tapering methotrexate; hence methotrexate dose was boosted, and a combination of chlorambucil and oral prednisone was restarted. The patient was on chlorambucil and oral prednisone for one year, with an average WBC count of 6200 ± 3300 cells/μl. The patient was then on chlorambucil alone for another two months. She had been flare-free for twenty months when she had another episode. This time she was treated with intravenous and subcutaneous methotrexate. She had another flare during tapering of methotrexate and she is currently on a combination of chlorambucil, prednisone, and subcutaneous methotrexate therapy. The total duration of follow-up has been 116 months. She has never been in remission for an extended period (Table 1).Fig. 4 A serpiginous choroiditis patient with multiple recurrences despite treatment with a combination of oral prednisone and chlorambucil therapy. (A) Color fundus photos and fluorescein angiography of both eyes at the first visit, which showed activity around the lesion in both eyes. (B) The second row shows the progression of lesions in both eyes during a recurrence on fundus photos and fundus autofluorescence. (C) Fundus autofluorescence and fluorescein angiography showed reactivation of the supratemporal area of the lesion in the right eye. (D) Optical coherence tomography shows the lesion, edema, and destruction of the supratemporal part of the lesion, compatible with fundus autofluorescence and fluorescein angiography. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)
Fig. 4
3 Discussion
The pathogenesis of serpiginous choroiditis (SC) is unknown. The course of the disease is indolent and can be asymptomatic until it involves the macula and the central vision. Many patients can have old scars even at the first visit when they are diagnosed with SC.14 Laatikainen and Erkkila et al. reported that new lesions may appear at an interval of 3 months–4 years. They also demonstrated that active lesions resolve in a few weeks; however, signs of activity may last between 1 and 9 months.14 Central vision is involved in 20%–50% of cases, with the likelihood increasing with longer duration of follow-up and disease activity.8,14 Recurrences that affect the macula can cause severe visual loss of less than 20/200, which is typically irreversible and may induce CNV in the macula or around the optic disc.15
There are no controlled trials for the treatment of SC due to the rarity of the disease. Cytosine arabinoside, azathioprine, and oral prednisone were used with reported improved visual acuity in one month.16 Employment of a combination of cyclosporine and oral prednisone as a treatment of active SC had conflicting results. Hopper and Kaplan reported a triple-agent regimen of azathioprine, cyclosporine, and oral prednisone that resulted in rapid control of the active SC and vision recovery; however, disease recurrence was the study's main problem.9 Akpek et al. employed the same regimen in a more extended study and found that this regimen helped keep the inflammation quiet during treatment; however, it did not maintain remission off medication.17
Alkylating agents can bind to DNA, interfere with DNA replication, and subsequently interfere with cell division. Cyclophosphamide is commonly used because of its predictable, dose-dependent, and reversible adverse effects on WBC count18; nonetheless, it can result in serious side effects, some of which are life-threatening. These side effects include reversible hematuria, hemorrhagic cystitis, reversible alopecia, sterility, bladder cancer, lymphoma, and leukemia. Chlorambucil is another alkylating agent primarily used for the treatment of several lymphoproliferative diseases. It is a stable derivative of the nitrogen mustard.19 Based on its ability to reduce circulating lymphocytes, chlorambucil is effective in the treatment of rheumatologic diseases, including juvenile rheumatoid arthritis, systemic lupus erythematosus, and nephrotic syndrome.20, 21, 22, 23 Given the availability of other conventional immunomodulatory agents and biologic response modifiers that yield better results with fewer unpredictable side effects, ophthalmologists are reluctant to use chlorambucil. Our knowledge about biologic response modifier agents is limited to a few case reports and some of our patients had already failed infliximab, mycophenolate mofetil, methotreaxte before their first presentation to us or during follow-up with us. Palmer et al. studied the side effects of chlorambucil and found that these side effects are related to the total dose and duration of treatment.24 However, Tessler et al. found chlorambucil to be a successful treatment for different types of uveitis with no severe complications during 12 years of follow-up. They also reported complete remission in all patients. Although chlorambucil dose in their study was administered regardless of body weight, it did not exceed 2.2 g per patient during the entire treatment.25 Based on these findings, recent studies still rely on alkylating agents including cyclophosphamide and chlorambucil for classical and macular SC.5,12,32
It may take more time for chlorambucil to show its therapeutic and toxic effects. Patients on this medication should be monitored with weekly blood counts, specifically WBC and platelet counts, since its side effects are not always dose-related.25 Chlorambucil is administered orally because it has excellent gastrointestinal absorption, and its superiority over cyclophosphamide is related to the absence of associated side effects such as hair loss, hemorrhagic cystitis, and bladder cancer.26
The recommendation for the daily and total dose of chlorambucil is equal to or less than 0.2 mg/kg and 2.2 g, respectively. These recommendations help avoid late complications such as lymphoma and leukemia.27 Various doses of chlorambucil have been employed in the past in the field of ophthalmology. The use of lower doses of chlorambucil over an extended period, such as more than one year, without provoking bone marrow toxicity is one approach.28, 29, 30, 31 However, it has been demonstrated that sustained remission of the disease is achievable when the WBC count remained depressed for at least six weeks. This finding suggests that effective treatment with chlorambucil requires the induction of a toxic hematologic response.25
The recent literature shows that alkylating agents are still the most potent and effective treatment in patients with SC.4,12,32 Venkatesh and colleagues showed that intravenous cyclophosphamide pulse therapy provided a rapid resolution of active lesions and helped maintain good functional visual acuity.4 However, they admitted that this treatment might not prevent recurrences in patients with SC.4 Venkatesh et al. also studied intravenous methylprednisolone and cyclophosphamide in macular SC; they, again demonstrated it could be effective in acute macular SC, yet admitted that this treatment had no effects on disease relapses in the long-term.32 Ebrahimiadib et al. retrospectively studied 17 patients on chlorambucil with dose escalation based on weekly WBC count, with the target of 3000–4500 white blood cells/μl. They concluded that chlorambucil was well tolerated by the patients and was effective in preventing recurrences.12 Although all these recent studies provided important facts regarding SC treatment, they did not discuss the next step for the patients who failed these treatments. In the current study, we decided to evaluate the possible causes of chlorambucil treatment failure in patients with resistant SC and to examine possible successful regimens in these patients. To the best of our knowledge, this study is the first one which evaluates the possible remedy for resistance to chlorambucil as one of the most commonly employed medications in SC patients.
Histopathological studies in SC have demonstrated that lymphocytes infiltrate the choroid, and less commonly, vessels, leading to subsequent choriocapillaris occlusive vasculitis. This finding may indicate the important roles of lymphocytes in the pathogenesis of the disease.5 The histopathology in SC is very similar to birdshot chorioretinopathy.33,34 On the other hand, multiple studies have discussed the effects of long-term systemic corticosteroids on lymphocyte proliferation and T-cell population.35,36 Ferrari et al. reported increased lymphocytes, including increased absolute numbers of T cells, CD4+ and CD8+ cells, after four weeks of corticosteroid therapy in idiopathic thrombocytopenic purpura (ITP).35 Moreover, lymphocyte redistribution has been discussed in long-term steroid therapy.36 These changes associated with long-term corticosteroid use may interfere with the aim of chlorambucil treatment, since cells with higher proliferation rates are the target of this therapy. The negative effect of long-term systemic corticosteroids on birdshot chorioretinopathy has been studied in the past.37,38 Due to similarities between birdshot chorioretinopathy and SC in terms of histopathology, these facts can be applied to SC patients as well.
The target WBC count for chlorambucil therapy for SC is between 3000 and 4500 cells/μl. Chlorambucil dose adjustment is based on a weekly WBC count. In our experience, patients might be considered cured if there is no recurrence during the treatment period, which is around one year. Our observation in this case series showed that patients on high doses of systemic corticosteroids have unstable WBC count during chlorambucil therapy. Keeping this count in the satisfactory range for a reasonable period of at least six weeks can be challenging since it has been shown that induced toxic hematologic response is required for effective treatment with chlorambucil.25 The first two patients in this case series achieved durable remission and were likely cured after employing local corticosteroids or systemic immunomodulatory therapy, which allowed us to stop systemic corticosteroid use during chlorambucil therapy. However, the third and fourth patients are still experiencing recurrences since all systemic immunomodulatory therapies were unable to induce steroid-free remission. Local corticosteroid therapy was also recommended for both of the patients, but its potential side effects and the patients’ monocular statuses made this option unappealing.
We might be criticized for not employing local corticosteroid monotherapy without any systemic therapy. We believe that, although corticosteroids are the best option for controlling of acute ocular inflammation of any type, they are not potent enough to prime or re-program the immune system12 and not to respond to self-antigens as we expect with immunomodulatory therapy. This is similar to what occurs to pathologic cancer cells especially in blood cancers (lymphoma and leukemia) in patients who achieve remission with chemotherapy which is an advanced and more aggressive form of immunomodulatory therapy. Based on the above mentioned theory, corticosteroids as monotherapy cannot halt the inflammation thoroughly, so the ongoing inflammation can cause more cells destruction and epitopes exposures which might result in more resistant ocular inflammation which is believed to happen in patients with resistant autoimmune SC. we assume that the employment of systemic corticosteroid therapy, along with chlorambucil, is the main obstacle in achieving remission in patients with SC. This combination therapy is mostly seen in monocular patients or in vision-threatening SC where there is a lower threshold for aggressive systemic corticosteroid therapy in these patients.
We might also be criticized for using different therapies in one patient; however, we follow the strategy of “one change at a time” and this means that any time a conventional IMT is tried, we wait for three months with no changes to assess its effectiveness. For biologic response modifier agents, we wait for two months. This strategy makes interaction between medications unlikely. Moreover, since our mission is systemic steroid free remission, we only consider a medication to be effective if the inflammation stays in remission even after the effects of steroids are gone. Furthermore, none of these therapies induced long term remission in our patients.
Dexamethasone intravitreal implants have been employed in the treatment of active SC and serpiginous-like choroiditis.39,40 In these studies, the authors showed the success of this implant in controlling active SC. Based on these studies, dexamethasone can be an alternative to high dose oral or intravenous corticosteroid without systemic side effects including its effects on bone marrow, secondary lymphoid tissues, and peripheral blood regarding WBC counts, especially lymphocytes.
One common fact between all patients in this case series is the instability of WBC count during chlorambucil therapy plus systemic corticosteroids. This issue was addressed in one patient with dexamethasone intravitreal implant and in another patient with infliximab therapy. Both patients allowed us to taper and stop oral prednisone during chlorambucil therapy. The latter patient has been in remission for four years, which is the time frame during which one would expect a new lesion based on the Laatikainen and Erkkila et al. study.14 Despite this, this patient continues to take infliximab at a dose of 300 mg every four weeks since there is a fear of SC recurrence once infliximab therapy is terminated. However, this concept and hypothesis need further, more sophisticated examination.
This study had inherent limitations given its retrospective study design with a small sample size due to the rarity of cases of SC. It was even more challenging to find refractory cases with a reasonable follow-up period to expect a recurrence as all of these patients have at least 8 years of follow-up at our center without any serious side effects. Furthermore, all confounding factors cannot be controlled in a retrospective study. Regardless, we believe that confounding factors related to WBC might not interfere in this study since chlorambucil dose is adjusted based on WBC count and in clinical practice, changes in WBC count are typically more related to changes in corticosteroid dosage. Based on all these limitations, the results of this case series should be interpreted with caution and justifies the need for more potent studies.
4 Conclusion
The stability of WBC counts within toxic levels close to normal or lower limits of normal (3000–4500 cells/μl) during treatment with chlorambucil is an essential factor for the success of this therapy. A combination of dexamethasone intravitreal implant with chlorambucil therapy can be an effective and promising regimen in inducing and maintaining remission in refractory SC patients who fail a combination of systemic corticosteroid and chlorambucil therapy as the first line therapy. However, this primitive hypothesis should be investigated with more potent studies and larger sample sizes.
Patient consent
Consent to publish the personal information and cases details was obtained from all the patients.
Financial supports
None.
All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.
Disclosures
Dr. C Stephen Foster declares the following: Consultancies with Aldeyra Therapeutics (Lexington, MA), Allakos (Redwood City, CA), Bausch & Lomb Surgical, Inc (Rancho Cucamonga, CA), Eyegate Pharma (Waltham, MA), Genentech (South San Francisco, CA), Novartis (Cambridge, MA), pSivida (Watertown, MA) Grants or grants pending with Aciont (Salt Lake City, UT), Alcon (Aliso Viejo, CA), Aldeyra Therapeutics (Lexington, MA), Bausch & Lomb (Rochester, NY), Clearside Biomedical (Alpharetta, GA), Dompé pharmaceutical (Milan, Italy), Eyegate Pharma (Waltham, MA), Mallinckrodt pharmaceuticals (Staines-upon-Thames, UK), Novartis Pharmaceuticals (Cambridge, MA), pSivida (Watertown, MA), Santen (Osaka, Japan). Payment for lectures including service on speaking bureaus: Alcon (Aliso Viejo, CA), Allergan (Dublin, Ireland), Mallinckrodt pharmaceuticals (Staines-upon-Thames, UK). Stock or Stock Options: Eyegate Pharma (Waltham, MA).
The other authors have nothing to declare.
Compliance with ethics guidelines
This study was approved by the New England Institutional Review Board, which has issued a waiver of informed consent for the retrospective chart review analysis. This study was performed in accordance with the Helsinki Declaration of 1964, and its later amendments. All participants provided consent for publication if any identifying information is included in the manuscript.
Data availability
The data that support the findings of this study are available from the corresponding author, upon reasonable request.
Declaration of competing interest
No conflicting relationship exists for any author. | Oral | DrugAdministrationRoute | CC BY-NC-ND | 33615036 | 19,884,508 | 2021-03 |
What was the dosage of drug 'BEVACIZUMAB'? | Chlorambucil combination therapy in refractory serpiginous choroiditis: A cure?
To find a remedy for serpiginous choroiditis refractory to oral prednisone and chlorambucil treatment.
Eight eyes of four patients (all female) with advanced macular involvement secondary to serpiginous choroiditis were included in the study. The average age of the patients was 45.2 years. One eye of each patient was legally blind and the lesion was close to the fovea in the other eye. All four patients failed oral prednisone and chlorambucil therapy. However, case 1 responded to chlorambucil treatment after intravitreal dexamethasone implant implantation and discontinuation of oral prednisone. Case 2 responded to chlorambucil therapy when oral prednisone was stopped in combination with infliximab therapy. Due to long follow-up period of more than four years, these two cases are considered to be cured. Case 3 and case 4 were not able to achieve remission with chlorambucil and immunomodulatory therapy. They refused intravitreal steroid implant due to side effects profile.
The stability of WBC counts within toxic levels close to normal or lower limits of normal (3000-4500 cells/μl) during treatment with chlorambucil is an essential factor for the success of this therapy. A combination of dexamethasone intravitreal implant with chlorambucil therapy can be an effective and promising regimen in inducing and maintaining remission in refractory serpiginous choroiditis patients who fail a combination of systemic corticosteroid and chlorambucil therapy.
1 Introduction
Serpiginous choroiditis (SC) is a rare, chronic, asymmetrically bilateral posterior uveitis with a recurrent course. The exact prevalence of SC is unknown; however, it is estimated between 1.6% and 5.3% of posterior uveitis cases in non-endemic areas for tuberculosis.1 Major features of SC include choriocapillaris occlusive vasculitis, secondary endothelial cell injury, and subsequent atrophy of the retinal pigment epithelium, outer retina, and choroid.2,3 Histopathology studies reveal lymphocytic infiltration in the choroid and, less commonly, around vessels.4 The peripapillary area is classically involved in SC and accounts for 80% of the cases.5 The prognosis of vision is poor when it involves the macula, especially in the macular variant of SC. Moreover, the macular variant has a higher risk of developing choroidal neovascularization in nearly half of the affected patients.6,7 Fluorescein angiography (FA), indocyanine green angiography (ICG), optical coherence tomography (OCT), fundus autofluorescence (FAF), and microperimetry are the ancillary diagnostic tools and tests which help in the diagnosis, follow-up, and monitoring for secondary complications.1
Historically, the administration of high doses of oral or intravenous steroids was considered as the standard of care for patients with SC.8 However, immunosuppressive agents such as azathioprine, cyclosporine, chlorambucil, and cyclophosphamide emerged as treatment options for steroid-free remission.4,9, 10, 11, 12 Of these, the alkylating agents cyclophosphamide and chlorambucil have been noted to have a high success rate in the treatment of SC.4,10,12 Chlorambucil, being a potent alkylating agent, can interfere with DNA replication and cell division.13 This medication can induce remission, maintain remission, and even cure this disease.12
Despite successful treatment of SC with alkylating agents, in some patients the disease can recur frequently and progress to affect the central vision. This becomes more important in patients with poor vision in the other eye secondary to SC or advanced SC encroaching the fovea in the affected eye. In this case series, we decided to evaluate possible remedies for refractory and recurrent SC in patients who have been treated with chlorambucil and oral or intravenous corticosteroids.
2 4 Cases
Case 1. A sixty-year-old female was referred to us for the evaluation of macular SC OU. She had noticed blurry vision OS one month before her first visit with us. A geographic lesion with indistinct and irregular borders was observed in both eyes. The lesion was uni-centric OU, temporal to fovea OD and peripapillary with extension to fovea OS. FA and ICG showed the activity of the lesions in both eyes (Fig. 1A). Her best-corrected visual acuity (BCVA) was 20/20 OD and decreased OS to 20/100. Complete blood work-up for uveitis ruled out non-infectious and infectious posterior uveitis, including syphilis and tuberculosis. Based on these findings, she was diagnosed with autoimmune SC OU and was started on a combination of chlorambucil and daily oral prednisone. Chlorambucil was titrated based on her white blood cell (WBC) count. She had another flare-up while she was on 2 mg/day prednisone and had already stopped chlorambucil for three weeks due to WBC 3200 cells/μl. BCVA OS decreased to 20/125, and ICGA confirmed enlargement of the lesion. Chlorambucil was restarted to 2 mg every other day, and oral prednisone was increased to 5 mg/day. With this change in her regimen, the vision increased to the baseline before her last flare, to 20/40. Treatment with chlorambucil was stopped after one year. Her follow-up visit increased to every three months from monthly. Then, six months later, she was started on oral methotrexate 7.5 mg weekly by her rheumatologist because of her joint issues. She was followed every three months for seven months until she noticed a change in OS again. At that time, she was on oral methotrexate 15 mg weekly. BCVA OS decreased to 20/125, and ancillary tests showed activity at the border of the lesions on the foveal side (Fig. 1B). She received one dose of 1 g intravenous methylprednisolone, intravitreal injection of triamcinolone and bevacizumab, and was restarted on oral prednisone 80 mg/day. A week later, her methotrexate dose was boosted to methotrexate 25 mg weekly subcutaneous injections, and we tapered prednisone 10 mg weekly. In three months, oral prednisone was tapered and stopped. Three months later, her lesion became active and she developed choroidal neovascularization (CNV) for which she received a bevacizumab injection. She was restarted on chlorambucil and oral prednisone. The decision for local therapy with dexamethasone implant was made at this point, and she was put back on chlorambucil 2 mg every three days. She was on chlorambucil without oral prednisone, titrating the dose based on WBC for seventeen months, after which she was considered cured (Fig. 1C). In her last visit with us, her BCVA OD and OS were 20/20 and 20/50, respectively. The patient's average WBC count while on chlorambucil with prednisone, chlorambucil without prednisone, and chlorambucil after dexamethasone intravitreal implant were 5500 ± 2900, 4700 ± 1100 and 4100 ± 500 cells/μl, respectively. The total duration of treatment before dexamethasone intravitreal implant was 60 months and 17 months after dexamethasone intravitreal implant. The total length of follow-up is 132 months, and the total duration of remission off medication is 48 months (Table 1).Fig. 1 A patient with bilateral serpiginous choroidopathy. (A) Serpiginous lesions in both eyes, encroaching the fovea in right eye and with foveal involvement in left eye. Fluoresecein angiography shows activity in both eyes. (B) The middle row shows progression towards the fovea with leakage pointing toward the fovea in the right eye. (C) Shows the stability of fundus photos and fluorescein angiography in both eyes at one year after intravitreal dexamethasone implant and chlorambucil treatment.
Fig. 1Table 1 Demographics and clinical characteristics of patients with resistant serpiginous choroiditis.
Table 1 Age years Sex Laterality BCVA first visit WBC (C + P) cells/μl
(x 10c) WBC (C) cells/μl
(x 10c) WBC (C + IMTor implan cells/μl (*10c) Duration of treatment before IMT Duration of treatment after IMT Duration of follow-up on chlorambucil Duration of follow-up off chlorambucil BCVA last visit
Patient 1 60 F Bilat 20/20 20/100 5.5 ± 2.9 4.7 ± 1.1 4.1 ± 0.5 60a months 17b months 60 months 83 months 20/20 20/50
OD
OS
Patient 2 42 F Bilat 1 mcf 20/20 5.7 ± 2.2 N/A 3.8 ± 0.5 40c months 19d months 49 months 60 months 1mcf
20/15
OD
OS
Patient 3 32 F Bilat HM 20/20 8.8 ± 3.4 N/A N/A 5 + 10 e months N/A 5 months N/A HM 20/50
OD
OS
Patient 4 47 F Bilat 20/30 1mcf 6.2 ± 3.3 N/A N/A N/A N/A 12 months N/A 20/50 1mcf
OD
OS
BCVA:best corrected visual acuity; Bilat:bilateral; C:chlorambucil; CF:counting fingers; HM:hand motion; IMT:immunomodulatory therapy; P:prednisone; N/A:not applicable.
a Before intravitreal dexamethasone implant.
b After intravitreal dexamethasone implant.
c Before starting infliximab.
d After starting infliximab.
e 5 months chlorambucil and 10 months cyclophosphamide.
Case 2. A 42-year-old female was referred to us with blurry vision and field distortion OD for ten years and OS for eight years. Her vision was counting fingers at 1 m OD and 20/20 OS. At the time of presentation, the patient had already received multiple intravitreal anti-VEGF (bevacizumab) and triamcinolone injections OD. The geographic lesions were peripapillary OU, with foveal involvement OD. Initial FA revealed chorioretinal scarring with window defects OU and leakage on borders OD (Fig. 2A). On ICG, the area of hypolucency OS extended further into the macula, which was not seen on FA (Fig. 2B). Complete blood work-up for uveitis ruled out non-infectious and infectious posterior uveitis, including syphilis and tuberculosis. Based on these findings, she was diagnosed with autoimmune SC OU and we recommended therapy with chlorambucil. She sought a second opinion elsewhere, where she was started on mycophenolate mofetil (MMF) 1 g daily with infliximab 300 mg IV every four weeks and oral prednisone 80 mg/day with taper. MMF and infliximab were eventually discontinued due to elevated LFTs. On follow up at our clinic eighteen months after the initial consult, chlorambucil was finally started with dose adjustment based on weekly monitoring of WBC count to reach the endpoint of WBC count 3000–4500 cells/μl. While on chlorambucil 20mg and prednisone 40mg daily, the patient became symptomatic OS with new changes and leakage on FA OS, prompting boosting of oral prednisone to 80 mg; she also received one ranibizumab injection OS locally. Six weeks after starting treatment with chlorambucil (20mg at this time) and oral prednisone 80 mg daily, WBC count dropped down to 4900 cells/μl, so we started tapering prednisone. Two months after initiation of chlorambucil therapy, chlorambucil was stopped while tapering prednisone at 30 mg/day with a WBC count of 3300 cells/μl. At this point, FA, FAF, and OCT showed stability and quiescence. On a subsequent visit with her local ophthalmologist, infliximab 600 mg infusions every four weeks was started for activity OS, and eventually increased to 900 mg every four weeks in combination with chlorambucil. WBC count increased to 7900 cells/μl while on prednisone 10 mg with taper, and chlorambucil was restarted at 4 mg daily, eventually going up to 6 mg daily (Fig. 2B). Chlorambucil dose adjustment with weekly WBC count was continued. Meanwhile, she received a bevacizumab injection with her local ophthalmologist due to central vision distortion OD. On her eight-month of treatment, WBC count dipped to 2000 cells/μl, and chlorambucil was stopped. After one week, with WBC count creeping back up to 4800 cells/μl, chlorambucil was restarted at 2 mg/day. Disease activity was then noted at ten months from treatment initiation with no interventions at that time. On follow up at our clinic fourteen months after starting chlorambucil, the activity noted at ten months prompted treatment extension, and the patient was educated on the risks vs. benefits of this decision. Chlorambucil treatment was continued for a total duration of twenty-one months. FA and OCT macula findings were stable and the patient was asymptomatic (Fig. 2C,D). Subsequent consults established disease stability with no new symptoms or activity. Infliximab was eventually tapered by 100 mg every four weeks. On her last consult at our clinic, she was on infliximab 100 mg infusions every four weeks with a final VA of 20/400 OD and 20/15 OS and stable findings on FA and macula OCT. Her average WBC count was 5700 ± 2200 cells/μl while on chlorambucil with prednisone, and 3800 ± 500 cells/μl when she was on chlorambucil after starting infliximab infusions without prednisone. The total duration of treatment before and after beginning infliximab infusions was 40 and 19 months, respectively. The total length of follow-up is 108 months. The total period of remission off chlorambucil is 60 months (Table 1).Fig. 2 (A) Fundus photo and fluorescein angiography of a patient with bilateral serpiginous choroiditis at the primary visit at our clinic. (B) The same patient during a recurrence in the left eye close to the fovea. (C,D) Stability of year after stopping chlorambucil while on infliximab tapering. (E) Macular optical coherence tomography at the first visit (left), during a recurrence (middle), and the last visit (right).
Fig. 2
Case 3. A 32-year-old female presented with decreased vision, floaters, and photophobia OS. Vision OD was poor due to retinal detachment after a motor vehicle accident. Before presenting to her initial consultation at our clinic, complete blood work-up for uveitis had ruled out non-infectious and infectious posterior uveitis, including syphilis and tuberculosis and she had already been diagnosed with idiopathic SC. She had been on MMF 2 g daily, cyclosporin 25 mg and prednisone 30 mg daily for fourteen months. Her vision was hand-motion OD and 20/20 OS at presentation. A fundus examination revealed optic atrophy and a horizontal scar OD in addition to diffuse chorioretinal (CR) scarring in both eyes. Given the possibility of the activity of the lesion potentially affecting the fovea OS and her monocular status, chlorambucil and cyclophosphamide were discussed as treatment options.
The patient was started on chlorambucil 4 mg daily and continued on 25 mg of prednisone daily. A month later, her WBC count dropped from 14,800 to 12,100 cells/μl. However, she felt her vision had decreased once again after two weeks on chlorambucil. She was advised to increase chlorambucil to 6 mg/day from 4 mg/day, as well as increase prednisone to 40 mg daily. After one week at this dose, she reported stable vision OD. Chlorambucil dose adjustment with weekly WBC count and oral prednisone were continued until she reported stable vision and no other symptoms. At this time, she was advised to increase chlorambucil to 12 mg daily.
Approximately four months after her initial visit, the patient presented to our clinic with worsening scotoma and floaters OS. At this point, she was on prednisone 5 mg daily and chlorambucil 10 mg daily. She had stopped chlorambucil for a week due to fever, and the WBC count was at 11,200 cells/μl. FA and ICG showed active choroidal inflammation at the lesion border, especially OS. Later on, she developed a diffuse, itchy rash, and because of this side effect, she was started on bi-weekly cyclophosphamide pulse therapy. She had five doses of cyclophosphamide pulse therapy, and her WBC count was between 4500 and 6300 cells/μl. However, a few days later, she complained of decreased vision OS with more central involvement. Her local ophthalmologist increased her prednisone to 60 mg, and she received her next cyclophosphamide infusion four days later with WBC count at 4000 cells/μl. Cyclophosphamide therapy was finally stopped due to persistent skin rash.
In the interim, she followed up with her local ophthalmologist while on oral prednisone with different doses based on disease activity. Her next visit with us was seven years later, and vision OS had deteriorated to 20/50. FA showed active inflammation OS in the form of enlarged CR lesions approaching the fovea with multifocal areas of leakage at the margins of the lesions (Fig. 3B). Up to that point, the patient had been off all immunomodulatory therapy (IMT) for seven years, yet only cyclophosphamide appeared to halt the progression of her disease. Monthly cyclophosphamide pulse therapy was resumed but was later stopped after eight months due to low WBC count. After this, she continued with oral prednisone 20 mg daily. At her last follow-up visit, chlorambucil was restarted due to the persistence of symptoms, worsening of vision OS, and the progression of lesion activity on imaging (Fig. 3C). Intravitreal steroid implants were also discussed. The patient was never able to taper off oral prednisone during treatment, and the average WBC count during her course of treatment was 8800 ± 3400 cells/μl. The total duration of treatment with chlorambucil was 5 months, cyclophosphamide was 10 months, and MMF plus cyclosporine was 14 months. The total duration of follow-up is 148 months. She has never been in remission for an extended period off medication (Table 1).Fig. 3 (A) Fundus photo of both eyes of a patient with bilateral serpiginous choroiditis. History of traumatic retinal detachment surgery with legal blindness in the right eye and active serpiginous choroiditis in the left eye. Fluorescein angiography shows an active lesion in the left eye. (B) Optical coherence tomography, fundus autofluorescence, and fluorescein angiography during a recurrence where the patient was started on cyclophosphamide pulse therapy. (C) Progression of the lesion in the left eye with an active lesion in fluorescein angiography at her last visit. Intravitreal dexamethasone and triamcinolone implants were discussed at this visit.
Fig. 3
Case 4. A 47-year-old female was referred to our center with decreased vision OU for one month and had been started on prednisone 50 mg daily before her first visit with us. Her vision OD and OS were 20/30 and counting fingers at 1 m, respectively, at presentation. Dilated fundoscopy showed bilateral geographic lesions nasal to the fovea OD and involving the fovea OS (Fig. 4A). Complete blood work-up for uveitis ruled out non-infectious and infectious posterior uveitis, including syphilis and tuberculosis. Based on these findings, and she was diagnosed with autoimmune SC OU. Oral prednisone was increased to 60 mg daily, and due to significant vision loss OS, she was started on chlorambucil 6 mg daily. Chlorambucil treatment with WBC count monitoring and tapering of oral prednisone was continued for a year. Once the oral prednisone taper was completed, she continued with chlorambucil monotherapy for five more months, at which time she had achieved remission. After four months; however, she had a flare-up OD, which was first treated with 1 g IV methylprednisolone infusion and intravenous methotrexate 200 mg/day. Subsequently, she was continued on subcutaneous methotrexate 15 mg weekly along with folic acid 1 mg/day for two years. She developed another flare-up when tapering methotrexate; hence methotrexate dose was boosted, and a combination of chlorambucil and oral prednisone was restarted. The patient was on chlorambucil and oral prednisone for one year, with an average WBC count of 6200 ± 3300 cells/μl. The patient was then on chlorambucil alone for another two months. She had been flare-free for twenty months when she had another episode. This time she was treated with intravenous and subcutaneous methotrexate. She had another flare during tapering of methotrexate and she is currently on a combination of chlorambucil, prednisone, and subcutaneous methotrexate therapy. The total duration of follow-up has been 116 months. She has never been in remission for an extended period (Table 1).Fig. 4 A serpiginous choroiditis patient with multiple recurrences despite treatment with a combination of oral prednisone and chlorambucil therapy. (A) Color fundus photos and fluorescein angiography of both eyes at the first visit, which showed activity around the lesion in both eyes. (B) The second row shows the progression of lesions in both eyes during a recurrence on fundus photos and fundus autofluorescence. (C) Fundus autofluorescence and fluorescein angiography showed reactivation of the supratemporal area of the lesion in the right eye. (D) Optical coherence tomography shows the lesion, edema, and destruction of the supratemporal part of the lesion, compatible with fundus autofluorescence and fluorescein angiography. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)
Fig. 4
3 Discussion
The pathogenesis of serpiginous choroiditis (SC) is unknown. The course of the disease is indolent and can be asymptomatic until it involves the macula and the central vision. Many patients can have old scars even at the first visit when they are diagnosed with SC.14 Laatikainen and Erkkila et al. reported that new lesions may appear at an interval of 3 months–4 years. They also demonstrated that active lesions resolve in a few weeks; however, signs of activity may last between 1 and 9 months.14 Central vision is involved in 20%–50% of cases, with the likelihood increasing with longer duration of follow-up and disease activity.8,14 Recurrences that affect the macula can cause severe visual loss of less than 20/200, which is typically irreversible and may induce CNV in the macula or around the optic disc.15
There are no controlled trials for the treatment of SC due to the rarity of the disease. Cytosine arabinoside, azathioprine, and oral prednisone were used with reported improved visual acuity in one month.16 Employment of a combination of cyclosporine and oral prednisone as a treatment of active SC had conflicting results. Hopper and Kaplan reported a triple-agent regimen of azathioprine, cyclosporine, and oral prednisone that resulted in rapid control of the active SC and vision recovery; however, disease recurrence was the study's main problem.9 Akpek et al. employed the same regimen in a more extended study and found that this regimen helped keep the inflammation quiet during treatment; however, it did not maintain remission off medication.17
Alkylating agents can bind to DNA, interfere with DNA replication, and subsequently interfere with cell division. Cyclophosphamide is commonly used because of its predictable, dose-dependent, and reversible adverse effects on WBC count18; nonetheless, it can result in serious side effects, some of which are life-threatening. These side effects include reversible hematuria, hemorrhagic cystitis, reversible alopecia, sterility, bladder cancer, lymphoma, and leukemia. Chlorambucil is another alkylating agent primarily used for the treatment of several lymphoproliferative diseases. It is a stable derivative of the nitrogen mustard.19 Based on its ability to reduce circulating lymphocytes, chlorambucil is effective in the treatment of rheumatologic diseases, including juvenile rheumatoid arthritis, systemic lupus erythematosus, and nephrotic syndrome.20, 21, 22, 23 Given the availability of other conventional immunomodulatory agents and biologic response modifiers that yield better results with fewer unpredictable side effects, ophthalmologists are reluctant to use chlorambucil. Our knowledge about biologic response modifier agents is limited to a few case reports and some of our patients had already failed infliximab, mycophenolate mofetil, methotreaxte before their first presentation to us or during follow-up with us. Palmer et al. studied the side effects of chlorambucil and found that these side effects are related to the total dose and duration of treatment.24 However, Tessler et al. found chlorambucil to be a successful treatment for different types of uveitis with no severe complications during 12 years of follow-up. They also reported complete remission in all patients. Although chlorambucil dose in their study was administered regardless of body weight, it did not exceed 2.2 g per patient during the entire treatment.25 Based on these findings, recent studies still rely on alkylating agents including cyclophosphamide and chlorambucil for classical and macular SC.5,12,32
It may take more time for chlorambucil to show its therapeutic and toxic effects. Patients on this medication should be monitored with weekly blood counts, specifically WBC and platelet counts, since its side effects are not always dose-related.25 Chlorambucil is administered orally because it has excellent gastrointestinal absorption, and its superiority over cyclophosphamide is related to the absence of associated side effects such as hair loss, hemorrhagic cystitis, and bladder cancer.26
The recommendation for the daily and total dose of chlorambucil is equal to or less than 0.2 mg/kg and 2.2 g, respectively. These recommendations help avoid late complications such as lymphoma and leukemia.27 Various doses of chlorambucil have been employed in the past in the field of ophthalmology. The use of lower doses of chlorambucil over an extended period, such as more than one year, without provoking bone marrow toxicity is one approach.28, 29, 30, 31 However, it has been demonstrated that sustained remission of the disease is achievable when the WBC count remained depressed for at least six weeks. This finding suggests that effective treatment with chlorambucil requires the induction of a toxic hematologic response.25
The recent literature shows that alkylating agents are still the most potent and effective treatment in patients with SC.4,12,32 Venkatesh and colleagues showed that intravenous cyclophosphamide pulse therapy provided a rapid resolution of active lesions and helped maintain good functional visual acuity.4 However, they admitted that this treatment might not prevent recurrences in patients with SC.4 Venkatesh et al. also studied intravenous methylprednisolone and cyclophosphamide in macular SC; they, again demonstrated it could be effective in acute macular SC, yet admitted that this treatment had no effects on disease relapses in the long-term.32 Ebrahimiadib et al. retrospectively studied 17 patients on chlorambucil with dose escalation based on weekly WBC count, with the target of 3000–4500 white blood cells/μl. They concluded that chlorambucil was well tolerated by the patients and was effective in preventing recurrences.12 Although all these recent studies provided important facts regarding SC treatment, they did not discuss the next step for the patients who failed these treatments. In the current study, we decided to evaluate the possible causes of chlorambucil treatment failure in patients with resistant SC and to examine possible successful regimens in these patients. To the best of our knowledge, this study is the first one which evaluates the possible remedy for resistance to chlorambucil as one of the most commonly employed medications in SC patients.
Histopathological studies in SC have demonstrated that lymphocytes infiltrate the choroid, and less commonly, vessels, leading to subsequent choriocapillaris occlusive vasculitis. This finding may indicate the important roles of lymphocytes in the pathogenesis of the disease.5 The histopathology in SC is very similar to birdshot chorioretinopathy.33,34 On the other hand, multiple studies have discussed the effects of long-term systemic corticosteroids on lymphocyte proliferation and T-cell population.35,36 Ferrari et al. reported increased lymphocytes, including increased absolute numbers of T cells, CD4+ and CD8+ cells, after four weeks of corticosteroid therapy in idiopathic thrombocytopenic purpura (ITP).35 Moreover, lymphocyte redistribution has been discussed in long-term steroid therapy.36 These changes associated with long-term corticosteroid use may interfere with the aim of chlorambucil treatment, since cells with higher proliferation rates are the target of this therapy. The negative effect of long-term systemic corticosteroids on birdshot chorioretinopathy has been studied in the past.37,38 Due to similarities between birdshot chorioretinopathy and SC in terms of histopathology, these facts can be applied to SC patients as well.
The target WBC count for chlorambucil therapy for SC is between 3000 and 4500 cells/μl. Chlorambucil dose adjustment is based on a weekly WBC count. In our experience, patients might be considered cured if there is no recurrence during the treatment period, which is around one year. Our observation in this case series showed that patients on high doses of systemic corticosteroids have unstable WBC count during chlorambucil therapy. Keeping this count in the satisfactory range for a reasonable period of at least six weeks can be challenging since it has been shown that induced toxic hematologic response is required for effective treatment with chlorambucil.25 The first two patients in this case series achieved durable remission and were likely cured after employing local corticosteroids or systemic immunomodulatory therapy, which allowed us to stop systemic corticosteroid use during chlorambucil therapy. However, the third and fourth patients are still experiencing recurrences since all systemic immunomodulatory therapies were unable to induce steroid-free remission. Local corticosteroid therapy was also recommended for both of the patients, but its potential side effects and the patients’ monocular statuses made this option unappealing.
We might be criticized for not employing local corticosteroid monotherapy without any systemic therapy. We believe that, although corticosteroids are the best option for controlling of acute ocular inflammation of any type, they are not potent enough to prime or re-program the immune system12 and not to respond to self-antigens as we expect with immunomodulatory therapy. This is similar to what occurs to pathologic cancer cells especially in blood cancers (lymphoma and leukemia) in patients who achieve remission with chemotherapy which is an advanced and more aggressive form of immunomodulatory therapy. Based on the above mentioned theory, corticosteroids as monotherapy cannot halt the inflammation thoroughly, so the ongoing inflammation can cause more cells destruction and epitopes exposures which might result in more resistant ocular inflammation which is believed to happen in patients with resistant autoimmune SC. we assume that the employment of systemic corticosteroid therapy, along with chlorambucil, is the main obstacle in achieving remission in patients with SC. This combination therapy is mostly seen in monocular patients or in vision-threatening SC where there is a lower threshold for aggressive systemic corticosteroid therapy in these patients.
We might also be criticized for using different therapies in one patient; however, we follow the strategy of “one change at a time” and this means that any time a conventional IMT is tried, we wait for three months with no changes to assess its effectiveness. For biologic response modifier agents, we wait for two months. This strategy makes interaction between medications unlikely. Moreover, since our mission is systemic steroid free remission, we only consider a medication to be effective if the inflammation stays in remission even after the effects of steroids are gone. Furthermore, none of these therapies induced long term remission in our patients.
Dexamethasone intravitreal implants have been employed in the treatment of active SC and serpiginous-like choroiditis.39,40 In these studies, the authors showed the success of this implant in controlling active SC. Based on these studies, dexamethasone can be an alternative to high dose oral or intravenous corticosteroid without systemic side effects including its effects on bone marrow, secondary lymphoid tissues, and peripheral blood regarding WBC counts, especially lymphocytes.
One common fact between all patients in this case series is the instability of WBC count during chlorambucil therapy plus systemic corticosteroids. This issue was addressed in one patient with dexamethasone intravitreal implant and in another patient with infliximab therapy. Both patients allowed us to taper and stop oral prednisone during chlorambucil therapy. The latter patient has been in remission for four years, which is the time frame during which one would expect a new lesion based on the Laatikainen and Erkkila et al. study.14 Despite this, this patient continues to take infliximab at a dose of 300 mg every four weeks since there is a fear of SC recurrence once infliximab therapy is terminated. However, this concept and hypothesis need further, more sophisticated examination.
This study had inherent limitations given its retrospective study design with a small sample size due to the rarity of cases of SC. It was even more challenging to find refractory cases with a reasonable follow-up period to expect a recurrence as all of these patients have at least 8 years of follow-up at our center without any serious side effects. Furthermore, all confounding factors cannot be controlled in a retrospective study. Regardless, we believe that confounding factors related to WBC might not interfere in this study since chlorambucil dose is adjusted based on WBC count and in clinical practice, changes in WBC count are typically more related to changes in corticosteroid dosage. Based on all these limitations, the results of this case series should be interpreted with caution and justifies the need for more potent studies.
4 Conclusion
The stability of WBC counts within toxic levels close to normal or lower limits of normal (3000–4500 cells/μl) during treatment with chlorambucil is an essential factor for the success of this therapy. A combination of dexamethasone intravitreal implant with chlorambucil therapy can be an effective and promising regimen in inducing and maintaining remission in refractory SC patients who fail a combination of systemic corticosteroid and chlorambucil therapy as the first line therapy. However, this primitive hypothesis should be investigated with more potent studies and larger sample sizes.
Patient consent
Consent to publish the personal information and cases details was obtained from all the patients.
Financial supports
None.
All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.
Disclosures
Dr. C Stephen Foster declares the following: Consultancies with Aldeyra Therapeutics (Lexington, MA), Allakos (Redwood City, CA), Bausch & Lomb Surgical, Inc (Rancho Cucamonga, CA), Eyegate Pharma (Waltham, MA), Genentech (South San Francisco, CA), Novartis (Cambridge, MA), pSivida (Watertown, MA) Grants or grants pending with Aciont (Salt Lake City, UT), Alcon (Aliso Viejo, CA), Aldeyra Therapeutics (Lexington, MA), Bausch & Lomb (Rochester, NY), Clearside Biomedical (Alpharetta, GA), Dompé pharmaceutical (Milan, Italy), Eyegate Pharma (Waltham, MA), Mallinckrodt pharmaceuticals (Staines-upon-Thames, UK), Novartis Pharmaceuticals (Cambridge, MA), pSivida (Watertown, MA), Santen (Osaka, Japan). Payment for lectures including service on speaking bureaus: Alcon (Aliso Viejo, CA), Allergan (Dublin, Ireland), Mallinckrodt pharmaceuticals (Staines-upon-Thames, UK). Stock or Stock Options: Eyegate Pharma (Waltham, MA).
The other authors have nothing to declare.
Compliance with ethics guidelines
This study was approved by the New England Institutional Review Board, which has issued a waiver of informed consent for the retrospective chart review analysis. This study was performed in accordance with the Helsinki Declaration of 1964, and its later amendments. All participants provided consent for publication if any identifying information is included in the manuscript.
Data availability
The data that support the findings of this study are available from the corresponding author, upon reasonable request.
Declaration of competing interest
No conflicting relationship exists for any author. | UNKNOWN, INTRAVITREAL ANTI VEGF | DrugDosageText | CC BY-NC-ND | 33615036 | 19,000,865 | 2021-03 |
What was the dosage of drug 'RANIBIZUMAB'? | Chlorambucil combination therapy in refractory serpiginous choroiditis: A cure?
To find a remedy for serpiginous choroiditis refractory to oral prednisone and chlorambucil treatment.
Eight eyes of four patients (all female) with advanced macular involvement secondary to serpiginous choroiditis were included in the study. The average age of the patients was 45.2 years. One eye of each patient was legally blind and the lesion was close to the fovea in the other eye. All four patients failed oral prednisone and chlorambucil therapy. However, case 1 responded to chlorambucil treatment after intravitreal dexamethasone implant implantation and discontinuation of oral prednisone. Case 2 responded to chlorambucil therapy when oral prednisone was stopped in combination with infliximab therapy. Due to long follow-up period of more than four years, these two cases are considered to be cured. Case 3 and case 4 were not able to achieve remission with chlorambucil and immunomodulatory therapy. They refused intravitreal steroid implant due to side effects profile.
The stability of WBC counts within toxic levels close to normal or lower limits of normal (3000-4500 cells/μl) during treatment with chlorambucil is an essential factor for the success of this therapy. A combination of dexamethasone intravitreal implant with chlorambucil therapy can be an effective and promising regimen in inducing and maintaining remission in refractory serpiginous choroiditis patients who fail a combination of systemic corticosteroid and chlorambucil therapy.
1 Introduction
Serpiginous choroiditis (SC) is a rare, chronic, asymmetrically bilateral posterior uveitis with a recurrent course. The exact prevalence of SC is unknown; however, it is estimated between 1.6% and 5.3% of posterior uveitis cases in non-endemic areas for tuberculosis.1 Major features of SC include choriocapillaris occlusive vasculitis, secondary endothelial cell injury, and subsequent atrophy of the retinal pigment epithelium, outer retina, and choroid.2,3 Histopathology studies reveal lymphocytic infiltration in the choroid and, less commonly, around vessels.4 The peripapillary area is classically involved in SC and accounts for 80% of the cases.5 The prognosis of vision is poor when it involves the macula, especially in the macular variant of SC. Moreover, the macular variant has a higher risk of developing choroidal neovascularization in nearly half of the affected patients.6,7 Fluorescein angiography (FA), indocyanine green angiography (ICG), optical coherence tomography (OCT), fundus autofluorescence (FAF), and microperimetry are the ancillary diagnostic tools and tests which help in the diagnosis, follow-up, and monitoring for secondary complications.1
Historically, the administration of high doses of oral or intravenous steroids was considered as the standard of care for patients with SC.8 However, immunosuppressive agents such as azathioprine, cyclosporine, chlorambucil, and cyclophosphamide emerged as treatment options for steroid-free remission.4,9, 10, 11, 12 Of these, the alkylating agents cyclophosphamide and chlorambucil have been noted to have a high success rate in the treatment of SC.4,10,12 Chlorambucil, being a potent alkylating agent, can interfere with DNA replication and cell division.13 This medication can induce remission, maintain remission, and even cure this disease.12
Despite successful treatment of SC with alkylating agents, in some patients the disease can recur frequently and progress to affect the central vision. This becomes more important in patients with poor vision in the other eye secondary to SC or advanced SC encroaching the fovea in the affected eye. In this case series, we decided to evaluate possible remedies for refractory and recurrent SC in patients who have been treated with chlorambucil and oral or intravenous corticosteroids.
2 4 Cases
Case 1. A sixty-year-old female was referred to us for the evaluation of macular SC OU. She had noticed blurry vision OS one month before her first visit with us. A geographic lesion with indistinct and irregular borders was observed in both eyes. The lesion was uni-centric OU, temporal to fovea OD and peripapillary with extension to fovea OS. FA and ICG showed the activity of the lesions in both eyes (Fig. 1A). Her best-corrected visual acuity (BCVA) was 20/20 OD and decreased OS to 20/100. Complete blood work-up for uveitis ruled out non-infectious and infectious posterior uveitis, including syphilis and tuberculosis. Based on these findings, she was diagnosed with autoimmune SC OU and was started on a combination of chlorambucil and daily oral prednisone. Chlorambucil was titrated based on her white blood cell (WBC) count. She had another flare-up while she was on 2 mg/day prednisone and had already stopped chlorambucil for three weeks due to WBC 3200 cells/μl. BCVA OS decreased to 20/125, and ICGA confirmed enlargement of the lesion. Chlorambucil was restarted to 2 mg every other day, and oral prednisone was increased to 5 mg/day. With this change in her regimen, the vision increased to the baseline before her last flare, to 20/40. Treatment with chlorambucil was stopped after one year. Her follow-up visit increased to every three months from monthly. Then, six months later, she was started on oral methotrexate 7.5 mg weekly by her rheumatologist because of her joint issues. She was followed every three months for seven months until she noticed a change in OS again. At that time, she was on oral methotrexate 15 mg weekly. BCVA OS decreased to 20/125, and ancillary tests showed activity at the border of the lesions on the foveal side (Fig. 1B). She received one dose of 1 g intravenous methylprednisolone, intravitreal injection of triamcinolone and bevacizumab, and was restarted on oral prednisone 80 mg/day. A week later, her methotrexate dose was boosted to methotrexate 25 mg weekly subcutaneous injections, and we tapered prednisone 10 mg weekly. In three months, oral prednisone was tapered and stopped. Three months later, her lesion became active and she developed choroidal neovascularization (CNV) for which she received a bevacizumab injection. She was restarted on chlorambucil and oral prednisone. The decision for local therapy with dexamethasone implant was made at this point, and she was put back on chlorambucil 2 mg every three days. She was on chlorambucil without oral prednisone, titrating the dose based on WBC for seventeen months, after which she was considered cured (Fig. 1C). In her last visit with us, her BCVA OD and OS were 20/20 and 20/50, respectively. The patient's average WBC count while on chlorambucil with prednisone, chlorambucil without prednisone, and chlorambucil after dexamethasone intravitreal implant were 5500 ± 2900, 4700 ± 1100 and 4100 ± 500 cells/μl, respectively. The total duration of treatment before dexamethasone intravitreal implant was 60 months and 17 months after dexamethasone intravitreal implant. The total length of follow-up is 132 months, and the total duration of remission off medication is 48 months (Table 1).Fig. 1 A patient with bilateral serpiginous choroidopathy. (A) Serpiginous lesions in both eyes, encroaching the fovea in right eye and with foveal involvement in left eye. Fluoresecein angiography shows activity in both eyes. (B) The middle row shows progression towards the fovea with leakage pointing toward the fovea in the right eye. (C) Shows the stability of fundus photos and fluorescein angiography in both eyes at one year after intravitreal dexamethasone implant and chlorambucil treatment.
Fig. 1Table 1 Demographics and clinical characteristics of patients with resistant serpiginous choroiditis.
Table 1 Age years Sex Laterality BCVA first visit WBC (C + P) cells/μl
(x 10c) WBC (C) cells/μl
(x 10c) WBC (C + IMTor implan cells/μl (*10c) Duration of treatment before IMT Duration of treatment after IMT Duration of follow-up on chlorambucil Duration of follow-up off chlorambucil BCVA last visit
Patient 1 60 F Bilat 20/20 20/100 5.5 ± 2.9 4.7 ± 1.1 4.1 ± 0.5 60a months 17b months 60 months 83 months 20/20 20/50
OD
OS
Patient 2 42 F Bilat 1 mcf 20/20 5.7 ± 2.2 N/A 3.8 ± 0.5 40c months 19d months 49 months 60 months 1mcf
20/15
OD
OS
Patient 3 32 F Bilat HM 20/20 8.8 ± 3.4 N/A N/A 5 + 10 e months N/A 5 months N/A HM 20/50
OD
OS
Patient 4 47 F Bilat 20/30 1mcf 6.2 ± 3.3 N/A N/A N/A N/A 12 months N/A 20/50 1mcf
OD
OS
BCVA:best corrected visual acuity; Bilat:bilateral; C:chlorambucil; CF:counting fingers; HM:hand motion; IMT:immunomodulatory therapy; P:prednisone; N/A:not applicable.
a Before intravitreal dexamethasone implant.
b After intravitreal dexamethasone implant.
c Before starting infliximab.
d After starting infliximab.
e 5 months chlorambucil and 10 months cyclophosphamide.
Case 2. A 42-year-old female was referred to us with blurry vision and field distortion OD for ten years and OS for eight years. Her vision was counting fingers at 1 m OD and 20/20 OS. At the time of presentation, the patient had already received multiple intravitreal anti-VEGF (bevacizumab) and triamcinolone injections OD. The geographic lesions were peripapillary OU, with foveal involvement OD. Initial FA revealed chorioretinal scarring with window defects OU and leakage on borders OD (Fig. 2A). On ICG, the area of hypolucency OS extended further into the macula, which was not seen on FA (Fig. 2B). Complete blood work-up for uveitis ruled out non-infectious and infectious posterior uveitis, including syphilis and tuberculosis. Based on these findings, she was diagnosed with autoimmune SC OU and we recommended therapy with chlorambucil. She sought a second opinion elsewhere, where she was started on mycophenolate mofetil (MMF) 1 g daily with infliximab 300 mg IV every four weeks and oral prednisone 80 mg/day with taper. MMF and infliximab were eventually discontinued due to elevated LFTs. On follow up at our clinic eighteen months after the initial consult, chlorambucil was finally started with dose adjustment based on weekly monitoring of WBC count to reach the endpoint of WBC count 3000–4500 cells/μl. While on chlorambucil 20mg and prednisone 40mg daily, the patient became symptomatic OS with new changes and leakage on FA OS, prompting boosting of oral prednisone to 80 mg; she also received one ranibizumab injection OS locally. Six weeks after starting treatment with chlorambucil (20mg at this time) and oral prednisone 80 mg daily, WBC count dropped down to 4900 cells/μl, so we started tapering prednisone. Two months after initiation of chlorambucil therapy, chlorambucil was stopped while tapering prednisone at 30 mg/day with a WBC count of 3300 cells/μl. At this point, FA, FAF, and OCT showed stability and quiescence. On a subsequent visit with her local ophthalmologist, infliximab 600 mg infusions every four weeks was started for activity OS, and eventually increased to 900 mg every four weeks in combination with chlorambucil. WBC count increased to 7900 cells/μl while on prednisone 10 mg with taper, and chlorambucil was restarted at 4 mg daily, eventually going up to 6 mg daily (Fig. 2B). Chlorambucil dose adjustment with weekly WBC count was continued. Meanwhile, she received a bevacizumab injection with her local ophthalmologist due to central vision distortion OD. On her eight-month of treatment, WBC count dipped to 2000 cells/μl, and chlorambucil was stopped. After one week, with WBC count creeping back up to 4800 cells/μl, chlorambucil was restarted at 2 mg/day. Disease activity was then noted at ten months from treatment initiation with no interventions at that time. On follow up at our clinic fourteen months after starting chlorambucil, the activity noted at ten months prompted treatment extension, and the patient was educated on the risks vs. benefits of this decision. Chlorambucil treatment was continued for a total duration of twenty-one months. FA and OCT macula findings were stable and the patient was asymptomatic (Fig. 2C,D). Subsequent consults established disease stability with no new symptoms or activity. Infliximab was eventually tapered by 100 mg every four weeks. On her last consult at our clinic, she was on infliximab 100 mg infusions every four weeks with a final VA of 20/400 OD and 20/15 OS and stable findings on FA and macula OCT. Her average WBC count was 5700 ± 2200 cells/μl while on chlorambucil with prednisone, and 3800 ± 500 cells/μl when she was on chlorambucil after starting infliximab infusions without prednisone. The total duration of treatment before and after beginning infliximab infusions was 40 and 19 months, respectively. The total length of follow-up is 108 months. The total period of remission off chlorambucil is 60 months (Table 1).Fig. 2 (A) Fundus photo and fluorescein angiography of a patient with bilateral serpiginous choroiditis at the primary visit at our clinic. (B) The same patient during a recurrence in the left eye close to the fovea. (C,D) Stability of year after stopping chlorambucil while on infliximab tapering. (E) Macular optical coherence tomography at the first visit (left), during a recurrence (middle), and the last visit (right).
Fig. 2
Case 3. A 32-year-old female presented with decreased vision, floaters, and photophobia OS. Vision OD was poor due to retinal detachment after a motor vehicle accident. Before presenting to her initial consultation at our clinic, complete blood work-up for uveitis had ruled out non-infectious and infectious posterior uveitis, including syphilis and tuberculosis and she had already been diagnosed with idiopathic SC. She had been on MMF 2 g daily, cyclosporin 25 mg and prednisone 30 mg daily for fourteen months. Her vision was hand-motion OD and 20/20 OS at presentation. A fundus examination revealed optic atrophy and a horizontal scar OD in addition to diffuse chorioretinal (CR) scarring in both eyes. Given the possibility of the activity of the lesion potentially affecting the fovea OS and her monocular status, chlorambucil and cyclophosphamide were discussed as treatment options.
The patient was started on chlorambucil 4 mg daily and continued on 25 mg of prednisone daily. A month later, her WBC count dropped from 14,800 to 12,100 cells/μl. However, she felt her vision had decreased once again after two weeks on chlorambucil. She was advised to increase chlorambucil to 6 mg/day from 4 mg/day, as well as increase prednisone to 40 mg daily. After one week at this dose, she reported stable vision OD. Chlorambucil dose adjustment with weekly WBC count and oral prednisone were continued until she reported stable vision and no other symptoms. At this time, she was advised to increase chlorambucil to 12 mg daily.
Approximately four months after her initial visit, the patient presented to our clinic with worsening scotoma and floaters OS. At this point, she was on prednisone 5 mg daily and chlorambucil 10 mg daily. She had stopped chlorambucil for a week due to fever, and the WBC count was at 11,200 cells/μl. FA and ICG showed active choroidal inflammation at the lesion border, especially OS. Later on, she developed a diffuse, itchy rash, and because of this side effect, she was started on bi-weekly cyclophosphamide pulse therapy. She had five doses of cyclophosphamide pulse therapy, and her WBC count was between 4500 and 6300 cells/μl. However, a few days later, she complained of decreased vision OS with more central involvement. Her local ophthalmologist increased her prednisone to 60 mg, and she received her next cyclophosphamide infusion four days later with WBC count at 4000 cells/μl. Cyclophosphamide therapy was finally stopped due to persistent skin rash.
In the interim, she followed up with her local ophthalmologist while on oral prednisone with different doses based on disease activity. Her next visit with us was seven years later, and vision OS had deteriorated to 20/50. FA showed active inflammation OS in the form of enlarged CR lesions approaching the fovea with multifocal areas of leakage at the margins of the lesions (Fig. 3B). Up to that point, the patient had been off all immunomodulatory therapy (IMT) for seven years, yet only cyclophosphamide appeared to halt the progression of her disease. Monthly cyclophosphamide pulse therapy was resumed but was later stopped after eight months due to low WBC count. After this, she continued with oral prednisone 20 mg daily. At her last follow-up visit, chlorambucil was restarted due to the persistence of symptoms, worsening of vision OS, and the progression of lesion activity on imaging (Fig. 3C). Intravitreal steroid implants were also discussed. The patient was never able to taper off oral prednisone during treatment, and the average WBC count during her course of treatment was 8800 ± 3400 cells/μl. The total duration of treatment with chlorambucil was 5 months, cyclophosphamide was 10 months, and MMF plus cyclosporine was 14 months. The total duration of follow-up is 148 months. She has never been in remission for an extended period off medication (Table 1).Fig. 3 (A) Fundus photo of both eyes of a patient with bilateral serpiginous choroiditis. History of traumatic retinal detachment surgery with legal blindness in the right eye and active serpiginous choroiditis in the left eye. Fluorescein angiography shows an active lesion in the left eye. (B) Optical coherence tomography, fundus autofluorescence, and fluorescein angiography during a recurrence where the patient was started on cyclophosphamide pulse therapy. (C) Progression of the lesion in the left eye with an active lesion in fluorescein angiography at her last visit. Intravitreal dexamethasone and triamcinolone implants were discussed at this visit.
Fig. 3
Case 4. A 47-year-old female was referred to our center with decreased vision OU for one month and had been started on prednisone 50 mg daily before her first visit with us. Her vision OD and OS were 20/30 and counting fingers at 1 m, respectively, at presentation. Dilated fundoscopy showed bilateral geographic lesions nasal to the fovea OD and involving the fovea OS (Fig. 4A). Complete blood work-up for uveitis ruled out non-infectious and infectious posterior uveitis, including syphilis and tuberculosis. Based on these findings, and she was diagnosed with autoimmune SC OU. Oral prednisone was increased to 60 mg daily, and due to significant vision loss OS, she was started on chlorambucil 6 mg daily. Chlorambucil treatment with WBC count monitoring and tapering of oral prednisone was continued for a year. Once the oral prednisone taper was completed, she continued with chlorambucil monotherapy for five more months, at which time she had achieved remission. After four months; however, she had a flare-up OD, which was first treated with 1 g IV methylprednisolone infusion and intravenous methotrexate 200 mg/day. Subsequently, she was continued on subcutaneous methotrexate 15 mg weekly along with folic acid 1 mg/day for two years. She developed another flare-up when tapering methotrexate; hence methotrexate dose was boosted, and a combination of chlorambucil and oral prednisone was restarted. The patient was on chlorambucil and oral prednisone for one year, with an average WBC count of 6200 ± 3300 cells/μl. The patient was then on chlorambucil alone for another two months. She had been flare-free for twenty months when she had another episode. This time she was treated with intravenous and subcutaneous methotrexate. She had another flare during tapering of methotrexate and she is currently on a combination of chlorambucil, prednisone, and subcutaneous methotrexate therapy. The total duration of follow-up has been 116 months. She has never been in remission for an extended period (Table 1).Fig. 4 A serpiginous choroiditis patient with multiple recurrences despite treatment with a combination of oral prednisone and chlorambucil therapy. (A) Color fundus photos and fluorescein angiography of both eyes at the first visit, which showed activity around the lesion in both eyes. (B) The second row shows the progression of lesions in both eyes during a recurrence on fundus photos and fundus autofluorescence. (C) Fundus autofluorescence and fluorescein angiography showed reactivation of the supratemporal area of the lesion in the right eye. (D) Optical coherence tomography shows the lesion, edema, and destruction of the supratemporal part of the lesion, compatible with fundus autofluorescence and fluorescein angiography. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)
Fig. 4
3 Discussion
The pathogenesis of serpiginous choroiditis (SC) is unknown. The course of the disease is indolent and can be asymptomatic until it involves the macula and the central vision. Many patients can have old scars even at the first visit when they are diagnosed with SC.14 Laatikainen and Erkkila et al. reported that new lesions may appear at an interval of 3 months–4 years. They also demonstrated that active lesions resolve in a few weeks; however, signs of activity may last between 1 and 9 months.14 Central vision is involved in 20%–50% of cases, with the likelihood increasing with longer duration of follow-up and disease activity.8,14 Recurrences that affect the macula can cause severe visual loss of less than 20/200, which is typically irreversible and may induce CNV in the macula or around the optic disc.15
There are no controlled trials for the treatment of SC due to the rarity of the disease. Cytosine arabinoside, azathioprine, and oral prednisone were used with reported improved visual acuity in one month.16 Employment of a combination of cyclosporine and oral prednisone as a treatment of active SC had conflicting results. Hopper and Kaplan reported a triple-agent regimen of azathioprine, cyclosporine, and oral prednisone that resulted in rapid control of the active SC and vision recovery; however, disease recurrence was the study's main problem.9 Akpek et al. employed the same regimen in a more extended study and found that this regimen helped keep the inflammation quiet during treatment; however, it did not maintain remission off medication.17
Alkylating agents can bind to DNA, interfere with DNA replication, and subsequently interfere with cell division. Cyclophosphamide is commonly used because of its predictable, dose-dependent, and reversible adverse effects on WBC count18; nonetheless, it can result in serious side effects, some of which are life-threatening. These side effects include reversible hematuria, hemorrhagic cystitis, reversible alopecia, sterility, bladder cancer, lymphoma, and leukemia. Chlorambucil is another alkylating agent primarily used for the treatment of several lymphoproliferative diseases. It is a stable derivative of the nitrogen mustard.19 Based on its ability to reduce circulating lymphocytes, chlorambucil is effective in the treatment of rheumatologic diseases, including juvenile rheumatoid arthritis, systemic lupus erythematosus, and nephrotic syndrome.20, 21, 22, 23 Given the availability of other conventional immunomodulatory agents and biologic response modifiers that yield better results with fewer unpredictable side effects, ophthalmologists are reluctant to use chlorambucil. Our knowledge about biologic response modifier agents is limited to a few case reports and some of our patients had already failed infliximab, mycophenolate mofetil, methotreaxte before their first presentation to us or during follow-up with us. Palmer et al. studied the side effects of chlorambucil and found that these side effects are related to the total dose and duration of treatment.24 However, Tessler et al. found chlorambucil to be a successful treatment for different types of uveitis with no severe complications during 12 years of follow-up. They also reported complete remission in all patients. Although chlorambucil dose in their study was administered regardless of body weight, it did not exceed 2.2 g per patient during the entire treatment.25 Based on these findings, recent studies still rely on alkylating agents including cyclophosphamide and chlorambucil for classical and macular SC.5,12,32
It may take more time for chlorambucil to show its therapeutic and toxic effects. Patients on this medication should be monitored with weekly blood counts, specifically WBC and platelet counts, since its side effects are not always dose-related.25 Chlorambucil is administered orally because it has excellent gastrointestinal absorption, and its superiority over cyclophosphamide is related to the absence of associated side effects such as hair loss, hemorrhagic cystitis, and bladder cancer.26
The recommendation for the daily and total dose of chlorambucil is equal to or less than 0.2 mg/kg and 2.2 g, respectively. These recommendations help avoid late complications such as lymphoma and leukemia.27 Various doses of chlorambucil have been employed in the past in the field of ophthalmology. The use of lower doses of chlorambucil over an extended period, such as more than one year, without provoking bone marrow toxicity is one approach.28, 29, 30, 31 However, it has been demonstrated that sustained remission of the disease is achievable when the WBC count remained depressed for at least six weeks. This finding suggests that effective treatment with chlorambucil requires the induction of a toxic hematologic response.25
The recent literature shows that alkylating agents are still the most potent and effective treatment in patients with SC.4,12,32 Venkatesh and colleagues showed that intravenous cyclophosphamide pulse therapy provided a rapid resolution of active lesions and helped maintain good functional visual acuity.4 However, they admitted that this treatment might not prevent recurrences in patients with SC.4 Venkatesh et al. also studied intravenous methylprednisolone and cyclophosphamide in macular SC; they, again demonstrated it could be effective in acute macular SC, yet admitted that this treatment had no effects on disease relapses in the long-term.32 Ebrahimiadib et al. retrospectively studied 17 patients on chlorambucil with dose escalation based on weekly WBC count, with the target of 3000–4500 white blood cells/μl. They concluded that chlorambucil was well tolerated by the patients and was effective in preventing recurrences.12 Although all these recent studies provided important facts regarding SC treatment, they did not discuss the next step for the patients who failed these treatments. In the current study, we decided to evaluate the possible causes of chlorambucil treatment failure in patients with resistant SC and to examine possible successful regimens in these patients. To the best of our knowledge, this study is the first one which evaluates the possible remedy for resistance to chlorambucil as one of the most commonly employed medications in SC patients.
Histopathological studies in SC have demonstrated that lymphocytes infiltrate the choroid, and less commonly, vessels, leading to subsequent choriocapillaris occlusive vasculitis. This finding may indicate the important roles of lymphocytes in the pathogenesis of the disease.5 The histopathology in SC is very similar to birdshot chorioretinopathy.33,34 On the other hand, multiple studies have discussed the effects of long-term systemic corticosteroids on lymphocyte proliferation and T-cell population.35,36 Ferrari et al. reported increased lymphocytes, including increased absolute numbers of T cells, CD4+ and CD8+ cells, after four weeks of corticosteroid therapy in idiopathic thrombocytopenic purpura (ITP).35 Moreover, lymphocyte redistribution has been discussed in long-term steroid therapy.36 These changes associated with long-term corticosteroid use may interfere with the aim of chlorambucil treatment, since cells with higher proliferation rates are the target of this therapy. The negative effect of long-term systemic corticosteroids on birdshot chorioretinopathy has been studied in the past.37,38 Due to similarities between birdshot chorioretinopathy and SC in terms of histopathology, these facts can be applied to SC patients as well.
The target WBC count for chlorambucil therapy for SC is between 3000 and 4500 cells/μl. Chlorambucil dose adjustment is based on a weekly WBC count. In our experience, patients might be considered cured if there is no recurrence during the treatment period, which is around one year. Our observation in this case series showed that patients on high doses of systemic corticosteroids have unstable WBC count during chlorambucil therapy. Keeping this count in the satisfactory range for a reasonable period of at least six weeks can be challenging since it has been shown that induced toxic hematologic response is required for effective treatment with chlorambucil.25 The first two patients in this case series achieved durable remission and were likely cured after employing local corticosteroids or systemic immunomodulatory therapy, which allowed us to stop systemic corticosteroid use during chlorambucil therapy. However, the third and fourth patients are still experiencing recurrences since all systemic immunomodulatory therapies were unable to induce steroid-free remission. Local corticosteroid therapy was also recommended for both of the patients, but its potential side effects and the patients’ monocular statuses made this option unappealing.
We might be criticized for not employing local corticosteroid monotherapy without any systemic therapy. We believe that, although corticosteroids are the best option for controlling of acute ocular inflammation of any type, they are not potent enough to prime or re-program the immune system12 and not to respond to self-antigens as we expect with immunomodulatory therapy. This is similar to what occurs to pathologic cancer cells especially in blood cancers (lymphoma and leukemia) in patients who achieve remission with chemotherapy which is an advanced and more aggressive form of immunomodulatory therapy. Based on the above mentioned theory, corticosteroids as monotherapy cannot halt the inflammation thoroughly, so the ongoing inflammation can cause more cells destruction and epitopes exposures which might result in more resistant ocular inflammation which is believed to happen in patients with resistant autoimmune SC. we assume that the employment of systemic corticosteroid therapy, along with chlorambucil, is the main obstacle in achieving remission in patients with SC. This combination therapy is mostly seen in monocular patients or in vision-threatening SC where there is a lower threshold for aggressive systemic corticosteroid therapy in these patients.
We might also be criticized for using different therapies in one patient; however, we follow the strategy of “one change at a time” and this means that any time a conventional IMT is tried, we wait for three months with no changes to assess its effectiveness. For biologic response modifier agents, we wait for two months. This strategy makes interaction between medications unlikely. Moreover, since our mission is systemic steroid free remission, we only consider a medication to be effective if the inflammation stays in remission even after the effects of steroids are gone. Furthermore, none of these therapies induced long term remission in our patients.
Dexamethasone intravitreal implants have been employed in the treatment of active SC and serpiginous-like choroiditis.39,40 In these studies, the authors showed the success of this implant in controlling active SC. Based on these studies, dexamethasone can be an alternative to high dose oral or intravenous corticosteroid without systemic side effects including its effects on bone marrow, secondary lymphoid tissues, and peripheral blood regarding WBC counts, especially lymphocytes.
One common fact between all patients in this case series is the instability of WBC count during chlorambucil therapy plus systemic corticosteroids. This issue was addressed in one patient with dexamethasone intravitreal implant and in another patient with infliximab therapy. Both patients allowed us to taper and stop oral prednisone during chlorambucil therapy. The latter patient has been in remission for four years, which is the time frame during which one would expect a new lesion based on the Laatikainen and Erkkila et al. study.14 Despite this, this patient continues to take infliximab at a dose of 300 mg every four weeks since there is a fear of SC recurrence once infliximab therapy is terminated. However, this concept and hypothesis need further, more sophisticated examination.
This study had inherent limitations given its retrospective study design with a small sample size due to the rarity of cases of SC. It was even more challenging to find refractory cases with a reasonable follow-up period to expect a recurrence as all of these patients have at least 8 years of follow-up at our center without any serious side effects. Furthermore, all confounding factors cannot be controlled in a retrospective study. Regardless, we believe that confounding factors related to WBC might not interfere in this study since chlorambucil dose is adjusted based on WBC count and in clinical practice, changes in WBC count are typically more related to changes in corticosteroid dosage. Based on all these limitations, the results of this case series should be interpreted with caution and justifies the need for more potent studies.
4 Conclusion
The stability of WBC counts within toxic levels close to normal or lower limits of normal (3000–4500 cells/μl) during treatment with chlorambucil is an essential factor for the success of this therapy. A combination of dexamethasone intravitreal implant with chlorambucil therapy can be an effective and promising regimen in inducing and maintaining remission in refractory SC patients who fail a combination of systemic corticosteroid and chlorambucil therapy as the first line therapy. However, this primitive hypothesis should be investigated with more potent studies and larger sample sizes.
Patient consent
Consent to publish the personal information and cases details was obtained from all the patients.
Financial supports
None.
All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.
Disclosures
Dr. C Stephen Foster declares the following: Consultancies with Aldeyra Therapeutics (Lexington, MA), Allakos (Redwood City, CA), Bausch & Lomb Surgical, Inc (Rancho Cucamonga, CA), Eyegate Pharma (Waltham, MA), Genentech (South San Francisco, CA), Novartis (Cambridge, MA), pSivida (Watertown, MA) Grants or grants pending with Aciont (Salt Lake City, UT), Alcon (Aliso Viejo, CA), Aldeyra Therapeutics (Lexington, MA), Bausch & Lomb (Rochester, NY), Clearside Biomedical (Alpharetta, GA), Dompé pharmaceutical (Milan, Italy), Eyegate Pharma (Waltham, MA), Mallinckrodt pharmaceuticals (Staines-upon-Thames, UK), Novartis Pharmaceuticals (Cambridge, MA), pSivida (Watertown, MA), Santen (Osaka, Japan). Payment for lectures including service on speaking bureaus: Alcon (Aliso Viejo, CA), Allergan (Dublin, Ireland), Mallinckrodt pharmaceuticals (Staines-upon-Thames, UK). Stock or Stock Options: Eyegate Pharma (Waltham, MA).
The other authors have nothing to declare.
Compliance with ethics guidelines
This study was approved by the New England Institutional Review Board, which has issued a waiver of informed consent for the retrospective chart review analysis. This study was performed in accordance with the Helsinki Declaration of 1964, and its later amendments. All participants provided consent for publication if any identifying information is included in the manuscript.
Data availability
The data that support the findings of this study are available from the corresponding author, upon reasonable request.
Declaration of competing interest
No conflicting relationship exists for any author. | OS LOCALLY | DrugDosageText | CC BY-NC-ND | 33615036 | 19,000,865 | 2021-03 |
What was the dosage of drug 'TRIAMCINOLONE'? | Chlorambucil combination therapy in refractory serpiginous choroiditis: A cure?
To find a remedy for serpiginous choroiditis refractory to oral prednisone and chlorambucil treatment.
Eight eyes of four patients (all female) with advanced macular involvement secondary to serpiginous choroiditis were included in the study. The average age of the patients was 45.2 years. One eye of each patient was legally blind and the lesion was close to the fovea in the other eye. All four patients failed oral prednisone and chlorambucil therapy. However, case 1 responded to chlorambucil treatment after intravitreal dexamethasone implant implantation and discontinuation of oral prednisone. Case 2 responded to chlorambucil therapy when oral prednisone was stopped in combination with infliximab therapy. Due to long follow-up period of more than four years, these two cases are considered to be cured. Case 3 and case 4 were not able to achieve remission with chlorambucil and immunomodulatory therapy. They refused intravitreal steroid implant due to side effects profile.
The stability of WBC counts within toxic levels close to normal or lower limits of normal (3000-4500 cells/μl) during treatment with chlorambucil is an essential factor for the success of this therapy. A combination of dexamethasone intravitreal implant with chlorambucil therapy can be an effective and promising regimen in inducing and maintaining remission in refractory serpiginous choroiditis patients who fail a combination of systemic corticosteroid and chlorambucil therapy.
1 Introduction
Serpiginous choroiditis (SC) is a rare, chronic, asymmetrically bilateral posterior uveitis with a recurrent course. The exact prevalence of SC is unknown; however, it is estimated between 1.6% and 5.3% of posterior uveitis cases in non-endemic areas for tuberculosis.1 Major features of SC include choriocapillaris occlusive vasculitis, secondary endothelial cell injury, and subsequent atrophy of the retinal pigment epithelium, outer retina, and choroid.2,3 Histopathology studies reveal lymphocytic infiltration in the choroid and, less commonly, around vessels.4 The peripapillary area is classically involved in SC and accounts for 80% of the cases.5 The prognosis of vision is poor when it involves the macula, especially in the macular variant of SC. Moreover, the macular variant has a higher risk of developing choroidal neovascularization in nearly half of the affected patients.6,7 Fluorescein angiography (FA), indocyanine green angiography (ICG), optical coherence tomography (OCT), fundus autofluorescence (FAF), and microperimetry are the ancillary diagnostic tools and tests which help in the diagnosis, follow-up, and monitoring for secondary complications.1
Historically, the administration of high doses of oral or intravenous steroids was considered as the standard of care for patients with SC.8 However, immunosuppressive agents such as azathioprine, cyclosporine, chlorambucil, and cyclophosphamide emerged as treatment options for steroid-free remission.4,9, 10, 11, 12 Of these, the alkylating agents cyclophosphamide and chlorambucil have been noted to have a high success rate in the treatment of SC.4,10,12 Chlorambucil, being a potent alkylating agent, can interfere with DNA replication and cell division.13 This medication can induce remission, maintain remission, and even cure this disease.12
Despite successful treatment of SC with alkylating agents, in some patients the disease can recur frequently and progress to affect the central vision. This becomes more important in patients with poor vision in the other eye secondary to SC or advanced SC encroaching the fovea in the affected eye. In this case series, we decided to evaluate possible remedies for refractory and recurrent SC in patients who have been treated with chlorambucil and oral or intravenous corticosteroids.
2 4 Cases
Case 1. A sixty-year-old female was referred to us for the evaluation of macular SC OU. She had noticed blurry vision OS one month before her first visit with us. A geographic lesion with indistinct and irregular borders was observed in both eyes. The lesion was uni-centric OU, temporal to fovea OD and peripapillary with extension to fovea OS. FA and ICG showed the activity of the lesions in both eyes (Fig. 1A). Her best-corrected visual acuity (BCVA) was 20/20 OD and decreased OS to 20/100. Complete blood work-up for uveitis ruled out non-infectious and infectious posterior uveitis, including syphilis and tuberculosis. Based on these findings, she was diagnosed with autoimmune SC OU and was started on a combination of chlorambucil and daily oral prednisone. Chlorambucil was titrated based on her white blood cell (WBC) count. She had another flare-up while she was on 2 mg/day prednisone and had already stopped chlorambucil for three weeks due to WBC 3200 cells/μl. BCVA OS decreased to 20/125, and ICGA confirmed enlargement of the lesion. Chlorambucil was restarted to 2 mg every other day, and oral prednisone was increased to 5 mg/day. With this change in her regimen, the vision increased to the baseline before her last flare, to 20/40. Treatment with chlorambucil was stopped after one year. Her follow-up visit increased to every three months from monthly. Then, six months later, she was started on oral methotrexate 7.5 mg weekly by her rheumatologist because of her joint issues. She was followed every three months for seven months until she noticed a change in OS again. At that time, she was on oral methotrexate 15 mg weekly. BCVA OS decreased to 20/125, and ancillary tests showed activity at the border of the lesions on the foveal side (Fig. 1B). She received one dose of 1 g intravenous methylprednisolone, intravitreal injection of triamcinolone and bevacizumab, and was restarted on oral prednisone 80 mg/day. A week later, her methotrexate dose was boosted to methotrexate 25 mg weekly subcutaneous injections, and we tapered prednisone 10 mg weekly. In three months, oral prednisone was tapered and stopped. Three months later, her lesion became active and she developed choroidal neovascularization (CNV) for which she received a bevacizumab injection. She was restarted on chlorambucil and oral prednisone. The decision for local therapy with dexamethasone implant was made at this point, and she was put back on chlorambucil 2 mg every three days. She was on chlorambucil without oral prednisone, titrating the dose based on WBC for seventeen months, after which she was considered cured (Fig. 1C). In her last visit with us, her BCVA OD and OS were 20/20 and 20/50, respectively. The patient's average WBC count while on chlorambucil with prednisone, chlorambucil without prednisone, and chlorambucil after dexamethasone intravitreal implant were 5500 ± 2900, 4700 ± 1100 and 4100 ± 500 cells/μl, respectively. The total duration of treatment before dexamethasone intravitreal implant was 60 months and 17 months after dexamethasone intravitreal implant. The total length of follow-up is 132 months, and the total duration of remission off medication is 48 months (Table 1).Fig. 1 A patient with bilateral serpiginous choroidopathy. (A) Serpiginous lesions in both eyes, encroaching the fovea in right eye and with foveal involvement in left eye. Fluoresecein angiography shows activity in both eyes. (B) The middle row shows progression towards the fovea with leakage pointing toward the fovea in the right eye. (C) Shows the stability of fundus photos and fluorescein angiography in both eyes at one year after intravitreal dexamethasone implant and chlorambucil treatment.
Fig. 1Table 1 Demographics and clinical characteristics of patients with resistant serpiginous choroiditis.
Table 1 Age years Sex Laterality BCVA first visit WBC (C + P) cells/μl
(x 10c) WBC (C) cells/μl
(x 10c) WBC (C + IMTor implan cells/μl (*10c) Duration of treatment before IMT Duration of treatment after IMT Duration of follow-up on chlorambucil Duration of follow-up off chlorambucil BCVA last visit
Patient 1 60 F Bilat 20/20 20/100 5.5 ± 2.9 4.7 ± 1.1 4.1 ± 0.5 60a months 17b months 60 months 83 months 20/20 20/50
OD
OS
Patient 2 42 F Bilat 1 mcf 20/20 5.7 ± 2.2 N/A 3.8 ± 0.5 40c months 19d months 49 months 60 months 1mcf
20/15
OD
OS
Patient 3 32 F Bilat HM 20/20 8.8 ± 3.4 N/A N/A 5 + 10 e months N/A 5 months N/A HM 20/50
OD
OS
Patient 4 47 F Bilat 20/30 1mcf 6.2 ± 3.3 N/A N/A N/A N/A 12 months N/A 20/50 1mcf
OD
OS
BCVA:best corrected visual acuity; Bilat:bilateral; C:chlorambucil; CF:counting fingers; HM:hand motion; IMT:immunomodulatory therapy; P:prednisone; N/A:not applicable.
a Before intravitreal dexamethasone implant.
b After intravitreal dexamethasone implant.
c Before starting infliximab.
d After starting infliximab.
e 5 months chlorambucil and 10 months cyclophosphamide.
Case 2. A 42-year-old female was referred to us with blurry vision and field distortion OD for ten years and OS for eight years. Her vision was counting fingers at 1 m OD and 20/20 OS. At the time of presentation, the patient had already received multiple intravitreal anti-VEGF (bevacizumab) and triamcinolone injections OD. The geographic lesions were peripapillary OU, with foveal involvement OD. Initial FA revealed chorioretinal scarring with window defects OU and leakage on borders OD (Fig. 2A). On ICG, the area of hypolucency OS extended further into the macula, which was not seen on FA (Fig. 2B). Complete blood work-up for uveitis ruled out non-infectious and infectious posterior uveitis, including syphilis and tuberculosis. Based on these findings, she was diagnosed with autoimmune SC OU and we recommended therapy with chlorambucil. She sought a second opinion elsewhere, where she was started on mycophenolate mofetil (MMF) 1 g daily with infliximab 300 mg IV every four weeks and oral prednisone 80 mg/day with taper. MMF and infliximab were eventually discontinued due to elevated LFTs. On follow up at our clinic eighteen months after the initial consult, chlorambucil was finally started with dose adjustment based on weekly monitoring of WBC count to reach the endpoint of WBC count 3000–4500 cells/μl. While on chlorambucil 20mg and prednisone 40mg daily, the patient became symptomatic OS with new changes and leakage on FA OS, prompting boosting of oral prednisone to 80 mg; she also received one ranibizumab injection OS locally. Six weeks after starting treatment with chlorambucil (20mg at this time) and oral prednisone 80 mg daily, WBC count dropped down to 4900 cells/μl, so we started tapering prednisone. Two months after initiation of chlorambucil therapy, chlorambucil was stopped while tapering prednisone at 30 mg/day with a WBC count of 3300 cells/μl. At this point, FA, FAF, and OCT showed stability and quiescence. On a subsequent visit with her local ophthalmologist, infliximab 600 mg infusions every four weeks was started for activity OS, and eventually increased to 900 mg every four weeks in combination with chlorambucil. WBC count increased to 7900 cells/μl while on prednisone 10 mg with taper, and chlorambucil was restarted at 4 mg daily, eventually going up to 6 mg daily (Fig. 2B). Chlorambucil dose adjustment with weekly WBC count was continued. Meanwhile, she received a bevacizumab injection with her local ophthalmologist due to central vision distortion OD. On her eight-month of treatment, WBC count dipped to 2000 cells/μl, and chlorambucil was stopped. After one week, with WBC count creeping back up to 4800 cells/μl, chlorambucil was restarted at 2 mg/day. Disease activity was then noted at ten months from treatment initiation with no interventions at that time. On follow up at our clinic fourteen months after starting chlorambucil, the activity noted at ten months prompted treatment extension, and the patient was educated on the risks vs. benefits of this decision. Chlorambucil treatment was continued for a total duration of twenty-one months. FA and OCT macula findings were stable and the patient was asymptomatic (Fig. 2C,D). Subsequent consults established disease stability with no new symptoms or activity. Infliximab was eventually tapered by 100 mg every four weeks. On her last consult at our clinic, she was on infliximab 100 mg infusions every four weeks with a final VA of 20/400 OD and 20/15 OS and stable findings on FA and macula OCT. Her average WBC count was 5700 ± 2200 cells/μl while on chlorambucil with prednisone, and 3800 ± 500 cells/μl when she was on chlorambucil after starting infliximab infusions without prednisone. The total duration of treatment before and after beginning infliximab infusions was 40 and 19 months, respectively. The total length of follow-up is 108 months. The total period of remission off chlorambucil is 60 months (Table 1).Fig. 2 (A) Fundus photo and fluorescein angiography of a patient with bilateral serpiginous choroiditis at the primary visit at our clinic. (B) The same patient during a recurrence in the left eye close to the fovea. (C,D) Stability of year after stopping chlorambucil while on infliximab tapering. (E) Macular optical coherence tomography at the first visit (left), during a recurrence (middle), and the last visit (right).
Fig. 2
Case 3. A 32-year-old female presented with decreased vision, floaters, and photophobia OS. Vision OD was poor due to retinal detachment after a motor vehicle accident. Before presenting to her initial consultation at our clinic, complete blood work-up for uveitis had ruled out non-infectious and infectious posterior uveitis, including syphilis and tuberculosis and she had already been diagnosed with idiopathic SC. She had been on MMF 2 g daily, cyclosporin 25 mg and prednisone 30 mg daily for fourteen months. Her vision was hand-motion OD and 20/20 OS at presentation. A fundus examination revealed optic atrophy and a horizontal scar OD in addition to diffuse chorioretinal (CR) scarring in both eyes. Given the possibility of the activity of the lesion potentially affecting the fovea OS and her monocular status, chlorambucil and cyclophosphamide were discussed as treatment options.
The patient was started on chlorambucil 4 mg daily and continued on 25 mg of prednisone daily. A month later, her WBC count dropped from 14,800 to 12,100 cells/μl. However, she felt her vision had decreased once again after two weeks on chlorambucil. She was advised to increase chlorambucil to 6 mg/day from 4 mg/day, as well as increase prednisone to 40 mg daily. After one week at this dose, she reported stable vision OD. Chlorambucil dose adjustment with weekly WBC count and oral prednisone were continued until she reported stable vision and no other symptoms. At this time, she was advised to increase chlorambucil to 12 mg daily.
Approximately four months after her initial visit, the patient presented to our clinic with worsening scotoma and floaters OS. At this point, she was on prednisone 5 mg daily and chlorambucil 10 mg daily. She had stopped chlorambucil for a week due to fever, and the WBC count was at 11,200 cells/μl. FA and ICG showed active choroidal inflammation at the lesion border, especially OS. Later on, she developed a diffuse, itchy rash, and because of this side effect, she was started on bi-weekly cyclophosphamide pulse therapy. She had five doses of cyclophosphamide pulse therapy, and her WBC count was between 4500 and 6300 cells/μl. However, a few days later, she complained of decreased vision OS with more central involvement. Her local ophthalmologist increased her prednisone to 60 mg, and she received her next cyclophosphamide infusion four days later with WBC count at 4000 cells/μl. Cyclophosphamide therapy was finally stopped due to persistent skin rash.
In the interim, she followed up with her local ophthalmologist while on oral prednisone with different doses based on disease activity. Her next visit with us was seven years later, and vision OS had deteriorated to 20/50. FA showed active inflammation OS in the form of enlarged CR lesions approaching the fovea with multifocal areas of leakage at the margins of the lesions (Fig. 3B). Up to that point, the patient had been off all immunomodulatory therapy (IMT) for seven years, yet only cyclophosphamide appeared to halt the progression of her disease. Monthly cyclophosphamide pulse therapy was resumed but was later stopped after eight months due to low WBC count. After this, she continued with oral prednisone 20 mg daily. At her last follow-up visit, chlorambucil was restarted due to the persistence of symptoms, worsening of vision OS, and the progression of lesion activity on imaging (Fig. 3C). Intravitreal steroid implants were also discussed. The patient was never able to taper off oral prednisone during treatment, and the average WBC count during her course of treatment was 8800 ± 3400 cells/μl. The total duration of treatment with chlorambucil was 5 months, cyclophosphamide was 10 months, and MMF plus cyclosporine was 14 months. The total duration of follow-up is 148 months. She has never been in remission for an extended period off medication (Table 1).Fig. 3 (A) Fundus photo of both eyes of a patient with bilateral serpiginous choroiditis. History of traumatic retinal detachment surgery with legal blindness in the right eye and active serpiginous choroiditis in the left eye. Fluorescein angiography shows an active lesion in the left eye. (B) Optical coherence tomography, fundus autofluorescence, and fluorescein angiography during a recurrence where the patient was started on cyclophosphamide pulse therapy. (C) Progression of the lesion in the left eye with an active lesion in fluorescein angiography at her last visit. Intravitreal dexamethasone and triamcinolone implants were discussed at this visit.
Fig. 3
Case 4. A 47-year-old female was referred to our center with decreased vision OU for one month and had been started on prednisone 50 mg daily before her first visit with us. Her vision OD and OS were 20/30 and counting fingers at 1 m, respectively, at presentation. Dilated fundoscopy showed bilateral geographic lesions nasal to the fovea OD and involving the fovea OS (Fig. 4A). Complete blood work-up for uveitis ruled out non-infectious and infectious posterior uveitis, including syphilis and tuberculosis. Based on these findings, and she was diagnosed with autoimmune SC OU. Oral prednisone was increased to 60 mg daily, and due to significant vision loss OS, she was started on chlorambucil 6 mg daily. Chlorambucil treatment with WBC count monitoring and tapering of oral prednisone was continued for a year. Once the oral prednisone taper was completed, she continued with chlorambucil monotherapy for five more months, at which time she had achieved remission. After four months; however, she had a flare-up OD, which was first treated with 1 g IV methylprednisolone infusion and intravenous methotrexate 200 mg/day. Subsequently, she was continued on subcutaneous methotrexate 15 mg weekly along with folic acid 1 mg/day for two years. She developed another flare-up when tapering methotrexate; hence methotrexate dose was boosted, and a combination of chlorambucil and oral prednisone was restarted. The patient was on chlorambucil and oral prednisone for one year, with an average WBC count of 6200 ± 3300 cells/μl. The patient was then on chlorambucil alone for another two months. She had been flare-free for twenty months when she had another episode. This time she was treated with intravenous and subcutaneous methotrexate. She had another flare during tapering of methotrexate and she is currently on a combination of chlorambucil, prednisone, and subcutaneous methotrexate therapy. The total duration of follow-up has been 116 months. She has never been in remission for an extended period (Table 1).Fig. 4 A serpiginous choroiditis patient with multiple recurrences despite treatment with a combination of oral prednisone and chlorambucil therapy. (A) Color fundus photos and fluorescein angiography of both eyes at the first visit, which showed activity around the lesion in both eyes. (B) The second row shows the progression of lesions in both eyes during a recurrence on fundus photos and fundus autofluorescence. (C) Fundus autofluorescence and fluorescein angiography showed reactivation of the supratemporal area of the lesion in the right eye. (D) Optical coherence tomography shows the lesion, edema, and destruction of the supratemporal part of the lesion, compatible with fundus autofluorescence and fluorescein angiography. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)
Fig. 4
3 Discussion
The pathogenesis of serpiginous choroiditis (SC) is unknown. The course of the disease is indolent and can be asymptomatic until it involves the macula and the central vision. Many patients can have old scars even at the first visit when they are diagnosed with SC.14 Laatikainen and Erkkila et al. reported that new lesions may appear at an interval of 3 months–4 years. They also demonstrated that active lesions resolve in a few weeks; however, signs of activity may last between 1 and 9 months.14 Central vision is involved in 20%–50% of cases, with the likelihood increasing with longer duration of follow-up and disease activity.8,14 Recurrences that affect the macula can cause severe visual loss of less than 20/200, which is typically irreversible and may induce CNV in the macula or around the optic disc.15
There are no controlled trials for the treatment of SC due to the rarity of the disease. Cytosine arabinoside, azathioprine, and oral prednisone were used with reported improved visual acuity in one month.16 Employment of a combination of cyclosporine and oral prednisone as a treatment of active SC had conflicting results. Hopper and Kaplan reported a triple-agent regimen of azathioprine, cyclosporine, and oral prednisone that resulted in rapid control of the active SC and vision recovery; however, disease recurrence was the study's main problem.9 Akpek et al. employed the same regimen in a more extended study and found that this regimen helped keep the inflammation quiet during treatment; however, it did not maintain remission off medication.17
Alkylating agents can bind to DNA, interfere with DNA replication, and subsequently interfere with cell division. Cyclophosphamide is commonly used because of its predictable, dose-dependent, and reversible adverse effects on WBC count18; nonetheless, it can result in serious side effects, some of which are life-threatening. These side effects include reversible hematuria, hemorrhagic cystitis, reversible alopecia, sterility, bladder cancer, lymphoma, and leukemia. Chlorambucil is another alkylating agent primarily used for the treatment of several lymphoproliferative diseases. It is a stable derivative of the nitrogen mustard.19 Based on its ability to reduce circulating lymphocytes, chlorambucil is effective in the treatment of rheumatologic diseases, including juvenile rheumatoid arthritis, systemic lupus erythematosus, and nephrotic syndrome.20, 21, 22, 23 Given the availability of other conventional immunomodulatory agents and biologic response modifiers that yield better results with fewer unpredictable side effects, ophthalmologists are reluctant to use chlorambucil. Our knowledge about biologic response modifier agents is limited to a few case reports and some of our patients had already failed infliximab, mycophenolate mofetil, methotreaxte before their first presentation to us or during follow-up with us. Palmer et al. studied the side effects of chlorambucil and found that these side effects are related to the total dose and duration of treatment.24 However, Tessler et al. found chlorambucil to be a successful treatment for different types of uveitis with no severe complications during 12 years of follow-up. They also reported complete remission in all patients. Although chlorambucil dose in their study was administered regardless of body weight, it did not exceed 2.2 g per patient during the entire treatment.25 Based on these findings, recent studies still rely on alkylating agents including cyclophosphamide and chlorambucil for classical and macular SC.5,12,32
It may take more time for chlorambucil to show its therapeutic and toxic effects. Patients on this medication should be monitored with weekly blood counts, specifically WBC and platelet counts, since its side effects are not always dose-related.25 Chlorambucil is administered orally because it has excellent gastrointestinal absorption, and its superiority over cyclophosphamide is related to the absence of associated side effects such as hair loss, hemorrhagic cystitis, and bladder cancer.26
The recommendation for the daily and total dose of chlorambucil is equal to or less than 0.2 mg/kg and 2.2 g, respectively. These recommendations help avoid late complications such as lymphoma and leukemia.27 Various doses of chlorambucil have been employed in the past in the field of ophthalmology. The use of lower doses of chlorambucil over an extended period, such as more than one year, without provoking bone marrow toxicity is one approach.28, 29, 30, 31 However, it has been demonstrated that sustained remission of the disease is achievable when the WBC count remained depressed for at least six weeks. This finding suggests that effective treatment with chlorambucil requires the induction of a toxic hematologic response.25
The recent literature shows that alkylating agents are still the most potent and effective treatment in patients with SC.4,12,32 Venkatesh and colleagues showed that intravenous cyclophosphamide pulse therapy provided a rapid resolution of active lesions and helped maintain good functional visual acuity.4 However, they admitted that this treatment might not prevent recurrences in patients with SC.4 Venkatesh et al. also studied intravenous methylprednisolone and cyclophosphamide in macular SC; they, again demonstrated it could be effective in acute macular SC, yet admitted that this treatment had no effects on disease relapses in the long-term.32 Ebrahimiadib et al. retrospectively studied 17 patients on chlorambucil with dose escalation based on weekly WBC count, with the target of 3000–4500 white blood cells/μl. They concluded that chlorambucil was well tolerated by the patients and was effective in preventing recurrences.12 Although all these recent studies provided important facts regarding SC treatment, they did not discuss the next step for the patients who failed these treatments. In the current study, we decided to evaluate the possible causes of chlorambucil treatment failure in patients with resistant SC and to examine possible successful regimens in these patients. To the best of our knowledge, this study is the first one which evaluates the possible remedy for resistance to chlorambucil as one of the most commonly employed medications in SC patients.
Histopathological studies in SC have demonstrated that lymphocytes infiltrate the choroid, and less commonly, vessels, leading to subsequent choriocapillaris occlusive vasculitis. This finding may indicate the important roles of lymphocytes in the pathogenesis of the disease.5 The histopathology in SC is very similar to birdshot chorioretinopathy.33,34 On the other hand, multiple studies have discussed the effects of long-term systemic corticosteroids on lymphocyte proliferation and T-cell population.35,36 Ferrari et al. reported increased lymphocytes, including increased absolute numbers of T cells, CD4+ and CD8+ cells, after four weeks of corticosteroid therapy in idiopathic thrombocytopenic purpura (ITP).35 Moreover, lymphocyte redistribution has been discussed in long-term steroid therapy.36 These changes associated with long-term corticosteroid use may interfere with the aim of chlorambucil treatment, since cells with higher proliferation rates are the target of this therapy. The negative effect of long-term systemic corticosteroids on birdshot chorioretinopathy has been studied in the past.37,38 Due to similarities between birdshot chorioretinopathy and SC in terms of histopathology, these facts can be applied to SC patients as well.
The target WBC count for chlorambucil therapy for SC is between 3000 and 4500 cells/μl. Chlorambucil dose adjustment is based on a weekly WBC count. In our experience, patients might be considered cured if there is no recurrence during the treatment period, which is around one year. Our observation in this case series showed that patients on high doses of systemic corticosteroids have unstable WBC count during chlorambucil therapy. Keeping this count in the satisfactory range for a reasonable period of at least six weeks can be challenging since it has been shown that induced toxic hematologic response is required for effective treatment with chlorambucil.25 The first two patients in this case series achieved durable remission and were likely cured after employing local corticosteroids or systemic immunomodulatory therapy, which allowed us to stop systemic corticosteroid use during chlorambucil therapy. However, the third and fourth patients are still experiencing recurrences since all systemic immunomodulatory therapies were unable to induce steroid-free remission. Local corticosteroid therapy was also recommended for both of the patients, but its potential side effects and the patients’ monocular statuses made this option unappealing.
We might be criticized for not employing local corticosteroid monotherapy without any systemic therapy. We believe that, although corticosteroids are the best option for controlling of acute ocular inflammation of any type, they are not potent enough to prime or re-program the immune system12 and not to respond to self-antigens as we expect with immunomodulatory therapy. This is similar to what occurs to pathologic cancer cells especially in blood cancers (lymphoma and leukemia) in patients who achieve remission with chemotherapy which is an advanced and more aggressive form of immunomodulatory therapy. Based on the above mentioned theory, corticosteroids as monotherapy cannot halt the inflammation thoroughly, so the ongoing inflammation can cause more cells destruction and epitopes exposures which might result in more resistant ocular inflammation which is believed to happen in patients with resistant autoimmune SC. we assume that the employment of systemic corticosteroid therapy, along with chlorambucil, is the main obstacle in achieving remission in patients with SC. This combination therapy is mostly seen in monocular patients or in vision-threatening SC where there is a lower threshold for aggressive systemic corticosteroid therapy in these patients.
We might also be criticized for using different therapies in one patient; however, we follow the strategy of “one change at a time” and this means that any time a conventional IMT is tried, we wait for three months with no changes to assess its effectiveness. For biologic response modifier agents, we wait for two months. This strategy makes interaction between medications unlikely. Moreover, since our mission is systemic steroid free remission, we only consider a medication to be effective if the inflammation stays in remission even after the effects of steroids are gone. Furthermore, none of these therapies induced long term remission in our patients.
Dexamethasone intravitreal implants have been employed in the treatment of active SC and serpiginous-like choroiditis.39,40 In these studies, the authors showed the success of this implant in controlling active SC. Based on these studies, dexamethasone can be an alternative to high dose oral or intravenous corticosteroid without systemic side effects including its effects on bone marrow, secondary lymphoid tissues, and peripheral blood regarding WBC counts, especially lymphocytes.
One common fact between all patients in this case series is the instability of WBC count during chlorambucil therapy plus systemic corticosteroids. This issue was addressed in one patient with dexamethasone intravitreal implant and in another patient with infliximab therapy. Both patients allowed us to taper and stop oral prednisone during chlorambucil therapy. The latter patient has been in remission for four years, which is the time frame during which one would expect a new lesion based on the Laatikainen and Erkkila et al. study.14 Despite this, this patient continues to take infliximab at a dose of 300 mg every four weeks since there is a fear of SC recurrence once infliximab therapy is terminated. However, this concept and hypothesis need further, more sophisticated examination.
This study had inherent limitations given its retrospective study design with a small sample size due to the rarity of cases of SC. It was even more challenging to find refractory cases with a reasonable follow-up period to expect a recurrence as all of these patients have at least 8 years of follow-up at our center without any serious side effects. Furthermore, all confounding factors cannot be controlled in a retrospective study. Regardless, we believe that confounding factors related to WBC might not interfere in this study since chlorambucil dose is adjusted based on WBC count and in clinical practice, changes in WBC count are typically more related to changes in corticosteroid dosage. Based on all these limitations, the results of this case series should be interpreted with caution and justifies the need for more potent studies.
4 Conclusion
The stability of WBC counts within toxic levels close to normal or lower limits of normal (3000–4500 cells/μl) during treatment with chlorambucil is an essential factor for the success of this therapy. A combination of dexamethasone intravitreal implant with chlorambucil therapy can be an effective and promising regimen in inducing and maintaining remission in refractory SC patients who fail a combination of systemic corticosteroid and chlorambucil therapy as the first line therapy. However, this primitive hypothesis should be investigated with more potent studies and larger sample sizes.
Patient consent
Consent to publish the personal information and cases details was obtained from all the patients.
Financial supports
None.
All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.
Disclosures
Dr. C Stephen Foster declares the following: Consultancies with Aldeyra Therapeutics (Lexington, MA), Allakos (Redwood City, CA), Bausch & Lomb Surgical, Inc (Rancho Cucamonga, CA), Eyegate Pharma (Waltham, MA), Genentech (South San Francisco, CA), Novartis (Cambridge, MA), pSivida (Watertown, MA) Grants or grants pending with Aciont (Salt Lake City, UT), Alcon (Aliso Viejo, CA), Aldeyra Therapeutics (Lexington, MA), Bausch & Lomb (Rochester, NY), Clearside Biomedical (Alpharetta, GA), Dompé pharmaceutical (Milan, Italy), Eyegate Pharma (Waltham, MA), Mallinckrodt pharmaceuticals (Staines-upon-Thames, UK), Novartis Pharmaceuticals (Cambridge, MA), pSivida (Watertown, MA), Santen (Osaka, Japan). Payment for lectures including service on speaking bureaus: Alcon (Aliso Viejo, CA), Allergan (Dublin, Ireland), Mallinckrodt pharmaceuticals (Staines-upon-Thames, UK). Stock or Stock Options: Eyegate Pharma (Waltham, MA).
The other authors have nothing to declare.
Compliance with ethics guidelines
This study was approved by the New England Institutional Review Board, which has issued a waiver of informed consent for the retrospective chart review analysis. This study was performed in accordance with the Helsinki Declaration of 1964, and its later amendments. All participants provided consent for publication if any identifying information is included in the manuscript.
Data availability
The data that support the findings of this study are available from the corresponding author, upon reasonable request.
Declaration of competing interest
No conflicting relationship exists for any author. | UNKNOWN, OD | DrugDosageText | CC BY-NC-ND | 33615036 | 19,000,865 | 2021-03 |
What was the outcome of reaction 'Metamorphopsia'? | Chlorambucil combination therapy in refractory serpiginous choroiditis: A cure?
To find a remedy for serpiginous choroiditis refractory to oral prednisone and chlorambucil treatment.
Eight eyes of four patients (all female) with advanced macular involvement secondary to serpiginous choroiditis were included in the study. The average age of the patients was 45.2 years. One eye of each patient was legally blind and the lesion was close to the fovea in the other eye. All four patients failed oral prednisone and chlorambucil therapy. However, case 1 responded to chlorambucil treatment after intravitreal dexamethasone implant implantation and discontinuation of oral prednisone. Case 2 responded to chlorambucil therapy when oral prednisone was stopped in combination with infliximab therapy. Due to long follow-up period of more than four years, these two cases are considered to be cured. Case 3 and case 4 were not able to achieve remission with chlorambucil and immunomodulatory therapy. They refused intravitreal steroid implant due to side effects profile.
The stability of WBC counts within toxic levels close to normal or lower limits of normal (3000-4500 cells/μl) during treatment with chlorambucil is an essential factor for the success of this therapy. A combination of dexamethasone intravitreal implant with chlorambucil therapy can be an effective and promising regimen in inducing and maintaining remission in refractory serpiginous choroiditis patients who fail a combination of systemic corticosteroid and chlorambucil therapy.
1 Introduction
Serpiginous choroiditis (SC) is a rare, chronic, asymmetrically bilateral posterior uveitis with a recurrent course. The exact prevalence of SC is unknown; however, it is estimated between 1.6% and 5.3% of posterior uveitis cases in non-endemic areas for tuberculosis.1 Major features of SC include choriocapillaris occlusive vasculitis, secondary endothelial cell injury, and subsequent atrophy of the retinal pigment epithelium, outer retina, and choroid.2,3 Histopathology studies reveal lymphocytic infiltration in the choroid and, less commonly, around vessels.4 The peripapillary area is classically involved in SC and accounts for 80% of the cases.5 The prognosis of vision is poor when it involves the macula, especially in the macular variant of SC. Moreover, the macular variant has a higher risk of developing choroidal neovascularization in nearly half of the affected patients.6,7 Fluorescein angiography (FA), indocyanine green angiography (ICG), optical coherence tomography (OCT), fundus autofluorescence (FAF), and microperimetry are the ancillary diagnostic tools and tests which help in the diagnosis, follow-up, and monitoring for secondary complications.1
Historically, the administration of high doses of oral or intravenous steroids was considered as the standard of care for patients with SC.8 However, immunosuppressive agents such as azathioprine, cyclosporine, chlorambucil, and cyclophosphamide emerged as treatment options for steroid-free remission.4,9, 10, 11, 12 Of these, the alkylating agents cyclophosphamide and chlorambucil have been noted to have a high success rate in the treatment of SC.4,10,12 Chlorambucil, being a potent alkylating agent, can interfere with DNA replication and cell division.13 This medication can induce remission, maintain remission, and even cure this disease.12
Despite successful treatment of SC with alkylating agents, in some patients the disease can recur frequently and progress to affect the central vision. This becomes more important in patients with poor vision in the other eye secondary to SC or advanced SC encroaching the fovea in the affected eye. In this case series, we decided to evaluate possible remedies for refractory and recurrent SC in patients who have been treated with chlorambucil and oral or intravenous corticosteroids.
2 4 Cases
Case 1. A sixty-year-old female was referred to us for the evaluation of macular SC OU. She had noticed blurry vision OS one month before her first visit with us. A geographic lesion with indistinct and irregular borders was observed in both eyes. The lesion was uni-centric OU, temporal to fovea OD and peripapillary with extension to fovea OS. FA and ICG showed the activity of the lesions in both eyes (Fig. 1A). Her best-corrected visual acuity (BCVA) was 20/20 OD and decreased OS to 20/100. Complete blood work-up for uveitis ruled out non-infectious and infectious posterior uveitis, including syphilis and tuberculosis. Based on these findings, she was diagnosed with autoimmune SC OU and was started on a combination of chlorambucil and daily oral prednisone. Chlorambucil was titrated based on her white blood cell (WBC) count. She had another flare-up while she was on 2 mg/day prednisone and had already stopped chlorambucil for three weeks due to WBC 3200 cells/μl. BCVA OS decreased to 20/125, and ICGA confirmed enlargement of the lesion. Chlorambucil was restarted to 2 mg every other day, and oral prednisone was increased to 5 mg/day. With this change in her regimen, the vision increased to the baseline before her last flare, to 20/40. Treatment with chlorambucil was stopped after one year. Her follow-up visit increased to every three months from monthly. Then, six months later, she was started on oral methotrexate 7.5 mg weekly by her rheumatologist because of her joint issues. She was followed every three months for seven months until she noticed a change in OS again. At that time, she was on oral methotrexate 15 mg weekly. BCVA OS decreased to 20/125, and ancillary tests showed activity at the border of the lesions on the foveal side (Fig. 1B). She received one dose of 1 g intravenous methylprednisolone, intravitreal injection of triamcinolone and bevacizumab, and was restarted on oral prednisone 80 mg/day. A week later, her methotrexate dose was boosted to methotrexate 25 mg weekly subcutaneous injections, and we tapered prednisone 10 mg weekly. In three months, oral prednisone was tapered and stopped. Three months later, her lesion became active and she developed choroidal neovascularization (CNV) for which she received a bevacizumab injection. She was restarted on chlorambucil and oral prednisone. The decision for local therapy with dexamethasone implant was made at this point, and she was put back on chlorambucil 2 mg every three days. She was on chlorambucil without oral prednisone, titrating the dose based on WBC for seventeen months, after which she was considered cured (Fig. 1C). In her last visit with us, her BCVA OD and OS were 20/20 and 20/50, respectively. The patient's average WBC count while on chlorambucil with prednisone, chlorambucil without prednisone, and chlorambucil after dexamethasone intravitreal implant were 5500 ± 2900, 4700 ± 1100 and 4100 ± 500 cells/μl, respectively. The total duration of treatment before dexamethasone intravitreal implant was 60 months and 17 months after dexamethasone intravitreal implant. The total length of follow-up is 132 months, and the total duration of remission off medication is 48 months (Table 1).Fig. 1 A patient with bilateral serpiginous choroidopathy. (A) Serpiginous lesions in both eyes, encroaching the fovea in right eye and with foveal involvement in left eye. Fluoresecein angiography shows activity in both eyes. (B) The middle row shows progression towards the fovea with leakage pointing toward the fovea in the right eye. (C) Shows the stability of fundus photos and fluorescein angiography in both eyes at one year after intravitreal dexamethasone implant and chlorambucil treatment.
Fig. 1Table 1 Demographics and clinical characteristics of patients with resistant serpiginous choroiditis.
Table 1 Age years Sex Laterality BCVA first visit WBC (C + P) cells/μl
(x 10c) WBC (C) cells/μl
(x 10c) WBC (C + IMTor implan cells/μl (*10c) Duration of treatment before IMT Duration of treatment after IMT Duration of follow-up on chlorambucil Duration of follow-up off chlorambucil BCVA last visit
Patient 1 60 F Bilat 20/20 20/100 5.5 ± 2.9 4.7 ± 1.1 4.1 ± 0.5 60a months 17b months 60 months 83 months 20/20 20/50
OD
OS
Patient 2 42 F Bilat 1 mcf 20/20 5.7 ± 2.2 N/A 3.8 ± 0.5 40c months 19d months 49 months 60 months 1mcf
20/15
OD
OS
Patient 3 32 F Bilat HM 20/20 8.8 ± 3.4 N/A N/A 5 + 10 e months N/A 5 months N/A HM 20/50
OD
OS
Patient 4 47 F Bilat 20/30 1mcf 6.2 ± 3.3 N/A N/A N/A N/A 12 months N/A 20/50 1mcf
OD
OS
BCVA:best corrected visual acuity; Bilat:bilateral; C:chlorambucil; CF:counting fingers; HM:hand motion; IMT:immunomodulatory therapy; P:prednisone; N/A:not applicable.
a Before intravitreal dexamethasone implant.
b After intravitreal dexamethasone implant.
c Before starting infliximab.
d After starting infliximab.
e 5 months chlorambucil and 10 months cyclophosphamide.
Case 2. A 42-year-old female was referred to us with blurry vision and field distortion OD for ten years and OS for eight years. Her vision was counting fingers at 1 m OD and 20/20 OS. At the time of presentation, the patient had already received multiple intravitreal anti-VEGF (bevacizumab) and triamcinolone injections OD. The geographic lesions were peripapillary OU, with foveal involvement OD. Initial FA revealed chorioretinal scarring with window defects OU and leakage on borders OD (Fig. 2A). On ICG, the area of hypolucency OS extended further into the macula, which was not seen on FA (Fig. 2B). Complete blood work-up for uveitis ruled out non-infectious and infectious posterior uveitis, including syphilis and tuberculosis. Based on these findings, she was diagnosed with autoimmune SC OU and we recommended therapy with chlorambucil. She sought a second opinion elsewhere, where she was started on mycophenolate mofetil (MMF) 1 g daily with infliximab 300 mg IV every four weeks and oral prednisone 80 mg/day with taper. MMF and infliximab were eventually discontinued due to elevated LFTs. On follow up at our clinic eighteen months after the initial consult, chlorambucil was finally started with dose adjustment based on weekly monitoring of WBC count to reach the endpoint of WBC count 3000–4500 cells/μl. While on chlorambucil 20mg and prednisone 40mg daily, the patient became symptomatic OS with new changes and leakage on FA OS, prompting boosting of oral prednisone to 80 mg; she also received one ranibizumab injection OS locally. Six weeks after starting treatment with chlorambucil (20mg at this time) and oral prednisone 80 mg daily, WBC count dropped down to 4900 cells/μl, so we started tapering prednisone. Two months after initiation of chlorambucil therapy, chlorambucil was stopped while tapering prednisone at 30 mg/day with a WBC count of 3300 cells/μl. At this point, FA, FAF, and OCT showed stability and quiescence. On a subsequent visit with her local ophthalmologist, infliximab 600 mg infusions every four weeks was started for activity OS, and eventually increased to 900 mg every four weeks in combination with chlorambucil. WBC count increased to 7900 cells/μl while on prednisone 10 mg with taper, and chlorambucil was restarted at 4 mg daily, eventually going up to 6 mg daily (Fig. 2B). Chlorambucil dose adjustment with weekly WBC count was continued. Meanwhile, she received a bevacizumab injection with her local ophthalmologist due to central vision distortion OD. On her eight-month of treatment, WBC count dipped to 2000 cells/μl, and chlorambucil was stopped. After one week, with WBC count creeping back up to 4800 cells/μl, chlorambucil was restarted at 2 mg/day. Disease activity was then noted at ten months from treatment initiation with no interventions at that time. On follow up at our clinic fourteen months after starting chlorambucil, the activity noted at ten months prompted treatment extension, and the patient was educated on the risks vs. benefits of this decision. Chlorambucil treatment was continued for a total duration of twenty-one months. FA and OCT macula findings were stable and the patient was asymptomatic (Fig. 2C,D). Subsequent consults established disease stability with no new symptoms or activity. Infliximab was eventually tapered by 100 mg every four weeks. On her last consult at our clinic, she was on infliximab 100 mg infusions every four weeks with a final VA of 20/400 OD and 20/15 OS and stable findings on FA and macula OCT. Her average WBC count was 5700 ± 2200 cells/μl while on chlorambucil with prednisone, and 3800 ± 500 cells/μl when she was on chlorambucil after starting infliximab infusions without prednisone. The total duration of treatment before and after beginning infliximab infusions was 40 and 19 months, respectively. The total length of follow-up is 108 months. The total period of remission off chlorambucil is 60 months (Table 1).Fig. 2 (A) Fundus photo and fluorescein angiography of a patient with bilateral serpiginous choroiditis at the primary visit at our clinic. (B) The same patient during a recurrence in the left eye close to the fovea. (C,D) Stability of year after stopping chlorambucil while on infliximab tapering. (E) Macular optical coherence tomography at the first visit (left), during a recurrence (middle), and the last visit (right).
Fig. 2
Case 3. A 32-year-old female presented with decreased vision, floaters, and photophobia OS. Vision OD was poor due to retinal detachment after a motor vehicle accident. Before presenting to her initial consultation at our clinic, complete blood work-up for uveitis had ruled out non-infectious and infectious posterior uveitis, including syphilis and tuberculosis and she had already been diagnosed with idiopathic SC. She had been on MMF 2 g daily, cyclosporin 25 mg and prednisone 30 mg daily for fourteen months. Her vision was hand-motion OD and 20/20 OS at presentation. A fundus examination revealed optic atrophy and a horizontal scar OD in addition to diffuse chorioretinal (CR) scarring in both eyes. Given the possibility of the activity of the lesion potentially affecting the fovea OS and her monocular status, chlorambucil and cyclophosphamide were discussed as treatment options.
The patient was started on chlorambucil 4 mg daily and continued on 25 mg of prednisone daily. A month later, her WBC count dropped from 14,800 to 12,100 cells/μl. However, she felt her vision had decreased once again after two weeks on chlorambucil. She was advised to increase chlorambucil to 6 mg/day from 4 mg/day, as well as increase prednisone to 40 mg daily. After one week at this dose, she reported stable vision OD. Chlorambucil dose adjustment with weekly WBC count and oral prednisone were continued until she reported stable vision and no other symptoms. At this time, she was advised to increase chlorambucil to 12 mg daily.
Approximately four months after her initial visit, the patient presented to our clinic with worsening scotoma and floaters OS. At this point, she was on prednisone 5 mg daily and chlorambucil 10 mg daily. She had stopped chlorambucil for a week due to fever, and the WBC count was at 11,200 cells/μl. FA and ICG showed active choroidal inflammation at the lesion border, especially OS. Later on, she developed a diffuse, itchy rash, and because of this side effect, she was started on bi-weekly cyclophosphamide pulse therapy. She had five doses of cyclophosphamide pulse therapy, and her WBC count was between 4500 and 6300 cells/μl. However, a few days later, she complained of decreased vision OS with more central involvement. Her local ophthalmologist increased her prednisone to 60 mg, and she received her next cyclophosphamide infusion four days later with WBC count at 4000 cells/μl. Cyclophosphamide therapy was finally stopped due to persistent skin rash.
In the interim, she followed up with her local ophthalmologist while on oral prednisone with different doses based on disease activity. Her next visit with us was seven years later, and vision OS had deteriorated to 20/50. FA showed active inflammation OS in the form of enlarged CR lesions approaching the fovea with multifocal areas of leakage at the margins of the lesions (Fig. 3B). Up to that point, the patient had been off all immunomodulatory therapy (IMT) for seven years, yet only cyclophosphamide appeared to halt the progression of her disease. Monthly cyclophosphamide pulse therapy was resumed but was later stopped after eight months due to low WBC count. After this, she continued with oral prednisone 20 mg daily. At her last follow-up visit, chlorambucil was restarted due to the persistence of symptoms, worsening of vision OS, and the progression of lesion activity on imaging (Fig. 3C). Intravitreal steroid implants were also discussed. The patient was never able to taper off oral prednisone during treatment, and the average WBC count during her course of treatment was 8800 ± 3400 cells/μl. The total duration of treatment with chlorambucil was 5 months, cyclophosphamide was 10 months, and MMF plus cyclosporine was 14 months. The total duration of follow-up is 148 months. She has never been in remission for an extended period off medication (Table 1).Fig. 3 (A) Fundus photo of both eyes of a patient with bilateral serpiginous choroiditis. History of traumatic retinal detachment surgery with legal blindness in the right eye and active serpiginous choroiditis in the left eye. Fluorescein angiography shows an active lesion in the left eye. (B) Optical coherence tomography, fundus autofluorescence, and fluorescein angiography during a recurrence where the patient was started on cyclophosphamide pulse therapy. (C) Progression of the lesion in the left eye with an active lesion in fluorescein angiography at her last visit. Intravitreal dexamethasone and triamcinolone implants were discussed at this visit.
Fig. 3
Case 4. A 47-year-old female was referred to our center with decreased vision OU for one month and had been started on prednisone 50 mg daily before her first visit with us. Her vision OD and OS were 20/30 and counting fingers at 1 m, respectively, at presentation. Dilated fundoscopy showed bilateral geographic lesions nasal to the fovea OD and involving the fovea OS (Fig. 4A). Complete blood work-up for uveitis ruled out non-infectious and infectious posterior uveitis, including syphilis and tuberculosis. Based on these findings, and she was diagnosed with autoimmune SC OU. Oral prednisone was increased to 60 mg daily, and due to significant vision loss OS, she was started on chlorambucil 6 mg daily. Chlorambucil treatment with WBC count monitoring and tapering of oral prednisone was continued for a year. Once the oral prednisone taper was completed, she continued with chlorambucil monotherapy for five more months, at which time she had achieved remission. After four months; however, she had a flare-up OD, which was first treated with 1 g IV methylprednisolone infusion and intravenous methotrexate 200 mg/day. Subsequently, she was continued on subcutaneous methotrexate 15 mg weekly along with folic acid 1 mg/day for two years. She developed another flare-up when tapering methotrexate; hence methotrexate dose was boosted, and a combination of chlorambucil and oral prednisone was restarted. The patient was on chlorambucil and oral prednisone for one year, with an average WBC count of 6200 ± 3300 cells/μl. The patient was then on chlorambucil alone for another two months. She had been flare-free for twenty months when she had another episode. This time she was treated with intravenous and subcutaneous methotrexate. She had another flare during tapering of methotrexate and she is currently on a combination of chlorambucil, prednisone, and subcutaneous methotrexate therapy. The total duration of follow-up has been 116 months. She has never been in remission for an extended period (Table 1).Fig. 4 A serpiginous choroiditis patient with multiple recurrences despite treatment with a combination of oral prednisone and chlorambucil therapy. (A) Color fundus photos and fluorescein angiography of both eyes at the first visit, which showed activity around the lesion in both eyes. (B) The second row shows the progression of lesions in both eyes during a recurrence on fundus photos and fundus autofluorescence. (C) Fundus autofluorescence and fluorescein angiography showed reactivation of the supratemporal area of the lesion in the right eye. (D) Optical coherence tomography shows the lesion, edema, and destruction of the supratemporal part of the lesion, compatible with fundus autofluorescence and fluorescein angiography. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)
Fig. 4
3 Discussion
The pathogenesis of serpiginous choroiditis (SC) is unknown. The course of the disease is indolent and can be asymptomatic until it involves the macula and the central vision. Many patients can have old scars even at the first visit when they are diagnosed with SC.14 Laatikainen and Erkkila et al. reported that new lesions may appear at an interval of 3 months–4 years. They also demonstrated that active lesions resolve in a few weeks; however, signs of activity may last between 1 and 9 months.14 Central vision is involved in 20%–50% of cases, with the likelihood increasing with longer duration of follow-up and disease activity.8,14 Recurrences that affect the macula can cause severe visual loss of less than 20/200, which is typically irreversible and may induce CNV in the macula or around the optic disc.15
There are no controlled trials for the treatment of SC due to the rarity of the disease. Cytosine arabinoside, azathioprine, and oral prednisone were used with reported improved visual acuity in one month.16 Employment of a combination of cyclosporine and oral prednisone as a treatment of active SC had conflicting results. Hopper and Kaplan reported a triple-agent regimen of azathioprine, cyclosporine, and oral prednisone that resulted in rapid control of the active SC and vision recovery; however, disease recurrence was the study's main problem.9 Akpek et al. employed the same regimen in a more extended study and found that this regimen helped keep the inflammation quiet during treatment; however, it did not maintain remission off medication.17
Alkylating agents can bind to DNA, interfere with DNA replication, and subsequently interfere with cell division. Cyclophosphamide is commonly used because of its predictable, dose-dependent, and reversible adverse effects on WBC count18; nonetheless, it can result in serious side effects, some of which are life-threatening. These side effects include reversible hematuria, hemorrhagic cystitis, reversible alopecia, sterility, bladder cancer, lymphoma, and leukemia. Chlorambucil is another alkylating agent primarily used for the treatment of several lymphoproliferative diseases. It is a stable derivative of the nitrogen mustard.19 Based on its ability to reduce circulating lymphocytes, chlorambucil is effective in the treatment of rheumatologic diseases, including juvenile rheumatoid arthritis, systemic lupus erythematosus, and nephrotic syndrome.20, 21, 22, 23 Given the availability of other conventional immunomodulatory agents and biologic response modifiers that yield better results with fewer unpredictable side effects, ophthalmologists are reluctant to use chlorambucil. Our knowledge about biologic response modifier agents is limited to a few case reports and some of our patients had already failed infliximab, mycophenolate mofetil, methotreaxte before their first presentation to us or during follow-up with us. Palmer et al. studied the side effects of chlorambucil and found that these side effects are related to the total dose and duration of treatment.24 However, Tessler et al. found chlorambucil to be a successful treatment for different types of uveitis with no severe complications during 12 years of follow-up. They also reported complete remission in all patients. Although chlorambucil dose in their study was administered regardless of body weight, it did not exceed 2.2 g per patient during the entire treatment.25 Based on these findings, recent studies still rely on alkylating agents including cyclophosphamide and chlorambucil for classical and macular SC.5,12,32
It may take more time for chlorambucil to show its therapeutic and toxic effects. Patients on this medication should be monitored with weekly blood counts, specifically WBC and platelet counts, since its side effects are not always dose-related.25 Chlorambucil is administered orally because it has excellent gastrointestinal absorption, and its superiority over cyclophosphamide is related to the absence of associated side effects such as hair loss, hemorrhagic cystitis, and bladder cancer.26
The recommendation for the daily and total dose of chlorambucil is equal to or less than 0.2 mg/kg and 2.2 g, respectively. These recommendations help avoid late complications such as lymphoma and leukemia.27 Various doses of chlorambucil have been employed in the past in the field of ophthalmology. The use of lower doses of chlorambucil over an extended period, such as more than one year, without provoking bone marrow toxicity is one approach.28, 29, 30, 31 However, it has been demonstrated that sustained remission of the disease is achievable when the WBC count remained depressed for at least six weeks. This finding suggests that effective treatment with chlorambucil requires the induction of a toxic hematologic response.25
The recent literature shows that alkylating agents are still the most potent and effective treatment in patients with SC.4,12,32 Venkatesh and colleagues showed that intravenous cyclophosphamide pulse therapy provided a rapid resolution of active lesions and helped maintain good functional visual acuity.4 However, they admitted that this treatment might not prevent recurrences in patients with SC.4 Venkatesh et al. also studied intravenous methylprednisolone and cyclophosphamide in macular SC; they, again demonstrated it could be effective in acute macular SC, yet admitted that this treatment had no effects on disease relapses in the long-term.32 Ebrahimiadib et al. retrospectively studied 17 patients on chlorambucil with dose escalation based on weekly WBC count, with the target of 3000–4500 white blood cells/μl. They concluded that chlorambucil was well tolerated by the patients and was effective in preventing recurrences.12 Although all these recent studies provided important facts regarding SC treatment, they did not discuss the next step for the patients who failed these treatments. In the current study, we decided to evaluate the possible causes of chlorambucil treatment failure in patients with resistant SC and to examine possible successful regimens in these patients. To the best of our knowledge, this study is the first one which evaluates the possible remedy for resistance to chlorambucil as one of the most commonly employed medications in SC patients.
Histopathological studies in SC have demonstrated that lymphocytes infiltrate the choroid, and less commonly, vessels, leading to subsequent choriocapillaris occlusive vasculitis. This finding may indicate the important roles of lymphocytes in the pathogenesis of the disease.5 The histopathology in SC is very similar to birdshot chorioretinopathy.33,34 On the other hand, multiple studies have discussed the effects of long-term systemic corticosteroids on lymphocyte proliferation and T-cell population.35,36 Ferrari et al. reported increased lymphocytes, including increased absolute numbers of T cells, CD4+ and CD8+ cells, after four weeks of corticosteroid therapy in idiopathic thrombocytopenic purpura (ITP).35 Moreover, lymphocyte redistribution has been discussed in long-term steroid therapy.36 These changes associated with long-term corticosteroid use may interfere with the aim of chlorambucil treatment, since cells with higher proliferation rates are the target of this therapy. The negative effect of long-term systemic corticosteroids on birdshot chorioretinopathy has been studied in the past.37,38 Due to similarities between birdshot chorioretinopathy and SC in terms of histopathology, these facts can be applied to SC patients as well.
The target WBC count for chlorambucil therapy for SC is between 3000 and 4500 cells/μl. Chlorambucil dose adjustment is based on a weekly WBC count. In our experience, patients might be considered cured if there is no recurrence during the treatment period, which is around one year. Our observation in this case series showed that patients on high doses of systemic corticosteroids have unstable WBC count during chlorambucil therapy. Keeping this count in the satisfactory range for a reasonable period of at least six weeks can be challenging since it has been shown that induced toxic hematologic response is required for effective treatment with chlorambucil.25 The first two patients in this case series achieved durable remission and were likely cured after employing local corticosteroids or systemic immunomodulatory therapy, which allowed us to stop systemic corticosteroid use during chlorambucil therapy. However, the third and fourth patients are still experiencing recurrences since all systemic immunomodulatory therapies were unable to induce steroid-free remission. Local corticosteroid therapy was also recommended for both of the patients, but its potential side effects and the patients’ monocular statuses made this option unappealing.
We might be criticized for not employing local corticosteroid monotherapy without any systemic therapy. We believe that, although corticosteroids are the best option for controlling of acute ocular inflammation of any type, they are not potent enough to prime or re-program the immune system12 and not to respond to self-antigens as we expect with immunomodulatory therapy. This is similar to what occurs to pathologic cancer cells especially in blood cancers (lymphoma and leukemia) in patients who achieve remission with chemotherapy which is an advanced and more aggressive form of immunomodulatory therapy. Based on the above mentioned theory, corticosteroids as monotherapy cannot halt the inflammation thoroughly, so the ongoing inflammation can cause more cells destruction and epitopes exposures which might result in more resistant ocular inflammation which is believed to happen in patients with resistant autoimmune SC. we assume that the employment of systemic corticosteroid therapy, along with chlorambucil, is the main obstacle in achieving remission in patients with SC. This combination therapy is mostly seen in monocular patients or in vision-threatening SC where there is a lower threshold for aggressive systemic corticosteroid therapy in these patients.
We might also be criticized for using different therapies in one patient; however, we follow the strategy of “one change at a time” and this means that any time a conventional IMT is tried, we wait for three months with no changes to assess its effectiveness. For biologic response modifier agents, we wait for two months. This strategy makes interaction between medications unlikely. Moreover, since our mission is systemic steroid free remission, we only consider a medication to be effective if the inflammation stays in remission even after the effects of steroids are gone. Furthermore, none of these therapies induced long term remission in our patients.
Dexamethasone intravitreal implants have been employed in the treatment of active SC and serpiginous-like choroiditis.39,40 In these studies, the authors showed the success of this implant in controlling active SC. Based on these studies, dexamethasone can be an alternative to high dose oral or intravenous corticosteroid without systemic side effects including its effects on bone marrow, secondary lymphoid tissues, and peripheral blood regarding WBC counts, especially lymphocytes.
One common fact between all patients in this case series is the instability of WBC count during chlorambucil therapy plus systemic corticosteroids. This issue was addressed in one patient with dexamethasone intravitreal implant and in another patient with infliximab therapy. Both patients allowed us to taper and stop oral prednisone during chlorambucil therapy. The latter patient has been in remission for four years, which is the time frame during which one would expect a new lesion based on the Laatikainen and Erkkila et al. study.14 Despite this, this patient continues to take infliximab at a dose of 300 mg every four weeks since there is a fear of SC recurrence once infliximab therapy is terminated. However, this concept and hypothesis need further, more sophisticated examination.
This study had inherent limitations given its retrospective study design with a small sample size due to the rarity of cases of SC. It was even more challenging to find refractory cases with a reasonable follow-up period to expect a recurrence as all of these patients have at least 8 years of follow-up at our center without any serious side effects. Furthermore, all confounding factors cannot be controlled in a retrospective study. Regardless, we believe that confounding factors related to WBC might not interfere in this study since chlorambucil dose is adjusted based on WBC count and in clinical practice, changes in WBC count are typically more related to changes in corticosteroid dosage. Based on all these limitations, the results of this case series should be interpreted with caution and justifies the need for more potent studies.
4 Conclusion
The stability of WBC counts within toxic levels close to normal or lower limits of normal (3000–4500 cells/μl) during treatment with chlorambucil is an essential factor for the success of this therapy. A combination of dexamethasone intravitreal implant with chlorambucil therapy can be an effective and promising regimen in inducing and maintaining remission in refractory SC patients who fail a combination of systemic corticosteroid and chlorambucil therapy as the first line therapy. However, this primitive hypothesis should be investigated with more potent studies and larger sample sizes.
Patient consent
Consent to publish the personal information and cases details was obtained from all the patients.
Financial supports
None.
All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.
Disclosures
Dr. C Stephen Foster declares the following: Consultancies with Aldeyra Therapeutics (Lexington, MA), Allakos (Redwood City, CA), Bausch & Lomb Surgical, Inc (Rancho Cucamonga, CA), Eyegate Pharma (Waltham, MA), Genentech (South San Francisco, CA), Novartis (Cambridge, MA), pSivida (Watertown, MA) Grants or grants pending with Aciont (Salt Lake City, UT), Alcon (Aliso Viejo, CA), Aldeyra Therapeutics (Lexington, MA), Bausch & Lomb (Rochester, NY), Clearside Biomedical (Alpharetta, GA), Dompé pharmaceutical (Milan, Italy), Eyegate Pharma (Waltham, MA), Mallinckrodt pharmaceuticals (Staines-upon-Thames, UK), Novartis Pharmaceuticals (Cambridge, MA), pSivida (Watertown, MA), Santen (Osaka, Japan). Payment for lectures including service on speaking bureaus: Alcon (Aliso Viejo, CA), Allergan (Dublin, Ireland), Mallinckrodt pharmaceuticals (Staines-upon-Thames, UK). Stock or Stock Options: Eyegate Pharma (Waltham, MA).
The other authors have nothing to declare.
Compliance with ethics guidelines
This study was approved by the New England Institutional Review Board, which has issued a waiver of informed consent for the retrospective chart review analysis. This study was performed in accordance with the Helsinki Declaration of 1964, and its later amendments. All participants provided consent for publication if any identifying information is included in the manuscript.
Data availability
The data that support the findings of this study are available from the corresponding author, upon reasonable request.
Declaration of competing interest
No conflicting relationship exists for any author. | Recovering | ReactionOutcome | CC BY-NC-ND | 33615036 | 19,000,865 | 2021-03 |
What was the outcome of reaction 'White blood cell count decreased'? | Chlorambucil combination therapy in refractory serpiginous choroiditis: A cure?
To find a remedy for serpiginous choroiditis refractory to oral prednisone and chlorambucil treatment.
Eight eyes of four patients (all female) with advanced macular involvement secondary to serpiginous choroiditis were included in the study. The average age of the patients was 45.2 years. One eye of each patient was legally blind and the lesion was close to the fovea in the other eye. All four patients failed oral prednisone and chlorambucil therapy. However, case 1 responded to chlorambucil treatment after intravitreal dexamethasone implant implantation and discontinuation of oral prednisone. Case 2 responded to chlorambucil therapy when oral prednisone was stopped in combination with infliximab therapy. Due to long follow-up period of more than four years, these two cases are considered to be cured. Case 3 and case 4 were not able to achieve remission with chlorambucil and immunomodulatory therapy. They refused intravitreal steroid implant due to side effects profile.
The stability of WBC counts within toxic levels close to normal or lower limits of normal (3000-4500 cells/μl) during treatment with chlorambucil is an essential factor for the success of this therapy. A combination of dexamethasone intravitreal implant with chlorambucil therapy can be an effective and promising regimen in inducing and maintaining remission in refractory serpiginous choroiditis patients who fail a combination of systemic corticosteroid and chlorambucil therapy.
1 Introduction
Serpiginous choroiditis (SC) is a rare, chronic, asymmetrically bilateral posterior uveitis with a recurrent course. The exact prevalence of SC is unknown; however, it is estimated between 1.6% and 5.3% of posterior uveitis cases in non-endemic areas for tuberculosis.1 Major features of SC include choriocapillaris occlusive vasculitis, secondary endothelial cell injury, and subsequent atrophy of the retinal pigment epithelium, outer retina, and choroid.2,3 Histopathology studies reveal lymphocytic infiltration in the choroid and, less commonly, around vessels.4 The peripapillary area is classically involved in SC and accounts for 80% of the cases.5 The prognosis of vision is poor when it involves the macula, especially in the macular variant of SC. Moreover, the macular variant has a higher risk of developing choroidal neovascularization in nearly half of the affected patients.6,7 Fluorescein angiography (FA), indocyanine green angiography (ICG), optical coherence tomography (OCT), fundus autofluorescence (FAF), and microperimetry are the ancillary diagnostic tools and tests which help in the diagnosis, follow-up, and monitoring for secondary complications.1
Historically, the administration of high doses of oral or intravenous steroids was considered as the standard of care for patients with SC.8 However, immunosuppressive agents such as azathioprine, cyclosporine, chlorambucil, and cyclophosphamide emerged as treatment options for steroid-free remission.4,9, 10, 11, 12 Of these, the alkylating agents cyclophosphamide and chlorambucil have been noted to have a high success rate in the treatment of SC.4,10,12 Chlorambucil, being a potent alkylating agent, can interfere with DNA replication and cell division.13 This medication can induce remission, maintain remission, and even cure this disease.12
Despite successful treatment of SC with alkylating agents, in some patients the disease can recur frequently and progress to affect the central vision. This becomes more important in patients with poor vision in the other eye secondary to SC or advanced SC encroaching the fovea in the affected eye. In this case series, we decided to evaluate possible remedies for refractory and recurrent SC in patients who have been treated with chlorambucil and oral or intravenous corticosteroids.
2 4 Cases
Case 1. A sixty-year-old female was referred to us for the evaluation of macular SC OU. She had noticed blurry vision OS one month before her first visit with us. A geographic lesion with indistinct and irregular borders was observed in both eyes. The lesion was uni-centric OU, temporal to fovea OD and peripapillary with extension to fovea OS. FA and ICG showed the activity of the lesions in both eyes (Fig. 1A). Her best-corrected visual acuity (BCVA) was 20/20 OD and decreased OS to 20/100. Complete blood work-up for uveitis ruled out non-infectious and infectious posterior uveitis, including syphilis and tuberculosis. Based on these findings, she was diagnosed with autoimmune SC OU and was started on a combination of chlorambucil and daily oral prednisone. Chlorambucil was titrated based on her white blood cell (WBC) count. She had another flare-up while she was on 2 mg/day prednisone and had already stopped chlorambucil for three weeks due to WBC 3200 cells/μl. BCVA OS decreased to 20/125, and ICGA confirmed enlargement of the lesion. Chlorambucil was restarted to 2 mg every other day, and oral prednisone was increased to 5 mg/day. With this change in her regimen, the vision increased to the baseline before her last flare, to 20/40. Treatment with chlorambucil was stopped after one year. Her follow-up visit increased to every three months from monthly. Then, six months later, she was started on oral methotrexate 7.5 mg weekly by her rheumatologist because of her joint issues. She was followed every three months for seven months until she noticed a change in OS again. At that time, she was on oral methotrexate 15 mg weekly. BCVA OS decreased to 20/125, and ancillary tests showed activity at the border of the lesions on the foveal side (Fig. 1B). She received one dose of 1 g intravenous methylprednisolone, intravitreal injection of triamcinolone and bevacizumab, and was restarted on oral prednisone 80 mg/day. A week later, her methotrexate dose was boosted to methotrexate 25 mg weekly subcutaneous injections, and we tapered prednisone 10 mg weekly. In three months, oral prednisone was tapered and stopped. Three months later, her lesion became active and she developed choroidal neovascularization (CNV) for which she received a bevacizumab injection. She was restarted on chlorambucil and oral prednisone. The decision for local therapy with dexamethasone implant was made at this point, and she was put back on chlorambucil 2 mg every three days. She was on chlorambucil without oral prednisone, titrating the dose based on WBC for seventeen months, after which she was considered cured (Fig. 1C). In her last visit with us, her BCVA OD and OS were 20/20 and 20/50, respectively. The patient's average WBC count while on chlorambucil with prednisone, chlorambucil without prednisone, and chlorambucil after dexamethasone intravitreal implant were 5500 ± 2900, 4700 ± 1100 and 4100 ± 500 cells/μl, respectively. The total duration of treatment before dexamethasone intravitreal implant was 60 months and 17 months after dexamethasone intravitreal implant. The total length of follow-up is 132 months, and the total duration of remission off medication is 48 months (Table 1).Fig. 1 A patient with bilateral serpiginous choroidopathy. (A) Serpiginous lesions in both eyes, encroaching the fovea in right eye and with foveal involvement in left eye. Fluoresecein angiography shows activity in both eyes. (B) The middle row shows progression towards the fovea with leakage pointing toward the fovea in the right eye. (C) Shows the stability of fundus photos and fluorescein angiography in both eyes at one year after intravitreal dexamethasone implant and chlorambucil treatment.
Fig. 1Table 1 Demographics and clinical characteristics of patients with resistant serpiginous choroiditis.
Table 1 Age years Sex Laterality BCVA first visit WBC (C + P) cells/μl
(x 10c) WBC (C) cells/μl
(x 10c) WBC (C + IMTor implan cells/μl (*10c) Duration of treatment before IMT Duration of treatment after IMT Duration of follow-up on chlorambucil Duration of follow-up off chlorambucil BCVA last visit
Patient 1 60 F Bilat 20/20 20/100 5.5 ± 2.9 4.7 ± 1.1 4.1 ± 0.5 60a months 17b months 60 months 83 months 20/20 20/50
OD
OS
Patient 2 42 F Bilat 1 mcf 20/20 5.7 ± 2.2 N/A 3.8 ± 0.5 40c months 19d months 49 months 60 months 1mcf
20/15
OD
OS
Patient 3 32 F Bilat HM 20/20 8.8 ± 3.4 N/A N/A 5 + 10 e months N/A 5 months N/A HM 20/50
OD
OS
Patient 4 47 F Bilat 20/30 1mcf 6.2 ± 3.3 N/A N/A N/A N/A 12 months N/A 20/50 1mcf
OD
OS
BCVA:best corrected visual acuity; Bilat:bilateral; C:chlorambucil; CF:counting fingers; HM:hand motion; IMT:immunomodulatory therapy; P:prednisone; N/A:not applicable.
a Before intravitreal dexamethasone implant.
b After intravitreal dexamethasone implant.
c Before starting infliximab.
d After starting infliximab.
e 5 months chlorambucil and 10 months cyclophosphamide.
Case 2. A 42-year-old female was referred to us with blurry vision and field distortion OD for ten years and OS for eight years. Her vision was counting fingers at 1 m OD and 20/20 OS. At the time of presentation, the patient had already received multiple intravitreal anti-VEGF (bevacizumab) and triamcinolone injections OD. The geographic lesions were peripapillary OU, with foveal involvement OD. Initial FA revealed chorioretinal scarring with window defects OU and leakage on borders OD (Fig. 2A). On ICG, the area of hypolucency OS extended further into the macula, which was not seen on FA (Fig. 2B). Complete blood work-up for uveitis ruled out non-infectious and infectious posterior uveitis, including syphilis and tuberculosis. Based on these findings, she was diagnosed with autoimmune SC OU and we recommended therapy with chlorambucil. She sought a second opinion elsewhere, where she was started on mycophenolate mofetil (MMF) 1 g daily with infliximab 300 mg IV every four weeks and oral prednisone 80 mg/day with taper. MMF and infliximab were eventually discontinued due to elevated LFTs. On follow up at our clinic eighteen months after the initial consult, chlorambucil was finally started with dose adjustment based on weekly monitoring of WBC count to reach the endpoint of WBC count 3000–4500 cells/μl. While on chlorambucil 20mg and prednisone 40mg daily, the patient became symptomatic OS with new changes and leakage on FA OS, prompting boosting of oral prednisone to 80 mg; she also received one ranibizumab injection OS locally. Six weeks after starting treatment with chlorambucil (20mg at this time) and oral prednisone 80 mg daily, WBC count dropped down to 4900 cells/μl, so we started tapering prednisone. Two months after initiation of chlorambucil therapy, chlorambucil was stopped while tapering prednisone at 30 mg/day with a WBC count of 3300 cells/μl. At this point, FA, FAF, and OCT showed stability and quiescence. On a subsequent visit with her local ophthalmologist, infliximab 600 mg infusions every four weeks was started for activity OS, and eventually increased to 900 mg every four weeks in combination with chlorambucil. WBC count increased to 7900 cells/μl while on prednisone 10 mg with taper, and chlorambucil was restarted at 4 mg daily, eventually going up to 6 mg daily (Fig. 2B). Chlorambucil dose adjustment with weekly WBC count was continued. Meanwhile, she received a bevacizumab injection with her local ophthalmologist due to central vision distortion OD. On her eight-month of treatment, WBC count dipped to 2000 cells/μl, and chlorambucil was stopped. After one week, with WBC count creeping back up to 4800 cells/μl, chlorambucil was restarted at 2 mg/day. Disease activity was then noted at ten months from treatment initiation with no interventions at that time. On follow up at our clinic fourteen months after starting chlorambucil, the activity noted at ten months prompted treatment extension, and the patient was educated on the risks vs. benefits of this decision. Chlorambucil treatment was continued for a total duration of twenty-one months. FA and OCT macula findings were stable and the patient was asymptomatic (Fig. 2C,D). Subsequent consults established disease stability with no new symptoms or activity. Infliximab was eventually tapered by 100 mg every four weeks. On her last consult at our clinic, she was on infliximab 100 mg infusions every four weeks with a final VA of 20/400 OD and 20/15 OS and stable findings on FA and macula OCT. Her average WBC count was 5700 ± 2200 cells/μl while on chlorambucil with prednisone, and 3800 ± 500 cells/μl when she was on chlorambucil after starting infliximab infusions without prednisone. The total duration of treatment before and after beginning infliximab infusions was 40 and 19 months, respectively. The total length of follow-up is 108 months. The total period of remission off chlorambucil is 60 months (Table 1).Fig. 2 (A) Fundus photo and fluorescein angiography of a patient with bilateral serpiginous choroiditis at the primary visit at our clinic. (B) The same patient during a recurrence in the left eye close to the fovea. (C,D) Stability of year after stopping chlorambucil while on infliximab tapering. (E) Macular optical coherence tomography at the first visit (left), during a recurrence (middle), and the last visit (right).
Fig. 2
Case 3. A 32-year-old female presented with decreased vision, floaters, and photophobia OS. Vision OD was poor due to retinal detachment after a motor vehicle accident. Before presenting to her initial consultation at our clinic, complete blood work-up for uveitis had ruled out non-infectious and infectious posterior uveitis, including syphilis and tuberculosis and she had already been diagnosed with idiopathic SC. She had been on MMF 2 g daily, cyclosporin 25 mg and prednisone 30 mg daily for fourteen months. Her vision was hand-motion OD and 20/20 OS at presentation. A fundus examination revealed optic atrophy and a horizontal scar OD in addition to diffuse chorioretinal (CR) scarring in both eyes. Given the possibility of the activity of the lesion potentially affecting the fovea OS and her monocular status, chlorambucil and cyclophosphamide were discussed as treatment options.
The patient was started on chlorambucil 4 mg daily and continued on 25 mg of prednisone daily. A month later, her WBC count dropped from 14,800 to 12,100 cells/μl. However, she felt her vision had decreased once again after two weeks on chlorambucil. She was advised to increase chlorambucil to 6 mg/day from 4 mg/day, as well as increase prednisone to 40 mg daily. After one week at this dose, she reported stable vision OD. Chlorambucil dose adjustment with weekly WBC count and oral prednisone were continued until she reported stable vision and no other symptoms. At this time, she was advised to increase chlorambucil to 12 mg daily.
Approximately four months after her initial visit, the patient presented to our clinic with worsening scotoma and floaters OS. At this point, she was on prednisone 5 mg daily and chlorambucil 10 mg daily. She had stopped chlorambucil for a week due to fever, and the WBC count was at 11,200 cells/μl. FA and ICG showed active choroidal inflammation at the lesion border, especially OS. Later on, she developed a diffuse, itchy rash, and because of this side effect, she was started on bi-weekly cyclophosphamide pulse therapy. She had five doses of cyclophosphamide pulse therapy, and her WBC count was between 4500 and 6300 cells/μl. However, a few days later, she complained of decreased vision OS with more central involvement. Her local ophthalmologist increased her prednisone to 60 mg, and she received her next cyclophosphamide infusion four days later with WBC count at 4000 cells/μl. Cyclophosphamide therapy was finally stopped due to persistent skin rash.
In the interim, she followed up with her local ophthalmologist while on oral prednisone with different doses based on disease activity. Her next visit with us was seven years later, and vision OS had deteriorated to 20/50. FA showed active inflammation OS in the form of enlarged CR lesions approaching the fovea with multifocal areas of leakage at the margins of the lesions (Fig. 3B). Up to that point, the patient had been off all immunomodulatory therapy (IMT) for seven years, yet only cyclophosphamide appeared to halt the progression of her disease. Monthly cyclophosphamide pulse therapy was resumed but was later stopped after eight months due to low WBC count. After this, she continued with oral prednisone 20 mg daily. At her last follow-up visit, chlorambucil was restarted due to the persistence of symptoms, worsening of vision OS, and the progression of lesion activity on imaging (Fig. 3C). Intravitreal steroid implants were also discussed. The patient was never able to taper off oral prednisone during treatment, and the average WBC count during her course of treatment was 8800 ± 3400 cells/μl. The total duration of treatment with chlorambucil was 5 months, cyclophosphamide was 10 months, and MMF plus cyclosporine was 14 months. The total duration of follow-up is 148 months. She has never been in remission for an extended period off medication (Table 1).Fig. 3 (A) Fundus photo of both eyes of a patient with bilateral serpiginous choroiditis. History of traumatic retinal detachment surgery with legal blindness in the right eye and active serpiginous choroiditis in the left eye. Fluorescein angiography shows an active lesion in the left eye. (B) Optical coherence tomography, fundus autofluorescence, and fluorescein angiography during a recurrence where the patient was started on cyclophosphamide pulse therapy. (C) Progression of the lesion in the left eye with an active lesion in fluorescein angiography at her last visit. Intravitreal dexamethasone and triamcinolone implants were discussed at this visit.
Fig. 3
Case 4. A 47-year-old female was referred to our center with decreased vision OU for one month and had been started on prednisone 50 mg daily before her first visit with us. Her vision OD and OS were 20/30 and counting fingers at 1 m, respectively, at presentation. Dilated fundoscopy showed bilateral geographic lesions nasal to the fovea OD and involving the fovea OS (Fig. 4A). Complete blood work-up for uveitis ruled out non-infectious and infectious posterior uveitis, including syphilis and tuberculosis. Based on these findings, and she was diagnosed with autoimmune SC OU. Oral prednisone was increased to 60 mg daily, and due to significant vision loss OS, she was started on chlorambucil 6 mg daily. Chlorambucil treatment with WBC count monitoring and tapering of oral prednisone was continued for a year. Once the oral prednisone taper was completed, she continued with chlorambucil monotherapy for five more months, at which time she had achieved remission. After four months; however, she had a flare-up OD, which was first treated with 1 g IV methylprednisolone infusion and intravenous methotrexate 200 mg/day. Subsequently, she was continued on subcutaneous methotrexate 15 mg weekly along with folic acid 1 mg/day for two years. She developed another flare-up when tapering methotrexate; hence methotrexate dose was boosted, and a combination of chlorambucil and oral prednisone was restarted. The patient was on chlorambucil and oral prednisone for one year, with an average WBC count of 6200 ± 3300 cells/μl. The patient was then on chlorambucil alone for another two months. She had been flare-free for twenty months when she had another episode. This time she was treated with intravenous and subcutaneous methotrexate. She had another flare during tapering of methotrexate and she is currently on a combination of chlorambucil, prednisone, and subcutaneous methotrexate therapy. The total duration of follow-up has been 116 months. She has never been in remission for an extended period (Table 1).Fig. 4 A serpiginous choroiditis patient with multiple recurrences despite treatment with a combination of oral prednisone and chlorambucil therapy. (A) Color fundus photos and fluorescein angiography of both eyes at the first visit, which showed activity around the lesion in both eyes. (B) The second row shows the progression of lesions in both eyes during a recurrence on fundus photos and fundus autofluorescence. (C) Fundus autofluorescence and fluorescein angiography showed reactivation of the supratemporal area of the lesion in the right eye. (D) Optical coherence tomography shows the lesion, edema, and destruction of the supratemporal part of the lesion, compatible with fundus autofluorescence and fluorescein angiography. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)
Fig. 4
3 Discussion
The pathogenesis of serpiginous choroiditis (SC) is unknown. The course of the disease is indolent and can be asymptomatic until it involves the macula and the central vision. Many patients can have old scars even at the first visit when they are diagnosed with SC.14 Laatikainen and Erkkila et al. reported that new lesions may appear at an interval of 3 months–4 years. They also demonstrated that active lesions resolve in a few weeks; however, signs of activity may last between 1 and 9 months.14 Central vision is involved in 20%–50% of cases, with the likelihood increasing with longer duration of follow-up and disease activity.8,14 Recurrences that affect the macula can cause severe visual loss of less than 20/200, which is typically irreversible and may induce CNV in the macula or around the optic disc.15
There are no controlled trials for the treatment of SC due to the rarity of the disease. Cytosine arabinoside, azathioprine, and oral prednisone were used with reported improved visual acuity in one month.16 Employment of a combination of cyclosporine and oral prednisone as a treatment of active SC had conflicting results. Hopper and Kaplan reported a triple-agent regimen of azathioprine, cyclosporine, and oral prednisone that resulted in rapid control of the active SC and vision recovery; however, disease recurrence was the study's main problem.9 Akpek et al. employed the same regimen in a more extended study and found that this regimen helped keep the inflammation quiet during treatment; however, it did not maintain remission off medication.17
Alkylating agents can bind to DNA, interfere with DNA replication, and subsequently interfere with cell division. Cyclophosphamide is commonly used because of its predictable, dose-dependent, and reversible adverse effects on WBC count18; nonetheless, it can result in serious side effects, some of which are life-threatening. These side effects include reversible hematuria, hemorrhagic cystitis, reversible alopecia, sterility, bladder cancer, lymphoma, and leukemia. Chlorambucil is another alkylating agent primarily used for the treatment of several lymphoproliferative diseases. It is a stable derivative of the nitrogen mustard.19 Based on its ability to reduce circulating lymphocytes, chlorambucil is effective in the treatment of rheumatologic diseases, including juvenile rheumatoid arthritis, systemic lupus erythematosus, and nephrotic syndrome.20, 21, 22, 23 Given the availability of other conventional immunomodulatory agents and biologic response modifiers that yield better results with fewer unpredictable side effects, ophthalmologists are reluctant to use chlorambucil. Our knowledge about biologic response modifier agents is limited to a few case reports and some of our patients had already failed infliximab, mycophenolate mofetil, methotreaxte before their first presentation to us or during follow-up with us. Palmer et al. studied the side effects of chlorambucil and found that these side effects are related to the total dose and duration of treatment.24 However, Tessler et al. found chlorambucil to be a successful treatment for different types of uveitis with no severe complications during 12 years of follow-up. They also reported complete remission in all patients. Although chlorambucil dose in their study was administered regardless of body weight, it did not exceed 2.2 g per patient during the entire treatment.25 Based on these findings, recent studies still rely on alkylating agents including cyclophosphamide and chlorambucil for classical and macular SC.5,12,32
It may take more time for chlorambucil to show its therapeutic and toxic effects. Patients on this medication should be monitored with weekly blood counts, specifically WBC and platelet counts, since its side effects are not always dose-related.25 Chlorambucil is administered orally because it has excellent gastrointestinal absorption, and its superiority over cyclophosphamide is related to the absence of associated side effects such as hair loss, hemorrhagic cystitis, and bladder cancer.26
The recommendation for the daily and total dose of chlorambucil is equal to or less than 0.2 mg/kg and 2.2 g, respectively. These recommendations help avoid late complications such as lymphoma and leukemia.27 Various doses of chlorambucil have been employed in the past in the field of ophthalmology. The use of lower doses of chlorambucil over an extended period, such as more than one year, without provoking bone marrow toxicity is one approach.28, 29, 30, 31 However, it has been demonstrated that sustained remission of the disease is achievable when the WBC count remained depressed for at least six weeks. This finding suggests that effective treatment with chlorambucil requires the induction of a toxic hematologic response.25
The recent literature shows that alkylating agents are still the most potent and effective treatment in patients with SC.4,12,32 Venkatesh and colleagues showed that intravenous cyclophosphamide pulse therapy provided a rapid resolution of active lesions and helped maintain good functional visual acuity.4 However, they admitted that this treatment might not prevent recurrences in patients with SC.4 Venkatesh et al. also studied intravenous methylprednisolone and cyclophosphamide in macular SC; they, again demonstrated it could be effective in acute macular SC, yet admitted that this treatment had no effects on disease relapses in the long-term.32 Ebrahimiadib et al. retrospectively studied 17 patients on chlorambucil with dose escalation based on weekly WBC count, with the target of 3000–4500 white blood cells/μl. They concluded that chlorambucil was well tolerated by the patients and was effective in preventing recurrences.12 Although all these recent studies provided important facts regarding SC treatment, they did not discuss the next step for the patients who failed these treatments. In the current study, we decided to evaluate the possible causes of chlorambucil treatment failure in patients with resistant SC and to examine possible successful regimens in these patients. To the best of our knowledge, this study is the first one which evaluates the possible remedy for resistance to chlorambucil as one of the most commonly employed medications in SC patients.
Histopathological studies in SC have demonstrated that lymphocytes infiltrate the choroid, and less commonly, vessels, leading to subsequent choriocapillaris occlusive vasculitis. This finding may indicate the important roles of lymphocytes in the pathogenesis of the disease.5 The histopathology in SC is very similar to birdshot chorioretinopathy.33,34 On the other hand, multiple studies have discussed the effects of long-term systemic corticosteroids on lymphocyte proliferation and T-cell population.35,36 Ferrari et al. reported increased lymphocytes, including increased absolute numbers of T cells, CD4+ and CD8+ cells, after four weeks of corticosteroid therapy in idiopathic thrombocytopenic purpura (ITP).35 Moreover, lymphocyte redistribution has been discussed in long-term steroid therapy.36 These changes associated with long-term corticosteroid use may interfere with the aim of chlorambucil treatment, since cells with higher proliferation rates are the target of this therapy. The negative effect of long-term systemic corticosteroids on birdshot chorioretinopathy has been studied in the past.37,38 Due to similarities between birdshot chorioretinopathy and SC in terms of histopathology, these facts can be applied to SC patients as well.
The target WBC count for chlorambucil therapy for SC is between 3000 and 4500 cells/μl. Chlorambucil dose adjustment is based on a weekly WBC count. In our experience, patients might be considered cured if there is no recurrence during the treatment period, which is around one year. Our observation in this case series showed that patients on high doses of systemic corticosteroids have unstable WBC count during chlorambucil therapy. Keeping this count in the satisfactory range for a reasonable period of at least six weeks can be challenging since it has been shown that induced toxic hematologic response is required for effective treatment with chlorambucil.25 The first two patients in this case series achieved durable remission and were likely cured after employing local corticosteroids or systemic immunomodulatory therapy, which allowed us to stop systemic corticosteroid use during chlorambucil therapy. However, the third and fourth patients are still experiencing recurrences since all systemic immunomodulatory therapies were unable to induce steroid-free remission. Local corticosteroid therapy was also recommended for both of the patients, but its potential side effects and the patients’ monocular statuses made this option unappealing.
We might be criticized for not employing local corticosteroid monotherapy without any systemic therapy. We believe that, although corticosteroids are the best option for controlling of acute ocular inflammation of any type, they are not potent enough to prime or re-program the immune system12 and not to respond to self-antigens as we expect with immunomodulatory therapy. This is similar to what occurs to pathologic cancer cells especially in blood cancers (lymphoma and leukemia) in patients who achieve remission with chemotherapy which is an advanced and more aggressive form of immunomodulatory therapy. Based on the above mentioned theory, corticosteroids as monotherapy cannot halt the inflammation thoroughly, so the ongoing inflammation can cause more cells destruction and epitopes exposures which might result in more resistant ocular inflammation which is believed to happen in patients with resistant autoimmune SC. we assume that the employment of systemic corticosteroid therapy, along with chlorambucil, is the main obstacle in achieving remission in patients with SC. This combination therapy is mostly seen in monocular patients or in vision-threatening SC where there is a lower threshold for aggressive systemic corticosteroid therapy in these patients.
We might also be criticized for using different therapies in one patient; however, we follow the strategy of “one change at a time” and this means that any time a conventional IMT is tried, we wait for three months with no changes to assess its effectiveness. For biologic response modifier agents, we wait for two months. This strategy makes interaction between medications unlikely. Moreover, since our mission is systemic steroid free remission, we only consider a medication to be effective if the inflammation stays in remission even after the effects of steroids are gone. Furthermore, none of these therapies induced long term remission in our patients.
Dexamethasone intravitreal implants have been employed in the treatment of active SC and serpiginous-like choroiditis.39,40 In these studies, the authors showed the success of this implant in controlling active SC. Based on these studies, dexamethasone can be an alternative to high dose oral or intravenous corticosteroid without systemic side effects including its effects on bone marrow, secondary lymphoid tissues, and peripheral blood regarding WBC counts, especially lymphocytes.
One common fact between all patients in this case series is the instability of WBC count during chlorambucil therapy plus systemic corticosteroids. This issue was addressed in one patient with dexamethasone intravitreal implant and in another patient with infliximab therapy. Both patients allowed us to taper and stop oral prednisone during chlorambucil therapy. The latter patient has been in remission for four years, which is the time frame during which one would expect a new lesion based on the Laatikainen and Erkkila et al. study.14 Despite this, this patient continues to take infliximab at a dose of 300 mg every four weeks since there is a fear of SC recurrence once infliximab therapy is terminated. However, this concept and hypothesis need further, more sophisticated examination.
This study had inherent limitations given its retrospective study design with a small sample size due to the rarity of cases of SC. It was even more challenging to find refractory cases with a reasonable follow-up period to expect a recurrence as all of these patients have at least 8 years of follow-up at our center without any serious side effects. Furthermore, all confounding factors cannot be controlled in a retrospective study. Regardless, we believe that confounding factors related to WBC might not interfere in this study since chlorambucil dose is adjusted based on WBC count and in clinical practice, changes in WBC count are typically more related to changes in corticosteroid dosage. Based on all these limitations, the results of this case series should be interpreted with caution and justifies the need for more potent studies.
4 Conclusion
The stability of WBC counts within toxic levels close to normal or lower limits of normal (3000–4500 cells/μl) during treatment with chlorambucil is an essential factor for the success of this therapy. A combination of dexamethasone intravitreal implant with chlorambucil therapy can be an effective and promising regimen in inducing and maintaining remission in refractory SC patients who fail a combination of systemic corticosteroid and chlorambucil therapy as the first line therapy. However, this primitive hypothesis should be investigated with more potent studies and larger sample sizes.
Patient consent
Consent to publish the personal information and cases details was obtained from all the patients.
Financial supports
None.
All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.
Disclosures
Dr. C Stephen Foster declares the following: Consultancies with Aldeyra Therapeutics (Lexington, MA), Allakos (Redwood City, CA), Bausch & Lomb Surgical, Inc (Rancho Cucamonga, CA), Eyegate Pharma (Waltham, MA), Genentech (South San Francisco, CA), Novartis (Cambridge, MA), pSivida (Watertown, MA) Grants or grants pending with Aciont (Salt Lake City, UT), Alcon (Aliso Viejo, CA), Aldeyra Therapeutics (Lexington, MA), Bausch & Lomb (Rochester, NY), Clearside Biomedical (Alpharetta, GA), Dompé pharmaceutical (Milan, Italy), Eyegate Pharma (Waltham, MA), Mallinckrodt pharmaceuticals (Staines-upon-Thames, UK), Novartis Pharmaceuticals (Cambridge, MA), pSivida (Watertown, MA), Santen (Osaka, Japan). Payment for lectures including service on speaking bureaus: Alcon (Aliso Viejo, CA), Allergan (Dublin, Ireland), Mallinckrodt pharmaceuticals (Staines-upon-Thames, UK). Stock or Stock Options: Eyegate Pharma (Waltham, MA).
The other authors have nothing to declare.
Compliance with ethics guidelines
This study was approved by the New England Institutional Review Board, which has issued a waiver of informed consent for the retrospective chart review analysis. This study was performed in accordance with the Helsinki Declaration of 1964, and its later amendments. All participants provided consent for publication if any identifying information is included in the manuscript.
Data availability
The data that support the findings of this study are available from the corresponding author, upon reasonable request.
Declaration of competing interest
No conflicting relationship exists for any author. | Recovering | ReactionOutcome | CC BY-NC-ND | 33615036 | 19,163,199 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Deep vein thrombosis'. | A Normal FGF23 Does Not Preclude Tumor-Induced Osteomalacia.
Tumor-induced osteomalacia (TIO) is a rare cause of impaired bone mineralization mediated by the osteocyte-derived, phosphaturic hormone: fibroblast growth factor 23 (FGF23). The case is presented of a previously healthy 45-year-old man who developed fragility fractures at multiple sites (initially metatarsals, eventually ribs, hips, spine, scapula, and sacrum) resulting in rapid functional deterioration, weakness, and the inability to bear weight and ambulate without a walker. Workup for secondary causes of bone loss was negative except for mild hypogonadotropic hypogonadism with normal pituitary MRI and hypophosphatemia that persisted despite aggressive supplementation. Testosterone was initiated but discontinued 6 months later because of deep vein thrombosis and pulmonary embolism, likely provoked by his new sedentary state, in addition to smoking history and possibly testosterone usage. Serum FGF23 was nonelevated at 138 mRU/mL (44-215). A genetic panel for OI variants was negative for a causal mutation. At the age of 48, 3 years after his initial fracture, he was referred to our academic endocrine clinic. We ruled out additional mutations that lead to hypophosphatemic rickets, including phosphate-regulating endopeptidase homolog, X-linked. PET/CT looking for a potential TIO locus revealed uptake in the left suprapatellar recess. Biopsy was consistent with a phosphaturic mesenchymal tumor. FGF23 was repeated for a preoperative baseline and now found to be elevated at 289 mRU/mL. In retrospect, it is likely that the initial level was inappropriately elevated for the degree of hypophosphatemia. After resection, he experienced marked improvement in physical function, decreased pain, and resolution of renal phosphate wasting. The principals of establishing a robust clinical diagnosis of TIO should be emphasized, excluding other entities and avoiding pitfalls in the interpretation of laboratory testing. © 2020 The Authors. JBMR Plus published by Wiley Periodicals LLC. on behalf of American Society for Bone and Mineral Research.
Case Presentation
A 45‐year‐old previously healthy white man presented with multiple fragility fractures over 2 years, as well as pain and functional deficits eventually rendering him nonambulatory. He carried no previously diagnosed medical history, although he was a former smoker with a 13 pack‐year smoking history. His family history was notable for grade 1 chondrosarcoma in his mother. He initially presented to an orthopedic clinic with foot pain and hip pain after starting an exercise program. Initially, he was counseled to participate in physical therapy; however, he continued to develop progressively disabling pain. Over the course of 8 months, he was diagnosed with bilateral metatarsal and subtrochanteric femur fractures on imaging.
A local endocrinologist was consulted based on suspicion for secondary causes of bone loss. His laboratory tests were notable for a low phosphorus at 2.1 mg/dL (2.7–4.5), elevated alkaline phosphatase (ALP) at 155 IU/L (34–104), elevated PTH at 211 pg/mL (12.0–72.0), low 25OHD, and 1,25(OH)2D3 at 27 ng/mL (30–80) and 12 pg/mL (20–80), respectively. However, calcium was normal at 8.8 mg/dL (8.4–10.4). Serum protein electrophoresis revealed no evidence of monoclonal gammopathy. Additional studies included a low free testosterone at 4.4 ng/mL (5–21) and luteinizing hormone at 2.2 mIU/mL (3.0–10.0). Other pituitary hormone levels and brain MRI were unremarkable.
Vitamin D3, calcitriol, phosphate, and testosterone were prescribed. Testosterone was discontinued 6 months later, after developing a venous thromboembolism of the left common femoral, superficial femoral, and popliteal veins, and pulmonary embolus of the left pulmonary artery. Workup for genetic causes of hypercoagulability was negative; he ultimately received anticoagulation for a year with rivaroxaban. Incidental rib fractures on a chest X‐ray at the time prompted a three‐phase 99Tc‐MDP bone scan, revealing multiple sites of uptake: ribs, scapulae, sternum, thoracolumbar spine, sacrum, bilateral ankles, and feet (Fig. 1A)
.
Fig 1 Key radiologic imaging and histology sections from our patient with tumor‐induced osteomalacia (TIO). Top panel: (A) 99mtechnetium methylene diphosphonate (99mTc MDP) bone scan shows increased uptake in bilateral anterior/posterior ribs, bilateral sternoclavicular joints, right proximal intertrochanteric femur, inferior sternum, multiple bilateral lumbar transverse processes, right posterior scapula, posterior elements along upper thoracic spine, posterior elements along lumbosacral junction, right posterior sacrum, bilateral ankles, likely bilateral mid‐feet. Overall impression: Extensive multifocal regions with increased uptake likely representing subacute, remodeling, or other active stress fractures. Middle panel: (B) Computed tomography/fluorodeoxyglucose ‐positron emission tomography (CT/FDG PET) scan shows an area of suprapatellar enhancement that was suspicious for a TIO locus (C) Sagittal MR image showing the patient's hypermetabolic lesion measuring 1.7 cm in largest dimension in the left suprapatellar recess, and corresponding to hypermetabolic area on PET/CT. Bottom panel: (D) suprapatellar tumor surgical pathology specimen stained with H&E: Pattern is consistent with phosphaturic mesenchymal tumor. Arrow indicates multinucleated giant cells.
Laboratory tests showed ongoing phosphate wasting, despite compliance with calcitriol 0.25 μg/d, cholecalciferol 5000 IU/d, and phosphorus 2250 mg/d in divided doses. Calculated tubular reabsorption of phosphate was 64% (>80%) and renal tubular maximal phosphate to glomerular reabsorption rate (TmP/GFR) was 1.74 mg/dL (2.5–4.5), indicating inappropriately low Pi reabsorption. Of note, it is unclear if the patient was taking phosphorus supplementation at the time of these measurements. Urine 24‐hour calcium was 244.8 mg (100–300). Testing for causal mutations in hypophosphatemic rickets and osteogenesis imperfecta was negative. Serum C‐terminal FGF23 level was tested based on concern for an acquired cause of hypophosphatemia such as TIO, and was within the reference range at 138 RU/mL (LabCorp ELISA 44–215; LabCorp, Burlington, NC, USA). At this point, 3 years after symptom onset, he was referred to our academic endocrinology practice for further workup of possible secondary causes of his phosphate wasting. His examination was remarkable only for an elevated BMI of 35, diffuse muscle and bone tenderness to palpation without evident deformities, and requirement for an ambulation‐assist device. We interpreted his normal serum FGF23 level as inappropriately high for his degree of hypophosphatemia, prompting a search for a suspected TIO locus, which was further considered based on rapid clinical deterioration in a previously healthy patient. 18F‐fluorodeoxyglucose positron emission tomography (18F‐FDG‐PET) exhibited a hypermetabolic focus at the left suprapatellar recess, which corresponded with a small 1.7‐cm mass that had previously been seen on CT 2 years prior but thought to be clinically insignificant because of its benign appearance (Fig. 1B
). MRI demonstrated stability in size over this time period with near homogenous enhancement suggestive of a benign process; signal intensity was slightly higher than muscle with punctate areas showing low signal foci, potentially indicative of a degree of mineralization (Fig. 1C
). Serum C‐terminal FGF23 measurement was measured with LabCorp ELISA again, and was now elevated at 289 RU/mL (44–215).
Biopsy showed a phosphaturic mesenchymal tumor (Fig. 1D
) and chromogenic in situ hybridization (Mayo Clinic, Rochester, MN, USA) was positive for FGF23 mRNA, confirming this site as a likely TIO locus (Table 1). After surgical resection of the tumor, serum C‐terminal FGF23 declined to <50 RU/mL 1‐week postoperative and was 90 RU/mL 3 weeks later (Mayo <180 RU/mL). Phosphorus and 25OHD level were rechecked at 1 month postsurgery and found to have normalized, permitting discontinuation of calcitriol and phosphorus. DEXA 8 weeks after surgery showed marked improvements, with lumbar spine T score increasing from −2.8 to −1.0 (BMD +64.29%) and femoral neck T score from −1.9 to −1.4 (BMD +26.32%). The patient also experienced significant improvement in physical function and pain after his operation.
Table 1 Clinical Characteristics Prior to and After Tumor Resection
Test Years prior to presentation Weeks after surgery Range
3 1 0.5 Initial visit 1 4 12 32
Phosphorus serum (mg/dL) 2.0 2.4 3.9 4.1 2.8 2.5–5.0
Urine spot ‐ Phos (mg/dL) ‐ Cr (mg/dL) Phos: 57 Cr: 47 Urine Phos: N/A Urine Cr: 30–125
TmP/GFR (mg/dL) 1.74 2.4–4.5
24‐h urine calcium (mg/24 h) 244.8 90.0 <100 Low Ca diet <300 Normal diet
Alk phos (IU/L) 166 177 99 126 125 125 34–104
iPTH (pg/mL) 105 211 69.2 62 12.0–72.0
Calcium (mg/dL) 9.2 8.7 9.2 9.3 9.3 8.6–10.3
25OHD (ng/mL) 24 33 41 31 30–80
1,25(OH)2D (pg/mL) 12.0 55.6 19.9–79.3
FGF23 (mRU/mL) <50 90 Mayo ELISA <180
138 289 LabCorp ELISA 44–215
Pituitary hormones LH (mIU/mL): 2.2 ACTH (pg/mL): 24.5 TSH (mIU/mL): 2.6 Prolactin (ng/mL): 4.6 LH 1.6 FSH (mIU/mL): 1.7 LH: 1.2–8.6 FSH: 1.3–19.3 ACTH: 7.2–63.3 TSH: 0.3–4.5 Prolactin: 4.0–15.2
24‐h urine–free cortisol (μg/dL/24 h) 12.0 0–50.0
Testosterone Total (ng/dL) Free (pg/mL) Total 175 Free 4.4 Total 151 Free 6.6 Total: 249–836 Free: 6.8–21.5
SPEP No monoclonal gammopathy N/A
Genetic testing OI panel negative CTGT panel negative
Imaging studies
MRI L Foot: Transverse fracture second MT, marrow edema, also medial cuneiform Hip X‐rays: Stress fractures‐ RFN & Left subtrochanteric CT and MRI lower extr: fractures as above, and with benign appearing L suprapatellar soft tissue nodule
3‐phase
99
Tc‐MDP bone scan: Multiple stress fractures MRI Brain: normal pituitary
DEXA Spine T − 2.8 FN T − 1.9 PET‐CT: hypermetabolic L suprapatellar lesion MRI L knee: stable appearing L suprapatellar lesion
MRI L Knee: no evidence of soft tissue lesion recurrence
DEXA Spine T − 1.0 FN T − 1.4
Connective tissue gene tests abnormal mineralization disorder panel, next‐generation sequencing. All coding regions for genes on the panel were analyzed for variants using Illumina (San Diego, CA, USA) MiSeq next‐generation sequencers (ALPL, ANKH, CASR, CLCN5, CYP27B1, DMP1, ENPP1, FAH, FGF23, OCRL, PHEX, SLC34A1, SLC34A3, SLC9A3R1, VDR).
Abbreviations: 25OHD = calcidiol; 1,25(OH)2D = calcitriol; ACTH = adrenocorticotropic hormone; Alk phos = alkaline phosphatase; CT = computed tomography; CTGT = connective tissue gene test; DEXA = dual energy X‐ray absorptiometry; ELISA = enzyme‐linked immunosorbent assay; FSH = follicle‐stimulating hormone; iPTH = intact parathyroid hormone; LH = luteinizing hormone; MRI = magnetic resonance imaging; MT = metatarsal; OI panel = osteogenesis imperfecta panel from Invitae analyzed clinically important regions of each specified gene (COL1A1, COL1A2, CRTAP, P3H1); PRL = prolactin; SPEP = serum protein electrophoresis; TMP/GFR = tubular max reabsorption of phosphate.
Background
In the late 1950s the Swiss pediatric endocrinologist Andrea Prader was the first to identify a case of acquired hypophosphatemia caused by a ricketogenic substance [FGF23].(
1
,
2
,
3
) It would take more than 40 years to clone this humoral factor, or phosphatonin, causing renal phosphate wasting.(
4
) Studies of autosomal dominant hypophosphatemic rickets led to identifying FGF23 as the most common phosphatonin, crucial in both physiologic phosphate regulation and the driver of phosphate wasting in multiple diseases.(
4
,
5
,
6
)
Bone‐derived FGF23 is upregulated with increased serum inorganic phosphate (Pi) and downregulated in the setting of hypophosphatemia.(
7
) Interestingly, tight regulation of FGF23 degradation, rather than its synthesis, permits its secretion.(
8
) GALNT3 functions to O‐glycosylate FGF23, thus protecting FGF23 from degradation and permitting its release.(
9
) On the other hand, the absence of the zinc metallopeptidase phosphate‐regulating endopeptidase homolog, X‐linked (PHEX) lowers FGF23 via unclear mechanisms.(
10
) Intact FGF23, secreted by osteocytes and their precursors, binds with coreceptor α‐klotho to FGFR1 in the renal proximal tubule, reducing expression of the sodium‐phosphate cotransporters NaPi‐2a and NaPi‐2c, and ultimately increasing urinary phosphate excretion.(
11
) In addition to its effect on renal Pi handling, FGF23 suppresses renal 1‐α‐hydroxylase (CYP27B1), thereby lowering calcitriol synthesis; FGF23 also upregulates vitamin D 24‐hydroxylase (CYP24), inactivating calcitriol.(
9
,
11
) In addition to FGF23 and vitamin D, PTH is also an important phosphate regulator. PTH (via PTHR1) promotes phosphaturia by a mechanism similar to FGF23, however in contrast, upregulates CYP27B1 and suppresses CYP24.(
12
)
The presence of multiple fragility fractures in young adults merits consideration of secondary causes of bone loss. The differential diagnosis includes disorders of the collagen matrix such as osteogenesis imperfecta and disorders of calcium and vitamin D metabolism.(
13
) Hypophosphatemia suggests a genetic versus acquired cause of Pi loss.(
14
) Common acquired causes of low Pi include primary hyperparathyroidism, secondary hyperparathyroidism from vitamin D deficiency, and alcohol abuse.(
12
,
14
) Fanconi syndrome presents with glycosuria and aminoaciduria in addition to phosphaturia; it can be either inherited or secondary to medications or other illnesses, such as multiple myeloma.(
12
,
15
) Distinguishing whether hypophosphatemia is driven by renal phosphate wasting is a key part of diagnostic evaluation, and is done by calculating the tubular maximal reabsorption rate of phosphate to glomerular filtration (TmP/GFR).(
16
) Causes such as hyperparathyroidism and Fanconi syndrome with renally mediated Pi losses typically have low TmP/GFR values, whereas extrarenal causes such as excess phosphate binder intake and refeeding syndrome should have appropriately high TmP/GFR for the degree of hypophosphatemia.(
16
)
If investigations reveal renal‐mediated hypophosphatemia unexplained by the above causes, serum FGF23 is measured. High FGF23, or a level inappropriately normal for the degree of hypophosphatemia, might indicate a disorder of FGF23 excess. X‐linked hypophosphatemic rickets (PHEX) and autosomal dominant hypophosphatemic rickets (FGF23) are genetic disorders resulting in decreased FGF23 breakdown.(
12
) Of note, several patients with FGF23 mutations, especially women, may be normophosphatemic during childhood; thus testing for this mutation should be part of the workup for adult onset fragility fractures with hypophosphatemia.(
12
) Autosomal recessive hypophosphatemic rickets type 1 (DMP1) leads to increased transcription of FGF23.(
9
,
12
) McCune‐Albright syndrome (GNAS somatic mutation) may rarely cause FGF23 overexpression.(
12
) Additionally, ferric carboxymaltose administration can cause osteomalacia through an increase in FGF23.(
17
)
TIO is caused by overproduction of FGF23 by small, typically benign mesenchymal tumors, leading to fragility fractures and diffuse bone and muscle pain.(
18
) Laboratory findings are similar to those of the FGF23 excess syndromes described above, with hypophosphatemia, renal phosphate wasting, and low to inappropriately normal 1,25(OH)2D3 for the degree of hypophosphatemia, however, without a previous history of these lab abnormalities.(
19
) Serum calcium, 25OHD, and PTH levels are normal, though persistently low 1,25(OH)2D3 may lead to secondary hyperparathyroidism, with elevated ALP.(
19
)
The time from symptom onset to diagnosis is over 2.5 years in most cases of TIO, in part because of delays in initial testing for hypophosphatemia, but also because of difficulty in localizing tumors.(
19
) Functional imaging, which takes advantage of the high expression of somatostatin receptors in TIO, is recommended and uses 111In‐octreotide or 68Gallium tetraazacyclododecanetetraacetic acid–DPhe1‐Tyr3‐octreotate (68Ga‐DOTATATE) for tumor localization.(
11
) DOTATATE PET/CT likely has the greatest sensitivity and specificity for TIO, with octreotide scanning also being a sensitive imaging method based on the presence of somatostatin receptors in TIO.(
11
,
20
) However, 18FDG‐PET‐CT is useful if somatostatin‐based scans are negative.(
11
,
20
) In some cases, biopsy has been discouraged based on the possibility of tumor seeding, with venous sampling being an alternate option if further diagnostic clarification is needed.(
14
) Successful tumor resection typically results in skeletal healing and reversal of biochemical defects; excision with wide, tumor‐free margins is essential because of the risk of tumor recurrence.(
14
,
19
) Histopathology shows a mesenchymal tumor of mixed connective tissue variant (PMT‐CT).(
21
) Immunohistochemical staining or RT‐PCR‐based detection of FGF23 mRNA transcription is often used to demonstrate increased FGF23 expression.(
21
,
22
) In our patientʼs case, chromogenic in situ hybridization was used to support the diagnosis.
Discussion
This case serves as an example of the importance of considering TIO in the differential diagnosis of fragility fractures, particularly with the constellation of new‐onset persistent renal phosphate wasting in the absence of genetic causes of hypophosphatemic osteomalacia. The presence of FGF23 level in the normal range should be interpreted as inappropriately elevated and potentially suggestive of TIO, as physiologically FGF23 should be downregulated with hypophosphatemia.
Interestingly, our patient's serum FGF23 level was elevated only on recheck 5 months after his initial level. Although his tumor could have expressed higher amounts of FGF23 mRNA during this period, this case also brings into question the reproducibility of FGF23 level and sensitivity of commercially available serum assays. For example, in a study by Imel and colleagues, the test sensitivity of one C‐terminal FGF23 assay (Immutopics, Inc., San Clemente, CA, USA) was 73% in TIO; although this specific assay is different from that used for our patient, this suggests that C‐terminal assays might miss a fraction of TIO cases.(
23
) Imel and colleague's study also investigated the an intact FGF23 (iFGF23; Kainos Laboratories, Tokyo, Japan) assay and Immutopics intact assay (now discontinued), which had sensitivities of 86% and 23%, respectively.(
23
) Of note, Mayo Clinic Laboratories has recently started offering an iFGF23 assay.(
24
) Further research examining the sensitivities of currently available assays, including head‐to‐head comparisons of C‐terminal to iFGF23 assays, will be important for improving diagnostic accuracy in TIO. Alternatively, lowering the cutoff used for TIO diagnosis may help improve test sensitivity. For example, Proposals have been made for using iFGF23 values just above the population median as a threshold for ruling in TIO, rather than the upper limit of normal; it is possible that a similar principle may apply to C‐terminal assays.(
25
)
Alternate testing modalities are needed for cases not easily diagnosed via imaging and/or FGF23 measurement. Venous sampling measuring FGF23 may have clinical utility in verifying a suspicious mass on imaging as being a TIO locus, and systematic sampling may guide locations for further imaging in patients with unrevealing radiographic studies.(
26
,
27
) Of note, current studies of venous sampling have been conducted using iFGF23 measurements, with subjects usually having elevated levels.(
26
,
27
) It is difficult to say if any of these patients would have had a normal C‐terminal FGF23, similar to our patient, if checked. Whether venous sampling may be of clinical utility in patients with normal iFGF23 or C‐terminal FGF23 levels merits further study, as this may be a relevant method in cases such as ours.
In some TIO patients with normal FGF23 levels, one may consider hypophosphatemia driven by a different paraneoplastic phosphaturic hormone, or whether FGF23 secretion may be partially responsive to serum phosphate levels in some tumors.(
23
) For example, matrix extracellular phosphoglycoprotein, secreted frizzled protein 4, and FGF‐7 are all additional phosphatonins that have rarely been associated with TIO.(
12
,
28
)
Of note, this patient's family history of chondrosarcoma raises the question of a genetic predisposition to developing TIO tumors in patients with a family history of skeletal malignancy. For example, an FN1‐FGFR1 fusion gene has been identified in several TIO tumors; this gene has been hypothesized to cause tumorigenesis in TIO through FGF23 binding, leading to autocrine or paracrine activation of the receptor tyrosine kinase.(
14
,
29
) Interestingly, FGFR1 fusion genes have been identified as pathogenic in the 8p11 myeloproliferative syndrome, breast cancer, glioblastoma, and lung squamous cell carcinoma.(
29
,
30
) Additionally, similar microRNA profiles were recently noted in osteosarcomas and TIO; both show upregulation of the biomarker miR‐197 and downregulation of miR‐20b, miR‐144, and miR‐335.(
31
) Further genetic studies of TIO may improve our understanding of the disease and identify patients missed by currently available modalities.
Conclusion
This case illustrates a potential pitfall in the diagnosis of tumor‐induced osteomalacia (TIO), highlighting that a normal serum C‐terminal or intact FGF23 might not exclude the disorder in a patient with high clinical suspicion based on acquired hypophosphatemic osteomalacia. Rather, a normal C‐terminal or intact FGF23 must be interpreted as inappropriately high in the setting of hypophosphatemia and warrants a search for FGF23‐excess syndromes such as TIO.
Disclosures
All authors report that there are no relevant conflicts of interest, no relevant financial or nonfinancial relationships, no patents (whether planned, pending, or issued) broadly relevant to this work, or any other relationships/conditions/circumstances that present a potential conflict of interest.
AUTHOR CONTRIBUTIONS
Neeharika Nandam: Conceptualization; data curation; investigation; project administration; writing‐original draft; writing‐review and editing. Sadia Ejaz: Conceptualization; writing‐original draft; writing‐review and editing. William Ahrens: Data curation; resources; software; visualization; writing‐review and editing. Maya Styner: Conceptualization; data curation; investigation; project administration; writing‐original draft; writing‐review and editing.
Acknowledgments
This work was funded by grant no. R01AR073264 from the National Institute of Health (NIH)/National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) and grant NIH/NCATS/NCTraCS no. KL2TR002490. We would like to acknowledge and thank the NIH/NIAMS for their funding. We also thank the patient described in this report, and confirm that they provided consent for the publication of their case.
Authors' roles: Data collection: NN and MS. Photographing, formatting, and captioning of surgical pathology pictures: WA. Drafting manuscript: NN, SE, and MS. Revising manuscript content: NN, SE, and MS. Approving final version of manuscript: NN, SE, WA, and MS. | TESTOSTERONE | DrugsGivenReaction | CC BY | 33615107 | 18,700,332 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Pulmonary embolism'. | A Normal FGF23 Does Not Preclude Tumor-Induced Osteomalacia.
Tumor-induced osteomalacia (TIO) is a rare cause of impaired bone mineralization mediated by the osteocyte-derived, phosphaturic hormone: fibroblast growth factor 23 (FGF23). The case is presented of a previously healthy 45-year-old man who developed fragility fractures at multiple sites (initially metatarsals, eventually ribs, hips, spine, scapula, and sacrum) resulting in rapid functional deterioration, weakness, and the inability to bear weight and ambulate without a walker. Workup for secondary causes of bone loss was negative except for mild hypogonadotropic hypogonadism with normal pituitary MRI and hypophosphatemia that persisted despite aggressive supplementation. Testosterone was initiated but discontinued 6 months later because of deep vein thrombosis and pulmonary embolism, likely provoked by his new sedentary state, in addition to smoking history and possibly testosterone usage. Serum FGF23 was nonelevated at 138 mRU/mL (44-215). A genetic panel for OI variants was negative for a causal mutation. At the age of 48, 3 years after his initial fracture, he was referred to our academic endocrine clinic. We ruled out additional mutations that lead to hypophosphatemic rickets, including phosphate-regulating endopeptidase homolog, X-linked. PET/CT looking for a potential TIO locus revealed uptake in the left suprapatellar recess. Biopsy was consistent with a phosphaturic mesenchymal tumor. FGF23 was repeated for a preoperative baseline and now found to be elevated at 289 mRU/mL. In retrospect, it is likely that the initial level was inappropriately elevated for the degree of hypophosphatemia. After resection, he experienced marked improvement in physical function, decreased pain, and resolution of renal phosphate wasting. The principals of establishing a robust clinical diagnosis of TIO should be emphasized, excluding other entities and avoiding pitfalls in the interpretation of laboratory testing. © 2020 The Authors. JBMR Plus published by Wiley Periodicals LLC. on behalf of American Society for Bone and Mineral Research.
Case Presentation
A 45‐year‐old previously healthy white man presented with multiple fragility fractures over 2 years, as well as pain and functional deficits eventually rendering him nonambulatory. He carried no previously diagnosed medical history, although he was a former smoker with a 13 pack‐year smoking history. His family history was notable for grade 1 chondrosarcoma in his mother. He initially presented to an orthopedic clinic with foot pain and hip pain after starting an exercise program. Initially, he was counseled to participate in physical therapy; however, he continued to develop progressively disabling pain. Over the course of 8 months, he was diagnosed with bilateral metatarsal and subtrochanteric femur fractures on imaging.
A local endocrinologist was consulted based on suspicion for secondary causes of bone loss. His laboratory tests were notable for a low phosphorus at 2.1 mg/dL (2.7–4.5), elevated alkaline phosphatase (ALP) at 155 IU/L (34–104), elevated PTH at 211 pg/mL (12.0–72.0), low 25OHD, and 1,25(OH)2D3 at 27 ng/mL (30–80) and 12 pg/mL (20–80), respectively. However, calcium was normal at 8.8 mg/dL (8.4–10.4). Serum protein electrophoresis revealed no evidence of monoclonal gammopathy. Additional studies included a low free testosterone at 4.4 ng/mL (5–21) and luteinizing hormone at 2.2 mIU/mL (3.0–10.0). Other pituitary hormone levels and brain MRI were unremarkable.
Vitamin D3, calcitriol, phosphate, and testosterone were prescribed. Testosterone was discontinued 6 months later, after developing a venous thromboembolism of the left common femoral, superficial femoral, and popliteal veins, and pulmonary embolus of the left pulmonary artery. Workup for genetic causes of hypercoagulability was negative; he ultimately received anticoagulation for a year with rivaroxaban. Incidental rib fractures on a chest X‐ray at the time prompted a three‐phase 99Tc‐MDP bone scan, revealing multiple sites of uptake: ribs, scapulae, sternum, thoracolumbar spine, sacrum, bilateral ankles, and feet (Fig. 1A)
.
Fig 1 Key radiologic imaging and histology sections from our patient with tumor‐induced osteomalacia (TIO). Top panel: (A) 99mtechnetium methylene diphosphonate (99mTc MDP) bone scan shows increased uptake in bilateral anterior/posterior ribs, bilateral sternoclavicular joints, right proximal intertrochanteric femur, inferior sternum, multiple bilateral lumbar transverse processes, right posterior scapula, posterior elements along upper thoracic spine, posterior elements along lumbosacral junction, right posterior sacrum, bilateral ankles, likely bilateral mid‐feet. Overall impression: Extensive multifocal regions with increased uptake likely representing subacute, remodeling, or other active stress fractures. Middle panel: (B) Computed tomography/fluorodeoxyglucose ‐positron emission tomography (CT/FDG PET) scan shows an area of suprapatellar enhancement that was suspicious for a TIO locus (C) Sagittal MR image showing the patient's hypermetabolic lesion measuring 1.7 cm in largest dimension in the left suprapatellar recess, and corresponding to hypermetabolic area on PET/CT. Bottom panel: (D) suprapatellar tumor surgical pathology specimen stained with H&E: Pattern is consistent with phosphaturic mesenchymal tumor. Arrow indicates multinucleated giant cells.
Laboratory tests showed ongoing phosphate wasting, despite compliance with calcitriol 0.25 μg/d, cholecalciferol 5000 IU/d, and phosphorus 2250 mg/d in divided doses. Calculated tubular reabsorption of phosphate was 64% (>80%) and renal tubular maximal phosphate to glomerular reabsorption rate (TmP/GFR) was 1.74 mg/dL (2.5–4.5), indicating inappropriately low Pi reabsorption. Of note, it is unclear if the patient was taking phosphorus supplementation at the time of these measurements. Urine 24‐hour calcium was 244.8 mg (100–300). Testing for causal mutations in hypophosphatemic rickets and osteogenesis imperfecta was negative. Serum C‐terminal FGF23 level was tested based on concern for an acquired cause of hypophosphatemia such as TIO, and was within the reference range at 138 RU/mL (LabCorp ELISA 44–215; LabCorp, Burlington, NC, USA). At this point, 3 years after symptom onset, he was referred to our academic endocrinology practice for further workup of possible secondary causes of his phosphate wasting. His examination was remarkable only for an elevated BMI of 35, diffuse muscle and bone tenderness to palpation without evident deformities, and requirement for an ambulation‐assist device. We interpreted his normal serum FGF23 level as inappropriately high for his degree of hypophosphatemia, prompting a search for a suspected TIO locus, which was further considered based on rapid clinical deterioration in a previously healthy patient. 18F‐fluorodeoxyglucose positron emission tomography (18F‐FDG‐PET) exhibited a hypermetabolic focus at the left suprapatellar recess, which corresponded with a small 1.7‐cm mass that had previously been seen on CT 2 years prior but thought to be clinically insignificant because of its benign appearance (Fig. 1B
). MRI demonstrated stability in size over this time period with near homogenous enhancement suggestive of a benign process; signal intensity was slightly higher than muscle with punctate areas showing low signal foci, potentially indicative of a degree of mineralization (Fig. 1C
). Serum C‐terminal FGF23 measurement was measured with LabCorp ELISA again, and was now elevated at 289 RU/mL (44–215).
Biopsy showed a phosphaturic mesenchymal tumor (Fig. 1D
) and chromogenic in situ hybridization (Mayo Clinic, Rochester, MN, USA) was positive for FGF23 mRNA, confirming this site as a likely TIO locus (Table 1). After surgical resection of the tumor, serum C‐terminal FGF23 declined to <50 RU/mL 1‐week postoperative and was 90 RU/mL 3 weeks later (Mayo <180 RU/mL). Phosphorus and 25OHD level were rechecked at 1 month postsurgery and found to have normalized, permitting discontinuation of calcitriol and phosphorus. DEXA 8 weeks after surgery showed marked improvements, with lumbar spine T score increasing from −2.8 to −1.0 (BMD +64.29%) and femoral neck T score from −1.9 to −1.4 (BMD +26.32%). The patient also experienced significant improvement in physical function and pain after his operation.
Table 1 Clinical Characteristics Prior to and After Tumor Resection
Test Years prior to presentation Weeks after surgery Range
3 1 0.5 Initial visit 1 4 12 32
Phosphorus serum (mg/dL) 2.0 2.4 3.9 4.1 2.8 2.5–5.0
Urine spot ‐ Phos (mg/dL) ‐ Cr (mg/dL) Phos: 57 Cr: 47 Urine Phos: N/A Urine Cr: 30–125
TmP/GFR (mg/dL) 1.74 2.4–4.5
24‐h urine calcium (mg/24 h) 244.8 90.0 <100 Low Ca diet <300 Normal diet
Alk phos (IU/L) 166 177 99 126 125 125 34–104
iPTH (pg/mL) 105 211 69.2 62 12.0–72.0
Calcium (mg/dL) 9.2 8.7 9.2 9.3 9.3 8.6–10.3
25OHD (ng/mL) 24 33 41 31 30–80
1,25(OH)2D (pg/mL) 12.0 55.6 19.9–79.3
FGF23 (mRU/mL) <50 90 Mayo ELISA <180
138 289 LabCorp ELISA 44–215
Pituitary hormones LH (mIU/mL): 2.2 ACTH (pg/mL): 24.5 TSH (mIU/mL): 2.6 Prolactin (ng/mL): 4.6 LH 1.6 FSH (mIU/mL): 1.7 LH: 1.2–8.6 FSH: 1.3–19.3 ACTH: 7.2–63.3 TSH: 0.3–4.5 Prolactin: 4.0–15.2
24‐h urine–free cortisol (μg/dL/24 h) 12.0 0–50.0
Testosterone Total (ng/dL) Free (pg/mL) Total 175 Free 4.4 Total 151 Free 6.6 Total: 249–836 Free: 6.8–21.5
SPEP No monoclonal gammopathy N/A
Genetic testing OI panel negative CTGT panel negative
Imaging studies
MRI L Foot: Transverse fracture second MT, marrow edema, also medial cuneiform Hip X‐rays: Stress fractures‐ RFN & Left subtrochanteric CT and MRI lower extr: fractures as above, and with benign appearing L suprapatellar soft tissue nodule
3‐phase
99
Tc‐MDP bone scan: Multiple stress fractures MRI Brain: normal pituitary
DEXA Spine T − 2.8 FN T − 1.9 PET‐CT: hypermetabolic L suprapatellar lesion MRI L knee: stable appearing L suprapatellar lesion
MRI L Knee: no evidence of soft tissue lesion recurrence
DEXA Spine T − 1.0 FN T − 1.4
Connective tissue gene tests abnormal mineralization disorder panel, next‐generation sequencing. All coding regions for genes on the panel were analyzed for variants using Illumina (San Diego, CA, USA) MiSeq next‐generation sequencers (ALPL, ANKH, CASR, CLCN5, CYP27B1, DMP1, ENPP1, FAH, FGF23, OCRL, PHEX, SLC34A1, SLC34A3, SLC9A3R1, VDR).
Abbreviations: 25OHD = calcidiol; 1,25(OH)2D = calcitriol; ACTH = adrenocorticotropic hormone; Alk phos = alkaline phosphatase; CT = computed tomography; CTGT = connective tissue gene test; DEXA = dual energy X‐ray absorptiometry; ELISA = enzyme‐linked immunosorbent assay; FSH = follicle‐stimulating hormone; iPTH = intact parathyroid hormone; LH = luteinizing hormone; MRI = magnetic resonance imaging; MT = metatarsal; OI panel = osteogenesis imperfecta panel from Invitae analyzed clinically important regions of each specified gene (COL1A1, COL1A2, CRTAP, P3H1); PRL = prolactin; SPEP = serum protein electrophoresis; TMP/GFR = tubular max reabsorption of phosphate.
Background
In the late 1950s the Swiss pediatric endocrinologist Andrea Prader was the first to identify a case of acquired hypophosphatemia caused by a ricketogenic substance [FGF23].(
1
,
2
,
3
) It would take more than 40 years to clone this humoral factor, or phosphatonin, causing renal phosphate wasting.(
4
) Studies of autosomal dominant hypophosphatemic rickets led to identifying FGF23 as the most common phosphatonin, crucial in both physiologic phosphate regulation and the driver of phosphate wasting in multiple diseases.(
4
,
5
,
6
)
Bone‐derived FGF23 is upregulated with increased serum inorganic phosphate (Pi) and downregulated in the setting of hypophosphatemia.(
7
) Interestingly, tight regulation of FGF23 degradation, rather than its synthesis, permits its secretion.(
8
) GALNT3 functions to O‐glycosylate FGF23, thus protecting FGF23 from degradation and permitting its release.(
9
) On the other hand, the absence of the zinc metallopeptidase phosphate‐regulating endopeptidase homolog, X‐linked (PHEX) lowers FGF23 via unclear mechanisms.(
10
) Intact FGF23, secreted by osteocytes and their precursors, binds with coreceptor α‐klotho to FGFR1 in the renal proximal tubule, reducing expression of the sodium‐phosphate cotransporters NaPi‐2a and NaPi‐2c, and ultimately increasing urinary phosphate excretion.(
11
) In addition to its effect on renal Pi handling, FGF23 suppresses renal 1‐α‐hydroxylase (CYP27B1), thereby lowering calcitriol synthesis; FGF23 also upregulates vitamin D 24‐hydroxylase (CYP24), inactivating calcitriol.(
9
,
11
) In addition to FGF23 and vitamin D, PTH is also an important phosphate regulator. PTH (via PTHR1) promotes phosphaturia by a mechanism similar to FGF23, however in contrast, upregulates CYP27B1 and suppresses CYP24.(
12
)
The presence of multiple fragility fractures in young adults merits consideration of secondary causes of bone loss. The differential diagnosis includes disorders of the collagen matrix such as osteogenesis imperfecta and disorders of calcium and vitamin D metabolism.(
13
) Hypophosphatemia suggests a genetic versus acquired cause of Pi loss.(
14
) Common acquired causes of low Pi include primary hyperparathyroidism, secondary hyperparathyroidism from vitamin D deficiency, and alcohol abuse.(
12
,
14
) Fanconi syndrome presents with glycosuria and aminoaciduria in addition to phosphaturia; it can be either inherited or secondary to medications or other illnesses, such as multiple myeloma.(
12
,
15
) Distinguishing whether hypophosphatemia is driven by renal phosphate wasting is a key part of diagnostic evaluation, and is done by calculating the tubular maximal reabsorption rate of phosphate to glomerular filtration (TmP/GFR).(
16
) Causes such as hyperparathyroidism and Fanconi syndrome with renally mediated Pi losses typically have low TmP/GFR values, whereas extrarenal causes such as excess phosphate binder intake and refeeding syndrome should have appropriately high TmP/GFR for the degree of hypophosphatemia.(
16
)
If investigations reveal renal‐mediated hypophosphatemia unexplained by the above causes, serum FGF23 is measured. High FGF23, or a level inappropriately normal for the degree of hypophosphatemia, might indicate a disorder of FGF23 excess. X‐linked hypophosphatemic rickets (PHEX) and autosomal dominant hypophosphatemic rickets (FGF23) are genetic disorders resulting in decreased FGF23 breakdown.(
12
) Of note, several patients with FGF23 mutations, especially women, may be normophosphatemic during childhood; thus testing for this mutation should be part of the workup for adult onset fragility fractures with hypophosphatemia.(
12
) Autosomal recessive hypophosphatemic rickets type 1 (DMP1) leads to increased transcription of FGF23.(
9
,
12
) McCune‐Albright syndrome (GNAS somatic mutation) may rarely cause FGF23 overexpression.(
12
) Additionally, ferric carboxymaltose administration can cause osteomalacia through an increase in FGF23.(
17
)
TIO is caused by overproduction of FGF23 by small, typically benign mesenchymal tumors, leading to fragility fractures and diffuse bone and muscle pain.(
18
) Laboratory findings are similar to those of the FGF23 excess syndromes described above, with hypophosphatemia, renal phosphate wasting, and low to inappropriately normal 1,25(OH)2D3 for the degree of hypophosphatemia, however, without a previous history of these lab abnormalities.(
19
) Serum calcium, 25OHD, and PTH levels are normal, though persistently low 1,25(OH)2D3 may lead to secondary hyperparathyroidism, with elevated ALP.(
19
)
The time from symptom onset to diagnosis is over 2.5 years in most cases of TIO, in part because of delays in initial testing for hypophosphatemia, but also because of difficulty in localizing tumors.(
19
) Functional imaging, which takes advantage of the high expression of somatostatin receptors in TIO, is recommended and uses 111In‐octreotide or 68Gallium tetraazacyclododecanetetraacetic acid–DPhe1‐Tyr3‐octreotate (68Ga‐DOTATATE) for tumor localization.(
11
) DOTATATE PET/CT likely has the greatest sensitivity and specificity for TIO, with octreotide scanning also being a sensitive imaging method based on the presence of somatostatin receptors in TIO.(
11
,
20
) However, 18FDG‐PET‐CT is useful if somatostatin‐based scans are negative.(
11
,
20
) In some cases, biopsy has been discouraged based on the possibility of tumor seeding, with venous sampling being an alternate option if further diagnostic clarification is needed.(
14
) Successful tumor resection typically results in skeletal healing and reversal of biochemical defects; excision with wide, tumor‐free margins is essential because of the risk of tumor recurrence.(
14
,
19
) Histopathology shows a mesenchymal tumor of mixed connective tissue variant (PMT‐CT).(
21
) Immunohistochemical staining or RT‐PCR‐based detection of FGF23 mRNA transcription is often used to demonstrate increased FGF23 expression.(
21
,
22
) In our patientʼs case, chromogenic in situ hybridization was used to support the diagnosis.
Discussion
This case serves as an example of the importance of considering TIO in the differential diagnosis of fragility fractures, particularly with the constellation of new‐onset persistent renal phosphate wasting in the absence of genetic causes of hypophosphatemic osteomalacia. The presence of FGF23 level in the normal range should be interpreted as inappropriately elevated and potentially suggestive of TIO, as physiologically FGF23 should be downregulated with hypophosphatemia.
Interestingly, our patient's serum FGF23 level was elevated only on recheck 5 months after his initial level. Although his tumor could have expressed higher amounts of FGF23 mRNA during this period, this case also brings into question the reproducibility of FGF23 level and sensitivity of commercially available serum assays. For example, in a study by Imel and colleagues, the test sensitivity of one C‐terminal FGF23 assay (Immutopics, Inc., San Clemente, CA, USA) was 73% in TIO; although this specific assay is different from that used for our patient, this suggests that C‐terminal assays might miss a fraction of TIO cases.(
23
) Imel and colleague's study also investigated the an intact FGF23 (iFGF23; Kainos Laboratories, Tokyo, Japan) assay and Immutopics intact assay (now discontinued), which had sensitivities of 86% and 23%, respectively.(
23
) Of note, Mayo Clinic Laboratories has recently started offering an iFGF23 assay.(
24
) Further research examining the sensitivities of currently available assays, including head‐to‐head comparisons of C‐terminal to iFGF23 assays, will be important for improving diagnostic accuracy in TIO. Alternatively, lowering the cutoff used for TIO diagnosis may help improve test sensitivity. For example, Proposals have been made for using iFGF23 values just above the population median as a threshold for ruling in TIO, rather than the upper limit of normal; it is possible that a similar principle may apply to C‐terminal assays.(
25
)
Alternate testing modalities are needed for cases not easily diagnosed via imaging and/or FGF23 measurement. Venous sampling measuring FGF23 may have clinical utility in verifying a suspicious mass on imaging as being a TIO locus, and systematic sampling may guide locations for further imaging in patients with unrevealing radiographic studies.(
26
,
27
) Of note, current studies of venous sampling have been conducted using iFGF23 measurements, with subjects usually having elevated levels.(
26
,
27
) It is difficult to say if any of these patients would have had a normal C‐terminal FGF23, similar to our patient, if checked. Whether venous sampling may be of clinical utility in patients with normal iFGF23 or C‐terminal FGF23 levels merits further study, as this may be a relevant method in cases such as ours.
In some TIO patients with normal FGF23 levels, one may consider hypophosphatemia driven by a different paraneoplastic phosphaturic hormone, or whether FGF23 secretion may be partially responsive to serum phosphate levels in some tumors.(
23
) For example, matrix extracellular phosphoglycoprotein, secreted frizzled protein 4, and FGF‐7 are all additional phosphatonins that have rarely been associated with TIO.(
12
,
28
)
Of note, this patient's family history of chondrosarcoma raises the question of a genetic predisposition to developing TIO tumors in patients with a family history of skeletal malignancy. For example, an FN1‐FGFR1 fusion gene has been identified in several TIO tumors; this gene has been hypothesized to cause tumorigenesis in TIO through FGF23 binding, leading to autocrine or paracrine activation of the receptor tyrosine kinase.(
14
,
29
) Interestingly, FGFR1 fusion genes have been identified as pathogenic in the 8p11 myeloproliferative syndrome, breast cancer, glioblastoma, and lung squamous cell carcinoma.(
29
,
30
) Additionally, similar microRNA profiles were recently noted in osteosarcomas and TIO; both show upregulation of the biomarker miR‐197 and downregulation of miR‐20b, miR‐144, and miR‐335.(
31
) Further genetic studies of TIO may improve our understanding of the disease and identify patients missed by currently available modalities.
Conclusion
This case illustrates a potential pitfall in the diagnosis of tumor‐induced osteomalacia (TIO), highlighting that a normal serum C‐terminal or intact FGF23 might not exclude the disorder in a patient with high clinical suspicion based on acquired hypophosphatemic osteomalacia. Rather, a normal C‐terminal or intact FGF23 must be interpreted as inappropriately high in the setting of hypophosphatemia and warrants a search for FGF23‐excess syndromes such as TIO.
Disclosures
All authors report that there are no relevant conflicts of interest, no relevant financial or nonfinancial relationships, no patents (whether planned, pending, or issued) broadly relevant to this work, or any other relationships/conditions/circumstances that present a potential conflict of interest.
AUTHOR CONTRIBUTIONS
Neeharika Nandam: Conceptualization; data curation; investigation; project administration; writing‐original draft; writing‐review and editing. Sadia Ejaz: Conceptualization; writing‐original draft; writing‐review and editing. William Ahrens: Data curation; resources; software; visualization; writing‐review and editing. Maya Styner: Conceptualization; data curation; investigation; project administration; writing‐original draft; writing‐review and editing.
Acknowledgments
This work was funded by grant no. R01AR073264 from the National Institute of Health (NIH)/National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) and grant NIH/NCATS/NCTraCS no. KL2TR002490. We would like to acknowledge and thank the NIH/NIAMS for their funding. We also thank the patient described in this report, and confirm that they provided consent for the publication of their case.
Authors' roles: Data collection: NN and MS. Photographing, formatting, and captioning of surgical pathology pictures: WA. Drafting manuscript: NN, SE, and MS. Revising manuscript content: NN, SE, and MS. Approving final version of manuscript: NN, SE, WA, and MS. | TESTOSTERONE | DrugsGivenReaction | CC BY | 33615107 | 18,700,332 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Steroid diabetes'. | Persumed sympathetic Ophthalmia after scleral buckling surgery: case report.
BACKGROUND
Scleral buckling (SB) is usually considered an extraocular operation premeditated to have a low risk of sympathetic ophthalmia (SO). Here we report a rare case of presumed SO in a young female patient following SB.
METHODS
A nineteen-year-old female patient was referred for visual loss in her left eye due to macula off inferior long-standing rhegmatogenous retinal detachment (RRD). The best corrected visual acuity (BCVA) was 20/400 in the left eye. SB with 360 degrees encircling band, an inferior segmental tire with one spot cryoretinopexy at the break site, and subretinal fluid drainage was performed. BCVA was improved to 20/80 and the retina was totally attached 1 week after the operation. The patient referred to the hospital 6 weeks later with severe visual loss in both eyes as counting finger 1 m. Patient examination indicated bilateral multifocal serous retinal detachment (SRD) and vitreous cells. The patient, diagnosed with SO, received intravenous corticosteroid pulse therapy and mycophenolate mofetil for treatment. The inflammation was controlled and SRD resolved after a 5-day intravenous treatment without being relapsed after 6 months. Consequently, BCVA became 20/20 and 20/50 in the right and left eye, respectively, after 6 months. The findings of systemic workup were negative for any extraocular disease or systemic involvement.
CONCLUSIONS
Since SB is a procedure without manipulating intraocular tissues, it is considered to impose a low risk for SO. This report presented SO occurrence after successful SB. Some factors may induce SO, including inciting the choroid and retinal pigment epithelium with cryoretinopexy or perforating for drainage.
Introduction
Sympathetic ophthalmia (SO) is a rare bilateral diffuse granulomatous panuveitis that may occur after surgery or trauma to one eye, as penetrating injury and exposure of the uvea [1]. The incidence of SO is reported ranging 0.01–0.5% after intraocular surgery [1–5]. Surgeries with manipulation and irritation of the choroid and retina are considered as risk factors [1]. The interval between the ocular injury and the onset of SO varies greatly, from a few days to decades, with most of the cases occurring within 3 months after the injury to the exciting eye and 90% during the first year [2–4]. The inciting ocular surgery varies, including cataract extraction, secondary intraocular lens placement, trabeculectomy, vitrectomy, cyclodestruction, iridectomy, and evisceration [1]. Recently, there has been an increasing trend of SO incidence after intraocular and vitreoretinal surgeries [6].
Scleral buckling (SB) is usually considered an extraocular operation, a privilege over vitrectomy, and SO is presumed to have a very low risk after SB. Here we report an unusual rare case of SO following successful SB surgery which was combined with subretinal fluid drainage (SRFD) and cryoretinopexy.
Case presentation
A nineteen-year-old female was referred for visual loss and superior visual field defect in her left eye (LE). Best corrected visual acuity (BCVA) was 20/20 and 20/400 in the right eye (RE) in the LE, respectively. The anterior segment examination was within normal limits except for the detection of Shaffer sign in the LE. The results of the fundus examination revealed macula off inferior long-standing rhegmatogenous retinal detachment (RRD), 3 h of proliferative vitreoretinopathy (PVR), retinal break, and lattice degeneration. The patient had no history of head or ocular trauma or any intraocular surgery. SB with 360 degrees encircling silicone band (silicone band type 240, FCI Inc., Paris, France) and inferior segmental silicone tire (asymmetrical silicone tire type 276, FCI Inc., Paris, France) with one spot cryoretinopexy at the break site, and SRFD due to chronicity of the RRD was performed. During this process, SRFD was not inadvertent. Scleral thinning was performed after passing the band and tire. Moreover, the needle of polyester spatula suture (Mersilene, Ethicon LLC, Johnson and Johnson Inc., USA) was used to drain the fluid after the cauterization of the choroid. BCVA was improved to 20/80 and the retina was totally attached 1 week after the operation. The patient was followed up receiving a topical antibiotic (Chlobiotic, Sina Darou, Tehran, Iran) and topical corticosteroid (Bethasonate, Sina Darou, Tehran, Iran) for 3 weeks.
The patient referred to the hospital with severe visual loss in both eyes 6 weeks later. On examination, BCVA of both eyes was counting finger at one meter and the anterior segment was within normal limits, except 1+ anterior chamber and anterior vitreous cells in both eyes. Bilateral multifocal serous retinal detachment (SRD) was obvious in funduscopy (Fig. 1a, b). The results of enhanced depth imaging optical coherence tomography (EDI-OCT) (Spectralis HRA +OCT, Heidelberg Engineering, Heidelberg, Germany) revealed multilobular SRD, septated subretinal spaces, hyperreflective dot reflexes in subretinal fluid, choroidal thickening, and retinal pigment epithelium undulation (Fig. 1c, d). Chorioscleral junction was not detected due to diffuse severe choroidal thickening. According to the results of examination and imaging, as well as the absence of any other ocular trauma history except for SB surgery, the diagnosis of SO was presumed incited by SB surgery. Therefore, the patient was admitted and received high-dose (1 g/day) intravenous methylprednisolone treatment for 5 days. This five-day pulse therapy led to the control of inflammation and the significant resolution of SRD (Fig. 1e, f). The patient underwent all systemic work-ups for common causes of choroiditis, including sarcoidosis, tuberculosis, syphilis, and autoimmunity markers were inconclusive. Moreover, familial, drug, and past medical history were unremarkable. After pulse therapy, oral prednisolone (50 mg/day) and mycophenolate mofetil (MMF) (2 g/day) were initiated. On the fourth day, fluorescein angiography showed no significant dye pooling except for mild leakage; also, it revealed mixed hypo- and hyper-fluorescent dots scattered at the posterior poles presumably due to choroidal hypoperfusion and abnormal leakage. Since indocyanine green angiography (ICGA) was not available at that time, it was not performed at the first presentation of SO. Prednisolone tapered rapidly due to the increased blood glucose, and subtenon triamcinolone acetonide (TriamHEXAL, Hexal AG, Holzkirchen, Germany) (40 mg/1 cc) was injected bilaterally. Induced diabetes was controlled with oral medication which was stopped after 1 month. Prednisolone was reached to 5 mg/d at the end of the second month with continuing MMF (2 g/d). The blood glucose was checked frequently, which was within normal limits during the follow-up and did not relapse during 6-months follow-ups. Following one-year treatment with MMF 2 g/d and prednisolone 5 mg/d, inflammation was reduced considerably and the retina was attached completely in both eyes. Final BCVA was obtained as 20/20 and 20/50 in the RE and LE, respectively. After 3 months of immunosuppressive treatment, ICGA disclosed only a few hypofluorescent dark dots in both eyes and mild background hyperflorescence at the posterior pole indicating a response to treatment with mild subclinical inflammation of choroidal stroma (Fig. 2).
Fig. 1 Fundus photography of the right (a) and the left (b) eye reveals bilateral disc swelling and multifocal serous retinal detachment at the posterior pole. Enhanced depth imaging optical coherent tomography (EDI-OCT) of the right (c) and the left (d) eye at the first presentation after the development of sympathetic ophthalmia (SO) discloses multi-lobular serous retinal detachment, septate subretinal spaces, hyperreflective dots in subretinal fluid, choroidal thickening, and undulation of the retinal pigment epithelium. The results of EDI-OCT of the right (e) and left (f) eye shows the significant response with resolution of serous retinal detachment and decreased choroidal thickening 5 days after pulse corticosteroid therapy
Fig. 2 Indocyanine green angiography of the right (a, b) and the left eye (d, e) at the third month disclosed only a few hypofluorescent dark dots (HDD) in both eyes and mild background hyperflorescence at the posterior pole indicating a response to treatment with mild subclinical inflammation of choroidal stroma. Enhanced depth imaging optical coherent tomography of the right (c) and left (f) eyes at 3 months follow-up showed complete response with resolution of serous retinal detachment and decreased choroidal thickening and inflammation
Discussion
Here, we report a rare case of SO following uncomplicated SB surgery accompanied by cryoretinopexy and SRFD. In this regard, it is recommended that SO be taken into consideration in any case of bilateral panuveitis associated with multiple SRD and a history of penetrating ocular surgery.
In several studies, the occurrence of SO has been reported after vitreoretinal surgery [2, 4–6]. It is postulated that trauma to the uveal tract in the context of inadvertent perforation, SRFD, or cryotherapy during SB surgery might be related to deliberate uveal antigens, melanin or outer photoreceptor antigens resulting to access to the lymphatic systems of the conjunctival tissue. This process may associated to exciting of delayed hypersensitivity reaction inside the eye [4–6]. The mechanism of hypersensitivity in the sympathizing eye may be due to the exposure of the uveal tissue to the conjunctival lymphatic system leading to a cell-mediated immune response [6]. This mechanism, owing to more uveal incarceration, can explain the relationship between an increase in the trend of transconjunctival sutureless vitrectomy application and a growth in the incidence of SO following vitreoretinal surgery [6]. In our case, SRFD seemingly increased the risk of uveal exposure to conjunctival lymphatic tissue. In a study conducted by Kilmartin et al., it was reported that RRD surgery was the most common procedure associated with the development of SO, with the risk of SO after vitrectomy being as twice as that of external scleral buckling, without any gender predilection [7].
The onset of SO symptoms after the operation usually occurs between 3 weeks and 6 months after surgery due to delayed hypersensitivity [8]. Regarding the subject in this study, SO was developed 6 weeks later. In a case series study carried out by Ozbek et al. [4], three cases of SO incidence occurred following SB; however, two patients had combined vitrectomy with SB. In the aforementioned research, SO occurred only in one case after encircling buckle combined with 360 indirect retinal photocoagulations and SRFD, in contrast to our case that had only one cryoretinopexy spot and one drainage site. In another similar case report by Parvaresh and Falavarjani, SO was found in a case with a history of SB revision after 4 years. In this case, the second surgery was combined with SRFD and cryoretinopexy [9]. Nonetheless, in our case, SO happened in the first operation without any surgical history.
In a recent study performed by Tyagi et al., the incidence of SO following vitreoretinal surgery was estimated at 0.038% of all vitrectomy cases, and vice versa, 9% of all cases of SO had vitreoretinal surgery [6]. In this research, 75% of cases underwent multiple ocular surgeries before the development of SO [6]. Furthermore, the most common anterior segment was non-granulomatous uveitis in 50% of subjects, in contrast to SRD occurring in 62.5% of cases [6]. In our case, it was found that anterior segment inflammation was less severe than the posterior segment chorioretinal findings.
Most of the cases presented in studies [4–9] had simultaneous SB and vitrectomy, previous trauma, or multiple surgeries. Nevertheless, the subject of our report had no extensive retinal or uveal tissue manipulation and no combined surgery or previous surgery, highlighting the importance of this report. One of the underlying reasons for this susceptibility might be related to the Asian ethnicity and higher prevalence of Vogt-Koyanagi-Harada (VKH) in this region.
One of the most important differential diagnoses of our case is related to VKH which is a common uveitis etiology with similar clinical and imaging findings with SO [1, 10]. Although sympathizing eye in SO presents clinically with nongranulomatous uveitis at first, it progresses to granulomatous uveitis afterward [8]. shows three successive stages: posterior uveitis, anterior segment involvement associated with posterior uveitis, and finally anterior granulomatous uveitis. Both anterior and posterior uveitis are present in SO patients within 2 weeks of disease onset [8]. Generally, the main differentiating clue between SO and VKH is the history of prior surgery or trauma in SO. Considering this, in our case, clinical features were more similar to SO than to VKH, as our patient had no systemic sign or symptom attributed to VKH or other systemic diseases causing choroiditis.
The results of SO imaging, based on FAG, revealed multiple hyperfluorescent pinpoints leakages associated with late pooling resembling VKH and hypofluorescent foci during the early phase of angiography. Moreover, the late phase of FAG showed hyperfluorescence similar to acute posterior multifocal placoid pigment epitheliopathy [10]. In our case, apparently due to the performance of FAG 4 days after the steroid therapy, hyperfluorscence was less prominent than hypofluorescence that was compatible with the location of granuloma and cellular infiltration. The most common features of ICGA imaging are multiple hypocyanescent spots. In the acute phase of SO, EDI-OCT discloses multiple SRD associated with hyperreflective septa, massive choroidal thickening, and loss of normal choroidal vascular architectures, as well as irregular photoreceptor outer segments similar to what was observed in the acute phase of VKH. The visual outcome is worse in SO as compared with VKH disease [8]. Moreover, BCVA was improved in our case due to early diagnosis and prompt, aggressive, and adequate treatment.
In conclusion, the diagnosis of sympathetic ophthalmia should be taken into account in any case of bilateral uveitis or bilateral SRD following scleral buckling with uveal tract violation, such as cryopexy or SRFD.
Abbreviations
BCVABest corrected visual acuity
EDI-OCTEnhanced depth imaging optical coherent tomography
OCTOptical coherent tomography
FAGFluorescein angiography
ICGAIndocyanine green angiography
RERight eye
LELeft eye
SRDSerous retinal detachment
RRDRhegmatogenous retinal detachment
RPERetinal pigment epithelium
SBScleral buckling
SRFDSubretinal fluid drainage
SOSympathetic ophthalmia
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
The authors would like to express their gratitude to Zahra Emaverdian MSc., Sepideh Nazari Noghabi MSc., Roghaye Kahani BSc., and Roya Gholamzadeh BSc. at Khatam-al-Anbia Eye Hospital, Mashhad, Iran. Moreover, the researchers appreciate the kind supports of Captain Mohammad Mahdi Sarshar.
Authors’ contributions
All the authors contributed significantly to this research and agreed to be accountable for all aspects of the work. SMH took part in patient’s participating in clinical analysis, and interpretation of imaging, and revising the draft. NS, MG, MAz helped to gather the patient’s evaluations and draft the manuscript. MAb participated in the acquisition of clinical data, clinical analysis and interpretation, and revising and finalizing the manuscript. All authors read and approved the final manuscript.
Funding
The authors received no funding. It is the authors’ own work, not funded by government or academicals institutes.
Availability of data and materials
The datasets used and/or analyzed during the current study can be provided by the corresponding author on reasonable request.
Ethics approval and consent to participate
Not Applicable.
Consent for publication
A consent form was obtained from the patient for imaging, data publication, and identifying clinical details.
Competing interests
The authors declare that they have no competing interests. | BETAMETHASONE VALERATE, CHLORAMPHENICOL, METHYLPREDNISOLONE, MYCOPHENOLATE MOFETIL, PREDNISOLONE, TRIAMCINOLONE | DrugsGivenReaction | CC BY | 33615391 | 20,222,014 | 2021-02-22 |
What was the administration route of drug 'BETAMETHASONE VALERATE'? | Persumed sympathetic Ophthalmia after scleral buckling surgery: case report.
BACKGROUND
Scleral buckling (SB) is usually considered an extraocular operation premeditated to have a low risk of sympathetic ophthalmia (SO). Here we report a rare case of presumed SO in a young female patient following SB.
METHODS
A nineteen-year-old female patient was referred for visual loss in her left eye due to macula off inferior long-standing rhegmatogenous retinal detachment (RRD). The best corrected visual acuity (BCVA) was 20/400 in the left eye. SB with 360 degrees encircling band, an inferior segmental tire with one spot cryoretinopexy at the break site, and subretinal fluid drainage was performed. BCVA was improved to 20/80 and the retina was totally attached 1 week after the operation. The patient referred to the hospital 6 weeks later with severe visual loss in both eyes as counting finger 1 m. Patient examination indicated bilateral multifocal serous retinal detachment (SRD) and vitreous cells. The patient, diagnosed with SO, received intravenous corticosteroid pulse therapy and mycophenolate mofetil for treatment. The inflammation was controlled and SRD resolved after a 5-day intravenous treatment without being relapsed after 6 months. Consequently, BCVA became 20/20 and 20/50 in the right and left eye, respectively, after 6 months. The findings of systemic workup were negative for any extraocular disease or systemic involvement.
CONCLUSIONS
Since SB is a procedure without manipulating intraocular tissues, it is considered to impose a low risk for SO. This report presented SO occurrence after successful SB. Some factors may induce SO, including inciting the choroid and retinal pigment epithelium with cryoretinopexy or perforating for drainage.
Introduction
Sympathetic ophthalmia (SO) is a rare bilateral diffuse granulomatous panuveitis that may occur after surgery or trauma to one eye, as penetrating injury and exposure of the uvea [1]. The incidence of SO is reported ranging 0.01–0.5% after intraocular surgery [1–5]. Surgeries with manipulation and irritation of the choroid and retina are considered as risk factors [1]. The interval between the ocular injury and the onset of SO varies greatly, from a few days to decades, with most of the cases occurring within 3 months after the injury to the exciting eye and 90% during the first year [2–4]. The inciting ocular surgery varies, including cataract extraction, secondary intraocular lens placement, trabeculectomy, vitrectomy, cyclodestruction, iridectomy, and evisceration [1]. Recently, there has been an increasing trend of SO incidence after intraocular and vitreoretinal surgeries [6].
Scleral buckling (SB) is usually considered an extraocular operation, a privilege over vitrectomy, and SO is presumed to have a very low risk after SB. Here we report an unusual rare case of SO following successful SB surgery which was combined with subretinal fluid drainage (SRFD) and cryoretinopexy.
Case presentation
A nineteen-year-old female was referred for visual loss and superior visual field defect in her left eye (LE). Best corrected visual acuity (BCVA) was 20/20 and 20/400 in the right eye (RE) in the LE, respectively. The anterior segment examination was within normal limits except for the detection of Shaffer sign in the LE. The results of the fundus examination revealed macula off inferior long-standing rhegmatogenous retinal detachment (RRD), 3 h of proliferative vitreoretinopathy (PVR), retinal break, and lattice degeneration. The patient had no history of head or ocular trauma or any intraocular surgery. SB with 360 degrees encircling silicone band (silicone band type 240, FCI Inc., Paris, France) and inferior segmental silicone tire (asymmetrical silicone tire type 276, FCI Inc., Paris, France) with one spot cryoretinopexy at the break site, and SRFD due to chronicity of the RRD was performed. During this process, SRFD was not inadvertent. Scleral thinning was performed after passing the band and tire. Moreover, the needle of polyester spatula suture (Mersilene, Ethicon LLC, Johnson and Johnson Inc., USA) was used to drain the fluid after the cauterization of the choroid. BCVA was improved to 20/80 and the retina was totally attached 1 week after the operation. The patient was followed up receiving a topical antibiotic (Chlobiotic, Sina Darou, Tehran, Iran) and topical corticosteroid (Bethasonate, Sina Darou, Tehran, Iran) for 3 weeks.
The patient referred to the hospital with severe visual loss in both eyes 6 weeks later. On examination, BCVA of both eyes was counting finger at one meter and the anterior segment was within normal limits, except 1+ anterior chamber and anterior vitreous cells in both eyes. Bilateral multifocal serous retinal detachment (SRD) was obvious in funduscopy (Fig. 1a, b). The results of enhanced depth imaging optical coherence tomography (EDI-OCT) (Spectralis HRA +OCT, Heidelberg Engineering, Heidelberg, Germany) revealed multilobular SRD, septated subretinal spaces, hyperreflective dot reflexes in subretinal fluid, choroidal thickening, and retinal pigment epithelium undulation (Fig. 1c, d). Chorioscleral junction was not detected due to diffuse severe choroidal thickening. According to the results of examination and imaging, as well as the absence of any other ocular trauma history except for SB surgery, the diagnosis of SO was presumed incited by SB surgery. Therefore, the patient was admitted and received high-dose (1 g/day) intravenous methylprednisolone treatment for 5 days. This five-day pulse therapy led to the control of inflammation and the significant resolution of SRD (Fig. 1e, f). The patient underwent all systemic work-ups for common causes of choroiditis, including sarcoidosis, tuberculosis, syphilis, and autoimmunity markers were inconclusive. Moreover, familial, drug, and past medical history were unremarkable. After pulse therapy, oral prednisolone (50 mg/day) and mycophenolate mofetil (MMF) (2 g/day) were initiated. On the fourth day, fluorescein angiography showed no significant dye pooling except for mild leakage; also, it revealed mixed hypo- and hyper-fluorescent dots scattered at the posterior poles presumably due to choroidal hypoperfusion and abnormal leakage. Since indocyanine green angiography (ICGA) was not available at that time, it was not performed at the first presentation of SO. Prednisolone tapered rapidly due to the increased blood glucose, and subtenon triamcinolone acetonide (TriamHEXAL, Hexal AG, Holzkirchen, Germany) (40 mg/1 cc) was injected bilaterally. Induced diabetes was controlled with oral medication which was stopped after 1 month. Prednisolone was reached to 5 mg/d at the end of the second month with continuing MMF (2 g/d). The blood glucose was checked frequently, which was within normal limits during the follow-up and did not relapse during 6-months follow-ups. Following one-year treatment with MMF 2 g/d and prednisolone 5 mg/d, inflammation was reduced considerably and the retina was attached completely in both eyes. Final BCVA was obtained as 20/20 and 20/50 in the RE and LE, respectively. After 3 months of immunosuppressive treatment, ICGA disclosed only a few hypofluorescent dark dots in both eyes and mild background hyperflorescence at the posterior pole indicating a response to treatment with mild subclinical inflammation of choroidal stroma (Fig. 2).
Fig. 1 Fundus photography of the right (a) and the left (b) eye reveals bilateral disc swelling and multifocal serous retinal detachment at the posterior pole. Enhanced depth imaging optical coherent tomography (EDI-OCT) of the right (c) and the left (d) eye at the first presentation after the development of sympathetic ophthalmia (SO) discloses multi-lobular serous retinal detachment, septate subretinal spaces, hyperreflective dots in subretinal fluid, choroidal thickening, and undulation of the retinal pigment epithelium. The results of EDI-OCT of the right (e) and left (f) eye shows the significant response with resolution of serous retinal detachment and decreased choroidal thickening 5 days after pulse corticosteroid therapy
Fig. 2 Indocyanine green angiography of the right (a, b) and the left eye (d, e) at the third month disclosed only a few hypofluorescent dark dots (HDD) in both eyes and mild background hyperflorescence at the posterior pole indicating a response to treatment with mild subclinical inflammation of choroidal stroma. Enhanced depth imaging optical coherent tomography of the right (c) and left (f) eyes at 3 months follow-up showed complete response with resolution of serous retinal detachment and decreased choroidal thickening and inflammation
Discussion
Here, we report a rare case of SO following uncomplicated SB surgery accompanied by cryoretinopexy and SRFD. In this regard, it is recommended that SO be taken into consideration in any case of bilateral panuveitis associated with multiple SRD and a history of penetrating ocular surgery.
In several studies, the occurrence of SO has been reported after vitreoretinal surgery [2, 4–6]. It is postulated that trauma to the uveal tract in the context of inadvertent perforation, SRFD, or cryotherapy during SB surgery might be related to deliberate uveal antigens, melanin or outer photoreceptor antigens resulting to access to the lymphatic systems of the conjunctival tissue. This process may associated to exciting of delayed hypersensitivity reaction inside the eye [4–6]. The mechanism of hypersensitivity in the sympathizing eye may be due to the exposure of the uveal tissue to the conjunctival lymphatic system leading to a cell-mediated immune response [6]. This mechanism, owing to more uveal incarceration, can explain the relationship between an increase in the trend of transconjunctival sutureless vitrectomy application and a growth in the incidence of SO following vitreoretinal surgery [6]. In our case, SRFD seemingly increased the risk of uveal exposure to conjunctival lymphatic tissue. In a study conducted by Kilmartin et al., it was reported that RRD surgery was the most common procedure associated with the development of SO, with the risk of SO after vitrectomy being as twice as that of external scleral buckling, without any gender predilection [7].
The onset of SO symptoms after the operation usually occurs between 3 weeks and 6 months after surgery due to delayed hypersensitivity [8]. Regarding the subject in this study, SO was developed 6 weeks later. In a case series study carried out by Ozbek et al. [4], three cases of SO incidence occurred following SB; however, two patients had combined vitrectomy with SB. In the aforementioned research, SO occurred only in one case after encircling buckle combined with 360 indirect retinal photocoagulations and SRFD, in contrast to our case that had only one cryoretinopexy spot and one drainage site. In another similar case report by Parvaresh and Falavarjani, SO was found in a case with a history of SB revision after 4 years. In this case, the second surgery was combined with SRFD and cryoretinopexy [9]. Nonetheless, in our case, SO happened in the first operation without any surgical history.
In a recent study performed by Tyagi et al., the incidence of SO following vitreoretinal surgery was estimated at 0.038% of all vitrectomy cases, and vice versa, 9% of all cases of SO had vitreoretinal surgery [6]. In this research, 75% of cases underwent multiple ocular surgeries before the development of SO [6]. Furthermore, the most common anterior segment was non-granulomatous uveitis in 50% of subjects, in contrast to SRD occurring in 62.5% of cases [6]. In our case, it was found that anterior segment inflammation was less severe than the posterior segment chorioretinal findings.
Most of the cases presented in studies [4–9] had simultaneous SB and vitrectomy, previous trauma, or multiple surgeries. Nevertheless, the subject of our report had no extensive retinal or uveal tissue manipulation and no combined surgery or previous surgery, highlighting the importance of this report. One of the underlying reasons for this susceptibility might be related to the Asian ethnicity and higher prevalence of Vogt-Koyanagi-Harada (VKH) in this region.
One of the most important differential diagnoses of our case is related to VKH which is a common uveitis etiology with similar clinical and imaging findings with SO [1, 10]. Although sympathizing eye in SO presents clinically with nongranulomatous uveitis at first, it progresses to granulomatous uveitis afterward [8]. shows three successive stages: posterior uveitis, anterior segment involvement associated with posterior uveitis, and finally anterior granulomatous uveitis. Both anterior and posterior uveitis are present in SO patients within 2 weeks of disease onset [8]. Generally, the main differentiating clue between SO and VKH is the history of prior surgery or trauma in SO. Considering this, in our case, clinical features were more similar to SO than to VKH, as our patient had no systemic sign or symptom attributed to VKH or other systemic diseases causing choroiditis.
The results of SO imaging, based on FAG, revealed multiple hyperfluorescent pinpoints leakages associated with late pooling resembling VKH and hypofluorescent foci during the early phase of angiography. Moreover, the late phase of FAG showed hyperfluorescence similar to acute posterior multifocal placoid pigment epitheliopathy [10]. In our case, apparently due to the performance of FAG 4 days after the steroid therapy, hyperfluorscence was less prominent than hypofluorescence that was compatible with the location of granuloma and cellular infiltration. The most common features of ICGA imaging are multiple hypocyanescent spots. In the acute phase of SO, EDI-OCT discloses multiple SRD associated with hyperreflective septa, massive choroidal thickening, and loss of normal choroidal vascular architectures, as well as irregular photoreceptor outer segments similar to what was observed in the acute phase of VKH. The visual outcome is worse in SO as compared with VKH disease [8]. Moreover, BCVA was improved in our case due to early diagnosis and prompt, aggressive, and adequate treatment.
In conclusion, the diagnosis of sympathetic ophthalmia should be taken into account in any case of bilateral uveitis or bilateral SRD following scleral buckling with uveal tract violation, such as cryopexy or SRFD.
Abbreviations
BCVABest corrected visual acuity
EDI-OCTEnhanced depth imaging optical coherent tomography
OCTOptical coherent tomography
FAGFluorescein angiography
ICGAIndocyanine green angiography
RERight eye
LELeft eye
SRDSerous retinal detachment
RRDRhegmatogenous retinal detachment
RPERetinal pigment epithelium
SBScleral buckling
SRFDSubretinal fluid drainage
SOSympathetic ophthalmia
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
The authors would like to express their gratitude to Zahra Emaverdian MSc., Sepideh Nazari Noghabi MSc., Roghaye Kahani BSc., and Roya Gholamzadeh BSc. at Khatam-al-Anbia Eye Hospital, Mashhad, Iran. Moreover, the researchers appreciate the kind supports of Captain Mohammad Mahdi Sarshar.
Authors’ contributions
All the authors contributed significantly to this research and agreed to be accountable for all aspects of the work. SMH took part in patient’s participating in clinical analysis, and interpretation of imaging, and revising the draft. NS, MG, MAz helped to gather the patient’s evaluations and draft the manuscript. MAb participated in the acquisition of clinical data, clinical analysis and interpretation, and revising and finalizing the manuscript. All authors read and approved the final manuscript.
Funding
The authors received no funding. It is the authors’ own work, not funded by government or academicals institutes.
Availability of data and materials
The datasets used and/or analyzed during the current study can be provided by the corresponding author on reasonable request.
Ethics approval and consent to participate
Not Applicable.
Consent for publication
A consent form was obtained from the patient for imaging, data publication, and identifying clinical details.
Competing interests
The authors declare that they have no competing interests. | Topical | DrugAdministrationRoute | CC BY | 33615391 | 20,222,014 | 2021-02-22 |
What was the administration route of drug 'CHLORAMPHENICOL'? | Persumed sympathetic Ophthalmia after scleral buckling surgery: case report.
BACKGROUND
Scleral buckling (SB) is usually considered an extraocular operation premeditated to have a low risk of sympathetic ophthalmia (SO). Here we report a rare case of presumed SO in a young female patient following SB.
METHODS
A nineteen-year-old female patient was referred for visual loss in her left eye due to macula off inferior long-standing rhegmatogenous retinal detachment (RRD). The best corrected visual acuity (BCVA) was 20/400 in the left eye. SB with 360 degrees encircling band, an inferior segmental tire with one spot cryoretinopexy at the break site, and subretinal fluid drainage was performed. BCVA was improved to 20/80 and the retina was totally attached 1 week after the operation. The patient referred to the hospital 6 weeks later with severe visual loss in both eyes as counting finger 1 m. Patient examination indicated bilateral multifocal serous retinal detachment (SRD) and vitreous cells. The patient, diagnosed with SO, received intravenous corticosteroid pulse therapy and mycophenolate mofetil for treatment. The inflammation was controlled and SRD resolved after a 5-day intravenous treatment without being relapsed after 6 months. Consequently, BCVA became 20/20 and 20/50 in the right and left eye, respectively, after 6 months. The findings of systemic workup were negative for any extraocular disease or systemic involvement.
CONCLUSIONS
Since SB is a procedure without manipulating intraocular tissues, it is considered to impose a low risk for SO. This report presented SO occurrence after successful SB. Some factors may induce SO, including inciting the choroid and retinal pigment epithelium with cryoretinopexy or perforating for drainage.
Introduction
Sympathetic ophthalmia (SO) is a rare bilateral diffuse granulomatous panuveitis that may occur after surgery or trauma to one eye, as penetrating injury and exposure of the uvea [1]. The incidence of SO is reported ranging 0.01–0.5% after intraocular surgery [1–5]. Surgeries with manipulation and irritation of the choroid and retina are considered as risk factors [1]. The interval between the ocular injury and the onset of SO varies greatly, from a few days to decades, with most of the cases occurring within 3 months after the injury to the exciting eye and 90% during the first year [2–4]. The inciting ocular surgery varies, including cataract extraction, secondary intraocular lens placement, trabeculectomy, vitrectomy, cyclodestruction, iridectomy, and evisceration [1]. Recently, there has been an increasing trend of SO incidence after intraocular and vitreoretinal surgeries [6].
Scleral buckling (SB) is usually considered an extraocular operation, a privilege over vitrectomy, and SO is presumed to have a very low risk after SB. Here we report an unusual rare case of SO following successful SB surgery which was combined with subretinal fluid drainage (SRFD) and cryoretinopexy.
Case presentation
A nineteen-year-old female was referred for visual loss and superior visual field defect in her left eye (LE). Best corrected visual acuity (BCVA) was 20/20 and 20/400 in the right eye (RE) in the LE, respectively. The anterior segment examination was within normal limits except for the detection of Shaffer sign in the LE. The results of the fundus examination revealed macula off inferior long-standing rhegmatogenous retinal detachment (RRD), 3 h of proliferative vitreoretinopathy (PVR), retinal break, and lattice degeneration. The patient had no history of head or ocular trauma or any intraocular surgery. SB with 360 degrees encircling silicone band (silicone band type 240, FCI Inc., Paris, France) and inferior segmental silicone tire (asymmetrical silicone tire type 276, FCI Inc., Paris, France) with one spot cryoretinopexy at the break site, and SRFD due to chronicity of the RRD was performed. During this process, SRFD was not inadvertent. Scleral thinning was performed after passing the band and tire. Moreover, the needle of polyester spatula suture (Mersilene, Ethicon LLC, Johnson and Johnson Inc., USA) was used to drain the fluid after the cauterization of the choroid. BCVA was improved to 20/80 and the retina was totally attached 1 week after the operation. The patient was followed up receiving a topical antibiotic (Chlobiotic, Sina Darou, Tehran, Iran) and topical corticosteroid (Bethasonate, Sina Darou, Tehran, Iran) for 3 weeks.
The patient referred to the hospital with severe visual loss in both eyes 6 weeks later. On examination, BCVA of both eyes was counting finger at one meter and the anterior segment was within normal limits, except 1+ anterior chamber and anterior vitreous cells in both eyes. Bilateral multifocal serous retinal detachment (SRD) was obvious in funduscopy (Fig. 1a, b). The results of enhanced depth imaging optical coherence tomography (EDI-OCT) (Spectralis HRA +OCT, Heidelberg Engineering, Heidelberg, Germany) revealed multilobular SRD, septated subretinal spaces, hyperreflective dot reflexes in subretinal fluid, choroidal thickening, and retinal pigment epithelium undulation (Fig. 1c, d). Chorioscleral junction was not detected due to diffuse severe choroidal thickening. According to the results of examination and imaging, as well as the absence of any other ocular trauma history except for SB surgery, the diagnosis of SO was presumed incited by SB surgery. Therefore, the patient was admitted and received high-dose (1 g/day) intravenous methylprednisolone treatment for 5 days. This five-day pulse therapy led to the control of inflammation and the significant resolution of SRD (Fig. 1e, f). The patient underwent all systemic work-ups for common causes of choroiditis, including sarcoidosis, tuberculosis, syphilis, and autoimmunity markers were inconclusive. Moreover, familial, drug, and past medical history were unremarkable. After pulse therapy, oral prednisolone (50 mg/day) and mycophenolate mofetil (MMF) (2 g/day) were initiated. On the fourth day, fluorescein angiography showed no significant dye pooling except for mild leakage; also, it revealed mixed hypo- and hyper-fluorescent dots scattered at the posterior poles presumably due to choroidal hypoperfusion and abnormal leakage. Since indocyanine green angiography (ICGA) was not available at that time, it was not performed at the first presentation of SO. Prednisolone tapered rapidly due to the increased blood glucose, and subtenon triamcinolone acetonide (TriamHEXAL, Hexal AG, Holzkirchen, Germany) (40 mg/1 cc) was injected bilaterally. Induced diabetes was controlled with oral medication which was stopped after 1 month. Prednisolone was reached to 5 mg/d at the end of the second month with continuing MMF (2 g/d). The blood glucose was checked frequently, which was within normal limits during the follow-up and did not relapse during 6-months follow-ups. Following one-year treatment with MMF 2 g/d and prednisolone 5 mg/d, inflammation was reduced considerably and the retina was attached completely in both eyes. Final BCVA was obtained as 20/20 and 20/50 in the RE and LE, respectively. After 3 months of immunosuppressive treatment, ICGA disclosed only a few hypofluorescent dark dots in both eyes and mild background hyperflorescence at the posterior pole indicating a response to treatment with mild subclinical inflammation of choroidal stroma (Fig. 2).
Fig. 1 Fundus photography of the right (a) and the left (b) eye reveals bilateral disc swelling and multifocal serous retinal detachment at the posterior pole. Enhanced depth imaging optical coherent tomography (EDI-OCT) of the right (c) and the left (d) eye at the first presentation after the development of sympathetic ophthalmia (SO) discloses multi-lobular serous retinal detachment, septate subretinal spaces, hyperreflective dots in subretinal fluid, choroidal thickening, and undulation of the retinal pigment epithelium. The results of EDI-OCT of the right (e) and left (f) eye shows the significant response with resolution of serous retinal detachment and decreased choroidal thickening 5 days after pulse corticosteroid therapy
Fig. 2 Indocyanine green angiography of the right (a, b) and the left eye (d, e) at the third month disclosed only a few hypofluorescent dark dots (HDD) in both eyes and mild background hyperflorescence at the posterior pole indicating a response to treatment with mild subclinical inflammation of choroidal stroma. Enhanced depth imaging optical coherent tomography of the right (c) and left (f) eyes at 3 months follow-up showed complete response with resolution of serous retinal detachment and decreased choroidal thickening and inflammation
Discussion
Here, we report a rare case of SO following uncomplicated SB surgery accompanied by cryoretinopexy and SRFD. In this regard, it is recommended that SO be taken into consideration in any case of bilateral panuveitis associated with multiple SRD and a history of penetrating ocular surgery.
In several studies, the occurrence of SO has been reported after vitreoretinal surgery [2, 4–6]. It is postulated that trauma to the uveal tract in the context of inadvertent perforation, SRFD, or cryotherapy during SB surgery might be related to deliberate uveal antigens, melanin or outer photoreceptor antigens resulting to access to the lymphatic systems of the conjunctival tissue. This process may associated to exciting of delayed hypersensitivity reaction inside the eye [4–6]. The mechanism of hypersensitivity in the sympathizing eye may be due to the exposure of the uveal tissue to the conjunctival lymphatic system leading to a cell-mediated immune response [6]. This mechanism, owing to more uveal incarceration, can explain the relationship between an increase in the trend of transconjunctival sutureless vitrectomy application and a growth in the incidence of SO following vitreoretinal surgery [6]. In our case, SRFD seemingly increased the risk of uveal exposure to conjunctival lymphatic tissue. In a study conducted by Kilmartin et al., it was reported that RRD surgery was the most common procedure associated with the development of SO, with the risk of SO after vitrectomy being as twice as that of external scleral buckling, without any gender predilection [7].
The onset of SO symptoms after the operation usually occurs between 3 weeks and 6 months after surgery due to delayed hypersensitivity [8]. Regarding the subject in this study, SO was developed 6 weeks later. In a case series study carried out by Ozbek et al. [4], three cases of SO incidence occurred following SB; however, two patients had combined vitrectomy with SB. In the aforementioned research, SO occurred only in one case after encircling buckle combined with 360 indirect retinal photocoagulations and SRFD, in contrast to our case that had only one cryoretinopexy spot and one drainage site. In another similar case report by Parvaresh and Falavarjani, SO was found in a case with a history of SB revision after 4 years. In this case, the second surgery was combined with SRFD and cryoretinopexy [9]. Nonetheless, in our case, SO happened in the first operation without any surgical history.
In a recent study performed by Tyagi et al., the incidence of SO following vitreoretinal surgery was estimated at 0.038% of all vitrectomy cases, and vice versa, 9% of all cases of SO had vitreoretinal surgery [6]. In this research, 75% of cases underwent multiple ocular surgeries before the development of SO [6]. Furthermore, the most common anterior segment was non-granulomatous uveitis in 50% of subjects, in contrast to SRD occurring in 62.5% of cases [6]. In our case, it was found that anterior segment inflammation was less severe than the posterior segment chorioretinal findings.
Most of the cases presented in studies [4–9] had simultaneous SB and vitrectomy, previous trauma, or multiple surgeries. Nevertheless, the subject of our report had no extensive retinal or uveal tissue manipulation and no combined surgery or previous surgery, highlighting the importance of this report. One of the underlying reasons for this susceptibility might be related to the Asian ethnicity and higher prevalence of Vogt-Koyanagi-Harada (VKH) in this region.
One of the most important differential diagnoses of our case is related to VKH which is a common uveitis etiology with similar clinical and imaging findings with SO [1, 10]. Although sympathizing eye in SO presents clinically with nongranulomatous uveitis at first, it progresses to granulomatous uveitis afterward [8]. shows three successive stages: posterior uveitis, anterior segment involvement associated with posterior uveitis, and finally anterior granulomatous uveitis. Both anterior and posterior uveitis are present in SO patients within 2 weeks of disease onset [8]. Generally, the main differentiating clue between SO and VKH is the history of prior surgery or trauma in SO. Considering this, in our case, clinical features were more similar to SO than to VKH, as our patient had no systemic sign or symptom attributed to VKH or other systemic diseases causing choroiditis.
The results of SO imaging, based on FAG, revealed multiple hyperfluorescent pinpoints leakages associated with late pooling resembling VKH and hypofluorescent foci during the early phase of angiography. Moreover, the late phase of FAG showed hyperfluorescence similar to acute posterior multifocal placoid pigment epitheliopathy [10]. In our case, apparently due to the performance of FAG 4 days after the steroid therapy, hyperfluorscence was less prominent than hypofluorescence that was compatible with the location of granuloma and cellular infiltration. The most common features of ICGA imaging are multiple hypocyanescent spots. In the acute phase of SO, EDI-OCT discloses multiple SRD associated with hyperreflective septa, massive choroidal thickening, and loss of normal choroidal vascular architectures, as well as irregular photoreceptor outer segments similar to what was observed in the acute phase of VKH. The visual outcome is worse in SO as compared with VKH disease [8]. Moreover, BCVA was improved in our case due to early diagnosis and prompt, aggressive, and adequate treatment.
In conclusion, the diagnosis of sympathetic ophthalmia should be taken into account in any case of bilateral uveitis or bilateral SRD following scleral buckling with uveal tract violation, such as cryopexy or SRFD.
Abbreviations
BCVABest corrected visual acuity
EDI-OCTEnhanced depth imaging optical coherent tomography
OCTOptical coherent tomography
FAGFluorescein angiography
ICGAIndocyanine green angiography
RERight eye
LELeft eye
SRDSerous retinal detachment
RRDRhegmatogenous retinal detachment
RPERetinal pigment epithelium
SBScleral buckling
SRFDSubretinal fluid drainage
SOSympathetic ophthalmia
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
The authors would like to express their gratitude to Zahra Emaverdian MSc., Sepideh Nazari Noghabi MSc., Roghaye Kahani BSc., and Roya Gholamzadeh BSc. at Khatam-al-Anbia Eye Hospital, Mashhad, Iran. Moreover, the researchers appreciate the kind supports of Captain Mohammad Mahdi Sarshar.
Authors’ contributions
All the authors contributed significantly to this research and agreed to be accountable for all aspects of the work. SMH took part in patient’s participating in clinical analysis, and interpretation of imaging, and revising the draft. NS, MG, MAz helped to gather the patient’s evaluations and draft the manuscript. MAb participated in the acquisition of clinical data, clinical analysis and interpretation, and revising and finalizing the manuscript. All authors read and approved the final manuscript.
Funding
The authors received no funding. It is the authors’ own work, not funded by government or academicals institutes.
Availability of data and materials
The datasets used and/or analyzed during the current study can be provided by the corresponding author on reasonable request.
Ethics approval and consent to participate
Not Applicable.
Consent for publication
A consent form was obtained from the patient for imaging, data publication, and identifying clinical details.
Competing interests
The authors declare that they have no competing interests. | Topical | DrugAdministrationRoute | CC BY | 33615391 | 20,222,014 | 2021-02-22 |
What was the administration route of drug 'METHYLPREDNISOLONE'? | Persumed sympathetic Ophthalmia after scleral buckling surgery: case report.
BACKGROUND
Scleral buckling (SB) is usually considered an extraocular operation premeditated to have a low risk of sympathetic ophthalmia (SO). Here we report a rare case of presumed SO in a young female patient following SB.
METHODS
A nineteen-year-old female patient was referred for visual loss in her left eye due to macula off inferior long-standing rhegmatogenous retinal detachment (RRD). The best corrected visual acuity (BCVA) was 20/400 in the left eye. SB with 360 degrees encircling band, an inferior segmental tire with one spot cryoretinopexy at the break site, and subretinal fluid drainage was performed. BCVA was improved to 20/80 and the retina was totally attached 1 week after the operation. The patient referred to the hospital 6 weeks later with severe visual loss in both eyes as counting finger 1 m. Patient examination indicated bilateral multifocal serous retinal detachment (SRD) and vitreous cells. The patient, diagnosed with SO, received intravenous corticosteroid pulse therapy and mycophenolate mofetil for treatment. The inflammation was controlled and SRD resolved after a 5-day intravenous treatment without being relapsed after 6 months. Consequently, BCVA became 20/20 and 20/50 in the right and left eye, respectively, after 6 months. The findings of systemic workup were negative for any extraocular disease or systemic involvement.
CONCLUSIONS
Since SB is a procedure without manipulating intraocular tissues, it is considered to impose a low risk for SO. This report presented SO occurrence after successful SB. Some factors may induce SO, including inciting the choroid and retinal pigment epithelium with cryoretinopexy or perforating for drainage.
Introduction
Sympathetic ophthalmia (SO) is a rare bilateral diffuse granulomatous panuveitis that may occur after surgery or trauma to one eye, as penetrating injury and exposure of the uvea [1]. The incidence of SO is reported ranging 0.01–0.5% after intraocular surgery [1–5]. Surgeries with manipulation and irritation of the choroid and retina are considered as risk factors [1]. The interval between the ocular injury and the onset of SO varies greatly, from a few days to decades, with most of the cases occurring within 3 months after the injury to the exciting eye and 90% during the first year [2–4]. The inciting ocular surgery varies, including cataract extraction, secondary intraocular lens placement, trabeculectomy, vitrectomy, cyclodestruction, iridectomy, and evisceration [1]. Recently, there has been an increasing trend of SO incidence after intraocular and vitreoretinal surgeries [6].
Scleral buckling (SB) is usually considered an extraocular operation, a privilege over vitrectomy, and SO is presumed to have a very low risk after SB. Here we report an unusual rare case of SO following successful SB surgery which was combined with subretinal fluid drainage (SRFD) and cryoretinopexy.
Case presentation
A nineteen-year-old female was referred for visual loss and superior visual field defect in her left eye (LE). Best corrected visual acuity (BCVA) was 20/20 and 20/400 in the right eye (RE) in the LE, respectively. The anterior segment examination was within normal limits except for the detection of Shaffer sign in the LE. The results of the fundus examination revealed macula off inferior long-standing rhegmatogenous retinal detachment (RRD), 3 h of proliferative vitreoretinopathy (PVR), retinal break, and lattice degeneration. The patient had no history of head or ocular trauma or any intraocular surgery. SB with 360 degrees encircling silicone band (silicone band type 240, FCI Inc., Paris, France) and inferior segmental silicone tire (asymmetrical silicone tire type 276, FCI Inc., Paris, France) with one spot cryoretinopexy at the break site, and SRFD due to chronicity of the RRD was performed. During this process, SRFD was not inadvertent. Scleral thinning was performed after passing the band and tire. Moreover, the needle of polyester spatula suture (Mersilene, Ethicon LLC, Johnson and Johnson Inc., USA) was used to drain the fluid after the cauterization of the choroid. BCVA was improved to 20/80 and the retina was totally attached 1 week after the operation. The patient was followed up receiving a topical antibiotic (Chlobiotic, Sina Darou, Tehran, Iran) and topical corticosteroid (Bethasonate, Sina Darou, Tehran, Iran) for 3 weeks.
The patient referred to the hospital with severe visual loss in both eyes 6 weeks later. On examination, BCVA of both eyes was counting finger at one meter and the anterior segment was within normal limits, except 1+ anterior chamber and anterior vitreous cells in both eyes. Bilateral multifocal serous retinal detachment (SRD) was obvious in funduscopy (Fig. 1a, b). The results of enhanced depth imaging optical coherence tomography (EDI-OCT) (Spectralis HRA +OCT, Heidelberg Engineering, Heidelberg, Germany) revealed multilobular SRD, septated subretinal spaces, hyperreflective dot reflexes in subretinal fluid, choroidal thickening, and retinal pigment epithelium undulation (Fig. 1c, d). Chorioscleral junction was not detected due to diffuse severe choroidal thickening. According to the results of examination and imaging, as well as the absence of any other ocular trauma history except for SB surgery, the diagnosis of SO was presumed incited by SB surgery. Therefore, the patient was admitted and received high-dose (1 g/day) intravenous methylprednisolone treatment for 5 days. This five-day pulse therapy led to the control of inflammation and the significant resolution of SRD (Fig. 1e, f). The patient underwent all systemic work-ups for common causes of choroiditis, including sarcoidosis, tuberculosis, syphilis, and autoimmunity markers were inconclusive. Moreover, familial, drug, and past medical history were unremarkable. After pulse therapy, oral prednisolone (50 mg/day) and mycophenolate mofetil (MMF) (2 g/day) were initiated. On the fourth day, fluorescein angiography showed no significant dye pooling except for mild leakage; also, it revealed mixed hypo- and hyper-fluorescent dots scattered at the posterior poles presumably due to choroidal hypoperfusion and abnormal leakage. Since indocyanine green angiography (ICGA) was not available at that time, it was not performed at the first presentation of SO. Prednisolone tapered rapidly due to the increased blood glucose, and subtenon triamcinolone acetonide (TriamHEXAL, Hexal AG, Holzkirchen, Germany) (40 mg/1 cc) was injected bilaterally. Induced diabetes was controlled with oral medication which was stopped after 1 month. Prednisolone was reached to 5 mg/d at the end of the second month with continuing MMF (2 g/d). The blood glucose was checked frequently, which was within normal limits during the follow-up and did not relapse during 6-months follow-ups. Following one-year treatment with MMF 2 g/d and prednisolone 5 mg/d, inflammation was reduced considerably and the retina was attached completely in both eyes. Final BCVA was obtained as 20/20 and 20/50 in the RE and LE, respectively. After 3 months of immunosuppressive treatment, ICGA disclosed only a few hypofluorescent dark dots in both eyes and mild background hyperflorescence at the posterior pole indicating a response to treatment with mild subclinical inflammation of choroidal stroma (Fig. 2).
Fig. 1 Fundus photography of the right (a) and the left (b) eye reveals bilateral disc swelling and multifocal serous retinal detachment at the posterior pole. Enhanced depth imaging optical coherent tomography (EDI-OCT) of the right (c) and the left (d) eye at the first presentation after the development of sympathetic ophthalmia (SO) discloses multi-lobular serous retinal detachment, septate subretinal spaces, hyperreflective dots in subretinal fluid, choroidal thickening, and undulation of the retinal pigment epithelium. The results of EDI-OCT of the right (e) and left (f) eye shows the significant response with resolution of serous retinal detachment and decreased choroidal thickening 5 days after pulse corticosteroid therapy
Fig. 2 Indocyanine green angiography of the right (a, b) and the left eye (d, e) at the third month disclosed only a few hypofluorescent dark dots (HDD) in both eyes and mild background hyperflorescence at the posterior pole indicating a response to treatment with mild subclinical inflammation of choroidal stroma. Enhanced depth imaging optical coherent tomography of the right (c) and left (f) eyes at 3 months follow-up showed complete response with resolution of serous retinal detachment and decreased choroidal thickening and inflammation
Discussion
Here, we report a rare case of SO following uncomplicated SB surgery accompanied by cryoretinopexy and SRFD. In this regard, it is recommended that SO be taken into consideration in any case of bilateral panuveitis associated with multiple SRD and a history of penetrating ocular surgery.
In several studies, the occurrence of SO has been reported after vitreoretinal surgery [2, 4–6]. It is postulated that trauma to the uveal tract in the context of inadvertent perforation, SRFD, or cryotherapy during SB surgery might be related to deliberate uveal antigens, melanin or outer photoreceptor antigens resulting to access to the lymphatic systems of the conjunctival tissue. This process may associated to exciting of delayed hypersensitivity reaction inside the eye [4–6]. The mechanism of hypersensitivity in the sympathizing eye may be due to the exposure of the uveal tissue to the conjunctival lymphatic system leading to a cell-mediated immune response [6]. This mechanism, owing to more uveal incarceration, can explain the relationship between an increase in the trend of transconjunctival sutureless vitrectomy application and a growth in the incidence of SO following vitreoretinal surgery [6]. In our case, SRFD seemingly increased the risk of uveal exposure to conjunctival lymphatic tissue. In a study conducted by Kilmartin et al., it was reported that RRD surgery was the most common procedure associated with the development of SO, with the risk of SO after vitrectomy being as twice as that of external scleral buckling, without any gender predilection [7].
The onset of SO symptoms after the operation usually occurs between 3 weeks and 6 months after surgery due to delayed hypersensitivity [8]. Regarding the subject in this study, SO was developed 6 weeks later. In a case series study carried out by Ozbek et al. [4], three cases of SO incidence occurred following SB; however, two patients had combined vitrectomy with SB. In the aforementioned research, SO occurred only in one case after encircling buckle combined with 360 indirect retinal photocoagulations and SRFD, in contrast to our case that had only one cryoretinopexy spot and one drainage site. In another similar case report by Parvaresh and Falavarjani, SO was found in a case with a history of SB revision after 4 years. In this case, the second surgery was combined with SRFD and cryoretinopexy [9]. Nonetheless, in our case, SO happened in the first operation without any surgical history.
In a recent study performed by Tyagi et al., the incidence of SO following vitreoretinal surgery was estimated at 0.038% of all vitrectomy cases, and vice versa, 9% of all cases of SO had vitreoretinal surgery [6]. In this research, 75% of cases underwent multiple ocular surgeries before the development of SO [6]. Furthermore, the most common anterior segment was non-granulomatous uveitis in 50% of subjects, in contrast to SRD occurring in 62.5% of cases [6]. In our case, it was found that anterior segment inflammation was less severe than the posterior segment chorioretinal findings.
Most of the cases presented in studies [4–9] had simultaneous SB and vitrectomy, previous trauma, or multiple surgeries. Nevertheless, the subject of our report had no extensive retinal or uveal tissue manipulation and no combined surgery or previous surgery, highlighting the importance of this report. One of the underlying reasons for this susceptibility might be related to the Asian ethnicity and higher prevalence of Vogt-Koyanagi-Harada (VKH) in this region.
One of the most important differential diagnoses of our case is related to VKH which is a common uveitis etiology with similar clinical and imaging findings with SO [1, 10]. Although sympathizing eye in SO presents clinically with nongranulomatous uveitis at first, it progresses to granulomatous uveitis afterward [8]. shows three successive stages: posterior uveitis, anterior segment involvement associated with posterior uveitis, and finally anterior granulomatous uveitis. Both anterior and posterior uveitis are present in SO patients within 2 weeks of disease onset [8]. Generally, the main differentiating clue between SO and VKH is the history of prior surgery or trauma in SO. Considering this, in our case, clinical features were more similar to SO than to VKH, as our patient had no systemic sign or symptom attributed to VKH or other systemic diseases causing choroiditis.
The results of SO imaging, based on FAG, revealed multiple hyperfluorescent pinpoints leakages associated with late pooling resembling VKH and hypofluorescent foci during the early phase of angiography. Moreover, the late phase of FAG showed hyperfluorescence similar to acute posterior multifocal placoid pigment epitheliopathy [10]. In our case, apparently due to the performance of FAG 4 days after the steroid therapy, hyperfluorscence was less prominent than hypofluorescence that was compatible with the location of granuloma and cellular infiltration. The most common features of ICGA imaging are multiple hypocyanescent spots. In the acute phase of SO, EDI-OCT discloses multiple SRD associated with hyperreflective septa, massive choroidal thickening, and loss of normal choroidal vascular architectures, as well as irregular photoreceptor outer segments similar to what was observed in the acute phase of VKH. The visual outcome is worse in SO as compared with VKH disease [8]. Moreover, BCVA was improved in our case due to early diagnosis and prompt, aggressive, and adequate treatment.
In conclusion, the diagnosis of sympathetic ophthalmia should be taken into account in any case of bilateral uveitis or bilateral SRD following scleral buckling with uveal tract violation, such as cryopexy or SRFD.
Abbreviations
BCVABest corrected visual acuity
EDI-OCTEnhanced depth imaging optical coherent tomography
OCTOptical coherent tomography
FAGFluorescein angiography
ICGAIndocyanine green angiography
RERight eye
LELeft eye
SRDSerous retinal detachment
RRDRhegmatogenous retinal detachment
RPERetinal pigment epithelium
SBScleral buckling
SRFDSubretinal fluid drainage
SOSympathetic ophthalmia
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
The authors would like to express their gratitude to Zahra Emaverdian MSc., Sepideh Nazari Noghabi MSc., Roghaye Kahani BSc., and Roya Gholamzadeh BSc. at Khatam-al-Anbia Eye Hospital, Mashhad, Iran. Moreover, the researchers appreciate the kind supports of Captain Mohammad Mahdi Sarshar.
Authors’ contributions
All the authors contributed significantly to this research and agreed to be accountable for all aspects of the work. SMH took part in patient’s participating in clinical analysis, and interpretation of imaging, and revising the draft. NS, MG, MAz helped to gather the patient’s evaluations and draft the manuscript. MAb participated in the acquisition of clinical data, clinical analysis and interpretation, and revising and finalizing the manuscript. All authors read and approved the final manuscript.
Funding
The authors received no funding. It is the authors’ own work, not funded by government or academicals institutes.
Availability of data and materials
The datasets used and/or analyzed during the current study can be provided by the corresponding author on reasonable request.
Ethics approval and consent to participate
Not Applicable.
Consent for publication
A consent form was obtained from the patient for imaging, data publication, and identifying clinical details.
Competing interests
The authors declare that they have no competing interests. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY | 33615391 | 20,222,014 | 2021-02-22 |
What was the administration route of drug 'PREDNISOLONE'? | Persumed sympathetic Ophthalmia after scleral buckling surgery: case report.
BACKGROUND
Scleral buckling (SB) is usually considered an extraocular operation premeditated to have a low risk of sympathetic ophthalmia (SO). Here we report a rare case of presumed SO in a young female patient following SB.
METHODS
A nineteen-year-old female patient was referred for visual loss in her left eye due to macula off inferior long-standing rhegmatogenous retinal detachment (RRD). The best corrected visual acuity (BCVA) was 20/400 in the left eye. SB with 360 degrees encircling band, an inferior segmental tire with one spot cryoretinopexy at the break site, and subretinal fluid drainage was performed. BCVA was improved to 20/80 and the retina was totally attached 1 week after the operation. The patient referred to the hospital 6 weeks later with severe visual loss in both eyes as counting finger 1 m. Patient examination indicated bilateral multifocal serous retinal detachment (SRD) and vitreous cells. The patient, diagnosed with SO, received intravenous corticosteroid pulse therapy and mycophenolate mofetil for treatment. The inflammation was controlled and SRD resolved after a 5-day intravenous treatment without being relapsed after 6 months. Consequently, BCVA became 20/20 and 20/50 in the right and left eye, respectively, after 6 months. The findings of systemic workup were negative for any extraocular disease or systemic involvement.
CONCLUSIONS
Since SB is a procedure without manipulating intraocular tissues, it is considered to impose a low risk for SO. This report presented SO occurrence after successful SB. Some factors may induce SO, including inciting the choroid and retinal pigment epithelium with cryoretinopexy or perforating for drainage.
Introduction
Sympathetic ophthalmia (SO) is a rare bilateral diffuse granulomatous panuveitis that may occur after surgery or trauma to one eye, as penetrating injury and exposure of the uvea [1]. The incidence of SO is reported ranging 0.01–0.5% after intraocular surgery [1–5]. Surgeries with manipulation and irritation of the choroid and retina are considered as risk factors [1]. The interval between the ocular injury and the onset of SO varies greatly, from a few days to decades, with most of the cases occurring within 3 months after the injury to the exciting eye and 90% during the first year [2–4]. The inciting ocular surgery varies, including cataract extraction, secondary intraocular lens placement, trabeculectomy, vitrectomy, cyclodestruction, iridectomy, and evisceration [1]. Recently, there has been an increasing trend of SO incidence after intraocular and vitreoretinal surgeries [6].
Scleral buckling (SB) is usually considered an extraocular operation, a privilege over vitrectomy, and SO is presumed to have a very low risk after SB. Here we report an unusual rare case of SO following successful SB surgery which was combined with subretinal fluid drainage (SRFD) and cryoretinopexy.
Case presentation
A nineteen-year-old female was referred for visual loss and superior visual field defect in her left eye (LE). Best corrected visual acuity (BCVA) was 20/20 and 20/400 in the right eye (RE) in the LE, respectively. The anterior segment examination was within normal limits except for the detection of Shaffer sign in the LE. The results of the fundus examination revealed macula off inferior long-standing rhegmatogenous retinal detachment (RRD), 3 h of proliferative vitreoretinopathy (PVR), retinal break, and lattice degeneration. The patient had no history of head or ocular trauma or any intraocular surgery. SB with 360 degrees encircling silicone band (silicone band type 240, FCI Inc., Paris, France) and inferior segmental silicone tire (asymmetrical silicone tire type 276, FCI Inc., Paris, France) with one spot cryoretinopexy at the break site, and SRFD due to chronicity of the RRD was performed. During this process, SRFD was not inadvertent. Scleral thinning was performed after passing the band and tire. Moreover, the needle of polyester spatula suture (Mersilene, Ethicon LLC, Johnson and Johnson Inc., USA) was used to drain the fluid after the cauterization of the choroid. BCVA was improved to 20/80 and the retina was totally attached 1 week after the operation. The patient was followed up receiving a topical antibiotic (Chlobiotic, Sina Darou, Tehran, Iran) and topical corticosteroid (Bethasonate, Sina Darou, Tehran, Iran) for 3 weeks.
The patient referred to the hospital with severe visual loss in both eyes 6 weeks later. On examination, BCVA of both eyes was counting finger at one meter and the anterior segment was within normal limits, except 1+ anterior chamber and anterior vitreous cells in both eyes. Bilateral multifocal serous retinal detachment (SRD) was obvious in funduscopy (Fig. 1a, b). The results of enhanced depth imaging optical coherence tomography (EDI-OCT) (Spectralis HRA +OCT, Heidelberg Engineering, Heidelberg, Germany) revealed multilobular SRD, septated subretinal spaces, hyperreflective dot reflexes in subretinal fluid, choroidal thickening, and retinal pigment epithelium undulation (Fig. 1c, d). Chorioscleral junction was not detected due to diffuse severe choroidal thickening. According to the results of examination and imaging, as well as the absence of any other ocular trauma history except for SB surgery, the diagnosis of SO was presumed incited by SB surgery. Therefore, the patient was admitted and received high-dose (1 g/day) intravenous methylprednisolone treatment for 5 days. This five-day pulse therapy led to the control of inflammation and the significant resolution of SRD (Fig. 1e, f). The patient underwent all systemic work-ups for common causes of choroiditis, including sarcoidosis, tuberculosis, syphilis, and autoimmunity markers were inconclusive. Moreover, familial, drug, and past medical history were unremarkable. After pulse therapy, oral prednisolone (50 mg/day) and mycophenolate mofetil (MMF) (2 g/day) were initiated. On the fourth day, fluorescein angiography showed no significant dye pooling except for mild leakage; also, it revealed mixed hypo- and hyper-fluorescent dots scattered at the posterior poles presumably due to choroidal hypoperfusion and abnormal leakage. Since indocyanine green angiography (ICGA) was not available at that time, it was not performed at the first presentation of SO. Prednisolone tapered rapidly due to the increased blood glucose, and subtenon triamcinolone acetonide (TriamHEXAL, Hexal AG, Holzkirchen, Germany) (40 mg/1 cc) was injected bilaterally. Induced diabetes was controlled with oral medication which was stopped after 1 month. Prednisolone was reached to 5 mg/d at the end of the second month with continuing MMF (2 g/d). The blood glucose was checked frequently, which was within normal limits during the follow-up and did not relapse during 6-months follow-ups. Following one-year treatment with MMF 2 g/d and prednisolone 5 mg/d, inflammation was reduced considerably and the retina was attached completely in both eyes. Final BCVA was obtained as 20/20 and 20/50 in the RE and LE, respectively. After 3 months of immunosuppressive treatment, ICGA disclosed only a few hypofluorescent dark dots in both eyes and mild background hyperflorescence at the posterior pole indicating a response to treatment with mild subclinical inflammation of choroidal stroma (Fig. 2).
Fig. 1 Fundus photography of the right (a) and the left (b) eye reveals bilateral disc swelling and multifocal serous retinal detachment at the posterior pole. Enhanced depth imaging optical coherent tomography (EDI-OCT) of the right (c) and the left (d) eye at the first presentation after the development of sympathetic ophthalmia (SO) discloses multi-lobular serous retinal detachment, septate subretinal spaces, hyperreflective dots in subretinal fluid, choroidal thickening, and undulation of the retinal pigment epithelium. The results of EDI-OCT of the right (e) and left (f) eye shows the significant response with resolution of serous retinal detachment and decreased choroidal thickening 5 days after pulse corticosteroid therapy
Fig. 2 Indocyanine green angiography of the right (a, b) and the left eye (d, e) at the third month disclosed only a few hypofluorescent dark dots (HDD) in both eyes and mild background hyperflorescence at the posterior pole indicating a response to treatment with mild subclinical inflammation of choroidal stroma. Enhanced depth imaging optical coherent tomography of the right (c) and left (f) eyes at 3 months follow-up showed complete response with resolution of serous retinal detachment and decreased choroidal thickening and inflammation
Discussion
Here, we report a rare case of SO following uncomplicated SB surgery accompanied by cryoretinopexy and SRFD. In this regard, it is recommended that SO be taken into consideration in any case of bilateral panuveitis associated with multiple SRD and a history of penetrating ocular surgery.
In several studies, the occurrence of SO has been reported after vitreoretinal surgery [2, 4–6]. It is postulated that trauma to the uveal tract in the context of inadvertent perforation, SRFD, or cryotherapy during SB surgery might be related to deliberate uveal antigens, melanin or outer photoreceptor antigens resulting to access to the lymphatic systems of the conjunctival tissue. This process may associated to exciting of delayed hypersensitivity reaction inside the eye [4–6]. The mechanism of hypersensitivity in the sympathizing eye may be due to the exposure of the uveal tissue to the conjunctival lymphatic system leading to a cell-mediated immune response [6]. This mechanism, owing to more uveal incarceration, can explain the relationship between an increase in the trend of transconjunctival sutureless vitrectomy application and a growth in the incidence of SO following vitreoretinal surgery [6]. In our case, SRFD seemingly increased the risk of uveal exposure to conjunctival lymphatic tissue. In a study conducted by Kilmartin et al., it was reported that RRD surgery was the most common procedure associated with the development of SO, with the risk of SO after vitrectomy being as twice as that of external scleral buckling, without any gender predilection [7].
The onset of SO symptoms after the operation usually occurs between 3 weeks and 6 months after surgery due to delayed hypersensitivity [8]. Regarding the subject in this study, SO was developed 6 weeks later. In a case series study carried out by Ozbek et al. [4], three cases of SO incidence occurred following SB; however, two patients had combined vitrectomy with SB. In the aforementioned research, SO occurred only in one case after encircling buckle combined with 360 indirect retinal photocoagulations and SRFD, in contrast to our case that had only one cryoretinopexy spot and one drainage site. In another similar case report by Parvaresh and Falavarjani, SO was found in a case with a history of SB revision after 4 years. In this case, the second surgery was combined with SRFD and cryoretinopexy [9]. Nonetheless, in our case, SO happened in the first operation without any surgical history.
In a recent study performed by Tyagi et al., the incidence of SO following vitreoretinal surgery was estimated at 0.038% of all vitrectomy cases, and vice versa, 9% of all cases of SO had vitreoretinal surgery [6]. In this research, 75% of cases underwent multiple ocular surgeries before the development of SO [6]. Furthermore, the most common anterior segment was non-granulomatous uveitis in 50% of subjects, in contrast to SRD occurring in 62.5% of cases [6]. In our case, it was found that anterior segment inflammation was less severe than the posterior segment chorioretinal findings.
Most of the cases presented in studies [4–9] had simultaneous SB and vitrectomy, previous trauma, or multiple surgeries. Nevertheless, the subject of our report had no extensive retinal or uveal tissue manipulation and no combined surgery or previous surgery, highlighting the importance of this report. One of the underlying reasons for this susceptibility might be related to the Asian ethnicity and higher prevalence of Vogt-Koyanagi-Harada (VKH) in this region.
One of the most important differential diagnoses of our case is related to VKH which is a common uveitis etiology with similar clinical and imaging findings with SO [1, 10]. Although sympathizing eye in SO presents clinically with nongranulomatous uveitis at first, it progresses to granulomatous uveitis afterward [8]. shows three successive stages: posterior uveitis, anterior segment involvement associated with posterior uveitis, and finally anterior granulomatous uveitis. Both anterior and posterior uveitis are present in SO patients within 2 weeks of disease onset [8]. Generally, the main differentiating clue between SO and VKH is the history of prior surgery or trauma in SO. Considering this, in our case, clinical features were more similar to SO than to VKH, as our patient had no systemic sign or symptom attributed to VKH or other systemic diseases causing choroiditis.
The results of SO imaging, based on FAG, revealed multiple hyperfluorescent pinpoints leakages associated with late pooling resembling VKH and hypofluorescent foci during the early phase of angiography. Moreover, the late phase of FAG showed hyperfluorescence similar to acute posterior multifocal placoid pigment epitheliopathy [10]. In our case, apparently due to the performance of FAG 4 days after the steroid therapy, hyperfluorscence was less prominent than hypofluorescence that was compatible with the location of granuloma and cellular infiltration. The most common features of ICGA imaging are multiple hypocyanescent spots. In the acute phase of SO, EDI-OCT discloses multiple SRD associated with hyperreflective septa, massive choroidal thickening, and loss of normal choroidal vascular architectures, as well as irregular photoreceptor outer segments similar to what was observed in the acute phase of VKH. The visual outcome is worse in SO as compared with VKH disease [8]. Moreover, BCVA was improved in our case due to early diagnosis and prompt, aggressive, and adequate treatment.
In conclusion, the diagnosis of sympathetic ophthalmia should be taken into account in any case of bilateral uveitis or bilateral SRD following scleral buckling with uveal tract violation, such as cryopexy or SRFD.
Abbreviations
BCVABest corrected visual acuity
EDI-OCTEnhanced depth imaging optical coherent tomography
OCTOptical coherent tomography
FAGFluorescein angiography
ICGAIndocyanine green angiography
RERight eye
LELeft eye
SRDSerous retinal detachment
RRDRhegmatogenous retinal detachment
RPERetinal pigment epithelium
SBScleral buckling
SRFDSubretinal fluid drainage
SOSympathetic ophthalmia
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
The authors would like to express their gratitude to Zahra Emaverdian MSc., Sepideh Nazari Noghabi MSc., Roghaye Kahani BSc., and Roya Gholamzadeh BSc. at Khatam-al-Anbia Eye Hospital, Mashhad, Iran. Moreover, the researchers appreciate the kind supports of Captain Mohammad Mahdi Sarshar.
Authors’ contributions
All the authors contributed significantly to this research and agreed to be accountable for all aspects of the work. SMH took part in patient’s participating in clinical analysis, and interpretation of imaging, and revising the draft. NS, MG, MAz helped to gather the patient’s evaluations and draft the manuscript. MAb participated in the acquisition of clinical data, clinical analysis and interpretation, and revising and finalizing the manuscript. All authors read and approved the final manuscript.
Funding
The authors received no funding. It is the authors’ own work, not funded by government or academicals institutes.
Availability of data and materials
The datasets used and/or analyzed during the current study can be provided by the corresponding author on reasonable request.
Ethics approval and consent to participate
Not Applicable.
Consent for publication
A consent form was obtained from the patient for imaging, data publication, and identifying clinical details.
Competing interests
The authors declare that they have no competing interests. | Oral | DrugAdministrationRoute | CC BY | 33615391 | 20,222,014 | 2021-02-22 |
What was the administration route of drug 'TRIAMCINOLONE'? | Persumed sympathetic Ophthalmia after scleral buckling surgery: case report.
BACKGROUND
Scleral buckling (SB) is usually considered an extraocular operation premeditated to have a low risk of sympathetic ophthalmia (SO). Here we report a rare case of presumed SO in a young female patient following SB.
METHODS
A nineteen-year-old female patient was referred for visual loss in her left eye due to macula off inferior long-standing rhegmatogenous retinal detachment (RRD). The best corrected visual acuity (BCVA) was 20/400 in the left eye. SB with 360 degrees encircling band, an inferior segmental tire with one spot cryoretinopexy at the break site, and subretinal fluid drainage was performed. BCVA was improved to 20/80 and the retina was totally attached 1 week after the operation. The patient referred to the hospital 6 weeks later with severe visual loss in both eyes as counting finger 1 m. Patient examination indicated bilateral multifocal serous retinal detachment (SRD) and vitreous cells. The patient, diagnosed with SO, received intravenous corticosteroid pulse therapy and mycophenolate mofetil for treatment. The inflammation was controlled and SRD resolved after a 5-day intravenous treatment without being relapsed after 6 months. Consequently, BCVA became 20/20 and 20/50 in the right and left eye, respectively, after 6 months. The findings of systemic workup were negative for any extraocular disease or systemic involvement.
CONCLUSIONS
Since SB is a procedure without manipulating intraocular tissues, it is considered to impose a low risk for SO. This report presented SO occurrence after successful SB. Some factors may induce SO, including inciting the choroid and retinal pigment epithelium with cryoretinopexy or perforating for drainage.
Introduction
Sympathetic ophthalmia (SO) is a rare bilateral diffuse granulomatous panuveitis that may occur after surgery or trauma to one eye, as penetrating injury and exposure of the uvea [1]. The incidence of SO is reported ranging 0.01–0.5% after intraocular surgery [1–5]. Surgeries with manipulation and irritation of the choroid and retina are considered as risk factors [1]. The interval between the ocular injury and the onset of SO varies greatly, from a few days to decades, with most of the cases occurring within 3 months after the injury to the exciting eye and 90% during the first year [2–4]. The inciting ocular surgery varies, including cataract extraction, secondary intraocular lens placement, trabeculectomy, vitrectomy, cyclodestruction, iridectomy, and evisceration [1]. Recently, there has been an increasing trend of SO incidence after intraocular and vitreoretinal surgeries [6].
Scleral buckling (SB) is usually considered an extraocular operation, a privilege over vitrectomy, and SO is presumed to have a very low risk after SB. Here we report an unusual rare case of SO following successful SB surgery which was combined with subretinal fluid drainage (SRFD) and cryoretinopexy.
Case presentation
A nineteen-year-old female was referred for visual loss and superior visual field defect in her left eye (LE). Best corrected visual acuity (BCVA) was 20/20 and 20/400 in the right eye (RE) in the LE, respectively. The anterior segment examination was within normal limits except for the detection of Shaffer sign in the LE. The results of the fundus examination revealed macula off inferior long-standing rhegmatogenous retinal detachment (RRD), 3 h of proliferative vitreoretinopathy (PVR), retinal break, and lattice degeneration. The patient had no history of head or ocular trauma or any intraocular surgery. SB with 360 degrees encircling silicone band (silicone band type 240, FCI Inc., Paris, France) and inferior segmental silicone tire (asymmetrical silicone tire type 276, FCI Inc., Paris, France) with one spot cryoretinopexy at the break site, and SRFD due to chronicity of the RRD was performed. During this process, SRFD was not inadvertent. Scleral thinning was performed after passing the band and tire. Moreover, the needle of polyester spatula suture (Mersilene, Ethicon LLC, Johnson and Johnson Inc., USA) was used to drain the fluid after the cauterization of the choroid. BCVA was improved to 20/80 and the retina was totally attached 1 week after the operation. The patient was followed up receiving a topical antibiotic (Chlobiotic, Sina Darou, Tehran, Iran) and topical corticosteroid (Bethasonate, Sina Darou, Tehran, Iran) for 3 weeks.
The patient referred to the hospital with severe visual loss in both eyes 6 weeks later. On examination, BCVA of both eyes was counting finger at one meter and the anterior segment was within normal limits, except 1+ anterior chamber and anterior vitreous cells in both eyes. Bilateral multifocal serous retinal detachment (SRD) was obvious in funduscopy (Fig. 1a, b). The results of enhanced depth imaging optical coherence tomography (EDI-OCT) (Spectralis HRA +OCT, Heidelberg Engineering, Heidelberg, Germany) revealed multilobular SRD, septated subretinal spaces, hyperreflective dot reflexes in subretinal fluid, choroidal thickening, and retinal pigment epithelium undulation (Fig. 1c, d). Chorioscleral junction was not detected due to diffuse severe choroidal thickening. According to the results of examination and imaging, as well as the absence of any other ocular trauma history except for SB surgery, the diagnosis of SO was presumed incited by SB surgery. Therefore, the patient was admitted and received high-dose (1 g/day) intravenous methylprednisolone treatment for 5 days. This five-day pulse therapy led to the control of inflammation and the significant resolution of SRD (Fig. 1e, f). The patient underwent all systemic work-ups for common causes of choroiditis, including sarcoidosis, tuberculosis, syphilis, and autoimmunity markers were inconclusive. Moreover, familial, drug, and past medical history were unremarkable. After pulse therapy, oral prednisolone (50 mg/day) and mycophenolate mofetil (MMF) (2 g/day) were initiated. On the fourth day, fluorescein angiography showed no significant dye pooling except for mild leakage; also, it revealed mixed hypo- and hyper-fluorescent dots scattered at the posterior poles presumably due to choroidal hypoperfusion and abnormal leakage. Since indocyanine green angiography (ICGA) was not available at that time, it was not performed at the first presentation of SO. Prednisolone tapered rapidly due to the increased blood glucose, and subtenon triamcinolone acetonide (TriamHEXAL, Hexal AG, Holzkirchen, Germany) (40 mg/1 cc) was injected bilaterally. Induced diabetes was controlled with oral medication which was stopped after 1 month. Prednisolone was reached to 5 mg/d at the end of the second month with continuing MMF (2 g/d). The blood glucose was checked frequently, which was within normal limits during the follow-up and did not relapse during 6-months follow-ups. Following one-year treatment with MMF 2 g/d and prednisolone 5 mg/d, inflammation was reduced considerably and the retina was attached completely in both eyes. Final BCVA was obtained as 20/20 and 20/50 in the RE and LE, respectively. After 3 months of immunosuppressive treatment, ICGA disclosed only a few hypofluorescent dark dots in both eyes and mild background hyperflorescence at the posterior pole indicating a response to treatment with mild subclinical inflammation of choroidal stroma (Fig. 2).
Fig. 1 Fundus photography of the right (a) and the left (b) eye reveals bilateral disc swelling and multifocal serous retinal detachment at the posterior pole. Enhanced depth imaging optical coherent tomography (EDI-OCT) of the right (c) and the left (d) eye at the first presentation after the development of sympathetic ophthalmia (SO) discloses multi-lobular serous retinal detachment, septate subretinal spaces, hyperreflective dots in subretinal fluid, choroidal thickening, and undulation of the retinal pigment epithelium. The results of EDI-OCT of the right (e) and left (f) eye shows the significant response with resolution of serous retinal detachment and decreased choroidal thickening 5 days after pulse corticosteroid therapy
Fig. 2 Indocyanine green angiography of the right (a, b) and the left eye (d, e) at the third month disclosed only a few hypofluorescent dark dots (HDD) in both eyes and mild background hyperflorescence at the posterior pole indicating a response to treatment with mild subclinical inflammation of choroidal stroma. Enhanced depth imaging optical coherent tomography of the right (c) and left (f) eyes at 3 months follow-up showed complete response with resolution of serous retinal detachment and decreased choroidal thickening and inflammation
Discussion
Here, we report a rare case of SO following uncomplicated SB surgery accompanied by cryoretinopexy and SRFD. In this regard, it is recommended that SO be taken into consideration in any case of bilateral panuveitis associated with multiple SRD and a history of penetrating ocular surgery.
In several studies, the occurrence of SO has been reported after vitreoretinal surgery [2, 4–6]. It is postulated that trauma to the uveal tract in the context of inadvertent perforation, SRFD, or cryotherapy during SB surgery might be related to deliberate uveal antigens, melanin or outer photoreceptor antigens resulting to access to the lymphatic systems of the conjunctival tissue. This process may associated to exciting of delayed hypersensitivity reaction inside the eye [4–6]. The mechanism of hypersensitivity in the sympathizing eye may be due to the exposure of the uveal tissue to the conjunctival lymphatic system leading to a cell-mediated immune response [6]. This mechanism, owing to more uveal incarceration, can explain the relationship between an increase in the trend of transconjunctival sutureless vitrectomy application and a growth in the incidence of SO following vitreoretinal surgery [6]. In our case, SRFD seemingly increased the risk of uveal exposure to conjunctival lymphatic tissue. In a study conducted by Kilmartin et al., it was reported that RRD surgery was the most common procedure associated with the development of SO, with the risk of SO after vitrectomy being as twice as that of external scleral buckling, without any gender predilection [7].
The onset of SO symptoms after the operation usually occurs between 3 weeks and 6 months after surgery due to delayed hypersensitivity [8]. Regarding the subject in this study, SO was developed 6 weeks later. In a case series study carried out by Ozbek et al. [4], three cases of SO incidence occurred following SB; however, two patients had combined vitrectomy with SB. In the aforementioned research, SO occurred only in one case after encircling buckle combined with 360 indirect retinal photocoagulations and SRFD, in contrast to our case that had only one cryoretinopexy spot and one drainage site. In another similar case report by Parvaresh and Falavarjani, SO was found in a case with a history of SB revision after 4 years. In this case, the second surgery was combined with SRFD and cryoretinopexy [9]. Nonetheless, in our case, SO happened in the first operation without any surgical history.
In a recent study performed by Tyagi et al., the incidence of SO following vitreoretinal surgery was estimated at 0.038% of all vitrectomy cases, and vice versa, 9% of all cases of SO had vitreoretinal surgery [6]. In this research, 75% of cases underwent multiple ocular surgeries before the development of SO [6]. Furthermore, the most common anterior segment was non-granulomatous uveitis in 50% of subjects, in contrast to SRD occurring in 62.5% of cases [6]. In our case, it was found that anterior segment inflammation was less severe than the posterior segment chorioretinal findings.
Most of the cases presented in studies [4–9] had simultaneous SB and vitrectomy, previous trauma, or multiple surgeries. Nevertheless, the subject of our report had no extensive retinal or uveal tissue manipulation and no combined surgery or previous surgery, highlighting the importance of this report. One of the underlying reasons for this susceptibility might be related to the Asian ethnicity and higher prevalence of Vogt-Koyanagi-Harada (VKH) in this region.
One of the most important differential diagnoses of our case is related to VKH which is a common uveitis etiology with similar clinical and imaging findings with SO [1, 10]. Although sympathizing eye in SO presents clinically with nongranulomatous uveitis at first, it progresses to granulomatous uveitis afterward [8]. shows three successive stages: posterior uveitis, anterior segment involvement associated with posterior uveitis, and finally anterior granulomatous uveitis. Both anterior and posterior uveitis are present in SO patients within 2 weeks of disease onset [8]. Generally, the main differentiating clue between SO and VKH is the history of prior surgery or trauma in SO. Considering this, in our case, clinical features were more similar to SO than to VKH, as our patient had no systemic sign or symptom attributed to VKH or other systemic diseases causing choroiditis.
The results of SO imaging, based on FAG, revealed multiple hyperfluorescent pinpoints leakages associated with late pooling resembling VKH and hypofluorescent foci during the early phase of angiography. Moreover, the late phase of FAG showed hyperfluorescence similar to acute posterior multifocal placoid pigment epitheliopathy [10]. In our case, apparently due to the performance of FAG 4 days after the steroid therapy, hyperfluorscence was less prominent than hypofluorescence that was compatible with the location of granuloma and cellular infiltration. The most common features of ICGA imaging are multiple hypocyanescent spots. In the acute phase of SO, EDI-OCT discloses multiple SRD associated with hyperreflective septa, massive choroidal thickening, and loss of normal choroidal vascular architectures, as well as irregular photoreceptor outer segments similar to what was observed in the acute phase of VKH. The visual outcome is worse in SO as compared with VKH disease [8]. Moreover, BCVA was improved in our case due to early diagnosis and prompt, aggressive, and adequate treatment.
In conclusion, the diagnosis of sympathetic ophthalmia should be taken into account in any case of bilateral uveitis or bilateral SRD following scleral buckling with uveal tract violation, such as cryopexy or SRFD.
Abbreviations
BCVABest corrected visual acuity
EDI-OCTEnhanced depth imaging optical coherent tomography
OCTOptical coherent tomography
FAGFluorescein angiography
ICGAIndocyanine green angiography
RERight eye
LELeft eye
SRDSerous retinal detachment
RRDRhegmatogenous retinal detachment
RPERetinal pigment epithelium
SBScleral buckling
SRFDSubretinal fluid drainage
SOSympathetic ophthalmia
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
The authors would like to express their gratitude to Zahra Emaverdian MSc., Sepideh Nazari Noghabi MSc., Roghaye Kahani BSc., and Roya Gholamzadeh BSc. at Khatam-al-Anbia Eye Hospital, Mashhad, Iran. Moreover, the researchers appreciate the kind supports of Captain Mohammad Mahdi Sarshar.
Authors’ contributions
All the authors contributed significantly to this research and agreed to be accountable for all aspects of the work. SMH took part in patient’s participating in clinical analysis, and interpretation of imaging, and revising the draft. NS, MG, MAz helped to gather the patient’s evaluations and draft the manuscript. MAb participated in the acquisition of clinical data, clinical analysis and interpretation, and revising and finalizing the manuscript. All authors read and approved the final manuscript.
Funding
The authors received no funding. It is the authors’ own work, not funded by government or academicals institutes.
Availability of data and materials
The datasets used and/or analyzed during the current study can be provided by the corresponding author on reasonable request.
Ethics approval and consent to participate
Not Applicable.
Consent for publication
A consent form was obtained from the patient for imaging, data publication, and identifying clinical details.
Competing interests
The authors declare that they have no competing interests. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY | 33615391 | 20,222,014 | 2021-02-22 |
What was the dosage of drug 'BETAMETHASONE VALERATE'? | Persumed sympathetic Ophthalmia after scleral buckling surgery: case report.
BACKGROUND
Scleral buckling (SB) is usually considered an extraocular operation premeditated to have a low risk of sympathetic ophthalmia (SO). Here we report a rare case of presumed SO in a young female patient following SB.
METHODS
A nineteen-year-old female patient was referred for visual loss in her left eye due to macula off inferior long-standing rhegmatogenous retinal detachment (RRD). The best corrected visual acuity (BCVA) was 20/400 in the left eye. SB with 360 degrees encircling band, an inferior segmental tire with one spot cryoretinopexy at the break site, and subretinal fluid drainage was performed. BCVA was improved to 20/80 and the retina was totally attached 1 week after the operation. The patient referred to the hospital 6 weeks later with severe visual loss in both eyes as counting finger 1 m. Patient examination indicated bilateral multifocal serous retinal detachment (SRD) and vitreous cells. The patient, diagnosed with SO, received intravenous corticosteroid pulse therapy and mycophenolate mofetil for treatment. The inflammation was controlled and SRD resolved after a 5-day intravenous treatment without being relapsed after 6 months. Consequently, BCVA became 20/20 and 20/50 in the right and left eye, respectively, after 6 months. The findings of systemic workup were negative for any extraocular disease or systemic involvement.
CONCLUSIONS
Since SB is a procedure without manipulating intraocular tissues, it is considered to impose a low risk for SO. This report presented SO occurrence after successful SB. Some factors may induce SO, including inciting the choroid and retinal pigment epithelium with cryoretinopexy or perforating for drainage.
Introduction
Sympathetic ophthalmia (SO) is a rare bilateral diffuse granulomatous panuveitis that may occur after surgery or trauma to one eye, as penetrating injury and exposure of the uvea [1]. The incidence of SO is reported ranging 0.01–0.5% after intraocular surgery [1–5]. Surgeries with manipulation and irritation of the choroid and retina are considered as risk factors [1]. The interval between the ocular injury and the onset of SO varies greatly, from a few days to decades, with most of the cases occurring within 3 months after the injury to the exciting eye and 90% during the first year [2–4]. The inciting ocular surgery varies, including cataract extraction, secondary intraocular lens placement, trabeculectomy, vitrectomy, cyclodestruction, iridectomy, and evisceration [1]. Recently, there has been an increasing trend of SO incidence after intraocular and vitreoretinal surgeries [6].
Scleral buckling (SB) is usually considered an extraocular operation, a privilege over vitrectomy, and SO is presumed to have a very low risk after SB. Here we report an unusual rare case of SO following successful SB surgery which was combined with subretinal fluid drainage (SRFD) and cryoretinopexy.
Case presentation
A nineteen-year-old female was referred for visual loss and superior visual field defect in her left eye (LE). Best corrected visual acuity (BCVA) was 20/20 and 20/400 in the right eye (RE) in the LE, respectively. The anterior segment examination was within normal limits except for the detection of Shaffer sign in the LE. The results of the fundus examination revealed macula off inferior long-standing rhegmatogenous retinal detachment (RRD), 3 h of proliferative vitreoretinopathy (PVR), retinal break, and lattice degeneration. The patient had no history of head or ocular trauma or any intraocular surgery. SB with 360 degrees encircling silicone band (silicone band type 240, FCI Inc., Paris, France) and inferior segmental silicone tire (asymmetrical silicone tire type 276, FCI Inc., Paris, France) with one spot cryoretinopexy at the break site, and SRFD due to chronicity of the RRD was performed. During this process, SRFD was not inadvertent. Scleral thinning was performed after passing the band and tire. Moreover, the needle of polyester spatula suture (Mersilene, Ethicon LLC, Johnson and Johnson Inc., USA) was used to drain the fluid after the cauterization of the choroid. BCVA was improved to 20/80 and the retina was totally attached 1 week after the operation. The patient was followed up receiving a topical antibiotic (Chlobiotic, Sina Darou, Tehran, Iran) and topical corticosteroid (Bethasonate, Sina Darou, Tehran, Iran) for 3 weeks.
The patient referred to the hospital with severe visual loss in both eyes 6 weeks later. On examination, BCVA of both eyes was counting finger at one meter and the anterior segment was within normal limits, except 1+ anterior chamber and anterior vitreous cells in both eyes. Bilateral multifocal serous retinal detachment (SRD) was obvious in funduscopy (Fig. 1a, b). The results of enhanced depth imaging optical coherence tomography (EDI-OCT) (Spectralis HRA +OCT, Heidelberg Engineering, Heidelberg, Germany) revealed multilobular SRD, septated subretinal spaces, hyperreflective dot reflexes in subretinal fluid, choroidal thickening, and retinal pigment epithelium undulation (Fig. 1c, d). Chorioscleral junction was not detected due to diffuse severe choroidal thickening. According to the results of examination and imaging, as well as the absence of any other ocular trauma history except for SB surgery, the diagnosis of SO was presumed incited by SB surgery. Therefore, the patient was admitted and received high-dose (1 g/day) intravenous methylprednisolone treatment for 5 days. This five-day pulse therapy led to the control of inflammation and the significant resolution of SRD (Fig. 1e, f). The patient underwent all systemic work-ups for common causes of choroiditis, including sarcoidosis, tuberculosis, syphilis, and autoimmunity markers were inconclusive. Moreover, familial, drug, and past medical history were unremarkable. After pulse therapy, oral prednisolone (50 mg/day) and mycophenolate mofetil (MMF) (2 g/day) were initiated. On the fourth day, fluorescein angiography showed no significant dye pooling except for mild leakage; also, it revealed mixed hypo- and hyper-fluorescent dots scattered at the posterior poles presumably due to choroidal hypoperfusion and abnormal leakage. Since indocyanine green angiography (ICGA) was not available at that time, it was not performed at the first presentation of SO. Prednisolone tapered rapidly due to the increased blood glucose, and subtenon triamcinolone acetonide (TriamHEXAL, Hexal AG, Holzkirchen, Germany) (40 mg/1 cc) was injected bilaterally. Induced diabetes was controlled with oral medication which was stopped after 1 month. Prednisolone was reached to 5 mg/d at the end of the second month with continuing MMF (2 g/d). The blood glucose was checked frequently, which was within normal limits during the follow-up and did not relapse during 6-months follow-ups. Following one-year treatment with MMF 2 g/d and prednisolone 5 mg/d, inflammation was reduced considerably and the retina was attached completely in both eyes. Final BCVA was obtained as 20/20 and 20/50 in the RE and LE, respectively. After 3 months of immunosuppressive treatment, ICGA disclosed only a few hypofluorescent dark dots in both eyes and mild background hyperflorescence at the posterior pole indicating a response to treatment with mild subclinical inflammation of choroidal stroma (Fig. 2).
Fig. 1 Fundus photography of the right (a) and the left (b) eye reveals bilateral disc swelling and multifocal serous retinal detachment at the posterior pole. Enhanced depth imaging optical coherent tomography (EDI-OCT) of the right (c) and the left (d) eye at the first presentation after the development of sympathetic ophthalmia (SO) discloses multi-lobular serous retinal detachment, septate subretinal spaces, hyperreflective dots in subretinal fluid, choroidal thickening, and undulation of the retinal pigment epithelium. The results of EDI-OCT of the right (e) and left (f) eye shows the significant response with resolution of serous retinal detachment and decreased choroidal thickening 5 days after pulse corticosteroid therapy
Fig. 2 Indocyanine green angiography of the right (a, b) and the left eye (d, e) at the third month disclosed only a few hypofluorescent dark dots (HDD) in both eyes and mild background hyperflorescence at the posterior pole indicating a response to treatment with mild subclinical inflammation of choroidal stroma. Enhanced depth imaging optical coherent tomography of the right (c) and left (f) eyes at 3 months follow-up showed complete response with resolution of serous retinal detachment and decreased choroidal thickening and inflammation
Discussion
Here, we report a rare case of SO following uncomplicated SB surgery accompanied by cryoretinopexy and SRFD. In this regard, it is recommended that SO be taken into consideration in any case of bilateral panuveitis associated with multiple SRD and a history of penetrating ocular surgery.
In several studies, the occurrence of SO has been reported after vitreoretinal surgery [2, 4–6]. It is postulated that trauma to the uveal tract in the context of inadvertent perforation, SRFD, or cryotherapy during SB surgery might be related to deliberate uveal antigens, melanin or outer photoreceptor antigens resulting to access to the lymphatic systems of the conjunctival tissue. This process may associated to exciting of delayed hypersensitivity reaction inside the eye [4–6]. The mechanism of hypersensitivity in the sympathizing eye may be due to the exposure of the uveal tissue to the conjunctival lymphatic system leading to a cell-mediated immune response [6]. This mechanism, owing to more uveal incarceration, can explain the relationship between an increase in the trend of transconjunctival sutureless vitrectomy application and a growth in the incidence of SO following vitreoretinal surgery [6]. In our case, SRFD seemingly increased the risk of uveal exposure to conjunctival lymphatic tissue. In a study conducted by Kilmartin et al., it was reported that RRD surgery was the most common procedure associated with the development of SO, with the risk of SO after vitrectomy being as twice as that of external scleral buckling, without any gender predilection [7].
The onset of SO symptoms after the operation usually occurs between 3 weeks and 6 months after surgery due to delayed hypersensitivity [8]. Regarding the subject in this study, SO was developed 6 weeks later. In a case series study carried out by Ozbek et al. [4], three cases of SO incidence occurred following SB; however, two patients had combined vitrectomy with SB. In the aforementioned research, SO occurred only in one case after encircling buckle combined with 360 indirect retinal photocoagulations and SRFD, in contrast to our case that had only one cryoretinopexy spot and one drainage site. In another similar case report by Parvaresh and Falavarjani, SO was found in a case with a history of SB revision after 4 years. In this case, the second surgery was combined with SRFD and cryoretinopexy [9]. Nonetheless, in our case, SO happened in the first operation without any surgical history.
In a recent study performed by Tyagi et al., the incidence of SO following vitreoretinal surgery was estimated at 0.038% of all vitrectomy cases, and vice versa, 9% of all cases of SO had vitreoretinal surgery [6]. In this research, 75% of cases underwent multiple ocular surgeries before the development of SO [6]. Furthermore, the most common anterior segment was non-granulomatous uveitis in 50% of subjects, in contrast to SRD occurring in 62.5% of cases [6]. In our case, it was found that anterior segment inflammation was less severe than the posterior segment chorioretinal findings.
Most of the cases presented in studies [4–9] had simultaneous SB and vitrectomy, previous trauma, or multiple surgeries. Nevertheless, the subject of our report had no extensive retinal or uveal tissue manipulation and no combined surgery or previous surgery, highlighting the importance of this report. One of the underlying reasons for this susceptibility might be related to the Asian ethnicity and higher prevalence of Vogt-Koyanagi-Harada (VKH) in this region.
One of the most important differential diagnoses of our case is related to VKH which is a common uveitis etiology with similar clinical and imaging findings with SO [1, 10]. Although sympathizing eye in SO presents clinically with nongranulomatous uveitis at first, it progresses to granulomatous uveitis afterward [8]. shows three successive stages: posterior uveitis, anterior segment involvement associated with posterior uveitis, and finally anterior granulomatous uveitis. Both anterior and posterior uveitis are present in SO patients within 2 weeks of disease onset [8]. Generally, the main differentiating clue between SO and VKH is the history of prior surgery or trauma in SO. Considering this, in our case, clinical features were more similar to SO than to VKH, as our patient had no systemic sign or symptom attributed to VKH or other systemic diseases causing choroiditis.
The results of SO imaging, based on FAG, revealed multiple hyperfluorescent pinpoints leakages associated with late pooling resembling VKH and hypofluorescent foci during the early phase of angiography. Moreover, the late phase of FAG showed hyperfluorescence similar to acute posterior multifocal placoid pigment epitheliopathy [10]. In our case, apparently due to the performance of FAG 4 days after the steroid therapy, hyperfluorscence was less prominent than hypofluorescence that was compatible with the location of granuloma and cellular infiltration. The most common features of ICGA imaging are multiple hypocyanescent spots. In the acute phase of SO, EDI-OCT discloses multiple SRD associated with hyperreflective septa, massive choroidal thickening, and loss of normal choroidal vascular architectures, as well as irregular photoreceptor outer segments similar to what was observed in the acute phase of VKH. The visual outcome is worse in SO as compared with VKH disease [8]. Moreover, BCVA was improved in our case due to early diagnosis and prompt, aggressive, and adequate treatment.
In conclusion, the diagnosis of sympathetic ophthalmia should be taken into account in any case of bilateral uveitis or bilateral SRD following scleral buckling with uveal tract violation, such as cryopexy or SRFD.
Abbreviations
BCVABest corrected visual acuity
EDI-OCTEnhanced depth imaging optical coherent tomography
OCTOptical coherent tomography
FAGFluorescein angiography
ICGAIndocyanine green angiography
RERight eye
LELeft eye
SRDSerous retinal detachment
RRDRhegmatogenous retinal detachment
RPERetinal pigment epithelium
SBScleral buckling
SRFDSubretinal fluid drainage
SOSympathetic ophthalmia
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
The authors would like to express their gratitude to Zahra Emaverdian MSc., Sepideh Nazari Noghabi MSc., Roghaye Kahani BSc., and Roya Gholamzadeh BSc. at Khatam-al-Anbia Eye Hospital, Mashhad, Iran. Moreover, the researchers appreciate the kind supports of Captain Mohammad Mahdi Sarshar.
Authors’ contributions
All the authors contributed significantly to this research and agreed to be accountable for all aspects of the work. SMH took part in patient’s participating in clinical analysis, and interpretation of imaging, and revising the draft. NS, MG, MAz helped to gather the patient’s evaluations and draft the manuscript. MAb participated in the acquisition of clinical data, clinical analysis and interpretation, and revising and finalizing the manuscript. All authors read and approved the final manuscript.
Funding
The authors received no funding. It is the authors’ own work, not funded by government or academicals institutes.
Availability of data and materials
The datasets used and/or analyzed during the current study can be provided by the corresponding author on reasonable request.
Ethics approval and consent to participate
Not Applicable.
Consent for publication
A consent form was obtained from the patient for imaging, data publication, and identifying clinical details.
Competing interests
The authors declare that they have no competing interests. | UNK (BETHASONATE) | DrugDosageText | CC BY | 33615391 | 20,222,014 | 2021-02-22 |
What was the dosage of drug 'CHLORAMPHENICOL'? | Persumed sympathetic Ophthalmia after scleral buckling surgery: case report.
BACKGROUND
Scleral buckling (SB) is usually considered an extraocular operation premeditated to have a low risk of sympathetic ophthalmia (SO). Here we report a rare case of presumed SO in a young female patient following SB.
METHODS
A nineteen-year-old female patient was referred for visual loss in her left eye due to macula off inferior long-standing rhegmatogenous retinal detachment (RRD). The best corrected visual acuity (BCVA) was 20/400 in the left eye. SB with 360 degrees encircling band, an inferior segmental tire with one spot cryoretinopexy at the break site, and subretinal fluid drainage was performed. BCVA was improved to 20/80 and the retina was totally attached 1 week after the operation. The patient referred to the hospital 6 weeks later with severe visual loss in both eyes as counting finger 1 m. Patient examination indicated bilateral multifocal serous retinal detachment (SRD) and vitreous cells. The patient, diagnosed with SO, received intravenous corticosteroid pulse therapy and mycophenolate mofetil for treatment. The inflammation was controlled and SRD resolved after a 5-day intravenous treatment without being relapsed after 6 months. Consequently, BCVA became 20/20 and 20/50 in the right and left eye, respectively, after 6 months. The findings of systemic workup were negative for any extraocular disease or systemic involvement.
CONCLUSIONS
Since SB is a procedure without manipulating intraocular tissues, it is considered to impose a low risk for SO. This report presented SO occurrence after successful SB. Some factors may induce SO, including inciting the choroid and retinal pigment epithelium with cryoretinopexy or perforating for drainage.
Introduction
Sympathetic ophthalmia (SO) is a rare bilateral diffuse granulomatous panuveitis that may occur after surgery or trauma to one eye, as penetrating injury and exposure of the uvea [1]. The incidence of SO is reported ranging 0.01–0.5% after intraocular surgery [1–5]. Surgeries with manipulation and irritation of the choroid and retina are considered as risk factors [1]. The interval between the ocular injury and the onset of SO varies greatly, from a few days to decades, with most of the cases occurring within 3 months after the injury to the exciting eye and 90% during the first year [2–4]. The inciting ocular surgery varies, including cataract extraction, secondary intraocular lens placement, trabeculectomy, vitrectomy, cyclodestruction, iridectomy, and evisceration [1]. Recently, there has been an increasing trend of SO incidence after intraocular and vitreoretinal surgeries [6].
Scleral buckling (SB) is usually considered an extraocular operation, a privilege over vitrectomy, and SO is presumed to have a very low risk after SB. Here we report an unusual rare case of SO following successful SB surgery which was combined with subretinal fluid drainage (SRFD) and cryoretinopexy.
Case presentation
A nineteen-year-old female was referred for visual loss and superior visual field defect in her left eye (LE). Best corrected visual acuity (BCVA) was 20/20 and 20/400 in the right eye (RE) in the LE, respectively. The anterior segment examination was within normal limits except for the detection of Shaffer sign in the LE. The results of the fundus examination revealed macula off inferior long-standing rhegmatogenous retinal detachment (RRD), 3 h of proliferative vitreoretinopathy (PVR), retinal break, and lattice degeneration. The patient had no history of head or ocular trauma or any intraocular surgery. SB with 360 degrees encircling silicone band (silicone band type 240, FCI Inc., Paris, France) and inferior segmental silicone tire (asymmetrical silicone tire type 276, FCI Inc., Paris, France) with one spot cryoretinopexy at the break site, and SRFD due to chronicity of the RRD was performed. During this process, SRFD was not inadvertent. Scleral thinning was performed after passing the band and tire. Moreover, the needle of polyester spatula suture (Mersilene, Ethicon LLC, Johnson and Johnson Inc., USA) was used to drain the fluid after the cauterization of the choroid. BCVA was improved to 20/80 and the retina was totally attached 1 week after the operation. The patient was followed up receiving a topical antibiotic (Chlobiotic, Sina Darou, Tehran, Iran) and topical corticosteroid (Bethasonate, Sina Darou, Tehran, Iran) for 3 weeks.
The patient referred to the hospital with severe visual loss in both eyes 6 weeks later. On examination, BCVA of both eyes was counting finger at one meter and the anterior segment was within normal limits, except 1+ anterior chamber and anterior vitreous cells in both eyes. Bilateral multifocal serous retinal detachment (SRD) was obvious in funduscopy (Fig. 1a, b). The results of enhanced depth imaging optical coherence tomography (EDI-OCT) (Spectralis HRA +OCT, Heidelberg Engineering, Heidelberg, Germany) revealed multilobular SRD, septated subretinal spaces, hyperreflective dot reflexes in subretinal fluid, choroidal thickening, and retinal pigment epithelium undulation (Fig. 1c, d). Chorioscleral junction was not detected due to diffuse severe choroidal thickening. According to the results of examination and imaging, as well as the absence of any other ocular trauma history except for SB surgery, the diagnosis of SO was presumed incited by SB surgery. Therefore, the patient was admitted and received high-dose (1 g/day) intravenous methylprednisolone treatment for 5 days. This five-day pulse therapy led to the control of inflammation and the significant resolution of SRD (Fig. 1e, f). The patient underwent all systemic work-ups for common causes of choroiditis, including sarcoidosis, tuberculosis, syphilis, and autoimmunity markers were inconclusive. Moreover, familial, drug, and past medical history were unremarkable. After pulse therapy, oral prednisolone (50 mg/day) and mycophenolate mofetil (MMF) (2 g/day) were initiated. On the fourth day, fluorescein angiography showed no significant dye pooling except for mild leakage; also, it revealed mixed hypo- and hyper-fluorescent dots scattered at the posterior poles presumably due to choroidal hypoperfusion and abnormal leakage. Since indocyanine green angiography (ICGA) was not available at that time, it was not performed at the first presentation of SO. Prednisolone tapered rapidly due to the increased blood glucose, and subtenon triamcinolone acetonide (TriamHEXAL, Hexal AG, Holzkirchen, Germany) (40 mg/1 cc) was injected bilaterally. Induced diabetes was controlled with oral medication which was stopped after 1 month. Prednisolone was reached to 5 mg/d at the end of the second month with continuing MMF (2 g/d). The blood glucose was checked frequently, which was within normal limits during the follow-up and did not relapse during 6-months follow-ups. Following one-year treatment with MMF 2 g/d and prednisolone 5 mg/d, inflammation was reduced considerably and the retina was attached completely in both eyes. Final BCVA was obtained as 20/20 and 20/50 in the RE and LE, respectively. After 3 months of immunosuppressive treatment, ICGA disclosed only a few hypofluorescent dark dots in both eyes and mild background hyperflorescence at the posterior pole indicating a response to treatment with mild subclinical inflammation of choroidal stroma (Fig. 2).
Fig. 1 Fundus photography of the right (a) and the left (b) eye reveals bilateral disc swelling and multifocal serous retinal detachment at the posterior pole. Enhanced depth imaging optical coherent tomography (EDI-OCT) of the right (c) and the left (d) eye at the first presentation after the development of sympathetic ophthalmia (SO) discloses multi-lobular serous retinal detachment, septate subretinal spaces, hyperreflective dots in subretinal fluid, choroidal thickening, and undulation of the retinal pigment epithelium. The results of EDI-OCT of the right (e) and left (f) eye shows the significant response with resolution of serous retinal detachment and decreased choroidal thickening 5 days after pulse corticosteroid therapy
Fig. 2 Indocyanine green angiography of the right (a, b) and the left eye (d, e) at the third month disclosed only a few hypofluorescent dark dots (HDD) in both eyes and mild background hyperflorescence at the posterior pole indicating a response to treatment with mild subclinical inflammation of choroidal stroma. Enhanced depth imaging optical coherent tomography of the right (c) and left (f) eyes at 3 months follow-up showed complete response with resolution of serous retinal detachment and decreased choroidal thickening and inflammation
Discussion
Here, we report a rare case of SO following uncomplicated SB surgery accompanied by cryoretinopexy and SRFD. In this regard, it is recommended that SO be taken into consideration in any case of bilateral panuveitis associated with multiple SRD and a history of penetrating ocular surgery.
In several studies, the occurrence of SO has been reported after vitreoretinal surgery [2, 4–6]. It is postulated that trauma to the uveal tract in the context of inadvertent perforation, SRFD, or cryotherapy during SB surgery might be related to deliberate uveal antigens, melanin or outer photoreceptor antigens resulting to access to the lymphatic systems of the conjunctival tissue. This process may associated to exciting of delayed hypersensitivity reaction inside the eye [4–6]. The mechanism of hypersensitivity in the sympathizing eye may be due to the exposure of the uveal tissue to the conjunctival lymphatic system leading to a cell-mediated immune response [6]. This mechanism, owing to more uveal incarceration, can explain the relationship between an increase in the trend of transconjunctival sutureless vitrectomy application and a growth in the incidence of SO following vitreoretinal surgery [6]. In our case, SRFD seemingly increased the risk of uveal exposure to conjunctival lymphatic tissue. In a study conducted by Kilmartin et al., it was reported that RRD surgery was the most common procedure associated with the development of SO, with the risk of SO after vitrectomy being as twice as that of external scleral buckling, without any gender predilection [7].
The onset of SO symptoms after the operation usually occurs between 3 weeks and 6 months after surgery due to delayed hypersensitivity [8]. Regarding the subject in this study, SO was developed 6 weeks later. In a case series study carried out by Ozbek et al. [4], three cases of SO incidence occurred following SB; however, two patients had combined vitrectomy with SB. In the aforementioned research, SO occurred only in one case after encircling buckle combined with 360 indirect retinal photocoagulations and SRFD, in contrast to our case that had only one cryoretinopexy spot and one drainage site. In another similar case report by Parvaresh and Falavarjani, SO was found in a case with a history of SB revision after 4 years. In this case, the second surgery was combined with SRFD and cryoretinopexy [9]. Nonetheless, in our case, SO happened in the first operation without any surgical history.
In a recent study performed by Tyagi et al., the incidence of SO following vitreoretinal surgery was estimated at 0.038% of all vitrectomy cases, and vice versa, 9% of all cases of SO had vitreoretinal surgery [6]. In this research, 75% of cases underwent multiple ocular surgeries before the development of SO [6]. Furthermore, the most common anterior segment was non-granulomatous uveitis in 50% of subjects, in contrast to SRD occurring in 62.5% of cases [6]. In our case, it was found that anterior segment inflammation was less severe than the posterior segment chorioretinal findings.
Most of the cases presented in studies [4–9] had simultaneous SB and vitrectomy, previous trauma, or multiple surgeries. Nevertheless, the subject of our report had no extensive retinal or uveal tissue manipulation and no combined surgery or previous surgery, highlighting the importance of this report. One of the underlying reasons for this susceptibility might be related to the Asian ethnicity and higher prevalence of Vogt-Koyanagi-Harada (VKH) in this region.
One of the most important differential diagnoses of our case is related to VKH which is a common uveitis etiology with similar clinical and imaging findings with SO [1, 10]. Although sympathizing eye in SO presents clinically with nongranulomatous uveitis at first, it progresses to granulomatous uveitis afterward [8]. shows three successive stages: posterior uveitis, anterior segment involvement associated with posterior uveitis, and finally anterior granulomatous uveitis. Both anterior and posterior uveitis are present in SO patients within 2 weeks of disease onset [8]. Generally, the main differentiating clue between SO and VKH is the history of prior surgery or trauma in SO. Considering this, in our case, clinical features were more similar to SO than to VKH, as our patient had no systemic sign or symptom attributed to VKH or other systemic diseases causing choroiditis.
The results of SO imaging, based on FAG, revealed multiple hyperfluorescent pinpoints leakages associated with late pooling resembling VKH and hypofluorescent foci during the early phase of angiography. Moreover, the late phase of FAG showed hyperfluorescence similar to acute posterior multifocal placoid pigment epitheliopathy [10]. In our case, apparently due to the performance of FAG 4 days after the steroid therapy, hyperfluorscence was less prominent than hypofluorescence that was compatible with the location of granuloma and cellular infiltration. The most common features of ICGA imaging are multiple hypocyanescent spots. In the acute phase of SO, EDI-OCT discloses multiple SRD associated with hyperreflective septa, massive choroidal thickening, and loss of normal choroidal vascular architectures, as well as irregular photoreceptor outer segments similar to what was observed in the acute phase of VKH. The visual outcome is worse in SO as compared with VKH disease [8]. Moreover, BCVA was improved in our case due to early diagnosis and prompt, aggressive, and adequate treatment.
In conclusion, the diagnosis of sympathetic ophthalmia should be taken into account in any case of bilateral uveitis or bilateral SRD following scleral buckling with uveal tract violation, such as cryopexy or SRFD.
Abbreviations
BCVABest corrected visual acuity
EDI-OCTEnhanced depth imaging optical coherent tomography
OCTOptical coherent tomography
FAGFluorescein angiography
ICGAIndocyanine green angiography
RERight eye
LELeft eye
SRDSerous retinal detachment
RRDRhegmatogenous retinal detachment
RPERetinal pigment epithelium
SBScleral buckling
SRFDSubretinal fluid drainage
SOSympathetic ophthalmia
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
The authors would like to express their gratitude to Zahra Emaverdian MSc., Sepideh Nazari Noghabi MSc., Roghaye Kahani BSc., and Roya Gholamzadeh BSc. at Khatam-al-Anbia Eye Hospital, Mashhad, Iran. Moreover, the researchers appreciate the kind supports of Captain Mohammad Mahdi Sarshar.
Authors’ contributions
All the authors contributed significantly to this research and agreed to be accountable for all aspects of the work. SMH took part in patient’s participating in clinical analysis, and interpretation of imaging, and revising the draft. NS, MG, MAz helped to gather the patient’s evaluations and draft the manuscript. MAb participated in the acquisition of clinical data, clinical analysis and interpretation, and revising and finalizing the manuscript. All authors read and approved the final manuscript.
Funding
The authors received no funding. It is the authors’ own work, not funded by government or academicals institutes.
Availability of data and materials
The datasets used and/or analyzed during the current study can be provided by the corresponding author on reasonable request.
Ethics approval and consent to participate
Not Applicable.
Consent for publication
A consent form was obtained from the patient for imaging, data publication, and identifying clinical details.
Competing interests
The authors declare that they have no competing interests. | UNK (CHLOBIOTIC) | DrugDosageText | CC BY | 33615391 | 20,222,014 | 2021-02-22 |
What was the dosage of drug 'TRIAMCINOLONE'? | Persumed sympathetic Ophthalmia after scleral buckling surgery: case report.
BACKGROUND
Scleral buckling (SB) is usually considered an extraocular operation premeditated to have a low risk of sympathetic ophthalmia (SO). Here we report a rare case of presumed SO in a young female patient following SB.
METHODS
A nineteen-year-old female patient was referred for visual loss in her left eye due to macula off inferior long-standing rhegmatogenous retinal detachment (RRD). The best corrected visual acuity (BCVA) was 20/400 in the left eye. SB with 360 degrees encircling band, an inferior segmental tire with one spot cryoretinopexy at the break site, and subretinal fluid drainage was performed. BCVA was improved to 20/80 and the retina was totally attached 1 week after the operation. The patient referred to the hospital 6 weeks later with severe visual loss in both eyes as counting finger 1 m. Patient examination indicated bilateral multifocal serous retinal detachment (SRD) and vitreous cells. The patient, diagnosed with SO, received intravenous corticosteroid pulse therapy and mycophenolate mofetil for treatment. The inflammation was controlled and SRD resolved after a 5-day intravenous treatment without being relapsed after 6 months. Consequently, BCVA became 20/20 and 20/50 in the right and left eye, respectively, after 6 months. The findings of systemic workup were negative for any extraocular disease or systemic involvement.
CONCLUSIONS
Since SB is a procedure without manipulating intraocular tissues, it is considered to impose a low risk for SO. This report presented SO occurrence after successful SB. Some factors may induce SO, including inciting the choroid and retinal pigment epithelium with cryoretinopexy or perforating for drainage.
Introduction
Sympathetic ophthalmia (SO) is a rare bilateral diffuse granulomatous panuveitis that may occur after surgery or trauma to one eye, as penetrating injury and exposure of the uvea [1]. The incidence of SO is reported ranging 0.01–0.5% after intraocular surgery [1–5]. Surgeries with manipulation and irritation of the choroid and retina are considered as risk factors [1]. The interval between the ocular injury and the onset of SO varies greatly, from a few days to decades, with most of the cases occurring within 3 months after the injury to the exciting eye and 90% during the first year [2–4]. The inciting ocular surgery varies, including cataract extraction, secondary intraocular lens placement, trabeculectomy, vitrectomy, cyclodestruction, iridectomy, and evisceration [1]. Recently, there has been an increasing trend of SO incidence after intraocular and vitreoretinal surgeries [6].
Scleral buckling (SB) is usually considered an extraocular operation, a privilege over vitrectomy, and SO is presumed to have a very low risk after SB. Here we report an unusual rare case of SO following successful SB surgery which was combined with subretinal fluid drainage (SRFD) and cryoretinopexy.
Case presentation
A nineteen-year-old female was referred for visual loss and superior visual field defect in her left eye (LE). Best corrected visual acuity (BCVA) was 20/20 and 20/400 in the right eye (RE) in the LE, respectively. The anterior segment examination was within normal limits except for the detection of Shaffer sign in the LE. The results of the fundus examination revealed macula off inferior long-standing rhegmatogenous retinal detachment (RRD), 3 h of proliferative vitreoretinopathy (PVR), retinal break, and lattice degeneration. The patient had no history of head or ocular trauma or any intraocular surgery. SB with 360 degrees encircling silicone band (silicone band type 240, FCI Inc., Paris, France) and inferior segmental silicone tire (asymmetrical silicone tire type 276, FCI Inc., Paris, France) with one spot cryoretinopexy at the break site, and SRFD due to chronicity of the RRD was performed. During this process, SRFD was not inadvertent. Scleral thinning was performed after passing the band and tire. Moreover, the needle of polyester spatula suture (Mersilene, Ethicon LLC, Johnson and Johnson Inc., USA) was used to drain the fluid after the cauterization of the choroid. BCVA was improved to 20/80 and the retina was totally attached 1 week after the operation. The patient was followed up receiving a topical antibiotic (Chlobiotic, Sina Darou, Tehran, Iran) and topical corticosteroid (Bethasonate, Sina Darou, Tehran, Iran) for 3 weeks.
The patient referred to the hospital with severe visual loss in both eyes 6 weeks later. On examination, BCVA of both eyes was counting finger at one meter and the anterior segment was within normal limits, except 1+ anterior chamber and anterior vitreous cells in both eyes. Bilateral multifocal serous retinal detachment (SRD) was obvious in funduscopy (Fig. 1a, b). The results of enhanced depth imaging optical coherence tomography (EDI-OCT) (Spectralis HRA +OCT, Heidelberg Engineering, Heidelberg, Germany) revealed multilobular SRD, septated subretinal spaces, hyperreflective dot reflexes in subretinal fluid, choroidal thickening, and retinal pigment epithelium undulation (Fig. 1c, d). Chorioscleral junction was not detected due to diffuse severe choroidal thickening. According to the results of examination and imaging, as well as the absence of any other ocular trauma history except for SB surgery, the diagnosis of SO was presumed incited by SB surgery. Therefore, the patient was admitted and received high-dose (1 g/day) intravenous methylprednisolone treatment for 5 days. This five-day pulse therapy led to the control of inflammation and the significant resolution of SRD (Fig. 1e, f). The patient underwent all systemic work-ups for common causes of choroiditis, including sarcoidosis, tuberculosis, syphilis, and autoimmunity markers were inconclusive. Moreover, familial, drug, and past medical history were unremarkable. After pulse therapy, oral prednisolone (50 mg/day) and mycophenolate mofetil (MMF) (2 g/day) were initiated. On the fourth day, fluorescein angiography showed no significant dye pooling except for mild leakage; also, it revealed mixed hypo- and hyper-fluorescent dots scattered at the posterior poles presumably due to choroidal hypoperfusion and abnormal leakage. Since indocyanine green angiography (ICGA) was not available at that time, it was not performed at the first presentation of SO. Prednisolone tapered rapidly due to the increased blood glucose, and subtenon triamcinolone acetonide (TriamHEXAL, Hexal AG, Holzkirchen, Germany) (40 mg/1 cc) was injected bilaterally. Induced diabetes was controlled with oral medication which was stopped after 1 month. Prednisolone was reached to 5 mg/d at the end of the second month with continuing MMF (2 g/d). The blood glucose was checked frequently, which was within normal limits during the follow-up and did not relapse during 6-months follow-ups. Following one-year treatment with MMF 2 g/d and prednisolone 5 mg/d, inflammation was reduced considerably and the retina was attached completely in both eyes. Final BCVA was obtained as 20/20 and 20/50 in the RE and LE, respectively. After 3 months of immunosuppressive treatment, ICGA disclosed only a few hypofluorescent dark dots in both eyes and mild background hyperflorescence at the posterior pole indicating a response to treatment with mild subclinical inflammation of choroidal stroma (Fig. 2).
Fig. 1 Fundus photography of the right (a) and the left (b) eye reveals bilateral disc swelling and multifocal serous retinal detachment at the posterior pole. Enhanced depth imaging optical coherent tomography (EDI-OCT) of the right (c) and the left (d) eye at the first presentation after the development of sympathetic ophthalmia (SO) discloses multi-lobular serous retinal detachment, septate subretinal spaces, hyperreflective dots in subretinal fluid, choroidal thickening, and undulation of the retinal pigment epithelium. The results of EDI-OCT of the right (e) and left (f) eye shows the significant response with resolution of serous retinal detachment and decreased choroidal thickening 5 days after pulse corticosteroid therapy
Fig. 2 Indocyanine green angiography of the right (a, b) and the left eye (d, e) at the third month disclosed only a few hypofluorescent dark dots (HDD) in both eyes and mild background hyperflorescence at the posterior pole indicating a response to treatment with mild subclinical inflammation of choroidal stroma. Enhanced depth imaging optical coherent tomography of the right (c) and left (f) eyes at 3 months follow-up showed complete response with resolution of serous retinal detachment and decreased choroidal thickening and inflammation
Discussion
Here, we report a rare case of SO following uncomplicated SB surgery accompanied by cryoretinopexy and SRFD. In this regard, it is recommended that SO be taken into consideration in any case of bilateral panuveitis associated with multiple SRD and a history of penetrating ocular surgery.
In several studies, the occurrence of SO has been reported after vitreoretinal surgery [2, 4–6]. It is postulated that trauma to the uveal tract in the context of inadvertent perforation, SRFD, or cryotherapy during SB surgery might be related to deliberate uveal antigens, melanin or outer photoreceptor antigens resulting to access to the lymphatic systems of the conjunctival tissue. This process may associated to exciting of delayed hypersensitivity reaction inside the eye [4–6]. The mechanism of hypersensitivity in the sympathizing eye may be due to the exposure of the uveal tissue to the conjunctival lymphatic system leading to a cell-mediated immune response [6]. This mechanism, owing to more uveal incarceration, can explain the relationship between an increase in the trend of transconjunctival sutureless vitrectomy application and a growth in the incidence of SO following vitreoretinal surgery [6]. In our case, SRFD seemingly increased the risk of uveal exposure to conjunctival lymphatic tissue. In a study conducted by Kilmartin et al., it was reported that RRD surgery was the most common procedure associated with the development of SO, with the risk of SO after vitrectomy being as twice as that of external scleral buckling, without any gender predilection [7].
The onset of SO symptoms after the operation usually occurs between 3 weeks and 6 months after surgery due to delayed hypersensitivity [8]. Regarding the subject in this study, SO was developed 6 weeks later. In a case series study carried out by Ozbek et al. [4], three cases of SO incidence occurred following SB; however, two patients had combined vitrectomy with SB. In the aforementioned research, SO occurred only in one case after encircling buckle combined with 360 indirect retinal photocoagulations and SRFD, in contrast to our case that had only one cryoretinopexy spot and one drainage site. In another similar case report by Parvaresh and Falavarjani, SO was found in a case with a history of SB revision after 4 years. In this case, the second surgery was combined with SRFD and cryoretinopexy [9]. Nonetheless, in our case, SO happened in the first operation without any surgical history.
In a recent study performed by Tyagi et al., the incidence of SO following vitreoretinal surgery was estimated at 0.038% of all vitrectomy cases, and vice versa, 9% of all cases of SO had vitreoretinal surgery [6]. In this research, 75% of cases underwent multiple ocular surgeries before the development of SO [6]. Furthermore, the most common anterior segment was non-granulomatous uveitis in 50% of subjects, in contrast to SRD occurring in 62.5% of cases [6]. In our case, it was found that anterior segment inflammation was less severe than the posterior segment chorioretinal findings.
Most of the cases presented in studies [4–9] had simultaneous SB and vitrectomy, previous trauma, or multiple surgeries. Nevertheless, the subject of our report had no extensive retinal or uveal tissue manipulation and no combined surgery or previous surgery, highlighting the importance of this report. One of the underlying reasons for this susceptibility might be related to the Asian ethnicity and higher prevalence of Vogt-Koyanagi-Harada (VKH) in this region.
One of the most important differential diagnoses of our case is related to VKH which is a common uveitis etiology with similar clinical and imaging findings with SO [1, 10]. Although sympathizing eye in SO presents clinically with nongranulomatous uveitis at first, it progresses to granulomatous uveitis afterward [8]. shows three successive stages: posterior uveitis, anterior segment involvement associated with posterior uveitis, and finally anterior granulomatous uveitis. Both anterior and posterior uveitis are present in SO patients within 2 weeks of disease onset [8]. Generally, the main differentiating clue between SO and VKH is the history of prior surgery or trauma in SO. Considering this, in our case, clinical features were more similar to SO than to VKH, as our patient had no systemic sign or symptom attributed to VKH or other systemic diseases causing choroiditis.
The results of SO imaging, based on FAG, revealed multiple hyperfluorescent pinpoints leakages associated with late pooling resembling VKH and hypofluorescent foci during the early phase of angiography. Moreover, the late phase of FAG showed hyperfluorescence similar to acute posterior multifocal placoid pigment epitheliopathy [10]. In our case, apparently due to the performance of FAG 4 days after the steroid therapy, hyperfluorscence was less prominent than hypofluorescence that was compatible with the location of granuloma and cellular infiltration. The most common features of ICGA imaging are multiple hypocyanescent spots. In the acute phase of SO, EDI-OCT discloses multiple SRD associated with hyperreflective septa, massive choroidal thickening, and loss of normal choroidal vascular architectures, as well as irregular photoreceptor outer segments similar to what was observed in the acute phase of VKH. The visual outcome is worse in SO as compared with VKH disease [8]. Moreover, BCVA was improved in our case due to early diagnosis and prompt, aggressive, and adequate treatment.
In conclusion, the diagnosis of sympathetic ophthalmia should be taken into account in any case of bilateral uveitis or bilateral SRD following scleral buckling with uveal tract violation, such as cryopexy or SRFD.
Abbreviations
BCVABest corrected visual acuity
EDI-OCTEnhanced depth imaging optical coherent tomography
OCTOptical coherent tomography
FAGFluorescein angiography
ICGAIndocyanine green angiography
RERight eye
LELeft eye
SRDSerous retinal detachment
RRDRhegmatogenous retinal detachment
RPERetinal pigment epithelium
SBScleral buckling
SRFDSubretinal fluid drainage
SOSympathetic ophthalmia
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
The authors would like to express their gratitude to Zahra Emaverdian MSc., Sepideh Nazari Noghabi MSc., Roghaye Kahani BSc., and Roya Gholamzadeh BSc. at Khatam-al-Anbia Eye Hospital, Mashhad, Iran. Moreover, the researchers appreciate the kind supports of Captain Mohammad Mahdi Sarshar.
Authors’ contributions
All the authors contributed significantly to this research and agreed to be accountable for all aspects of the work. SMH took part in patient’s participating in clinical analysis, and interpretation of imaging, and revising the draft. NS, MG, MAz helped to gather the patient’s evaluations and draft the manuscript. MAb participated in the acquisition of clinical data, clinical analysis and interpretation, and revising and finalizing the manuscript. All authors read and approved the final manuscript.
Funding
The authors received no funding. It is the authors’ own work, not funded by government or academicals institutes.
Availability of data and materials
The datasets used and/or analyzed during the current study can be provided by the corresponding author on reasonable request.
Ethics approval and consent to participate
Not Applicable.
Consent for publication
A consent form was obtained from the patient for imaging, data publication, and identifying clinical details.
Competing interests
The authors declare that they have no competing interests. | UNK, 40 MG/1 CC; BILATERALLY (SUBTENON) | DrugDosageText | CC BY | 33615391 | 20,222,014 | 2021-02-22 |
What was the outcome of reaction 'Steroid diabetes'? | Persumed sympathetic Ophthalmia after scleral buckling surgery: case report.
BACKGROUND
Scleral buckling (SB) is usually considered an extraocular operation premeditated to have a low risk of sympathetic ophthalmia (SO). Here we report a rare case of presumed SO in a young female patient following SB.
METHODS
A nineteen-year-old female patient was referred for visual loss in her left eye due to macula off inferior long-standing rhegmatogenous retinal detachment (RRD). The best corrected visual acuity (BCVA) was 20/400 in the left eye. SB with 360 degrees encircling band, an inferior segmental tire with one spot cryoretinopexy at the break site, and subretinal fluid drainage was performed. BCVA was improved to 20/80 and the retina was totally attached 1 week after the operation. The patient referred to the hospital 6 weeks later with severe visual loss in both eyes as counting finger 1 m. Patient examination indicated bilateral multifocal serous retinal detachment (SRD) and vitreous cells. The patient, diagnosed with SO, received intravenous corticosteroid pulse therapy and mycophenolate mofetil for treatment. The inflammation was controlled and SRD resolved after a 5-day intravenous treatment without being relapsed after 6 months. Consequently, BCVA became 20/20 and 20/50 in the right and left eye, respectively, after 6 months. The findings of systemic workup were negative for any extraocular disease or systemic involvement.
CONCLUSIONS
Since SB is a procedure without manipulating intraocular tissues, it is considered to impose a low risk for SO. This report presented SO occurrence after successful SB. Some factors may induce SO, including inciting the choroid and retinal pigment epithelium with cryoretinopexy or perforating for drainage.
Introduction
Sympathetic ophthalmia (SO) is a rare bilateral diffuse granulomatous panuveitis that may occur after surgery or trauma to one eye, as penetrating injury and exposure of the uvea [1]. The incidence of SO is reported ranging 0.01–0.5% after intraocular surgery [1–5]. Surgeries with manipulation and irritation of the choroid and retina are considered as risk factors [1]. The interval between the ocular injury and the onset of SO varies greatly, from a few days to decades, with most of the cases occurring within 3 months after the injury to the exciting eye and 90% during the first year [2–4]. The inciting ocular surgery varies, including cataract extraction, secondary intraocular lens placement, trabeculectomy, vitrectomy, cyclodestruction, iridectomy, and evisceration [1]. Recently, there has been an increasing trend of SO incidence after intraocular and vitreoretinal surgeries [6].
Scleral buckling (SB) is usually considered an extraocular operation, a privilege over vitrectomy, and SO is presumed to have a very low risk after SB. Here we report an unusual rare case of SO following successful SB surgery which was combined with subretinal fluid drainage (SRFD) and cryoretinopexy.
Case presentation
A nineteen-year-old female was referred for visual loss and superior visual field defect in her left eye (LE). Best corrected visual acuity (BCVA) was 20/20 and 20/400 in the right eye (RE) in the LE, respectively. The anterior segment examination was within normal limits except for the detection of Shaffer sign in the LE. The results of the fundus examination revealed macula off inferior long-standing rhegmatogenous retinal detachment (RRD), 3 h of proliferative vitreoretinopathy (PVR), retinal break, and lattice degeneration. The patient had no history of head or ocular trauma or any intraocular surgery. SB with 360 degrees encircling silicone band (silicone band type 240, FCI Inc., Paris, France) and inferior segmental silicone tire (asymmetrical silicone tire type 276, FCI Inc., Paris, France) with one spot cryoretinopexy at the break site, and SRFD due to chronicity of the RRD was performed. During this process, SRFD was not inadvertent. Scleral thinning was performed after passing the band and tire. Moreover, the needle of polyester spatula suture (Mersilene, Ethicon LLC, Johnson and Johnson Inc., USA) was used to drain the fluid after the cauterization of the choroid. BCVA was improved to 20/80 and the retina was totally attached 1 week after the operation. The patient was followed up receiving a topical antibiotic (Chlobiotic, Sina Darou, Tehran, Iran) and topical corticosteroid (Bethasonate, Sina Darou, Tehran, Iran) for 3 weeks.
The patient referred to the hospital with severe visual loss in both eyes 6 weeks later. On examination, BCVA of both eyes was counting finger at one meter and the anterior segment was within normal limits, except 1+ anterior chamber and anterior vitreous cells in both eyes. Bilateral multifocal serous retinal detachment (SRD) was obvious in funduscopy (Fig. 1a, b). The results of enhanced depth imaging optical coherence tomography (EDI-OCT) (Spectralis HRA +OCT, Heidelberg Engineering, Heidelberg, Germany) revealed multilobular SRD, septated subretinal spaces, hyperreflective dot reflexes in subretinal fluid, choroidal thickening, and retinal pigment epithelium undulation (Fig. 1c, d). Chorioscleral junction was not detected due to diffuse severe choroidal thickening. According to the results of examination and imaging, as well as the absence of any other ocular trauma history except for SB surgery, the diagnosis of SO was presumed incited by SB surgery. Therefore, the patient was admitted and received high-dose (1 g/day) intravenous methylprednisolone treatment for 5 days. This five-day pulse therapy led to the control of inflammation and the significant resolution of SRD (Fig. 1e, f). The patient underwent all systemic work-ups for common causes of choroiditis, including sarcoidosis, tuberculosis, syphilis, and autoimmunity markers were inconclusive. Moreover, familial, drug, and past medical history were unremarkable. After pulse therapy, oral prednisolone (50 mg/day) and mycophenolate mofetil (MMF) (2 g/day) were initiated. On the fourth day, fluorescein angiography showed no significant dye pooling except for mild leakage; also, it revealed mixed hypo- and hyper-fluorescent dots scattered at the posterior poles presumably due to choroidal hypoperfusion and abnormal leakage. Since indocyanine green angiography (ICGA) was not available at that time, it was not performed at the first presentation of SO. Prednisolone tapered rapidly due to the increased blood glucose, and subtenon triamcinolone acetonide (TriamHEXAL, Hexal AG, Holzkirchen, Germany) (40 mg/1 cc) was injected bilaterally. Induced diabetes was controlled with oral medication which was stopped after 1 month. Prednisolone was reached to 5 mg/d at the end of the second month with continuing MMF (2 g/d). The blood glucose was checked frequently, which was within normal limits during the follow-up and did not relapse during 6-months follow-ups. Following one-year treatment with MMF 2 g/d and prednisolone 5 mg/d, inflammation was reduced considerably and the retina was attached completely in both eyes. Final BCVA was obtained as 20/20 and 20/50 in the RE and LE, respectively. After 3 months of immunosuppressive treatment, ICGA disclosed only a few hypofluorescent dark dots in both eyes and mild background hyperflorescence at the posterior pole indicating a response to treatment with mild subclinical inflammation of choroidal stroma (Fig. 2).
Fig. 1 Fundus photography of the right (a) and the left (b) eye reveals bilateral disc swelling and multifocal serous retinal detachment at the posterior pole. Enhanced depth imaging optical coherent tomography (EDI-OCT) of the right (c) and the left (d) eye at the first presentation after the development of sympathetic ophthalmia (SO) discloses multi-lobular serous retinal detachment, septate subretinal spaces, hyperreflective dots in subretinal fluid, choroidal thickening, and undulation of the retinal pigment epithelium. The results of EDI-OCT of the right (e) and left (f) eye shows the significant response with resolution of serous retinal detachment and decreased choroidal thickening 5 days after pulse corticosteroid therapy
Fig. 2 Indocyanine green angiography of the right (a, b) and the left eye (d, e) at the third month disclosed only a few hypofluorescent dark dots (HDD) in both eyes and mild background hyperflorescence at the posterior pole indicating a response to treatment with mild subclinical inflammation of choroidal stroma. Enhanced depth imaging optical coherent tomography of the right (c) and left (f) eyes at 3 months follow-up showed complete response with resolution of serous retinal detachment and decreased choroidal thickening and inflammation
Discussion
Here, we report a rare case of SO following uncomplicated SB surgery accompanied by cryoretinopexy and SRFD. In this regard, it is recommended that SO be taken into consideration in any case of bilateral panuveitis associated with multiple SRD and a history of penetrating ocular surgery.
In several studies, the occurrence of SO has been reported after vitreoretinal surgery [2, 4–6]. It is postulated that trauma to the uveal tract in the context of inadvertent perforation, SRFD, or cryotherapy during SB surgery might be related to deliberate uveal antigens, melanin or outer photoreceptor antigens resulting to access to the lymphatic systems of the conjunctival tissue. This process may associated to exciting of delayed hypersensitivity reaction inside the eye [4–6]. The mechanism of hypersensitivity in the sympathizing eye may be due to the exposure of the uveal tissue to the conjunctival lymphatic system leading to a cell-mediated immune response [6]. This mechanism, owing to more uveal incarceration, can explain the relationship between an increase in the trend of transconjunctival sutureless vitrectomy application and a growth in the incidence of SO following vitreoretinal surgery [6]. In our case, SRFD seemingly increased the risk of uveal exposure to conjunctival lymphatic tissue. In a study conducted by Kilmartin et al., it was reported that RRD surgery was the most common procedure associated with the development of SO, with the risk of SO after vitrectomy being as twice as that of external scleral buckling, without any gender predilection [7].
The onset of SO symptoms after the operation usually occurs between 3 weeks and 6 months after surgery due to delayed hypersensitivity [8]. Regarding the subject in this study, SO was developed 6 weeks later. In a case series study carried out by Ozbek et al. [4], three cases of SO incidence occurred following SB; however, two patients had combined vitrectomy with SB. In the aforementioned research, SO occurred only in one case after encircling buckle combined with 360 indirect retinal photocoagulations and SRFD, in contrast to our case that had only one cryoretinopexy spot and one drainage site. In another similar case report by Parvaresh and Falavarjani, SO was found in a case with a history of SB revision after 4 years. In this case, the second surgery was combined with SRFD and cryoretinopexy [9]. Nonetheless, in our case, SO happened in the first operation without any surgical history.
In a recent study performed by Tyagi et al., the incidence of SO following vitreoretinal surgery was estimated at 0.038% of all vitrectomy cases, and vice versa, 9% of all cases of SO had vitreoretinal surgery [6]. In this research, 75% of cases underwent multiple ocular surgeries before the development of SO [6]. Furthermore, the most common anterior segment was non-granulomatous uveitis in 50% of subjects, in contrast to SRD occurring in 62.5% of cases [6]. In our case, it was found that anterior segment inflammation was less severe than the posterior segment chorioretinal findings.
Most of the cases presented in studies [4–9] had simultaneous SB and vitrectomy, previous trauma, or multiple surgeries. Nevertheless, the subject of our report had no extensive retinal or uveal tissue manipulation and no combined surgery or previous surgery, highlighting the importance of this report. One of the underlying reasons for this susceptibility might be related to the Asian ethnicity and higher prevalence of Vogt-Koyanagi-Harada (VKH) in this region.
One of the most important differential diagnoses of our case is related to VKH which is a common uveitis etiology with similar clinical and imaging findings with SO [1, 10]. Although sympathizing eye in SO presents clinically with nongranulomatous uveitis at first, it progresses to granulomatous uveitis afterward [8]. shows three successive stages: posterior uveitis, anterior segment involvement associated with posterior uveitis, and finally anterior granulomatous uveitis. Both anterior and posterior uveitis are present in SO patients within 2 weeks of disease onset [8]. Generally, the main differentiating clue between SO and VKH is the history of prior surgery or trauma in SO. Considering this, in our case, clinical features were more similar to SO than to VKH, as our patient had no systemic sign or symptom attributed to VKH or other systemic diseases causing choroiditis.
The results of SO imaging, based on FAG, revealed multiple hyperfluorescent pinpoints leakages associated with late pooling resembling VKH and hypofluorescent foci during the early phase of angiography. Moreover, the late phase of FAG showed hyperfluorescence similar to acute posterior multifocal placoid pigment epitheliopathy [10]. In our case, apparently due to the performance of FAG 4 days after the steroid therapy, hyperfluorscence was less prominent than hypofluorescence that was compatible with the location of granuloma and cellular infiltration. The most common features of ICGA imaging are multiple hypocyanescent spots. In the acute phase of SO, EDI-OCT discloses multiple SRD associated with hyperreflective septa, massive choroidal thickening, and loss of normal choroidal vascular architectures, as well as irregular photoreceptor outer segments similar to what was observed in the acute phase of VKH. The visual outcome is worse in SO as compared with VKH disease [8]. Moreover, BCVA was improved in our case due to early diagnosis and prompt, aggressive, and adequate treatment.
In conclusion, the diagnosis of sympathetic ophthalmia should be taken into account in any case of bilateral uveitis or bilateral SRD following scleral buckling with uveal tract violation, such as cryopexy or SRFD.
Abbreviations
BCVABest corrected visual acuity
EDI-OCTEnhanced depth imaging optical coherent tomography
OCTOptical coherent tomography
FAGFluorescein angiography
ICGAIndocyanine green angiography
RERight eye
LELeft eye
SRDSerous retinal detachment
RRDRhegmatogenous retinal detachment
RPERetinal pigment epithelium
SBScleral buckling
SRFDSubretinal fluid drainage
SOSympathetic ophthalmia
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
The authors would like to express their gratitude to Zahra Emaverdian MSc., Sepideh Nazari Noghabi MSc., Roghaye Kahani BSc., and Roya Gholamzadeh BSc. at Khatam-al-Anbia Eye Hospital, Mashhad, Iran. Moreover, the researchers appreciate the kind supports of Captain Mohammad Mahdi Sarshar.
Authors’ contributions
All the authors contributed significantly to this research and agreed to be accountable for all aspects of the work. SMH took part in patient’s participating in clinical analysis, and interpretation of imaging, and revising the draft. NS, MG, MAz helped to gather the patient’s evaluations and draft the manuscript. MAb participated in the acquisition of clinical data, clinical analysis and interpretation, and revising and finalizing the manuscript. All authors read and approved the final manuscript.
Funding
The authors received no funding. It is the authors’ own work, not funded by government or academicals institutes.
Availability of data and materials
The datasets used and/or analyzed during the current study can be provided by the corresponding author on reasonable request.
Ethics approval and consent to participate
Not Applicable.
Consent for publication
A consent form was obtained from the patient for imaging, data publication, and identifying clinical details.
Competing interests
The authors declare that they have no competing interests. | Recovered | ReactionOutcome | CC BY | 33615391 | 20,222,014 | 2021-02-22 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Drug ineffective'. | Fulminant inflammatory demyelination presenting as stroke-in-evolution in an elderly subject.
Fulminant inflammatory demyelination is a possible presentation of inflammatory demyelinating disorders, thus representing a potential stroke mimic especially in younger patients.
To describe clinical and diagnostic pitfalls in a case of fulminant inflammatory demyelination presenting with stroke-like symptoms in an elderly patient.
Case report and case-based review of the literature.
A 67-year-old woman, who accessed the emergency room as suspect stroke for hyperacute onset of rapidly worsening speech impairment and drowsiness, was later diagnosed with a huge brain inflammatory demyelination. Clinical, laboratory, and neuroimaging tests did not allow to put a more specific diagnosis. Due to the rapidly deteriorating course, she received immunosuppression with benefit.
This report is meant to highlight the diagnostic challenges connected with fulminant inflammatory demyelination, which sometime can resemble a stroke-in evolution and appear clinically unfitting for inclusion in any specific pathological entities within the broad-spectrum of inflammatory demyelinating disorders.
pmc1 BACKGROUND
Inflammatory demyelinating disorders (IDD) represent a potential, although uncommon, stroke mimic, which should always be considered in the emergency department (ED) setting, particularly in young subjects showing acute onset of focal neurological deficits (Gibson & Whiteley, 2013).
Acute‐onset IDD can indeed be associated with rapid neurological deterioration configuring a clinical entity defined as fulminant inflammatory demyelination (FID). FID, which can be expression of several pathological entities within central nervous system (CNS) IDD spectrum, is classically associated with poor outcome, but prompt recognition through MRI and early, aggressive treatment can improve the prognosis (Bevan & Cree, 2015).
Here, we describe a case of FID in an elderly woman, where the hyperacute onset and the rapid worsening of symptoms resembled a stroke‐in evolution.
2 CASE REPORT
A 67‐year‐old woman, without remarkable medical and neurological history, accessed the ED for acute onset of speech impairment and drowsiness. Clinical assessment revealed moderate hypertension (165/85 mmHg) and mild leukocytosis (12.1 × 103/microL; r.v. 4.8–10.8) without fever. Neurological examination, at 2 hr from onset, revealed normal alertness, nonfluent aphasia and moderate motor and sensory right‐side impairment (NIHSS 9). In the suspect of a left middle cerebral artery stroke, a brain CT was performed, detecting a wide, pale hypodensity, with finger‐like borders and flattened cerebral sulci in the left hemisphere (Figure 1). Intra and extra‐cranial vessels CT angiography resulted normal excluding eligibility for reperfusion treatments and leading to hospitalization. Within 24 hr from the onset, the patient showed rapid neurological deterioration, up to comatose state and right hemiplegia‐hemianesthesia (GCS = 5, NIHSS = 25).*
FIGURE 1 Brain CT performed at the ED, revealing in the left hemisphere an extensive, pale hypodensity with finger‐like borders associated to flattened cerebral sulci*
Anamnestic revision detected symptoms of upper respiratory tract infection with slight fever and headache, during the preceding 3 days. Cerebrospinal fluid (CSF) examination showed mild pleocytosis (11 lymphocytes/mm3, r.v. <2), hyperproteinorrachia (albumin 63 mg/dl, r.v. 10–30), and “mirror pattern” oligoclonal bands. An extensive infective screening on blood and CSF (bacterial and mycobacterial cultures, PCRs/antibody testing for HIV, HSV1‐2, JCV, Enterovirus, VZV, West Nile virus, Panflavivirus, Mycoplasma, Legionella, and Pneumococcus) resulted negative. A broad‐spectrum, empirical therapy with ceftriaxone and acyclovir was started. No CNS‐specific autoantibodies (anti‐AQP4, anti‐MOG; onconeural panel: anti‐ Hu, Ma/Ta, GAD, amphiphysin, CV2/CRMP5; autoimmune encephalitis panel: anti‐NMDA‐R, LG1, CASPR2, GABA‐A and B, AMPA, Glu‐R1, Gly‐R1, and D2) were detected. Blood and CSF cellular immunophenotypes were normal without signs suggesting either systemic or CNS‐specific hematological disorders. Brain MRI, performed 24 hr after symptoms onset, showed, within the anterior portion of the left hemisphere white matter (WM), a diffuse T2‐hyperintense alteration, which involved the corpus callosum and spared the cortical gray matter. No restricted diffusion was detectable within the lesion. After gadolinium administration, a peripheral open‐ring pattern of contrast enhancement suggestive for IDD was detected (Figure 2a). No other brain alterations suggestive for demyelinating lesions were detected. No spinal cord involvement was detected by spine MRI and somatosensory evoked potentials. EEG excluded epileptic activity.
FIGURE 2 Axial FLAIR and postcontrast T1w images at different time points: additionally, for A and B, DWI trace and ADC sequences are shown. (a) 24 hr after symptoms onset: diffuse hyperintense alteration involving the left frontal lobe and deep white matter of the right frontal lobe, associated with a peripheral ring of contrast enhancement; there is no evidence of restricted diffusion on DWI trace and ADC sequences. (b) 11 days after symptoms onset (after conclusion of intravenous methylprednisolone treatment): disappearing of peripheral ring of contrast enhancement with progression of hyperintense alteration now partially involving the left parietal lobe and, more extensively, the right frontal lobe; there is no evidence of restricted diffusion on DWI trace and ADC sequences. (c) 25 days after symptoms onset (after first cyclophosphamide administration): initial reduction in size of T2 hyperintense alteration, without contrast enhancement. (d) 50 days after symptoms onset (after second cyclophosphamide administration): further reduction in size of T2 hyperintense alteration without contrast enhancement*
Treatment with methylprednisolone 1 g daily was started within 48 hr from onset and continued for 10 days, without any clinical improvement. Follow‐up MRI showed a widening of T2‐hyperintense alterations (Figure 2b), suggesting the need for a second‐line treatment. A single dose of cyclophosphamide (1 g/m2 body surface = 1.75 g, i.v.) was thus administrated. After 10 days, the patient showed a notable neurological improvement, with full recovery of consciousness, soon followed by partial improvement of verbal fluency and sensory‐motor deficits. After 35 days from the first, a second dose of cyclophosphamide (1.75 g, i.v.) was administered. A substantially complete clinical recovery was rapidly reached, and no other treatment was applied. Follow‐up neurological examinations after 1 month, 1 and 2 years revealed only residual right‐side pyramidal signs. Follow‐up MRIs revealed progressive improvement with almost complete resolution of previously described findings (Figure 2c,d). Over a 2‐year observation, no new brain or spinal cord alterations were detected and the subject did not experience neurological relapses or clinical worsening. Due to the favorable, monophasic course and the disappearance of the cerebral lesions at follow‐up MRIs, cerebral biopsy was not performed.*
3 DISCUSSION
The goal of the present report is to emphasize the diagnostic challenge connected with FID, particularly when affecting elderly. Whereas the hyperacute onset of focal neurological signs and the age of our patient initially suggested a cerebrovascular disorder, the subsequent clinical course and the neuroradiological features of the lesion oriented toward a possible IDD.
The prototypical IDD is represented by multiple sclerosis (MS), which generally affects young subjects showing space‐ and time‐disseminated WM lesions (Thompson et al., 2018). Uncommonly, certain subjects might show, since from the onset, atypical WM lesions with size >2.5 cm and mass effect (Wallner‐blazek et al., 2013) sometimes associated with a monophasic course of disease. The terms referring to these conditions are heterogeneous and range from rare MS variants such as tumefactive MS (TMS), Marburg's MS (MVMS), Balo's concentric sclerosis (BCS) to other distinct pathological entities with a presumable autoimmune inflammatory origin, such as acute disseminated encephalomyelitis (ADEM) (Bevan & Cree, 2015). Other Authors (Poser et al., 1992; Rahmlow & Kantarci, 2013) introduced the encompassing concept of tumefactive demyelinating lesions (TDL), defined as solitary large signal abnormalities associated with mass effect, perilesional edema, and/or ring enhancement, which may represent atypical presentation of the abovementioned IDD and a stand‐alone diagnosis. Clinical presentation includes headache, encephalopathy signs, and focal cortical signs depending on lesion size and location.
Besides the stroke‐mimic deception we faced in the ED, the diagnostic challenge of the present case is represented by the difficulty in formulating a definite diagnosis based on clinic‐ radiological data in the absence of histo‐pathological assessment. The clinical course during the 2‐year follow‐up period, coherently with the negative hematological tests performed at onset, helped to exclude cerebral lymphoma from the neuroradiological differential diagnosis (Chiavazza et al., 2018). Furthermore, no diffusion restriction was indeed evident at any time‐point within the lesion described, making less likely the possibility of lymphoma and ruling out the possibility of a stroke outside of the ED setting. It is, however, important to remember that in FID there can be association of gadolinium enhancement and restricted diffusion, with the former sometime chronologically following the latter (Hyland et al., 2013) BCS was excluded by the lack of the classical “onion‐like” MRI appearance, showing alternated iso‐ and hyperintense rings on T2‐weighted imaging, likely as expression of layers with relatively preserved or lost myelin (Bevan & Cree, 2015). MVMS could as well be excluded given the absence of progressive deterioration overtime, usually leading to death within months from onset (Bevan and Cree, 2015). TMS mostly occurs during the 2nd and 3rd decade (Lucchinetti et al., 2008), thus is atypical in the elderly. In our case, the lack of previous neurological history and pre‐existing demyelinating lesions, as well as the 2‐year follow‐up, ruled out MS.*
Acute disseminated encephalomyelitis affects mainly children and young individuals, with an incidence of 0.6 per 100,000 per year. This diagnosis is rare among young adults and almost exceptional beyond the age of 65, with only few cases reported in literature (Wang et al., 1996; Kaunzner et al., 2017). No criteria, indeed, have ever been established for diagnosis among adults. ADEM usually follows infections or vaccinations (Pohl et al., 2016) and occurs within 6 days to 6 weeks from an antigenic challenge; overlapping of neurologic and infective symptoms, as here described, is unusual and may point to a parainfective, rather than postinfective process. It is well known, however, that up to 26% of ADEM lacks of clear prodromal manifestations (Tenembaum et al., 2002).
Typically, ADEM patients develop neurological deficits sub‐acutely, conveying to peak within 2–5 days instead of the 24 hr here reported. Aggressive variants, such as Hurst's disease, present neurological deterioration within hours (Rahmlow & Kantarci, 2013) but are associated with hemorrhagic lesions, which were never detected in our patient.
Our report highlights the difficulty in defining a clear‐cut diagnosis in FID presenting some clinical features of multiple pathological entities (TDL, TMS, ADEM, Hurst's disease, parainfective demyelination) but also some relevant atypia precluding a conclusive labeling. The outcome‐arranged agreement to overlook pathological examination, deriving from a thoughtful risk‐benefit evaluation, contributed to this diagnostic pitfall (Hardy et al., 2016).
First‐line treatment with high‐dose intravenous steroids may show scarce efficacy, especially in IDD with atypical presentation (Jaskowiak, 2016). In these cases, progressive neurological and radiological deterioration can justify aggressive immunosuppression strategies (Berzero et al., 2016; Rahmlow and Kantarci, 2013). Plasma exchange is generally considered the second‐line therapy for FID patients not responding to corticosteroids (Hardy and Chataway, 2013), especially children and in patients with ring‐enhancing lesions and mass effect (Magaña et al., 2011), and however, given the rarity of the disease, no randomized controlled clinical studies are available and there are no evidences for effect on eventual disease reactivation. Other therapeutic options include immunosuppressors such as cyclophosphamide (Berzero et al., 2016; Rahmlow & Kantarci, 2013) that in our patient was associated with an impressive recovery. It is unclear, however, whether the recovery was associated with the treatment rather than the disease's nature itself. Clinical recovery is indeed frequent in ADEM, and follow‐up imaging demonstrates, in the majority of cases, partial or complete resolution usually conveying to a monophasic course of disease (Rahmlow and Kantarci, 2013; Tenembaum et al., 2002).
Fulminant inflammatory demyelination is usually not included among stroke differential diagnosis (Gibson & Whiteley, 2013). Nonetheless, a recent case series described the stroke‐mimic, fulminant course of pathologically proven ADEM affecting 5 subjects with age ranging from 57 to 85 (Tenembaum et al., 2002). The authors suggested that an exceptionally fulminant course in this population may be due to an age‐related decrease in repair efficacy and oligodendrocyte response.
4 CONCLUSION
Among the broad IDD spectrum, several pathological entities can present as FID. Specific IDD such as ADEM might show a particular fulminant course among elderly subjects. When dealing with hyperacute onset and rapidly worsening focal neurologic signs, once vascular etiology has been excluded, it is therefore always advisable considering FID among differential diagnoses. The diagnostic work‐up remains difficult for the presence of many partially and potentially overlapping IDDs often hindering clinical management. In the presence of severe and progressive neurological deterioration, not responsive to first‐line treatments, early, and aggressive immunosuppressive therapy can be considered.
CONFLICT OF INTEREST
None to declare.
AUTHOR CONTRIBUTION
All authors participated in the study and manuscript editing and take public responsibilities for the manuscript contents. 1) Simone Sacco and Ilaria Callegari involved in analysis and interpretation of data, drafting the article and revising it critically. 2) Isabella Canavero involved in acquisition, analysis and interpretation of data, coordination of contributors, and critical revision of the article. 3) Elisa Coloberti, Sabrina Ravaglia, Anna Simoncelli, and Lisa Maria Farina: involved in acquisition of data and critical revision of the article. 4) Anna Pichiecchio and Giuseppe Micieli involved in conception and design, acquisition, analysis and interpretation of data, and critical revision of the article.
ETHICAL APPROVAL
Written informed consent was obtained from the patient.
PEER REVIEW
The peer review history for this article is available at https://publons.com/publon/10.1002/brb3.1967.
DATA AVAILABILITY STATEMENT
Complete clinical data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy restrictions. Other data sharing is not applicable to this article as no datasets were generated or analyzed during the current study (case report and case‐based narrative review).
* Corrections added on March 18, 2021, after first online publication: The text “the following” was removed from the first paragraph in Section 2; the text “ at the MRI” was removed from the last paragraph in Section 2; Figures 1 and 2 were updated; the citation “(Bevan and Cree, 2015)” was added near the end of the third paragraph in Section 3. | ACYCLOVIR, CEFTRIAXONE, METHYLPREDNISOLONE | DrugsGivenReaction | CC BY | 33615744 | 20,069,045 | 2021-08 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Product use in unapproved indication'. | Fulminant inflammatory demyelination presenting as stroke-in-evolution in an elderly subject.
Fulminant inflammatory demyelination is a possible presentation of inflammatory demyelinating disorders, thus representing a potential stroke mimic especially in younger patients.
To describe clinical and diagnostic pitfalls in a case of fulminant inflammatory demyelination presenting with stroke-like symptoms in an elderly patient.
Case report and case-based review of the literature.
A 67-year-old woman, who accessed the emergency room as suspect stroke for hyperacute onset of rapidly worsening speech impairment and drowsiness, was later diagnosed with a huge brain inflammatory demyelination. Clinical, laboratory, and neuroimaging tests did not allow to put a more specific diagnosis. Due to the rapidly deteriorating course, she received immunosuppression with benefit.
This report is meant to highlight the diagnostic challenges connected with fulminant inflammatory demyelination, which sometime can resemble a stroke-in evolution and appear clinically unfitting for inclusion in any specific pathological entities within the broad-spectrum of inflammatory demyelinating disorders.
pmc1 BACKGROUND
Inflammatory demyelinating disorders (IDD) represent a potential, although uncommon, stroke mimic, which should always be considered in the emergency department (ED) setting, particularly in young subjects showing acute onset of focal neurological deficits (Gibson & Whiteley, 2013).
Acute‐onset IDD can indeed be associated with rapid neurological deterioration configuring a clinical entity defined as fulminant inflammatory demyelination (FID). FID, which can be expression of several pathological entities within central nervous system (CNS) IDD spectrum, is classically associated with poor outcome, but prompt recognition through MRI and early, aggressive treatment can improve the prognosis (Bevan & Cree, 2015).
Here, we describe a case of FID in an elderly woman, where the hyperacute onset and the rapid worsening of symptoms resembled a stroke‐in evolution.
2 CASE REPORT
A 67‐year‐old woman, without remarkable medical and neurological history, accessed the ED for acute onset of speech impairment and drowsiness. Clinical assessment revealed moderate hypertension (165/85 mmHg) and mild leukocytosis (12.1 × 103/microL; r.v. 4.8–10.8) without fever. Neurological examination, at 2 hr from onset, revealed normal alertness, nonfluent aphasia and moderate motor and sensory right‐side impairment (NIHSS 9). In the suspect of a left middle cerebral artery stroke, a brain CT was performed, detecting a wide, pale hypodensity, with finger‐like borders and flattened cerebral sulci in the left hemisphere (Figure 1). Intra and extra‐cranial vessels CT angiography resulted normal excluding eligibility for reperfusion treatments and leading to hospitalization. Within 24 hr from the onset, the patient showed rapid neurological deterioration, up to comatose state and right hemiplegia‐hemianesthesia (GCS = 5, NIHSS = 25).*
FIGURE 1 Brain CT performed at the ED, revealing in the left hemisphere an extensive, pale hypodensity with finger‐like borders associated to flattened cerebral sulci*
Anamnestic revision detected symptoms of upper respiratory tract infection with slight fever and headache, during the preceding 3 days. Cerebrospinal fluid (CSF) examination showed mild pleocytosis (11 lymphocytes/mm3, r.v. <2), hyperproteinorrachia (albumin 63 mg/dl, r.v. 10–30), and “mirror pattern” oligoclonal bands. An extensive infective screening on blood and CSF (bacterial and mycobacterial cultures, PCRs/antibody testing for HIV, HSV1‐2, JCV, Enterovirus, VZV, West Nile virus, Panflavivirus, Mycoplasma, Legionella, and Pneumococcus) resulted negative. A broad‐spectrum, empirical therapy with ceftriaxone and acyclovir was started. No CNS‐specific autoantibodies (anti‐AQP4, anti‐MOG; onconeural panel: anti‐ Hu, Ma/Ta, GAD, amphiphysin, CV2/CRMP5; autoimmune encephalitis panel: anti‐NMDA‐R, LG1, CASPR2, GABA‐A and B, AMPA, Glu‐R1, Gly‐R1, and D2) were detected. Blood and CSF cellular immunophenotypes were normal without signs suggesting either systemic or CNS‐specific hematological disorders. Brain MRI, performed 24 hr after symptoms onset, showed, within the anterior portion of the left hemisphere white matter (WM), a diffuse T2‐hyperintense alteration, which involved the corpus callosum and spared the cortical gray matter. No restricted diffusion was detectable within the lesion. After gadolinium administration, a peripheral open‐ring pattern of contrast enhancement suggestive for IDD was detected (Figure 2a). No other brain alterations suggestive for demyelinating lesions were detected. No spinal cord involvement was detected by spine MRI and somatosensory evoked potentials. EEG excluded epileptic activity.
FIGURE 2 Axial FLAIR and postcontrast T1w images at different time points: additionally, for A and B, DWI trace and ADC sequences are shown. (a) 24 hr after symptoms onset: diffuse hyperintense alteration involving the left frontal lobe and deep white matter of the right frontal lobe, associated with a peripheral ring of contrast enhancement; there is no evidence of restricted diffusion on DWI trace and ADC sequences. (b) 11 days after symptoms onset (after conclusion of intravenous methylprednisolone treatment): disappearing of peripheral ring of contrast enhancement with progression of hyperintense alteration now partially involving the left parietal lobe and, more extensively, the right frontal lobe; there is no evidence of restricted diffusion on DWI trace and ADC sequences. (c) 25 days after symptoms onset (after first cyclophosphamide administration): initial reduction in size of T2 hyperintense alteration, without contrast enhancement. (d) 50 days after symptoms onset (after second cyclophosphamide administration): further reduction in size of T2 hyperintense alteration without contrast enhancement*
Treatment with methylprednisolone 1 g daily was started within 48 hr from onset and continued for 10 days, without any clinical improvement. Follow‐up MRI showed a widening of T2‐hyperintense alterations (Figure 2b), suggesting the need for a second‐line treatment. A single dose of cyclophosphamide (1 g/m2 body surface = 1.75 g, i.v.) was thus administrated. After 10 days, the patient showed a notable neurological improvement, with full recovery of consciousness, soon followed by partial improvement of verbal fluency and sensory‐motor deficits. After 35 days from the first, a second dose of cyclophosphamide (1.75 g, i.v.) was administered. A substantially complete clinical recovery was rapidly reached, and no other treatment was applied. Follow‐up neurological examinations after 1 month, 1 and 2 years revealed only residual right‐side pyramidal signs. Follow‐up MRIs revealed progressive improvement with almost complete resolution of previously described findings (Figure 2c,d). Over a 2‐year observation, no new brain or spinal cord alterations were detected and the subject did not experience neurological relapses or clinical worsening. Due to the favorable, monophasic course and the disappearance of the cerebral lesions at follow‐up MRIs, cerebral biopsy was not performed.*
3 DISCUSSION
The goal of the present report is to emphasize the diagnostic challenge connected with FID, particularly when affecting elderly. Whereas the hyperacute onset of focal neurological signs and the age of our patient initially suggested a cerebrovascular disorder, the subsequent clinical course and the neuroradiological features of the lesion oriented toward a possible IDD.
The prototypical IDD is represented by multiple sclerosis (MS), which generally affects young subjects showing space‐ and time‐disseminated WM lesions (Thompson et al., 2018). Uncommonly, certain subjects might show, since from the onset, atypical WM lesions with size >2.5 cm and mass effect (Wallner‐blazek et al., 2013) sometimes associated with a monophasic course of disease. The terms referring to these conditions are heterogeneous and range from rare MS variants such as tumefactive MS (TMS), Marburg's MS (MVMS), Balo's concentric sclerosis (BCS) to other distinct pathological entities with a presumable autoimmune inflammatory origin, such as acute disseminated encephalomyelitis (ADEM) (Bevan & Cree, 2015). Other Authors (Poser et al., 1992; Rahmlow & Kantarci, 2013) introduced the encompassing concept of tumefactive demyelinating lesions (TDL), defined as solitary large signal abnormalities associated with mass effect, perilesional edema, and/or ring enhancement, which may represent atypical presentation of the abovementioned IDD and a stand‐alone diagnosis. Clinical presentation includes headache, encephalopathy signs, and focal cortical signs depending on lesion size and location.
Besides the stroke‐mimic deception we faced in the ED, the diagnostic challenge of the present case is represented by the difficulty in formulating a definite diagnosis based on clinic‐ radiological data in the absence of histo‐pathological assessment. The clinical course during the 2‐year follow‐up period, coherently with the negative hematological tests performed at onset, helped to exclude cerebral lymphoma from the neuroradiological differential diagnosis (Chiavazza et al., 2018). Furthermore, no diffusion restriction was indeed evident at any time‐point within the lesion described, making less likely the possibility of lymphoma and ruling out the possibility of a stroke outside of the ED setting. It is, however, important to remember that in FID there can be association of gadolinium enhancement and restricted diffusion, with the former sometime chronologically following the latter (Hyland et al., 2013) BCS was excluded by the lack of the classical “onion‐like” MRI appearance, showing alternated iso‐ and hyperintense rings on T2‐weighted imaging, likely as expression of layers with relatively preserved or lost myelin (Bevan & Cree, 2015). MVMS could as well be excluded given the absence of progressive deterioration overtime, usually leading to death within months from onset (Bevan and Cree, 2015). TMS mostly occurs during the 2nd and 3rd decade (Lucchinetti et al., 2008), thus is atypical in the elderly. In our case, the lack of previous neurological history and pre‐existing demyelinating lesions, as well as the 2‐year follow‐up, ruled out MS.*
Acute disseminated encephalomyelitis affects mainly children and young individuals, with an incidence of 0.6 per 100,000 per year. This diagnosis is rare among young adults and almost exceptional beyond the age of 65, with only few cases reported in literature (Wang et al., 1996; Kaunzner et al., 2017). No criteria, indeed, have ever been established for diagnosis among adults. ADEM usually follows infections or vaccinations (Pohl et al., 2016) and occurs within 6 days to 6 weeks from an antigenic challenge; overlapping of neurologic and infective symptoms, as here described, is unusual and may point to a parainfective, rather than postinfective process. It is well known, however, that up to 26% of ADEM lacks of clear prodromal manifestations (Tenembaum et al., 2002).
Typically, ADEM patients develop neurological deficits sub‐acutely, conveying to peak within 2–5 days instead of the 24 hr here reported. Aggressive variants, such as Hurst's disease, present neurological deterioration within hours (Rahmlow & Kantarci, 2013) but are associated with hemorrhagic lesions, which were never detected in our patient.
Our report highlights the difficulty in defining a clear‐cut diagnosis in FID presenting some clinical features of multiple pathological entities (TDL, TMS, ADEM, Hurst's disease, parainfective demyelination) but also some relevant atypia precluding a conclusive labeling. The outcome‐arranged agreement to overlook pathological examination, deriving from a thoughtful risk‐benefit evaluation, contributed to this diagnostic pitfall (Hardy et al., 2016).
First‐line treatment with high‐dose intravenous steroids may show scarce efficacy, especially in IDD with atypical presentation (Jaskowiak, 2016). In these cases, progressive neurological and radiological deterioration can justify aggressive immunosuppression strategies (Berzero et al., 2016; Rahmlow and Kantarci, 2013). Plasma exchange is generally considered the second‐line therapy for FID patients not responding to corticosteroids (Hardy and Chataway, 2013), especially children and in patients with ring‐enhancing lesions and mass effect (Magaña et al., 2011), and however, given the rarity of the disease, no randomized controlled clinical studies are available and there are no evidences for effect on eventual disease reactivation. Other therapeutic options include immunosuppressors such as cyclophosphamide (Berzero et al., 2016; Rahmlow & Kantarci, 2013) that in our patient was associated with an impressive recovery. It is unclear, however, whether the recovery was associated with the treatment rather than the disease's nature itself. Clinical recovery is indeed frequent in ADEM, and follow‐up imaging demonstrates, in the majority of cases, partial or complete resolution usually conveying to a monophasic course of disease (Rahmlow and Kantarci, 2013; Tenembaum et al., 2002).
Fulminant inflammatory demyelination is usually not included among stroke differential diagnosis (Gibson & Whiteley, 2013). Nonetheless, a recent case series described the stroke‐mimic, fulminant course of pathologically proven ADEM affecting 5 subjects with age ranging from 57 to 85 (Tenembaum et al., 2002). The authors suggested that an exceptionally fulminant course in this population may be due to an age‐related decrease in repair efficacy and oligodendrocyte response.
4 CONCLUSION
Among the broad IDD spectrum, several pathological entities can present as FID. Specific IDD such as ADEM might show a particular fulminant course among elderly subjects. When dealing with hyperacute onset and rapidly worsening focal neurologic signs, once vascular etiology has been excluded, it is therefore always advisable considering FID among differential diagnoses. The diagnostic work‐up remains difficult for the presence of many partially and potentially overlapping IDDs often hindering clinical management. In the presence of severe and progressive neurological deterioration, not responsive to first‐line treatments, early, and aggressive immunosuppressive therapy can be considered.
CONFLICT OF INTEREST
None to declare.
AUTHOR CONTRIBUTION
All authors participated in the study and manuscript editing and take public responsibilities for the manuscript contents. 1) Simone Sacco and Ilaria Callegari involved in analysis and interpretation of data, drafting the article and revising it critically. 2) Isabella Canavero involved in acquisition, analysis and interpretation of data, coordination of contributors, and critical revision of the article. 3) Elisa Coloberti, Sabrina Ravaglia, Anna Simoncelli, and Lisa Maria Farina: involved in acquisition of data and critical revision of the article. 4) Anna Pichiecchio and Giuseppe Micieli involved in conception and design, acquisition, analysis and interpretation of data, and critical revision of the article.
ETHICAL APPROVAL
Written informed consent was obtained from the patient.
PEER REVIEW
The peer review history for this article is available at https://publons.com/publon/10.1002/brb3.1967.
DATA AVAILABILITY STATEMENT
Complete clinical data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy restrictions. Other data sharing is not applicable to this article as no datasets were generated or analyzed during the current study (case report and case‐based narrative review).
* Corrections added on March 18, 2021, after first online publication: The text “the following” was removed from the first paragraph in Section 2; the text “ at the MRI” was removed from the last paragraph in Section 2; Figures 1 and 2 were updated; the citation “(Bevan and Cree, 2015)” was added near the end of the third paragraph in Section 3. | ACYCLOVIR, CEFTRIAXONE, METHYLPREDNISOLONE | DrugsGivenReaction | CC BY | 33615744 | 20,069,045 | 2021-08 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Agitation'. | Comprehensive clinical phenotyping of nitroglycerin infusion induced cluster headache attacks.
Nitroglycerin administration allows the study of cluster headache attacks in their entirety in a standardised way.
A single-blind, placebo-controlled, cross-over study using weight-calculated intravenous nitroglycerin administration at 0.5 µg/kg/min over 20 minutes to study cluster headache attacks, including accompanying non-headache symptoms and cranial autonomic symptoms.
Thirty-three subjects with cluster headache were included in the study; 24 completed all three study visits. Nitroglycerin-induced attacks developed in 26 out of 33 subjects (79%) receiving unblinded nitroglycerin infusion, and in 19 out of 25 subjects (76%) receiving single-blinded nitroglycerin infusion, compared with one out of 24 subjects (4%) receiving single-blinded placebo infusion. Episodic cluster headache subjects had a shorter latency period to a nitroglycerin-induced attack compared to the chronic cluster headache (CCH) subjects (U = 15, z = -2.399, p = 0.016). Sixteen of nineteen episodic cluster headache (mean, 84%; 95% confidence interval, 66-100%) and 11 of 14 chronic cluster headache subjects developed a nitroglycerin-induced attack (79%, 54-100%) following the unblinded nitroglycerin infusion. Following the single-blinded nitroglycerin infusion, eight out of 13 episodic cluster headache (62%, 31-92%) and 11 out of 12 chronic cluster headache (92%, 73-100%) subjects developed nitroglycerin-induced attacks. Nitroglycerin induced non-headache symptoms in the majority of subjects receiving it: 91% in the open unblinded nitroglycerin visit and 84% in the single-blinded nitroglycerin visits, compared with 33% in the single-blinded placebo visit. Cranial autonomic symptoms were induced by nitroglycerin infusion, 94% in the open unblinded nitroglycerin visit and 84% in the single-blinded nitroglycerin visit, compared with 17% in the single-blinded placebo visit.
Intravenous weight-adjusted nitroglycerin administration in both episodic cluster headache in bout and chronic cluster headache is effective and reliable in inducing cluster headache attacks, cranial autonomic symptoms and non-headache symptoms.
Introduction
Due to the episodic nature of acute attacks of cluster headache, a standardised and reliable method for triggering attacks is necessary for their complete study. There have been several substances used to trigger attacks, including histamine (1,2), meta-chloro-phenylpiperazine (mCPP) (3) and more recently calcitonin gene-related peptide (CGRP) (4). Nitroglycerin (NTG) is the most frequently employed substance in human experimental modelling of cluster headache attacks, being used since 1953 (2) (Table 1).
Table 1. Review of studies using nitroglycerin to induce cluster headache attacks.
Study Number of CH patients NTG dose and route Control Placebo Rate of induced CH attack Latency period before onset of headache
(range in minutes)
Peters 1953 (2) 14 1.3 mg sublingual No, but compared with migraine, combination of CH and migraine, vasodilating head pain and tension headache No, but compared with histamine and nicotinic acid 78.6% Not reported
Ekbom 1968 (5) 38 ECH: 28 in bout, 15 out of bout (of which five were tested in bout as well) 1 mg sublingual No No In bout ECH 100% (n = 28)
Out of bout 0% (n = 15) 12–72
Barre 1982 (6) 10 CH: two CCH, nine ECH in bout 1 mg sublingual No No 100% 34–52
Mean 45.9
Drummond et al. 1984 (7) 29 CH 0.9 mg sublingual No No 76% Within 90 min
Drummond et al. 1985 (8) 22 CH: 10 CCH, 12 ECH in bout
0.9 mg sublingual Yes, 10 in the control group without headache No ECH 75% (n = 9)
CCH 60% (n = 6) 9–90
Mean 44
Bogucki 1990 (9) 21 ECH in bout 1 mg sublingual No No 67% (n = 14)
30–65
Dahl et al. 1990 (10) 15 ECH in bout 1 mg sublingual 10 healthy controls No 53% (n = 8)
Controls: not reported 30–65
Hannerz et al. 1992 (11) Eight ECH: five in bout and three out of bout 1 mg sublingual No No In bout ECH 100% (n = 5) Not reported
Fanciullacci et al. 1995 (12) 18 in bout ECH, 12 out of bout ECH 0.9 mg sublingual No No In bout ECH 100% (n = 18)
Out of bout ECH 0% (n = 12) 39–86
Fanciullacci et al. 1997 (13) 11 in bout ECH, eight out of bout ECH 0.9 mg sublingual No No In bout ECH 100% (n = 11)
Out of bout ECH 0% (n = 8) 18–50
Hsieh et al. 1996 (14) Seven ECH: four in bout ECH, three out of bout 1 mg sublingual No No In bout ECH 100%
Out of bout ECH 0% 18–35
May et al. 1998 (15) Nine CCH, eight out of bout ECH 1.0–1.2 mg spray No No CCH 100%
Out of bout ECH 0% Not reported
Costa et al. 2000 (16) 15 CH: Six ECH, nine CCH 0.9 mg sublingual No No ECH 33% (n = 2)
CCH 78% (n = 7) 19–41
Costa et al. 2003 (17) 18 ECH in bout 0.9 mg sublingual Yes, 12 healthy sex and age-matched No ECH 67% (n = 12)
Controls 0% 19–41
Sances et al. 2004 (18) 42 CH: 29 ECH (11 out of bout), 13 CCH 0.9 mg sublingual Yes, 53 healthy controls No In bout ECH and CCH 81% (n = 25 out of 31)
Controls 7.5% developed headache in 7-hour post-NTG Mean onset latency of 65.4 ± 54.7
Cluster headache patients suffer from recurrent episodes of severe unilateral pain in the trigeminal region; therefore, historically, the main emphasis has been centred around the pain onset of a cluster headache, and indeed this is often used as the indicator of the start of the attack. However, from clinical practice, there has been growing awareness of nonpainful symptoms preceding the onset of pain (19,20) and in recent years, the clinical phenotype of cluster headache has been further characterised by retrospective accounts (21–23) and prospective diaries (24,25).
The most frequent route of administration of NTG has been sublingual; however, the bioavailability of sublingual NTG is extremely variable (26). Therefore, we used a weight-calculated dose for intravenous infusion in a standardised single-blind, placebo-controlled study. NTG is a pro-drug of nitric oxide, with predominant actions on the cyclic guanylate phosphate (cGMP) pathway (27), and from pre-clinical studies there are indications of neural actions more centrally. This study is the first single-blind, placebo-controlled cross-over study using a weight-adjusted dose of nitroglycerin administered intravenously in cluster headache patients, thereby allowing comprehensive investigation of the various stages of the acute attack of cluster headache.
Methods
Subject selection and recruitment
The study was advertised on the UK cluster headache patient website OUCH (UK) (Organisation for the Understanding of Cluster Headache UK) (https://ouchuk.org/research/research-volunteers-needed) and in the tertiary Headache centre in King’s College Hospital, London. Subjects interested in participating would make contact via a dedicated research email. Subjects would then be screened for eligibility for the study via emails and a telephone call; those who met the criteria and were interested in participating were invited to attend the study visit. The study was approved by the London, City & East Research Ethics Committee (Ref Number 16/LO/0693). Data were collected from August 2016 until January 2019.
The subjects enrolled fulfilled the ICHD-3 beta criteria for cluster headache (28), and were between the ages of 18 and 60, with no significant previous medical history and no previous syncope or history of autonomic dysfunction. They had had a reliable response to high flow oxygen and/or subcutaneous sumatriptan during spontaneous attacks and normal brain neuroimaging. Women in child-bearing age were required to use reliable contraceptive methods during the study. Subjects were excluded if they were pregnant or breastfeeding, and who had any significant psychiatric disease, diagnosis of another primary headache type (other than migraine) or chronic pain syndrome, any medical history that would have contraindications to receiving NTG, use of preventive medication other than verapamil, or taking indomethacin for any reason, allergies to the medications used in the study or intolerance to high flow oxygen, and use of illicit drugs during the study.
Study visits
The study comprised of three visits in total, with each visit separated by a minimum of 1 week. During the first visit, subjects consented and a full headache history with a physical examination of the neurological and cardiovascular systems was performed, along with recordings of the baseline blood pressure, lying and standing blood pressure, heart rate, oxygen saturation, weight and electrocardiogram. Female subjects were required to have a urinary pregnancy test before the start of the infusion.
Open NTG infusion
If deemed eligible, subjects received an intravenous infusion of nitroglycerin at 0.5 µg/kg/min over 20 minutes. Subjects remained recumbent for 30 minutes before the infusion, and after the NTG infusion, subjects received 250 mL of 0.9% sodium chloride intravenously. The blood pressure and pulse were checked at the start of the infusion, and every 5 min during the infusion.
Phenotypic characterisation
Every 5 minutes, subjects were asked to rate their pain level from a scale from no pain, mild, moderate to severe, where severe equates to their most severe attack, and they were asked a questionnaire of non-headache symptoms and cranial autonomic symptoms (CAS) (Figure 1). If the subject experienced pain, further details were obtained regarding the location and characteristic. Beyond the cluster headache attack, subjects were asked to report any other headache types and in particular NTG headache, which has been well described from migraine studies (29). The NTG headache was assessed for severity, phenotype, accompanying non-headache symptoms and duration. Subjects were actively encouraged to report any symptoms as and when they developed. Following the infusion, at 10 minute intervals, any developments in pain, non-headache symptoms and CAS were recorded for a total of 120 minutes after the infusion, based on the latency period reported from previous studies (Table 1).
Figure 1. Questionnaire for non-headache and cranial autonomic symptoms.
B: bilateral; R: right-sided; L: left-sided.
Single-blinded NTG and placebo infusions
During the two single-blinded visits, subjects either received intravenous nitroglycerin at 0.5 µg/kg/min over 20 minutes or an equal volume of 0.9% sodium chloride at the same rate over 20 minutes, followed by the same 120 minutes of observations (Figure 2). The sequence was pre-determined using the randomise function in Excel; however, the investigator was able to amend this in certain situations if the subject was episodic and due to finish their bout.
Figure 2. Outline of events from open unblinded nitroglycerin visit.
BP: blood pressure; CAS: cranial autonomic symptoms; NTG: nitroglycerin; IV: intravenous.
Treatment of acute attacks
Acute treatment was administered at 20 minutes from the start of attack either with sumatriptan 6 mg subcutaneous injection (Imigran 6 mg/0.5 ml solution for injection pre-filled syringes, GlaxoSmithKline UK Ltd, or sumatriptan 6 mg/0.5 ml solution for injection pre-filled pens, Sun Pharmaceuticals Industries Europe B.V.) or with 15 L/min oxygen via a non-rebreather mask (O2Star™ non-rebreather oxygen mask M/L, Dräger). The visit was concluded only when the subject was pain free.
Statistical analysis
The data was tabulated (Excel for Mac v 16.30), and descriptive statistics were performed to summarise data (SPSS Statistics version 26 for Mac and Excel). Mann-Whitney tests were performed on time until attack onset and time until CAS onset for those that developed NTG-triggered cluster headache attacks and CAS, comparing the differences in ECH with CCH subgroups. Kaplan-Meier survival graphs were used to examine the time until onset of event; that is, survival of no cluster headache attack status, or absence of CAS after NTG infusion for 140 minutes (20 minutes of infusion and 120 minutes of post-infusion observation), with log-rank statistical testing; P < 0.05 was considered significant. Graphs were made using SPSS and violin plots were made using GraphPad Prism 8 for Mac OS.
Results
Demography
A total of 229 subjects were contacted to check for eligibility, of which 33 were included in the study; 24 completed all three study visits (Figure 3). All patients fulfilled the ICHD-3 beta criteria for cluster headache, 19 episodic cluster headache in bout (58%) and 14 chronic cluster headache (42%) (Table 2). The majority were male (n = 24, 73%) with a male: female ratio of 3:1. The average age was 41 (SD 10), with the mean age of females (34 years, SD 9) younger than in males (44 years, SD 9) in this cohort. Subjects had had the condition for a median of 9 years (IQR 5–16).
Figure 3. Subject numbers throughout the study.
Table 2. Subject characteristics.
Subject Age Sex Subtype Side of attacks Time since first attack (years) Average attack frequency (per day) Average attack duration when untreated (mins) Average bout duration (weeks) Verapamil (total daily dose in mg)
1 55 M Chronic Right 5 2 45 – 480
2 28 F Chronic Right 12 7 150 – –
3 40 M Episodic Right 20 3 150 8 –
4 38 F Episodic Left 12 2 120 4 –
5 53 M Chronic Left 15 4 35 – 960
6 48 M Episodic Left 25 5 52.5 5 480
7 23 M Episodic Left 8 2 120 10 –
8 43 M Chronic Right 9 1 40 – –
9 43 M Episodic Right 13 3 60 5 240
10 44 M Episodic Right 27 6 45 6 –
11 47 M Episodic Right 3 1 105 20 –
12 48 M Episodic Left 26 3 180 10 560
13 40 M Episodic Right 5 3 60 8 –
14 50 M Episodic Right 10 2 105 8 –
15 56 M Episodic* Right 24 1 45 – –
16 35 M Episodic Left 7 2 150 6 240
17 58 M Episodic Left 3 1 135 24 –
18 43 M Chronic Left 4 2 60 – –
19 32 M Episodic Left 3 3 50 12 600
20 49 F Episodic Right 8 5 50 9 –
21 49 M Chronic Right 35 2 90 – –
22 57 M Chronic Right 20 5 65 –
23 40 F Chronic Left 4 1.5 120 – 640
24 44 M Chronic Right 6 2 90 – 720
25 23 F Episodic Right 9 2.5 90 6 –
26 40 M Chronic Left 17 1.5 180 – –
27 20 F Chronic Right 6 1.5 150 – –
28 31 F Episodic Right 14 2 75 11 –
29 35 M Episodic Left 9 2 90 3 –
30 38 F Chronic Left 6 1.5 180 – 240
31 49 M Episodic Left 0.5 1.5 37.5 21 400
32 35 F Chronic Left 4 0.3 30 – 600
33 32 M Chronic Left 10 6 60 – –
M: male; F: female.
*Subject was chronic but became episodic during study with no attacks in 6 months.
Clinical phenotyping of subjects by history
Pain features
There was a near-equal split between the laterality of attacks; 17 subjects had right-sided attacks (52%), and 16 subjects had left-sided attacks (49%). The median number of attacks per day was two (IQR 1.5–3) lasting a median of 90 minutes (IQR 50–128). Verapamil was the only preventive allowed on the study; 12 subjects (36%) were on verapamil ranging from 240 mg to 960 mg per day.
Migraine, accompanying features and non-headache symptoms in spontaneous attacks
In this cohort, 58% (n = 19) had a concurrent migraine (28): five had migraine with aura, of which four had visual aura and one had facial sensory aura. Of the subjects who did not meet the diagnostic criteria for migraine (28) (n = 14, 42%), the majority had either migraine markers and/or a family history of migraine. Migraine markers were defined if subjects experienced: childhood cyclic nausea and vomiting, motion sickness, cold stimulus-induced headache, hangover headache and jetlag. Four subjects did not have migraine markers, and three subjects (9%) did not have either migraine marker or a family history of migraine. Subjects (n = 24, 73%) reported accompanying symptoms with their spontaneous attacks, the most common symptoms being cranial allodynia (n = 15), photophobia (n = 15), nausea (n = 11) and phonophobia (n = 10).
Non-headache attack symptoms
The majority reported non-headache symptoms in the lead up to their spontaneous cluster headache attacks (n = 27, 82%), with the commonest symptoms being concentration difficulties (n = 18), mood changes (n = 15), neck stiffness (n = 13) and yawning (n = 8). The median onset time of symptoms was 10 minutes (IQR 2–30) before the onset of pain. Although most symptoms start before the onset of pain, five subjects only reported developing the symptoms during the attack.
Twenty-eight subjects reported non-headache symptoms following their cluster headache attacks (85%), the commonest symptoms being tiredness (n = 27), mood changes (n = 13), concentration difficulties (n = 12), and neck stiffness (n = 7). The median duration of symptoms was 120 minutes (IQR 53–315).
Attack triggers
The most commonly reported triggers for spontaneous attacks were alcohol ingestion (n = 22), followed by changes in temperature (n = 12), strong smells such as from nail varnish, paint (n = 11) followed by disrupted sleep (n = 4) and exercise (n = 3). Other triggers mentioned were stress (n = 2), caffeine (n = 2), changing time zones (n = 1), let down from stress (n = 1), being in a pressurised cabin on an airplane (n = 1), vardenafil (n = 1), and dehydration (n = 1). All subjects reported attacks within a few hours of alcohol ingestion, no one reported a next-day effect.
Clinical phenotyping of open NTG visit
NTG triggered cluster headache-like attacks (n = 26, 79%), CAS (n = 31, 94%) and agitation (n = 24, 73%) during the open unblinded NTG visit. In the episodic cluster headache group, 16 out of 19 developed an NTG-induced attack (mean, 84%; 95% CI, 66–100%) and in the chronic cluster headache group, 11 out of 14 developed an NTG-induced attack (79%, 54–100%). Five out of the 31 subjects developed CAS, but did not develop an attack; of these subjects, three developed mild generalised pain, one developed restless legs, and one developed CAS on the contralateral side to the subject’s spontaneous attack phenotype, with a generalised headache. These cases were excluded.
The median onset time for CAS to develop from the start of the NTG infusion was 31 minutes (IQR 13–46). The median onset for an NTG-induced attack was 30 minutes (IQR 20–39) and the median time to maximum pain, if reached, was 51 minutes (IQR 39–70). The most common first cranial autonomic symptoms brought on by NTG infusion were nasal congestion (n = 10), conjunctival injection (n = 5), lacrimation (n = 4) and periorbital oedema (n = 3).
Clinical phenotyping of single-blinded NTG and placebo visit
During the single-blinded visits, NTG induced attacks in 19 subjects (76%); three subjects did not have an attack (12%), two subjects developed migraine-like headache (8%) and one subject developed unilateral mild pain without CAS or agitation (4%) (Table 3). In the placebo group, only one developed an attack (4%), two subjects developed unilateral mild pain without CAS or agitation (8%) and two subjects experienced short-lived unilateral CAS (8%). Of the subjects receiving NTG, eight out of 13 ECH (mean, 62%; 95% CI, 31%-92%) and 11 out of 12 CCH (92%, 73–100%) developed NTG-induced attacks (Figure 4(a)).
Table 3. Subject characteristics and comparison between spontaneous attack and triggered attack from single-blinded nitroglycerin visit, M = male, F = female, ECH = episodic cluster headache, CCH = chronic cluster headache, L = Left, R = Right, Y = Yes, N = No, VRS = verbal rating scale, mod = moderate, O2 = high flow oxygen via non-rebreather mask, suma = sumatriptan.
Subject Age Sex Subtype Migraine Verapamil (total daily dose in mg) Spontaneous attack Triggered attack- single-blinded NTG visit
Laterality Severity CAS Agitation Laterality Severity/VRS CAS Agitation Feels like spontaneous attack Treatment Last spontaneous attack (days)
1 55 M CCH N 480 R 9/10 Conjunctival injection, nasal congestion, lacrimation. 3 months of R Horner’s syndrome in 2007, now resolved Y R 10/10
VRS 3 Conjunctival injection, nasal congestion, lacrimation, periorbital oedema Y Y O2 158
2 28 F CCH Y
– R 10/10 Periorbital oedema/ptosis, nasal congestion, dry eye then lacrimation Y R 10/10
VRS 3 Periorbital oedema, nasal congestion, facial flushing Y Y O2 128
3 40 M ECH N – R 10/10 Lacrimation, rhinorrhoea, ptosis Y R 10/10
VRS 3 Lacrimation, conjunctival injection, periorbital oedema, nasal congestion, aural fullness and facial droop Y Y Suma 1
4 38 F ECH Y – L 10/10 Lacrimation, conjunctival injection, periorbital oedema, nasal congestion, ptosis, facial flushing Y No attack, developed generalised pain 4/10 Y N N/A 1
5 53 M CCH N 960 L 10/10 Rhinorrhoea, ptosis Y L 10/10
VRS 3 Conjunctival injection, eye grittiness, lacrimation Y Y O2 4
6 48 M ECH N
480 L 8/10 Nasal congestion, lacrimation Y Did not attend
7 23 M ECH Y – L 10/10 Lacrimation, conjunctival injection, nasal congestion, ptosis, facial flushing Y Did not attend
8 43 M CCH N – R 10/10 Nasal congestion, rhinorrhoea, lacrimation, facial flushing Y R 10/10
VRS 3 Nasal congestion, conjunctival injection, eye grittiness Y Y Suma <1
9 43 M ECH N 240 R 10/10 Lacrimation, conjunctival injection, facial flushing, ptosis, facial droop Y Did not attend
10 44 M ECH N – R 10/10 Nasal congestion, ptosis, periorbital oedema, lacrimation, flushing Y No attack, L mild hangover like headache, with nasal congestion.
After study visit felt nauseous and vomited, then slept, headache free at 7pm N N O2- no response <1
11 47 M ECH N – R Severe attacks 10/10 Nasal congestion, aural fullness Y R 7/10
VRS 2/3 moderate/
severe Nasal congestion, conjunctival injection, aural fullness Y Y Suma 13
12 48 M ECH N 560 L 10/10 Lacrimation, nasal congestion, periorbital oedema Y Did not attend
13 40 M ECH Y – R 10/10 Nasal congestion, ptosis, conjunctival injection, lacrimation, throat tightness, rhinorrhoea Y No attack, bilateral mild headache 4/10 with nasal congestion Y, brief (7 mins) N N/A 19
14 50 M ECH Y – R 10/10
Lacrimation, periorbital oedema, nasal congestion, rhinorrhoea Y Did not attend
15 56 M ECH Y – R 10/10 Lacrimation, rhinorrhoea, facial flushing, gritty eyes, conjunctival injection Y with severe attacks Did not attend
16 35 M ECH Y 240 L 10/10 Nasal congestion, conjunctival injection, ptosis, lacrimation, rhinorrhoea Y Not attack, milder than a shadow and no CAS N N N/A 16
17 58 M ECH Y – L 10/10 Nasal congestion, rhinorrhoea, lacrimation, aural fullness, throat swelling Y L 7/10
VRS 2–3 (mod-severe) Nasal congestion, rhinorrhoea, voice change, lacrimation Y Y Suma 1
18 43 M CCH Y – L (70%) Mild 6/10, severe 10/10 Nasal congestion, periorbital oedema, aural fullness, facial flushing Y L Mild,
VRS 1 Nasal congestion Y Y- shadow O2 7
19 32 M ECH Y 600 L 10/10 Lacrimation, conjunctival injection, facial flushing Y L 7–8/10
VRS 2–3
(mod-severe) Lacrimation, eye grittiness, nasal congestion, facial flushing Y Y O2 <1
20 49 F ECH Y – R 10/10 Ptosis, periorbital oedema, lacrimation, nasal congestion, rhinorrhoea, (aural fullness with severe attacks) Y R 6–7/10
VRS 2 mod Nasal congestion, periorbital oedema, lacrimation, conjunctival injection Y Y O2 7
21 49 M CCH Y – R 4–10/10 Facial flushing, nasal congestion, ptosis, lacrimation, rhinorrhoea, conjunctival injection Y L 8/10
VRS 2–3
(mod-severe)
Facial flushing, lacrimation, periorbital oedema, conjunctival injection Y Y, but on L rather than R Suma <1
22 57 M CCH N – R 10/10 Lacrimation, conjunctival injection, nasal congestion, rhinorrhoea Y No attack, no pain and no CAS N N N/A 26
23 40 F CCH Y 640 L 10/10
Lacrimation, conjunctival injection, periorbital oedema, rhinorrhoea, ptosis, aural fullness Y Did not attend
24 44 M CCH N 720 R 10/10 Lacrimation, conjunctival injection, periorbital oedema, facial flushing Y Did not attend
25 23 F ECH Y – R 6–10/10 Nasal congestion, lacrimation, periorbital oedema. Rhinorrhoea and facial flushing with severe attacks Y R 7/10
VRS 2
(moderate) Nasal congestion, periorbital oedema Y Y O2 3
26 40 M CCH Y – L Shadow 4/10, daytime attacks 6–7/10, full attack 10/10 Ptosis, aural fullness, lacrimation, conjunctival injection, periorbital oedema, nasal congestion Y L 8.5–9/10
VRS 3 severe Nasal congestion, periorbital oedema, lacrimation Y Y Suma 3
27 20 F CCH N – R 8–9/10 Nasal congestion, lacrimation, rhinorrhoea, ptosis, aural fullness Y R 8/10
VRS 3
severe Nasal congestion, periorbital oedema Y Y O2 <1
28 31 F ECH Y – R 10/10 Nasal congestion, periorbital oedema, rhinorrhoea, ptosis, aural fullness Y R 2/10
VRS 1 (mild) Nasal congestion, facial swelling Y Y, but milder Suma 3
29 35 M ECH N – L Max pain 10/10 Nasal congestion, periorbital oedema, lacrimation, voice change (croaky). Facial flushing with severe attacks and rhinorrhoea after attack Y L 6–7/10
VRS 2 (moderate) Nasal congestion, lacrimation, conjunctival injection, voice change Y Y Suma <1
30 38 F CCH Y 240 L 4–10/10 Lacrimation, rhinorrhoea, conjunctival injection, facial flushing. Ptosis with severe attacks Y L 6–7/10
VRS 2 (moderate) Aural fullness Y Y Suma 1
31 49 M ECH Y 400 L 10/10 Nasal congestion, lacrimation, conjunctival injection, rhinorrhoea, ptosis, aural fullness. Prominent miosis after attack Y No attack, whole head felt heavy N N N/A 10
32 35 F CCH N 600 L 4/10 (on verapamil),
7/10 average Periorbital oedema, eye grittiness, facial flushing, lacrimation Y L 7/10
VRS 2–3
(mod-severe) Nasal congestion, conjunctival injection, facial flushing, lacrimation Y Y Suma 1
33 32 M CCH Y – L Severe attacks 10/10 Lacrimation, ptosis, nasal congestion, conjunctival injection, ptosis, facial flushing, eye grittiness Y L 6/10
VRS 2 (mod-severe) Lacrimation, nasal congestion, ptosis Y Y Suma <1
Figure 4. (a) Kaplan-Meier graph comparing time until cluster headache attack between the eight episodic cluster headache (ECH) and the 11 chronic cluster headache (CCH) subjects during single-blinded nitroglycerin (NTG) infusion, from the start of the infusion in minutes, log-rank P = 0.534. (b) Kaplan-Meier graph comparing time until cluster headache attack onset between the open unblinded (n = 33) and single-blinded (n =25) nitroglycerin (NTG) infusions with single-blinded placebo infusions (n = 24). Log-rank P = 0.000.
The median onset time to an induced attack was 33 minutes (IQR 15–42) from the start of the single-blinded NTG infusion, and in the single-blinded placebo visit only one subject developed an attack; the onset time was 10 minutes. On comparison of the attack onset time for the unblinded NTG, single-blinded NTG and single-blinded placebo visits, there was a difference between the placebo and NTG visits (P = 0.000, Figure 4(b)).
NTG headache
The majority of subjects developed an NTG headache (n = 28, 85%) following the NTG infusion in the unblinded open visit, of which 27 subjects had a migraine diagnosis (n = 18), had migraine markers (n = 10) and a family history of migraine (n = 18); only one subject did not have migraine, migraine markers or a family history of migraine. The median time from the start of NTG infusion was 3 minutes (IQR 2–6), and the median duration of NTG headache was 26 minutes (IQR 14–41).
Of the 25 subjects that went on to the single-blinded NTG visits, 18 (72%) developed NTG headache following NTG infusion, of which all had either migraine (n = 11), migraine markers (n = 7) or family history (n = 10). The median time of NTG headache onset from the start of NTG infusion in the blinded visit was 4 minutes (IQR 3–8), with a median duration of 26 minutes (IQR 9–45).
In the placebo visit, three of the 24 subjects (13%) developed NTG headache, median onset time was 13 minutes (range 1–18), and the median duration was 10 minutes (range 3–16).
Non-headache symptoms
The majority of subjects reported non-headache symptoms in both the open unblinded NTG visit (n = 30, 91%) and the single-blinded NTG visit (n = 21, 84%) visits. In the single-blinded placebo visit, eight subjects (33%) reported non-headache symptoms. The most common non-headache symptoms from the open unblinded NTG visit were neck stiffness, photophobia, thirst and allodynia. The most common non-headache symptoms from the single-blinded NTG visit were neck stiffness, yawning, thirst and photophobia (Table 4). The median number of non-headache symptoms reported in the open unblinded NTG visit was three (IQR 2–5), and from the single-blinded NTG visit was three (IQR 2–6), compared with two (IQR 2–3) on-headache symptoms in the single-blinded placebo group.
Table 4. Frequencies of non-headache symptoms reported during each visit.
Non-headache symptom Open unblinded NTG visit (n = 33) Single-blinded NTG visit
(n = 25) Single-blinded placebo visit
(n = 24)
Thirst 15 10 3
Craving 0 0 0
Yawning 8 12 4
Tiredness 4 3 0
Mood changes 5 4 1
Visual blurring 4 3 1
Neck stiffness 21 15 3
Irritability 3 3 0
Photophobia 18 10 1
Concentration difficulties 6 4 1
Phonophobia 4 6 0
Urinary symptoms 0 0 0
Speech disturbances 0 0 0
Nausea 6 3 0
Gastrointestinal discomfort 0 0 0
Movement sensitivity 5 5 1
Allodynia 9 8 2
In the open unblinded NTG visit, the median onset time of non-headache symptoms from the start of the infusion was 9 minutes (IQR 4–17) with the median maximum duration of the symptoms being 50 minutes (IQR 24–64), the duration is calculated from the first symptom until the end of the last symptom. In the single-blinded NTG visit, the median onset time was 5 minutes (IQR 3–9) from the start of the infusion, and the median maximum duration of symptoms was 59 minutes (IQR 35–76). The outlier was a subject who developed allodynia and neck stiffness during their attack. For those that developed non-headache symptoms during the single-blinded placebo visit, the median onset time was 9 minutes (IQR 2–9), with a median duration of 16 minutes (IQR 6–34).
Cranial autonomic symptoms
NTG triggered CAS in the majority of the subjects during the open unblinded NTG visit (n = 31, 94%). In all, five subjects out of the 31 (19%) developed unilateral CAS; however, they did not have a cluster headache attack. Two subjects had CAS with generalised headache, one had CAS without any pain, one subject developed CAS on the contralateral side to their attacks with mild generalised pain, and one subject with CAS developed restless leg symptoms, but no cluster headache attack. Of the subjects who developed unilateral CAS and cluster headache attack (n = 26, 79%), the median number of CAS was four (IQR 2–5), with the most common CAS being nasal congestion (n = 21), lacrimation (n = 16) and periorbital oedema (n = 15) (Table 5).
Table 5. Frequencies of cranial autonomic symptoms reported in subjects who had attacks following NTG infusion.
Cranial autonomicsymptoms Open unblinded NTG visit, total number of attacks (n = 26) Single-blinded NTG visit, total number of attacks (n = 19)
Lacrimation 16 11
Conjunctival injection 12 9
Periorbital oedema 15 8
Eye grittiness/itchiness 3 3
Nasal congestion 21 16
Rhinorrhoea 2 1
Ptosis 4 1
Aural fullness 5 2
Facial flushing 7 4
Sialorrhoea 1 0
Throat swelling 2 0
Voice change 4 2
Facial swelling 3 1
Similarly, NTG brought on CAS in the majority of subjects during the single-blinded NTG visit (n = 21, 84%), of which two were not accompanied by a cluster headache attack, compared with four out of 24 in the single-blinded placebo group developing CAS (Figure 5(a)). One of the subjects from the single-blinded NTG group had a generalised headache similar to a hangover headache with unilateral CAS, and the other subject had a migraine-like headache with CAS. Of the 19 subjects (76%) that had unilateral CAS and a cluster headache attack, the median number of symptoms was three (IQR 2–4) and the most frequent symptoms were nasal congestion (n = 16), lacrimation ( n = 11) and conjunctival injection (n = 9) (Table 5). In comparing the time until all CAS onset between ECH and CCH after blinded NTG infusion, there was no difference between the two groups (log-rank P = 0.740; Figure 5(b)).
Figure 5. (a) Kaplan-Meier graph showing time until onset of cranial autonomic symptoms (CAS) following open unblinded (n = 33) and single-blinded NTG (n = 25) infusions compared with the single-blinded placebo infusion (n = 24). Log-rank P = 0.000. (b) Kaplan-Meier graph showing the time until CAS onset in the single-blinded NTG visit, comparing episodic cluster headache (ECH) with chronic cluster headache (CCH). Log-rank P = 0.740.
The median time until CAS onset for those that developed cluster headache attacks was 31 min (IQR 13–46) in the open unblinded NTG visit and 12 min (IQR 6–30) in the single-blinded NTG visit. Subjects sequentially reported CAS development.
During the single-blinded placebo visit, four subjects (17%) developed unilateral CAS, of which one subject developed a spontaneous attack, and three developed CAS but no pain. The median number of symptoms reported in the placebo group was two (IQR 1–2) and the symptoms reported were nasal congestion (n = 2), conjunctival injection (n = 1), periorbital swelling (n = 1), rhinorrhoea (n = 1) and aural fullness (n = 1).
Agitation
Nitroglycerin brought on agitation in the majority of subjects, open unblinded NTG visit (n = 24, 73%) and single-blinded NTG visit (n= 20, 80%), compared with none in the single-blinded placebo visit.
Non-headache symptoms post-attack
The non-headache symptoms were not studied here, as all attacks were treated with sumatriptan or oxygen after 20 minutes, thus altering the natural progression and development of symptoms.
Episodic cluster headache compared with chronic cluster headache
For the subjects that developed an NTG-induced attack following the single-blinded NTG infusion, the time until NTG-induced attack was shorter in the episodic cluster headache group compared with the chronic cluster headache group (U = 15, z = −2.399, P = 0.016). The time until CAS onset, in the subjects that developed CAS following single-blinded NTG infusion was not different between episodic cluster headache and chronic cluster headache groups (U = 38, z = −1.2000, P = 0.230).
Effect of verapamil on NTG triggering
There were seven subjects on verapamil that attended the single-blinded NTG visits, of which two did not develop NTG-triggered cluster headache attacks (29%). Using χ2, there was no difference between verapamil and NTG triggering (χ2 (df = 1) = 0.111, P = 0.739).
Effect of migraine on NTG-triggered attacks
Within the cohort that attended the single-blinded NTG visits, 15 had migraine (60%). There was no difference between the number of non-headache symptoms (U = 67, z = −0.449, P = 0.654) or number of CAS (U = 57, z = −1.019, P = 0.308), between the subjects with migraine and those without migraine. Furthermore, there was no association between subjects with migraine and NTG triggering (χ2 (df = 1) = 0.146, P = 0.702); similarly, there was no association between subjects with migraine and development of NTG headache (χ2 (df = 1) = 0.033, P = 0.856).
Discussion
This study demonstrates that weight-calculated intravenous NTG effectively triggers cluster headache attacks in both chronic cluster headache and episodic cluster headache subjects within bout when compared with placebo. The approach is reliable in terms of triggering a fully-featured attack that allows careful observation of symptoms and their development during acute attacks of cluster headache.
The benefit of weight-calculated intravenous NTG compared to intranasal and sublingual administration is that this is more reliable and has more stable bioavailability. The median time until cluster headache attack onset was 30 minutes (open unblinded NTG visit) and 33 minutes (single-blinded NTG visit), with the overall maximum onset time of 81 minutes. Subjects who did not develop an attack during the 140 minutes of observation were asked to report if they developed an attack later on that day, and none did. The median onset time is similar to the reported latency period reported in the literature (Table 1). The minimum onset time for NTG-induced attacks was 2 minutes, and this is less than reported from the sublingual route, where the shortest time until onset time was 9 minutes (8); this is expected, given the intravenous route has a half-life of 2.3–2.8 minutes (30,31). Two subjects started experiencing mild attack pain before the start of the NTG infusion, and within the placebo group we observed one subject who developed a spontaneous attack. Spontaneous attacks could be anticipated given the subjects are within bout; there were three subjects with only short-lasting CAS symptoms and two subjects who experienced a mild pain without CAS, similar to a shadow.
This study delineates the development of the various stages of an NTG-induced cluster headache attack, including the non-headache symptoms and CAS (Figure 6). The majority of subjects developed NTG headache shortly after the infusion started. This headache was generalised, mild and progressive in nature, predominantly in the bi-occipital and bi-temporal regions. Subjects described it as pressure-like or band-like ache, and they reported it to be distinct from their cluster headache attacks; if there were an overlap, the cluster headache attack would clearly ramp up and supersede the NTG headache. It is difficult to disentangle whether NTG headache developed because there was a high proportion of subjects with either a migraine diagnosis, migraine marker or family history of migraine. However, from a previous study with 25 healthy volunteers without a migraine diagnosis, 16 (64%) developed NTG headache following 0.5 mg NTG sublingual administration (32).
Figure 6. Violin plots of the stages of cluster headache attack from the 19 subjects that developed cluster headache attacks and subdivided by chronicity. The timeline starts with 20 minutes of single-blinded nitroglycerin (NTG) infusion, followed by 120 minutes of post-infusion observation. CAS = cranial autonomic symptoms.
Following the NTG headache, the majority of subjects reported non-headache symptoms in the lead-up to the onset of the pain from the attack and in some subjects, non-headache symptoms accompanied their attacks. The non-headache symptoms included homeostatic symptoms (thirst, cravings, yawning, frequency of urination), fatigue/cognitive symptoms (concentration difficulty, fatigue, memory impairment, mood changes, irritability) and sensitised sensory symptoms (neck stiffness, photophobia, phonophobia, osmophobia, nausea), as are reported in the premonitory phase of migraine (33). The most common symptoms were neck stiffness, photophobia and thirst. During their spontaneous attacks, subjects reported that non-headache symptoms would precede the attack at a median of 10 minutes (IQR 2–30) before the onset of pain, although it is known that there are discrepancies between retrospective and prospective reporting (25). Comparing the symptoms observed from NTG-induced attacks in this study with the prospective observational questionnaire study (24), the most reported general symptoms in the pre-pain phase in this study were concentration difficulties, photophobia and mood changes. Patients in the observational study also reported general symptoms during their attacks and postictal symptoms similar to the symptoms seen during the NTG-induced attacks and the reported symptoms by the subjects in this study during the postdrome phase of their spontaneous attacks. Non-headache symptoms such as photophobia, phonophobia, and localised allodynia were often reported during the attacks, as has been reported previously (21,34). In one semi-structured questionnaire study, they found a high proportion of cluster headache patients (73.2%) reported phonophobia or photophobia with their attacks (35), cluster headache patients with migraine did not more frequently report these symptoms compared with those without co-existing migraine. Furthermore, allodynia was more often reported in cluster headache patients with migraine. From pre-clinical studies, high dose NTG causes a sustained increase in spontaneous firing of Aδ and C-fibre trigeminal neurons (36), which migraine biology may unmask.
Similar to the prospective questionnaire study by Snoer and colleagues (24), in some subjects CAS presented before the onset of the attack pain (Figure 6). In this study, the median onset time for CAS was 31 minutes (IQR 13–46) in the open unblinded NTG visit and 12 minutes (IQR 6–30) in the single-blinded NTG visit, whereas the onset of NTG-induced attack was 30 minutes (IQR 20–39) in the open unblinded visit and 33 minutes (IQR 15–42) in the single-blinded NTG visit. From the open unblinded NTG visit, 38% presented with CAS before the attack, 15% presented with CAS with the onset of the attack, and from the single-blinded NTG visit, 58% presented with CAS before the attack and 16% presented with CAS with the onset of the attack.
Vollesen and colleagues used calcitonin gene-related peptide (CGRP) infusion to trigger cluster headache attacks, finding CGRP induced 50% of subjects with CCH and 89% for ECH subjects in bout (4). In our study, NTG induced attacks in 79% of the CCH subjects and 84% in ECH subjects in bout, in the open unblinded NTG visits, and 92% CCH and 62% ECH in bout in the single-blinded NTG visits. There are some differences in the number of chronic cluster headache subjects on verapamil between the studies; in this study, 33% of CCH subjects were on verapamil and in the study by Vollesen and colleagues, 57% of CCH subjects were on verapamil (of which one was on both verapamil and lithium) and one was on 4 mg melatonin. Vollesen and colleagues proposed that the CCH patients who did not develop an attack following CGRP infusion had a lower median attack frequency in the preceding 30 days prior to the study compared to the CCH patients that did develop an attack. However, in this study, subjects reported having their last attack as long ago as 128 and 158 days and still had NTG-induced attacks (Table 3).
NTG is a pro-drug of nitric oxide (NO) and has effects on blood vessel dilation through mechanisms of the NO-cyclic guanylate phosphate (cGMP) pathway (27). However, the vasodilatory effects of NTG are not sufficient to explain the cluster headache attack that occurs after a latency and the central features associated with the attack. Indeed, experimental studies demonstrate that NTG has central effects (37,38). Interestingly, in studies where NO donors were administered in vivo and in vitro, there was a local release of CGRP (39–42). The difference in the rate of cluster headache attacks induced by NTG and CGRP in ECH and CCH subjects could reflect in part the underlying biological processes and systems that are more active in the different subtypes of cluster headache. The difference between ECH and CCH is also suggested by the treatment response to a CGRP monoclonal antibody, galcanezumab (43,44), and non-invasive vagal nerve stimulator (45,46).
Limitations
The main limitations to the study were the recruitment of eligible subjects and the dropout rate at each stage due to the nature of the condition. Therefore, a pragmatic approach was taken with the study design regarding randomisation. Although there was a randomisation sequence, this was modified by the investigator if deemed necessary. This would be in the case of episodic cluster headache patients that were near the end of their bout missing the NTG visit if they followed the randomised sequence. For this reason, it was designed to be a single-blind cross-over study and not a double-blind and randomised study. Expectation bias was reduced by maintaining blinding of the subjects until the end of the study and having both infusions identical in volume, appearance and duration of infusion. Furthermore, given the stark difference between placebo and NTG, there was no difference between attack onset in the open unblinded compared with the single-blinded NTG visits (Figure 4(b)), is an indication that randomisation was not a factor in this study.
Conclusion
We present the results of the first placebo-controlled study using intravenous NTG administration to systematically study NTG-induced cluster headache attacks. We have shown that NTG can reliably bring on cluster headache attacks as well as the development of non-headache symptoms and CAS. This study highlights differences between NTG-induced attack onset times between the ECH and CCH subjects. Understanding the stages of cluster headache is essential; by recognising the non-headache symptoms in the lead up to the onset of pain and the underlying pathogenesis of this, we may be able to uncover new therapeutic targets to abort attacks before the onset of the severe and devastating pain experienced by our cluster headache patients.
Article highlights
Weight-calculated standardised intravenous nitroglycerin administration is a reliable method to induce cluster headache attacks, cranial autonomic symptoms and non-headache symptoms that accompany cluster headache attacks.
Accompanying non-headache symptoms in cluster headache attacks are important to recognise for both clinical and research purposes.
There may be inherent differences between episodic cluster headache and chronic cluster headache.
Acknowledgement
This study would not have been possible without the support of OUCH(UK), all the cluster headache patients who were interested in helping us with this study and all the subjects who took part in this study.
Ethics or Institutional Review Board approval: This study 16/LO/0693 obtained approval from the London, City & East NHS Research Ethics Committee on 23 June 2016. This study was carried out in accordance with the World Medical Association Declaration of Helsinki (1964), the Research Governance Framework for Health and Social Care (2nd edition, 2005), the Data Protection Act (1998) and the Principles of Good Clinical Practice (GCP); all subjects gave informed consent before taking part.
Declaration of conflicting interests: The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: DYW no reported competing interests. PJG reports, over the last 36 months, grants and personal fees from Amgen and Eli-Lilly and Company, grant from Celegene, and personal fees from Alder Biopharmaceuticals, Aeon Biopharma, Allergan, Biohaven Pharmaceuticals Inc., Clexio, Electrocore LLC, eNeura, Epalex, GlaxoSmithKline, Impel Neuropharma, MundiPharma, Novartis, Pfizer, Praxis, Sanofi, Santara Therapeutics Satsuma, Teva Pharmaceuticals, Trigemina Inc., WL Gore, and personal fees from MedicoLegal work, Massachusetts Medical Society, Up-to-Date, Oxford University Press, and Wolters Kluwer; and a patent magnetic stimulation for headache assigned to eNeura without fee.
Funding: The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study is part-funded by the National Institute for Health Research (NIHR) Maudsley Biomedical Research Centre at South London Maudsley Foundation Trust and King’s College London. The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care.
ORCID iDs: Diana Y Wei https://orcid.org/0000-0003-0644-7172
Peter J Goadsby https://orcid.org/0000-0003-3260-5904 | NITROGLYCERIN | DrugsGivenReaction | CC BY | 33615843 | 19,017,453 | 2021-07 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Cluster headache'. | Comprehensive clinical phenotyping of nitroglycerin infusion induced cluster headache attacks.
Nitroglycerin administration allows the study of cluster headache attacks in their entirety in a standardised way.
A single-blind, placebo-controlled, cross-over study using weight-calculated intravenous nitroglycerin administration at 0.5 µg/kg/min over 20 minutes to study cluster headache attacks, including accompanying non-headache symptoms and cranial autonomic symptoms.
Thirty-three subjects with cluster headache were included in the study; 24 completed all three study visits. Nitroglycerin-induced attacks developed in 26 out of 33 subjects (79%) receiving unblinded nitroglycerin infusion, and in 19 out of 25 subjects (76%) receiving single-blinded nitroglycerin infusion, compared with one out of 24 subjects (4%) receiving single-blinded placebo infusion. Episodic cluster headache subjects had a shorter latency period to a nitroglycerin-induced attack compared to the chronic cluster headache (CCH) subjects (U = 15, z = -2.399, p = 0.016). Sixteen of nineteen episodic cluster headache (mean, 84%; 95% confidence interval, 66-100%) and 11 of 14 chronic cluster headache subjects developed a nitroglycerin-induced attack (79%, 54-100%) following the unblinded nitroglycerin infusion. Following the single-blinded nitroglycerin infusion, eight out of 13 episodic cluster headache (62%, 31-92%) and 11 out of 12 chronic cluster headache (92%, 73-100%) subjects developed nitroglycerin-induced attacks. Nitroglycerin induced non-headache symptoms in the majority of subjects receiving it: 91% in the open unblinded nitroglycerin visit and 84% in the single-blinded nitroglycerin visits, compared with 33% in the single-blinded placebo visit. Cranial autonomic symptoms were induced by nitroglycerin infusion, 94% in the open unblinded nitroglycerin visit and 84% in the single-blinded nitroglycerin visit, compared with 17% in the single-blinded placebo visit.
Intravenous weight-adjusted nitroglycerin administration in both episodic cluster headache in bout and chronic cluster headache is effective and reliable in inducing cluster headache attacks, cranial autonomic symptoms and non-headache symptoms.
Introduction
Due to the episodic nature of acute attacks of cluster headache, a standardised and reliable method for triggering attacks is necessary for their complete study. There have been several substances used to trigger attacks, including histamine (1,2), meta-chloro-phenylpiperazine (mCPP) (3) and more recently calcitonin gene-related peptide (CGRP) (4). Nitroglycerin (NTG) is the most frequently employed substance in human experimental modelling of cluster headache attacks, being used since 1953 (2) (Table 1).
Table 1. Review of studies using nitroglycerin to induce cluster headache attacks.
Study Number of CH patients NTG dose and route Control Placebo Rate of induced CH attack Latency period before onset of headache
(range in minutes)
Peters 1953 (2) 14 1.3 mg sublingual No, but compared with migraine, combination of CH and migraine, vasodilating head pain and tension headache No, but compared with histamine and nicotinic acid 78.6% Not reported
Ekbom 1968 (5) 38 ECH: 28 in bout, 15 out of bout (of which five were tested in bout as well) 1 mg sublingual No No In bout ECH 100% (n = 28)
Out of bout 0% (n = 15) 12–72
Barre 1982 (6) 10 CH: two CCH, nine ECH in bout 1 mg sublingual No No 100% 34–52
Mean 45.9
Drummond et al. 1984 (7) 29 CH 0.9 mg sublingual No No 76% Within 90 min
Drummond et al. 1985 (8) 22 CH: 10 CCH, 12 ECH in bout
0.9 mg sublingual Yes, 10 in the control group without headache No ECH 75% (n = 9)
CCH 60% (n = 6) 9–90
Mean 44
Bogucki 1990 (9) 21 ECH in bout 1 mg sublingual No No 67% (n = 14)
30–65
Dahl et al. 1990 (10) 15 ECH in bout 1 mg sublingual 10 healthy controls No 53% (n = 8)
Controls: not reported 30–65
Hannerz et al. 1992 (11) Eight ECH: five in bout and three out of bout 1 mg sublingual No No In bout ECH 100% (n = 5) Not reported
Fanciullacci et al. 1995 (12) 18 in bout ECH, 12 out of bout ECH 0.9 mg sublingual No No In bout ECH 100% (n = 18)
Out of bout ECH 0% (n = 12) 39–86
Fanciullacci et al. 1997 (13) 11 in bout ECH, eight out of bout ECH 0.9 mg sublingual No No In bout ECH 100% (n = 11)
Out of bout ECH 0% (n = 8) 18–50
Hsieh et al. 1996 (14) Seven ECH: four in bout ECH, three out of bout 1 mg sublingual No No In bout ECH 100%
Out of bout ECH 0% 18–35
May et al. 1998 (15) Nine CCH, eight out of bout ECH 1.0–1.2 mg spray No No CCH 100%
Out of bout ECH 0% Not reported
Costa et al. 2000 (16) 15 CH: Six ECH, nine CCH 0.9 mg sublingual No No ECH 33% (n = 2)
CCH 78% (n = 7) 19–41
Costa et al. 2003 (17) 18 ECH in bout 0.9 mg sublingual Yes, 12 healthy sex and age-matched No ECH 67% (n = 12)
Controls 0% 19–41
Sances et al. 2004 (18) 42 CH: 29 ECH (11 out of bout), 13 CCH 0.9 mg sublingual Yes, 53 healthy controls No In bout ECH and CCH 81% (n = 25 out of 31)
Controls 7.5% developed headache in 7-hour post-NTG Mean onset latency of 65.4 ± 54.7
Cluster headache patients suffer from recurrent episodes of severe unilateral pain in the trigeminal region; therefore, historically, the main emphasis has been centred around the pain onset of a cluster headache, and indeed this is often used as the indicator of the start of the attack. However, from clinical practice, there has been growing awareness of nonpainful symptoms preceding the onset of pain (19,20) and in recent years, the clinical phenotype of cluster headache has been further characterised by retrospective accounts (21–23) and prospective diaries (24,25).
The most frequent route of administration of NTG has been sublingual; however, the bioavailability of sublingual NTG is extremely variable (26). Therefore, we used a weight-calculated dose for intravenous infusion in a standardised single-blind, placebo-controlled study. NTG is a pro-drug of nitric oxide, with predominant actions on the cyclic guanylate phosphate (cGMP) pathway (27), and from pre-clinical studies there are indications of neural actions more centrally. This study is the first single-blind, placebo-controlled cross-over study using a weight-adjusted dose of nitroglycerin administered intravenously in cluster headache patients, thereby allowing comprehensive investigation of the various stages of the acute attack of cluster headache.
Methods
Subject selection and recruitment
The study was advertised on the UK cluster headache patient website OUCH (UK) (Organisation for the Understanding of Cluster Headache UK) (https://ouchuk.org/research/research-volunteers-needed) and in the tertiary Headache centre in King’s College Hospital, London. Subjects interested in participating would make contact via a dedicated research email. Subjects would then be screened for eligibility for the study via emails and a telephone call; those who met the criteria and were interested in participating were invited to attend the study visit. The study was approved by the London, City & East Research Ethics Committee (Ref Number 16/LO/0693). Data were collected from August 2016 until January 2019.
The subjects enrolled fulfilled the ICHD-3 beta criteria for cluster headache (28), and were between the ages of 18 and 60, with no significant previous medical history and no previous syncope or history of autonomic dysfunction. They had had a reliable response to high flow oxygen and/or subcutaneous sumatriptan during spontaneous attacks and normal brain neuroimaging. Women in child-bearing age were required to use reliable contraceptive methods during the study. Subjects were excluded if they were pregnant or breastfeeding, and who had any significant psychiatric disease, diagnosis of another primary headache type (other than migraine) or chronic pain syndrome, any medical history that would have contraindications to receiving NTG, use of preventive medication other than verapamil, or taking indomethacin for any reason, allergies to the medications used in the study or intolerance to high flow oxygen, and use of illicit drugs during the study.
Study visits
The study comprised of three visits in total, with each visit separated by a minimum of 1 week. During the first visit, subjects consented and a full headache history with a physical examination of the neurological and cardiovascular systems was performed, along with recordings of the baseline blood pressure, lying and standing blood pressure, heart rate, oxygen saturation, weight and electrocardiogram. Female subjects were required to have a urinary pregnancy test before the start of the infusion.
Open NTG infusion
If deemed eligible, subjects received an intravenous infusion of nitroglycerin at 0.5 µg/kg/min over 20 minutes. Subjects remained recumbent for 30 minutes before the infusion, and after the NTG infusion, subjects received 250 mL of 0.9% sodium chloride intravenously. The blood pressure and pulse were checked at the start of the infusion, and every 5 min during the infusion.
Phenotypic characterisation
Every 5 minutes, subjects were asked to rate their pain level from a scale from no pain, mild, moderate to severe, where severe equates to their most severe attack, and they were asked a questionnaire of non-headache symptoms and cranial autonomic symptoms (CAS) (Figure 1). If the subject experienced pain, further details were obtained regarding the location and characteristic. Beyond the cluster headache attack, subjects were asked to report any other headache types and in particular NTG headache, which has been well described from migraine studies (29). The NTG headache was assessed for severity, phenotype, accompanying non-headache symptoms and duration. Subjects were actively encouraged to report any symptoms as and when they developed. Following the infusion, at 10 minute intervals, any developments in pain, non-headache symptoms and CAS were recorded for a total of 120 minutes after the infusion, based on the latency period reported from previous studies (Table 1).
Figure 1. Questionnaire for non-headache and cranial autonomic symptoms.
B: bilateral; R: right-sided; L: left-sided.
Single-blinded NTG and placebo infusions
During the two single-blinded visits, subjects either received intravenous nitroglycerin at 0.5 µg/kg/min over 20 minutes or an equal volume of 0.9% sodium chloride at the same rate over 20 minutes, followed by the same 120 minutes of observations (Figure 2). The sequence was pre-determined using the randomise function in Excel; however, the investigator was able to amend this in certain situations if the subject was episodic and due to finish their bout.
Figure 2. Outline of events from open unblinded nitroglycerin visit.
BP: blood pressure; CAS: cranial autonomic symptoms; NTG: nitroglycerin; IV: intravenous.
Treatment of acute attacks
Acute treatment was administered at 20 minutes from the start of attack either with sumatriptan 6 mg subcutaneous injection (Imigran 6 mg/0.5 ml solution for injection pre-filled syringes, GlaxoSmithKline UK Ltd, or sumatriptan 6 mg/0.5 ml solution for injection pre-filled pens, Sun Pharmaceuticals Industries Europe B.V.) or with 15 L/min oxygen via a non-rebreather mask (O2Star™ non-rebreather oxygen mask M/L, Dräger). The visit was concluded only when the subject was pain free.
Statistical analysis
The data was tabulated (Excel for Mac v 16.30), and descriptive statistics were performed to summarise data (SPSS Statistics version 26 for Mac and Excel). Mann-Whitney tests were performed on time until attack onset and time until CAS onset for those that developed NTG-triggered cluster headache attacks and CAS, comparing the differences in ECH with CCH subgroups. Kaplan-Meier survival graphs were used to examine the time until onset of event; that is, survival of no cluster headache attack status, or absence of CAS after NTG infusion for 140 minutes (20 minutes of infusion and 120 minutes of post-infusion observation), with log-rank statistical testing; P < 0.05 was considered significant. Graphs were made using SPSS and violin plots were made using GraphPad Prism 8 for Mac OS.
Results
Demography
A total of 229 subjects were contacted to check for eligibility, of which 33 were included in the study; 24 completed all three study visits (Figure 3). All patients fulfilled the ICHD-3 beta criteria for cluster headache, 19 episodic cluster headache in bout (58%) and 14 chronic cluster headache (42%) (Table 2). The majority were male (n = 24, 73%) with a male: female ratio of 3:1. The average age was 41 (SD 10), with the mean age of females (34 years, SD 9) younger than in males (44 years, SD 9) in this cohort. Subjects had had the condition for a median of 9 years (IQR 5–16).
Figure 3. Subject numbers throughout the study.
Table 2. Subject characteristics.
Subject Age Sex Subtype Side of attacks Time since first attack (years) Average attack frequency (per day) Average attack duration when untreated (mins) Average bout duration (weeks) Verapamil (total daily dose in mg)
1 55 M Chronic Right 5 2 45 – 480
2 28 F Chronic Right 12 7 150 – –
3 40 M Episodic Right 20 3 150 8 –
4 38 F Episodic Left 12 2 120 4 –
5 53 M Chronic Left 15 4 35 – 960
6 48 M Episodic Left 25 5 52.5 5 480
7 23 M Episodic Left 8 2 120 10 –
8 43 M Chronic Right 9 1 40 – –
9 43 M Episodic Right 13 3 60 5 240
10 44 M Episodic Right 27 6 45 6 –
11 47 M Episodic Right 3 1 105 20 –
12 48 M Episodic Left 26 3 180 10 560
13 40 M Episodic Right 5 3 60 8 –
14 50 M Episodic Right 10 2 105 8 –
15 56 M Episodic* Right 24 1 45 – –
16 35 M Episodic Left 7 2 150 6 240
17 58 M Episodic Left 3 1 135 24 –
18 43 M Chronic Left 4 2 60 – –
19 32 M Episodic Left 3 3 50 12 600
20 49 F Episodic Right 8 5 50 9 –
21 49 M Chronic Right 35 2 90 – –
22 57 M Chronic Right 20 5 65 –
23 40 F Chronic Left 4 1.5 120 – 640
24 44 M Chronic Right 6 2 90 – 720
25 23 F Episodic Right 9 2.5 90 6 –
26 40 M Chronic Left 17 1.5 180 – –
27 20 F Chronic Right 6 1.5 150 – –
28 31 F Episodic Right 14 2 75 11 –
29 35 M Episodic Left 9 2 90 3 –
30 38 F Chronic Left 6 1.5 180 – 240
31 49 M Episodic Left 0.5 1.5 37.5 21 400
32 35 F Chronic Left 4 0.3 30 – 600
33 32 M Chronic Left 10 6 60 – –
M: male; F: female.
*Subject was chronic but became episodic during study with no attacks in 6 months.
Clinical phenotyping of subjects by history
Pain features
There was a near-equal split between the laterality of attacks; 17 subjects had right-sided attacks (52%), and 16 subjects had left-sided attacks (49%). The median number of attacks per day was two (IQR 1.5–3) lasting a median of 90 minutes (IQR 50–128). Verapamil was the only preventive allowed on the study; 12 subjects (36%) were on verapamil ranging from 240 mg to 960 mg per day.
Migraine, accompanying features and non-headache symptoms in spontaneous attacks
In this cohort, 58% (n = 19) had a concurrent migraine (28): five had migraine with aura, of which four had visual aura and one had facial sensory aura. Of the subjects who did not meet the diagnostic criteria for migraine (28) (n = 14, 42%), the majority had either migraine markers and/or a family history of migraine. Migraine markers were defined if subjects experienced: childhood cyclic nausea and vomiting, motion sickness, cold stimulus-induced headache, hangover headache and jetlag. Four subjects did not have migraine markers, and three subjects (9%) did not have either migraine marker or a family history of migraine. Subjects (n = 24, 73%) reported accompanying symptoms with their spontaneous attacks, the most common symptoms being cranial allodynia (n = 15), photophobia (n = 15), nausea (n = 11) and phonophobia (n = 10).
Non-headache attack symptoms
The majority reported non-headache symptoms in the lead up to their spontaneous cluster headache attacks (n = 27, 82%), with the commonest symptoms being concentration difficulties (n = 18), mood changes (n = 15), neck stiffness (n = 13) and yawning (n = 8). The median onset time of symptoms was 10 minutes (IQR 2–30) before the onset of pain. Although most symptoms start before the onset of pain, five subjects only reported developing the symptoms during the attack.
Twenty-eight subjects reported non-headache symptoms following their cluster headache attacks (85%), the commonest symptoms being tiredness (n = 27), mood changes (n = 13), concentration difficulties (n = 12), and neck stiffness (n = 7). The median duration of symptoms was 120 minutes (IQR 53–315).
Attack triggers
The most commonly reported triggers for spontaneous attacks were alcohol ingestion (n = 22), followed by changes in temperature (n = 12), strong smells such as from nail varnish, paint (n = 11) followed by disrupted sleep (n = 4) and exercise (n = 3). Other triggers mentioned were stress (n = 2), caffeine (n = 2), changing time zones (n = 1), let down from stress (n = 1), being in a pressurised cabin on an airplane (n = 1), vardenafil (n = 1), and dehydration (n = 1). All subjects reported attacks within a few hours of alcohol ingestion, no one reported a next-day effect.
Clinical phenotyping of open NTG visit
NTG triggered cluster headache-like attacks (n = 26, 79%), CAS (n = 31, 94%) and agitation (n = 24, 73%) during the open unblinded NTG visit. In the episodic cluster headache group, 16 out of 19 developed an NTG-induced attack (mean, 84%; 95% CI, 66–100%) and in the chronic cluster headache group, 11 out of 14 developed an NTG-induced attack (79%, 54–100%). Five out of the 31 subjects developed CAS, but did not develop an attack; of these subjects, three developed mild generalised pain, one developed restless legs, and one developed CAS on the contralateral side to the subject’s spontaneous attack phenotype, with a generalised headache. These cases were excluded.
The median onset time for CAS to develop from the start of the NTG infusion was 31 minutes (IQR 13–46). The median onset for an NTG-induced attack was 30 minutes (IQR 20–39) and the median time to maximum pain, if reached, was 51 minutes (IQR 39–70). The most common first cranial autonomic symptoms brought on by NTG infusion were nasal congestion (n = 10), conjunctival injection (n = 5), lacrimation (n = 4) and periorbital oedema (n = 3).
Clinical phenotyping of single-blinded NTG and placebo visit
During the single-blinded visits, NTG induced attacks in 19 subjects (76%); three subjects did not have an attack (12%), two subjects developed migraine-like headache (8%) and one subject developed unilateral mild pain without CAS or agitation (4%) (Table 3). In the placebo group, only one developed an attack (4%), two subjects developed unilateral mild pain without CAS or agitation (8%) and two subjects experienced short-lived unilateral CAS (8%). Of the subjects receiving NTG, eight out of 13 ECH (mean, 62%; 95% CI, 31%-92%) and 11 out of 12 CCH (92%, 73–100%) developed NTG-induced attacks (Figure 4(a)).
Table 3. Subject characteristics and comparison between spontaneous attack and triggered attack from single-blinded nitroglycerin visit, M = male, F = female, ECH = episodic cluster headache, CCH = chronic cluster headache, L = Left, R = Right, Y = Yes, N = No, VRS = verbal rating scale, mod = moderate, O2 = high flow oxygen via non-rebreather mask, suma = sumatriptan.
Subject Age Sex Subtype Migraine Verapamil (total daily dose in mg) Spontaneous attack Triggered attack- single-blinded NTG visit
Laterality Severity CAS Agitation Laterality Severity/VRS CAS Agitation Feels like spontaneous attack Treatment Last spontaneous attack (days)
1 55 M CCH N 480 R 9/10 Conjunctival injection, nasal congestion, lacrimation. 3 months of R Horner’s syndrome in 2007, now resolved Y R 10/10
VRS 3 Conjunctival injection, nasal congestion, lacrimation, periorbital oedema Y Y O2 158
2 28 F CCH Y
– R 10/10 Periorbital oedema/ptosis, nasal congestion, dry eye then lacrimation Y R 10/10
VRS 3 Periorbital oedema, nasal congestion, facial flushing Y Y O2 128
3 40 M ECH N – R 10/10 Lacrimation, rhinorrhoea, ptosis Y R 10/10
VRS 3 Lacrimation, conjunctival injection, periorbital oedema, nasal congestion, aural fullness and facial droop Y Y Suma 1
4 38 F ECH Y – L 10/10 Lacrimation, conjunctival injection, periorbital oedema, nasal congestion, ptosis, facial flushing Y No attack, developed generalised pain 4/10 Y N N/A 1
5 53 M CCH N 960 L 10/10 Rhinorrhoea, ptosis Y L 10/10
VRS 3 Conjunctival injection, eye grittiness, lacrimation Y Y O2 4
6 48 M ECH N
480 L 8/10 Nasal congestion, lacrimation Y Did not attend
7 23 M ECH Y – L 10/10 Lacrimation, conjunctival injection, nasal congestion, ptosis, facial flushing Y Did not attend
8 43 M CCH N – R 10/10 Nasal congestion, rhinorrhoea, lacrimation, facial flushing Y R 10/10
VRS 3 Nasal congestion, conjunctival injection, eye grittiness Y Y Suma <1
9 43 M ECH N 240 R 10/10 Lacrimation, conjunctival injection, facial flushing, ptosis, facial droop Y Did not attend
10 44 M ECH N – R 10/10 Nasal congestion, ptosis, periorbital oedema, lacrimation, flushing Y No attack, L mild hangover like headache, with nasal congestion.
After study visit felt nauseous and vomited, then slept, headache free at 7pm N N O2- no response <1
11 47 M ECH N – R Severe attacks 10/10 Nasal congestion, aural fullness Y R 7/10
VRS 2/3 moderate/
severe Nasal congestion, conjunctival injection, aural fullness Y Y Suma 13
12 48 M ECH N 560 L 10/10 Lacrimation, nasal congestion, periorbital oedema Y Did not attend
13 40 M ECH Y – R 10/10 Nasal congestion, ptosis, conjunctival injection, lacrimation, throat tightness, rhinorrhoea Y No attack, bilateral mild headache 4/10 with nasal congestion Y, brief (7 mins) N N/A 19
14 50 M ECH Y – R 10/10
Lacrimation, periorbital oedema, nasal congestion, rhinorrhoea Y Did not attend
15 56 M ECH Y – R 10/10 Lacrimation, rhinorrhoea, facial flushing, gritty eyes, conjunctival injection Y with severe attacks Did not attend
16 35 M ECH Y 240 L 10/10 Nasal congestion, conjunctival injection, ptosis, lacrimation, rhinorrhoea Y Not attack, milder than a shadow and no CAS N N N/A 16
17 58 M ECH Y – L 10/10 Nasal congestion, rhinorrhoea, lacrimation, aural fullness, throat swelling Y L 7/10
VRS 2–3 (mod-severe) Nasal congestion, rhinorrhoea, voice change, lacrimation Y Y Suma 1
18 43 M CCH Y – L (70%) Mild 6/10, severe 10/10 Nasal congestion, periorbital oedema, aural fullness, facial flushing Y L Mild,
VRS 1 Nasal congestion Y Y- shadow O2 7
19 32 M ECH Y 600 L 10/10 Lacrimation, conjunctival injection, facial flushing Y L 7–8/10
VRS 2–3
(mod-severe) Lacrimation, eye grittiness, nasal congestion, facial flushing Y Y O2 <1
20 49 F ECH Y – R 10/10 Ptosis, periorbital oedema, lacrimation, nasal congestion, rhinorrhoea, (aural fullness with severe attacks) Y R 6–7/10
VRS 2 mod Nasal congestion, periorbital oedema, lacrimation, conjunctival injection Y Y O2 7
21 49 M CCH Y – R 4–10/10 Facial flushing, nasal congestion, ptosis, lacrimation, rhinorrhoea, conjunctival injection Y L 8/10
VRS 2–3
(mod-severe)
Facial flushing, lacrimation, periorbital oedema, conjunctival injection Y Y, but on L rather than R Suma <1
22 57 M CCH N – R 10/10 Lacrimation, conjunctival injection, nasal congestion, rhinorrhoea Y No attack, no pain and no CAS N N N/A 26
23 40 F CCH Y 640 L 10/10
Lacrimation, conjunctival injection, periorbital oedema, rhinorrhoea, ptosis, aural fullness Y Did not attend
24 44 M CCH N 720 R 10/10 Lacrimation, conjunctival injection, periorbital oedema, facial flushing Y Did not attend
25 23 F ECH Y – R 6–10/10 Nasal congestion, lacrimation, periorbital oedema. Rhinorrhoea and facial flushing with severe attacks Y R 7/10
VRS 2
(moderate) Nasal congestion, periorbital oedema Y Y O2 3
26 40 M CCH Y – L Shadow 4/10, daytime attacks 6–7/10, full attack 10/10 Ptosis, aural fullness, lacrimation, conjunctival injection, periorbital oedema, nasal congestion Y L 8.5–9/10
VRS 3 severe Nasal congestion, periorbital oedema, lacrimation Y Y Suma 3
27 20 F CCH N – R 8–9/10 Nasal congestion, lacrimation, rhinorrhoea, ptosis, aural fullness Y R 8/10
VRS 3
severe Nasal congestion, periorbital oedema Y Y O2 <1
28 31 F ECH Y – R 10/10 Nasal congestion, periorbital oedema, rhinorrhoea, ptosis, aural fullness Y R 2/10
VRS 1 (mild) Nasal congestion, facial swelling Y Y, but milder Suma 3
29 35 M ECH N – L Max pain 10/10 Nasal congestion, periorbital oedema, lacrimation, voice change (croaky). Facial flushing with severe attacks and rhinorrhoea after attack Y L 6–7/10
VRS 2 (moderate) Nasal congestion, lacrimation, conjunctival injection, voice change Y Y Suma <1
30 38 F CCH Y 240 L 4–10/10 Lacrimation, rhinorrhoea, conjunctival injection, facial flushing. Ptosis with severe attacks Y L 6–7/10
VRS 2 (moderate) Aural fullness Y Y Suma 1
31 49 M ECH Y 400 L 10/10 Nasal congestion, lacrimation, conjunctival injection, rhinorrhoea, ptosis, aural fullness. Prominent miosis after attack Y No attack, whole head felt heavy N N N/A 10
32 35 F CCH N 600 L 4/10 (on verapamil),
7/10 average Periorbital oedema, eye grittiness, facial flushing, lacrimation Y L 7/10
VRS 2–3
(mod-severe) Nasal congestion, conjunctival injection, facial flushing, lacrimation Y Y Suma 1
33 32 M CCH Y – L Severe attacks 10/10 Lacrimation, ptosis, nasal congestion, conjunctival injection, ptosis, facial flushing, eye grittiness Y L 6/10
VRS 2 (mod-severe) Lacrimation, nasal congestion, ptosis Y Y Suma <1
Figure 4. (a) Kaplan-Meier graph comparing time until cluster headache attack between the eight episodic cluster headache (ECH) and the 11 chronic cluster headache (CCH) subjects during single-blinded nitroglycerin (NTG) infusion, from the start of the infusion in minutes, log-rank P = 0.534. (b) Kaplan-Meier graph comparing time until cluster headache attack onset between the open unblinded (n = 33) and single-blinded (n =25) nitroglycerin (NTG) infusions with single-blinded placebo infusions (n = 24). Log-rank P = 0.000.
The median onset time to an induced attack was 33 minutes (IQR 15–42) from the start of the single-blinded NTG infusion, and in the single-blinded placebo visit only one subject developed an attack; the onset time was 10 minutes. On comparison of the attack onset time for the unblinded NTG, single-blinded NTG and single-blinded placebo visits, there was a difference between the placebo and NTG visits (P = 0.000, Figure 4(b)).
NTG headache
The majority of subjects developed an NTG headache (n = 28, 85%) following the NTG infusion in the unblinded open visit, of which 27 subjects had a migraine diagnosis (n = 18), had migraine markers (n = 10) and a family history of migraine (n = 18); only one subject did not have migraine, migraine markers or a family history of migraine. The median time from the start of NTG infusion was 3 minutes (IQR 2–6), and the median duration of NTG headache was 26 minutes (IQR 14–41).
Of the 25 subjects that went on to the single-blinded NTG visits, 18 (72%) developed NTG headache following NTG infusion, of which all had either migraine (n = 11), migraine markers (n = 7) or family history (n = 10). The median time of NTG headache onset from the start of NTG infusion in the blinded visit was 4 minutes (IQR 3–8), with a median duration of 26 minutes (IQR 9–45).
In the placebo visit, three of the 24 subjects (13%) developed NTG headache, median onset time was 13 minutes (range 1–18), and the median duration was 10 minutes (range 3–16).
Non-headache symptoms
The majority of subjects reported non-headache symptoms in both the open unblinded NTG visit (n = 30, 91%) and the single-blinded NTG visit (n = 21, 84%) visits. In the single-blinded placebo visit, eight subjects (33%) reported non-headache symptoms. The most common non-headache symptoms from the open unblinded NTG visit were neck stiffness, photophobia, thirst and allodynia. The most common non-headache symptoms from the single-blinded NTG visit were neck stiffness, yawning, thirst and photophobia (Table 4). The median number of non-headache symptoms reported in the open unblinded NTG visit was three (IQR 2–5), and from the single-blinded NTG visit was three (IQR 2–6), compared with two (IQR 2–3) on-headache symptoms in the single-blinded placebo group.
Table 4. Frequencies of non-headache symptoms reported during each visit.
Non-headache symptom Open unblinded NTG visit (n = 33) Single-blinded NTG visit
(n = 25) Single-blinded placebo visit
(n = 24)
Thirst 15 10 3
Craving 0 0 0
Yawning 8 12 4
Tiredness 4 3 0
Mood changes 5 4 1
Visual blurring 4 3 1
Neck stiffness 21 15 3
Irritability 3 3 0
Photophobia 18 10 1
Concentration difficulties 6 4 1
Phonophobia 4 6 0
Urinary symptoms 0 0 0
Speech disturbances 0 0 0
Nausea 6 3 0
Gastrointestinal discomfort 0 0 0
Movement sensitivity 5 5 1
Allodynia 9 8 2
In the open unblinded NTG visit, the median onset time of non-headache symptoms from the start of the infusion was 9 minutes (IQR 4–17) with the median maximum duration of the symptoms being 50 minutes (IQR 24–64), the duration is calculated from the first symptom until the end of the last symptom. In the single-blinded NTG visit, the median onset time was 5 minutes (IQR 3–9) from the start of the infusion, and the median maximum duration of symptoms was 59 minutes (IQR 35–76). The outlier was a subject who developed allodynia and neck stiffness during their attack. For those that developed non-headache symptoms during the single-blinded placebo visit, the median onset time was 9 minutes (IQR 2–9), with a median duration of 16 minutes (IQR 6–34).
Cranial autonomic symptoms
NTG triggered CAS in the majority of the subjects during the open unblinded NTG visit (n = 31, 94%). In all, five subjects out of the 31 (19%) developed unilateral CAS; however, they did not have a cluster headache attack. Two subjects had CAS with generalised headache, one had CAS without any pain, one subject developed CAS on the contralateral side to their attacks with mild generalised pain, and one subject with CAS developed restless leg symptoms, but no cluster headache attack. Of the subjects who developed unilateral CAS and cluster headache attack (n = 26, 79%), the median number of CAS was four (IQR 2–5), with the most common CAS being nasal congestion (n = 21), lacrimation (n = 16) and periorbital oedema (n = 15) (Table 5).
Table 5. Frequencies of cranial autonomic symptoms reported in subjects who had attacks following NTG infusion.
Cranial autonomicsymptoms Open unblinded NTG visit, total number of attacks (n = 26) Single-blinded NTG visit, total number of attacks (n = 19)
Lacrimation 16 11
Conjunctival injection 12 9
Periorbital oedema 15 8
Eye grittiness/itchiness 3 3
Nasal congestion 21 16
Rhinorrhoea 2 1
Ptosis 4 1
Aural fullness 5 2
Facial flushing 7 4
Sialorrhoea 1 0
Throat swelling 2 0
Voice change 4 2
Facial swelling 3 1
Similarly, NTG brought on CAS in the majority of subjects during the single-blinded NTG visit (n = 21, 84%), of which two were not accompanied by a cluster headache attack, compared with four out of 24 in the single-blinded placebo group developing CAS (Figure 5(a)). One of the subjects from the single-blinded NTG group had a generalised headache similar to a hangover headache with unilateral CAS, and the other subject had a migraine-like headache with CAS. Of the 19 subjects (76%) that had unilateral CAS and a cluster headache attack, the median number of symptoms was three (IQR 2–4) and the most frequent symptoms were nasal congestion (n = 16), lacrimation ( n = 11) and conjunctival injection (n = 9) (Table 5). In comparing the time until all CAS onset between ECH and CCH after blinded NTG infusion, there was no difference between the two groups (log-rank P = 0.740; Figure 5(b)).
Figure 5. (a) Kaplan-Meier graph showing time until onset of cranial autonomic symptoms (CAS) following open unblinded (n = 33) and single-blinded NTG (n = 25) infusions compared with the single-blinded placebo infusion (n = 24). Log-rank P = 0.000. (b) Kaplan-Meier graph showing the time until CAS onset in the single-blinded NTG visit, comparing episodic cluster headache (ECH) with chronic cluster headache (CCH). Log-rank P = 0.740.
The median time until CAS onset for those that developed cluster headache attacks was 31 min (IQR 13–46) in the open unblinded NTG visit and 12 min (IQR 6–30) in the single-blinded NTG visit. Subjects sequentially reported CAS development.
During the single-blinded placebo visit, four subjects (17%) developed unilateral CAS, of which one subject developed a spontaneous attack, and three developed CAS but no pain. The median number of symptoms reported in the placebo group was two (IQR 1–2) and the symptoms reported were nasal congestion (n = 2), conjunctival injection (n = 1), periorbital swelling (n = 1), rhinorrhoea (n = 1) and aural fullness (n = 1).
Agitation
Nitroglycerin brought on agitation in the majority of subjects, open unblinded NTG visit (n = 24, 73%) and single-blinded NTG visit (n= 20, 80%), compared with none in the single-blinded placebo visit.
Non-headache symptoms post-attack
The non-headache symptoms were not studied here, as all attacks were treated with sumatriptan or oxygen after 20 minutes, thus altering the natural progression and development of symptoms.
Episodic cluster headache compared with chronic cluster headache
For the subjects that developed an NTG-induced attack following the single-blinded NTG infusion, the time until NTG-induced attack was shorter in the episodic cluster headache group compared with the chronic cluster headache group (U = 15, z = −2.399, P = 0.016). The time until CAS onset, in the subjects that developed CAS following single-blinded NTG infusion was not different between episodic cluster headache and chronic cluster headache groups (U = 38, z = −1.2000, P = 0.230).
Effect of verapamil on NTG triggering
There were seven subjects on verapamil that attended the single-blinded NTG visits, of which two did not develop NTG-triggered cluster headache attacks (29%). Using χ2, there was no difference between verapamil and NTG triggering (χ2 (df = 1) = 0.111, P = 0.739).
Effect of migraine on NTG-triggered attacks
Within the cohort that attended the single-blinded NTG visits, 15 had migraine (60%). There was no difference between the number of non-headache symptoms (U = 67, z = −0.449, P = 0.654) or number of CAS (U = 57, z = −1.019, P = 0.308), between the subjects with migraine and those without migraine. Furthermore, there was no association between subjects with migraine and NTG triggering (χ2 (df = 1) = 0.146, P = 0.702); similarly, there was no association between subjects with migraine and development of NTG headache (χ2 (df = 1) = 0.033, P = 0.856).
Discussion
This study demonstrates that weight-calculated intravenous NTG effectively triggers cluster headache attacks in both chronic cluster headache and episodic cluster headache subjects within bout when compared with placebo. The approach is reliable in terms of triggering a fully-featured attack that allows careful observation of symptoms and their development during acute attacks of cluster headache.
The benefit of weight-calculated intravenous NTG compared to intranasal and sublingual administration is that this is more reliable and has more stable bioavailability. The median time until cluster headache attack onset was 30 minutes (open unblinded NTG visit) and 33 minutes (single-blinded NTG visit), with the overall maximum onset time of 81 minutes. Subjects who did not develop an attack during the 140 minutes of observation were asked to report if they developed an attack later on that day, and none did. The median onset time is similar to the reported latency period reported in the literature (Table 1). The minimum onset time for NTG-induced attacks was 2 minutes, and this is less than reported from the sublingual route, where the shortest time until onset time was 9 minutes (8); this is expected, given the intravenous route has a half-life of 2.3–2.8 minutes (30,31). Two subjects started experiencing mild attack pain before the start of the NTG infusion, and within the placebo group we observed one subject who developed a spontaneous attack. Spontaneous attacks could be anticipated given the subjects are within bout; there were three subjects with only short-lasting CAS symptoms and two subjects who experienced a mild pain without CAS, similar to a shadow.
This study delineates the development of the various stages of an NTG-induced cluster headache attack, including the non-headache symptoms and CAS (Figure 6). The majority of subjects developed NTG headache shortly after the infusion started. This headache was generalised, mild and progressive in nature, predominantly in the bi-occipital and bi-temporal regions. Subjects described it as pressure-like or band-like ache, and they reported it to be distinct from their cluster headache attacks; if there were an overlap, the cluster headache attack would clearly ramp up and supersede the NTG headache. It is difficult to disentangle whether NTG headache developed because there was a high proportion of subjects with either a migraine diagnosis, migraine marker or family history of migraine. However, from a previous study with 25 healthy volunteers without a migraine diagnosis, 16 (64%) developed NTG headache following 0.5 mg NTG sublingual administration (32).
Figure 6. Violin plots of the stages of cluster headache attack from the 19 subjects that developed cluster headache attacks and subdivided by chronicity. The timeline starts with 20 minutes of single-blinded nitroglycerin (NTG) infusion, followed by 120 minutes of post-infusion observation. CAS = cranial autonomic symptoms.
Following the NTG headache, the majority of subjects reported non-headache symptoms in the lead-up to the onset of the pain from the attack and in some subjects, non-headache symptoms accompanied their attacks. The non-headache symptoms included homeostatic symptoms (thirst, cravings, yawning, frequency of urination), fatigue/cognitive symptoms (concentration difficulty, fatigue, memory impairment, mood changes, irritability) and sensitised sensory symptoms (neck stiffness, photophobia, phonophobia, osmophobia, nausea), as are reported in the premonitory phase of migraine (33). The most common symptoms were neck stiffness, photophobia and thirst. During their spontaneous attacks, subjects reported that non-headache symptoms would precede the attack at a median of 10 minutes (IQR 2–30) before the onset of pain, although it is known that there are discrepancies between retrospective and prospective reporting (25). Comparing the symptoms observed from NTG-induced attacks in this study with the prospective observational questionnaire study (24), the most reported general symptoms in the pre-pain phase in this study were concentration difficulties, photophobia and mood changes. Patients in the observational study also reported general symptoms during their attacks and postictal symptoms similar to the symptoms seen during the NTG-induced attacks and the reported symptoms by the subjects in this study during the postdrome phase of their spontaneous attacks. Non-headache symptoms such as photophobia, phonophobia, and localised allodynia were often reported during the attacks, as has been reported previously (21,34). In one semi-structured questionnaire study, they found a high proportion of cluster headache patients (73.2%) reported phonophobia or photophobia with their attacks (35), cluster headache patients with migraine did not more frequently report these symptoms compared with those without co-existing migraine. Furthermore, allodynia was more often reported in cluster headache patients with migraine. From pre-clinical studies, high dose NTG causes a sustained increase in spontaneous firing of Aδ and C-fibre trigeminal neurons (36), which migraine biology may unmask.
Similar to the prospective questionnaire study by Snoer and colleagues (24), in some subjects CAS presented before the onset of the attack pain (Figure 6). In this study, the median onset time for CAS was 31 minutes (IQR 13–46) in the open unblinded NTG visit and 12 minutes (IQR 6–30) in the single-blinded NTG visit, whereas the onset of NTG-induced attack was 30 minutes (IQR 20–39) in the open unblinded visit and 33 minutes (IQR 15–42) in the single-blinded NTG visit. From the open unblinded NTG visit, 38% presented with CAS before the attack, 15% presented with CAS with the onset of the attack, and from the single-blinded NTG visit, 58% presented with CAS before the attack and 16% presented with CAS with the onset of the attack.
Vollesen and colleagues used calcitonin gene-related peptide (CGRP) infusion to trigger cluster headache attacks, finding CGRP induced 50% of subjects with CCH and 89% for ECH subjects in bout (4). In our study, NTG induced attacks in 79% of the CCH subjects and 84% in ECH subjects in bout, in the open unblinded NTG visits, and 92% CCH and 62% ECH in bout in the single-blinded NTG visits. There are some differences in the number of chronic cluster headache subjects on verapamil between the studies; in this study, 33% of CCH subjects were on verapamil and in the study by Vollesen and colleagues, 57% of CCH subjects were on verapamil (of which one was on both verapamil and lithium) and one was on 4 mg melatonin. Vollesen and colleagues proposed that the CCH patients who did not develop an attack following CGRP infusion had a lower median attack frequency in the preceding 30 days prior to the study compared to the CCH patients that did develop an attack. However, in this study, subjects reported having their last attack as long ago as 128 and 158 days and still had NTG-induced attacks (Table 3).
NTG is a pro-drug of nitric oxide (NO) and has effects on blood vessel dilation through mechanisms of the NO-cyclic guanylate phosphate (cGMP) pathway (27). However, the vasodilatory effects of NTG are not sufficient to explain the cluster headache attack that occurs after a latency and the central features associated with the attack. Indeed, experimental studies demonstrate that NTG has central effects (37,38). Interestingly, in studies where NO donors were administered in vivo and in vitro, there was a local release of CGRP (39–42). The difference in the rate of cluster headache attacks induced by NTG and CGRP in ECH and CCH subjects could reflect in part the underlying biological processes and systems that are more active in the different subtypes of cluster headache. The difference between ECH and CCH is also suggested by the treatment response to a CGRP monoclonal antibody, galcanezumab (43,44), and non-invasive vagal nerve stimulator (45,46).
Limitations
The main limitations to the study were the recruitment of eligible subjects and the dropout rate at each stage due to the nature of the condition. Therefore, a pragmatic approach was taken with the study design regarding randomisation. Although there was a randomisation sequence, this was modified by the investigator if deemed necessary. This would be in the case of episodic cluster headache patients that were near the end of their bout missing the NTG visit if they followed the randomised sequence. For this reason, it was designed to be a single-blind cross-over study and not a double-blind and randomised study. Expectation bias was reduced by maintaining blinding of the subjects until the end of the study and having both infusions identical in volume, appearance and duration of infusion. Furthermore, given the stark difference between placebo and NTG, there was no difference between attack onset in the open unblinded compared with the single-blinded NTG visits (Figure 4(b)), is an indication that randomisation was not a factor in this study.
Conclusion
We present the results of the first placebo-controlled study using intravenous NTG administration to systematically study NTG-induced cluster headache attacks. We have shown that NTG can reliably bring on cluster headache attacks as well as the development of non-headache symptoms and CAS. This study highlights differences between NTG-induced attack onset times between the ECH and CCH subjects. Understanding the stages of cluster headache is essential; by recognising the non-headache symptoms in the lead up to the onset of pain and the underlying pathogenesis of this, we may be able to uncover new therapeutic targets to abort attacks before the onset of the severe and devastating pain experienced by our cluster headache patients.
Article highlights
Weight-calculated standardised intravenous nitroglycerin administration is a reliable method to induce cluster headache attacks, cranial autonomic symptoms and non-headache symptoms that accompany cluster headache attacks.
Accompanying non-headache symptoms in cluster headache attacks are important to recognise for both clinical and research purposes.
There may be inherent differences between episodic cluster headache and chronic cluster headache.
Acknowledgement
This study would not have been possible without the support of OUCH(UK), all the cluster headache patients who were interested in helping us with this study and all the subjects who took part in this study.
Ethics or Institutional Review Board approval: This study 16/LO/0693 obtained approval from the London, City & East NHS Research Ethics Committee on 23 June 2016. This study was carried out in accordance with the World Medical Association Declaration of Helsinki (1964), the Research Governance Framework for Health and Social Care (2nd edition, 2005), the Data Protection Act (1998) and the Principles of Good Clinical Practice (GCP); all subjects gave informed consent before taking part.
Declaration of conflicting interests: The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: DYW no reported competing interests. PJG reports, over the last 36 months, grants and personal fees from Amgen and Eli-Lilly and Company, grant from Celegene, and personal fees from Alder Biopharmaceuticals, Aeon Biopharma, Allergan, Biohaven Pharmaceuticals Inc., Clexio, Electrocore LLC, eNeura, Epalex, GlaxoSmithKline, Impel Neuropharma, MundiPharma, Novartis, Pfizer, Praxis, Sanofi, Santara Therapeutics Satsuma, Teva Pharmaceuticals, Trigemina Inc., WL Gore, and personal fees from MedicoLegal work, Massachusetts Medical Society, Up-to-Date, Oxford University Press, and Wolters Kluwer; and a patent magnetic stimulation for headache assigned to eNeura without fee.
Funding: The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study is part-funded by the National Institute for Health Research (NIHR) Maudsley Biomedical Research Centre at South London Maudsley Foundation Trust and King’s College London. The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care.
ORCID iDs: Diana Y Wei https://orcid.org/0000-0003-0644-7172
Peter J Goadsby https://orcid.org/0000-0003-3260-5904 | NITROGLYCERIN | DrugsGivenReaction | CC BY | 33615843 | 19,017,453 | 2021-07 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Conjunctival hyperaemia'. | Comprehensive clinical phenotyping of nitroglycerin infusion induced cluster headache attacks.
Nitroglycerin administration allows the study of cluster headache attacks in their entirety in a standardised way.
A single-blind, placebo-controlled, cross-over study using weight-calculated intravenous nitroglycerin administration at 0.5 µg/kg/min over 20 minutes to study cluster headache attacks, including accompanying non-headache symptoms and cranial autonomic symptoms.
Thirty-three subjects with cluster headache were included in the study; 24 completed all three study visits. Nitroglycerin-induced attacks developed in 26 out of 33 subjects (79%) receiving unblinded nitroglycerin infusion, and in 19 out of 25 subjects (76%) receiving single-blinded nitroglycerin infusion, compared with one out of 24 subjects (4%) receiving single-blinded placebo infusion. Episodic cluster headache subjects had a shorter latency period to a nitroglycerin-induced attack compared to the chronic cluster headache (CCH) subjects (U = 15, z = -2.399, p = 0.016). Sixteen of nineteen episodic cluster headache (mean, 84%; 95% confidence interval, 66-100%) and 11 of 14 chronic cluster headache subjects developed a nitroglycerin-induced attack (79%, 54-100%) following the unblinded nitroglycerin infusion. Following the single-blinded nitroglycerin infusion, eight out of 13 episodic cluster headache (62%, 31-92%) and 11 out of 12 chronic cluster headache (92%, 73-100%) subjects developed nitroglycerin-induced attacks. Nitroglycerin induced non-headache symptoms in the majority of subjects receiving it: 91% in the open unblinded nitroglycerin visit and 84% in the single-blinded nitroglycerin visits, compared with 33% in the single-blinded placebo visit. Cranial autonomic symptoms were induced by nitroglycerin infusion, 94% in the open unblinded nitroglycerin visit and 84% in the single-blinded nitroglycerin visit, compared with 17% in the single-blinded placebo visit.
Intravenous weight-adjusted nitroglycerin administration in both episodic cluster headache in bout and chronic cluster headache is effective and reliable in inducing cluster headache attacks, cranial autonomic symptoms and non-headache symptoms.
Introduction
Due to the episodic nature of acute attacks of cluster headache, a standardised and reliable method for triggering attacks is necessary for their complete study. There have been several substances used to trigger attacks, including histamine (1,2), meta-chloro-phenylpiperazine (mCPP) (3) and more recently calcitonin gene-related peptide (CGRP) (4). Nitroglycerin (NTG) is the most frequently employed substance in human experimental modelling of cluster headache attacks, being used since 1953 (2) (Table 1).
Table 1. Review of studies using nitroglycerin to induce cluster headache attacks.
Study Number of CH patients NTG dose and route Control Placebo Rate of induced CH attack Latency period before onset of headache
(range in minutes)
Peters 1953 (2) 14 1.3 mg sublingual No, but compared with migraine, combination of CH and migraine, vasodilating head pain and tension headache No, but compared with histamine and nicotinic acid 78.6% Not reported
Ekbom 1968 (5) 38 ECH: 28 in bout, 15 out of bout (of which five were tested in bout as well) 1 mg sublingual No No In bout ECH 100% (n = 28)
Out of bout 0% (n = 15) 12–72
Barre 1982 (6) 10 CH: two CCH, nine ECH in bout 1 mg sublingual No No 100% 34–52
Mean 45.9
Drummond et al. 1984 (7) 29 CH 0.9 mg sublingual No No 76% Within 90 min
Drummond et al. 1985 (8) 22 CH: 10 CCH, 12 ECH in bout
0.9 mg sublingual Yes, 10 in the control group without headache No ECH 75% (n = 9)
CCH 60% (n = 6) 9–90
Mean 44
Bogucki 1990 (9) 21 ECH in bout 1 mg sublingual No No 67% (n = 14)
30–65
Dahl et al. 1990 (10) 15 ECH in bout 1 mg sublingual 10 healthy controls No 53% (n = 8)
Controls: not reported 30–65
Hannerz et al. 1992 (11) Eight ECH: five in bout and three out of bout 1 mg sublingual No No In bout ECH 100% (n = 5) Not reported
Fanciullacci et al. 1995 (12) 18 in bout ECH, 12 out of bout ECH 0.9 mg sublingual No No In bout ECH 100% (n = 18)
Out of bout ECH 0% (n = 12) 39–86
Fanciullacci et al. 1997 (13) 11 in bout ECH, eight out of bout ECH 0.9 mg sublingual No No In bout ECH 100% (n = 11)
Out of bout ECH 0% (n = 8) 18–50
Hsieh et al. 1996 (14) Seven ECH: four in bout ECH, three out of bout 1 mg sublingual No No In bout ECH 100%
Out of bout ECH 0% 18–35
May et al. 1998 (15) Nine CCH, eight out of bout ECH 1.0–1.2 mg spray No No CCH 100%
Out of bout ECH 0% Not reported
Costa et al. 2000 (16) 15 CH: Six ECH, nine CCH 0.9 mg sublingual No No ECH 33% (n = 2)
CCH 78% (n = 7) 19–41
Costa et al. 2003 (17) 18 ECH in bout 0.9 mg sublingual Yes, 12 healthy sex and age-matched No ECH 67% (n = 12)
Controls 0% 19–41
Sances et al. 2004 (18) 42 CH: 29 ECH (11 out of bout), 13 CCH 0.9 mg sublingual Yes, 53 healthy controls No In bout ECH and CCH 81% (n = 25 out of 31)
Controls 7.5% developed headache in 7-hour post-NTG Mean onset latency of 65.4 ± 54.7
Cluster headache patients suffer from recurrent episodes of severe unilateral pain in the trigeminal region; therefore, historically, the main emphasis has been centred around the pain onset of a cluster headache, and indeed this is often used as the indicator of the start of the attack. However, from clinical practice, there has been growing awareness of nonpainful symptoms preceding the onset of pain (19,20) and in recent years, the clinical phenotype of cluster headache has been further characterised by retrospective accounts (21–23) and prospective diaries (24,25).
The most frequent route of administration of NTG has been sublingual; however, the bioavailability of sublingual NTG is extremely variable (26). Therefore, we used a weight-calculated dose for intravenous infusion in a standardised single-blind, placebo-controlled study. NTG is a pro-drug of nitric oxide, with predominant actions on the cyclic guanylate phosphate (cGMP) pathway (27), and from pre-clinical studies there are indications of neural actions more centrally. This study is the first single-blind, placebo-controlled cross-over study using a weight-adjusted dose of nitroglycerin administered intravenously in cluster headache patients, thereby allowing comprehensive investigation of the various stages of the acute attack of cluster headache.
Methods
Subject selection and recruitment
The study was advertised on the UK cluster headache patient website OUCH (UK) (Organisation for the Understanding of Cluster Headache UK) (https://ouchuk.org/research/research-volunteers-needed) and in the tertiary Headache centre in King’s College Hospital, London. Subjects interested in participating would make contact via a dedicated research email. Subjects would then be screened for eligibility for the study via emails and a telephone call; those who met the criteria and were interested in participating were invited to attend the study visit. The study was approved by the London, City & East Research Ethics Committee (Ref Number 16/LO/0693). Data were collected from August 2016 until January 2019.
The subjects enrolled fulfilled the ICHD-3 beta criteria for cluster headache (28), and were between the ages of 18 and 60, with no significant previous medical history and no previous syncope or history of autonomic dysfunction. They had had a reliable response to high flow oxygen and/or subcutaneous sumatriptan during spontaneous attacks and normal brain neuroimaging. Women in child-bearing age were required to use reliable contraceptive methods during the study. Subjects were excluded if they were pregnant or breastfeeding, and who had any significant psychiatric disease, diagnosis of another primary headache type (other than migraine) or chronic pain syndrome, any medical history that would have contraindications to receiving NTG, use of preventive medication other than verapamil, or taking indomethacin for any reason, allergies to the medications used in the study or intolerance to high flow oxygen, and use of illicit drugs during the study.
Study visits
The study comprised of three visits in total, with each visit separated by a minimum of 1 week. During the first visit, subjects consented and a full headache history with a physical examination of the neurological and cardiovascular systems was performed, along with recordings of the baseline blood pressure, lying and standing blood pressure, heart rate, oxygen saturation, weight and electrocardiogram. Female subjects were required to have a urinary pregnancy test before the start of the infusion.
Open NTG infusion
If deemed eligible, subjects received an intravenous infusion of nitroglycerin at 0.5 µg/kg/min over 20 minutes. Subjects remained recumbent for 30 minutes before the infusion, and after the NTG infusion, subjects received 250 mL of 0.9% sodium chloride intravenously. The blood pressure and pulse were checked at the start of the infusion, and every 5 min during the infusion.
Phenotypic characterisation
Every 5 minutes, subjects were asked to rate their pain level from a scale from no pain, mild, moderate to severe, where severe equates to their most severe attack, and they were asked a questionnaire of non-headache symptoms and cranial autonomic symptoms (CAS) (Figure 1). If the subject experienced pain, further details were obtained regarding the location and characteristic. Beyond the cluster headache attack, subjects were asked to report any other headache types and in particular NTG headache, which has been well described from migraine studies (29). The NTG headache was assessed for severity, phenotype, accompanying non-headache symptoms and duration. Subjects were actively encouraged to report any symptoms as and when they developed. Following the infusion, at 10 minute intervals, any developments in pain, non-headache symptoms and CAS were recorded for a total of 120 minutes after the infusion, based on the latency period reported from previous studies (Table 1).
Figure 1. Questionnaire for non-headache and cranial autonomic symptoms.
B: bilateral; R: right-sided; L: left-sided.
Single-blinded NTG and placebo infusions
During the two single-blinded visits, subjects either received intravenous nitroglycerin at 0.5 µg/kg/min over 20 minutes or an equal volume of 0.9% sodium chloride at the same rate over 20 minutes, followed by the same 120 minutes of observations (Figure 2). The sequence was pre-determined using the randomise function in Excel; however, the investigator was able to amend this in certain situations if the subject was episodic and due to finish their bout.
Figure 2. Outline of events from open unblinded nitroglycerin visit.
BP: blood pressure; CAS: cranial autonomic symptoms; NTG: nitroglycerin; IV: intravenous.
Treatment of acute attacks
Acute treatment was administered at 20 minutes from the start of attack either with sumatriptan 6 mg subcutaneous injection (Imigran 6 mg/0.5 ml solution for injection pre-filled syringes, GlaxoSmithKline UK Ltd, or sumatriptan 6 mg/0.5 ml solution for injection pre-filled pens, Sun Pharmaceuticals Industries Europe B.V.) or with 15 L/min oxygen via a non-rebreather mask (O2Star™ non-rebreather oxygen mask M/L, Dräger). The visit was concluded only when the subject was pain free.
Statistical analysis
The data was tabulated (Excel for Mac v 16.30), and descriptive statistics were performed to summarise data (SPSS Statistics version 26 for Mac and Excel). Mann-Whitney tests were performed on time until attack onset and time until CAS onset for those that developed NTG-triggered cluster headache attacks and CAS, comparing the differences in ECH with CCH subgroups. Kaplan-Meier survival graphs were used to examine the time until onset of event; that is, survival of no cluster headache attack status, or absence of CAS after NTG infusion for 140 minutes (20 minutes of infusion and 120 minutes of post-infusion observation), with log-rank statistical testing; P < 0.05 was considered significant. Graphs were made using SPSS and violin plots were made using GraphPad Prism 8 for Mac OS.
Results
Demography
A total of 229 subjects were contacted to check for eligibility, of which 33 were included in the study; 24 completed all three study visits (Figure 3). All patients fulfilled the ICHD-3 beta criteria for cluster headache, 19 episodic cluster headache in bout (58%) and 14 chronic cluster headache (42%) (Table 2). The majority were male (n = 24, 73%) with a male: female ratio of 3:1. The average age was 41 (SD 10), with the mean age of females (34 years, SD 9) younger than in males (44 years, SD 9) in this cohort. Subjects had had the condition for a median of 9 years (IQR 5–16).
Figure 3. Subject numbers throughout the study.
Table 2. Subject characteristics.
Subject Age Sex Subtype Side of attacks Time since first attack (years) Average attack frequency (per day) Average attack duration when untreated (mins) Average bout duration (weeks) Verapamil (total daily dose in mg)
1 55 M Chronic Right 5 2 45 – 480
2 28 F Chronic Right 12 7 150 – –
3 40 M Episodic Right 20 3 150 8 –
4 38 F Episodic Left 12 2 120 4 –
5 53 M Chronic Left 15 4 35 – 960
6 48 M Episodic Left 25 5 52.5 5 480
7 23 M Episodic Left 8 2 120 10 –
8 43 M Chronic Right 9 1 40 – –
9 43 M Episodic Right 13 3 60 5 240
10 44 M Episodic Right 27 6 45 6 –
11 47 M Episodic Right 3 1 105 20 –
12 48 M Episodic Left 26 3 180 10 560
13 40 M Episodic Right 5 3 60 8 –
14 50 M Episodic Right 10 2 105 8 –
15 56 M Episodic* Right 24 1 45 – –
16 35 M Episodic Left 7 2 150 6 240
17 58 M Episodic Left 3 1 135 24 –
18 43 M Chronic Left 4 2 60 – –
19 32 M Episodic Left 3 3 50 12 600
20 49 F Episodic Right 8 5 50 9 –
21 49 M Chronic Right 35 2 90 – –
22 57 M Chronic Right 20 5 65 –
23 40 F Chronic Left 4 1.5 120 – 640
24 44 M Chronic Right 6 2 90 – 720
25 23 F Episodic Right 9 2.5 90 6 –
26 40 M Chronic Left 17 1.5 180 – –
27 20 F Chronic Right 6 1.5 150 – –
28 31 F Episodic Right 14 2 75 11 –
29 35 M Episodic Left 9 2 90 3 –
30 38 F Chronic Left 6 1.5 180 – 240
31 49 M Episodic Left 0.5 1.5 37.5 21 400
32 35 F Chronic Left 4 0.3 30 – 600
33 32 M Chronic Left 10 6 60 – –
M: male; F: female.
*Subject was chronic but became episodic during study with no attacks in 6 months.
Clinical phenotyping of subjects by history
Pain features
There was a near-equal split between the laterality of attacks; 17 subjects had right-sided attacks (52%), and 16 subjects had left-sided attacks (49%). The median number of attacks per day was two (IQR 1.5–3) lasting a median of 90 minutes (IQR 50–128). Verapamil was the only preventive allowed on the study; 12 subjects (36%) were on verapamil ranging from 240 mg to 960 mg per day.
Migraine, accompanying features and non-headache symptoms in spontaneous attacks
In this cohort, 58% (n = 19) had a concurrent migraine (28): five had migraine with aura, of which four had visual aura and one had facial sensory aura. Of the subjects who did not meet the diagnostic criteria for migraine (28) (n = 14, 42%), the majority had either migraine markers and/or a family history of migraine. Migraine markers were defined if subjects experienced: childhood cyclic nausea and vomiting, motion sickness, cold stimulus-induced headache, hangover headache and jetlag. Four subjects did not have migraine markers, and three subjects (9%) did not have either migraine marker or a family history of migraine. Subjects (n = 24, 73%) reported accompanying symptoms with their spontaneous attacks, the most common symptoms being cranial allodynia (n = 15), photophobia (n = 15), nausea (n = 11) and phonophobia (n = 10).
Non-headache attack symptoms
The majority reported non-headache symptoms in the lead up to their spontaneous cluster headache attacks (n = 27, 82%), with the commonest symptoms being concentration difficulties (n = 18), mood changes (n = 15), neck stiffness (n = 13) and yawning (n = 8). The median onset time of symptoms was 10 minutes (IQR 2–30) before the onset of pain. Although most symptoms start before the onset of pain, five subjects only reported developing the symptoms during the attack.
Twenty-eight subjects reported non-headache symptoms following their cluster headache attacks (85%), the commonest symptoms being tiredness (n = 27), mood changes (n = 13), concentration difficulties (n = 12), and neck stiffness (n = 7). The median duration of symptoms was 120 minutes (IQR 53–315).
Attack triggers
The most commonly reported triggers for spontaneous attacks were alcohol ingestion (n = 22), followed by changes in temperature (n = 12), strong smells such as from nail varnish, paint (n = 11) followed by disrupted sleep (n = 4) and exercise (n = 3). Other triggers mentioned were stress (n = 2), caffeine (n = 2), changing time zones (n = 1), let down from stress (n = 1), being in a pressurised cabin on an airplane (n = 1), vardenafil (n = 1), and dehydration (n = 1). All subjects reported attacks within a few hours of alcohol ingestion, no one reported a next-day effect.
Clinical phenotyping of open NTG visit
NTG triggered cluster headache-like attacks (n = 26, 79%), CAS (n = 31, 94%) and agitation (n = 24, 73%) during the open unblinded NTG visit. In the episodic cluster headache group, 16 out of 19 developed an NTG-induced attack (mean, 84%; 95% CI, 66–100%) and in the chronic cluster headache group, 11 out of 14 developed an NTG-induced attack (79%, 54–100%). Five out of the 31 subjects developed CAS, but did not develop an attack; of these subjects, three developed mild generalised pain, one developed restless legs, and one developed CAS on the contralateral side to the subject’s spontaneous attack phenotype, with a generalised headache. These cases were excluded.
The median onset time for CAS to develop from the start of the NTG infusion was 31 minutes (IQR 13–46). The median onset for an NTG-induced attack was 30 minutes (IQR 20–39) and the median time to maximum pain, if reached, was 51 minutes (IQR 39–70). The most common first cranial autonomic symptoms brought on by NTG infusion were nasal congestion (n = 10), conjunctival injection (n = 5), lacrimation (n = 4) and periorbital oedema (n = 3).
Clinical phenotyping of single-blinded NTG and placebo visit
During the single-blinded visits, NTG induced attacks in 19 subjects (76%); three subjects did not have an attack (12%), two subjects developed migraine-like headache (8%) and one subject developed unilateral mild pain without CAS or agitation (4%) (Table 3). In the placebo group, only one developed an attack (4%), two subjects developed unilateral mild pain without CAS or agitation (8%) and two subjects experienced short-lived unilateral CAS (8%). Of the subjects receiving NTG, eight out of 13 ECH (mean, 62%; 95% CI, 31%-92%) and 11 out of 12 CCH (92%, 73–100%) developed NTG-induced attacks (Figure 4(a)).
Table 3. Subject characteristics and comparison between spontaneous attack and triggered attack from single-blinded nitroglycerin visit, M = male, F = female, ECH = episodic cluster headache, CCH = chronic cluster headache, L = Left, R = Right, Y = Yes, N = No, VRS = verbal rating scale, mod = moderate, O2 = high flow oxygen via non-rebreather mask, suma = sumatriptan.
Subject Age Sex Subtype Migraine Verapamil (total daily dose in mg) Spontaneous attack Triggered attack- single-blinded NTG visit
Laterality Severity CAS Agitation Laterality Severity/VRS CAS Agitation Feels like spontaneous attack Treatment Last spontaneous attack (days)
1 55 M CCH N 480 R 9/10 Conjunctival injection, nasal congestion, lacrimation. 3 months of R Horner’s syndrome in 2007, now resolved Y R 10/10
VRS 3 Conjunctival injection, nasal congestion, lacrimation, periorbital oedema Y Y O2 158
2 28 F CCH Y
– R 10/10 Periorbital oedema/ptosis, nasal congestion, dry eye then lacrimation Y R 10/10
VRS 3 Periorbital oedema, nasal congestion, facial flushing Y Y O2 128
3 40 M ECH N – R 10/10 Lacrimation, rhinorrhoea, ptosis Y R 10/10
VRS 3 Lacrimation, conjunctival injection, periorbital oedema, nasal congestion, aural fullness and facial droop Y Y Suma 1
4 38 F ECH Y – L 10/10 Lacrimation, conjunctival injection, periorbital oedema, nasal congestion, ptosis, facial flushing Y No attack, developed generalised pain 4/10 Y N N/A 1
5 53 M CCH N 960 L 10/10 Rhinorrhoea, ptosis Y L 10/10
VRS 3 Conjunctival injection, eye grittiness, lacrimation Y Y O2 4
6 48 M ECH N
480 L 8/10 Nasal congestion, lacrimation Y Did not attend
7 23 M ECH Y – L 10/10 Lacrimation, conjunctival injection, nasal congestion, ptosis, facial flushing Y Did not attend
8 43 M CCH N – R 10/10 Nasal congestion, rhinorrhoea, lacrimation, facial flushing Y R 10/10
VRS 3 Nasal congestion, conjunctival injection, eye grittiness Y Y Suma <1
9 43 M ECH N 240 R 10/10 Lacrimation, conjunctival injection, facial flushing, ptosis, facial droop Y Did not attend
10 44 M ECH N – R 10/10 Nasal congestion, ptosis, periorbital oedema, lacrimation, flushing Y No attack, L mild hangover like headache, with nasal congestion.
After study visit felt nauseous and vomited, then slept, headache free at 7pm N N O2- no response <1
11 47 M ECH N – R Severe attacks 10/10 Nasal congestion, aural fullness Y R 7/10
VRS 2/3 moderate/
severe Nasal congestion, conjunctival injection, aural fullness Y Y Suma 13
12 48 M ECH N 560 L 10/10 Lacrimation, nasal congestion, periorbital oedema Y Did not attend
13 40 M ECH Y – R 10/10 Nasal congestion, ptosis, conjunctival injection, lacrimation, throat tightness, rhinorrhoea Y No attack, bilateral mild headache 4/10 with nasal congestion Y, brief (7 mins) N N/A 19
14 50 M ECH Y – R 10/10
Lacrimation, periorbital oedema, nasal congestion, rhinorrhoea Y Did not attend
15 56 M ECH Y – R 10/10 Lacrimation, rhinorrhoea, facial flushing, gritty eyes, conjunctival injection Y with severe attacks Did not attend
16 35 M ECH Y 240 L 10/10 Nasal congestion, conjunctival injection, ptosis, lacrimation, rhinorrhoea Y Not attack, milder than a shadow and no CAS N N N/A 16
17 58 M ECH Y – L 10/10 Nasal congestion, rhinorrhoea, lacrimation, aural fullness, throat swelling Y L 7/10
VRS 2–3 (mod-severe) Nasal congestion, rhinorrhoea, voice change, lacrimation Y Y Suma 1
18 43 M CCH Y – L (70%) Mild 6/10, severe 10/10 Nasal congestion, periorbital oedema, aural fullness, facial flushing Y L Mild,
VRS 1 Nasal congestion Y Y- shadow O2 7
19 32 M ECH Y 600 L 10/10 Lacrimation, conjunctival injection, facial flushing Y L 7–8/10
VRS 2–3
(mod-severe) Lacrimation, eye grittiness, nasal congestion, facial flushing Y Y O2 <1
20 49 F ECH Y – R 10/10 Ptosis, periorbital oedema, lacrimation, nasal congestion, rhinorrhoea, (aural fullness with severe attacks) Y R 6–7/10
VRS 2 mod Nasal congestion, periorbital oedema, lacrimation, conjunctival injection Y Y O2 7
21 49 M CCH Y – R 4–10/10 Facial flushing, nasal congestion, ptosis, lacrimation, rhinorrhoea, conjunctival injection Y L 8/10
VRS 2–3
(mod-severe)
Facial flushing, lacrimation, periorbital oedema, conjunctival injection Y Y, but on L rather than R Suma <1
22 57 M CCH N – R 10/10 Lacrimation, conjunctival injection, nasal congestion, rhinorrhoea Y No attack, no pain and no CAS N N N/A 26
23 40 F CCH Y 640 L 10/10
Lacrimation, conjunctival injection, periorbital oedema, rhinorrhoea, ptosis, aural fullness Y Did not attend
24 44 M CCH N 720 R 10/10 Lacrimation, conjunctival injection, periorbital oedema, facial flushing Y Did not attend
25 23 F ECH Y – R 6–10/10 Nasal congestion, lacrimation, periorbital oedema. Rhinorrhoea and facial flushing with severe attacks Y R 7/10
VRS 2
(moderate) Nasal congestion, periorbital oedema Y Y O2 3
26 40 M CCH Y – L Shadow 4/10, daytime attacks 6–7/10, full attack 10/10 Ptosis, aural fullness, lacrimation, conjunctival injection, periorbital oedema, nasal congestion Y L 8.5–9/10
VRS 3 severe Nasal congestion, periorbital oedema, lacrimation Y Y Suma 3
27 20 F CCH N – R 8–9/10 Nasal congestion, lacrimation, rhinorrhoea, ptosis, aural fullness Y R 8/10
VRS 3
severe Nasal congestion, periorbital oedema Y Y O2 <1
28 31 F ECH Y – R 10/10 Nasal congestion, periorbital oedema, rhinorrhoea, ptosis, aural fullness Y R 2/10
VRS 1 (mild) Nasal congestion, facial swelling Y Y, but milder Suma 3
29 35 M ECH N – L Max pain 10/10 Nasal congestion, periorbital oedema, lacrimation, voice change (croaky). Facial flushing with severe attacks and rhinorrhoea after attack Y L 6–7/10
VRS 2 (moderate) Nasal congestion, lacrimation, conjunctival injection, voice change Y Y Suma <1
30 38 F CCH Y 240 L 4–10/10 Lacrimation, rhinorrhoea, conjunctival injection, facial flushing. Ptosis with severe attacks Y L 6–7/10
VRS 2 (moderate) Aural fullness Y Y Suma 1
31 49 M ECH Y 400 L 10/10 Nasal congestion, lacrimation, conjunctival injection, rhinorrhoea, ptosis, aural fullness. Prominent miosis after attack Y No attack, whole head felt heavy N N N/A 10
32 35 F CCH N 600 L 4/10 (on verapamil),
7/10 average Periorbital oedema, eye grittiness, facial flushing, lacrimation Y L 7/10
VRS 2–3
(mod-severe) Nasal congestion, conjunctival injection, facial flushing, lacrimation Y Y Suma 1
33 32 M CCH Y – L Severe attacks 10/10 Lacrimation, ptosis, nasal congestion, conjunctival injection, ptosis, facial flushing, eye grittiness Y L 6/10
VRS 2 (mod-severe) Lacrimation, nasal congestion, ptosis Y Y Suma <1
Figure 4. (a) Kaplan-Meier graph comparing time until cluster headache attack between the eight episodic cluster headache (ECH) and the 11 chronic cluster headache (CCH) subjects during single-blinded nitroglycerin (NTG) infusion, from the start of the infusion in minutes, log-rank P = 0.534. (b) Kaplan-Meier graph comparing time until cluster headache attack onset between the open unblinded (n = 33) and single-blinded (n =25) nitroglycerin (NTG) infusions with single-blinded placebo infusions (n = 24). Log-rank P = 0.000.
The median onset time to an induced attack was 33 minutes (IQR 15–42) from the start of the single-blinded NTG infusion, and in the single-blinded placebo visit only one subject developed an attack; the onset time was 10 minutes. On comparison of the attack onset time for the unblinded NTG, single-blinded NTG and single-blinded placebo visits, there was a difference between the placebo and NTG visits (P = 0.000, Figure 4(b)).
NTG headache
The majority of subjects developed an NTG headache (n = 28, 85%) following the NTG infusion in the unblinded open visit, of which 27 subjects had a migraine diagnosis (n = 18), had migraine markers (n = 10) and a family history of migraine (n = 18); only one subject did not have migraine, migraine markers or a family history of migraine. The median time from the start of NTG infusion was 3 minutes (IQR 2–6), and the median duration of NTG headache was 26 minutes (IQR 14–41).
Of the 25 subjects that went on to the single-blinded NTG visits, 18 (72%) developed NTG headache following NTG infusion, of which all had either migraine (n = 11), migraine markers (n = 7) or family history (n = 10). The median time of NTG headache onset from the start of NTG infusion in the blinded visit was 4 minutes (IQR 3–8), with a median duration of 26 minutes (IQR 9–45).
In the placebo visit, three of the 24 subjects (13%) developed NTG headache, median onset time was 13 minutes (range 1–18), and the median duration was 10 minutes (range 3–16).
Non-headache symptoms
The majority of subjects reported non-headache symptoms in both the open unblinded NTG visit (n = 30, 91%) and the single-blinded NTG visit (n = 21, 84%) visits. In the single-blinded placebo visit, eight subjects (33%) reported non-headache symptoms. The most common non-headache symptoms from the open unblinded NTG visit were neck stiffness, photophobia, thirst and allodynia. The most common non-headache symptoms from the single-blinded NTG visit were neck stiffness, yawning, thirst and photophobia (Table 4). The median number of non-headache symptoms reported in the open unblinded NTG visit was three (IQR 2–5), and from the single-blinded NTG visit was three (IQR 2–6), compared with two (IQR 2–3) on-headache symptoms in the single-blinded placebo group.
Table 4. Frequencies of non-headache symptoms reported during each visit.
Non-headache symptom Open unblinded NTG visit (n = 33) Single-blinded NTG visit
(n = 25) Single-blinded placebo visit
(n = 24)
Thirst 15 10 3
Craving 0 0 0
Yawning 8 12 4
Tiredness 4 3 0
Mood changes 5 4 1
Visual blurring 4 3 1
Neck stiffness 21 15 3
Irritability 3 3 0
Photophobia 18 10 1
Concentration difficulties 6 4 1
Phonophobia 4 6 0
Urinary symptoms 0 0 0
Speech disturbances 0 0 0
Nausea 6 3 0
Gastrointestinal discomfort 0 0 0
Movement sensitivity 5 5 1
Allodynia 9 8 2
In the open unblinded NTG visit, the median onset time of non-headache symptoms from the start of the infusion was 9 minutes (IQR 4–17) with the median maximum duration of the symptoms being 50 minutes (IQR 24–64), the duration is calculated from the first symptom until the end of the last symptom. In the single-blinded NTG visit, the median onset time was 5 minutes (IQR 3–9) from the start of the infusion, and the median maximum duration of symptoms was 59 minutes (IQR 35–76). The outlier was a subject who developed allodynia and neck stiffness during their attack. For those that developed non-headache symptoms during the single-blinded placebo visit, the median onset time was 9 minutes (IQR 2–9), with a median duration of 16 minutes (IQR 6–34).
Cranial autonomic symptoms
NTG triggered CAS in the majority of the subjects during the open unblinded NTG visit (n = 31, 94%). In all, five subjects out of the 31 (19%) developed unilateral CAS; however, they did not have a cluster headache attack. Two subjects had CAS with generalised headache, one had CAS without any pain, one subject developed CAS on the contralateral side to their attacks with mild generalised pain, and one subject with CAS developed restless leg symptoms, but no cluster headache attack. Of the subjects who developed unilateral CAS and cluster headache attack (n = 26, 79%), the median number of CAS was four (IQR 2–5), with the most common CAS being nasal congestion (n = 21), lacrimation (n = 16) and periorbital oedema (n = 15) (Table 5).
Table 5. Frequencies of cranial autonomic symptoms reported in subjects who had attacks following NTG infusion.
Cranial autonomicsymptoms Open unblinded NTG visit, total number of attacks (n = 26) Single-blinded NTG visit, total number of attacks (n = 19)
Lacrimation 16 11
Conjunctival injection 12 9
Periorbital oedema 15 8
Eye grittiness/itchiness 3 3
Nasal congestion 21 16
Rhinorrhoea 2 1
Ptosis 4 1
Aural fullness 5 2
Facial flushing 7 4
Sialorrhoea 1 0
Throat swelling 2 0
Voice change 4 2
Facial swelling 3 1
Similarly, NTG brought on CAS in the majority of subjects during the single-blinded NTG visit (n = 21, 84%), of which two were not accompanied by a cluster headache attack, compared with four out of 24 in the single-blinded placebo group developing CAS (Figure 5(a)). One of the subjects from the single-blinded NTG group had a generalised headache similar to a hangover headache with unilateral CAS, and the other subject had a migraine-like headache with CAS. Of the 19 subjects (76%) that had unilateral CAS and a cluster headache attack, the median number of symptoms was three (IQR 2–4) and the most frequent symptoms were nasal congestion (n = 16), lacrimation ( n = 11) and conjunctival injection (n = 9) (Table 5). In comparing the time until all CAS onset between ECH and CCH after blinded NTG infusion, there was no difference between the two groups (log-rank P = 0.740; Figure 5(b)).
Figure 5. (a) Kaplan-Meier graph showing time until onset of cranial autonomic symptoms (CAS) following open unblinded (n = 33) and single-blinded NTG (n = 25) infusions compared with the single-blinded placebo infusion (n = 24). Log-rank P = 0.000. (b) Kaplan-Meier graph showing the time until CAS onset in the single-blinded NTG visit, comparing episodic cluster headache (ECH) with chronic cluster headache (CCH). Log-rank P = 0.740.
The median time until CAS onset for those that developed cluster headache attacks was 31 min (IQR 13–46) in the open unblinded NTG visit and 12 min (IQR 6–30) in the single-blinded NTG visit. Subjects sequentially reported CAS development.
During the single-blinded placebo visit, four subjects (17%) developed unilateral CAS, of which one subject developed a spontaneous attack, and three developed CAS but no pain. The median number of symptoms reported in the placebo group was two (IQR 1–2) and the symptoms reported were nasal congestion (n = 2), conjunctival injection (n = 1), periorbital swelling (n = 1), rhinorrhoea (n = 1) and aural fullness (n = 1).
Agitation
Nitroglycerin brought on agitation in the majority of subjects, open unblinded NTG visit (n = 24, 73%) and single-blinded NTG visit (n= 20, 80%), compared with none in the single-blinded placebo visit.
Non-headache symptoms post-attack
The non-headache symptoms were not studied here, as all attacks were treated with sumatriptan or oxygen after 20 minutes, thus altering the natural progression and development of symptoms.
Episodic cluster headache compared with chronic cluster headache
For the subjects that developed an NTG-induced attack following the single-blinded NTG infusion, the time until NTG-induced attack was shorter in the episodic cluster headache group compared with the chronic cluster headache group (U = 15, z = −2.399, P = 0.016). The time until CAS onset, in the subjects that developed CAS following single-blinded NTG infusion was not different between episodic cluster headache and chronic cluster headache groups (U = 38, z = −1.2000, P = 0.230).
Effect of verapamil on NTG triggering
There were seven subjects on verapamil that attended the single-blinded NTG visits, of which two did not develop NTG-triggered cluster headache attacks (29%). Using χ2, there was no difference between verapamil and NTG triggering (χ2 (df = 1) = 0.111, P = 0.739).
Effect of migraine on NTG-triggered attacks
Within the cohort that attended the single-blinded NTG visits, 15 had migraine (60%). There was no difference between the number of non-headache symptoms (U = 67, z = −0.449, P = 0.654) or number of CAS (U = 57, z = −1.019, P = 0.308), between the subjects with migraine and those without migraine. Furthermore, there was no association between subjects with migraine and NTG triggering (χ2 (df = 1) = 0.146, P = 0.702); similarly, there was no association between subjects with migraine and development of NTG headache (χ2 (df = 1) = 0.033, P = 0.856).
Discussion
This study demonstrates that weight-calculated intravenous NTG effectively triggers cluster headache attacks in both chronic cluster headache and episodic cluster headache subjects within bout when compared with placebo. The approach is reliable in terms of triggering a fully-featured attack that allows careful observation of symptoms and their development during acute attacks of cluster headache.
The benefit of weight-calculated intravenous NTG compared to intranasal and sublingual administration is that this is more reliable and has more stable bioavailability. The median time until cluster headache attack onset was 30 minutes (open unblinded NTG visit) and 33 minutes (single-blinded NTG visit), with the overall maximum onset time of 81 minutes. Subjects who did not develop an attack during the 140 minutes of observation were asked to report if they developed an attack later on that day, and none did. The median onset time is similar to the reported latency period reported in the literature (Table 1). The minimum onset time for NTG-induced attacks was 2 minutes, and this is less than reported from the sublingual route, where the shortest time until onset time was 9 minutes (8); this is expected, given the intravenous route has a half-life of 2.3–2.8 minutes (30,31). Two subjects started experiencing mild attack pain before the start of the NTG infusion, and within the placebo group we observed one subject who developed a spontaneous attack. Spontaneous attacks could be anticipated given the subjects are within bout; there were three subjects with only short-lasting CAS symptoms and two subjects who experienced a mild pain without CAS, similar to a shadow.
This study delineates the development of the various stages of an NTG-induced cluster headache attack, including the non-headache symptoms and CAS (Figure 6). The majority of subjects developed NTG headache shortly after the infusion started. This headache was generalised, mild and progressive in nature, predominantly in the bi-occipital and bi-temporal regions. Subjects described it as pressure-like or band-like ache, and they reported it to be distinct from their cluster headache attacks; if there were an overlap, the cluster headache attack would clearly ramp up and supersede the NTG headache. It is difficult to disentangle whether NTG headache developed because there was a high proportion of subjects with either a migraine diagnosis, migraine marker or family history of migraine. However, from a previous study with 25 healthy volunteers without a migraine diagnosis, 16 (64%) developed NTG headache following 0.5 mg NTG sublingual administration (32).
Figure 6. Violin plots of the stages of cluster headache attack from the 19 subjects that developed cluster headache attacks and subdivided by chronicity. The timeline starts with 20 minutes of single-blinded nitroglycerin (NTG) infusion, followed by 120 minutes of post-infusion observation. CAS = cranial autonomic symptoms.
Following the NTG headache, the majority of subjects reported non-headache symptoms in the lead-up to the onset of the pain from the attack and in some subjects, non-headache symptoms accompanied their attacks. The non-headache symptoms included homeostatic symptoms (thirst, cravings, yawning, frequency of urination), fatigue/cognitive symptoms (concentration difficulty, fatigue, memory impairment, mood changes, irritability) and sensitised sensory symptoms (neck stiffness, photophobia, phonophobia, osmophobia, nausea), as are reported in the premonitory phase of migraine (33). The most common symptoms were neck stiffness, photophobia and thirst. During their spontaneous attacks, subjects reported that non-headache symptoms would precede the attack at a median of 10 minutes (IQR 2–30) before the onset of pain, although it is known that there are discrepancies between retrospective and prospective reporting (25). Comparing the symptoms observed from NTG-induced attacks in this study with the prospective observational questionnaire study (24), the most reported general symptoms in the pre-pain phase in this study were concentration difficulties, photophobia and mood changes. Patients in the observational study also reported general symptoms during their attacks and postictal symptoms similar to the symptoms seen during the NTG-induced attacks and the reported symptoms by the subjects in this study during the postdrome phase of their spontaneous attacks. Non-headache symptoms such as photophobia, phonophobia, and localised allodynia were often reported during the attacks, as has been reported previously (21,34). In one semi-structured questionnaire study, they found a high proportion of cluster headache patients (73.2%) reported phonophobia or photophobia with their attacks (35), cluster headache patients with migraine did not more frequently report these symptoms compared with those without co-existing migraine. Furthermore, allodynia was more often reported in cluster headache patients with migraine. From pre-clinical studies, high dose NTG causes a sustained increase in spontaneous firing of Aδ and C-fibre trigeminal neurons (36), which migraine biology may unmask.
Similar to the prospective questionnaire study by Snoer and colleagues (24), in some subjects CAS presented before the onset of the attack pain (Figure 6). In this study, the median onset time for CAS was 31 minutes (IQR 13–46) in the open unblinded NTG visit and 12 minutes (IQR 6–30) in the single-blinded NTG visit, whereas the onset of NTG-induced attack was 30 minutes (IQR 20–39) in the open unblinded visit and 33 minutes (IQR 15–42) in the single-blinded NTG visit. From the open unblinded NTG visit, 38% presented with CAS before the attack, 15% presented with CAS with the onset of the attack, and from the single-blinded NTG visit, 58% presented with CAS before the attack and 16% presented with CAS with the onset of the attack.
Vollesen and colleagues used calcitonin gene-related peptide (CGRP) infusion to trigger cluster headache attacks, finding CGRP induced 50% of subjects with CCH and 89% for ECH subjects in bout (4). In our study, NTG induced attacks in 79% of the CCH subjects and 84% in ECH subjects in bout, in the open unblinded NTG visits, and 92% CCH and 62% ECH in bout in the single-blinded NTG visits. There are some differences in the number of chronic cluster headache subjects on verapamil between the studies; in this study, 33% of CCH subjects were on verapamil and in the study by Vollesen and colleagues, 57% of CCH subjects were on verapamil (of which one was on both verapamil and lithium) and one was on 4 mg melatonin. Vollesen and colleagues proposed that the CCH patients who did not develop an attack following CGRP infusion had a lower median attack frequency in the preceding 30 days prior to the study compared to the CCH patients that did develop an attack. However, in this study, subjects reported having their last attack as long ago as 128 and 158 days and still had NTG-induced attacks (Table 3).
NTG is a pro-drug of nitric oxide (NO) and has effects on blood vessel dilation through mechanisms of the NO-cyclic guanylate phosphate (cGMP) pathway (27). However, the vasodilatory effects of NTG are not sufficient to explain the cluster headache attack that occurs after a latency and the central features associated with the attack. Indeed, experimental studies demonstrate that NTG has central effects (37,38). Interestingly, in studies where NO donors were administered in vivo and in vitro, there was a local release of CGRP (39–42). The difference in the rate of cluster headache attacks induced by NTG and CGRP in ECH and CCH subjects could reflect in part the underlying biological processes and systems that are more active in the different subtypes of cluster headache. The difference between ECH and CCH is also suggested by the treatment response to a CGRP monoclonal antibody, galcanezumab (43,44), and non-invasive vagal nerve stimulator (45,46).
Limitations
The main limitations to the study were the recruitment of eligible subjects and the dropout rate at each stage due to the nature of the condition. Therefore, a pragmatic approach was taken with the study design regarding randomisation. Although there was a randomisation sequence, this was modified by the investigator if deemed necessary. This would be in the case of episodic cluster headache patients that were near the end of their bout missing the NTG visit if they followed the randomised sequence. For this reason, it was designed to be a single-blind cross-over study and not a double-blind and randomised study. Expectation bias was reduced by maintaining blinding of the subjects until the end of the study and having both infusions identical in volume, appearance and duration of infusion. Furthermore, given the stark difference between placebo and NTG, there was no difference between attack onset in the open unblinded compared with the single-blinded NTG visits (Figure 4(b)), is an indication that randomisation was not a factor in this study.
Conclusion
We present the results of the first placebo-controlled study using intravenous NTG administration to systematically study NTG-induced cluster headache attacks. We have shown that NTG can reliably bring on cluster headache attacks as well as the development of non-headache symptoms and CAS. This study highlights differences between NTG-induced attack onset times between the ECH and CCH subjects. Understanding the stages of cluster headache is essential; by recognising the non-headache symptoms in the lead up to the onset of pain and the underlying pathogenesis of this, we may be able to uncover new therapeutic targets to abort attacks before the onset of the severe and devastating pain experienced by our cluster headache patients.
Article highlights
Weight-calculated standardised intravenous nitroglycerin administration is a reliable method to induce cluster headache attacks, cranial autonomic symptoms and non-headache symptoms that accompany cluster headache attacks.
Accompanying non-headache symptoms in cluster headache attacks are important to recognise for both clinical and research purposes.
There may be inherent differences between episodic cluster headache and chronic cluster headache.
Acknowledgement
This study would not have been possible without the support of OUCH(UK), all the cluster headache patients who were interested in helping us with this study and all the subjects who took part in this study.
Ethics or Institutional Review Board approval: This study 16/LO/0693 obtained approval from the London, City & East NHS Research Ethics Committee on 23 June 2016. This study was carried out in accordance with the World Medical Association Declaration of Helsinki (1964), the Research Governance Framework for Health and Social Care (2nd edition, 2005), the Data Protection Act (1998) and the Principles of Good Clinical Practice (GCP); all subjects gave informed consent before taking part.
Declaration of conflicting interests: The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: DYW no reported competing interests. PJG reports, over the last 36 months, grants and personal fees from Amgen and Eli-Lilly and Company, grant from Celegene, and personal fees from Alder Biopharmaceuticals, Aeon Biopharma, Allergan, Biohaven Pharmaceuticals Inc., Clexio, Electrocore LLC, eNeura, Epalex, GlaxoSmithKline, Impel Neuropharma, MundiPharma, Novartis, Pfizer, Praxis, Sanofi, Santara Therapeutics Satsuma, Teva Pharmaceuticals, Trigemina Inc., WL Gore, and personal fees from MedicoLegal work, Massachusetts Medical Society, Up-to-Date, Oxford University Press, and Wolters Kluwer; and a patent magnetic stimulation for headache assigned to eNeura without fee.
Funding: The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study is part-funded by the National Institute for Health Research (NIHR) Maudsley Biomedical Research Centre at South London Maudsley Foundation Trust and King’s College London. The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care.
ORCID iDs: Diana Y Wei https://orcid.org/0000-0003-0644-7172
Peter J Goadsby https://orcid.org/0000-0003-3260-5904 | NITROGLYCERIN | DrugsGivenReaction | CC BY | 33615843 | 19,017,453 | 2021-07 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Ear congestion'. | Comprehensive clinical phenotyping of nitroglycerin infusion induced cluster headache attacks.
Nitroglycerin administration allows the study of cluster headache attacks in their entirety in a standardised way.
A single-blind, placebo-controlled, cross-over study using weight-calculated intravenous nitroglycerin administration at 0.5 µg/kg/min over 20 minutes to study cluster headache attacks, including accompanying non-headache symptoms and cranial autonomic symptoms.
Thirty-three subjects with cluster headache were included in the study; 24 completed all three study visits. Nitroglycerin-induced attacks developed in 26 out of 33 subjects (79%) receiving unblinded nitroglycerin infusion, and in 19 out of 25 subjects (76%) receiving single-blinded nitroglycerin infusion, compared with one out of 24 subjects (4%) receiving single-blinded placebo infusion. Episodic cluster headache subjects had a shorter latency period to a nitroglycerin-induced attack compared to the chronic cluster headache (CCH) subjects (U = 15, z = -2.399, p = 0.016). Sixteen of nineteen episodic cluster headache (mean, 84%; 95% confidence interval, 66-100%) and 11 of 14 chronic cluster headache subjects developed a nitroglycerin-induced attack (79%, 54-100%) following the unblinded nitroglycerin infusion. Following the single-blinded nitroglycerin infusion, eight out of 13 episodic cluster headache (62%, 31-92%) and 11 out of 12 chronic cluster headache (92%, 73-100%) subjects developed nitroglycerin-induced attacks. Nitroglycerin induced non-headache symptoms in the majority of subjects receiving it: 91% in the open unblinded nitroglycerin visit and 84% in the single-blinded nitroglycerin visits, compared with 33% in the single-blinded placebo visit. Cranial autonomic symptoms were induced by nitroglycerin infusion, 94% in the open unblinded nitroglycerin visit and 84% in the single-blinded nitroglycerin visit, compared with 17% in the single-blinded placebo visit.
Intravenous weight-adjusted nitroglycerin administration in both episodic cluster headache in bout and chronic cluster headache is effective and reliable in inducing cluster headache attacks, cranial autonomic symptoms and non-headache symptoms.
Introduction
Due to the episodic nature of acute attacks of cluster headache, a standardised and reliable method for triggering attacks is necessary for their complete study. There have been several substances used to trigger attacks, including histamine (1,2), meta-chloro-phenylpiperazine (mCPP) (3) and more recently calcitonin gene-related peptide (CGRP) (4). Nitroglycerin (NTG) is the most frequently employed substance in human experimental modelling of cluster headache attacks, being used since 1953 (2) (Table 1).
Table 1. Review of studies using nitroglycerin to induce cluster headache attacks.
Study Number of CH patients NTG dose and route Control Placebo Rate of induced CH attack Latency period before onset of headache
(range in minutes)
Peters 1953 (2) 14 1.3 mg sublingual No, but compared with migraine, combination of CH and migraine, vasodilating head pain and tension headache No, but compared with histamine and nicotinic acid 78.6% Not reported
Ekbom 1968 (5) 38 ECH: 28 in bout, 15 out of bout (of which five were tested in bout as well) 1 mg sublingual No No In bout ECH 100% (n = 28)
Out of bout 0% (n = 15) 12–72
Barre 1982 (6) 10 CH: two CCH, nine ECH in bout 1 mg sublingual No No 100% 34–52
Mean 45.9
Drummond et al. 1984 (7) 29 CH 0.9 mg sublingual No No 76% Within 90 min
Drummond et al. 1985 (8) 22 CH: 10 CCH, 12 ECH in bout
0.9 mg sublingual Yes, 10 in the control group without headache No ECH 75% (n = 9)
CCH 60% (n = 6) 9–90
Mean 44
Bogucki 1990 (9) 21 ECH in bout 1 mg sublingual No No 67% (n = 14)
30–65
Dahl et al. 1990 (10) 15 ECH in bout 1 mg sublingual 10 healthy controls No 53% (n = 8)
Controls: not reported 30–65
Hannerz et al. 1992 (11) Eight ECH: five in bout and three out of bout 1 mg sublingual No No In bout ECH 100% (n = 5) Not reported
Fanciullacci et al. 1995 (12) 18 in bout ECH, 12 out of bout ECH 0.9 mg sublingual No No In bout ECH 100% (n = 18)
Out of bout ECH 0% (n = 12) 39–86
Fanciullacci et al. 1997 (13) 11 in bout ECH, eight out of bout ECH 0.9 mg sublingual No No In bout ECH 100% (n = 11)
Out of bout ECH 0% (n = 8) 18–50
Hsieh et al. 1996 (14) Seven ECH: four in bout ECH, three out of bout 1 mg sublingual No No In bout ECH 100%
Out of bout ECH 0% 18–35
May et al. 1998 (15) Nine CCH, eight out of bout ECH 1.0–1.2 mg spray No No CCH 100%
Out of bout ECH 0% Not reported
Costa et al. 2000 (16) 15 CH: Six ECH, nine CCH 0.9 mg sublingual No No ECH 33% (n = 2)
CCH 78% (n = 7) 19–41
Costa et al. 2003 (17) 18 ECH in bout 0.9 mg sublingual Yes, 12 healthy sex and age-matched No ECH 67% (n = 12)
Controls 0% 19–41
Sances et al. 2004 (18) 42 CH: 29 ECH (11 out of bout), 13 CCH 0.9 mg sublingual Yes, 53 healthy controls No In bout ECH and CCH 81% (n = 25 out of 31)
Controls 7.5% developed headache in 7-hour post-NTG Mean onset latency of 65.4 ± 54.7
Cluster headache patients suffer from recurrent episodes of severe unilateral pain in the trigeminal region; therefore, historically, the main emphasis has been centred around the pain onset of a cluster headache, and indeed this is often used as the indicator of the start of the attack. However, from clinical practice, there has been growing awareness of nonpainful symptoms preceding the onset of pain (19,20) and in recent years, the clinical phenotype of cluster headache has been further characterised by retrospective accounts (21–23) and prospective diaries (24,25).
The most frequent route of administration of NTG has been sublingual; however, the bioavailability of sublingual NTG is extremely variable (26). Therefore, we used a weight-calculated dose for intravenous infusion in a standardised single-blind, placebo-controlled study. NTG is a pro-drug of nitric oxide, with predominant actions on the cyclic guanylate phosphate (cGMP) pathway (27), and from pre-clinical studies there are indications of neural actions more centrally. This study is the first single-blind, placebo-controlled cross-over study using a weight-adjusted dose of nitroglycerin administered intravenously in cluster headache patients, thereby allowing comprehensive investigation of the various stages of the acute attack of cluster headache.
Methods
Subject selection and recruitment
The study was advertised on the UK cluster headache patient website OUCH (UK) (Organisation for the Understanding of Cluster Headache UK) (https://ouchuk.org/research/research-volunteers-needed) and in the tertiary Headache centre in King’s College Hospital, London. Subjects interested in participating would make contact via a dedicated research email. Subjects would then be screened for eligibility for the study via emails and a telephone call; those who met the criteria and were interested in participating were invited to attend the study visit. The study was approved by the London, City & East Research Ethics Committee (Ref Number 16/LO/0693). Data were collected from August 2016 until January 2019.
The subjects enrolled fulfilled the ICHD-3 beta criteria for cluster headache (28), and were between the ages of 18 and 60, with no significant previous medical history and no previous syncope or history of autonomic dysfunction. They had had a reliable response to high flow oxygen and/or subcutaneous sumatriptan during spontaneous attacks and normal brain neuroimaging. Women in child-bearing age were required to use reliable contraceptive methods during the study. Subjects were excluded if they were pregnant or breastfeeding, and who had any significant psychiatric disease, diagnosis of another primary headache type (other than migraine) or chronic pain syndrome, any medical history that would have contraindications to receiving NTG, use of preventive medication other than verapamil, or taking indomethacin for any reason, allergies to the medications used in the study or intolerance to high flow oxygen, and use of illicit drugs during the study.
Study visits
The study comprised of three visits in total, with each visit separated by a minimum of 1 week. During the first visit, subjects consented and a full headache history with a physical examination of the neurological and cardiovascular systems was performed, along with recordings of the baseline blood pressure, lying and standing blood pressure, heart rate, oxygen saturation, weight and electrocardiogram. Female subjects were required to have a urinary pregnancy test before the start of the infusion.
Open NTG infusion
If deemed eligible, subjects received an intravenous infusion of nitroglycerin at 0.5 µg/kg/min over 20 minutes. Subjects remained recumbent for 30 minutes before the infusion, and after the NTG infusion, subjects received 250 mL of 0.9% sodium chloride intravenously. The blood pressure and pulse were checked at the start of the infusion, and every 5 min during the infusion.
Phenotypic characterisation
Every 5 minutes, subjects were asked to rate their pain level from a scale from no pain, mild, moderate to severe, where severe equates to their most severe attack, and they were asked a questionnaire of non-headache symptoms and cranial autonomic symptoms (CAS) (Figure 1). If the subject experienced pain, further details were obtained regarding the location and characteristic. Beyond the cluster headache attack, subjects were asked to report any other headache types and in particular NTG headache, which has been well described from migraine studies (29). The NTG headache was assessed for severity, phenotype, accompanying non-headache symptoms and duration. Subjects were actively encouraged to report any symptoms as and when they developed. Following the infusion, at 10 minute intervals, any developments in pain, non-headache symptoms and CAS were recorded for a total of 120 minutes after the infusion, based on the latency period reported from previous studies (Table 1).
Figure 1. Questionnaire for non-headache and cranial autonomic symptoms.
B: bilateral; R: right-sided; L: left-sided.
Single-blinded NTG and placebo infusions
During the two single-blinded visits, subjects either received intravenous nitroglycerin at 0.5 µg/kg/min over 20 minutes or an equal volume of 0.9% sodium chloride at the same rate over 20 minutes, followed by the same 120 minutes of observations (Figure 2). The sequence was pre-determined using the randomise function in Excel; however, the investigator was able to amend this in certain situations if the subject was episodic and due to finish their bout.
Figure 2. Outline of events from open unblinded nitroglycerin visit.
BP: blood pressure; CAS: cranial autonomic symptoms; NTG: nitroglycerin; IV: intravenous.
Treatment of acute attacks
Acute treatment was administered at 20 minutes from the start of attack either with sumatriptan 6 mg subcutaneous injection (Imigran 6 mg/0.5 ml solution for injection pre-filled syringes, GlaxoSmithKline UK Ltd, or sumatriptan 6 mg/0.5 ml solution for injection pre-filled pens, Sun Pharmaceuticals Industries Europe B.V.) or with 15 L/min oxygen via a non-rebreather mask (O2Star™ non-rebreather oxygen mask M/L, Dräger). The visit was concluded only when the subject was pain free.
Statistical analysis
The data was tabulated (Excel for Mac v 16.30), and descriptive statistics were performed to summarise data (SPSS Statistics version 26 for Mac and Excel). Mann-Whitney tests were performed on time until attack onset and time until CAS onset for those that developed NTG-triggered cluster headache attacks and CAS, comparing the differences in ECH with CCH subgroups. Kaplan-Meier survival graphs were used to examine the time until onset of event; that is, survival of no cluster headache attack status, or absence of CAS after NTG infusion for 140 minutes (20 minutes of infusion and 120 minutes of post-infusion observation), with log-rank statistical testing; P < 0.05 was considered significant. Graphs were made using SPSS and violin plots were made using GraphPad Prism 8 for Mac OS.
Results
Demography
A total of 229 subjects were contacted to check for eligibility, of which 33 were included in the study; 24 completed all three study visits (Figure 3). All patients fulfilled the ICHD-3 beta criteria for cluster headache, 19 episodic cluster headache in bout (58%) and 14 chronic cluster headache (42%) (Table 2). The majority were male (n = 24, 73%) with a male: female ratio of 3:1. The average age was 41 (SD 10), with the mean age of females (34 years, SD 9) younger than in males (44 years, SD 9) in this cohort. Subjects had had the condition for a median of 9 years (IQR 5–16).
Figure 3. Subject numbers throughout the study.
Table 2. Subject characteristics.
Subject Age Sex Subtype Side of attacks Time since first attack (years) Average attack frequency (per day) Average attack duration when untreated (mins) Average bout duration (weeks) Verapamil (total daily dose in mg)
1 55 M Chronic Right 5 2 45 – 480
2 28 F Chronic Right 12 7 150 – –
3 40 M Episodic Right 20 3 150 8 –
4 38 F Episodic Left 12 2 120 4 –
5 53 M Chronic Left 15 4 35 – 960
6 48 M Episodic Left 25 5 52.5 5 480
7 23 M Episodic Left 8 2 120 10 –
8 43 M Chronic Right 9 1 40 – –
9 43 M Episodic Right 13 3 60 5 240
10 44 M Episodic Right 27 6 45 6 –
11 47 M Episodic Right 3 1 105 20 –
12 48 M Episodic Left 26 3 180 10 560
13 40 M Episodic Right 5 3 60 8 –
14 50 M Episodic Right 10 2 105 8 –
15 56 M Episodic* Right 24 1 45 – –
16 35 M Episodic Left 7 2 150 6 240
17 58 M Episodic Left 3 1 135 24 –
18 43 M Chronic Left 4 2 60 – –
19 32 M Episodic Left 3 3 50 12 600
20 49 F Episodic Right 8 5 50 9 –
21 49 M Chronic Right 35 2 90 – –
22 57 M Chronic Right 20 5 65 –
23 40 F Chronic Left 4 1.5 120 – 640
24 44 M Chronic Right 6 2 90 – 720
25 23 F Episodic Right 9 2.5 90 6 –
26 40 M Chronic Left 17 1.5 180 – –
27 20 F Chronic Right 6 1.5 150 – –
28 31 F Episodic Right 14 2 75 11 –
29 35 M Episodic Left 9 2 90 3 –
30 38 F Chronic Left 6 1.5 180 – 240
31 49 M Episodic Left 0.5 1.5 37.5 21 400
32 35 F Chronic Left 4 0.3 30 – 600
33 32 M Chronic Left 10 6 60 – –
M: male; F: female.
*Subject was chronic but became episodic during study with no attacks in 6 months.
Clinical phenotyping of subjects by history
Pain features
There was a near-equal split between the laterality of attacks; 17 subjects had right-sided attacks (52%), and 16 subjects had left-sided attacks (49%). The median number of attacks per day was two (IQR 1.5–3) lasting a median of 90 minutes (IQR 50–128). Verapamil was the only preventive allowed on the study; 12 subjects (36%) were on verapamil ranging from 240 mg to 960 mg per day.
Migraine, accompanying features and non-headache symptoms in spontaneous attacks
In this cohort, 58% (n = 19) had a concurrent migraine (28): five had migraine with aura, of which four had visual aura and one had facial sensory aura. Of the subjects who did not meet the diagnostic criteria for migraine (28) (n = 14, 42%), the majority had either migraine markers and/or a family history of migraine. Migraine markers were defined if subjects experienced: childhood cyclic nausea and vomiting, motion sickness, cold stimulus-induced headache, hangover headache and jetlag. Four subjects did not have migraine markers, and three subjects (9%) did not have either migraine marker or a family history of migraine. Subjects (n = 24, 73%) reported accompanying symptoms with their spontaneous attacks, the most common symptoms being cranial allodynia (n = 15), photophobia (n = 15), nausea (n = 11) and phonophobia (n = 10).
Non-headache attack symptoms
The majority reported non-headache symptoms in the lead up to their spontaneous cluster headache attacks (n = 27, 82%), with the commonest symptoms being concentration difficulties (n = 18), mood changes (n = 15), neck stiffness (n = 13) and yawning (n = 8). The median onset time of symptoms was 10 minutes (IQR 2–30) before the onset of pain. Although most symptoms start before the onset of pain, five subjects only reported developing the symptoms during the attack.
Twenty-eight subjects reported non-headache symptoms following their cluster headache attacks (85%), the commonest symptoms being tiredness (n = 27), mood changes (n = 13), concentration difficulties (n = 12), and neck stiffness (n = 7). The median duration of symptoms was 120 minutes (IQR 53–315).
Attack triggers
The most commonly reported triggers for spontaneous attacks were alcohol ingestion (n = 22), followed by changes in temperature (n = 12), strong smells such as from nail varnish, paint (n = 11) followed by disrupted sleep (n = 4) and exercise (n = 3). Other triggers mentioned were stress (n = 2), caffeine (n = 2), changing time zones (n = 1), let down from stress (n = 1), being in a pressurised cabin on an airplane (n = 1), vardenafil (n = 1), and dehydration (n = 1). All subjects reported attacks within a few hours of alcohol ingestion, no one reported a next-day effect.
Clinical phenotyping of open NTG visit
NTG triggered cluster headache-like attacks (n = 26, 79%), CAS (n = 31, 94%) and agitation (n = 24, 73%) during the open unblinded NTG visit. In the episodic cluster headache group, 16 out of 19 developed an NTG-induced attack (mean, 84%; 95% CI, 66–100%) and in the chronic cluster headache group, 11 out of 14 developed an NTG-induced attack (79%, 54–100%). Five out of the 31 subjects developed CAS, but did not develop an attack; of these subjects, three developed mild generalised pain, one developed restless legs, and one developed CAS on the contralateral side to the subject’s spontaneous attack phenotype, with a generalised headache. These cases were excluded.
The median onset time for CAS to develop from the start of the NTG infusion was 31 minutes (IQR 13–46). The median onset for an NTG-induced attack was 30 minutes (IQR 20–39) and the median time to maximum pain, if reached, was 51 minutes (IQR 39–70). The most common first cranial autonomic symptoms brought on by NTG infusion were nasal congestion (n = 10), conjunctival injection (n = 5), lacrimation (n = 4) and periorbital oedema (n = 3).
Clinical phenotyping of single-blinded NTG and placebo visit
During the single-blinded visits, NTG induced attacks in 19 subjects (76%); three subjects did not have an attack (12%), two subjects developed migraine-like headache (8%) and one subject developed unilateral mild pain without CAS or agitation (4%) (Table 3). In the placebo group, only one developed an attack (4%), two subjects developed unilateral mild pain without CAS or agitation (8%) and two subjects experienced short-lived unilateral CAS (8%). Of the subjects receiving NTG, eight out of 13 ECH (mean, 62%; 95% CI, 31%-92%) and 11 out of 12 CCH (92%, 73–100%) developed NTG-induced attacks (Figure 4(a)).
Table 3. Subject characteristics and comparison between spontaneous attack and triggered attack from single-blinded nitroglycerin visit, M = male, F = female, ECH = episodic cluster headache, CCH = chronic cluster headache, L = Left, R = Right, Y = Yes, N = No, VRS = verbal rating scale, mod = moderate, O2 = high flow oxygen via non-rebreather mask, suma = sumatriptan.
Subject Age Sex Subtype Migraine Verapamil (total daily dose in mg) Spontaneous attack Triggered attack- single-blinded NTG visit
Laterality Severity CAS Agitation Laterality Severity/VRS CAS Agitation Feels like spontaneous attack Treatment Last spontaneous attack (days)
1 55 M CCH N 480 R 9/10 Conjunctival injection, nasal congestion, lacrimation. 3 months of R Horner’s syndrome in 2007, now resolved Y R 10/10
VRS 3 Conjunctival injection, nasal congestion, lacrimation, periorbital oedema Y Y O2 158
2 28 F CCH Y
– R 10/10 Periorbital oedema/ptosis, nasal congestion, dry eye then lacrimation Y R 10/10
VRS 3 Periorbital oedema, nasal congestion, facial flushing Y Y O2 128
3 40 M ECH N – R 10/10 Lacrimation, rhinorrhoea, ptosis Y R 10/10
VRS 3 Lacrimation, conjunctival injection, periorbital oedema, nasal congestion, aural fullness and facial droop Y Y Suma 1
4 38 F ECH Y – L 10/10 Lacrimation, conjunctival injection, periorbital oedema, nasal congestion, ptosis, facial flushing Y No attack, developed generalised pain 4/10 Y N N/A 1
5 53 M CCH N 960 L 10/10 Rhinorrhoea, ptosis Y L 10/10
VRS 3 Conjunctival injection, eye grittiness, lacrimation Y Y O2 4
6 48 M ECH N
480 L 8/10 Nasal congestion, lacrimation Y Did not attend
7 23 M ECH Y – L 10/10 Lacrimation, conjunctival injection, nasal congestion, ptosis, facial flushing Y Did not attend
8 43 M CCH N – R 10/10 Nasal congestion, rhinorrhoea, lacrimation, facial flushing Y R 10/10
VRS 3 Nasal congestion, conjunctival injection, eye grittiness Y Y Suma <1
9 43 M ECH N 240 R 10/10 Lacrimation, conjunctival injection, facial flushing, ptosis, facial droop Y Did not attend
10 44 M ECH N – R 10/10 Nasal congestion, ptosis, periorbital oedema, lacrimation, flushing Y No attack, L mild hangover like headache, with nasal congestion.
After study visit felt nauseous and vomited, then slept, headache free at 7pm N N O2- no response <1
11 47 M ECH N – R Severe attacks 10/10 Nasal congestion, aural fullness Y R 7/10
VRS 2/3 moderate/
severe Nasal congestion, conjunctival injection, aural fullness Y Y Suma 13
12 48 M ECH N 560 L 10/10 Lacrimation, nasal congestion, periorbital oedema Y Did not attend
13 40 M ECH Y – R 10/10 Nasal congestion, ptosis, conjunctival injection, lacrimation, throat tightness, rhinorrhoea Y No attack, bilateral mild headache 4/10 with nasal congestion Y, brief (7 mins) N N/A 19
14 50 M ECH Y – R 10/10
Lacrimation, periorbital oedema, nasal congestion, rhinorrhoea Y Did not attend
15 56 M ECH Y – R 10/10 Lacrimation, rhinorrhoea, facial flushing, gritty eyes, conjunctival injection Y with severe attacks Did not attend
16 35 M ECH Y 240 L 10/10 Nasal congestion, conjunctival injection, ptosis, lacrimation, rhinorrhoea Y Not attack, milder than a shadow and no CAS N N N/A 16
17 58 M ECH Y – L 10/10 Nasal congestion, rhinorrhoea, lacrimation, aural fullness, throat swelling Y L 7/10
VRS 2–3 (mod-severe) Nasal congestion, rhinorrhoea, voice change, lacrimation Y Y Suma 1
18 43 M CCH Y – L (70%) Mild 6/10, severe 10/10 Nasal congestion, periorbital oedema, aural fullness, facial flushing Y L Mild,
VRS 1 Nasal congestion Y Y- shadow O2 7
19 32 M ECH Y 600 L 10/10 Lacrimation, conjunctival injection, facial flushing Y L 7–8/10
VRS 2–3
(mod-severe) Lacrimation, eye grittiness, nasal congestion, facial flushing Y Y O2 <1
20 49 F ECH Y – R 10/10 Ptosis, periorbital oedema, lacrimation, nasal congestion, rhinorrhoea, (aural fullness with severe attacks) Y R 6–7/10
VRS 2 mod Nasal congestion, periorbital oedema, lacrimation, conjunctival injection Y Y O2 7
21 49 M CCH Y – R 4–10/10 Facial flushing, nasal congestion, ptosis, lacrimation, rhinorrhoea, conjunctival injection Y L 8/10
VRS 2–3
(mod-severe)
Facial flushing, lacrimation, periorbital oedema, conjunctival injection Y Y, but on L rather than R Suma <1
22 57 M CCH N – R 10/10 Lacrimation, conjunctival injection, nasal congestion, rhinorrhoea Y No attack, no pain and no CAS N N N/A 26
23 40 F CCH Y 640 L 10/10
Lacrimation, conjunctival injection, periorbital oedema, rhinorrhoea, ptosis, aural fullness Y Did not attend
24 44 M CCH N 720 R 10/10 Lacrimation, conjunctival injection, periorbital oedema, facial flushing Y Did not attend
25 23 F ECH Y – R 6–10/10 Nasal congestion, lacrimation, periorbital oedema. Rhinorrhoea and facial flushing with severe attacks Y R 7/10
VRS 2
(moderate) Nasal congestion, periorbital oedema Y Y O2 3
26 40 M CCH Y – L Shadow 4/10, daytime attacks 6–7/10, full attack 10/10 Ptosis, aural fullness, lacrimation, conjunctival injection, periorbital oedema, nasal congestion Y L 8.5–9/10
VRS 3 severe Nasal congestion, periorbital oedema, lacrimation Y Y Suma 3
27 20 F CCH N – R 8–9/10 Nasal congestion, lacrimation, rhinorrhoea, ptosis, aural fullness Y R 8/10
VRS 3
severe Nasal congestion, periorbital oedema Y Y O2 <1
28 31 F ECH Y – R 10/10 Nasal congestion, periorbital oedema, rhinorrhoea, ptosis, aural fullness Y R 2/10
VRS 1 (mild) Nasal congestion, facial swelling Y Y, but milder Suma 3
29 35 M ECH N – L Max pain 10/10 Nasal congestion, periorbital oedema, lacrimation, voice change (croaky). Facial flushing with severe attacks and rhinorrhoea after attack Y L 6–7/10
VRS 2 (moderate) Nasal congestion, lacrimation, conjunctival injection, voice change Y Y Suma <1
30 38 F CCH Y 240 L 4–10/10 Lacrimation, rhinorrhoea, conjunctival injection, facial flushing. Ptosis with severe attacks Y L 6–7/10
VRS 2 (moderate) Aural fullness Y Y Suma 1
31 49 M ECH Y 400 L 10/10 Nasal congestion, lacrimation, conjunctival injection, rhinorrhoea, ptosis, aural fullness. Prominent miosis after attack Y No attack, whole head felt heavy N N N/A 10
32 35 F CCH N 600 L 4/10 (on verapamil),
7/10 average Periorbital oedema, eye grittiness, facial flushing, lacrimation Y L 7/10
VRS 2–3
(mod-severe) Nasal congestion, conjunctival injection, facial flushing, lacrimation Y Y Suma 1
33 32 M CCH Y – L Severe attacks 10/10 Lacrimation, ptosis, nasal congestion, conjunctival injection, ptosis, facial flushing, eye grittiness Y L 6/10
VRS 2 (mod-severe) Lacrimation, nasal congestion, ptosis Y Y Suma <1
Figure 4. (a) Kaplan-Meier graph comparing time until cluster headache attack between the eight episodic cluster headache (ECH) and the 11 chronic cluster headache (CCH) subjects during single-blinded nitroglycerin (NTG) infusion, from the start of the infusion in minutes, log-rank P = 0.534. (b) Kaplan-Meier graph comparing time until cluster headache attack onset between the open unblinded (n = 33) and single-blinded (n =25) nitroglycerin (NTG) infusions with single-blinded placebo infusions (n = 24). Log-rank P = 0.000.
The median onset time to an induced attack was 33 minutes (IQR 15–42) from the start of the single-blinded NTG infusion, and in the single-blinded placebo visit only one subject developed an attack; the onset time was 10 minutes. On comparison of the attack onset time for the unblinded NTG, single-blinded NTG and single-blinded placebo visits, there was a difference between the placebo and NTG visits (P = 0.000, Figure 4(b)).
NTG headache
The majority of subjects developed an NTG headache (n = 28, 85%) following the NTG infusion in the unblinded open visit, of which 27 subjects had a migraine diagnosis (n = 18), had migraine markers (n = 10) and a family history of migraine (n = 18); only one subject did not have migraine, migraine markers or a family history of migraine. The median time from the start of NTG infusion was 3 minutes (IQR 2–6), and the median duration of NTG headache was 26 minutes (IQR 14–41).
Of the 25 subjects that went on to the single-blinded NTG visits, 18 (72%) developed NTG headache following NTG infusion, of which all had either migraine (n = 11), migraine markers (n = 7) or family history (n = 10). The median time of NTG headache onset from the start of NTG infusion in the blinded visit was 4 minutes (IQR 3–8), with a median duration of 26 minutes (IQR 9–45).
In the placebo visit, three of the 24 subjects (13%) developed NTG headache, median onset time was 13 minutes (range 1–18), and the median duration was 10 minutes (range 3–16).
Non-headache symptoms
The majority of subjects reported non-headache symptoms in both the open unblinded NTG visit (n = 30, 91%) and the single-blinded NTG visit (n = 21, 84%) visits. In the single-blinded placebo visit, eight subjects (33%) reported non-headache symptoms. The most common non-headache symptoms from the open unblinded NTG visit were neck stiffness, photophobia, thirst and allodynia. The most common non-headache symptoms from the single-blinded NTG visit were neck stiffness, yawning, thirst and photophobia (Table 4). The median number of non-headache symptoms reported in the open unblinded NTG visit was three (IQR 2–5), and from the single-blinded NTG visit was three (IQR 2–6), compared with two (IQR 2–3) on-headache symptoms in the single-blinded placebo group.
Table 4. Frequencies of non-headache symptoms reported during each visit.
Non-headache symptom Open unblinded NTG visit (n = 33) Single-blinded NTG visit
(n = 25) Single-blinded placebo visit
(n = 24)
Thirst 15 10 3
Craving 0 0 0
Yawning 8 12 4
Tiredness 4 3 0
Mood changes 5 4 1
Visual blurring 4 3 1
Neck stiffness 21 15 3
Irritability 3 3 0
Photophobia 18 10 1
Concentration difficulties 6 4 1
Phonophobia 4 6 0
Urinary symptoms 0 0 0
Speech disturbances 0 0 0
Nausea 6 3 0
Gastrointestinal discomfort 0 0 0
Movement sensitivity 5 5 1
Allodynia 9 8 2
In the open unblinded NTG visit, the median onset time of non-headache symptoms from the start of the infusion was 9 minutes (IQR 4–17) with the median maximum duration of the symptoms being 50 minutes (IQR 24–64), the duration is calculated from the first symptom until the end of the last symptom. In the single-blinded NTG visit, the median onset time was 5 minutes (IQR 3–9) from the start of the infusion, and the median maximum duration of symptoms was 59 minutes (IQR 35–76). The outlier was a subject who developed allodynia and neck stiffness during their attack. For those that developed non-headache symptoms during the single-blinded placebo visit, the median onset time was 9 minutes (IQR 2–9), with a median duration of 16 minutes (IQR 6–34).
Cranial autonomic symptoms
NTG triggered CAS in the majority of the subjects during the open unblinded NTG visit (n = 31, 94%). In all, five subjects out of the 31 (19%) developed unilateral CAS; however, they did not have a cluster headache attack. Two subjects had CAS with generalised headache, one had CAS without any pain, one subject developed CAS on the contralateral side to their attacks with mild generalised pain, and one subject with CAS developed restless leg symptoms, but no cluster headache attack. Of the subjects who developed unilateral CAS and cluster headache attack (n = 26, 79%), the median number of CAS was four (IQR 2–5), with the most common CAS being nasal congestion (n = 21), lacrimation (n = 16) and periorbital oedema (n = 15) (Table 5).
Table 5. Frequencies of cranial autonomic symptoms reported in subjects who had attacks following NTG infusion.
Cranial autonomicsymptoms Open unblinded NTG visit, total number of attacks (n = 26) Single-blinded NTG visit, total number of attacks (n = 19)
Lacrimation 16 11
Conjunctival injection 12 9
Periorbital oedema 15 8
Eye grittiness/itchiness 3 3
Nasal congestion 21 16
Rhinorrhoea 2 1
Ptosis 4 1
Aural fullness 5 2
Facial flushing 7 4
Sialorrhoea 1 0
Throat swelling 2 0
Voice change 4 2
Facial swelling 3 1
Similarly, NTG brought on CAS in the majority of subjects during the single-blinded NTG visit (n = 21, 84%), of which two were not accompanied by a cluster headache attack, compared with four out of 24 in the single-blinded placebo group developing CAS (Figure 5(a)). One of the subjects from the single-blinded NTG group had a generalised headache similar to a hangover headache with unilateral CAS, and the other subject had a migraine-like headache with CAS. Of the 19 subjects (76%) that had unilateral CAS and a cluster headache attack, the median number of symptoms was three (IQR 2–4) and the most frequent symptoms were nasal congestion (n = 16), lacrimation ( n = 11) and conjunctival injection (n = 9) (Table 5). In comparing the time until all CAS onset between ECH and CCH after blinded NTG infusion, there was no difference between the two groups (log-rank P = 0.740; Figure 5(b)).
Figure 5. (a) Kaplan-Meier graph showing time until onset of cranial autonomic symptoms (CAS) following open unblinded (n = 33) and single-blinded NTG (n = 25) infusions compared with the single-blinded placebo infusion (n = 24). Log-rank P = 0.000. (b) Kaplan-Meier graph showing the time until CAS onset in the single-blinded NTG visit, comparing episodic cluster headache (ECH) with chronic cluster headache (CCH). Log-rank P = 0.740.
The median time until CAS onset for those that developed cluster headache attacks was 31 min (IQR 13–46) in the open unblinded NTG visit and 12 min (IQR 6–30) in the single-blinded NTG visit. Subjects sequentially reported CAS development.
During the single-blinded placebo visit, four subjects (17%) developed unilateral CAS, of which one subject developed a spontaneous attack, and three developed CAS but no pain. The median number of symptoms reported in the placebo group was two (IQR 1–2) and the symptoms reported were nasal congestion (n = 2), conjunctival injection (n = 1), periorbital swelling (n = 1), rhinorrhoea (n = 1) and aural fullness (n = 1).
Agitation
Nitroglycerin brought on agitation in the majority of subjects, open unblinded NTG visit (n = 24, 73%) and single-blinded NTG visit (n= 20, 80%), compared with none in the single-blinded placebo visit.
Non-headache symptoms post-attack
The non-headache symptoms were not studied here, as all attacks were treated with sumatriptan or oxygen after 20 minutes, thus altering the natural progression and development of symptoms.
Episodic cluster headache compared with chronic cluster headache
For the subjects that developed an NTG-induced attack following the single-blinded NTG infusion, the time until NTG-induced attack was shorter in the episodic cluster headache group compared with the chronic cluster headache group (U = 15, z = −2.399, P = 0.016). The time until CAS onset, in the subjects that developed CAS following single-blinded NTG infusion was not different between episodic cluster headache and chronic cluster headache groups (U = 38, z = −1.2000, P = 0.230).
Effect of verapamil on NTG triggering
There were seven subjects on verapamil that attended the single-blinded NTG visits, of which two did not develop NTG-triggered cluster headache attacks (29%). Using χ2, there was no difference between verapamil and NTG triggering (χ2 (df = 1) = 0.111, P = 0.739).
Effect of migraine on NTG-triggered attacks
Within the cohort that attended the single-blinded NTG visits, 15 had migraine (60%). There was no difference between the number of non-headache symptoms (U = 67, z = −0.449, P = 0.654) or number of CAS (U = 57, z = −1.019, P = 0.308), between the subjects with migraine and those without migraine. Furthermore, there was no association between subjects with migraine and NTG triggering (χ2 (df = 1) = 0.146, P = 0.702); similarly, there was no association between subjects with migraine and development of NTG headache (χ2 (df = 1) = 0.033, P = 0.856).
Discussion
This study demonstrates that weight-calculated intravenous NTG effectively triggers cluster headache attacks in both chronic cluster headache and episodic cluster headache subjects within bout when compared with placebo. The approach is reliable in terms of triggering a fully-featured attack that allows careful observation of symptoms and their development during acute attacks of cluster headache.
The benefit of weight-calculated intravenous NTG compared to intranasal and sublingual administration is that this is more reliable and has more stable bioavailability. The median time until cluster headache attack onset was 30 minutes (open unblinded NTG visit) and 33 minutes (single-blinded NTG visit), with the overall maximum onset time of 81 minutes. Subjects who did not develop an attack during the 140 minutes of observation were asked to report if they developed an attack later on that day, and none did. The median onset time is similar to the reported latency period reported in the literature (Table 1). The minimum onset time for NTG-induced attacks was 2 minutes, and this is less than reported from the sublingual route, where the shortest time until onset time was 9 minutes (8); this is expected, given the intravenous route has a half-life of 2.3–2.8 minutes (30,31). Two subjects started experiencing mild attack pain before the start of the NTG infusion, and within the placebo group we observed one subject who developed a spontaneous attack. Spontaneous attacks could be anticipated given the subjects are within bout; there were three subjects with only short-lasting CAS symptoms and two subjects who experienced a mild pain without CAS, similar to a shadow.
This study delineates the development of the various stages of an NTG-induced cluster headache attack, including the non-headache symptoms and CAS (Figure 6). The majority of subjects developed NTG headache shortly after the infusion started. This headache was generalised, mild and progressive in nature, predominantly in the bi-occipital and bi-temporal regions. Subjects described it as pressure-like or band-like ache, and they reported it to be distinct from their cluster headache attacks; if there were an overlap, the cluster headache attack would clearly ramp up and supersede the NTG headache. It is difficult to disentangle whether NTG headache developed because there was a high proportion of subjects with either a migraine diagnosis, migraine marker or family history of migraine. However, from a previous study with 25 healthy volunteers without a migraine diagnosis, 16 (64%) developed NTG headache following 0.5 mg NTG sublingual administration (32).
Figure 6. Violin plots of the stages of cluster headache attack from the 19 subjects that developed cluster headache attacks and subdivided by chronicity. The timeline starts with 20 minutes of single-blinded nitroglycerin (NTG) infusion, followed by 120 minutes of post-infusion observation. CAS = cranial autonomic symptoms.
Following the NTG headache, the majority of subjects reported non-headache symptoms in the lead-up to the onset of the pain from the attack and in some subjects, non-headache symptoms accompanied their attacks. The non-headache symptoms included homeostatic symptoms (thirst, cravings, yawning, frequency of urination), fatigue/cognitive symptoms (concentration difficulty, fatigue, memory impairment, mood changes, irritability) and sensitised sensory symptoms (neck stiffness, photophobia, phonophobia, osmophobia, nausea), as are reported in the premonitory phase of migraine (33). The most common symptoms were neck stiffness, photophobia and thirst. During their spontaneous attacks, subjects reported that non-headache symptoms would precede the attack at a median of 10 minutes (IQR 2–30) before the onset of pain, although it is known that there are discrepancies between retrospective and prospective reporting (25). Comparing the symptoms observed from NTG-induced attacks in this study with the prospective observational questionnaire study (24), the most reported general symptoms in the pre-pain phase in this study were concentration difficulties, photophobia and mood changes. Patients in the observational study also reported general symptoms during their attacks and postictal symptoms similar to the symptoms seen during the NTG-induced attacks and the reported symptoms by the subjects in this study during the postdrome phase of their spontaneous attacks. Non-headache symptoms such as photophobia, phonophobia, and localised allodynia were often reported during the attacks, as has been reported previously (21,34). In one semi-structured questionnaire study, they found a high proportion of cluster headache patients (73.2%) reported phonophobia or photophobia with their attacks (35), cluster headache patients with migraine did not more frequently report these symptoms compared with those without co-existing migraine. Furthermore, allodynia was more often reported in cluster headache patients with migraine. From pre-clinical studies, high dose NTG causes a sustained increase in spontaneous firing of Aδ and C-fibre trigeminal neurons (36), which migraine biology may unmask.
Similar to the prospective questionnaire study by Snoer and colleagues (24), in some subjects CAS presented before the onset of the attack pain (Figure 6). In this study, the median onset time for CAS was 31 minutes (IQR 13–46) in the open unblinded NTG visit and 12 minutes (IQR 6–30) in the single-blinded NTG visit, whereas the onset of NTG-induced attack was 30 minutes (IQR 20–39) in the open unblinded visit and 33 minutes (IQR 15–42) in the single-blinded NTG visit. From the open unblinded NTG visit, 38% presented with CAS before the attack, 15% presented with CAS with the onset of the attack, and from the single-blinded NTG visit, 58% presented with CAS before the attack and 16% presented with CAS with the onset of the attack.
Vollesen and colleagues used calcitonin gene-related peptide (CGRP) infusion to trigger cluster headache attacks, finding CGRP induced 50% of subjects with CCH and 89% for ECH subjects in bout (4). In our study, NTG induced attacks in 79% of the CCH subjects and 84% in ECH subjects in bout, in the open unblinded NTG visits, and 92% CCH and 62% ECH in bout in the single-blinded NTG visits. There are some differences in the number of chronic cluster headache subjects on verapamil between the studies; in this study, 33% of CCH subjects were on verapamil and in the study by Vollesen and colleagues, 57% of CCH subjects were on verapamil (of which one was on both verapamil and lithium) and one was on 4 mg melatonin. Vollesen and colleagues proposed that the CCH patients who did not develop an attack following CGRP infusion had a lower median attack frequency in the preceding 30 days prior to the study compared to the CCH patients that did develop an attack. However, in this study, subjects reported having their last attack as long ago as 128 and 158 days and still had NTG-induced attacks (Table 3).
NTG is a pro-drug of nitric oxide (NO) and has effects on blood vessel dilation through mechanisms of the NO-cyclic guanylate phosphate (cGMP) pathway (27). However, the vasodilatory effects of NTG are not sufficient to explain the cluster headache attack that occurs after a latency and the central features associated with the attack. Indeed, experimental studies demonstrate that NTG has central effects (37,38). Interestingly, in studies where NO donors were administered in vivo and in vitro, there was a local release of CGRP (39–42). The difference in the rate of cluster headache attacks induced by NTG and CGRP in ECH and CCH subjects could reflect in part the underlying biological processes and systems that are more active in the different subtypes of cluster headache. The difference between ECH and CCH is also suggested by the treatment response to a CGRP monoclonal antibody, galcanezumab (43,44), and non-invasive vagal nerve stimulator (45,46).
Limitations
The main limitations to the study were the recruitment of eligible subjects and the dropout rate at each stage due to the nature of the condition. Therefore, a pragmatic approach was taken with the study design regarding randomisation. Although there was a randomisation sequence, this was modified by the investigator if deemed necessary. This would be in the case of episodic cluster headache patients that were near the end of their bout missing the NTG visit if they followed the randomised sequence. For this reason, it was designed to be a single-blind cross-over study and not a double-blind and randomised study. Expectation bias was reduced by maintaining blinding of the subjects until the end of the study and having both infusions identical in volume, appearance and duration of infusion. Furthermore, given the stark difference between placebo and NTG, there was no difference between attack onset in the open unblinded compared with the single-blinded NTG visits (Figure 4(b)), is an indication that randomisation was not a factor in this study.
Conclusion
We present the results of the first placebo-controlled study using intravenous NTG administration to systematically study NTG-induced cluster headache attacks. We have shown that NTG can reliably bring on cluster headache attacks as well as the development of non-headache symptoms and CAS. This study highlights differences between NTG-induced attack onset times between the ECH and CCH subjects. Understanding the stages of cluster headache is essential; by recognising the non-headache symptoms in the lead up to the onset of pain and the underlying pathogenesis of this, we may be able to uncover new therapeutic targets to abort attacks before the onset of the severe and devastating pain experienced by our cluster headache patients.
Article highlights
Weight-calculated standardised intravenous nitroglycerin administration is a reliable method to induce cluster headache attacks, cranial autonomic symptoms and non-headache symptoms that accompany cluster headache attacks.
Accompanying non-headache symptoms in cluster headache attacks are important to recognise for both clinical and research purposes.
There may be inherent differences between episodic cluster headache and chronic cluster headache.
Acknowledgement
This study would not have been possible without the support of OUCH(UK), all the cluster headache patients who were interested in helping us with this study and all the subjects who took part in this study.
Ethics or Institutional Review Board approval: This study 16/LO/0693 obtained approval from the London, City & East NHS Research Ethics Committee on 23 June 2016. This study was carried out in accordance with the World Medical Association Declaration of Helsinki (1964), the Research Governance Framework for Health and Social Care (2nd edition, 2005), the Data Protection Act (1998) and the Principles of Good Clinical Practice (GCP); all subjects gave informed consent before taking part.
Declaration of conflicting interests: The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: DYW no reported competing interests. PJG reports, over the last 36 months, grants and personal fees from Amgen and Eli-Lilly and Company, grant from Celegene, and personal fees from Alder Biopharmaceuticals, Aeon Biopharma, Allergan, Biohaven Pharmaceuticals Inc., Clexio, Electrocore LLC, eNeura, Epalex, GlaxoSmithKline, Impel Neuropharma, MundiPharma, Novartis, Pfizer, Praxis, Sanofi, Santara Therapeutics Satsuma, Teva Pharmaceuticals, Trigemina Inc., WL Gore, and personal fees from MedicoLegal work, Massachusetts Medical Society, Up-to-Date, Oxford University Press, and Wolters Kluwer; and a patent magnetic stimulation for headache assigned to eNeura without fee.
Funding: The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study is part-funded by the National Institute for Health Research (NIHR) Maudsley Biomedical Research Centre at South London Maudsley Foundation Trust and King’s College London. The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care.
ORCID iDs: Diana Y Wei https://orcid.org/0000-0003-0644-7172
Peter J Goadsby https://orcid.org/0000-0003-3260-5904 | NITROGLYCERIN | DrugsGivenReaction | CC BY | 33615843 | 19,017,453 | 2021-07 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Facial paralysis'. | Comprehensive clinical phenotyping of nitroglycerin infusion induced cluster headache attacks.
Nitroglycerin administration allows the study of cluster headache attacks in their entirety in a standardised way.
A single-blind, placebo-controlled, cross-over study using weight-calculated intravenous nitroglycerin administration at 0.5 µg/kg/min over 20 minutes to study cluster headache attacks, including accompanying non-headache symptoms and cranial autonomic symptoms.
Thirty-three subjects with cluster headache were included in the study; 24 completed all three study visits. Nitroglycerin-induced attacks developed in 26 out of 33 subjects (79%) receiving unblinded nitroglycerin infusion, and in 19 out of 25 subjects (76%) receiving single-blinded nitroglycerin infusion, compared with one out of 24 subjects (4%) receiving single-blinded placebo infusion. Episodic cluster headache subjects had a shorter latency period to a nitroglycerin-induced attack compared to the chronic cluster headache (CCH) subjects (U = 15, z = -2.399, p = 0.016). Sixteen of nineteen episodic cluster headache (mean, 84%; 95% confidence interval, 66-100%) and 11 of 14 chronic cluster headache subjects developed a nitroglycerin-induced attack (79%, 54-100%) following the unblinded nitroglycerin infusion. Following the single-blinded nitroglycerin infusion, eight out of 13 episodic cluster headache (62%, 31-92%) and 11 out of 12 chronic cluster headache (92%, 73-100%) subjects developed nitroglycerin-induced attacks. Nitroglycerin induced non-headache symptoms in the majority of subjects receiving it: 91% in the open unblinded nitroglycerin visit and 84% in the single-blinded nitroglycerin visits, compared with 33% in the single-blinded placebo visit. Cranial autonomic symptoms were induced by nitroglycerin infusion, 94% in the open unblinded nitroglycerin visit and 84% in the single-blinded nitroglycerin visit, compared with 17% in the single-blinded placebo visit.
Intravenous weight-adjusted nitroglycerin administration in both episodic cluster headache in bout and chronic cluster headache is effective and reliable in inducing cluster headache attacks, cranial autonomic symptoms and non-headache symptoms.
Introduction
Due to the episodic nature of acute attacks of cluster headache, a standardised and reliable method for triggering attacks is necessary for their complete study. There have been several substances used to trigger attacks, including histamine (1,2), meta-chloro-phenylpiperazine (mCPP) (3) and more recently calcitonin gene-related peptide (CGRP) (4). Nitroglycerin (NTG) is the most frequently employed substance in human experimental modelling of cluster headache attacks, being used since 1953 (2) (Table 1).
Table 1. Review of studies using nitroglycerin to induce cluster headache attacks.
Study Number of CH patients NTG dose and route Control Placebo Rate of induced CH attack Latency period before onset of headache
(range in minutes)
Peters 1953 (2) 14 1.3 mg sublingual No, but compared with migraine, combination of CH and migraine, vasodilating head pain and tension headache No, but compared with histamine and nicotinic acid 78.6% Not reported
Ekbom 1968 (5) 38 ECH: 28 in bout, 15 out of bout (of which five were tested in bout as well) 1 mg sublingual No No In bout ECH 100% (n = 28)
Out of bout 0% (n = 15) 12–72
Barre 1982 (6) 10 CH: two CCH, nine ECH in bout 1 mg sublingual No No 100% 34–52
Mean 45.9
Drummond et al. 1984 (7) 29 CH 0.9 mg sublingual No No 76% Within 90 min
Drummond et al. 1985 (8) 22 CH: 10 CCH, 12 ECH in bout
0.9 mg sublingual Yes, 10 in the control group without headache No ECH 75% (n = 9)
CCH 60% (n = 6) 9–90
Mean 44
Bogucki 1990 (9) 21 ECH in bout 1 mg sublingual No No 67% (n = 14)
30–65
Dahl et al. 1990 (10) 15 ECH in bout 1 mg sublingual 10 healthy controls No 53% (n = 8)
Controls: not reported 30–65
Hannerz et al. 1992 (11) Eight ECH: five in bout and three out of bout 1 mg sublingual No No In bout ECH 100% (n = 5) Not reported
Fanciullacci et al. 1995 (12) 18 in bout ECH, 12 out of bout ECH 0.9 mg sublingual No No In bout ECH 100% (n = 18)
Out of bout ECH 0% (n = 12) 39–86
Fanciullacci et al. 1997 (13) 11 in bout ECH, eight out of bout ECH 0.9 mg sublingual No No In bout ECH 100% (n = 11)
Out of bout ECH 0% (n = 8) 18–50
Hsieh et al. 1996 (14) Seven ECH: four in bout ECH, three out of bout 1 mg sublingual No No In bout ECH 100%
Out of bout ECH 0% 18–35
May et al. 1998 (15) Nine CCH, eight out of bout ECH 1.0–1.2 mg spray No No CCH 100%
Out of bout ECH 0% Not reported
Costa et al. 2000 (16) 15 CH: Six ECH, nine CCH 0.9 mg sublingual No No ECH 33% (n = 2)
CCH 78% (n = 7) 19–41
Costa et al. 2003 (17) 18 ECH in bout 0.9 mg sublingual Yes, 12 healthy sex and age-matched No ECH 67% (n = 12)
Controls 0% 19–41
Sances et al. 2004 (18) 42 CH: 29 ECH (11 out of bout), 13 CCH 0.9 mg sublingual Yes, 53 healthy controls No In bout ECH and CCH 81% (n = 25 out of 31)
Controls 7.5% developed headache in 7-hour post-NTG Mean onset latency of 65.4 ± 54.7
Cluster headache patients suffer from recurrent episodes of severe unilateral pain in the trigeminal region; therefore, historically, the main emphasis has been centred around the pain onset of a cluster headache, and indeed this is often used as the indicator of the start of the attack. However, from clinical practice, there has been growing awareness of nonpainful symptoms preceding the onset of pain (19,20) and in recent years, the clinical phenotype of cluster headache has been further characterised by retrospective accounts (21–23) and prospective diaries (24,25).
The most frequent route of administration of NTG has been sublingual; however, the bioavailability of sublingual NTG is extremely variable (26). Therefore, we used a weight-calculated dose for intravenous infusion in a standardised single-blind, placebo-controlled study. NTG is a pro-drug of nitric oxide, with predominant actions on the cyclic guanylate phosphate (cGMP) pathway (27), and from pre-clinical studies there are indications of neural actions more centrally. This study is the first single-blind, placebo-controlled cross-over study using a weight-adjusted dose of nitroglycerin administered intravenously in cluster headache patients, thereby allowing comprehensive investigation of the various stages of the acute attack of cluster headache.
Methods
Subject selection and recruitment
The study was advertised on the UK cluster headache patient website OUCH (UK) (Organisation for the Understanding of Cluster Headache UK) (https://ouchuk.org/research/research-volunteers-needed) and in the tertiary Headache centre in King’s College Hospital, London. Subjects interested in participating would make contact via a dedicated research email. Subjects would then be screened for eligibility for the study via emails and a telephone call; those who met the criteria and were interested in participating were invited to attend the study visit. The study was approved by the London, City & East Research Ethics Committee (Ref Number 16/LO/0693). Data were collected from August 2016 until January 2019.
The subjects enrolled fulfilled the ICHD-3 beta criteria for cluster headache (28), and were between the ages of 18 and 60, with no significant previous medical history and no previous syncope or history of autonomic dysfunction. They had had a reliable response to high flow oxygen and/or subcutaneous sumatriptan during spontaneous attacks and normal brain neuroimaging. Women in child-bearing age were required to use reliable contraceptive methods during the study. Subjects were excluded if they were pregnant or breastfeeding, and who had any significant psychiatric disease, diagnosis of another primary headache type (other than migraine) or chronic pain syndrome, any medical history that would have contraindications to receiving NTG, use of preventive medication other than verapamil, or taking indomethacin for any reason, allergies to the medications used in the study or intolerance to high flow oxygen, and use of illicit drugs during the study.
Study visits
The study comprised of three visits in total, with each visit separated by a minimum of 1 week. During the first visit, subjects consented and a full headache history with a physical examination of the neurological and cardiovascular systems was performed, along with recordings of the baseline blood pressure, lying and standing blood pressure, heart rate, oxygen saturation, weight and electrocardiogram. Female subjects were required to have a urinary pregnancy test before the start of the infusion.
Open NTG infusion
If deemed eligible, subjects received an intravenous infusion of nitroglycerin at 0.5 µg/kg/min over 20 minutes. Subjects remained recumbent for 30 minutes before the infusion, and after the NTG infusion, subjects received 250 mL of 0.9% sodium chloride intravenously. The blood pressure and pulse were checked at the start of the infusion, and every 5 min during the infusion.
Phenotypic characterisation
Every 5 minutes, subjects were asked to rate their pain level from a scale from no pain, mild, moderate to severe, where severe equates to their most severe attack, and they were asked a questionnaire of non-headache symptoms and cranial autonomic symptoms (CAS) (Figure 1). If the subject experienced pain, further details were obtained regarding the location and characteristic. Beyond the cluster headache attack, subjects were asked to report any other headache types and in particular NTG headache, which has been well described from migraine studies (29). The NTG headache was assessed for severity, phenotype, accompanying non-headache symptoms and duration. Subjects were actively encouraged to report any symptoms as and when they developed. Following the infusion, at 10 minute intervals, any developments in pain, non-headache symptoms and CAS were recorded for a total of 120 minutes after the infusion, based on the latency period reported from previous studies (Table 1).
Figure 1. Questionnaire for non-headache and cranial autonomic symptoms.
B: bilateral; R: right-sided; L: left-sided.
Single-blinded NTG and placebo infusions
During the two single-blinded visits, subjects either received intravenous nitroglycerin at 0.5 µg/kg/min over 20 minutes or an equal volume of 0.9% sodium chloride at the same rate over 20 minutes, followed by the same 120 minutes of observations (Figure 2). The sequence was pre-determined using the randomise function in Excel; however, the investigator was able to amend this in certain situations if the subject was episodic and due to finish their bout.
Figure 2. Outline of events from open unblinded nitroglycerin visit.
BP: blood pressure; CAS: cranial autonomic symptoms; NTG: nitroglycerin; IV: intravenous.
Treatment of acute attacks
Acute treatment was administered at 20 minutes from the start of attack either with sumatriptan 6 mg subcutaneous injection (Imigran 6 mg/0.5 ml solution for injection pre-filled syringes, GlaxoSmithKline UK Ltd, or sumatriptan 6 mg/0.5 ml solution for injection pre-filled pens, Sun Pharmaceuticals Industries Europe B.V.) or with 15 L/min oxygen via a non-rebreather mask (O2Star™ non-rebreather oxygen mask M/L, Dräger). The visit was concluded only when the subject was pain free.
Statistical analysis
The data was tabulated (Excel for Mac v 16.30), and descriptive statistics were performed to summarise data (SPSS Statistics version 26 for Mac and Excel). Mann-Whitney tests were performed on time until attack onset and time until CAS onset for those that developed NTG-triggered cluster headache attacks and CAS, comparing the differences in ECH with CCH subgroups. Kaplan-Meier survival graphs were used to examine the time until onset of event; that is, survival of no cluster headache attack status, or absence of CAS after NTG infusion for 140 minutes (20 minutes of infusion and 120 minutes of post-infusion observation), with log-rank statistical testing; P < 0.05 was considered significant. Graphs were made using SPSS and violin plots were made using GraphPad Prism 8 for Mac OS.
Results
Demography
A total of 229 subjects were contacted to check for eligibility, of which 33 were included in the study; 24 completed all three study visits (Figure 3). All patients fulfilled the ICHD-3 beta criteria for cluster headache, 19 episodic cluster headache in bout (58%) and 14 chronic cluster headache (42%) (Table 2). The majority were male (n = 24, 73%) with a male: female ratio of 3:1. The average age was 41 (SD 10), with the mean age of females (34 years, SD 9) younger than in males (44 years, SD 9) in this cohort. Subjects had had the condition for a median of 9 years (IQR 5–16).
Figure 3. Subject numbers throughout the study.
Table 2. Subject characteristics.
Subject Age Sex Subtype Side of attacks Time since first attack (years) Average attack frequency (per day) Average attack duration when untreated (mins) Average bout duration (weeks) Verapamil (total daily dose in mg)
1 55 M Chronic Right 5 2 45 – 480
2 28 F Chronic Right 12 7 150 – –
3 40 M Episodic Right 20 3 150 8 –
4 38 F Episodic Left 12 2 120 4 –
5 53 M Chronic Left 15 4 35 – 960
6 48 M Episodic Left 25 5 52.5 5 480
7 23 M Episodic Left 8 2 120 10 –
8 43 M Chronic Right 9 1 40 – –
9 43 M Episodic Right 13 3 60 5 240
10 44 M Episodic Right 27 6 45 6 –
11 47 M Episodic Right 3 1 105 20 –
12 48 M Episodic Left 26 3 180 10 560
13 40 M Episodic Right 5 3 60 8 –
14 50 M Episodic Right 10 2 105 8 –
15 56 M Episodic* Right 24 1 45 – –
16 35 M Episodic Left 7 2 150 6 240
17 58 M Episodic Left 3 1 135 24 –
18 43 M Chronic Left 4 2 60 – –
19 32 M Episodic Left 3 3 50 12 600
20 49 F Episodic Right 8 5 50 9 –
21 49 M Chronic Right 35 2 90 – –
22 57 M Chronic Right 20 5 65 –
23 40 F Chronic Left 4 1.5 120 – 640
24 44 M Chronic Right 6 2 90 – 720
25 23 F Episodic Right 9 2.5 90 6 –
26 40 M Chronic Left 17 1.5 180 – –
27 20 F Chronic Right 6 1.5 150 – –
28 31 F Episodic Right 14 2 75 11 –
29 35 M Episodic Left 9 2 90 3 –
30 38 F Chronic Left 6 1.5 180 – 240
31 49 M Episodic Left 0.5 1.5 37.5 21 400
32 35 F Chronic Left 4 0.3 30 – 600
33 32 M Chronic Left 10 6 60 – –
M: male; F: female.
*Subject was chronic but became episodic during study with no attacks in 6 months.
Clinical phenotyping of subjects by history
Pain features
There was a near-equal split between the laterality of attacks; 17 subjects had right-sided attacks (52%), and 16 subjects had left-sided attacks (49%). The median number of attacks per day was two (IQR 1.5–3) lasting a median of 90 minutes (IQR 50–128). Verapamil was the only preventive allowed on the study; 12 subjects (36%) were on verapamil ranging from 240 mg to 960 mg per day.
Migraine, accompanying features and non-headache symptoms in spontaneous attacks
In this cohort, 58% (n = 19) had a concurrent migraine (28): five had migraine with aura, of which four had visual aura and one had facial sensory aura. Of the subjects who did not meet the diagnostic criteria for migraine (28) (n = 14, 42%), the majority had either migraine markers and/or a family history of migraine. Migraine markers were defined if subjects experienced: childhood cyclic nausea and vomiting, motion sickness, cold stimulus-induced headache, hangover headache and jetlag. Four subjects did not have migraine markers, and three subjects (9%) did not have either migraine marker or a family history of migraine. Subjects (n = 24, 73%) reported accompanying symptoms with their spontaneous attacks, the most common symptoms being cranial allodynia (n = 15), photophobia (n = 15), nausea (n = 11) and phonophobia (n = 10).
Non-headache attack symptoms
The majority reported non-headache symptoms in the lead up to their spontaneous cluster headache attacks (n = 27, 82%), with the commonest symptoms being concentration difficulties (n = 18), mood changes (n = 15), neck stiffness (n = 13) and yawning (n = 8). The median onset time of symptoms was 10 minutes (IQR 2–30) before the onset of pain. Although most symptoms start before the onset of pain, five subjects only reported developing the symptoms during the attack.
Twenty-eight subjects reported non-headache symptoms following their cluster headache attacks (85%), the commonest symptoms being tiredness (n = 27), mood changes (n = 13), concentration difficulties (n = 12), and neck stiffness (n = 7). The median duration of symptoms was 120 minutes (IQR 53–315).
Attack triggers
The most commonly reported triggers for spontaneous attacks were alcohol ingestion (n = 22), followed by changes in temperature (n = 12), strong smells such as from nail varnish, paint (n = 11) followed by disrupted sleep (n = 4) and exercise (n = 3). Other triggers mentioned were stress (n = 2), caffeine (n = 2), changing time zones (n = 1), let down from stress (n = 1), being in a pressurised cabin on an airplane (n = 1), vardenafil (n = 1), and dehydration (n = 1). All subjects reported attacks within a few hours of alcohol ingestion, no one reported a next-day effect.
Clinical phenotyping of open NTG visit
NTG triggered cluster headache-like attacks (n = 26, 79%), CAS (n = 31, 94%) and agitation (n = 24, 73%) during the open unblinded NTG visit. In the episodic cluster headache group, 16 out of 19 developed an NTG-induced attack (mean, 84%; 95% CI, 66–100%) and in the chronic cluster headache group, 11 out of 14 developed an NTG-induced attack (79%, 54–100%). Five out of the 31 subjects developed CAS, but did not develop an attack; of these subjects, three developed mild generalised pain, one developed restless legs, and one developed CAS on the contralateral side to the subject’s spontaneous attack phenotype, with a generalised headache. These cases were excluded.
The median onset time for CAS to develop from the start of the NTG infusion was 31 minutes (IQR 13–46). The median onset for an NTG-induced attack was 30 minutes (IQR 20–39) and the median time to maximum pain, if reached, was 51 minutes (IQR 39–70). The most common first cranial autonomic symptoms brought on by NTG infusion were nasal congestion (n = 10), conjunctival injection (n = 5), lacrimation (n = 4) and periorbital oedema (n = 3).
Clinical phenotyping of single-blinded NTG and placebo visit
During the single-blinded visits, NTG induced attacks in 19 subjects (76%); three subjects did not have an attack (12%), two subjects developed migraine-like headache (8%) and one subject developed unilateral mild pain without CAS or agitation (4%) (Table 3). In the placebo group, only one developed an attack (4%), two subjects developed unilateral mild pain without CAS or agitation (8%) and two subjects experienced short-lived unilateral CAS (8%). Of the subjects receiving NTG, eight out of 13 ECH (mean, 62%; 95% CI, 31%-92%) and 11 out of 12 CCH (92%, 73–100%) developed NTG-induced attacks (Figure 4(a)).
Table 3. Subject characteristics and comparison between spontaneous attack and triggered attack from single-blinded nitroglycerin visit, M = male, F = female, ECH = episodic cluster headache, CCH = chronic cluster headache, L = Left, R = Right, Y = Yes, N = No, VRS = verbal rating scale, mod = moderate, O2 = high flow oxygen via non-rebreather mask, suma = sumatriptan.
Subject Age Sex Subtype Migraine Verapamil (total daily dose in mg) Spontaneous attack Triggered attack- single-blinded NTG visit
Laterality Severity CAS Agitation Laterality Severity/VRS CAS Agitation Feels like spontaneous attack Treatment Last spontaneous attack (days)
1 55 M CCH N 480 R 9/10 Conjunctival injection, nasal congestion, lacrimation. 3 months of R Horner’s syndrome in 2007, now resolved Y R 10/10
VRS 3 Conjunctival injection, nasal congestion, lacrimation, periorbital oedema Y Y O2 158
2 28 F CCH Y
– R 10/10 Periorbital oedema/ptosis, nasal congestion, dry eye then lacrimation Y R 10/10
VRS 3 Periorbital oedema, nasal congestion, facial flushing Y Y O2 128
3 40 M ECH N – R 10/10 Lacrimation, rhinorrhoea, ptosis Y R 10/10
VRS 3 Lacrimation, conjunctival injection, periorbital oedema, nasal congestion, aural fullness and facial droop Y Y Suma 1
4 38 F ECH Y – L 10/10 Lacrimation, conjunctival injection, periorbital oedema, nasal congestion, ptosis, facial flushing Y No attack, developed generalised pain 4/10 Y N N/A 1
5 53 M CCH N 960 L 10/10 Rhinorrhoea, ptosis Y L 10/10
VRS 3 Conjunctival injection, eye grittiness, lacrimation Y Y O2 4
6 48 M ECH N
480 L 8/10 Nasal congestion, lacrimation Y Did not attend
7 23 M ECH Y – L 10/10 Lacrimation, conjunctival injection, nasal congestion, ptosis, facial flushing Y Did not attend
8 43 M CCH N – R 10/10 Nasal congestion, rhinorrhoea, lacrimation, facial flushing Y R 10/10
VRS 3 Nasal congestion, conjunctival injection, eye grittiness Y Y Suma <1
9 43 M ECH N 240 R 10/10 Lacrimation, conjunctival injection, facial flushing, ptosis, facial droop Y Did not attend
10 44 M ECH N – R 10/10 Nasal congestion, ptosis, periorbital oedema, lacrimation, flushing Y No attack, L mild hangover like headache, with nasal congestion.
After study visit felt nauseous and vomited, then slept, headache free at 7pm N N O2- no response <1
11 47 M ECH N – R Severe attacks 10/10 Nasal congestion, aural fullness Y R 7/10
VRS 2/3 moderate/
severe Nasal congestion, conjunctival injection, aural fullness Y Y Suma 13
12 48 M ECH N 560 L 10/10 Lacrimation, nasal congestion, periorbital oedema Y Did not attend
13 40 M ECH Y – R 10/10 Nasal congestion, ptosis, conjunctival injection, lacrimation, throat tightness, rhinorrhoea Y No attack, bilateral mild headache 4/10 with nasal congestion Y, brief (7 mins) N N/A 19
14 50 M ECH Y – R 10/10
Lacrimation, periorbital oedema, nasal congestion, rhinorrhoea Y Did not attend
15 56 M ECH Y – R 10/10 Lacrimation, rhinorrhoea, facial flushing, gritty eyes, conjunctival injection Y with severe attacks Did not attend
16 35 M ECH Y 240 L 10/10 Nasal congestion, conjunctival injection, ptosis, lacrimation, rhinorrhoea Y Not attack, milder than a shadow and no CAS N N N/A 16
17 58 M ECH Y – L 10/10 Nasal congestion, rhinorrhoea, lacrimation, aural fullness, throat swelling Y L 7/10
VRS 2–3 (mod-severe) Nasal congestion, rhinorrhoea, voice change, lacrimation Y Y Suma 1
18 43 M CCH Y – L (70%) Mild 6/10, severe 10/10 Nasal congestion, periorbital oedema, aural fullness, facial flushing Y L Mild,
VRS 1 Nasal congestion Y Y- shadow O2 7
19 32 M ECH Y 600 L 10/10 Lacrimation, conjunctival injection, facial flushing Y L 7–8/10
VRS 2–3
(mod-severe) Lacrimation, eye grittiness, nasal congestion, facial flushing Y Y O2 <1
20 49 F ECH Y – R 10/10 Ptosis, periorbital oedema, lacrimation, nasal congestion, rhinorrhoea, (aural fullness with severe attacks) Y R 6–7/10
VRS 2 mod Nasal congestion, periorbital oedema, lacrimation, conjunctival injection Y Y O2 7
21 49 M CCH Y – R 4–10/10 Facial flushing, nasal congestion, ptosis, lacrimation, rhinorrhoea, conjunctival injection Y L 8/10
VRS 2–3
(mod-severe)
Facial flushing, lacrimation, periorbital oedema, conjunctival injection Y Y, but on L rather than R Suma <1
22 57 M CCH N – R 10/10 Lacrimation, conjunctival injection, nasal congestion, rhinorrhoea Y No attack, no pain and no CAS N N N/A 26
23 40 F CCH Y 640 L 10/10
Lacrimation, conjunctival injection, periorbital oedema, rhinorrhoea, ptosis, aural fullness Y Did not attend
24 44 M CCH N 720 R 10/10 Lacrimation, conjunctival injection, periorbital oedema, facial flushing Y Did not attend
25 23 F ECH Y – R 6–10/10 Nasal congestion, lacrimation, periorbital oedema. Rhinorrhoea and facial flushing with severe attacks Y R 7/10
VRS 2
(moderate) Nasal congestion, periorbital oedema Y Y O2 3
26 40 M CCH Y – L Shadow 4/10, daytime attacks 6–7/10, full attack 10/10 Ptosis, aural fullness, lacrimation, conjunctival injection, periorbital oedema, nasal congestion Y L 8.5–9/10
VRS 3 severe Nasal congestion, periorbital oedema, lacrimation Y Y Suma 3
27 20 F CCH N – R 8–9/10 Nasal congestion, lacrimation, rhinorrhoea, ptosis, aural fullness Y R 8/10
VRS 3
severe Nasal congestion, periorbital oedema Y Y O2 <1
28 31 F ECH Y – R 10/10 Nasal congestion, periorbital oedema, rhinorrhoea, ptosis, aural fullness Y R 2/10
VRS 1 (mild) Nasal congestion, facial swelling Y Y, but milder Suma 3
29 35 M ECH N – L Max pain 10/10 Nasal congestion, periorbital oedema, lacrimation, voice change (croaky). Facial flushing with severe attacks and rhinorrhoea after attack Y L 6–7/10
VRS 2 (moderate) Nasal congestion, lacrimation, conjunctival injection, voice change Y Y Suma <1
30 38 F CCH Y 240 L 4–10/10 Lacrimation, rhinorrhoea, conjunctival injection, facial flushing. Ptosis with severe attacks Y L 6–7/10
VRS 2 (moderate) Aural fullness Y Y Suma 1
31 49 M ECH Y 400 L 10/10 Nasal congestion, lacrimation, conjunctival injection, rhinorrhoea, ptosis, aural fullness. Prominent miosis after attack Y No attack, whole head felt heavy N N N/A 10
32 35 F CCH N 600 L 4/10 (on verapamil),
7/10 average Periorbital oedema, eye grittiness, facial flushing, lacrimation Y L 7/10
VRS 2–3
(mod-severe) Nasal congestion, conjunctival injection, facial flushing, lacrimation Y Y Suma 1
33 32 M CCH Y – L Severe attacks 10/10 Lacrimation, ptosis, nasal congestion, conjunctival injection, ptosis, facial flushing, eye grittiness Y L 6/10
VRS 2 (mod-severe) Lacrimation, nasal congestion, ptosis Y Y Suma <1
Figure 4. (a) Kaplan-Meier graph comparing time until cluster headache attack between the eight episodic cluster headache (ECH) and the 11 chronic cluster headache (CCH) subjects during single-blinded nitroglycerin (NTG) infusion, from the start of the infusion in minutes, log-rank P = 0.534. (b) Kaplan-Meier graph comparing time until cluster headache attack onset between the open unblinded (n = 33) and single-blinded (n =25) nitroglycerin (NTG) infusions with single-blinded placebo infusions (n = 24). Log-rank P = 0.000.
The median onset time to an induced attack was 33 minutes (IQR 15–42) from the start of the single-blinded NTG infusion, and in the single-blinded placebo visit only one subject developed an attack; the onset time was 10 minutes. On comparison of the attack onset time for the unblinded NTG, single-blinded NTG and single-blinded placebo visits, there was a difference between the placebo and NTG visits (P = 0.000, Figure 4(b)).
NTG headache
The majority of subjects developed an NTG headache (n = 28, 85%) following the NTG infusion in the unblinded open visit, of which 27 subjects had a migraine diagnosis (n = 18), had migraine markers (n = 10) and a family history of migraine (n = 18); only one subject did not have migraine, migraine markers or a family history of migraine. The median time from the start of NTG infusion was 3 minutes (IQR 2–6), and the median duration of NTG headache was 26 minutes (IQR 14–41).
Of the 25 subjects that went on to the single-blinded NTG visits, 18 (72%) developed NTG headache following NTG infusion, of which all had either migraine (n = 11), migraine markers (n = 7) or family history (n = 10). The median time of NTG headache onset from the start of NTG infusion in the blinded visit was 4 minutes (IQR 3–8), with a median duration of 26 minutes (IQR 9–45).
In the placebo visit, three of the 24 subjects (13%) developed NTG headache, median onset time was 13 minutes (range 1–18), and the median duration was 10 minutes (range 3–16).
Non-headache symptoms
The majority of subjects reported non-headache symptoms in both the open unblinded NTG visit (n = 30, 91%) and the single-blinded NTG visit (n = 21, 84%) visits. In the single-blinded placebo visit, eight subjects (33%) reported non-headache symptoms. The most common non-headache symptoms from the open unblinded NTG visit were neck stiffness, photophobia, thirst and allodynia. The most common non-headache symptoms from the single-blinded NTG visit were neck stiffness, yawning, thirst and photophobia (Table 4). The median number of non-headache symptoms reported in the open unblinded NTG visit was three (IQR 2–5), and from the single-blinded NTG visit was three (IQR 2–6), compared with two (IQR 2–3) on-headache symptoms in the single-blinded placebo group.
Table 4. Frequencies of non-headache symptoms reported during each visit.
Non-headache symptom Open unblinded NTG visit (n = 33) Single-blinded NTG visit
(n = 25) Single-blinded placebo visit
(n = 24)
Thirst 15 10 3
Craving 0 0 0
Yawning 8 12 4
Tiredness 4 3 0
Mood changes 5 4 1
Visual blurring 4 3 1
Neck stiffness 21 15 3
Irritability 3 3 0
Photophobia 18 10 1
Concentration difficulties 6 4 1
Phonophobia 4 6 0
Urinary symptoms 0 0 0
Speech disturbances 0 0 0
Nausea 6 3 0
Gastrointestinal discomfort 0 0 0
Movement sensitivity 5 5 1
Allodynia 9 8 2
In the open unblinded NTG visit, the median onset time of non-headache symptoms from the start of the infusion was 9 minutes (IQR 4–17) with the median maximum duration of the symptoms being 50 minutes (IQR 24–64), the duration is calculated from the first symptom until the end of the last symptom. In the single-blinded NTG visit, the median onset time was 5 minutes (IQR 3–9) from the start of the infusion, and the median maximum duration of symptoms was 59 minutes (IQR 35–76). The outlier was a subject who developed allodynia and neck stiffness during their attack. For those that developed non-headache symptoms during the single-blinded placebo visit, the median onset time was 9 minutes (IQR 2–9), with a median duration of 16 minutes (IQR 6–34).
Cranial autonomic symptoms
NTG triggered CAS in the majority of the subjects during the open unblinded NTG visit (n = 31, 94%). In all, five subjects out of the 31 (19%) developed unilateral CAS; however, they did not have a cluster headache attack. Two subjects had CAS with generalised headache, one had CAS without any pain, one subject developed CAS on the contralateral side to their attacks with mild generalised pain, and one subject with CAS developed restless leg symptoms, but no cluster headache attack. Of the subjects who developed unilateral CAS and cluster headache attack (n = 26, 79%), the median number of CAS was four (IQR 2–5), with the most common CAS being nasal congestion (n = 21), lacrimation (n = 16) and periorbital oedema (n = 15) (Table 5).
Table 5. Frequencies of cranial autonomic symptoms reported in subjects who had attacks following NTG infusion.
Cranial autonomicsymptoms Open unblinded NTG visit, total number of attacks (n = 26) Single-blinded NTG visit, total number of attacks (n = 19)
Lacrimation 16 11
Conjunctival injection 12 9
Periorbital oedema 15 8
Eye grittiness/itchiness 3 3
Nasal congestion 21 16
Rhinorrhoea 2 1
Ptosis 4 1
Aural fullness 5 2
Facial flushing 7 4
Sialorrhoea 1 0
Throat swelling 2 0
Voice change 4 2
Facial swelling 3 1
Similarly, NTG brought on CAS in the majority of subjects during the single-blinded NTG visit (n = 21, 84%), of which two were not accompanied by a cluster headache attack, compared with four out of 24 in the single-blinded placebo group developing CAS (Figure 5(a)). One of the subjects from the single-blinded NTG group had a generalised headache similar to a hangover headache with unilateral CAS, and the other subject had a migraine-like headache with CAS. Of the 19 subjects (76%) that had unilateral CAS and a cluster headache attack, the median number of symptoms was three (IQR 2–4) and the most frequent symptoms were nasal congestion (n = 16), lacrimation ( n = 11) and conjunctival injection (n = 9) (Table 5). In comparing the time until all CAS onset between ECH and CCH after blinded NTG infusion, there was no difference between the two groups (log-rank P = 0.740; Figure 5(b)).
Figure 5. (a) Kaplan-Meier graph showing time until onset of cranial autonomic symptoms (CAS) following open unblinded (n = 33) and single-blinded NTG (n = 25) infusions compared with the single-blinded placebo infusion (n = 24). Log-rank P = 0.000. (b) Kaplan-Meier graph showing the time until CAS onset in the single-blinded NTG visit, comparing episodic cluster headache (ECH) with chronic cluster headache (CCH). Log-rank P = 0.740.
The median time until CAS onset for those that developed cluster headache attacks was 31 min (IQR 13–46) in the open unblinded NTG visit and 12 min (IQR 6–30) in the single-blinded NTG visit. Subjects sequentially reported CAS development.
During the single-blinded placebo visit, four subjects (17%) developed unilateral CAS, of which one subject developed a spontaneous attack, and three developed CAS but no pain. The median number of symptoms reported in the placebo group was two (IQR 1–2) and the symptoms reported were nasal congestion (n = 2), conjunctival injection (n = 1), periorbital swelling (n = 1), rhinorrhoea (n = 1) and aural fullness (n = 1).
Agitation
Nitroglycerin brought on agitation in the majority of subjects, open unblinded NTG visit (n = 24, 73%) and single-blinded NTG visit (n= 20, 80%), compared with none in the single-blinded placebo visit.
Non-headache symptoms post-attack
The non-headache symptoms were not studied here, as all attacks were treated with sumatriptan or oxygen after 20 minutes, thus altering the natural progression and development of symptoms.
Episodic cluster headache compared with chronic cluster headache
For the subjects that developed an NTG-induced attack following the single-blinded NTG infusion, the time until NTG-induced attack was shorter in the episodic cluster headache group compared with the chronic cluster headache group (U = 15, z = −2.399, P = 0.016). The time until CAS onset, in the subjects that developed CAS following single-blinded NTG infusion was not different between episodic cluster headache and chronic cluster headache groups (U = 38, z = −1.2000, P = 0.230).
Effect of verapamil on NTG triggering
There were seven subjects on verapamil that attended the single-blinded NTG visits, of which two did not develop NTG-triggered cluster headache attacks (29%). Using χ2, there was no difference between verapamil and NTG triggering (χ2 (df = 1) = 0.111, P = 0.739).
Effect of migraine on NTG-triggered attacks
Within the cohort that attended the single-blinded NTG visits, 15 had migraine (60%). There was no difference between the number of non-headache symptoms (U = 67, z = −0.449, P = 0.654) or number of CAS (U = 57, z = −1.019, P = 0.308), between the subjects with migraine and those without migraine. Furthermore, there was no association between subjects with migraine and NTG triggering (χ2 (df = 1) = 0.146, P = 0.702); similarly, there was no association between subjects with migraine and development of NTG headache (χ2 (df = 1) = 0.033, P = 0.856).
Discussion
This study demonstrates that weight-calculated intravenous NTG effectively triggers cluster headache attacks in both chronic cluster headache and episodic cluster headache subjects within bout when compared with placebo. The approach is reliable in terms of triggering a fully-featured attack that allows careful observation of symptoms and their development during acute attacks of cluster headache.
The benefit of weight-calculated intravenous NTG compared to intranasal and sublingual administration is that this is more reliable and has more stable bioavailability. The median time until cluster headache attack onset was 30 minutes (open unblinded NTG visit) and 33 minutes (single-blinded NTG visit), with the overall maximum onset time of 81 minutes. Subjects who did not develop an attack during the 140 minutes of observation were asked to report if they developed an attack later on that day, and none did. The median onset time is similar to the reported latency period reported in the literature (Table 1). The minimum onset time for NTG-induced attacks was 2 minutes, and this is less than reported from the sublingual route, where the shortest time until onset time was 9 minutes (8); this is expected, given the intravenous route has a half-life of 2.3–2.8 minutes (30,31). Two subjects started experiencing mild attack pain before the start of the NTG infusion, and within the placebo group we observed one subject who developed a spontaneous attack. Spontaneous attacks could be anticipated given the subjects are within bout; there were three subjects with only short-lasting CAS symptoms and two subjects who experienced a mild pain without CAS, similar to a shadow.
This study delineates the development of the various stages of an NTG-induced cluster headache attack, including the non-headache symptoms and CAS (Figure 6). The majority of subjects developed NTG headache shortly after the infusion started. This headache was generalised, mild and progressive in nature, predominantly in the bi-occipital and bi-temporal regions. Subjects described it as pressure-like or band-like ache, and they reported it to be distinct from their cluster headache attacks; if there were an overlap, the cluster headache attack would clearly ramp up and supersede the NTG headache. It is difficult to disentangle whether NTG headache developed because there was a high proportion of subjects with either a migraine diagnosis, migraine marker or family history of migraine. However, from a previous study with 25 healthy volunteers without a migraine diagnosis, 16 (64%) developed NTG headache following 0.5 mg NTG sublingual administration (32).
Figure 6. Violin plots of the stages of cluster headache attack from the 19 subjects that developed cluster headache attacks and subdivided by chronicity. The timeline starts with 20 minutes of single-blinded nitroglycerin (NTG) infusion, followed by 120 minutes of post-infusion observation. CAS = cranial autonomic symptoms.
Following the NTG headache, the majority of subjects reported non-headache symptoms in the lead-up to the onset of the pain from the attack and in some subjects, non-headache symptoms accompanied their attacks. The non-headache symptoms included homeostatic symptoms (thirst, cravings, yawning, frequency of urination), fatigue/cognitive symptoms (concentration difficulty, fatigue, memory impairment, mood changes, irritability) and sensitised sensory symptoms (neck stiffness, photophobia, phonophobia, osmophobia, nausea), as are reported in the premonitory phase of migraine (33). The most common symptoms were neck stiffness, photophobia and thirst. During their spontaneous attacks, subjects reported that non-headache symptoms would precede the attack at a median of 10 minutes (IQR 2–30) before the onset of pain, although it is known that there are discrepancies between retrospective and prospective reporting (25). Comparing the symptoms observed from NTG-induced attacks in this study with the prospective observational questionnaire study (24), the most reported general symptoms in the pre-pain phase in this study were concentration difficulties, photophobia and mood changes. Patients in the observational study also reported general symptoms during their attacks and postictal symptoms similar to the symptoms seen during the NTG-induced attacks and the reported symptoms by the subjects in this study during the postdrome phase of their spontaneous attacks. Non-headache symptoms such as photophobia, phonophobia, and localised allodynia were often reported during the attacks, as has been reported previously (21,34). In one semi-structured questionnaire study, they found a high proportion of cluster headache patients (73.2%) reported phonophobia or photophobia with their attacks (35), cluster headache patients with migraine did not more frequently report these symptoms compared with those without co-existing migraine. Furthermore, allodynia was more often reported in cluster headache patients with migraine. From pre-clinical studies, high dose NTG causes a sustained increase in spontaneous firing of Aδ and C-fibre trigeminal neurons (36), which migraine biology may unmask.
Similar to the prospective questionnaire study by Snoer and colleagues (24), in some subjects CAS presented before the onset of the attack pain (Figure 6). In this study, the median onset time for CAS was 31 minutes (IQR 13–46) in the open unblinded NTG visit and 12 minutes (IQR 6–30) in the single-blinded NTG visit, whereas the onset of NTG-induced attack was 30 minutes (IQR 20–39) in the open unblinded visit and 33 minutes (IQR 15–42) in the single-blinded NTG visit. From the open unblinded NTG visit, 38% presented with CAS before the attack, 15% presented with CAS with the onset of the attack, and from the single-blinded NTG visit, 58% presented with CAS before the attack and 16% presented with CAS with the onset of the attack.
Vollesen and colleagues used calcitonin gene-related peptide (CGRP) infusion to trigger cluster headache attacks, finding CGRP induced 50% of subjects with CCH and 89% for ECH subjects in bout (4). In our study, NTG induced attacks in 79% of the CCH subjects and 84% in ECH subjects in bout, in the open unblinded NTG visits, and 92% CCH and 62% ECH in bout in the single-blinded NTG visits. There are some differences in the number of chronic cluster headache subjects on verapamil between the studies; in this study, 33% of CCH subjects were on verapamil and in the study by Vollesen and colleagues, 57% of CCH subjects were on verapamil (of which one was on both verapamil and lithium) and one was on 4 mg melatonin. Vollesen and colleagues proposed that the CCH patients who did not develop an attack following CGRP infusion had a lower median attack frequency in the preceding 30 days prior to the study compared to the CCH patients that did develop an attack. However, in this study, subjects reported having their last attack as long ago as 128 and 158 days and still had NTG-induced attacks (Table 3).
NTG is a pro-drug of nitric oxide (NO) and has effects on blood vessel dilation through mechanisms of the NO-cyclic guanylate phosphate (cGMP) pathway (27). However, the vasodilatory effects of NTG are not sufficient to explain the cluster headache attack that occurs after a latency and the central features associated with the attack. Indeed, experimental studies demonstrate that NTG has central effects (37,38). Interestingly, in studies where NO donors were administered in vivo and in vitro, there was a local release of CGRP (39–42). The difference in the rate of cluster headache attacks induced by NTG and CGRP in ECH and CCH subjects could reflect in part the underlying biological processes and systems that are more active in the different subtypes of cluster headache. The difference between ECH and CCH is also suggested by the treatment response to a CGRP monoclonal antibody, galcanezumab (43,44), and non-invasive vagal nerve stimulator (45,46).
Limitations
The main limitations to the study were the recruitment of eligible subjects and the dropout rate at each stage due to the nature of the condition. Therefore, a pragmatic approach was taken with the study design regarding randomisation. Although there was a randomisation sequence, this was modified by the investigator if deemed necessary. This would be in the case of episodic cluster headache patients that were near the end of their bout missing the NTG visit if they followed the randomised sequence. For this reason, it was designed to be a single-blind cross-over study and not a double-blind and randomised study. Expectation bias was reduced by maintaining blinding of the subjects until the end of the study and having both infusions identical in volume, appearance and duration of infusion. Furthermore, given the stark difference between placebo and NTG, there was no difference between attack onset in the open unblinded compared with the single-blinded NTG visits (Figure 4(b)), is an indication that randomisation was not a factor in this study.
Conclusion
We present the results of the first placebo-controlled study using intravenous NTG administration to systematically study NTG-induced cluster headache attacks. We have shown that NTG can reliably bring on cluster headache attacks as well as the development of non-headache symptoms and CAS. This study highlights differences between NTG-induced attack onset times between the ECH and CCH subjects. Understanding the stages of cluster headache is essential; by recognising the non-headache symptoms in the lead up to the onset of pain and the underlying pathogenesis of this, we may be able to uncover new therapeutic targets to abort attacks before the onset of the severe and devastating pain experienced by our cluster headache patients.
Article highlights
Weight-calculated standardised intravenous nitroglycerin administration is a reliable method to induce cluster headache attacks, cranial autonomic symptoms and non-headache symptoms that accompany cluster headache attacks.
Accompanying non-headache symptoms in cluster headache attacks are important to recognise for both clinical and research purposes.
There may be inherent differences between episodic cluster headache and chronic cluster headache.
Acknowledgement
This study would not have been possible without the support of OUCH(UK), all the cluster headache patients who were interested in helping us with this study and all the subjects who took part in this study.
Ethics or Institutional Review Board approval: This study 16/LO/0693 obtained approval from the London, City & East NHS Research Ethics Committee on 23 June 2016. This study was carried out in accordance with the World Medical Association Declaration of Helsinki (1964), the Research Governance Framework for Health and Social Care (2nd edition, 2005), the Data Protection Act (1998) and the Principles of Good Clinical Practice (GCP); all subjects gave informed consent before taking part.
Declaration of conflicting interests: The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: DYW no reported competing interests. PJG reports, over the last 36 months, grants and personal fees from Amgen and Eli-Lilly and Company, grant from Celegene, and personal fees from Alder Biopharmaceuticals, Aeon Biopharma, Allergan, Biohaven Pharmaceuticals Inc., Clexio, Electrocore LLC, eNeura, Epalex, GlaxoSmithKline, Impel Neuropharma, MundiPharma, Novartis, Pfizer, Praxis, Sanofi, Santara Therapeutics Satsuma, Teva Pharmaceuticals, Trigemina Inc., WL Gore, and personal fees from MedicoLegal work, Massachusetts Medical Society, Up-to-Date, Oxford University Press, and Wolters Kluwer; and a patent magnetic stimulation for headache assigned to eNeura without fee.
Funding: The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study is part-funded by the National Institute for Health Research (NIHR) Maudsley Biomedical Research Centre at South London Maudsley Foundation Trust and King’s College London. The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care.
ORCID iDs: Diana Y Wei https://orcid.org/0000-0003-0644-7172
Peter J Goadsby https://orcid.org/0000-0003-3260-5904 | NITROGLYCERIN | DrugsGivenReaction | CC BY | 33615843 | 19,017,453 | 2021-07 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Lacrimation increased'. | Comprehensive clinical phenotyping of nitroglycerin infusion induced cluster headache attacks.
Nitroglycerin administration allows the study of cluster headache attacks in their entirety in a standardised way.
A single-blind, placebo-controlled, cross-over study using weight-calculated intravenous nitroglycerin administration at 0.5 µg/kg/min over 20 minutes to study cluster headache attacks, including accompanying non-headache symptoms and cranial autonomic symptoms.
Thirty-three subjects with cluster headache were included in the study; 24 completed all three study visits. Nitroglycerin-induced attacks developed in 26 out of 33 subjects (79%) receiving unblinded nitroglycerin infusion, and in 19 out of 25 subjects (76%) receiving single-blinded nitroglycerin infusion, compared with one out of 24 subjects (4%) receiving single-blinded placebo infusion. Episodic cluster headache subjects had a shorter latency period to a nitroglycerin-induced attack compared to the chronic cluster headache (CCH) subjects (U = 15, z = -2.399, p = 0.016). Sixteen of nineteen episodic cluster headache (mean, 84%; 95% confidence interval, 66-100%) and 11 of 14 chronic cluster headache subjects developed a nitroglycerin-induced attack (79%, 54-100%) following the unblinded nitroglycerin infusion. Following the single-blinded nitroglycerin infusion, eight out of 13 episodic cluster headache (62%, 31-92%) and 11 out of 12 chronic cluster headache (92%, 73-100%) subjects developed nitroglycerin-induced attacks. Nitroglycerin induced non-headache symptoms in the majority of subjects receiving it: 91% in the open unblinded nitroglycerin visit and 84% in the single-blinded nitroglycerin visits, compared with 33% in the single-blinded placebo visit. Cranial autonomic symptoms were induced by nitroglycerin infusion, 94% in the open unblinded nitroglycerin visit and 84% in the single-blinded nitroglycerin visit, compared with 17% in the single-blinded placebo visit.
Intravenous weight-adjusted nitroglycerin administration in both episodic cluster headache in bout and chronic cluster headache is effective and reliable in inducing cluster headache attacks, cranial autonomic symptoms and non-headache symptoms.
Introduction
Due to the episodic nature of acute attacks of cluster headache, a standardised and reliable method for triggering attacks is necessary for their complete study. There have been several substances used to trigger attacks, including histamine (1,2), meta-chloro-phenylpiperazine (mCPP) (3) and more recently calcitonin gene-related peptide (CGRP) (4). Nitroglycerin (NTG) is the most frequently employed substance in human experimental modelling of cluster headache attacks, being used since 1953 (2) (Table 1).
Table 1. Review of studies using nitroglycerin to induce cluster headache attacks.
Study Number of CH patients NTG dose and route Control Placebo Rate of induced CH attack Latency period before onset of headache
(range in minutes)
Peters 1953 (2) 14 1.3 mg sublingual No, but compared with migraine, combination of CH and migraine, vasodilating head pain and tension headache No, but compared with histamine and nicotinic acid 78.6% Not reported
Ekbom 1968 (5) 38 ECH: 28 in bout, 15 out of bout (of which five were tested in bout as well) 1 mg sublingual No No In bout ECH 100% (n = 28)
Out of bout 0% (n = 15) 12–72
Barre 1982 (6) 10 CH: two CCH, nine ECH in bout 1 mg sublingual No No 100% 34–52
Mean 45.9
Drummond et al. 1984 (7) 29 CH 0.9 mg sublingual No No 76% Within 90 min
Drummond et al. 1985 (8) 22 CH: 10 CCH, 12 ECH in bout
0.9 mg sublingual Yes, 10 in the control group without headache No ECH 75% (n = 9)
CCH 60% (n = 6) 9–90
Mean 44
Bogucki 1990 (9) 21 ECH in bout 1 mg sublingual No No 67% (n = 14)
30–65
Dahl et al. 1990 (10) 15 ECH in bout 1 mg sublingual 10 healthy controls No 53% (n = 8)
Controls: not reported 30–65
Hannerz et al. 1992 (11) Eight ECH: five in bout and three out of bout 1 mg sublingual No No In bout ECH 100% (n = 5) Not reported
Fanciullacci et al. 1995 (12) 18 in bout ECH, 12 out of bout ECH 0.9 mg sublingual No No In bout ECH 100% (n = 18)
Out of bout ECH 0% (n = 12) 39–86
Fanciullacci et al. 1997 (13) 11 in bout ECH, eight out of bout ECH 0.9 mg sublingual No No In bout ECH 100% (n = 11)
Out of bout ECH 0% (n = 8) 18–50
Hsieh et al. 1996 (14) Seven ECH: four in bout ECH, three out of bout 1 mg sublingual No No In bout ECH 100%
Out of bout ECH 0% 18–35
May et al. 1998 (15) Nine CCH, eight out of bout ECH 1.0–1.2 mg spray No No CCH 100%
Out of bout ECH 0% Not reported
Costa et al. 2000 (16) 15 CH: Six ECH, nine CCH 0.9 mg sublingual No No ECH 33% (n = 2)
CCH 78% (n = 7) 19–41
Costa et al. 2003 (17) 18 ECH in bout 0.9 mg sublingual Yes, 12 healthy sex and age-matched No ECH 67% (n = 12)
Controls 0% 19–41
Sances et al. 2004 (18) 42 CH: 29 ECH (11 out of bout), 13 CCH 0.9 mg sublingual Yes, 53 healthy controls No In bout ECH and CCH 81% (n = 25 out of 31)
Controls 7.5% developed headache in 7-hour post-NTG Mean onset latency of 65.4 ± 54.7
Cluster headache patients suffer from recurrent episodes of severe unilateral pain in the trigeminal region; therefore, historically, the main emphasis has been centred around the pain onset of a cluster headache, and indeed this is often used as the indicator of the start of the attack. However, from clinical practice, there has been growing awareness of nonpainful symptoms preceding the onset of pain (19,20) and in recent years, the clinical phenotype of cluster headache has been further characterised by retrospective accounts (21–23) and prospective diaries (24,25).
The most frequent route of administration of NTG has been sublingual; however, the bioavailability of sublingual NTG is extremely variable (26). Therefore, we used a weight-calculated dose for intravenous infusion in a standardised single-blind, placebo-controlled study. NTG is a pro-drug of nitric oxide, with predominant actions on the cyclic guanylate phosphate (cGMP) pathway (27), and from pre-clinical studies there are indications of neural actions more centrally. This study is the first single-blind, placebo-controlled cross-over study using a weight-adjusted dose of nitroglycerin administered intravenously in cluster headache patients, thereby allowing comprehensive investigation of the various stages of the acute attack of cluster headache.
Methods
Subject selection and recruitment
The study was advertised on the UK cluster headache patient website OUCH (UK) (Organisation for the Understanding of Cluster Headache UK) (https://ouchuk.org/research/research-volunteers-needed) and in the tertiary Headache centre in King’s College Hospital, London. Subjects interested in participating would make contact via a dedicated research email. Subjects would then be screened for eligibility for the study via emails and a telephone call; those who met the criteria and were interested in participating were invited to attend the study visit. The study was approved by the London, City & East Research Ethics Committee (Ref Number 16/LO/0693). Data were collected from August 2016 until January 2019.
The subjects enrolled fulfilled the ICHD-3 beta criteria for cluster headache (28), and were between the ages of 18 and 60, with no significant previous medical history and no previous syncope or history of autonomic dysfunction. They had had a reliable response to high flow oxygen and/or subcutaneous sumatriptan during spontaneous attacks and normal brain neuroimaging. Women in child-bearing age were required to use reliable contraceptive methods during the study. Subjects were excluded if they were pregnant or breastfeeding, and who had any significant psychiatric disease, diagnosis of another primary headache type (other than migraine) or chronic pain syndrome, any medical history that would have contraindications to receiving NTG, use of preventive medication other than verapamil, or taking indomethacin for any reason, allergies to the medications used in the study or intolerance to high flow oxygen, and use of illicit drugs during the study.
Study visits
The study comprised of three visits in total, with each visit separated by a minimum of 1 week. During the first visit, subjects consented and a full headache history with a physical examination of the neurological and cardiovascular systems was performed, along with recordings of the baseline blood pressure, lying and standing blood pressure, heart rate, oxygen saturation, weight and electrocardiogram. Female subjects were required to have a urinary pregnancy test before the start of the infusion.
Open NTG infusion
If deemed eligible, subjects received an intravenous infusion of nitroglycerin at 0.5 µg/kg/min over 20 minutes. Subjects remained recumbent for 30 minutes before the infusion, and after the NTG infusion, subjects received 250 mL of 0.9% sodium chloride intravenously. The blood pressure and pulse were checked at the start of the infusion, and every 5 min during the infusion.
Phenotypic characterisation
Every 5 minutes, subjects were asked to rate their pain level from a scale from no pain, mild, moderate to severe, where severe equates to their most severe attack, and they were asked a questionnaire of non-headache symptoms and cranial autonomic symptoms (CAS) (Figure 1). If the subject experienced pain, further details were obtained regarding the location and characteristic. Beyond the cluster headache attack, subjects were asked to report any other headache types and in particular NTG headache, which has been well described from migraine studies (29). The NTG headache was assessed for severity, phenotype, accompanying non-headache symptoms and duration. Subjects were actively encouraged to report any symptoms as and when they developed. Following the infusion, at 10 minute intervals, any developments in pain, non-headache symptoms and CAS were recorded for a total of 120 minutes after the infusion, based on the latency period reported from previous studies (Table 1).
Figure 1. Questionnaire for non-headache and cranial autonomic symptoms.
B: bilateral; R: right-sided; L: left-sided.
Single-blinded NTG and placebo infusions
During the two single-blinded visits, subjects either received intravenous nitroglycerin at 0.5 µg/kg/min over 20 minutes or an equal volume of 0.9% sodium chloride at the same rate over 20 minutes, followed by the same 120 minutes of observations (Figure 2). The sequence was pre-determined using the randomise function in Excel; however, the investigator was able to amend this in certain situations if the subject was episodic and due to finish their bout.
Figure 2. Outline of events from open unblinded nitroglycerin visit.
BP: blood pressure; CAS: cranial autonomic symptoms; NTG: nitroglycerin; IV: intravenous.
Treatment of acute attacks
Acute treatment was administered at 20 minutes from the start of attack either with sumatriptan 6 mg subcutaneous injection (Imigran 6 mg/0.5 ml solution for injection pre-filled syringes, GlaxoSmithKline UK Ltd, or sumatriptan 6 mg/0.5 ml solution for injection pre-filled pens, Sun Pharmaceuticals Industries Europe B.V.) or with 15 L/min oxygen via a non-rebreather mask (O2Star™ non-rebreather oxygen mask M/L, Dräger). The visit was concluded only when the subject was pain free.
Statistical analysis
The data was tabulated (Excel for Mac v 16.30), and descriptive statistics were performed to summarise data (SPSS Statistics version 26 for Mac and Excel). Mann-Whitney tests were performed on time until attack onset and time until CAS onset for those that developed NTG-triggered cluster headache attacks and CAS, comparing the differences in ECH with CCH subgroups. Kaplan-Meier survival graphs were used to examine the time until onset of event; that is, survival of no cluster headache attack status, or absence of CAS after NTG infusion for 140 minutes (20 minutes of infusion and 120 minutes of post-infusion observation), with log-rank statistical testing; P < 0.05 was considered significant. Graphs were made using SPSS and violin plots were made using GraphPad Prism 8 for Mac OS.
Results
Demography
A total of 229 subjects were contacted to check for eligibility, of which 33 were included in the study; 24 completed all three study visits (Figure 3). All patients fulfilled the ICHD-3 beta criteria for cluster headache, 19 episodic cluster headache in bout (58%) and 14 chronic cluster headache (42%) (Table 2). The majority were male (n = 24, 73%) with a male: female ratio of 3:1. The average age was 41 (SD 10), with the mean age of females (34 years, SD 9) younger than in males (44 years, SD 9) in this cohort. Subjects had had the condition for a median of 9 years (IQR 5–16).
Figure 3. Subject numbers throughout the study.
Table 2. Subject characteristics.
Subject Age Sex Subtype Side of attacks Time since first attack (years) Average attack frequency (per day) Average attack duration when untreated (mins) Average bout duration (weeks) Verapamil (total daily dose in mg)
1 55 M Chronic Right 5 2 45 – 480
2 28 F Chronic Right 12 7 150 – –
3 40 M Episodic Right 20 3 150 8 –
4 38 F Episodic Left 12 2 120 4 –
5 53 M Chronic Left 15 4 35 – 960
6 48 M Episodic Left 25 5 52.5 5 480
7 23 M Episodic Left 8 2 120 10 –
8 43 M Chronic Right 9 1 40 – –
9 43 M Episodic Right 13 3 60 5 240
10 44 M Episodic Right 27 6 45 6 –
11 47 M Episodic Right 3 1 105 20 –
12 48 M Episodic Left 26 3 180 10 560
13 40 M Episodic Right 5 3 60 8 –
14 50 M Episodic Right 10 2 105 8 –
15 56 M Episodic* Right 24 1 45 – –
16 35 M Episodic Left 7 2 150 6 240
17 58 M Episodic Left 3 1 135 24 –
18 43 M Chronic Left 4 2 60 – –
19 32 M Episodic Left 3 3 50 12 600
20 49 F Episodic Right 8 5 50 9 –
21 49 M Chronic Right 35 2 90 – –
22 57 M Chronic Right 20 5 65 –
23 40 F Chronic Left 4 1.5 120 – 640
24 44 M Chronic Right 6 2 90 – 720
25 23 F Episodic Right 9 2.5 90 6 –
26 40 M Chronic Left 17 1.5 180 – –
27 20 F Chronic Right 6 1.5 150 – –
28 31 F Episodic Right 14 2 75 11 –
29 35 M Episodic Left 9 2 90 3 –
30 38 F Chronic Left 6 1.5 180 – 240
31 49 M Episodic Left 0.5 1.5 37.5 21 400
32 35 F Chronic Left 4 0.3 30 – 600
33 32 M Chronic Left 10 6 60 – –
M: male; F: female.
*Subject was chronic but became episodic during study with no attacks in 6 months.
Clinical phenotyping of subjects by history
Pain features
There was a near-equal split between the laterality of attacks; 17 subjects had right-sided attacks (52%), and 16 subjects had left-sided attacks (49%). The median number of attacks per day was two (IQR 1.5–3) lasting a median of 90 minutes (IQR 50–128). Verapamil was the only preventive allowed on the study; 12 subjects (36%) were on verapamil ranging from 240 mg to 960 mg per day.
Migraine, accompanying features and non-headache symptoms in spontaneous attacks
In this cohort, 58% (n = 19) had a concurrent migraine (28): five had migraine with aura, of which four had visual aura and one had facial sensory aura. Of the subjects who did not meet the diagnostic criteria for migraine (28) (n = 14, 42%), the majority had either migraine markers and/or a family history of migraine. Migraine markers were defined if subjects experienced: childhood cyclic nausea and vomiting, motion sickness, cold stimulus-induced headache, hangover headache and jetlag. Four subjects did not have migraine markers, and three subjects (9%) did not have either migraine marker or a family history of migraine. Subjects (n = 24, 73%) reported accompanying symptoms with their spontaneous attacks, the most common symptoms being cranial allodynia (n = 15), photophobia (n = 15), nausea (n = 11) and phonophobia (n = 10).
Non-headache attack symptoms
The majority reported non-headache symptoms in the lead up to their spontaneous cluster headache attacks (n = 27, 82%), with the commonest symptoms being concentration difficulties (n = 18), mood changes (n = 15), neck stiffness (n = 13) and yawning (n = 8). The median onset time of symptoms was 10 minutes (IQR 2–30) before the onset of pain. Although most symptoms start before the onset of pain, five subjects only reported developing the symptoms during the attack.
Twenty-eight subjects reported non-headache symptoms following their cluster headache attacks (85%), the commonest symptoms being tiredness (n = 27), mood changes (n = 13), concentration difficulties (n = 12), and neck stiffness (n = 7). The median duration of symptoms was 120 minutes (IQR 53–315).
Attack triggers
The most commonly reported triggers for spontaneous attacks were alcohol ingestion (n = 22), followed by changes in temperature (n = 12), strong smells such as from nail varnish, paint (n = 11) followed by disrupted sleep (n = 4) and exercise (n = 3). Other triggers mentioned were stress (n = 2), caffeine (n = 2), changing time zones (n = 1), let down from stress (n = 1), being in a pressurised cabin on an airplane (n = 1), vardenafil (n = 1), and dehydration (n = 1). All subjects reported attacks within a few hours of alcohol ingestion, no one reported a next-day effect.
Clinical phenotyping of open NTG visit
NTG triggered cluster headache-like attacks (n = 26, 79%), CAS (n = 31, 94%) and agitation (n = 24, 73%) during the open unblinded NTG visit. In the episodic cluster headache group, 16 out of 19 developed an NTG-induced attack (mean, 84%; 95% CI, 66–100%) and in the chronic cluster headache group, 11 out of 14 developed an NTG-induced attack (79%, 54–100%). Five out of the 31 subjects developed CAS, but did not develop an attack; of these subjects, three developed mild generalised pain, one developed restless legs, and one developed CAS on the contralateral side to the subject’s spontaneous attack phenotype, with a generalised headache. These cases were excluded.
The median onset time for CAS to develop from the start of the NTG infusion was 31 minutes (IQR 13–46). The median onset for an NTG-induced attack was 30 minutes (IQR 20–39) and the median time to maximum pain, if reached, was 51 minutes (IQR 39–70). The most common first cranial autonomic symptoms brought on by NTG infusion were nasal congestion (n = 10), conjunctival injection (n = 5), lacrimation (n = 4) and periorbital oedema (n = 3).
Clinical phenotyping of single-blinded NTG and placebo visit
During the single-blinded visits, NTG induced attacks in 19 subjects (76%); three subjects did not have an attack (12%), two subjects developed migraine-like headache (8%) and one subject developed unilateral mild pain without CAS or agitation (4%) (Table 3). In the placebo group, only one developed an attack (4%), two subjects developed unilateral mild pain without CAS or agitation (8%) and two subjects experienced short-lived unilateral CAS (8%). Of the subjects receiving NTG, eight out of 13 ECH (mean, 62%; 95% CI, 31%-92%) and 11 out of 12 CCH (92%, 73–100%) developed NTG-induced attacks (Figure 4(a)).
Table 3. Subject characteristics and comparison between spontaneous attack and triggered attack from single-blinded nitroglycerin visit, M = male, F = female, ECH = episodic cluster headache, CCH = chronic cluster headache, L = Left, R = Right, Y = Yes, N = No, VRS = verbal rating scale, mod = moderate, O2 = high flow oxygen via non-rebreather mask, suma = sumatriptan.
Subject Age Sex Subtype Migraine Verapamil (total daily dose in mg) Spontaneous attack Triggered attack- single-blinded NTG visit
Laterality Severity CAS Agitation Laterality Severity/VRS CAS Agitation Feels like spontaneous attack Treatment Last spontaneous attack (days)
1 55 M CCH N 480 R 9/10 Conjunctival injection, nasal congestion, lacrimation. 3 months of R Horner’s syndrome in 2007, now resolved Y R 10/10
VRS 3 Conjunctival injection, nasal congestion, lacrimation, periorbital oedema Y Y O2 158
2 28 F CCH Y
– R 10/10 Periorbital oedema/ptosis, nasal congestion, dry eye then lacrimation Y R 10/10
VRS 3 Periorbital oedema, nasal congestion, facial flushing Y Y O2 128
3 40 M ECH N – R 10/10 Lacrimation, rhinorrhoea, ptosis Y R 10/10
VRS 3 Lacrimation, conjunctival injection, periorbital oedema, nasal congestion, aural fullness and facial droop Y Y Suma 1
4 38 F ECH Y – L 10/10 Lacrimation, conjunctival injection, periorbital oedema, nasal congestion, ptosis, facial flushing Y No attack, developed generalised pain 4/10 Y N N/A 1
5 53 M CCH N 960 L 10/10 Rhinorrhoea, ptosis Y L 10/10
VRS 3 Conjunctival injection, eye grittiness, lacrimation Y Y O2 4
6 48 M ECH N
480 L 8/10 Nasal congestion, lacrimation Y Did not attend
7 23 M ECH Y – L 10/10 Lacrimation, conjunctival injection, nasal congestion, ptosis, facial flushing Y Did not attend
8 43 M CCH N – R 10/10 Nasal congestion, rhinorrhoea, lacrimation, facial flushing Y R 10/10
VRS 3 Nasal congestion, conjunctival injection, eye grittiness Y Y Suma <1
9 43 M ECH N 240 R 10/10 Lacrimation, conjunctival injection, facial flushing, ptosis, facial droop Y Did not attend
10 44 M ECH N – R 10/10 Nasal congestion, ptosis, periorbital oedema, lacrimation, flushing Y No attack, L mild hangover like headache, with nasal congestion.
After study visit felt nauseous and vomited, then slept, headache free at 7pm N N O2- no response <1
11 47 M ECH N – R Severe attacks 10/10 Nasal congestion, aural fullness Y R 7/10
VRS 2/3 moderate/
severe Nasal congestion, conjunctival injection, aural fullness Y Y Suma 13
12 48 M ECH N 560 L 10/10 Lacrimation, nasal congestion, periorbital oedema Y Did not attend
13 40 M ECH Y – R 10/10 Nasal congestion, ptosis, conjunctival injection, lacrimation, throat tightness, rhinorrhoea Y No attack, bilateral mild headache 4/10 with nasal congestion Y, brief (7 mins) N N/A 19
14 50 M ECH Y – R 10/10
Lacrimation, periorbital oedema, nasal congestion, rhinorrhoea Y Did not attend
15 56 M ECH Y – R 10/10 Lacrimation, rhinorrhoea, facial flushing, gritty eyes, conjunctival injection Y with severe attacks Did not attend
16 35 M ECH Y 240 L 10/10 Nasal congestion, conjunctival injection, ptosis, lacrimation, rhinorrhoea Y Not attack, milder than a shadow and no CAS N N N/A 16
17 58 M ECH Y – L 10/10 Nasal congestion, rhinorrhoea, lacrimation, aural fullness, throat swelling Y L 7/10
VRS 2–3 (mod-severe) Nasal congestion, rhinorrhoea, voice change, lacrimation Y Y Suma 1
18 43 M CCH Y – L (70%) Mild 6/10, severe 10/10 Nasal congestion, periorbital oedema, aural fullness, facial flushing Y L Mild,
VRS 1 Nasal congestion Y Y- shadow O2 7
19 32 M ECH Y 600 L 10/10 Lacrimation, conjunctival injection, facial flushing Y L 7–8/10
VRS 2–3
(mod-severe) Lacrimation, eye grittiness, nasal congestion, facial flushing Y Y O2 <1
20 49 F ECH Y – R 10/10 Ptosis, periorbital oedema, lacrimation, nasal congestion, rhinorrhoea, (aural fullness with severe attacks) Y R 6–7/10
VRS 2 mod Nasal congestion, periorbital oedema, lacrimation, conjunctival injection Y Y O2 7
21 49 M CCH Y – R 4–10/10 Facial flushing, nasal congestion, ptosis, lacrimation, rhinorrhoea, conjunctival injection Y L 8/10
VRS 2–3
(mod-severe)
Facial flushing, lacrimation, periorbital oedema, conjunctival injection Y Y, but on L rather than R Suma <1
22 57 M CCH N – R 10/10 Lacrimation, conjunctival injection, nasal congestion, rhinorrhoea Y No attack, no pain and no CAS N N N/A 26
23 40 F CCH Y 640 L 10/10
Lacrimation, conjunctival injection, periorbital oedema, rhinorrhoea, ptosis, aural fullness Y Did not attend
24 44 M CCH N 720 R 10/10 Lacrimation, conjunctival injection, periorbital oedema, facial flushing Y Did not attend
25 23 F ECH Y – R 6–10/10 Nasal congestion, lacrimation, periorbital oedema. Rhinorrhoea and facial flushing with severe attacks Y R 7/10
VRS 2
(moderate) Nasal congestion, periorbital oedema Y Y O2 3
26 40 M CCH Y – L Shadow 4/10, daytime attacks 6–7/10, full attack 10/10 Ptosis, aural fullness, lacrimation, conjunctival injection, periorbital oedema, nasal congestion Y L 8.5–9/10
VRS 3 severe Nasal congestion, periorbital oedema, lacrimation Y Y Suma 3
27 20 F CCH N – R 8–9/10 Nasal congestion, lacrimation, rhinorrhoea, ptosis, aural fullness Y R 8/10
VRS 3
severe Nasal congestion, periorbital oedema Y Y O2 <1
28 31 F ECH Y – R 10/10 Nasal congestion, periorbital oedema, rhinorrhoea, ptosis, aural fullness Y R 2/10
VRS 1 (mild) Nasal congestion, facial swelling Y Y, but milder Suma 3
29 35 M ECH N – L Max pain 10/10 Nasal congestion, periorbital oedema, lacrimation, voice change (croaky). Facial flushing with severe attacks and rhinorrhoea after attack Y L 6–7/10
VRS 2 (moderate) Nasal congestion, lacrimation, conjunctival injection, voice change Y Y Suma <1
30 38 F CCH Y 240 L 4–10/10 Lacrimation, rhinorrhoea, conjunctival injection, facial flushing. Ptosis with severe attacks Y L 6–7/10
VRS 2 (moderate) Aural fullness Y Y Suma 1
31 49 M ECH Y 400 L 10/10 Nasal congestion, lacrimation, conjunctival injection, rhinorrhoea, ptosis, aural fullness. Prominent miosis after attack Y No attack, whole head felt heavy N N N/A 10
32 35 F CCH N 600 L 4/10 (on verapamil),
7/10 average Periorbital oedema, eye grittiness, facial flushing, lacrimation Y L 7/10
VRS 2–3
(mod-severe) Nasal congestion, conjunctival injection, facial flushing, lacrimation Y Y Suma 1
33 32 M CCH Y – L Severe attacks 10/10 Lacrimation, ptosis, nasal congestion, conjunctival injection, ptosis, facial flushing, eye grittiness Y L 6/10
VRS 2 (mod-severe) Lacrimation, nasal congestion, ptosis Y Y Suma <1
Figure 4. (a) Kaplan-Meier graph comparing time until cluster headache attack between the eight episodic cluster headache (ECH) and the 11 chronic cluster headache (CCH) subjects during single-blinded nitroglycerin (NTG) infusion, from the start of the infusion in minutes, log-rank P = 0.534. (b) Kaplan-Meier graph comparing time until cluster headache attack onset between the open unblinded (n = 33) and single-blinded (n =25) nitroglycerin (NTG) infusions with single-blinded placebo infusions (n = 24). Log-rank P = 0.000.
The median onset time to an induced attack was 33 minutes (IQR 15–42) from the start of the single-blinded NTG infusion, and in the single-blinded placebo visit only one subject developed an attack; the onset time was 10 minutes. On comparison of the attack onset time for the unblinded NTG, single-blinded NTG and single-blinded placebo visits, there was a difference between the placebo and NTG visits (P = 0.000, Figure 4(b)).
NTG headache
The majority of subjects developed an NTG headache (n = 28, 85%) following the NTG infusion in the unblinded open visit, of which 27 subjects had a migraine diagnosis (n = 18), had migraine markers (n = 10) and a family history of migraine (n = 18); only one subject did not have migraine, migraine markers or a family history of migraine. The median time from the start of NTG infusion was 3 minutes (IQR 2–6), and the median duration of NTG headache was 26 minutes (IQR 14–41).
Of the 25 subjects that went on to the single-blinded NTG visits, 18 (72%) developed NTG headache following NTG infusion, of which all had either migraine (n = 11), migraine markers (n = 7) or family history (n = 10). The median time of NTG headache onset from the start of NTG infusion in the blinded visit was 4 minutes (IQR 3–8), with a median duration of 26 minutes (IQR 9–45).
In the placebo visit, three of the 24 subjects (13%) developed NTG headache, median onset time was 13 minutes (range 1–18), and the median duration was 10 minutes (range 3–16).
Non-headache symptoms
The majority of subjects reported non-headache symptoms in both the open unblinded NTG visit (n = 30, 91%) and the single-blinded NTG visit (n = 21, 84%) visits. In the single-blinded placebo visit, eight subjects (33%) reported non-headache symptoms. The most common non-headache symptoms from the open unblinded NTG visit were neck stiffness, photophobia, thirst and allodynia. The most common non-headache symptoms from the single-blinded NTG visit were neck stiffness, yawning, thirst and photophobia (Table 4). The median number of non-headache symptoms reported in the open unblinded NTG visit was three (IQR 2–5), and from the single-blinded NTG visit was three (IQR 2–6), compared with two (IQR 2–3) on-headache symptoms in the single-blinded placebo group.
Table 4. Frequencies of non-headache symptoms reported during each visit.
Non-headache symptom Open unblinded NTG visit (n = 33) Single-blinded NTG visit
(n = 25) Single-blinded placebo visit
(n = 24)
Thirst 15 10 3
Craving 0 0 0
Yawning 8 12 4
Tiredness 4 3 0
Mood changes 5 4 1
Visual blurring 4 3 1
Neck stiffness 21 15 3
Irritability 3 3 0
Photophobia 18 10 1
Concentration difficulties 6 4 1
Phonophobia 4 6 0
Urinary symptoms 0 0 0
Speech disturbances 0 0 0
Nausea 6 3 0
Gastrointestinal discomfort 0 0 0
Movement sensitivity 5 5 1
Allodynia 9 8 2
In the open unblinded NTG visit, the median onset time of non-headache symptoms from the start of the infusion was 9 minutes (IQR 4–17) with the median maximum duration of the symptoms being 50 minutes (IQR 24–64), the duration is calculated from the first symptom until the end of the last symptom. In the single-blinded NTG visit, the median onset time was 5 minutes (IQR 3–9) from the start of the infusion, and the median maximum duration of symptoms was 59 minutes (IQR 35–76). The outlier was a subject who developed allodynia and neck stiffness during their attack. For those that developed non-headache symptoms during the single-blinded placebo visit, the median onset time was 9 minutes (IQR 2–9), with a median duration of 16 minutes (IQR 6–34).
Cranial autonomic symptoms
NTG triggered CAS in the majority of the subjects during the open unblinded NTG visit (n = 31, 94%). In all, five subjects out of the 31 (19%) developed unilateral CAS; however, they did not have a cluster headache attack. Two subjects had CAS with generalised headache, one had CAS without any pain, one subject developed CAS on the contralateral side to their attacks with mild generalised pain, and one subject with CAS developed restless leg symptoms, but no cluster headache attack. Of the subjects who developed unilateral CAS and cluster headache attack (n = 26, 79%), the median number of CAS was four (IQR 2–5), with the most common CAS being nasal congestion (n = 21), lacrimation (n = 16) and periorbital oedema (n = 15) (Table 5).
Table 5. Frequencies of cranial autonomic symptoms reported in subjects who had attacks following NTG infusion.
Cranial autonomicsymptoms Open unblinded NTG visit, total number of attacks (n = 26) Single-blinded NTG visit, total number of attacks (n = 19)
Lacrimation 16 11
Conjunctival injection 12 9
Periorbital oedema 15 8
Eye grittiness/itchiness 3 3
Nasal congestion 21 16
Rhinorrhoea 2 1
Ptosis 4 1
Aural fullness 5 2
Facial flushing 7 4
Sialorrhoea 1 0
Throat swelling 2 0
Voice change 4 2
Facial swelling 3 1
Similarly, NTG brought on CAS in the majority of subjects during the single-blinded NTG visit (n = 21, 84%), of which two were not accompanied by a cluster headache attack, compared with four out of 24 in the single-blinded placebo group developing CAS (Figure 5(a)). One of the subjects from the single-blinded NTG group had a generalised headache similar to a hangover headache with unilateral CAS, and the other subject had a migraine-like headache with CAS. Of the 19 subjects (76%) that had unilateral CAS and a cluster headache attack, the median number of symptoms was three (IQR 2–4) and the most frequent symptoms were nasal congestion (n = 16), lacrimation ( n = 11) and conjunctival injection (n = 9) (Table 5). In comparing the time until all CAS onset between ECH and CCH after blinded NTG infusion, there was no difference between the two groups (log-rank P = 0.740; Figure 5(b)).
Figure 5. (a) Kaplan-Meier graph showing time until onset of cranial autonomic symptoms (CAS) following open unblinded (n = 33) and single-blinded NTG (n = 25) infusions compared with the single-blinded placebo infusion (n = 24). Log-rank P = 0.000. (b) Kaplan-Meier graph showing the time until CAS onset in the single-blinded NTG visit, comparing episodic cluster headache (ECH) with chronic cluster headache (CCH). Log-rank P = 0.740.
The median time until CAS onset for those that developed cluster headache attacks was 31 min (IQR 13–46) in the open unblinded NTG visit and 12 min (IQR 6–30) in the single-blinded NTG visit. Subjects sequentially reported CAS development.
During the single-blinded placebo visit, four subjects (17%) developed unilateral CAS, of which one subject developed a spontaneous attack, and three developed CAS but no pain. The median number of symptoms reported in the placebo group was two (IQR 1–2) and the symptoms reported were nasal congestion (n = 2), conjunctival injection (n = 1), periorbital swelling (n = 1), rhinorrhoea (n = 1) and aural fullness (n = 1).
Agitation
Nitroglycerin brought on agitation in the majority of subjects, open unblinded NTG visit (n = 24, 73%) and single-blinded NTG visit (n= 20, 80%), compared with none in the single-blinded placebo visit.
Non-headache symptoms post-attack
The non-headache symptoms were not studied here, as all attacks were treated with sumatriptan or oxygen after 20 minutes, thus altering the natural progression and development of symptoms.
Episodic cluster headache compared with chronic cluster headache
For the subjects that developed an NTG-induced attack following the single-blinded NTG infusion, the time until NTG-induced attack was shorter in the episodic cluster headache group compared with the chronic cluster headache group (U = 15, z = −2.399, P = 0.016). The time until CAS onset, in the subjects that developed CAS following single-blinded NTG infusion was not different between episodic cluster headache and chronic cluster headache groups (U = 38, z = −1.2000, P = 0.230).
Effect of verapamil on NTG triggering
There were seven subjects on verapamil that attended the single-blinded NTG visits, of which two did not develop NTG-triggered cluster headache attacks (29%). Using χ2, there was no difference between verapamil and NTG triggering (χ2 (df = 1) = 0.111, P = 0.739).
Effect of migraine on NTG-triggered attacks
Within the cohort that attended the single-blinded NTG visits, 15 had migraine (60%). There was no difference between the number of non-headache symptoms (U = 67, z = −0.449, P = 0.654) or number of CAS (U = 57, z = −1.019, P = 0.308), between the subjects with migraine and those without migraine. Furthermore, there was no association between subjects with migraine and NTG triggering (χ2 (df = 1) = 0.146, P = 0.702); similarly, there was no association between subjects with migraine and development of NTG headache (χ2 (df = 1) = 0.033, P = 0.856).
Discussion
This study demonstrates that weight-calculated intravenous NTG effectively triggers cluster headache attacks in both chronic cluster headache and episodic cluster headache subjects within bout when compared with placebo. The approach is reliable in terms of triggering a fully-featured attack that allows careful observation of symptoms and their development during acute attacks of cluster headache.
The benefit of weight-calculated intravenous NTG compared to intranasal and sublingual administration is that this is more reliable and has more stable bioavailability. The median time until cluster headache attack onset was 30 minutes (open unblinded NTG visit) and 33 minutes (single-blinded NTG visit), with the overall maximum onset time of 81 minutes. Subjects who did not develop an attack during the 140 minutes of observation were asked to report if they developed an attack later on that day, and none did. The median onset time is similar to the reported latency period reported in the literature (Table 1). The minimum onset time for NTG-induced attacks was 2 minutes, and this is less than reported from the sublingual route, where the shortest time until onset time was 9 minutes (8); this is expected, given the intravenous route has a half-life of 2.3–2.8 minutes (30,31). Two subjects started experiencing mild attack pain before the start of the NTG infusion, and within the placebo group we observed one subject who developed a spontaneous attack. Spontaneous attacks could be anticipated given the subjects are within bout; there were three subjects with only short-lasting CAS symptoms and two subjects who experienced a mild pain without CAS, similar to a shadow.
This study delineates the development of the various stages of an NTG-induced cluster headache attack, including the non-headache symptoms and CAS (Figure 6). The majority of subjects developed NTG headache shortly after the infusion started. This headache was generalised, mild and progressive in nature, predominantly in the bi-occipital and bi-temporal regions. Subjects described it as pressure-like or band-like ache, and they reported it to be distinct from their cluster headache attacks; if there were an overlap, the cluster headache attack would clearly ramp up and supersede the NTG headache. It is difficult to disentangle whether NTG headache developed because there was a high proportion of subjects with either a migraine diagnosis, migraine marker or family history of migraine. However, from a previous study with 25 healthy volunteers without a migraine diagnosis, 16 (64%) developed NTG headache following 0.5 mg NTG sublingual administration (32).
Figure 6. Violin plots of the stages of cluster headache attack from the 19 subjects that developed cluster headache attacks and subdivided by chronicity. The timeline starts with 20 minutes of single-blinded nitroglycerin (NTG) infusion, followed by 120 minutes of post-infusion observation. CAS = cranial autonomic symptoms.
Following the NTG headache, the majority of subjects reported non-headache symptoms in the lead-up to the onset of the pain from the attack and in some subjects, non-headache symptoms accompanied their attacks. The non-headache symptoms included homeostatic symptoms (thirst, cravings, yawning, frequency of urination), fatigue/cognitive symptoms (concentration difficulty, fatigue, memory impairment, mood changes, irritability) and sensitised sensory symptoms (neck stiffness, photophobia, phonophobia, osmophobia, nausea), as are reported in the premonitory phase of migraine (33). The most common symptoms were neck stiffness, photophobia and thirst. During their spontaneous attacks, subjects reported that non-headache symptoms would precede the attack at a median of 10 minutes (IQR 2–30) before the onset of pain, although it is known that there are discrepancies between retrospective and prospective reporting (25). Comparing the symptoms observed from NTG-induced attacks in this study with the prospective observational questionnaire study (24), the most reported general symptoms in the pre-pain phase in this study were concentration difficulties, photophobia and mood changes. Patients in the observational study also reported general symptoms during their attacks and postictal symptoms similar to the symptoms seen during the NTG-induced attacks and the reported symptoms by the subjects in this study during the postdrome phase of their spontaneous attacks. Non-headache symptoms such as photophobia, phonophobia, and localised allodynia were often reported during the attacks, as has been reported previously (21,34). In one semi-structured questionnaire study, they found a high proportion of cluster headache patients (73.2%) reported phonophobia or photophobia with their attacks (35), cluster headache patients with migraine did not more frequently report these symptoms compared with those without co-existing migraine. Furthermore, allodynia was more often reported in cluster headache patients with migraine. From pre-clinical studies, high dose NTG causes a sustained increase in spontaneous firing of Aδ and C-fibre trigeminal neurons (36), which migraine biology may unmask.
Similar to the prospective questionnaire study by Snoer and colleagues (24), in some subjects CAS presented before the onset of the attack pain (Figure 6). In this study, the median onset time for CAS was 31 minutes (IQR 13–46) in the open unblinded NTG visit and 12 minutes (IQR 6–30) in the single-blinded NTG visit, whereas the onset of NTG-induced attack was 30 minutes (IQR 20–39) in the open unblinded visit and 33 minutes (IQR 15–42) in the single-blinded NTG visit. From the open unblinded NTG visit, 38% presented with CAS before the attack, 15% presented with CAS with the onset of the attack, and from the single-blinded NTG visit, 58% presented with CAS before the attack and 16% presented with CAS with the onset of the attack.
Vollesen and colleagues used calcitonin gene-related peptide (CGRP) infusion to trigger cluster headache attacks, finding CGRP induced 50% of subjects with CCH and 89% for ECH subjects in bout (4). In our study, NTG induced attacks in 79% of the CCH subjects and 84% in ECH subjects in bout, in the open unblinded NTG visits, and 92% CCH and 62% ECH in bout in the single-blinded NTG visits. There are some differences in the number of chronic cluster headache subjects on verapamil between the studies; in this study, 33% of CCH subjects were on verapamil and in the study by Vollesen and colleagues, 57% of CCH subjects were on verapamil (of which one was on both verapamil and lithium) and one was on 4 mg melatonin. Vollesen and colleagues proposed that the CCH patients who did not develop an attack following CGRP infusion had a lower median attack frequency in the preceding 30 days prior to the study compared to the CCH patients that did develop an attack. However, in this study, subjects reported having their last attack as long ago as 128 and 158 days and still had NTG-induced attacks (Table 3).
NTG is a pro-drug of nitric oxide (NO) and has effects on blood vessel dilation through mechanisms of the NO-cyclic guanylate phosphate (cGMP) pathway (27). However, the vasodilatory effects of NTG are not sufficient to explain the cluster headache attack that occurs after a latency and the central features associated with the attack. Indeed, experimental studies demonstrate that NTG has central effects (37,38). Interestingly, in studies where NO donors were administered in vivo and in vitro, there was a local release of CGRP (39–42). The difference in the rate of cluster headache attacks induced by NTG and CGRP in ECH and CCH subjects could reflect in part the underlying biological processes and systems that are more active in the different subtypes of cluster headache. The difference between ECH and CCH is also suggested by the treatment response to a CGRP monoclonal antibody, galcanezumab (43,44), and non-invasive vagal nerve stimulator (45,46).
Limitations
The main limitations to the study were the recruitment of eligible subjects and the dropout rate at each stage due to the nature of the condition. Therefore, a pragmatic approach was taken with the study design regarding randomisation. Although there was a randomisation sequence, this was modified by the investigator if deemed necessary. This would be in the case of episodic cluster headache patients that were near the end of their bout missing the NTG visit if they followed the randomised sequence. For this reason, it was designed to be a single-blind cross-over study and not a double-blind and randomised study. Expectation bias was reduced by maintaining blinding of the subjects until the end of the study and having both infusions identical in volume, appearance and duration of infusion. Furthermore, given the stark difference between placebo and NTG, there was no difference between attack onset in the open unblinded compared with the single-blinded NTG visits (Figure 4(b)), is an indication that randomisation was not a factor in this study.
Conclusion
We present the results of the first placebo-controlled study using intravenous NTG administration to systematically study NTG-induced cluster headache attacks. We have shown that NTG can reliably bring on cluster headache attacks as well as the development of non-headache symptoms and CAS. This study highlights differences between NTG-induced attack onset times between the ECH and CCH subjects. Understanding the stages of cluster headache is essential; by recognising the non-headache symptoms in the lead up to the onset of pain and the underlying pathogenesis of this, we may be able to uncover new therapeutic targets to abort attacks before the onset of the severe and devastating pain experienced by our cluster headache patients.
Article highlights
Weight-calculated standardised intravenous nitroglycerin administration is a reliable method to induce cluster headache attacks, cranial autonomic symptoms and non-headache symptoms that accompany cluster headache attacks.
Accompanying non-headache symptoms in cluster headache attacks are important to recognise for both clinical and research purposes.
There may be inherent differences between episodic cluster headache and chronic cluster headache.
Acknowledgement
This study would not have been possible without the support of OUCH(UK), all the cluster headache patients who were interested in helping us with this study and all the subjects who took part in this study.
Ethics or Institutional Review Board approval: This study 16/LO/0693 obtained approval from the London, City & East NHS Research Ethics Committee on 23 June 2016. This study was carried out in accordance with the World Medical Association Declaration of Helsinki (1964), the Research Governance Framework for Health and Social Care (2nd edition, 2005), the Data Protection Act (1998) and the Principles of Good Clinical Practice (GCP); all subjects gave informed consent before taking part.
Declaration of conflicting interests: The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: DYW no reported competing interests. PJG reports, over the last 36 months, grants and personal fees from Amgen and Eli-Lilly and Company, grant from Celegene, and personal fees from Alder Biopharmaceuticals, Aeon Biopharma, Allergan, Biohaven Pharmaceuticals Inc., Clexio, Electrocore LLC, eNeura, Epalex, GlaxoSmithKline, Impel Neuropharma, MundiPharma, Novartis, Pfizer, Praxis, Sanofi, Santara Therapeutics Satsuma, Teva Pharmaceuticals, Trigemina Inc., WL Gore, and personal fees from MedicoLegal work, Massachusetts Medical Society, Up-to-Date, Oxford University Press, and Wolters Kluwer; and a patent magnetic stimulation for headache assigned to eNeura without fee.
Funding: The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study is part-funded by the National Institute for Health Research (NIHR) Maudsley Biomedical Research Centre at South London Maudsley Foundation Trust and King’s College London. The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care.
ORCID iDs: Diana Y Wei https://orcid.org/0000-0003-0644-7172
Peter J Goadsby https://orcid.org/0000-0003-3260-5904 | NITROGLYCERIN | DrugsGivenReaction | CC BY | 33615843 | 19,017,453 | 2021-07 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Nasal congestion'. | Comprehensive clinical phenotyping of nitroglycerin infusion induced cluster headache attacks.
Nitroglycerin administration allows the study of cluster headache attacks in their entirety in a standardised way.
A single-blind, placebo-controlled, cross-over study using weight-calculated intravenous nitroglycerin administration at 0.5 µg/kg/min over 20 minutes to study cluster headache attacks, including accompanying non-headache symptoms and cranial autonomic symptoms.
Thirty-three subjects with cluster headache were included in the study; 24 completed all three study visits. Nitroglycerin-induced attacks developed in 26 out of 33 subjects (79%) receiving unblinded nitroglycerin infusion, and in 19 out of 25 subjects (76%) receiving single-blinded nitroglycerin infusion, compared with one out of 24 subjects (4%) receiving single-blinded placebo infusion. Episodic cluster headache subjects had a shorter latency period to a nitroglycerin-induced attack compared to the chronic cluster headache (CCH) subjects (U = 15, z = -2.399, p = 0.016). Sixteen of nineteen episodic cluster headache (mean, 84%; 95% confidence interval, 66-100%) and 11 of 14 chronic cluster headache subjects developed a nitroglycerin-induced attack (79%, 54-100%) following the unblinded nitroglycerin infusion. Following the single-blinded nitroglycerin infusion, eight out of 13 episodic cluster headache (62%, 31-92%) and 11 out of 12 chronic cluster headache (92%, 73-100%) subjects developed nitroglycerin-induced attacks. Nitroglycerin induced non-headache symptoms in the majority of subjects receiving it: 91% in the open unblinded nitroglycerin visit and 84% in the single-blinded nitroglycerin visits, compared with 33% in the single-blinded placebo visit. Cranial autonomic symptoms were induced by nitroglycerin infusion, 94% in the open unblinded nitroglycerin visit and 84% in the single-blinded nitroglycerin visit, compared with 17% in the single-blinded placebo visit.
Intravenous weight-adjusted nitroglycerin administration in both episodic cluster headache in bout and chronic cluster headache is effective and reliable in inducing cluster headache attacks, cranial autonomic symptoms and non-headache symptoms.
Introduction
Due to the episodic nature of acute attacks of cluster headache, a standardised and reliable method for triggering attacks is necessary for their complete study. There have been several substances used to trigger attacks, including histamine (1,2), meta-chloro-phenylpiperazine (mCPP) (3) and more recently calcitonin gene-related peptide (CGRP) (4). Nitroglycerin (NTG) is the most frequently employed substance in human experimental modelling of cluster headache attacks, being used since 1953 (2) (Table 1).
Table 1. Review of studies using nitroglycerin to induce cluster headache attacks.
Study Number of CH patients NTG dose and route Control Placebo Rate of induced CH attack Latency period before onset of headache
(range in minutes)
Peters 1953 (2) 14 1.3 mg sublingual No, but compared with migraine, combination of CH and migraine, vasodilating head pain and tension headache No, but compared with histamine and nicotinic acid 78.6% Not reported
Ekbom 1968 (5) 38 ECH: 28 in bout, 15 out of bout (of which five were tested in bout as well) 1 mg sublingual No No In bout ECH 100% (n = 28)
Out of bout 0% (n = 15) 12–72
Barre 1982 (6) 10 CH: two CCH, nine ECH in bout 1 mg sublingual No No 100% 34–52
Mean 45.9
Drummond et al. 1984 (7) 29 CH 0.9 mg sublingual No No 76% Within 90 min
Drummond et al. 1985 (8) 22 CH: 10 CCH, 12 ECH in bout
0.9 mg sublingual Yes, 10 in the control group without headache No ECH 75% (n = 9)
CCH 60% (n = 6) 9–90
Mean 44
Bogucki 1990 (9) 21 ECH in bout 1 mg sublingual No No 67% (n = 14)
30–65
Dahl et al. 1990 (10) 15 ECH in bout 1 mg sublingual 10 healthy controls No 53% (n = 8)
Controls: not reported 30–65
Hannerz et al. 1992 (11) Eight ECH: five in bout and three out of bout 1 mg sublingual No No In bout ECH 100% (n = 5) Not reported
Fanciullacci et al. 1995 (12) 18 in bout ECH, 12 out of bout ECH 0.9 mg sublingual No No In bout ECH 100% (n = 18)
Out of bout ECH 0% (n = 12) 39–86
Fanciullacci et al. 1997 (13) 11 in bout ECH, eight out of bout ECH 0.9 mg sublingual No No In bout ECH 100% (n = 11)
Out of bout ECH 0% (n = 8) 18–50
Hsieh et al. 1996 (14) Seven ECH: four in bout ECH, three out of bout 1 mg sublingual No No In bout ECH 100%
Out of bout ECH 0% 18–35
May et al. 1998 (15) Nine CCH, eight out of bout ECH 1.0–1.2 mg spray No No CCH 100%
Out of bout ECH 0% Not reported
Costa et al. 2000 (16) 15 CH: Six ECH, nine CCH 0.9 mg sublingual No No ECH 33% (n = 2)
CCH 78% (n = 7) 19–41
Costa et al. 2003 (17) 18 ECH in bout 0.9 mg sublingual Yes, 12 healthy sex and age-matched No ECH 67% (n = 12)
Controls 0% 19–41
Sances et al. 2004 (18) 42 CH: 29 ECH (11 out of bout), 13 CCH 0.9 mg sublingual Yes, 53 healthy controls No In bout ECH and CCH 81% (n = 25 out of 31)
Controls 7.5% developed headache in 7-hour post-NTG Mean onset latency of 65.4 ± 54.7
Cluster headache patients suffer from recurrent episodes of severe unilateral pain in the trigeminal region; therefore, historically, the main emphasis has been centred around the pain onset of a cluster headache, and indeed this is often used as the indicator of the start of the attack. However, from clinical practice, there has been growing awareness of nonpainful symptoms preceding the onset of pain (19,20) and in recent years, the clinical phenotype of cluster headache has been further characterised by retrospective accounts (21–23) and prospective diaries (24,25).
The most frequent route of administration of NTG has been sublingual; however, the bioavailability of sublingual NTG is extremely variable (26). Therefore, we used a weight-calculated dose for intravenous infusion in a standardised single-blind, placebo-controlled study. NTG is a pro-drug of nitric oxide, with predominant actions on the cyclic guanylate phosphate (cGMP) pathway (27), and from pre-clinical studies there are indications of neural actions more centrally. This study is the first single-blind, placebo-controlled cross-over study using a weight-adjusted dose of nitroglycerin administered intravenously in cluster headache patients, thereby allowing comprehensive investigation of the various stages of the acute attack of cluster headache.
Methods
Subject selection and recruitment
The study was advertised on the UK cluster headache patient website OUCH (UK) (Organisation for the Understanding of Cluster Headache UK) (https://ouchuk.org/research/research-volunteers-needed) and in the tertiary Headache centre in King’s College Hospital, London. Subjects interested in participating would make contact via a dedicated research email. Subjects would then be screened for eligibility for the study via emails and a telephone call; those who met the criteria and were interested in participating were invited to attend the study visit. The study was approved by the London, City & East Research Ethics Committee (Ref Number 16/LO/0693). Data were collected from August 2016 until January 2019.
The subjects enrolled fulfilled the ICHD-3 beta criteria for cluster headache (28), and were between the ages of 18 and 60, with no significant previous medical history and no previous syncope or history of autonomic dysfunction. They had had a reliable response to high flow oxygen and/or subcutaneous sumatriptan during spontaneous attacks and normal brain neuroimaging. Women in child-bearing age were required to use reliable contraceptive methods during the study. Subjects were excluded if they were pregnant or breastfeeding, and who had any significant psychiatric disease, diagnosis of another primary headache type (other than migraine) or chronic pain syndrome, any medical history that would have contraindications to receiving NTG, use of preventive medication other than verapamil, or taking indomethacin for any reason, allergies to the medications used in the study or intolerance to high flow oxygen, and use of illicit drugs during the study.
Study visits
The study comprised of three visits in total, with each visit separated by a minimum of 1 week. During the first visit, subjects consented and a full headache history with a physical examination of the neurological and cardiovascular systems was performed, along with recordings of the baseline blood pressure, lying and standing blood pressure, heart rate, oxygen saturation, weight and electrocardiogram. Female subjects were required to have a urinary pregnancy test before the start of the infusion.
Open NTG infusion
If deemed eligible, subjects received an intravenous infusion of nitroglycerin at 0.5 µg/kg/min over 20 minutes. Subjects remained recumbent for 30 minutes before the infusion, and after the NTG infusion, subjects received 250 mL of 0.9% sodium chloride intravenously. The blood pressure and pulse were checked at the start of the infusion, and every 5 min during the infusion.
Phenotypic characterisation
Every 5 minutes, subjects were asked to rate their pain level from a scale from no pain, mild, moderate to severe, where severe equates to their most severe attack, and they were asked a questionnaire of non-headache symptoms and cranial autonomic symptoms (CAS) (Figure 1). If the subject experienced pain, further details were obtained regarding the location and characteristic. Beyond the cluster headache attack, subjects were asked to report any other headache types and in particular NTG headache, which has been well described from migraine studies (29). The NTG headache was assessed for severity, phenotype, accompanying non-headache symptoms and duration. Subjects were actively encouraged to report any symptoms as and when they developed. Following the infusion, at 10 minute intervals, any developments in pain, non-headache symptoms and CAS were recorded for a total of 120 minutes after the infusion, based on the latency period reported from previous studies (Table 1).
Figure 1. Questionnaire for non-headache and cranial autonomic symptoms.
B: bilateral; R: right-sided; L: left-sided.
Single-blinded NTG and placebo infusions
During the two single-blinded visits, subjects either received intravenous nitroglycerin at 0.5 µg/kg/min over 20 minutes or an equal volume of 0.9% sodium chloride at the same rate over 20 minutes, followed by the same 120 minutes of observations (Figure 2). The sequence was pre-determined using the randomise function in Excel; however, the investigator was able to amend this in certain situations if the subject was episodic and due to finish their bout.
Figure 2. Outline of events from open unblinded nitroglycerin visit.
BP: blood pressure; CAS: cranial autonomic symptoms; NTG: nitroglycerin; IV: intravenous.
Treatment of acute attacks
Acute treatment was administered at 20 minutes from the start of attack either with sumatriptan 6 mg subcutaneous injection (Imigran 6 mg/0.5 ml solution for injection pre-filled syringes, GlaxoSmithKline UK Ltd, or sumatriptan 6 mg/0.5 ml solution for injection pre-filled pens, Sun Pharmaceuticals Industries Europe B.V.) or with 15 L/min oxygen via a non-rebreather mask (O2Star™ non-rebreather oxygen mask M/L, Dräger). The visit was concluded only when the subject was pain free.
Statistical analysis
The data was tabulated (Excel for Mac v 16.30), and descriptive statistics were performed to summarise data (SPSS Statistics version 26 for Mac and Excel). Mann-Whitney tests were performed on time until attack onset and time until CAS onset for those that developed NTG-triggered cluster headache attacks and CAS, comparing the differences in ECH with CCH subgroups. Kaplan-Meier survival graphs were used to examine the time until onset of event; that is, survival of no cluster headache attack status, or absence of CAS after NTG infusion for 140 minutes (20 minutes of infusion and 120 minutes of post-infusion observation), with log-rank statistical testing; P < 0.05 was considered significant. Graphs were made using SPSS and violin plots were made using GraphPad Prism 8 for Mac OS.
Results
Demography
A total of 229 subjects were contacted to check for eligibility, of which 33 were included in the study; 24 completed all three study visits (Figure 3). All patients fulfilled the ICHD-3 beta criteria for cluster headache, 19 episodic cluster headache in bout (58%) and 14 chronic cluster headache (42%) (Table 2). The majority were male (n = 24, 73%) with a male: female ratio of 3:1. The average age was 41 (SD 10), with the mean age of females (34 years, SD 9) younger than in males (44 years, SD 9) in this cohort. Subjects had had the condition for a median of 9 years (IQR 5–16).
Figure 3. Subject numbers throughout the study.
Table 2. Subject characteristics.
Subject Age Sex Subtype Side of attacks Time since first attack (years) Average attack frequency (per day) Average attack duration when untreated (mins) Average bout duration (weeks) Verapamil (total daily dose in mg)
1 55 M Chronic Right 5 2 45 – 480
2 28 F Chronic Right 12 7 150 – –
3 40 M Episodic Right 20 3 150 8 –
4 38 F Episodic Left 12 2 120 4 –
5 53 M Chronic Left 15 4 35 – 960
6 48 M Episodic Left 25 5 52.5 5 480
7 23 M Episodic Left 8 2 120 10 –
8 43 M Chronic Right 9 1 40 – –
9 43 M Episodic Right 13 3 60 5 240
10 44 M Episodic Right 27 6 45 6 –
11 47 M Episodic Right 3 1 105 20 –
12 48 M Episodic Left 26 3 180 10 560
13 40 M Episodic Right 5 3 60 8 –
14 50 M Episodic Right 10 2 105 8 –
15 56 M Episodic* Right 24 1 45 – –
16 35 M Episodic Left 7 2 150 6 240
17 58 M Episodic Left 3 1 135 24 –
18 43 M Chronic Left 4 2 60 – –
19 32 M Episodic Left 3 3 50 12 600
20 49 F Episodic Right 8 5 50 9 –
21 49 M Chronic Right 35 2 90 – –
22 57 M Chronic Right 20 5 65 –
23 40 F Chronic Left 4 1.5 120 – 640
24 44 M Chronic Right 6 2 90 – 720
25 23 F Episodic Right 9 2.5 90 6 –
26 40 M Chronic Left 17 1.5 180 – –
27 20 F Chronic Right 6 1.5 150 – –
28 31 F Episodic Right 14 2 75 11 –
29 35 M Episodic Left 9 2 90 3 –
30 38 F Chronic Left 6 1.5 180 – 240
31 49 M Episodic Left 0.5 1.5 37.5 21 400
32 35 F Chronic Left 4 0.3 30 – 600
33 32 M Chronic Left 10 6 60 – –
M: male; F: female.
*Subject was chronic but became episodic during study with no attacks in 6 months.
Clinical phenotyping of subjects by history
Pain features
There was a near-equal split between the laterality of attacks; 17 subjects had right-sided attacks (52%), and 16 subjects had left-sided attacks (49%). The median number of attacks per day was two (IQR 1.5–3) lasting a median of 90 minutes (IQR 50–128). Verapamil was the only preventive allowed on the study; 12 subjects (36%) were on verapamil ranging from 240 mg to 960 mg per day.
Migraine, accompanying features and non-headache symptoms in spontaneous attacks
In this cohort, 58% (n = 19) had a concurrent migraine (28): five had migraine with aura, of which four had visual aura and one had facial sensory aura. Of the subjects who did not meet the diagnostic criteria for migraine (28) (n = 14, 42%), the majority had either migraine markers and/or a family history of migraine. Migraine markers were defined if subjects experienced: childhood cyclic nausea and vomiting, motion sickness, cold stimulus-induced headache, hangover headache and jetlag. Four subjects did not have migraine markers, and three subjects (9%) did not have either migraine marker or a family history of migraine. Subjects (n = 24, 73%) reported accompanying symptoms with their spontaneous attacks, the most common symptoms being cranial allodynia (n = 15), photophobia (n = 15), nausea (n = 11) and phonophobia (n = 10).
Non-headache attack symptoms
The majority reported non-headache symptoms in the lead up to their spontaneous cluster headache attacks (n = 27, 82%), with the commonest symptoms being concentration difficulties (n = 18), mood changes (n = 15), neck stiffness (n = 13) and yawning (n = 8). The median onset time of symptoms was 10 minutes (IQR 2–30) before the onset of pain. Although most symptoms start before the onset of pain, five subjects only reported developing the symptoms during the attack.
Twenty-eight subjects reported non-headache symptoms following their cluster headache attacks (85%), the commonest symptoms being tiredness (n = 27), mood changes (n = 13), concentration difficulties (n = 12), and neck stiffness (n = 7). The median duration of symptoms was 120 minutes (IQR 53–315).
Attack triggers
The most commonly reported triggers for spontaneous attacks were alcohol ingestion (n = 22), followed by changes in temperature (n = 12), strong smells such as from nail varnish, paint (n = 11) followed by disrupted sleep (n = 4) and exercise (n = 3). Other triggers mentioned were stress (n = 2), caffeine (n = 2), changing time zones (n = 1), let down from stress (n = 1), being in a pressurised cabin on an airplane (n = 1), vardenafil (n = 1), and dehydration (n = 1). All subjects reported attacks within a few hours of alcohol ingestion, no one reported a next-day effect.
Clinical phenotyping of open NTG visit
NTG triggered cluster headache-like attacks (n = 26, 79%), CAS (n = 31, 94%) and agitation (n = 24, 73%) during the open unblinded NTG visit. In the episodic cluster headache group, 16 out of 19 developed an NTG-induced attack (mean, 84%; 95% CI, 66–100%) and in the chronic cluster headache group, 11 out of 14 developed an NTG-induced attack (79%, 54–100%). Five out of the 31 subjects developed CAS, but did not develop an attack; of these subjects, three developed mild generalised pain, one developed restless legs, and one developed CAS on the contralateral side to the subject’s spontaneous attack phenotype, with a generalised headache. These cases were excluded.
The median onset time for CAS to develop from the start of the NTG infusion was 31 minutes (IQR 13–46). The median onset for an NTG-induced attack was 30 minutes (IQR 20–39) and the median time to maximum pain, if reached, was 51 minutes (IQR 39–70). The most common first cranial autonomic symptoms brought on by NTG infusion were nasal congestion (n = 10), conjunctival injection (n = 5), lacrimation (n = 4) and periorbital oedema (n = 3).
Clinical phenotyping of single-blinded NTG and placebo visit
During the single-blinded visits, NTG induced attacks in 19 subjects (76%); three subjects did not have an attack (12%), two subjects developed migraine-like headache (8%) and one subject developed unilateral mild pain without CAS or agitation (4%) (Table 3). In the placebo group, only one developed an attack (4%), two subjects developed unilateral mild pain without CAS or agitation (8%) and two subjects experienced short-lived unilateral CAS (8%). Of the subjects receiving NTG, eight out of 13 ECH (mean, 62%; 95% CI, 31%-92%) and 11 out of 12 CCH (92%, 73–100%) developed NTG-induced attacks (Figure 4(a)).
Table 3. Subject characteristics and comparison between spontaneous attack and triggered attack from single-blinded nitroglycerin visit, M = male, F = female, ECH = episodic cluster headache, CCH = chronic cluster headache, L = Left, R = Right, Y = Yes, N = No, VRS = verbal rating scale, mod = moderate, O2 = high flow oxygen via non-rebreather mask, suma = sumatriptan.
Subject Age Sex Subtype Migraine Verapamil (total daily dose in mg) Spontaneous attack Triggered attack- single-blinded NTG visit
Laterality Severity CAS Agitation Laterality Severity/VRS CAS Agitation Feels like spontaneous attack Treatment Last spontaneous attack (days)
1 55 M CCH N 480 R 9/10 Conjunctival injection, nasal congestion, lacrimation. 3 months of R Horner’s syndrome in 2007, now resolved Y R 10/10
VRS 3 Conjunctival injection, nasal congestion, lacrimation, periorbital oedema Y Y O2 158
2 28 F CCH Y
– R 10/10 Periorbital oedema/ptosis, nasal congestion, dry eye then lacrimation Y R 10/10
VRS 3 Periorbital oedema, nasal congestion, facial flushing Y Y O2 128
3 40 M ECH N – R 10/10 Lacrimation, rhinorrhoea, ptosis Y R 10/10
VRS 3 Lacrimation, conjunctival injection, periorbital oedema, nasal congestion, aural fullness and facial droop Y Y Suma 1
4 38 F ECH Y – L 10/10 Lacrimation, conjunctival injection, periorbital oedema, nasal congestion, ptosis, facial flushing Y No attack, developed generalised pain 4/10 Y N N/A 1
5 53 M CCH N 960 L 10/10 Rhinorrhoea, ptosis Y L 10/10
VRS 3 Conjunctival injection, eye grittiness, lacrimation Y Y O2 4
6 48 M ECH N
480 L 8/10 Nasal congestion, lacrimation Y Did not attend
7 23 M ECH Y – L 10/10 Lacrimation, conjunctival injection, nasal congestion, ptosis, facial flushing Y Did not attend
8 43 M CCH N – R 10/10 Nasal congestion, rhinorrhoea, lacrimation, facial flushing Y R 10/10
VRS 3 Nasal congestion, conjunctival injection, eye grittiness Y Y Suma <1
9 43 M ECH N 240 R 10/10 Lacrimation, conjunctival injection, facial flushing, ptosis, facial droop Y Did not attend
10 44 M ECH N – R 10/10 Nasal congestion, ptosis, periorbital oedema, lacrimation, flushing Y No attack, L mild hangover like headache, with nasal congestion.
After study visit felt nauseous and vomited, then slept, headache free at 7pm N N O2- no response <1
11 47 M ECH N – R Severe attacks 10/10 Nasal congestion, aural fullness Y R 7/10
VRS 2/3 moderate/
severe Nasal congestion, conjunctival injection, aural fullness Y Y Suma 13
12 48 M ECH N 560 L 10/10 Lacrimation, nasal congestion, periorbital oedema Y Did not attend
13 40 M ECH Y – R 10/10 Nasal congestion, ptosis, conjunctival injection, lacrimation, throat tightness, rhinorrhoea Y No attack, bilateral mild headache 4/10 with nasal congestion Y, brief (7 mins) N N/A 19
14 50 M ECH Y – R 10/10
Lacrimation, periorbital oedema, nasal congestion, rhinorrhoea Y Did not attend
15 56 M ECH Y – R 10/10 Lacrimation, rhinorrhoea, facial flushing, gritty eyes, conjunctival injection Y with severe attacks Did not attend
16 35 M ECH Y 240 L 10/10 Nasal congestion, conjunctival injection, ptosis, lacrimation, rhinorrhoea Y Not attack, milder than a shadow and no CAS N N N/A 16
17 58 M ECH Y – L 10/10 Nasal congestion, rhinorrhoea, lacrimation, aural fullness, throat swelling Y L 7/10
VRS 2–3 (mod-severe) Nasal congestion, rhinorrhoea, voice change, lacrimation Y Y Suma 1
18 43 M CCH Y – L (70%) Mild 6/10, severe 10/10 Nasal congestion, periorbital oedema, aural fullness, facial flushing Y L Mild,
VRS 1 Nasal congestion Y Y- shadow O2 7
19 32 M ECH Y 600 L 10/10 Lacrimation, conjunctival injection, facial flushing Y L 7–8/10
VRS 2–3
(mod-severe) Lacrimation, eye grittiness, nasal congestion, facial flushing Y Y O2 <1
20 49 F ECH Y – R 10/10 Ptosis, periorbital oedema, lacrimation, nasal congestion, rhinorrhoea, (aural fullness with severe attacks) Y R 6–7/10
VRS 2 mod Nasal congestion, periorbital oedema, lacrimation, conjunctival injection Y Y O2 7
21 49 M CCH Y – R 4–10/10 Facial flushing, nasal congestion, ptosis, lacrimation, rhinorrhoea, conjunctival injection Y L 8/10
VRS 2–3
(mod-severe)
Facial flushing, lacrimation, periorbital oedema, conjunctival injection Y Y, but on L rather than R Suma <1
22 57 M CCH N – R 10/10 Lacrimation, conjunctival injection, nasal congestion, rhinorrhoea Y No attack, no pain and no CAS N N N/A 26
23 40 F CCH Y 640 L 10/10
Lacrimation, conjunctival injection, periorbital oedema, rhinorrhoea, ptosis, aural fullness Y Did not attend
24 44 M CCH N 720 R 10/10 Lacrimation, conjunctival injection, periorbital oedema, facial flushing Y Did not attend
25 23 F ECH Y – R 6–10/10 Nasal congestion, lacrimation, periorbital oedema. Rhinorrhoea and facial flushing with severe attacks Y R 7/10
VRS 2
(moderate) Nasal congestion, periorbital oedema Y Y O2 3
26 40 M CCH Y – L Shadow 4/10, daytime attacks 6–7/10, full attack 10/10 Ptosis, aural fullness, lacrimation, conjunctival injection, periorbital oedema, nasal congestion Y L 8.5–9/10
VRS 3 severe Nasal congestion, periorbital oedema, lacrimation Y Y Suma 3
27 20 F CCH N – R 8–9/10 Nasal congestion, lacrimation, rhinorrhoea, ptosis, aural fullness Y R 8/10
VRS 3
severe Nasal congestion, periorbital oedema Y Y O2 <1
28 31 F ECH Y – R 10/10 Nasal congestion, periorbital oedema, rhinorrhoea, ptosis, aural fullness Y R 2/10
VRS 1 (mild) Nasal congestion, facial swelling Y Y, but milder Suma 3
29 35 M ECH N – L Max pain 10/10 Nasal congestion, periorbital oedema, lacrimation, voice change (croaky). Facial flushing with severe attacks and rhinorrhoea after attack Y L 6–7/10
VRS 2 (moderate) Nasal congestion, lacrimation, conjunctival injection, voice change Y Y Suma <1
30 38 F CCH Y 240 L 4–10/10 Lacrimation, rhinorrhoea, conjunctival injection, facial flushing. Ptosis with severe attacks Y L 6–7/10
VRS 2 (moderate) Aural fullness Y Y Suma 1
31 49 M ECH Y 400 L 10/10 Nasal congestion, lacrimation, conjunctival injection, rhinorrhoea, ptosis, aural fullness. Prominent miosis after attack Y No attack, whole head felt heavy N N N/A 10
32 35 F CCH N 600 L 4/10 (on verapamil),
7/10 average Periorbital oedema, eye grittiness, facial flushing, lacrimation Y L 7/10
VRS 2–3
(mod-severe) Nasal congestion, conjunctival injection, facial flushing, lacrimation Y Y Suma 1
33 32 M CCH Y – L Severe attacks 10/10 Lacrimation, ptosis, nasal congestion, conjunctival injection, ptosis, facial flushing, eye grittiness Y L 6/10
VRS 2 (mod-severe) Lacrimation, nasal congestion, ptosis Y Y Suma <1
Figure 4. (a) Kaplan-Meier graph comparing time until cluster headache attack between the eight episodic cluster headache (ECH) and the 11 chronic cluster headache (CCH) subjects during single-blinded nitroglycerin (NTG) infusion, from the start of the infusion in minutes, log-rank P = 0.534. (b) Kaplan-Meier graph comparing time until cluster headache attack onset between the open unblinded (n = 33) and single-blinded (n =25) nitroglycerin (NTG) infusions with single-blinded placebo infusions (n = 24). Log-rank P = 0.000.
The median onset time to an induced attack was 33 minutes (IQR 15–42) from the start of the single-blinded NTG infusion, and in the single-blinded placebo visit only one subject developed an attack; the onset time was 10 minutes. On comparison of the attack onset time for the unblinded NTG, single-blinded NTG and single-blinded placebo visits, there was a difference between the placebo and NTG visits (P = 0.000, Figure 4(b)).
NTG headache
The majority of subjects developed an NTG headache (n = 28, 85%) following the NTG infusion in the unblinded open visit, of which 27 subjects had a migraine diagnosis (n = 18), had migraine markers (n = 10) and a family history of migraine (n = 18); only one subject did not have migraine, migraine markers or a family history of migraine. The median time from the start of NTG infusion was 3 minutes (IQR 2–6), and the median duration of NTG headache was 26 minutes (IQR 14–41).
Of the 25 subjects that went on to the single-blinded NTG visits, 18 (72%) developed NTG headache following NTG infusion, of which all had either migraine (n = 11), migraine markers (n = 7) or family history (n = 10). The median time of NTG headache onset from the start of NTG infusion in the blinded visit was 4 minutes (IQR 3–8), with a median duration of 26 minutes (IQR 9–45).
In the placebo visit, three of the 24 subjects (13%) developed NTG headache, median onset time was 13 minutes (range 1–18), and the median duration was 10 minutes (range 3–16).
Non-headache symptoms
The majority of subjects reported non-headache symptoms in both the open unblinded NTG visit (n = 30, 91%) and the single-blinded NTG visit (n = 21, 84%) visits. In the single-blinded placebo visit, eight subjects (33%) reported non-headache symptoms. The most common non-headache symptoms from the open unblinded NTG visit were neck stiffness, photophobia, thirst and allodynia. The most common non-headache symptoms from the single-blinded NTG visit were neck stiffness, yawning, thirst and photophobia (Table 4). The median number of non-headache symptoms reported in the open unblinded NTG visit was three (IQR 2–5), and from the single-blinded NTG visit was three (IQR 2–6), compared with two (IQR 2–3) on-headache symptoms in the single-blinded placebo group.
Table 4. Frequencies of non-headache symptoms reported during each visit.
Non-headache symptom Open unblinded NTG visit (n = 33) Single-blinded NTG visit
(n = 25) Single-blinded placebo visit
(n = 24)
Thirst 15 10 3
Craving 0 0 0
Yawning 8 12 4
Tiredness 4 3 0
Mood changes 5 4 1
Visual blurring 4 3 1
Neck stiffness 21 15 3
Irritability 3 3 0
Photophobia 18 10 1
Concentration difficulties 6 4 1
Phonophobia 4 6 0
Urinary symptoms 0 0 0
Speech disturbances 0 0 0
Nausea 6 3 0
Gastrointestinal discomfort 0 0 0
Movement sensitivity 5 5 1
Allodynia 9 8 2
In the open unblinded NTG visit, the median onset time of non-headache symptoms from the start of the infusion was 9 minutes (IQR 4–17) with the median maximum duration of the symptoms being 50 minutes (IQR 24–64), the duration is calculated from the first symptom until the end of the last symptom. In the single-blinded NTG visit, the median onset time was 5 minutes (IQR 3–9) from the start of the infusion, and the median maximum duration of symptoms was 59 minutes (IQR 35–76). The outlier was a subject who developed allodynia and neck stiffness during their attack. For those that developed non-headache symptoms during the single-blinded placebo visit, the median onset time was 9 minutes (IQR 2–9), with a median duration of 16 minutes (IQR 6–34).
Cranial autonomic symptoms
NTG triggered CAS in the majority of the subjects during the open unblinded NTG visit (n = 31, 94%). In all, five subjects out of the 31 (19%) developed unilateral CAS; however, they did not have a cluster headache attack. Two subjects had CAS with generalised headache, one had CAS without any pain, one subject developed CAS on the contralateral side to their attacks with mild generalised pain, and one subject with CAS developed restless leg symptoms, but no cluster headache attack. Of the subjects who developed unilateral CAS and cluster headache attack (n = 26, 79%), the median number of CAS was four (IQR 2–5), with the most common CAS being nasal congestion (n = 21), lacrimation (n = 16) and periorbital oedema (n = 15) (Table 5).
Table 5. Frequencies of cranial autonomic symptoms reported in subjects who had attacks following NTG infusion.
Cranial autonomicsymptoms Open unblinded NTG visit, total number of attacks (n = 26) Single-blinded NTG visit, total number of attacks (n = 19)
Lacrimation 16 11
Conjunctival injection 12 9
Periorbital oedema 15 8
Eye grittiness/itchiness 3 3
Nasal congestion 21 16
Rhinorrhoea 2 1
Ptosis 4 1
Aural fullness 5 2
Facial flushing 7 4
Sialorrhoea 1 0
Throat swelling 2 0
Voice change 4 2
Facial swelling 3 1
Similarly, NTG brought on CAS in the majority of subjects during the single-blinded NTG visit (n = 21, 84%), of which two were not accompanied by a cluster headache attack, compared with four out of 24 in the single-blinded placebo group developing CAS (Figure 5(a)). One of the subjects from the single-blinded NTG group had a generalised headache similar to a hangover headache with unilateral CAS, and the other subject had a migraine-like headache with CAS. Of the 19 subjects (76%) that had unilateral CAS and a cluster headache attack, the median number of symptoms was three (IQR 2–4) and the most frequent symptoms were nasal congestion (n = 16), lacrimation ( n = 11) and conjunctival injection (n = 9) (Table 5). In comparing the time until all CAS onset between ECH and CCH after blinded NTG infusion, there was no difference between the two groups (log-rank P = 0.740; Figure 5(b)).
Figure 5. (a) Kaplan-Meier graph showing time until onset of cranial autonomic symptoms (CAS) following open unblinded (n = 33) and single-blinded NTG (n = 25) infusions compared with the single-blinded placebo infusion (n = 24). Log-rank P = 0.000. (b) Kaplan-Meier graph showing the time until CAS onset in the single-blinded NTG visit, comparing episodic cluster headache (ECH) with chronic cluster headache (CCH). Log-rank P = 0.740.
The median time until CAS onset for those that developed cluster headache attacks was 31 min (IQR 13–46) in the open unblinded NTG visit and 12 min (IQR 6–30) in the single-blinded NTG visit. Subjects sequentially reported CAS development.
During the single-blinded placebo visit, four subjects (17%) developed unilateral CAS, of which one subject developed a spontaneous attack, and three developed CAS but no pain. The median number of symptoms reported in the placebo group was two (IQR 1–2) and the symptoms reported were nasal congestion (n = 2), conjunctival injection (n = 1), periorbital swelling (n = 1), rhinorrhoea (n = 1) and aural fullness (n = 1).
Agitation
Nitroglycerin brought on agitation in the majority of subjects, open unblinded NTG visit (n = 24, 73%) and single-blinded NTG visit (n= 20, 80%), compared with none in the single-blinded placebo visit.
Non-headache symptoms post-attack
The non-headache symptoms were not studied here, as all attacks were treated with sumatriptan or oxygen after 20 minutes, thus altering the natural progression and development of symptoms.
Episodic cluster headache compared with chronic cluster headache
For the subjects that developed an NTG-induced attack following the single-blinded NTG infusion, the time until NTG-induced attack was shorter in the episodic cluster headache group compared with the chronic cluster headache group (U = 15, z = −2.399, P = 0.016). The time until CAS onset, in the subjects that developed CAS following single-blinded NTG infusion was not different between episodic cluster headache and chronic cluster headache groups (U = 38, z = −1.2000, P = 0.230).
Effect of verapamil on NTG triggering
There were seven subjects on verapamil that attended the single-blinded NTG visits, of which two did not develop NTG-triggered cluster headache attacks (29%). Using χ2, there was no difference between verapamil and NTG triggering (χ2 (df = 1) = 0.111, P = 0.739).
Effect of migraine on NTG-triggered attacks
Within the cohort that attended the single-blinded NTG visits, 15 had migraine (60%). There was no difference between the number of non-headache symptoms (U = 67, z = −0.449, P = 0.654) or number of CAS (U = 57, z = −1.019, P = 0.308), between the subjects with migraine and those without migraine. Furthermore, there was no association between subjects with migraine and NTG triggering (χ2 (df = 1) = 0.146, P = 0.702); similarly, there was no association between subjects with migraine and development of NTG headache (χ2 (df = 1) = 0.033, P = 0.856).
Discussion
This study demonstrates that weight-calculated intravenous NTG effectively triggers cluster headache attacks in both chronic cluster headache and episodic cluster headache subjects within bout when compared with placebo. The approach is reliable in terms of triggering a fully-featured attack that allows careful observation of symptoms and their development during acute attacks of cluster headache.
The benefit of weight-calculated intravenous NTG compared to intranasal and sublingual administration is that this is more reliable and has more stable bioavailability. The median time until cluster headache attack onset was 30 minutes (open unblinded NTG visit) and 33 minutes (single-blinded NTG visit), with the overall maximum onset time of 81 minutes. Subjects who did not develop an attack during the 140 minutes of observation were asked to report if they developed an attack later on that day, and none did. The median onset time is similar to the reported latency period reported in the literature (Table 1). The minimum onset time for NTG-induced attacks was 2 minutes, and this is less than reported from the sublingual route, where the shortest time until onset time was 9 minutes (8); this is expected, given the intravenous route has a half-life of 2.3–2.8 minutes (30,31). Two subjects started experiencing mild attack pain before the start of the NTG infusion, and within the placebo group we observed one subject who developed a spontaneous attack. Spontaneous attacks could be anticipated given the subjects are within bout; there were three subjects with only short-lasting CAS symptoms and two subjects who experienced a mild pain without CAS, similar to a shadow.
This study delineates the development of the various stages of an NTG-induced cluster headache attack, including the non-headache symptoms and CAS (Figure 6). The majority of subjects developed NTG headache shortly after the infusion started. This headache was generalised, mild and progressive in nature, predominantly in the bi-occipital and bi-temporal regions. Subjects described it as pressure-like or band-like ache, and they reported it to be distinct from their cluster headache attacks; if there were an overlap, the cluster headache attack would clearly ramp up and supersede the NTG headache. It is difficult to disentangle whether NTG headache developed because there was a high proportion of subjects with either a migraine diagnosis, migraine marker or family history of migraine. However, from a previous study with 25 healthy volunteers without a migraine diagnosis, 16 (64%) developed NTG headache following 0.5 mg NTG sublingual administration (32).
Figure 6. Violin plots of the stages of cluster headache attack from the 19 subjects that developed cluster headache attacks and subdivided by chronicity. The timeline starts with 20 minutes of single-blinded nitroglycerin (NTG) infusion, followed by 120 minutes of post-infusion observation. CAS = cranial autonomic symptoms.
Following the NTG headache, the majority of subjects reported non-headache symptoms in the lead-up to the onset of the pain from the attack and in some subjects, non-headache symptoms accompanied their attacks. The non-headache symptoms included homeostatic symptoms (thirst, cravings, yawning, frequency of urination), fatigue/cognitive symptoms (concentration difficulty, fatigue, memory impairment, mood changes, irritability) and sensitised sensory symptoms (neck stiffness, photophobia, phonophobia, osmophobia, nausea), as are reported in the premonitory phase of migraine (33). The most common symptoms were neck stiffness, photophobia and thirst. During their spontaneous attacks, subjects reported that non-headache symptoms would precede the attack at a median of 10 minutes (IQR 2–30) before the onset of pain, although it is known that there are discrepancies between retrospective and prospective reporting (25). Comparing the symptoms observed from NTG-induced attacks in this study with the prospective observational questionnaire study (24), the most reported general symptoms in the pre-pain phase in this study were concentration difficulties, photophobia and mood changes. Patients in the observational study also reported general symptoms during their attacks and postictal symptoms similar to the symptoms seen during the NTG-induced attacks and the reported symptoms by the subjects in this study during the postdrome phase of their spontaneous attacks. Non-headache symptoms such as photophobia, phonophobia, and localised allodynia were often reported during the attacks, as has been reported previously (21,34). In one semi-structured questionnaire study, they found a high proportion of cluster headache patients (73.2%) reported phonophobia or photophobia with their attacks (35), cluster headache patients with migraine did not more frequently report these symptoms compared with those without co-existing migraine. Furthermore, allodynia was more often reported in cluster headache patients with migraine. From pre-clinical studies, high dose NTG causes a sustained increase in spontaneous firing of Aδ and C-fibre trigeminal neurons (36), which migraine biology may unmask.
Similar to the prospective questionnaire study by Snoer and colleagues (24), in some subjects CAS presented before the onset of the attack pain (Figure 6). In this study, the median onset time for CAS was 31 minutes (IQR 13–46) in the open unblinded NTG visit and 12 minutes (IQR 6–30) in the single-blinded NTG visit, whereas the onset of NTG-induced attack was 30 minutes (IQR 20–39) in the open unblinded visit and 33 minutes (IQR 15–42) in the single-blinded NTG visit. From the open unblinded NTG visit, 38% presented with CAS before the attack, 15% presented with CAS with the onset of the attack, and from the single-blinded NTG visit, 58% presented with CAS before the attack and 16% presented with CAS with the onset of the attack.
Vollesen and colleagues used calcitonin gene-related peptide (CGRP) infusion to trigger cluster headache attacks, finding CGRP induced 50% of subjects with CCH and 89% for ECH subjects in bout (4). In our study, NTG induced attacks in 79% of the CCH subjects and 84% in ECH subjects in bout, in the open unblinded NTG visits, and 92% CCH and 62% ECH in bout in the single-blinded NTG visits. There are some differences in the number of chronic cluster headache subjects on verapamil between the studies; in this study, 33% of CCH subjects were on verapamil and in the study by Vollesen and colleagues, 57% of CCH subjects were on verapamil (of which one was on both verapamil and lithium) and one was on 4 mg melatonin. Vollesen and colleagues proposed that the CCH patients who did not develop an attack following CGRP infusion had a lower median attack frequency in the preceding 30 days prior to the study compared to the CCH patients that did develop an attack. However, in this study, subjects reported having their last attack as long ago as 128 and 158 days and still had NTG-induced attacks (Table 3).
NTG is a pro-drug of nitric oxide (NO) and has effects on blood vessel dilation through mechanisms of the NO-cyclic guanylate phosphate (cGMP) pathway (27). However, the vasodilatory effects of NTG are not sufficient to explain the cluster headache attack that occurs after a latency and the central features associated with the attack. Indeed, experimental studies demonstrate that NTG has central effects (37,38). Interestingly, in studies where NO donors were administered in vivo and in vitro, there was a local release of CGRP (39–42). The difference in the rate of cluster headache attacks induced by NTG and CGRP in ECH and CCH subjects could reflect in part the underlying biological processes and systems that are more active in the different subtypes of cluster headache. The difference between ECH and CCH is also suggested by the treatment response to a CGRP monoclonal antibody, galcanezumab (43,44), and non-invasive vagal nerve stimulator (45,46).
Limitations
The main limitations to the study were the recruitment of eligible subjects and the dropout rate at each stage due to the nature of the condition. Therefore, a pragmatic approach was taken with the study design regarding randomisation. Although there was a randomisation sequence, this was modified by the investigator if deemed necessary. This would be in the case of episodic cluster headache patients that were near the end of their bout missing the NTG visit if they followed the randomised sequence. For this reason, it was designed to be a single-blind cross-over study and not a double-blind and randomised study. Expectation bias was reduced by maintaining blinding of the subjects until the end of the study and having both infusions identical in volume, appearance and duration of infusion. Furthermore, given the stark difference between placebo and NTG, there was no difference between attack onset in the open unblinded compared with the single-blinded NTG visits (Figure 4(b)), is an indication that randomisation was not a factor in this study.
Conclusion
We present the results of the first placebo-controlled study using intravenous NTG administration to systematically study NTG-induced cluster headache attacks. We have shown that NTG can reliably bring on cluster headache attacks as well as the development of non-headache symptoms and CAS. This study highlights differences between NTG-induced attack onset times between the ECH and CCH subjects. Understanding the stages of cluster headache is essential; by recognising the non-headache symptoms in the lead up to the onset of pain and the underlying pathogenesis of this, we may be able to uncover new therapeutic targets to abort attacks before the onset of the severe and devastating pain experienced by our cluster headache patients.
Article highlights
Weight-calculated standardised intravenous nitroglycerin administration is a reliable method to induce cluster headache attacks, cranial autonomic symptoms and non-headache symptoms that accompany cluster headache attacks.
Accompanying non-headache symptoms in cluster headache attacks are important to recognise for both clinical and research purposes.
There may be inherent differences between episodic cluster headache and chronic cluster headache.
Acknowledgement
This study would not have been possible without the support of OUCH(UK), all the cluster headache patients who were interested in helping us with this study and all the subjects who took part in this study.
Ethics or Institutional Review Board approval: This study 16/LO/0693 obtained approval from the London, City & East NHS Research Ethics Committee on 23 June 2016. This study was carried out in accordance with the World Medical Association Declaration of Helsinki (1964), the Research Governance Framework for Health and Social Care (2nd edition, 2005), the Data Protection Act (1998) and the Principles of Good Clinical Practice (GCP); all subjects gave informed consent before taking part.
Declaration of conflicting interests: The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: DYW no reported competing interests. PJG reports, over the last 36 months, grants and personal fees from Amgen and Eli-Lilly and Company, grant from Celegene, and personal fees from Alder Biopharmaceuticals, Aeon Biopharma, Allergan, Biohaven Pharmaceuticals Inc., Clexio, Electrocore LLC, eNeura, Epalex, GlaxoSmithKline, Impel Neuropharma, MundiPharma, Novartis, Pfizer, Praxis, Sanofi, Santara Therapeutics Satsuma, Teva Pharmaceuticals, Trigemina Inc., WL Gore, and personal fees from MedicoLegal work, Massachusetts Medical Society, Up-to-Date, Oxford University Press, and Wolters Kluwer; and a patent magnetic stimulation for headache assigned to eNeura without fee.
Funding: The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study is part-funded by the National Institute for Health Research (NIHR) Maudsley Biomedical Research Centre at South London Maudsley Foundation Trust and King’s College London. The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care.
ORCID iDs: Diana Y Wei https://orcid.org/0000-0003-0644-7172
Peter J Goadsby https://orcid.org/0000-0003-3260-5904 | NITROGLYCERIN | DrugsGivenReaction | CC BY | 33615843 | 19,017,453 | 2021-07 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Periorbital oedema'. | Comprehensive clinical phenotyping of nitroglycerin infusion induced cluster headache attacks.
Nitroglycerin administration allows the study of cluster headache attacks in their entirety in a standardised way.
A single-blind, placebo-controlled, cross-over study using weight-calculated intravenous nitroglycerin administration at 0.5 µg/kg/min over 20 minutes to study cluster headache attacks, including accompanying non-headache symptoms and cranial autonomic symptoms.
Thirty-three subjects with cluster headache were included in the study; 24 completed all three study visits. Nitroglycerin-induced attacks developed in 26 out of 33 subjects (79%) receiving unblinded nitroglycerin infusion, and in 19 out of 25 subjects (76%) receiving single-blinded nitroglycerin infusion, compared with one out of 24 subjects (4%) receiving single-blinded placebo infusion. Episodic cluster headache subjects had a shorter latency period to a nitroglycerin-induced attack compared to the chronic cluster headache (CCH) subjects (U = 15, z = -2.399, p = 0.016). Sixteen of nineteen episodic cluster headache (mean, 84%; 95% confidence interval, 66-100%) and 11 of 14 chronic cluster headache subjects developed a nitroglycerin-induced attack (79%, 54-100%) following the unblinded nitroglycerin infusion. Following the single-blinded nitroglycerin infusion, eight out of 13 episodic cluster headache (62%, 31-92%) and 11 out of 12 chronic cluster headache (92%, 73-100%) subjects developed nitroglycerin-induced attacks. Nitroglycerin induced non-headache symptoms in the majority of subjects receiving it: 91% in the open unblinded nitroglycerin visit and 84% in the single-blinded nitroglycerin visits, compared with 33% in the single-blinded placebo visit. Cranial autonomic symptoms were induced by nitroglycerin infusion, 94% in the open unblinded nitroglycerin visit and 84% in the single-blinded nitroglycerin visit, compared with 17% in the single-blinded placebo visit.
Intravenous weight-adjusted nitroglycerin administration in both episodic cluster headache in bout and chronic cluster headache is effective and reliable in inducing cluster headache attacks, cranial autonomic symptoms and non-headache symptoms.
Introduction
Due to the episodic nature of acute attacks of cluster headache, a standardised and reliable method for triggering attacks is necessary for their complete study. There have been several substances used to trigger attacks, including histamine (1,2), meta-chloro-phenylpiperazine (mCPP) (3) and more recently calcitonin gene-related peptide (CGRP) (4). Nitroglycerin (NTG) is the most frequently employed substance in human experimental modelling of cluster headache attacks, being used since 1953 (2) (Table 1).
Table 1. Review of studies using nitroglycerin to induce cluster headache attacks.
Study Number of CH patients NTG dose and route Control Placebo Rate of induced CH attack Latency period before onset of headache
(range in minutes)
Peters 1953 (2) 14 1.3 mg sublingual No, but compared with migraine, combination of CH and migraine, vasodilating head pain and tension headache No, but compared with histamine and nicotinic acid 78.6% Not reported
Ekbom 1968 (5) 38 ECH: 28 in bout, 15 out of bout (of which five were tested in bout as well) 1 mg sublingual No No In bout ECH 100% (n = 28)
Out of bout 0% (n = 15) 12–72
Barre 1982 (6) 10 CH: two CCH, nine ECH in bout 1 mg sublingual No No 100% 34–52
Mean 45.9
Drummond et al. 1984 (7) 29 CH 0.9 mg sublingual No No 76% Within 90 min
Drummond et al. 1985 (8) 22 CH: 10 CCH, 12 ECH in bout
0.9 mg sublingual Yes, 10 in the control group without headache No ECH 75% (n = 9)
CCH 60% (n = 6) 9–90
Mean 44
Bogucki 1990 (9) 21 ECH in bout 1 mg sublingual No No 67% (n = 14)
30–65
Dahl et al. 1990 (10) 15 ECH in bout 1 mg sublingual 10 healthy controls No 53% (n = 8)
Controls: not reported 30–65
Hannerz et al. 1992 (11) Eight ECH: five in bout and three out of bout 1 mg sublingual No No In bout ECH 100% (n = 5) Not reported
Fanciullacci et al. 1995 (12) 18 in bout ECH, 12 out of bout ECH 0.9 mg sublingual No No In bout ECH 100% (n = 18)
Out of bout ECH 0% (n = 12) 39–86
Fanciullacci et al. 1997 (13) 11 in bout ECH, eight out of bout ECH 0.9 mg sublingual No No In bout ECH 100% (n = 11)
Out of bout ECH 0% (n = 8) 18–50
Hsieh et al. 1996 (14) Seven ECH: four in bout ECH, three out of bout 1 mg sublingual No No In bout ECH 100%
Out of bout ECH 0% 18–35
May et al. 1998 (15) Nine CCH, eight out of bout ECH 1.0–1.2 mg spray No No CCH 100%
Out of bout ECH 0% Not reported
Costa et al. 2000 (16) 15 CH: Six ECH, nine CCH 0.9 mg sublingual No No ECH 33% (n = 2)
CCH 78% (n = 7) 19–41
Costa et al. 2003 (17) 18 ECH in bout 0.9 mg sublingual Yes, 12 healthy sex and age-matched No ECH 67% (n = 12)
Controls 0% 19–41
Sances et al. 2004 (18) 42 CH: 29 ECH (11 out of bout), 13 CCH 0.9 mg sublingual Yes, 53 healthy controls No In bout ECH and CCH 81% (n = 25 out of 31)
Controls 7.5% developed headache in 7-hour post-NTG Mean onset latency of 65.4 ± 54.7
Cluster headache patients suffer from recurrent episodes of severe unilateral pain in the trigeminal region; therefore, historically, the main emphasis has been centred around the pain onset of a cluster headache, and indeed this is often used as the indicator of the start of the attack. However, from clinical practice, there has been growing awareness of nonpainful symptoms preceding the onset of pain (19,20) and in recent years, the clinical phenotype of cluster headache has been further characterised by retrospective accounts (21–23) and prospective diaries (24,25).
The most frequent route of administration of NTG has been sublingual; however, the bioavailability of sublingual NTG is extremely variable (26). Therefore, we used a weight-calculated dose for intravenous infusion in a standardised single-blind, placebo-controlled study. NTG is a pro-drug of nitric oxide, with predominant actions on the cyclic guanylate phosphate (cGMP) pathway (27), and from pre-clinical studies there are indications of neural actions more centrally. This study is the first single-blind, placebo-controlled cross-over study using a weight-adjusted dose of nitroglycerin administered intravenously in cluster headache patients, thereby allowing comprehensive investigation of the various stages of the acute attack of cluster headache.
Methods
Subject selection and recruitment
The study was advertised on the UK cluster headache patient website OUCH (UK) (Organisation for the Understanding of Cluster Headache UK) (https://ouchuk.org/research/research-volunteers-needed) and in the tertiary Headache centre in King’s College Hospital, London. Subjects interested in participating would make contact via a dedicated research email. Subjects would then be screened for eligibility for the study via emails and a telephone call; those who met the criteria and were interested in participating were invited to attend the study visit. The study was approved by the London, City & East Research Ethics Committee (Ref Number 16/LO/0693). Data were collected from August 2016 until January 2019.
The subjects enrolled fulfilled the ICHD-3 beta criteria for cluster headache (28), and were between the ages of 18 and 60, with no significant previous medical history and no previous syncope or history of autonomic dysfunction. They had had a reliable response to high flow oxygen and/or subcutaneous sumatriptan during spontaneous attacks and normal brain neuroimaging. Women in child-bearing age were required to use reliable contraceptive methods during the study. Subjects were excluded if they were pregnant or breastfeeding, and who had any significant psychiatric disease, diagnosis of another primary headache type (other than migraine) or chronic pain syndrome, any medical history that would have contraindications to receiving NTG, use of preventive medication other than verapamil, or taking indomethacin for any reason, allergies to the medications used in the study or intolerance to high flow oxygen, and use of illicit drugs during the study.
Study visits
The study comprised of three visits in total, with each visit separated by a minimum of 1 week. During the first visit, subjects consented and a full headache history with a physical examination of the neurological and cardiovascular systems was performed, along with recordings of the baseline blood pressure, lying and standing blood pressure, heart rate, oxygen saturation, weight and electrocardiogram. Female subjects were required to have a urinary pregnancy test before the start of the infusion.
Open NTG infusion
If deemed eligible, subjects received an intravenous infusion of nitroglycerin at 0.5 µg/kg/min over 20 minutes. Subjects remained recumbent for 30 minutes before the infusion, and after the NTG infusion, subjects received 250 mL of 0.9% sodium chloride intravenously. The blood pressure and pulse were checked at the start of the infusion, and every 5 min during the infusion.
Phenotypic characterisation
Every 5 minutes, subjects were asked to rate their pain level from a scale from no pain, mild, moderate to severe, where severe equates to their most severe attack, and they were asked a questionnaire of non-headache symptoms and cranial autonomic symptoms (CAS) (Figure 1). If the subject experienced pain, further details were obtained regarding the location and characteristic. Beyond the cluster headache attack, subjects were asked to report any other headache types and in particular NTG headache, which has been well described from migraine studies (29). The NTG headache was assessed for severity, phenotype, accompanying non-headache symptoms and duration. Subjects were actively encouraged to report any symptoms as and when they developed. Following the infusion, at 10 minute intervals, any developments in pain, non-headache symptoms and CAS were recorded for a total of 120 minutes after the infusion, based on the latency period reported from previous studies (Table 1).
Figure 1. Questionnaire for non-headache and cranial autonomic symptoms.
B: bilateral; R: right-sided; L: left-sided.
Single-blinded NTG and placebo infusions
During the two single-blinded visits, subjects either received intravenous nitroglycerin at 0.5 µg/kg/min over 20 minutes or an equal volume of 0.9% sodium chloride at the same rate over 20 minutes, followed by the same 120 minutes of observations (Figure 2). The sequence was pre-determined using the randomise function in Excel; however, the investigator was able to amend this in certain situations if the subject was episodic and due to finish their bout.
Figure 2. Outline of events from open unblinded nitroglycerin visit.
BP: blood pressure; CAS: cranial autonomic symptoms; NTG: nitroglycerin; IV: intravenous.
Treatment of acute attacks
Acute treatment was administered at 20 minutes from the start of attack either with sumatriptan 6 mg subcutaneous injection (Imigran 6 mg/0.5 ml solution for injection pre-filled syringes, GlaxoSmithKline UK Ltd, or sumatriptan 6 mg/0.5 ml solution for injection pre-filled pens, Sun Pharmaceuticals Industries Europe B.V.) or with 15 L/min oxygen via a non-rebreather mask (O2Star™ non-rebreather oxygen mask M/L, Dräger). The visit was concluded only when the subject was pain free.
Statistical analysis
The data was tabulated (Excel for Mac v 16.30), and descriptive statistics were performed to summarise data (SPSS Statistics version 26 for Mac and Excel). Mann-Whitney tests were performed on time until attack onset and time until CAS onset for those that developed NTG-triggered cluster headache attacks and CAS, comparing the differences in ECH with CCH subgroups. Kaplan-Meier survival graphs were used to examine the time until onset of event; that is, survival of no cluster headache attack status, or absence of CAS after NTG infusion for 140 minutes (20 minutes of infusion and 120 minutes of post-infusion observation), with log-rank statistical testing; P < 0.05 was considered significant. Graphs were made using SPSS and violin plots were made using GraphPad Prism 8 for Mac OS.
Results
Demography
A total of 229 subjects were contacted to check for eligibility, of which 33 were included in the study; 24 completed all three study visits (Figure 3). All patients fulfilled the ICHD-3 beta criteria for cluster headache, 19 episodic cluster headache in bout (58%) and 14 chronic cluster headache (42%) (Table 2). The majority were male (n = 24, 73%) with a male: female ratio of 3:1. The average age was 41 (SD 10), with the mean age of females (34 years, SD 9) younger than in males (44 years, SD 9) in this cohort. Subjects had had the condition for a median of 9 years (IQR 5–16).
Figure 3. Subject numbers throughout the study.
Table 2. Subject characteristics.
Subject Age Sex Subtype Side of attacks Time since first attack (years) Average attack frequency (per day) Average attack duration when untreated (mins) Average bout duration (weeks) Verapamil (total daily dose in mg)
1 55 M Chronic Right 5 2 45 – 480
2 28 F Chronic Right 12 7 150 – –
3 40 M Episodic Right 20 3 150 8 –
4 38 F Episodic Left 12 2 120 4 –
5 53 M Chronic Left 15 4 35 – 960
6 48 M Episodic Left 25 5 52.5 5 480
7 23 M Episodic Left 8 2 120 10 –
8 43 M Chronic Right 9 1 40 – –
9 43 M Episodic Right 13 3 60 5 240
10 44 M Episodic Right 27 6 45 6 –
11 47 M Episodic Right 3 1 105 20 –
12 48 M Episodic Left 26 3 180 10 560
13 40 M Episodic Right 5 3 60 8 –
14 50 M Episodic Right 10 2 105 8 –
15 56 M Episodic* Right 24 1 45 – –
16 35 M Episodic Left 7 2 150 6 240
17 58 M Episodic Left 3 1 135 24 –
18 43 M Chronic Left 4 2 60 – –
19 32 M Episodic Left 3 3 50 12 600
20 49 F Episodic Right 8 5 50 9 –
21 49 M Chronic Right 35 2 90 – –
22 57 M Chronic Right 20 5 65 –
23 40 F Chronic Left 4 1.5 120 – 640
24 44 M Chronic Right 6 2 90 – 720
25 23 F Episodic Right 9 2.5 90 6 –
26 40 M Chronic Left 17 1.5 180 – –
27 20 F Chronic Right 6 1.5 150 – –
28 31 F Episodic Right 14 2 75 11 –
29 35 M Episodic Left 9 2 90 3 –
30 38 F Chronic Left 6 1.5 180 – 240
31 49 M Episodic Left 0.5 1.5 37.5 21 400
32 35 F Chronic Left 4 0.3 30 – 600
33 32 M Chronic Left 10 6 60 – –
M: male; F: female.
*Subject was chronic but became episodic during study with no attacks in 6 months.
Clinical phenotyping of subjects by history
Pain features
There was a near-equal split between the laterality of attacks; 17 subjects had right-sided attacks (52%), and 16 subjects had left-sided attacks (49%). The median number of attacks per day was two (IQR 1.5–3) lasting a median of 90 minutes (IQR 50–128). Verapamil was the only preventive allowed on the study; 12 subjects (36%) were on verapamil ranging from 240 mg to 960 mg per day.
Migraine, accompanying features and non-headache symptoms in spontaneous attacks
In this cohort, 58% (n = 19) had a concurrent migraine (28): five had migraine with aura, of which four had visual aura and one had facial sensory aura. Of the subjects who did not meet the diagnostic criteria for migraine (28) (n = 14, 42%), the majority had either migraine markers and/or a family history of migraine. Migraine markers were defined if subjects experienced: childhood cyclic nausea and vomiting, motion sickness, cold stimulus-induced headache, hangover headache and jetlag. Four subjects did not have migraine markers, and three subjects (9%) did not have either migraine marker or a family history of migraine. Subjects (n = 24, 73%) reported accompanying symptoms with their spontaneous attacks, the most common symptoms being cranial allodynia (n = 15), photophobia (n = 15), nausea (n = 11) and phonophobia (n = 10).
Non-headache attack symptoms
The majority reported non-headache symptoms in the lead up to their spontaneous cluster headache attacks (n = 27, 82%), with the commonest symptoms being concentration difficulties (n = 18), mood changes (n = 15), neck stiffness (n = 13) and yawning (n = 8). The median onset time of symptoms was 10 minutes (IQR 2–30) before the onset of pain. Although most symptoms start before the onset of pain, five subjects only reported developing the symptoms during the attack.
Twenty-eight subjects reported non-headache symptoms following their cluster headache attacks (85%), the commonest symptoms being tiredness (n = 27), mood changes (n = 13), concentration difficulties (n = 12), and neck stiffness (n = 7). The median duration of symptoms was 120 minutes (IQR 53–315).
Attack triggers
The most commonly reported triggers for spontaneous attacks were alcohol ingestion (n = 22), followed by changes in temperature (n = 12), strong smells such as from nail varnish, paint (n = 11) followed by disrupted sleep (n = 4) and exercise (n = 3). Other triggers mentioned were stress (n = 2), caffeine (n = 2), changing time zones (n = 1), let down from stress (n = 1), being in a pressurised cabin on an airplane (n = 1), vardenafil (n = 1), and dehydration (n = 1). All subjects reported attacks within a few hours of alcohol ingestion, no one reported a next-day effect.
Clinical phenotyping of open NTG visit
NTG triggered cluster headache-like attacks (n = 26, 79%), CAS (n = 31, 94%) and agitation (n = 24, 73%) during the open unblinded NTG visit. In the episodic cluster headache group, 16 out of 19 developed an NTG-induced attack (mean, 84%; 95% CI, 66–100%) and in the chronic cluster headache group, 11 out of 14 developed an NTG-induced attack (79%, 54–100%). Five out of the 31 subjects developed CAS, but did not develop an attack; of these subjects, three developed mild generalised pain, one developed restless legs, and one developed CAS on the contralateral side to the subject’s spontaneous attack phenotype, with a generalised headache. These cases were excluded.
The median onset time for CAS to develop from the start of the NTG infusion was 31 minutes (IQR 13–46). The median onset for an NTG-induced attack was 30 minutes (IQR 20–39) and the median time to maximum pain, if reached, was 51 minutes (IQR 39–70). The most common first cranial autonomic symptoms brought on by NTG infusion were nasal congestion (n = 10), conjunctival injection (n = 5), lacrimation (n = 4) and periorbital oedema (n = 3).
Clinical phenotyping of single-blinded NTG and placebo visit
During the single-blinded visits, NTG induced attacks in 19 subjects (76%); three subjects did not have an attack (12%), two subjects developed migraine-like headache (8%) and one subject developed unilateral mild pain without CAS or agitation (4%) (Table 3). In the placebo group, only one developed an attack (4%), two subjects developed unilateral mild pain without CAS or agitation (8%) and two subjects experienced short-lived unilateral CAS (8%). Of the subjects receiving NTG, eight out of 13 ECH (mean, 62%; 95% CI, 31%-92%) and 11 out of 12 CCH (92%, 73–100%) developed NTG-induced attacks (Figure 4(a)).
Table 3. Subject characteristics and comparison between spontaneous attack and triggered attack from single-blinded nitroglycerin visit, M = male, F = female, ECH = episodic cluster headache, CCH = chronic cluster headache, L = Left, R = Right, Y = Yes, N = No, VRS = verbal rating scale, mod = moderate, O2 = high flow oxygen via non-rebreather mask, suma = sumatriptan.
Subject Age Sex Subtype Migraine Verapamil (total daily dose in mg) Spontaneous attack Triggered attack- single-blinded NTG visit
Laterality Severity CAS Agitation Laterality Severity/VRS CAS Agitation Feels like spontaneous attack Treatment Last spontaneous attack (days)
1 55 M CCH N 480 R 9/10 Conjunctival injection, nasal congestion, lacrimation. 3 months of R Horner’s syndrome in 2007, now resolved Y R 10/10
VRS 3 Conjunctival injection, nasal congestion, lacrimation, periorbital oedema Y Y O2 158
2 28 F CCH Y
– R 10/10 Periorbital oedema/ptosis, nasal congestion, dry eye then lacrimation Y R 10/10
VRS 3 Periorbital oedema, nasal congestion, facial flushing Y Y O2 128
3 40 M ECH N – R 10/10 Lacrimation, rhinorrhoea, ptosis Y R 10/10
VRS 3 Lacrimation, conjunctival injection, periorbital oedema, nasal congestion, aural fullness and facial droop Y Y Suma 1
4 38 F ECH Y – L 10/10 Lacrimation, conjunctival injection, periorbital oedema, nasal congestion, ptosis, facial flushing Y No attack, developed generalised pain 4/10 Y N N/A 1
5 53 M CCH N 960 L 10/10 Rhinorrhoea, ptosis Y L 10/10
VRS 3 Conjunctival injection, eye grittiness, lacrimation Y Y O2 4
6 48 M ECH N
480 L 8/10 Nasal congestion, lacrimation Y Did not attend
7 23 M ECH Y – L 10/10 Lacrimation, conjunctival injection, nasal congestion, ptosis, facial flushing Y Did not attend
8 43 M CCH N – R 10/10 Nasal congestion, rhinorrhoea, lacrimation, facial flushing Y R 10/10
VRS 3 Nasal congestion, conjunctival injection, eye grittiness Y Y Suma <1
9 43 M ECH N 240 R 10/10 Lacrimation, conjunctival injection, facial flushing, ptosis, facial droop Y Did not attend
10 44 M ECH N – R 10/10 Nasal congestion, ptosis, periorbital oedema, lacrimation, flushing Y No attack, L mild hangover like headache, with nasal congestion.
After study visit felt nauseous and vomited, then slept, headache free at 7pm N N O2- no response <1
11 47 M ECH N – R Severe attacks 10/10 Nasal congestion, aural fullness Y R 7/10
VRS 2/3 moderate/
severe Nasal congestion, conjunctival injection, aural fullness Y Y Suma 13
12 48 M ECH N 560 L 10/10 Lacrimation, nasal congestion, periorbital oedema Y Did not attend
13 40 M ECH Y – R 10/10 Nasal congestion, ptosis, conjunctival injection, lacrimation, throat tightness, rhinorrhoea Y No attack, bilateral mild headache 4/10 with nasal congestion Y, brief (7 mins) N N/A 19
14 50 M ECH Y – R 10/10
Lacrimation, periorbital oedema, nasal congestion, rhinorrhoea Y Did not attend
15 56 M ECH Y – R 10/10 Lacrimation, rhinorrhoea, facial flushing, gritty eyes, conjunctival injection Y with severe attacks Did not attend
16 35 M ECH Y 240 L 10/10 Nasal congestion, conjunctival injection, ptosis, lacrimation, rhinorrhoea Y Not attack, milder than a shadow and no CAS N N N/A 16
17 58 M ECH Y – L 10/10 Nasal congestion, rhinorrhoea, lacrimation, aural fullness, throat swelling Y L 7/10
VRS 2–3 (mod-severe) Nasal congestion, rhinorrhoea, voice change, lacrimation Y Y Suma 1
18 43 M CCH Y – L (70%) Mild 6/10, severe 10/10 Nasal congestion, periorbital oedema, aural fullness, facial flushing Y L Mild,
VRS 1 Nasal congestion Y Y- shadow O2 7
19 32 M ECH Y 600 L 10/10 Lacrimation, conjunctival injection, facial flushing Y L 7–8/10
VRS 2–3
(mod-severe) Lacrimation, eye grittiness, nasal congestion, facial flushing Y Y O2 <1
20 49 F ECH Y – R 10/10 Ptosis, periorbital oedema, lacrimation, nasal congestion, rhinorrhoea, (aural fullness with severe attacks) Y R 6–7/10
VRS 2 mod Nasal congestion, periorbital oedema, lacrimation, conjunctival injection Y Y O2 7
21 49 M CCH Y – R 4–10/10 Facial flushing, nasal congestion, ptosis, lacrimation, rhinorrhoea, conjunctival injection Y L 8/10
VRS 2–3
(mod-severe)
Facial flushing, lacrimation, periorbital oedema, conjunctival injection Y Y, but on L rather than R Suma <1
22 57 M CCH N – R 10/10 Lacrimation, conjunctival injection, nasal congestion, rhinorrhoea Y No attack, no pain and no CAS N N N/A 26
23 40 F CCH Y 640 L 10/10
Lacrimation, conjunctival injection, periorbital oedema, rhinorrhoea, ptosis, aural fullness Y Did not attend
24 44 M CCH N 720 R 10/10 Lacrimation, conjunctival injection, periorbital oedema, facial flushing Y Did not attend
25 23 F ECH Y – R 6–10/10 Nasal congestion, lacrimation, periorbital oedema. Rhinorrhoea and facial flushing with severe attacks Y R 7/10
VRS 2
(moderate) Nasal congestion, periorbital oedema Y Y O2 3
26 40 M CCH Y – L Shadow 4/10, daytime attacks 6–7/10, full attack 10/10 Ptosis, aural fullness, lacrimation, conjunctival injection, periorbital oedema, nasal congestion Y L 8.5–9/10
VRS 3 severe Nasal congestion, periorbital oedema, lacrimation Y Y Suma 3
27 20 F CCH N – R 8–9/10 Nasal congestion, lacrimation, rhinorrhoea, ptosis, aural fullness Y R 8/10
VRS 3
severe Nasal congestion, periorbital oedema Y Y O2 <1
28 31 F ECH Y – R 10/10 Nasal congestion, periorbital oedema, rhinorrhoea, ptosis, aural fullness Y R 2/10
VRS 1 (mild) Nasal congestion, facial swelling Y Y, but milder Suma 3
29 35 M ECH N – L Max pain 10/10 Nasal congestion, periorbital oedema, lacrimation, voice change (croaky). Facial flushing with severe attacks and rhinorrhoea after attack Y L 6–7/10
VRS 2 (moderate) Nasal congestion, lacrimation, conjunctival injection, voice change Y Y Suma <1
30 38 F CCH Y 240 L 4–10/10 Lacrimation, rhinorrhoea, conjunctival injection, facial flushing. Ptosis with severe attacks Y L 6–7/10
VRS 2 (moderate) Aural fullness Y Y Suma 1
31 49 M ECH Y 400 L 10/10 Nasal congestion, lacrimation, conjunctival injection, rhinorrhoea, ptosis, aural fullness. Prominent miosis after attack Y No attack, whole head felt heavy N N N/A 10
32 35 F CCH N 600 L 4/10 (on verapamil),
7/10 average Periorbital oedema, eye grittiness, facial flushing, lacrimation Y L 7/10
VRS 2–3
(mod-severe) Nasal congestion, conjunctival injection, facial flushing, lacrimation Y Y Suma 1
33 32 M CCH Y – L Severe attacks 10/10 Lacrimation, ptosis, nasal congestion, conjunctival injection, ptosis, facial flushing, eye grittiness Y L 6/10
VRS 2 (mod-severe) Lacrimation, nasal congestion, ptosis Y Y Suma <1
Figure 4. (a) Kaplan-Meier graph comparing time until cluster headache attack between the eight episodic cluster headache (ECH) and the 11 chronic cluster headache (CCH) subjects during single-blinded nitroglycerin (NTG) infusion, from the start of the infusion in minutes, log-rank P = 0.534. (b) Kaplan-Meier graph comparing time until cluster headache attack onset between the open unblinded (n = 33) and single-blinded (n =25) nitroglycerin (NTG) infusions with single-blinded placebo infusions (n = 24). Log-rank P = 0.000.
The median onset time to an induced attack was 33 minutes (IQR 15–42) from the start of the single-blinded NTG infusion, and in the single-blinded placebo visit only one subject developed an attack; the onset time was 10 minutes. On comparison of the attack onset time for the unblinded NTG, single-blinded NTG and single-blinded placebo visits, there was a difference between the placebo and NTG visits (P = 0.000, Figure 4(b)).
NTG headache
The majority of subjects developed an NTG headache (n = 28, 85%) following the NTG infusion in the unblinded open visit, of which 27 subjects had a migraine diagnosis (n = 18), had migraine markers (n = 10) and a family history of migraine (n = 18); only one subject did not have migraine, migraine markers or a family history of migraine. The median time from the start of NTG infusion was 3 minutes (IQR 2–6), and the median duration of NTG headache was 26 minutes (IQR 14–41).
Of the 25 subjects that went on to the single-blinded NTG visits, 18 (72%) developed NTG headache following NTG infusion, of which all had either migraine (n = 11), migraine markers (n = 7) or family history (n = 10). The median time of NTG headache onset from the start of NTG infusion in the blinded visit was 4 minutes (IQR 3–8), with a median duration of 26 minutes (IQR 9–45).
In the placebo visit, three of the 24 subjects (13%) developed NTG headache, median onset time was 13 minutes (range 1–18), and the median duration was 10 minutes (range 3–16).
Non-headache symptoms
The majority of subjects reported non-headache symptoms in both the open unblinded NTG visit (n = 30, 91%) and the single-blinded NTG visit (n = 21, 84%) visits. In the single-blinded placebo visit, eight subjects (33%) reported non-headache symptoms. The most common non-headache symptoms from the open unblinded NTG visit were neck stiffness, photophobia, thirst and allodynia. The most common non-headache symptoms from the single-blinded NTG visit were neck stiffness, yawning, thirst and photophobia (Table 4). The median number of non-headache symptoms reported in the open unblinded NTG visit was three (IQR 2–5), and from the single-blinded NTG visit was three (IQR 2–6), compared with two (IQR 2–3) on-headache symptoms in the single-blinded placebo group.
Table 4. Frequencies of non-headache symptoms reported during each visit.
Non-headache symptom Open unblinded NTG visit (n = 33) Single-blinded NTG visit
(n = 25) Single-blinded placebo visit
(n = 24)
Thirst 15 10 3
Craving 0 0 0
Yawning 8 12 4
Tiredness 4 3 0
Mood changes 5 4 1
Visual blurring 4 3 1
Neck stiffness 21 15 3
Irritability 3 3 0
Photophobia 18 10 1
Concentration difficulties 6 4 1
Phonophobia 4 6 0
Urinary symptoms 0 0 0
Speech disturbances 0 0 0
Nausea 6 3 0
Gastrointestinal discomfort 0 0 0
Movement sensitivity 5 5 1
Allodynia 9 8 2
In the open unblinded NTG visit, the median onset time of non-headache symptoms from the start of the infusion was 9 minutes (IQR 4–17) with the median maximum duration of the symptoms being 50 minutes (IQR 24–64), the duration is calculated from the first symptom until the end of the last symptom. In the single-blinded NTG visit, the median onset time was 5 minutes (IQR 3–9) from the start of the infusion, and the median maximum duration of symptoms was 59 minutes (IQR 35–76). The outlier was a subject who developed allodynia and neck stiffness during their attack. For those that developed non-headache symptoms during the single-blinded placebo visit, the median onset time was 9 minutes (IQR 2–9), with a median duration of 16 minutes (IQR 6–34).
Cranial autonomic symptoms
NTG triggered CAS in the majority of the subjects during the open unblinded NTG visit (n = 31, 94%). In all, five subjects out of the 31 (19%) developed unilateral CAS; however, they did not have a cluster headache attack. Two subjects had CAS with generalised headache, one had CAS without any pain, one subject developed CAS on the contralateral side to their attacks with mild generalised pain, and one subject with CAS developed restless leg symptoms, but no cluster headache attack. Of the subjects who developed unilateral CAS and cluster headache attack (n = 26, 79%), the median number of CAS was four (IQR 2–5), with the most common CAS being nasal congestion (n = 21), lacrimation (n = 16) and periorbital oedema (n = 15) (Table 5).
Table 5. Frequencies of cranial autonomic symptoms reported in subjects who had attacks following NTG infusion.
Cranial autonomicsymptoms Open unblinded NTG visit, total number of attacks (n = 26) Single-blinded NTG visit, total number of attacks (n = 19)
Lacrimation 16 11
Conjunctival injection 12 9
Periorbital oedema 15 8
Eye grittiness/itchiness 3 3
Nasal congestion 21 16
Rhinorrhoea 2 1
Ptosis 4 1
Aural fullness 5 2
Facial flushing 7 4
Sialorrhoea 1 0
Throat swelling 2 0
Voice change 4 2
Facial swelling 3 1
Similarly, NTG brought on CAS in the majority of subjects during the single-blinded NTG visit (n = 21, 84%), of which two were not accompanied by a cluster headache attack, compared with four out of 24 in the single-blinded placebo group developing CAS (Figure 5(a)). One of the subjects from the single-blinded NTG group had a generalised headache similar to a hangover headache with unilateral CAS, and the other subject had a migraine-like headache with CAS. Of the 19 subjects (76%) that had unilateral CAS and a cluster headache attack, the median number of symptoms was three (IQR 2–4) and the most frequent symptoms were nasal congestion (n = 16), lacrimation ( n = 11) and conjunctival injection (n = 9) (Table 5). In comparing the time until all CAS onset between ECH and CCH after blinded NTG infusion, there was no difference between the two groups (log-rank P = 0.740; Figure 5(b)).
Figure 5. (a) Kaplan-Meier graph showing time until onset of cranial autonomic symptoms (CAS) following open unblinded (n = 33) and single-blinded NTG (n = 25) infusions compared with the single-blinded placebo infusion (n = 24). Log-rank P = 0.000. (b) Kaplan-Meier graph showing the time until CAS onset in the single-blinded NTG visit, comparing episodic cluster headache (ECH) with chronic cluster headache (CCH). Log-rank P = 0.740.
The median time until CAS onset for those that developed cluster headache attacks was 31 min (IQR 13–46) in the open unblinded NTG visit and 12 min (IQR 6–30) in the single-blinded NTG visit. Subjects sequentially reported CAS development.
During the single-blinded placebo visit, four subjects (17%) developed unilateral CAS, of which one subject developed a spontaneous attack, and three developed CAS but no pain. The median number of symptoms reported in the placebo group was two (IQR 1–2) and the symptoms reported were nasal congestion (n = 2), conjunctival injection (n = 1), periorbital swelling (n = 1), rhinorrhoea (n = 1) and aural fullness (n = 1).
Agitation
Nitroglycerin brought on agitation in the majority of subjects, open unblinded NTG visit (n = 24, 73%) and single-blinded NTG visit (n= 20, 80%), compared with none in the single-blinded placebo visit.
Non-headache symptoms post-attack
The non-headache symptoms were not studied here, as all attacks were treated with sumatriptan or oxygen after 20 minutes, thus altering the natural progression and development of symptoms.
Episodic cluster headache compared with chronic cluster headache
For the subjects that developed an NTG-induced attack following the single-blinded NTG infusion, the time until NTG-induced attack was shorter in the episodic cluster headache group compared with the chronic cluster headache group (U = 15, z = −2.399, P = 0.016). The time until CAS onset, in the subjects that developed CAS following single-blinded NTG infusion was not different between episodic cluster headache and chronic cluster headache groups (U = 38, z = −1.2000, P = 0.230).
Effect of verapamil on NTG triggering
There were seven subjects on verapamil that attended the single-blinded NTG visits, of which two did not develop NTG-triggered cluster headache attacks (29%). Using χ2, there was no difference between verapamil and NTG triggering (χ2 (df = 1) = 0.111, P = 0.739).
Effect of migraine on NTG-triggered attacks
Within the cohort that attended the single-blinded NTG visits, 15 had migraine (60%). There was no difference between the number of non-headache symptoms (U = 67, z = −0.449, P = 0.654) or number of CAS (U = 57, z = −1.019, P = 0.308), between the subjects with migraine and those without migraine. Furthermore, there was no association between subjects with migraine and NTG triggering (χ2 (df = 1) = 0.146, P = 0.702); similarly, there was no association between subjects with migraine and development of NTG headache (χ2 (df = 1) = 0.033, P = 0.856).
Discussion
This study demonstrates that weight-calculated intravenous NTG effectively triggers cluster headache attacks in both chronic cluster headache and episodic cluster headache subjects within bout when compared with placebo. The approach is reliable in terms of triggering a fully-featured attack that allows careful observation of symptoms and their development during acute attacks of cluster headache.
The benefit of weight-calculated intravenous NTG compared to intranasal and sublingual administration is that this is more reliable and has more stable bioavailability. The median time until cluster headache attack onset was 30 minutes (open unblinded NTG visit) and 33 minutes (single-blinded NTG visit), with the overall maximum onset time of 81 minutes. Subjects who did not develop an attack during the 140 minutes of observation were asked to report if they developed an attack later on that day, and none did. The median onset time is similar to the reported latency period reported in the literature (Table 1). The minimum onset time for NTG-induced attacks was 2 minutes, and this is less than reported from the sublingual route, where the shortest time until onset time was 9 minutes (8); this is expected, given the intravenous route has a half-life of 2.3–2.8 minutes (30,31). Two subjects started experiencing mild attack pain before the start of the NTG infusion, and within the placebo group we observed one subject who developed a spontaneous attack. Spontaneous attacks could be anticipated given the subjects are within bout; there were three subjects with only short-lasting CAS symptoms and two subjects who experienced a mild pain without CAS, similar to a shadow.
This study delineates the development of the various stages of an NTG-induced cluster headache attack, including the non-headache symptoms and CAS (Figure 6). The majority of subjects developed NTG headache shortly after the infusion started. This headache was generalised, mild and progressive in nature, predominantly in the bi-occipital and bi-temporal regions. Subjects described it as pressure-like or band-like ache, and they reported it to be distinct from their cluster headache attacks; if there were an overlap, the cluster headache attack would clearly ramp up and supersede the NTG headache. It is difficult to disentangle whether NTG headache developed because there was a high proportion of subjects with either a migraine diagnosis, migraine marker or family history of migraine. However, from a previous study with 25 healthy volunteers without a migraine diagnosis, 16 (64%) developed NTG headache following 0.5 mg NTG sublingual administration (32).
Figure 6. Violin plots of the stages of cluster headache attack from the 19 subjects that developed cluster headache attacks and subdivided by chronicity. The timeline starts with 20 minutes of single-blinded nitroglycerin (NTG) infusion, followed by 120 minutes of post-infusion observation. CAS = cranial autonomic symptoms.
Following the NTG headache, the majority of subjects reported non-headache symptoms in the lead-up to the onset of the pain from the attack and in some subjects, non-headache symptoms accompanied their attacks. The non-headache symptoms included homeostatic symptoms (thirst, cravings, yawning, frequency of urination), fatigue/cognitive symptoms (concentration difficulty, fatigue, memory impairment, mood changes, irritability) and sensitised sensory symptoms (neck stiffness, photophobia, phonophobia, osmophobia, nausea), as are reported in the premonitory phase of migraine (33). The most common symptoms were neck stiffness, photophobia and thirst. During their spontaneous attacks, subjects reported that non-headache symptoms would precede the attack at a median of 10 minutes (IQR 2–30) before the onset of pain, although it is known that there are discrepancies between retrospective and prospective reporting (25). Comparing the symptoms observed from NTG-induced attacks in this study with the prospective observational questionnaire study (24), the most reported general symptoms in the pre-pain phase in this study were concentration difficulties, photophobia and mood changes. Patients in the observational study also reported general symptoms during their attacks and postictal symptoms similar to the symptoms seen during the NTG-induced attacks and the reported symptoms by the subjects in this study during the postdrome phase of their spontaneous attacks. Non-headache symptoms such as photophobia, phonophobia, and localised allodynia were often reported during the attacks, as has been reported previously (21,34). In one semi-structured questionnaire study, they found a high proportion of cluster headache patients (73.2%) reported phonophobia or photophobia with their attacks (35), cluster headache patients with migraine did not more frequently report these symptoms compared with those without co-existing migraine. Furthermore, allodynia was more often reported in cluster headache patients with migraine. From pre-clinical studies, high dose NTG causes a sustained increase in spontaneous firing of Aδ and C-fibre trigeminal neurons (36), which migraine biology may unmask.
Similar to the prospective questionnaire study by Snoer and colleagues (24), in some subjects CAS presented before the onset of the attack pain (Figure 6). In this study, the median onset time for CAS was 31 minutes (IQR 13–46) in the open unblinded NTG visit and 12 minutes (IQR 6–30) in the single-blinded NTG visit, whereas the onset of NTG-induced attack was 30 minutes (IQR 20–39) in the open unblinded visit and 33 minutes (IQR 15–42) in the single-blinded NTG visit. From the open unblinded NTG visit, 38% presented with CAS before the attack, 15% presented with CAS with the onset of the attack, and from the single-blinded NTG visit, 58% presented with CAS before the attack and 16% presented with CAS with the onset of the attack.
Vollesen and colleagues used calcitonin gene-related peptide (CGRP) infusion to trigger cluster headache attacks, finding CGRP induced 50% of subjects with CCH and 89% for ECH subjects in bout (4). In our study, NTG induced attacks in 79% of the CCH subjects and 84% in ECH subjects in bout, in the open unblinded NTG visits, and 92% CCH and 62% ECH in bout in the single-blinded NTG visits. There are some differences in the number of chronic cluster headache subjects on verapamil between the studies; in this study, 33% of CCH subjects were on verapamil and in the study by Vollesen and colleagues, 57% of CCH subjects were on verapamil (of which one was on both verapamil and lithium) and one was on 4 mg melatonin. Vollesen and colleagues proposed that the CCH patients who did not develop an attack following CGRP infusion had a lower median attack frequency in the preceding 30 days prior to the study compared to the CCH patients that did develop an attack. However, in this study, subjects reported having their last attack as long ago as 128 and 158 days and still had NTG-induced attacks (Table 3).
NTG is a pro-drug of nitric oxide (NO) and has effects on blood vessel dilation through mechanisms of the NO-cyclic guanylate phosphate (cGMP) pathway (27). However, the vasodilatory effects of NTG are not sufficient to explain the cluster headache attack that occurs after a latency and the central features associated with the attack. Indeed, experimental studies demonstrate that NTG has central effects (37,38). Interestingly, in studies where NO donors were administered in vivo and in vitro, there was a local release of CGRP (39–42). The difference in the rate of cluster headache attacks induced by NTG and CGRP in ECH and CCH subjects could reflect in part the underlying biological processes and systems that are more active in the different subtypes of cluster headache. The difference between ECH and CCH is also suggested by the treatment response to a CGRP monoclonal antibody, galcanezumab (43,44), and non-invasive vagal nerve stimulator (45,46).
Limitations
The main limitations to the study were the recruitment of eligible subjects and the dropout rate at each stage due to the nature of the condition. Therefore, a pragmatic approach was taken with the study design regarding randomisation. Although there was a randomisation sequence, this was modified by the investigator if deemed necessary. This would be in the case of episodic cluster headache patients that were near the end of their bout missing the NTG visit if they followed the randomised sequence. For this reason, it was designed to be a single-blind cross-over study and not a double-blind and randomised study. Expectation bias was reduced by maintaining blinding of the subjects until the end of the study and having both infusions identical in volume, appearance and duration of infusion. Furthermore, given the stark difference between placebo and NTG, there was no difference between attack onset in the open unblinded compared with the single-blinded NTG visits (Figure 4(b)), is an indication that randomisation was not a factor in this study.
Conclusion
We present the results of the first placebo-controlled study using intravenous NTG administration to systematically study NTG-induced cluster headache attacks. We have shown that NTG can reliably bring on cluster headache attacks as well as the development of non-headache symptoms and CAS. This study highlights differences between NTG-induced attack onset times between the ECH and CCH subjects. Understanding the stages of cluster headache is essential; by recognising the non-headache symptoms in the lead up to the onset of pain and the underlying pathogenesis of this, we may be able to uncover new therapeutic targets to abort attacks before the onset of the severe and devastating pain experienced by our cluster headache patients.
Article highlights
Weight-calculated standardised intravenous nitroglycerin administration is a reliable method to induce cluster headache attacks, cranial autonomic symptoms and non-headache symptoms that accompany cluster headache attacks.
Accompanying non-headache symptoms in cluster headache attacks are important to recognise for both clinical and research purposes.
There may be inherent differences between episodic cluster headache and chronic cluster headache.
Acknowledgement
This study would not have been possible without the support of OUCH(UK), all the cluster headache patients who were interested in helping us with this study and all the subjects who took part in this study.
Ethics or Institutional Review Board approval: This study 16/LO/0693 obtained approval from the London, City & East NHS Research Ethics Committee on 23 June 2016. This study was carried out in accordance with the World Medical Association Declaration of Helsinki (1964), the Research Governance Framework for Health and Social Care (2nd edition, 2005), the Data Protection Act (1998) and the Principles of Good Clinical Practice (GCP); all subjects gave informed consent before taking part.
Declaration of conflicting interests: The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: DYW no reported competing interests. PJG reports, over the last 36 months, grants and personal fees from Amgen and Eli-Lilly and Company, grant from Celegene, and personal fees from Alder Biopharmaceuticals, Aeon Biopharma, Allergan, Biohaven Pharmaceuticals Inc., Clexio, Electrocore LLC, eNeura, Epalex, GlaxoSmithKline, Impel Neuropharma, MundiPharma, Novartis, Pfizer, Praxis, Sanofi, Santara Therapeutics Satsuma, Teva Pharmaceuticals, Trigemina Inc., WL Gore, and personal fees from MedicoLegal work, Massachusetts Medical Society, Up-to-Date, Oxford University Press, and Wolters Kluwer; and a patent magnetic stimulation for headache assigned to eNeura without fee.
Funding: The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study is part-funded by the National Institute for Health Research (NIHR) Maudsley Biomedical Research Centre at South London Maudsley Foundation Trust and King’s College London. The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care.
ORCID iDs: Diana Y Wei https://orcid.org/0000-0003-0644-7172
Peter J Goadsby https://orcid.org/0000-0003-3260-5904 | NITROGLYCERIN | DrugsGivenReaction | CC BY | 33615843 | 19,017,453 | 2021-07 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Product use in unapproved indication'. | Comprehensive clinical phenotyping of nitroglycerin infusion induced cluster headache attacks.
Nitroglycerin administration allows the study of cluster headache attacks in their entirety in a standardised way.
A single-blind, placebo-controlled, cross-over study using weight-calculated intravenous nitroglycerin administration at 0.5 µg/kg/min over 20 minutes to study cluster headache attacks, including accompanying non-headache symptoms and cranial autonomic symptoms.
Thirty-three subjects with cluster headache were included in the study; 24 completed all three study visits. Nitroglycerin-induced attacks developed in 26 out of 33 subjects (79%) receiving unblinded nitroglycerin infusion, and in 19 out of 25 subjects (76%) receiving single-blinded nitroglycerin infusion, compared with one out of 24 subjects (4%) receiving single-blinded placebo infusion. Episodic cluster headache subjects had a shorter latency period to a nitroglycerin-induced attack compared to the chronic cluster headache (CCH) subjects (U = 15, z = -2.399, p = 0.016). Sixteen of nineteen episodic cluster headache (mean, 84%; 95% confidence interval, 66-100%) and 11 of 14 chronic cluster headache subjects developed a nitroglycerin-induced attack (79%, 54-100%) following the unblinded nitroglycerin infusion. Following the single-blinded nitroglycerin infusion, eight out of 13 episodic cluster headache (62%, 31-92%) and 11 out of 12 chronic cluster headache (92%, 73-100%) subjects developed nitroglycerin-induced attacks. Nitroglycerin induced non-headache symptoms in the majority of subjects receiving it: 91% in the open unblinded nitroglycerin visit and 84% in the single-blinded nitroglycerin visits, compared with 33% in the single-blinded placebo visit. Cranial autonomic symptoms were induced by nitroglycerin infusion, 94% in the open unblinded nitroglycerin visit and 84% in the single-blinded nitroglycerin visit, compared with 17% in the single-blinded placebo visit.
Intravenous weight-adjusted nitroglycerin administration in both episodic cluster headache in bout and chronic cluster headache is effective and reliable in inducing cluster headache attacks, cranial autonomic symptoms and non-headache symptoms.
Introduction
Due to the episodic nature of acute attacks of cluster headache, a standardised and reliable method for triggering attacks is necessary for their complete study. There have been several substances used to trigger attacks, including histamine (1,2), meta-chloro-phenylpiperazine (mCPP) (3) and more recently calcitonin gene-related peptide (CGRP) (4). Nitroglycerin (NTG) is the most frequently employed substance in human experimental modelling of cluster headache attacks, being used since 1953 (2) (Table 1).
Table 1. Review of studies using nitroglycerin to induce cluster headache attacks.
Study Number of CH patients NTG dose and route Control Placebo Rate of induced CH attack Latency period before onset of headache
(range in minutes)
Peters 1953 (2) 14 1.3 mg sublingual No, but compared with migraine, combination of CH and migraine, vasodilating head pain and tension headache No, but compared with histamine and nicotinic acid 78.6% Not reported
Ekbom 1968 (5) 38 ECH: 28 in bout, 15 out of bout (of which five were tested in bout as well) 1 mg sublingual No No In bout ECH 100% (n = 28)
Out of bout 0% (n = 15) 12–72
Barre 1982 (6) 10 CH: two CCH, nine ECH in bout 1 mg sublingual No No 100% 34–52
Mean 45.9
Drummond et al. 1984 (7) 29 CH 0.9 mg sublingual No No 76% Within 90 min
Drummond et al. 1985 (8) 22 CH: 10 CCH, 12 ECH in bout
0.9 mg sublingual Yes, 10 in the control group without headache No ECH 75% (n = 9)
CCH 60% (n = 6) 9–90
Mean 44
Bogucki 1990 (9) 21 ECH in bout 1 mg sublingual No No 67% (n = 14)
30–65
Dahl et al. 1990 (10) 15 ECH in bout 1 mg sublingual 10 healthy controls No 53% (n = 8)
Controls: not reported 30–65
Hannerz et al. 1992 (11) Eight ECH: five in bout and three out of bout 1 mg sublingual No No In bout ECH 100% (n = 5) Not reported
Fanciullacci et al. 1995 (12) 18 in bout ECH, 12 out of bout ECH 0.9 mg sublingual No No In bout ECH 100% (n = 18)
Out of bout ECH 0% (n = 12) 39–86
Fanciullacci et al. 1997 (13) 11 in bout ECH, eight out of bout ECH 0.9 mg sublingual No No In bout ECH 100% (n = 11)
Out of bout ECH 0% (n = 8) 18–50
Hsieh et al. 1996 (14) Seven ECH: four in bout ECH, three out of bout 1 mg sublingual No No In bout ECH 100%
Out of bout ECH 0% 18–35
May et al. 1998 (15) Nine CCH, eight out of bout ECH 1.0–1.2 mg spray No No CCH 100%
Out of bout ECH 0% Not reported
Costa et al. 2000 (16) 15 CH: Six ECH, nine CCH 0.9 mg sublingual No No ECH 33% (n = 2)
CCH 78% (n = 7) 19–41
Costa et al. 2003 (17) 18 ECH in bout 0.9 mg sublingual Yes, 12 healthy sex and age-matched No ECH 67% (n = 12)
Controls 0% 19–41
Sances et al. 2004 (18) 42 CH: 29 ECH (11 out of bout), 13 CCH 0.9 mg sublingual Yes, 53 healthy controls No In bout ECH and CCH 81% (n = 25 out of 31)
Controls 7.5% developed headache in 7-hour post-NTG Mean onset latency of 65.4 ± 54.7
Cluster headache patients suffer from recurrent episodes of severe unilateral pain in the trigeminal region; therefore, historically, the main emphasis has been centred around the pain onset of a cluster headache, and indeed this is often used as the indicator of the start of the attack. However, from clinical practice, there has been growing awareness of nonpainful symptoms preceding the onset of pain (19,20) and in recent years, the clinical phenotype of cluster headache has been further characterised by retrospective accounts (21–23) and prospective diaries (24,25).
The most frequent route of administration of NTG has been sublingual; however, the bioavailability of sublingual NTG is extremely variable (26). Therefore, we used a weight-calculated dose for intravenous infusion in a standardised single-blind, placebo-controlled study. NTG is a pro-drug of nitric oxide, with predominant actions on the cyclic guanylate phosphate (cGMP) pathway (27), and from pre-clinical studies there are indications of neural actions more centrally. This study is the first single-blind, placebo-controlled cross-over study using a weight-adjusted dose of nitroglycerin administered intravenously in cluster headache patients, thereby allowing comprehensive investigation of the various stages of the acute attack of cluster headache.
Methods
Subject selection and recruitment
The study was advertised on the UK cluster headache patient website OUCH (UK) (Organisation for the Understanding of Cluster Headache UK) (https://ouchuk.org/research/research-volunteers-needed) and in the tertiary Headache centre in King’s College Hospital, London. Subjects interested in participating would make contact via a dedicated research email. Subjects would then be screened for eligibility for the study via emails and a telephone call; those who met the criteria and were interested in participating were invited to attend the study visit. The study was approved by the London, City & East Research Ethics Committee (Ref Number 16/LO/0693). Data were collected from August 2016 until January 2019.
The subjects enrolled fulfilled the ICHD-3 beta criteria for cluster headache (28), and were between the ages of 18 and 60, with no significant previous medical history and no previous syncope or history of autonomic dysfunction. They had had a reliable response to high flow oxygen and/or subcutaneous sumatriptan during spontaneous attacks and normal brain neuroimaging. Women in child-bearing age were required to use reliable contraceptive methods during the study. Subjects were excluded if they were pregnant or breastfeeding, and who had any significant psychiatric disease, diagnosis of another primary headache type (other than migraine) or chronic pain syndrome, any medical history that would have contraindications to receiving NTG, use of preventive medication other than verapamil, or taking indomethacin for any reason, allergies to the medications used in the study or intolerance to high flow oxygen, and use of illicit drugs during the study.
Study visits
The study comprised of three visits in total, with each visit separated by a minimum of 1 week. During the first visit, subjects consented and a full headache history with a physical examination of the neurological and cardiovascular systems was performed, along with recordings of the baseline blood pressure, lying and standing blood pressure, heart rate, oxygen saturation, weight and electrocardiogram. Female subjects were required to have a urinary pregnancy test before the start of the infusion.
Open NTG infusion
If deemed eligible, subjects received an intravenous infusion of nitroglycerin at 0.5 µg/kg/min over 20 minutes. Subjects remained recumbent for 30 minutes before the infusion, and after the NTG infusion, subjects received 250 mL of 0.9% sodium chloride intravenously. The blood pressure and pulse were checked at the start of the infusion, and every 5 min during the infusion.
Phenotypic characterisation
Every 5 minutes, subjects were asked to rate their pain level from a scale from no pain, mild, moderate to severe, where severe equates to their most severe attack, and they were asked a questionnaire of non-headache symptoms and cranial autonomic symptoms (CAS) (Figure 1). If the subject experienced pain, further details were obtained regarding the location and characteristic. Beyond the cluster headache attack, subjects were asked to report any other headache types and in particular NTG headache, which has been well described from migraine studies (29). The NTG headache was assessed for severity, phenotype, accompanying non-headache symptoms and duration. Subjects were actively encouraged to report any symptoms as and when they developed. Following the infusion, at 10 minute intervals, any developments in pain, non-headache symptoms and CAS were recorded for a total of 120 minutes after the infusion, based on the latency period reported from previous studies (Table 1).
Figure 1. Questionnaire for non-headache and cranial autonomic symptoms.
B: bilateral; R: right-sided; L: left-sided.
Single-blinded NTG and placebo infusions
During the two single-blinded visits, subjects either received intravenous nitroglycerin at 0.5 µg/kg/min over 20 minutes or an equal volume of 0.9% sodium chloride at the same rate over 20 minutes, followed by the same 120 minutes of observations (Figure 2). The sequence was pre-determined using the randomise function in Excel; however, the investigator was able to amend this in certain situations if the subject was episodic and due to finish their bout.
Figure 2. Outline of events from open unblinded nitroglycerin visit.
BP: blood pressure; CAS: cranial autonomic symptoms; NTG: nitroglycerin; IV: intravenous.
Treatment of acute attacks
Acute treatment was administered at 20 minutes from the start of attack either with sumatriptan 6 mg subcutaneous injection (Imigran 6 mg/0.5 ml solution for injection pre-filled syringes, GlaxoSmithKline UK Ltd, or sumatriptan 6 mg/0.5 ml solution for injection pre-filled pens, Sun Pharmaceuticals Industries Europe B.V.) or with 15 L/min oxygen via a non-rebreather mask (O2Star™ non-rebreather oxygen mask M/L, Dräger). The visit was concluded only when the subject was pain free.
Statistical analysis
The data was tabulated (Excel for Mac v 16.30), and descriptive statistics were performed to summarise data (SPSS Statistics version 26 for Mac and Excel). Mann-Whitney tests were performed on time until attack onset and time until CAS onset for those that developed NTG-triggered cluster headache attacks and CAS, comparing the differences in ECH with CCH subgroups. Kaplan-Meier survival graphs were used to examine the time until onset of event; that is, survival of no cluster headache attack status, or absence of CAS after NTG infusion for 140 minutes (20 minutes of infusion and 120 minutes of post-infusion observation), with log-rank statistical testing; P < 0.05 was considered significant. Graphs were made using SPSS and violin plots were made using GraphPad Prism 8 for Mac OS.
Results
Demography
A total of 229 subjects were contacted to check for eligibility, of which 33 were included in the study; 24 completed all three study visits (Figure 3). All patients fulfilled the ICHD-3 beta criteria for cluster headache, 19 episodic cluster headache in bout (58%) and 14 chronic cluster headache (42%) (Table 2). The majority were male (n = 24, 73%) with a male: female ratio of 3:1. The average age was 41 (SD 10), with the mean age of females (34 years, SD 9) younger than in males (44 years, SD 9) in this cohort. Subjects had had the condition for a median of 9 years (IQR 5–16).
Figure 3. Subject numbers throughout the study.
Table 2. Subject characteristics.
Subject Age Sex Subtype Side of attacks Time since first attack (years) Average attack frequency (per day) Average attack duration when untreated (mins) Average bout duration (weeks) Verapamil (total daily dose in mg)
1 55 M Chronic Right 5 2 45 – 480
2 28 F Chronic Right 12 7 150 – –
3 40 M Episodic Right 20 3 150 8 –
4 38 F Episodic Left 12 2 120 4 –
5 53 M Chronic Left 15 4 35 – 960
6 48 M Episodic Left 25 5 52.5 5 480
7 23 M Episodic Left 8 2 120 10 –
8 43 M Chronic Right 9 1 40 – –
9 43 M Episodic Right 13 3 60 5 240
10 44 M Episodic Right 27 6 45 6 –
11 47 M Episodic Right 3 1 105 20 –
12 48 M Episodic Left 26 3 180 10 560
13 40 M Episodic Right 5 3 60 8 –
14 50 M Episodic Right 10 2 105 8 –
15 56 M Episodic* Right 24 1 45 – –
16 35 M Episodic Left 7 2 150 6 240
17 58 M Episodic Left 3 1 135 24 –
18 43 M Chronic Left 4 2 60 – –
19 32 M Episodic Left 3 3 50 12 600
20 49 F Episodic Right 8 5 50 9 –
21 49 M Chronic Right 35 2 90 – –
22 57 M Chronic Right 20 5 65 –
23 40 F Chronic Left 4 1.5 120 – 640
24 44 M Chronic Right 6 2 90 – 720
25 23 F Episodic Right 9 2.5 90 6 –
26 40 M Chronic Left 17 1.5 180 – –
27 20 F Chronic Right 6 1.5 150 – –
28 31 F Episodic Right 14 2 75 11 –
29 35 M Episodic Left 9 2 90 3 –
30 38 F Chronic Left 6 1.5 180 – 240
31 49 M Episodic Left 0.5 1.5 37.5 21 400
32 35 F Chronic Left 4 0.3 30 – 600
33 32 M Chronic Left 10 6 60 – –
M: male; F: female.
*Subject was chronic but became episodic during study with no attacks in 6 months.
Clinical phenotyping of subjects by history
Pain features
There was a near-equal split between the laterality of attacks; 17 subjects had right-sided attacks (52%), and 16 subjects had left-sided attacks (49%). The median number of attacks per day was two (IQR 1.5–3) lasting a median of 90 minutes (IQR 50–128). Verapamil was the only preventive allowed on the study; 12 subjects (36%) were on verapamil ranging from 240 mg to 960 mg per day.
Migraine, accompanying features and non-headache symptoms in spontaneous attacks
In this cohort, 58% (n = 19) had a concurrent migraine (28): five had migraine with aura, of which four had visual aura and one had facial sensory aura. Of the subjects who did not meet the diagnostic criteria for migraine (28) (n = 14, 42%), the majority had either migraine markers and/or a family history of migraine. Migraine markers were defined if subjects experienced: childhood cyclic nausea and vomiting, motion sickness, cold stimulus-induced headache, hangover headache and jetlag. Four subjects did not have migraine markers, and three subjects (9%) did not have either migraine marker or a family history of migraine. Subjects (n = 24, 73%) reported accompanying symptoms with their spontaneous attacks, the most common symptoms being cranial allodynia (n = 15), photophobia (n = 15), nausea (n = 11) and phonophobia (n = 10).
Non-headache attack symptoms
The majority reported non-headache symptoms in the lead up to their spontaneous cluster headache attacks (n = 27, 82%), with the commonest symptoms being concentration difficulties (n = 18), mood changes (n = 15), neck stiffness (n = 13) and yawning (n = 8). The median onset time of symptoms was 10 minutes (IQR 2–30) before the onset of pain. Although most symptoms start before the onset of pain, five subjects only reported developing the symptoms during the attack.
Twenty-eight subjects reported non-headache symptoms following their cluster headache attacks (85%), the commonest symptoms being tiredness (n = 27), mood changes (n = 13), concentration difficulties (n = 12), and neck stiffness (n = 7). The median duration of symptoms was 120 minutes (IQR 53–315).
Attack triggers
The most commonly reported triggers for spontaneous attacks were alcohol ingestion (n = 22), followed by changes in temperature (n = 12), strong smells such as from nail varnish, paint (n = 11) followed by disrupted sleep (n = 4) and exercise (n = 3). Other triggers mentioned were stress (n = 2), caffeine (n = 2), changing time zones (n = 1), let down from stress (n = 1), being in a pressurised cabin on an airplane (n = 1), vardenafil (n = 1), and dehydration (n = 1). All subjects reported attacks within a few hours of alcohol ingestion, no one reported a next-day effect.
Clinical phenotyping of open NTG visit
NTG triggered cluster headache-like attacks (n = 26, 79%), CAS (n = 31, 94%) and agitation (n = 24, 73%) during the open unblinded NTG visit. In the episodic cluster headache group, 16 out of 19 developed an NTG-induced attack (mean, 84%; 95% CI, 66–100%) and in the chronic cluster headache group, 11 out of 14 developed an NTG-induced attack (79%, 54–100%). Five out of the 31 subjects developed CAS, but did not develop an attack; of these subjects, three developed mild generalised pain, one developed restless legs, and one developed CAS on the contralateral side to the subject’s spontaneous attack phenotype, with a generalised headache. These cases were excluded.
The median onset time for CAS to develop from the start of the NTG infusion was 31 minutes (IQR 13–46). The median onset for an NTG-induced attack was 30 minutes (IQR 20–39) and the median time to maximum pain, if reached, was 51 minutes (IQR 39–70). The most common first cranial autonomic symptoms brought on by NTG infusion were nasal congestion (n = 10), conjunctival injection (n = 5), lacrimation (n = 4) and periorbital oedema (n = 3).
Clinical phenotyping of single-blinded NTG and placebo visit
During the single-blinded visits, NTG induced attacks in 19 subjects (76%); three subjects did not have an attack (12%), two subjects developed migraine-like headache (8%) and one subject developed unilateral mild pain without CAS or agitation (4%) (Table 3). In the placebo group, only one developed an attack (4%), two subjects developed unilateral mild pain without CAS or agitation (8%) and two subjects experienced short-lived unilateral CAS (8%). Of the subjects receiving NTG, eight out of 13 ECH (mean, 62%; 95% CI, 31%-92%) and 11 out of 12 CCH (92%, 73–100%) developed NTG-induced attacks (Figure 4(a)).
Table 3. Subject characteristics and comparison between spontaneous attack and triggered attack from single-blinded nitroglycerin visit, M = male, F = female, ECH = episodic cluster headache, CCH = chronic cluster headache, L = Left, R = Right, Y = Yes, N = No, VRS = verbal rating scale, mod = moderate, O2 = high flow oxygen via non-rebreather mask, suma = sumatriptan.
Subject Age Sex Subtype Migraine Verapamil (total daily dose in mg) Spontaneous attack Triggered attack- single-blinded NTG visit
Laterality Severity CAS Agitation Laterality Severity/VRS CAS Agitation Feels like spontaneous attack Treatment Last spontaneous attack (days)
1 55 M CCH N 480 R 9/10 Conjunctival injection, nasal congestion, lacrimation. 3 months of R Horner’s syndrome in 2007, now resolved Y R 10/10
VRS 3 Conjunctival injection, nasal congestion, lacrimation, periorbital oedema Y Y O2 158
2 28 F CCH Y
– R 10/10 Periorbital oedema/ptosis, nasal congestion, dry eye then lacrimation Y R 10/10
VRS 3 Periorbital oedema, nasal congestion, facial flushing Y Y O2 128
3 40 M ECH N – R 10/10 Lacrimation, rhinorrhoea, ptosis Y R 10/10
VRS 3 Lacrimation, conjunctival injection, periorbital oedema, nasal congestion, aural fullness and facial droop Y Y Suma 1
4 38 F ECH Y – L 10/10 Lacrimation, conjunctival injection, periorbital oedema, nasal congestion, ptosis, facial flushing Y No attack, developed generalised pain 4/10 Y N N/A 1
5 53 M CCH N 960 L 10/10 Rhinorrhoea, ptosis Y L 10/10
VRS 3 Conjunctival injection, eye grittiness, lacrimation Y Y O2 4
6 48 M ECH N
480 L 8/10 Nasal congestion, lacrimation Y Did not attend
7 23 M ECH Y – L 10/10 Lacrimation, conjunctival injection, nasal congestion, ptosis, facial flushing Y Did not attend
8 43 M CCH N – R 10/10 Nasal congestion, rhinorrhoea, lacrimation, facial flushing Y R 10/10
VRS 3 Nasal congestion, conjunctival injection, eye grittiness Y Y Suma <1
9 43 M ECH N 240 R 10/10 Lacrimation, conjunctival injection, facial flushing, ptosis, facial droop Y Did not attend
10 44 M ECH N – R 10/10 Nasal congestion, ptosis, periorbital oedema, lacrimation, flushing Y No attack, L mild hangover like headache, with nasal congestion.
After study visit felt nauseous and vomited, then slept, headache free at 7pm N N O2- no response <1
11 47 M ECH N – R Severe attacks 10/10 Nasal congestion, aural fullness Y R 7/10
VRS 2/3 moderate/
severe Nasal congestion, conjunctival injection, aural fullness Y Y Suma 13
12 48 M ECH N 560 L 10/10 Lacrimation, nasal congestion, periorbital oedema Y Did not attend
13 40 M ECH Y – R 10/10 Nasal congestion, ptosis, conjunctival injection, lacrimation, throat tightness, rhinorrhoea Y No attack, bilateral mild headache 4/10 with nasal congestion Y, brief (7 mins) N N/A 19
14 50 M ECH Y – R 10/10
Lacrimation, periorbital oedema, nasal congestion, rhinorrhoea Y Did not attend
15 56 M ECH Y – R 10/10 Lacrimation, rhinorrhoea, facial flushing, gritty eyes, conjunctival injection Y with severe attacks Did not attend
16 35 M ECH Y 240 L 10/10 Nasal congestion, conjunctival injection, ptosis, lacrimation, rhinorrhoea Y Not attack, milder than a shadow and no CAS N N N/A 16
17 58 M ECH Y – L 10/10 Nasal congestion, rhinorrhoea, lacrimation, aural fullness, throat swelling Y L 7/10
VRS 2–3 (mod-severe) Nasal congestion, rhinorrhoea, voice change, lacrimation Y Y Suma 1
18 43 M CCH Y – L (70%) Mild 6/10, severe 10/10 Nasal congestion, periorbital oedema, aural fullness, facial flushing Y L Mild,
VRS 1 Nasal congestion Y Y- shadow O2 7
19 32 M ECH Y 600 L 10/10 Lacrimation, conjunctival injection, facial flushing Y L 7–8/10
VRS 2–3
(mod-severe) Lacrimation, eye grittiness, nasal congestion, facial flushing Y Y O2 <1
20 49 F ECH Y – R 10/10 Ptosis, periorbital oedema, lacrimation, nasal congestion, rhinorrhoea, (aural fullness with severe attacks) Y R 6–7/10
VRS 2 mod Nasal congestion, periorbital oedema, lacrimation, conjunctival injection Y Y O2 7
21 49 M CCH Y – R 4–10/10 Facial flushing, nasal congestion, ptosis, lacrimation, rhinorrhoea, conjunctival injection Y L 8/10
VRS 2–3
(mod-severe)
Facial flushing, lacrimation, periorbital oedema, conjunctival injection Y Y, but on L rather than R Suma <1
22 57 M CCH N – R 10/10 Lacrimation, conjunctival injection, nasal congestion, rhinorrhoea Y No attack, no pain and no CAS N N N/A 26
23 40 F CCH Y 640 L 10/10
Lacrimation, conjunctival injection, periorbital oedema, rhinorrhoea, ptosis, aural fullness Y Did not attend
24 44 M CCH N 720 R 10/10 Lacrimation, conjunctival injection, periorbital oedema, facial flushing Y Did not attend
25 23 F ECH Y – R 6–10/10 Nasal congestion, lacrimation, periorbital oedema. Rhinorrhoea and facial flushing with severe attacks Y R 7/10
VRS 2
(moderate) Nasal congestion, periorbital oedema Y Y O2 3
26 40 M CCH Y – L Shadow 4/10, daytime attacks 6–7/10, full attack 10/10 Ptosis, aural fullness, lacrimation, conjunctival injection, periorbital oedema, nasal congestion Y L 8.5–9/10
VRS 3 severe Nasal congestion, periorbital oedema, lacrimation Y Y Suma 3
27 20 F CCH N – R 8–9/10 Nasal congestion, lacrimation, rhinorrhoea, ptosis, aural fullness Y R 8/10
VRS 3
severe Nasal congestion, periorbital oedema Y Y O2 <1
28 31 F ECH Y – R 10/10 Nasal congestion, periorbital oedema, rhinorrhoea, ptosis, aural fullness Y R 2/10
VRS 1 (mild) Nasal congestion, facial swelling Y Y, but milder Suma 3
29 35 M ECH N – L Max pain 10/10 Nasal congestion, periorbital oedema, lacrimation, voice change (croaky). Facial flushing with severe attacks and rhinorrhoea after attack Y L 6–7/10
VRS 2 (moderate) Nasal congestion, lacrimation, conjunctival injection, voice change Y Y Suma <1
30 38 F CCH Y 240 L 4–10/10 Lacrimation, rhinorrhoea, conjunctival injection, facial flushing. Ptosis with severe attacks Y L 6–7/10
VRS 2 (moderate) Aural fullness Y Y Suma 1
31 49 M ECH Y 400 L 10/10 Nasal congestion, lacrimation, conjunctival injection, rhinorrhoea, ptosis, aural fullness. Prominent miosis after attack Y No attack, whole head felt heavy N N N/A 10
32 35 F CCH N 600 L 4/10 (on verapamil),
7/10 average Periorbital oedema, eye grittiness, facial flushing, lacrimation Y L 7/10
VRS 2–3
(mod-severe) Nasal congestion, conjunctival injection, facial flushing, lacrimation Y Y Suma 1
33 32 M CCH Y – L Severe attacks 10/10 Lacrimation, ptosis, nasal congestion, conjunctival injection, ptosis, facial flushing, eye grittiness Y L 6/10
VRS 2 (mod-severe) Lacrimation, nasal congestion, ptosis Y Y Suma <1
Figure 4. (a) Kaplan-Meier graph comparing time until cluster headache attack between the eight episodic cluster headache (ECH) and the 11 chronic cluster headache (CCH) subjects during single-blinded nitroglycerin (NTG) infusion, from the start of the infusion in minutes, log-rank P = 0.534. (b) Kaplan-Meier graph comparing time until cluster headache attack onset between the open unblinded (n = 33) and single-blinded (n =25) nitroglycerin (NTG) infusions with single-blinded placebo infusions (n = 24). Log-rank P = 0.000.
The median onset time to an induced attack was 33 minutes (IQR 15–42) from the start of the single-blinded NTG infusion, and in the single-blinded placebo visit only one subject developed an attack; the onset time was 10 minutes. On comparison of the attack onset time for the unblinded NTG, single-blinded NTG and single-blinded placebo visits, there was a difference between the placebo and NTG visits (P = 0.000, Figure 4(b)).
NTG headache
The majority of subjects developed an NTG headache (n = 28, 85%) following the NTG infusion in the unblinded open visit, of which 27 subjects had a migraine diagnosis (n = 18), had migraine markers (n = 10) and a family history of migraine (n = 18); only one subject did not have migraine, migraine markers or a family history of migraine. The median time from the start of NTG infusion was 3 minutes (IQR 2–6), and the median duration of NTG headache was 26 minutes (IQR 14–41).
Of the 25 subjects that went on to the single-blinded NTG visits, 18 (72%) developed NTG headache following NTG infusion, of which all had either migraine (n = 11), migraine markers (n = 7) or family history (n = 10). The median time of NTG headache onset from the start of NTG infusion in the blinded visit was 4 minutes (IQR 3–8), with a median duration of 26 minutes (IQR 9–45).
In the placebo visit, three of the 24 subjects (13%) developed NTG headache, median onset time was 13 minutes (range 1–18), and the median duration was 10 minutes (range 3–16).
Non-headache symptoms
The majority of subjects reported non-headache symptoms in both the open unblinded NTG visit (n = 30, 91%) and the single-blinded NTG visit (n = 21, 84%) visits. In the single-blinded placebo visit, eight subjects (33%) reported non-headache symptoms. The most common non-headache symptoms from the open unblinded NTG visit were neck stiffness, photophobia, thirst and allodynia. The most common non-headache symptoms from the single-blinded NTG visit were neck stiffness, yawning, thirst and photophobia (Table 4). The median number of non-headache symptoms reported in the open unblinded NTG visit was three (IQR 2–5), and from the single-blinded NTG visit was three (IQR 2–6), compared with two (IQR 2–3) on-headache symptoms in the single-blinded placebo group.
Table 4. Frequencies of non-headache symptoms reported during each visit.
Non-headache symptom Open unblinded NTG visit (n = 33) Single-blinded NTG visit
(n = 25) Single-blinded placebo visit
(n = 24)
Thirst 15 10 3
Craving 0 0 0
Yawning 8 12 4
Tiredness 4 3 0
Mood changes 5 4 1
Visual blurring 4 3 1
Neck stiffness 21 15 3
Irritability 3 3 0
Photophobia 18 10 1
Concentration difficulties 6 4 1
Phonophobia 4 6 0
Urinary symptoms 0 0 0
Speech disturbances 0 0 0
Nausea 6 3 0
Gastrointestinal discomfort 0 0 0
Movement sensitivity 5 5 1
Allodynia 9 8 2
In the open unblinded NTG visit, the median onset time of non-headache symptoms from the start of the infusion was 9 minutes (IQR 4–17) with the median maximum duration of the symptoms being 50 minutes (IQR 24–64), the duration is calculated from the first symptom until the end of the last symptom. In the single-blinded NTG visit, the median onset time was 5 minutes (IQR 3–9) from the start of the infusion, and the median maximum duration of symptoms was 59 minutes (IQR 35–76). The outlier was a subject who developed allodynia and neck stiffness during their attack. For those that developed non-headache symptoms during the single-blinded placebo visit, the median onset time was 9 minutes (IQR 2–9), with a median duration of 16 minutes (IQR 6–34).
Cranial autonomic symptoms
NTG triggered CAS in the majority of the subjects during the open unblinded NTG visit (n = 31, 94%). In all, five subjects out of the 31 (19%) developed unilateral CAS; however, they did not have a cluster headache attack. Two subjects had CAS with generalised headache, one had CAS without any pain, one subject developed CAS on the contralateral side to their attacks with mild generalised pain, and one subject with CAS developed restless leg symptoms, but no cluster headache attack. Of the subjects who developed unilateral CAS and cluster headache attack (n = 26, 79%), the median number of CAS was four (IQR 2–5), with the most common CAS being nasal congestion (n = 21), lacrimation (n = 16) and periorbital oedema (n = 15) (Table 5).
Table 5. Frequencies of cranial autonomic symptoms reported in subjects who had attacks following NTG infusion.
Cranial autonomicsymptoms Open unblinded NTG visit, total number of attacks (n = 26) Single-blinded NTG visit, total number of attacks (n = 19)
Lacrimation 16 11
Conjunctival injection 12 9
Periorbital oedema 15 8
Eye grittiness/itchiness 3 3
Nasal congestion 21 16
Rhinorrhoea 2 1
Ptosis 4 1
Aural fullness 5 2
Facial flushing 7 4
Sialorrhoea 1 0
Throat swelling 2 0
Voice change 4 2
Facial swelling 3 1
Similarly, NTG brought on CAS in the majority of subjects during the single-blinded NTG visit (n = 21, 84%), of which two were not accompanied by a cluster headache attack, compared with four out of 24 in the single-blinded placebo group developing CAS (Figure 5(a)). One of the subjects from the single-blinded NTG group had a generalised headache similar to a hangover headache with unilateral CAS, and the other subject had a migraine-like headache with CAS. Of the 19 subjects (76%) that had unilateral CAS and a cluster headache attack, the median number of symptoms was three (IQR 2–4) and the most frequent symptoms were nasal congestion (n = 16), lacrimation ( n = 11) and conjunctival injection (n = 9) (Table 5). In comparing the time until all CAS onset between ECH and CCH after blinded NTG infusion, there was no difference between the two groups (log-rank P = 0.740; Figure 5(b)).
Figure 5. (a) Kaplan-Meier graph showing time until onset of cranial autonomic symptoms (CAS) following open unblinded (n = 33) and single-blinded NTG (n = 25) infusions compared with the single-blinded placebo infusion (n = 24). Log-rank P = 0.000. (b) Kaplan-Meier graph showing the time until CAS onset in the single-blinded NTG visit, comparing episodic cluster headache (ECH) with chronic cluster headache (CCH). Log-rank P = 0.740.
The median time until CAS onset for those that developed cluster headache attacks was 31 min (IQR 13–46) in the open unblinded NTG visit and 12 min (IQR 6–30) in the single-blinded NTG visit. Subjects sequentially reported CAS development.
During the single-blinded placebo visit, four subjects (17%) developed unilateral CAS, of which one subject developed a spontaneous attack, and three developed CAS but no pain. The median number of symptoms reported in the placebo group was two (IQR 1–2) and the symptoms reported were nasal congestion (n = 2), conjunctival injection (n = 1), periorbital swelling (n = 1), rhinorrhoea (n = 1) and aural fullness (n = 1).
Agitation
Nitroglycerin brought on agitation in the majority of subjects, open unblinded NTG visit (n = 24, 73%) and single-blinded NTG visit (n= 20, 80%), compared with none in the single-blinded placebo visit.
Non-headache symptoms post-attack
The non-headache symptoms were not studied here, as all attacks were treated with sumatriptan or oxygen after 20 minutes, thus altering the natural progression and development of symptoms.
Episodic cluster headache compared with chronic cluster headache
For the subjects that developed an NTG-induced attack following the single-blinded NTG infusion, the time until NTG-induced attack was shorter in the episodic cluster headache group compared with the chronic cluster headache group (U = 15, z = −2.399, P = 0.016). The time until CAS onset, in the subjects that developed CAS following single-blinded NTG infusion was not different between episodic cluster headache and chronic cluster headache groups (U = 38, z = −1.2000, P = 0.230).
Effect of verapamil on NTG triggering
There were seven subjects on verapamil that attended the single-blinded NTG visits, of which two did not develop NTG-triggered cluster headache attacks (29%). Using χ2, there was no difference between verapamil and NTG triggering (χ2 (df = 1) = 0.111, P = 0.739).
Effect of migraine on NTG-triggered attacks
Within the cohort that attended the single-blinded NTG visits, 15 had migraine (60%). There was no difference between the number of non-headache symptoms (U = 67, z = −0.449, P = 0.654) or number of CAS (U = 57, z = −1.019, P = 0.308), between the subjects with migraine and those without migraine. Furthermore, there was no association between subjects with migraine and NTG triggering (χ2 (df = 1) = 0.146, P = 0.702); similarly, there was no association between subjects with migraine and development of NTG headache (χ2 (df = 1) = 0.033, P = 0.856).
Discussion
This study demonstrates that weight-calculated intravenous NTG effectively triggers cluster headache attacks in both chronic cluster headache and episodic cluster headache subjects within bout when compared with placebo. The approach is reliable in terms of triggering a fully-featured attack that allows careful observation of symptoms and their development during acute attacks of cluster headache.
The benefit of weight-calculated intravenous NTG compared to intranasal and sublingual administration is that this is more reliable and has more stable bioavailability. The median time until cluster headache attack onset was 30 minutes (open unblinded NTG visit) and 33 minutes (single-blinded NTG visit), with the overall maximum onset time of 81 minutes. Subjects who did not develop an attack during the 140 minutes of observation were asked to report if they developed an attack later on that day, and none did. The median onset time is similar to the reported latency period reported in the literature (Table 1). The minimum onset time for NTG-induced attacks was 2 minutes, and this is less than reported from the sublingual route, where the shortest time until onset time was 9 minutes (8); this is expected, given the intravenous route has a half-life of 2.3–2.8 minutes (30,31). Two subjects started experiencing mild attack pain before the start of the NTG infusion, and within the placebo group we observed one subject who developed a spontaneous attack. Spontaneous attacks could be anticipated given the subjects are within bout; there were three subjects with only short-lasting CAS symptoms and two subjects who experienced a mild pain without CAS, similar to a shadow.
This study delineates the development of the various stages of an NTG-induced cluster headache attack, including the non-headache symptoms and CAS (Figure 6). The majority of subjects developed NTG headache shortly after the infusion started. This headache was generalised, mild and progressive in nature, predominantly in the bi-occipital and bi-temporal regions. Subjects described it as pressure-like or band-like ache, and they reported it to be distinct from their cluster headache attacks; if there were an overlap, the cluster headache attack would clearly ramp up and supersede the NTG headache. It is difficult to disentangle whether NTG headache developed because there was a high proportion of subjects with either a migraine diagnosis, migraine marker or family history of migraine. However, from a previous study with 25 healthy volunteers without a migraine diagnosis, 16 (64%) developed NTG headache following 0.5 mg NTG sublingual administration (32).
Figure 6. Violin plots of the stages of cluster headache attack from the 19 subjects that developed cluster headache attacks and subdivided by chronicity. The timeline starts with 20 minutes of single-blinded nitroglycerin (NTG) infusion, followed by 120 minutes of post-infusion observation. CAS = cranial autonomic symptoms.
Following the NTG headache, the majority of subjects reported non-headache symptoms in the lead-up to the onset of the pain from the attack and in some subjects, non-headache symptoms accompanied their attacks. The non-headache symptoms included homeostatic symptoms (thirst, cravings, yawning, frequency of urination), fatigue/cognitive symptoms (concentration difficulty, fatigue, memory impairment, mood changes, irritability) and sensitised sensory symptoms (neck stiffness, photophobia, phonophobia, osmophobia, nausea), as are reported in the premonitory phase of migraine (33). The most common symptoms were neck stiffness, photophobia and thirst. During their spontaneous attacks, subjects reported that non-headache symptoms would precede the attack at a median of 10 minutes (IQR 2–30) before the onset of pain, although it is known that there are discrepancies between retrospective and prospective reporting (25). Comparing the symptoms observed from NTG-induced attacks in this study with the prospective observational questionnaire study (24), the most reported general symptoms in the pre-pain phase in this study were concentration difficulties, photophobia and mood changes. Patients in the observational study also reported general symptoms during their attacks and postictal symptoms similar to the symptoms seen during the NTG-induced attacks and the reported symptoms by the subjects in this study during the postdrome phase of their spontaneous attacks. Non-headache symptoms such as photophobia, phonophobia, and localised allodynia were often reported during the attacks, as has been reported previously (21,34). In one semi-structured questionnaire study, they found a high proportion of cluster headache patients (73.2%) reported phonophobia or photophobia with their attacks (35), cluster headache patients with migraine did not more frequently report these symptoms compared with those without co-existing migraine. Furthermore, allodynia was more often reported in cluster headache patients with migraine. From pre-clinical studies, high dose NTG causes a sustained increase in spontaneous firing of Aδ and C-fibre trigeminal neurons (36), which migraine biology may unmask.
Similar to the prospective questionnaire study by Snoer and colleagues (24), in some subjects CAS presented before the onset of the attack pain (Figure 6). In this study, the median onset time for CAS was 31 minutes (IQR 13–46) in the open unblinded NTG visit and 12 minutes (IQR 6–30) in the single-blinded NTG visit, whereas the onset of NTG-induced attack was 30 minutes (IQR 20–39) in the open unblinded visit and 33 minutes (IQR 15–42) in the single-blinded NTG visit. From the open unblinded NTG visit, 38% presented with CAS before the attack, 15% presented with CAS with the onset of the attack, and from the single-blinded NTG visit, 58% presented with CAS before the attack and 16% presented with CAS with the onset of the attack.
Vollesen and colleagues used calcitonin gene-related peptide (CGRP) infusion to trigger cluster headache attacks, finding CGRP induced 50% of subjects with CCH and 89% for ECH subjects in bout (4). In our study, NTG induced attacks in 79% of the CCH subjects and 84% in ECH subjects in bout, in the open unblinded NTG visits, and 92% CCH and 62% ECH in bout in the single-blinded NTG visits. There are some differences in the number of chronic cluster headache subjects on verapamil between the studies; in this study, 33% of CCH subjects were on verapamil and in the study by Vollesen and colleagues, 57% of CCH subjects were on verapamil (of which one was on both verapamil and lithium) and one was on 4 mg melatonin. Vollesen and colleagues proposed that the CCH patients who did not develop an attack following CGRP infusion had a lower median attack frequency in the preceding 30 days prior to the study compared to the CCH patients that did develop an attack. However, in this study, subjects reported having their last attack as long ago as 128 and 158 days and still had NTG-induced attacks (Table 3).
NTG is a pro-drug of nitric oxide (NO) and has effects on blood vessel dilation through mechanisms of the NO-cyclic guanylate phosphate (cGMP) pathway (27). However, the vasodilatory effects of NTG are not sufficient to explain the cluster headache attack that occurs after a latency and the central features associated with the attack. Indeed, experimental studies demonstrate that NTG has central effects (37,38). Interestingly, in studies where NO donors were administered in vivo and in vitro, there was a local release of CGRP (39–42). The difference in the rate of cluster headache attacks induced by NTG and CGRP in ECH and CCH subjects could reflect in part the underlying biological processes and systems that are more active in the different subtypes of cluster headache. The difference between ECH and CCH is also suggested by the treatment response to a CGRP monoclonal antibody, galcanezumab (43,44), and non-invasive vagal nerve stimulator (45,46).
Limitations
The main limitations to the study were the recruitment of eligible subjects and the dropout rate at each stage due to the nature of the condition. Therefore, a pragmatic approach was taken with the study design regarding randomisation. Although there was a randomisation sequence, this was modified by the investigator if deemed necessary. This would be in the case of episodic cluster headache patients that were near the end of their bout missing the NTG visit if they followed the randomised sequence. For this reason, it was designed to be a single-blind cross-over study and not a double-blind and randomised study. Expectation bias was reduced by maintaining blinding of the subjects until the end of the study and having both infusions identical in volume, appearance and duration of infusion. Furthermore, given the stark difference between placebo and NTG, there was no difference between attack onset in the open unblinded compared with the single-blinded NTG visits (Figure 4(b)), is an indication that randomisation was not a factor in this study.
Conclusion
We present the results of the first placebo-controlled study using intravenous NTG administration to systematically study NTG-induced cluster headache attacks. We have shown that NTG can reliably bring on cluster headache attacks as well as the development of non-headache symptoms and CAS. This study highlights differences between NTG-induced attack onset times between the ECH and CCH subjects. Understanding the stages of cluster headache is essential; by recognising the non-headache symptoms in the lead up to the onset of pain and the underlying pathogenesis of this, we may be able to uncover new therapeutic targets to abort attacks before the onset of the severe and devastating pain experienced by our cluster headache patients.
Article highlights
Weight-calculated standardised intravenous nitroglycerin administration is a reliable method to induce cluster headache attacks, cranial autonomic symptoms and non-headache symptoms that accompany cluster headache attacks.
Accompanying non-headache symptoms in cluster headache attacks are important to recognise for both clinical and research purposes.
There may be inherent differences between episodic cluster headache and chronic cluster headache.
Acknowledgement
This study would not have been possible without the support of OUCH(UK), all the cluster headache patients who were interested in helping us with this study and all the subjects who took part in this study.
Ethics or Institutional Review Board approval: This study 16/LO/0693 obtained approval from the London, City & East NHS Research Ethics Committee on 23 June 2016. This study was carried out in accordance with the World Medical Association Declaration of Helsinki (1964), the Research Governance Framework for Health and Social Care (2nd edition, 2005), the Data Protection Act (1998) and the Principles of Good Clinical Practice (GCP); all subjects gave informed consent before taking part.
Declaration of conflicting interests: The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: DYW no reported competing interests. PJG reports, over the last 36 months, grants and personal fees from Amgen and Eli-Lilly and Company, grant from Celegene, and personal fees from Alder Biopharmaceuticals, Aeon Biopharma, Allergan, Biohaven Pharmaceuticals Inc., Clexio, Electrocore LLC, eNeura, Epalex, GlaxoSmithKline, Impel Neuropharma, MundiPharma, Novartis, Pfizer, Praxis, Sanofi, Santara Therapeutics Satsuma, Teva Pharmaceuticals, Trigemina Inc., WL Gore, and personal fees from MedicoLegal work, Massachusetts Medical Society, Up-to-Date, Oxford University Press, and Wolters Kluwer; and a patent magnetic stimulation for headache assigned to eNeura without fee.
Funding: The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study is part-funded by the National Institute for Health Research (NIHR) Maudsley Biomedical Research Centre at South London Maudsley Foundation Trust and King’s College London. The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care.
ORCID iDs: Diana Y Wei https://orcid.org/0000-0003-0644-7172
Peter J Goadsby https://orcid.org/0000-0003-3260-5904 | NITROGLYCERIN | DrugsGivenReaction | CC BY | 33615843 | 19,017,453 | 2021-07 |
What was the administration route of drug 'NITROGLYCERIN'? | Comprehensive clinical phenotyping of nitroglycerin infusion induced cluster headache attacks.
Nitroglycerin administration allows the study of cluster headache attacks in their entirety in a standardised way.
A single-blind, placebo-controlled, cross-over study using weight-calculated intravenous nitroglycerin administration at 0.5 µg/kg/min over 20 minutes to study cluster headache attacks, including accompanying non-headache symptoms and cranial autonomic symptoms.
Thirty-three subjects with cluster headache were included in the study; 24 completed all three study visits. Nitroglycerin-induced attacks developed in 26 out of 33 subjects (79%) receiving unblinded nitroglycerin infusion, and in 19 out of 25 subjects (76%) receiving single-blinded nitroglycerin infusion, compared with one out of 24 subjects (4%) receiving single-blinded placebo infusion. Episodic cluster headache subjects had a shorter latency period to a nitroglycerin-induced attack compared to the chronic cluster headache (CCH) subjects (U = 15, z = -2.399, p = 0.016). Sixteen of nineteen episodic cluster headache (mean, 84%; 95% confidence interval, 66-100%) and 11 of 14 chronic cluster headache subjects developed a nitroglycerin-induced attack (79%, 54-100%) following the unblinded nitroglycerin infusion. Following the single-blinded nitroglycerin infusion, eight out of 13 episodic cluster headache (62%, 31-92%) and 11 out of 12 chronic cluster headache (92%, 73-100%) subjects developed nitroglycerin-induced attacks. Nitroglycerin induced non-headache symptoms in the majority of subjects receiving it: 91% in the open unblinded nitroglycerin visit and 84% in the single-blinded nitroglycerin visits, compared with 33% in the single-blinded placebo visit. Cranial autonomic symptoms were induced by nitroglycerin infusion, 94% in the open unblinded nitroglycerin visit and 84% in the single-blinded nitroglycerin visit, compared with 17% in the single-blinded placebo visit.
Intravenous weight-adjusted nitroglycerin administration in both episodic cluster headache in bout and chronic cluster headache is effective and reliable in inducing cluster headache attacks, cranial autonomic symptoms and non-headache symptoms.
Introduction
Due to the episodic nature of acute attacks of cluster headache, a standardised and reliable method for triggering attacks is necessary for their complete study. There have been several substances used to trigger attacks, including histamine (1,2), meta-chloro-phenylpiperazine (mCPP) (3) and more recently calcitonin gene-related peptide (CGRP) (4). Nitroglycerin (NTG) is the most frequently employed substance in human experimental modelling of cluster headache attacks, being used since 1953 (2) (Table 1).
Table 1. Review of studies using nitroglycerin to induce cluster headache attacks.
Study Number of CH patients NTG dose and route Control Placebo Rate of induced CH attack Latency period before onset of headache
(range in minutes)
Peters 1953 (2) 14 1.3 mg sublingual No, but compared with migraine, combination of CH and migraine, vasodilating head pain and tension headache No, but compared with histamine and nicotinic acid 78.6% Not reported
Ekbom 1968 (5) 38 ECH: 28 in bout, 15 out of bout (of which five were tested in bout as well) 1 mg sublingual No No In bout ECH 100% (n = 28)
Out of bout 0% (n = 15) 12–72
Barre 1982 (6) 10 CH: two CCH, nine ECH in bout 1 mg sublingual No No 100% 34–52
Mean 45.9
Drummond et al. 1984 (7) 29 CH 0.9 mg sublingual No No 76% Within 90 min
Drummond et al. 1985 (8) 22 CH: 10 CCH, 12 ECH in bout
0.9 mg sublingual Yes, 10 in the control group without headache No ECH 75% (n = 9)
CCH 60% (n = 6) 9–90
Mean 44
Bogucki 1990 (9) 21 ECH in bout 1 mg sublingual No No 67% (n = 14)
30–65
Dahl et al. 1990 (10) 15 ECH in bout 1 mg sublingual 10 healthy controls No 53% (n = 8)
Controls: not reported 30–65
Hannerz et al. 1992 (11) Eight ECH: five in bout and three out of bout 1 mg sublingual No No In bout ECH 100% (n = 5) Not reported
Fanciullacci et al. 1995 (12) 18 in bout ECH, 12 out of bout ECH 0.9 mg sublingual No No In bout ECH 100% (n = 18)
Out of bout ECH 0% (n = 12) 39–86
Fanciullacci et al. 1997 (13) 11 in bout ECH, eight out of bout ECH 0.9 mg sublingual No No In bout ECH 100% (n = 11)
Out of bout ECH 0% (n = 8) 18–50
Hsieh et al. 1996 (14) Seven ECH: four in bout ECH, three out of bout 1 mg sublingual No No In bout ECH 100%
Out of bout ECH 0% 18–35
May et al. 1998 (15) Nine CCH, eight out of bout ECH 1.0–1.2 mg spray No No CCH 100%
Out of bout ECH 0% Not reported
Costa et al. 2000 (16) 15 CH: Six ECH, nine CCH 0.9 mg sublingual No No ECH 33% (n = 2)
CCH 78% (n = 7) 19–41
Costa et al. 2003 (17) 18 ECH in bout 0.9 mg sublingual Yes, 12 healthy sex and age-matched No ECH 67% (n = 12)
Controls 0% 19–41
Sances et al. 2004 (18) 42 CH: 29 ECH (11 out of bout), 13 CCH 0.9 mg sublingual Yes, 53 healthy controls No In bout ECH and CCH 81% (n = 25 out of 31)
Controls 7.5% developed headache in 7-hour post-NTG Mean onset latency of 65.4 ± 54.7
Cluster headache patients suffer from recurrent episodes of severe unilateral pain in the trigeminal region; therefore, historically, the main emphasis has been centred around the pain onset of a cluster headache, and indeed this is often used as the indicator of the start of the attack. However, from clinical practice, there has been growing awareness of nonpainful symptoms preceding the onset of pain (19,20) and in recent years, the clinical phenotype of cluster headache has been further characterised by retrospective accounts (21–23) and prospective diaries (24,25).
The most frequent route of administration of NTG has been sublingual; however, the bioavailability of sublingual NTG is extremely variable (26). Therefore, we used a weight-calculated dose for intravenous infusion in a standardised single-blind, placebo-controlled study. NTG is a pro-drug of nitric oxide, with predominant actions on the cyclic guanylate phosphate (cGMP) pathway (27), and from pre-clinical studies there are indications of neural actions more centrally. This study is the first single-blind, placebo-controlled cross-over study using a weight-adjusted dose of nitroglycerin administered intravenously in cluster headache patients, thereby allowing comprehensive investigation of the various stages of the acute attack of cluster headache.
Methods
Subject selection and recruitment
The study was advertised on the UK cluster headache patient website OUCH (UK) (Organisation for the Understanding of Cluster Headache UK) (https://ouchuk.org/research/research-volunteers-needed) and in the tertiary Headache centre in King’s College Hospital, London. Subjects interested in participating would make contact via a dedicated research email. Subjects would then be screened for eligibility for the study via emails and a telephone call; those who met the criteria and were interested in participating were invited to attend the study visit. The study was approved by the London, City & East Research Ethics Committee (Ref Number 16/LO/0693). Data were collected from August 2016 until January 2019.
The subjects enrolled fulfilled the ICHD-3 beta criteria for cluster headache (28), and were between the ages of 18 and 60, with no significant previous medical history and no previous syncope or history of autonomic dysfunction. They had had a reliable response to high flow oxygen and/or subcutaneous sumatriptan during spontaneous attacks and normal brain neuroimaging. Women in child-bearing age were required to use reliable contraceptive methods during the study. Subjects were excluded if they were pregnant or breastfeeding, and who had any significant psychiatric disease, diagnosis of another primary headache type (other than migraine) or chronic pain syndrome, any medical history that would have contraindications to receiving NTG, use of preventive medication other than verapamil, or taking indomethacin for any reason, allergies to the medications used in the study or intolerance to high flow oxygen, and use of illicit drugs during the study.
Study visits
The study comprised of three visits in total, with each visit separated by a minimum of 1 week. During the first visit, subjects consented and a full headache history with a physical examination of the neurological and cardiovascular systems was performed, along with recordings of the baseline blood pressure, lying and standing blood pressure, heart rate, oxygen saturation, weight and electrocardiogram. Female subjects were required to have a urinary pregnancy test before the start of the infusion.
Open NTG infusion
If deemed eligible, subjects received an intravenous infusion of nitroglycerin at 0.5 µg/kg/min over 20 minutes. Subjects remained recumbent for 30 minutes before the infusion, and after the NTG infusion, subjects received 250 mL of 0.9% sodium chloride intravenously. The blood pressure and pulse were checked at the start of the infusion, and every 5 min during the infusion.
Phenotypic characterisation
Every 5 minutes, subjects were asked to rate their pain level from a scale from no pain, mild, moderate to severe, where severe equates to their most severe attack, and they were asked a questionnaire of non-headache symptoms and cranial autonomic symptoms (CAS) (Figure 1). If the subject experienced pain, further details were obtained regarding the location and characteristic. Beyond the cluster headache attack, subjects were asked to report any other headache types and in particular NTG headache, which has been well described from migraine studies (29). The NTG headache was assessed for severity, phenotype, accompanying non-headache symptoms and duration. Subjects were actively encouraged to report any symptoms as and when they developed. Following the infusion, at 10 minute intervals, any developments in pain, non-headache symptoms and CAS were recorded for a total of 120 minutes after the infusion, based on the latency period reported from previous studies (Table 1).
Figure 1. Questionnaire for non-headache and cranial autonomic symptoms.
B: bilateral; R: right-sided; L: left-sided.
Single-blinded NTG and placebo infusions
During the two single-blinded visits, subjects either received intravenous nitroglycerin at 0.5 µg/kg/min over 20 minutes or an equal volume of 0.9% sodium chloride at the same rate over 20 minutes, followed by the same 120 minutes of observations (Figure 2). The sequence was pre-determined using the randomise function in Excel; however, the investigator was able to amend this in certain situations if the subject was episodic and due to finish their bout.
Figure 2. Outline of events from open unblinded nitroglycerin visit.
BP: blood pressure; CAS: cranial autonomic symptoms; NTG: nitroglycerin; IV: intravenous.
Treatment of acute attacks
Acute treatment was administered at 20 minutes from the start of attack either with sumatriptan 6 mg subcutaneous injection (Imigran 6 mg/0.5 ml solution for injection pre-filled syringes, GlaxoSmithKline UK Ltd, or sumatriptan 6 mg/0.5 ml solution for injection pre-filled pens, Sun Pharmaceuticals Industries Europe B.V.) or with 15 L/min oxygen via a non-rebreather mask (O2Star™ non-rebreather oxygen mask M/L, Dräger). The visit was concluded only when the subject was pain free.
Statistical analysis
The data was tabulated (Excel for Mac v 16.30), and descriptive statistics were performed to summarise data (SPSS Statistics version 26 for Mac and Excel). Mann-Whitney tests were performed on time until attack onset and time until CAS onset for those that developed NTG-triggered cluster headache attacks and CAS, comparing the differences in ECH with CCH subgroups. Kaplan-Meier survival graphs were used to examine the time until onset of event; that is, survival of no cluster headache attack status, or absence of CAS after NTG infusion for 140 minutes (20 minutes of infusion and 120 minutes of post-infusion observation), with log-rank statistical testing; P < 0.05 was considered significant. Graphs were made using SPSS and violin plots were made using GraphPad Prism 8 for Mac OS.
Results
Demography
A total of 229 subjects were contacted to check for eligibility, of which 33 were included in the study; 24 completed all three study visits (Figure 3). All patients fulfilled the ICHD-3 beta criteria for cluster headache, 19 episodic cluster headache in bout (58%) and 14 chronic cluster headache (42%) (Table 2). The majority were male (n = 24, 73%) with a male: female ratio of 3:1. The average age was 41 (SD 10), with the mean age of females (34 years, SD 9) younger than in males (44 years, SD 9) in this cohort. Subjects had had the condition for a median of 9 years (IQR 5–16).
Figure 3. Subject numbers throughout the study.
Table 2. Subject characteristics.
Subject Age Sex Subtype Side of attacks Time since first attack (years) Average attack frequency (per day) Average attack duration when untreated (mins) Average bout duration (weeks) Verapamil (total daily dose in mg)
1 55 M Chronic Right 5 2 45 – 480
2 28 F Chronic Right 12 7 150 – –
3 40 M Episodic Right 20 3 150 8 –
4 38 F Episodic Left 12 2 120 4 –
5 53 M Chronic Left 15 4 35 – 960
6 48 M Episodic Left 25 5 52.5 5 480
7 23 M Episodic Left 8 2 120 10 –
8 43 M Chronic Right 9 1 40 – –
9 43 M Episodic Right 13 3 60 5 240
10 44 M Episodic Right 27 6 45 6 –
11 47 M Episodic Right 3 1 105 20 –
12 48 M Episodic Left 26 3 180 10 560
13 40 M Episodic Right 5 3 60 8 –
14 50 M Episodic Right 10 2 105 8 –
15 56 M Episodic* Right 24 1 45 – –
16 35 M Episodic Left 7 2 150 6 240
17 58 M Episodic Left 3 1 135 24 –
18 43 M Chronic Left 4 2 60 – –
19 32 M Episodic Left 3 3 50 12 600
20 49 F Episodic Right 8 5 50 9 –
21 49 M Chronic Right 35 2 90 – –
22 57 M Chronic Right 20 5 65 –
23 40 F Chronic Left 4 1.5 120 – 640
24 44 M Chronic Right 6 2 90 – 720
25 23 F Episodic Right 9 2.5 90 6 –
26 40 M Chronic Left 17 1.5 180 – –
27 20 F Chronic Right 6 1.5 150 – –
28 31 F Episodic Right 14 2 75 11 –
29 35 M Episodic Left 9 2 90 3 –
30 38 F Chronic Left 6 1.5 180 – 240
31 49 M Episodic Left 0.5 1.5 37.5 21 400
32 35 F Chronic Left 4 0.3 30 – 600
33 32 M Chronic Left 10 6 60 – –
M: male; F: female.
*Subject was chronic but became episodic during study with no attacks in 6 months.
Clinical phenotyping of subjects by history
Pain features
There was a near-equal split between the laterality of attacks; 17 subjects had right-sided attacks (52%), and 16 subjects had left-sided attacks (49%). The median number of attacks per day was two (IQR 1.5–3) lasting a median of 90 minutes (IQR 50–128). Verapamil was the only preventive allowed on the study; 12 subjects (36%) were on verapamil ranging from 240 mg to 960 mg per day.
Migraine, accompanying features and non-headache symptoms in spontaneous attacks
In this cohort, 58% (n = 19) had a concurrent migraine (28): five had migraine with aura, of which four had visual aura and one had facial sensory aura. Of the subjects who did not meet the diagnostic criteria for migraine (28) (n = 14, 42%), the majority had either migraine markers and/or a family history of migraine. Migraine markers were defined if subjects experienced: childhood cyclic nausea and vomiting, motion sickness, cold stimulus-induced headache, hangover headache and jetlag. Four subjects did not have migraine markers, and three subjects (9%) did not have either migraine marker or a family history of migraine. Subjects (n = 24, 73%) reported accompanying symptoms with their spontaneous attacks, the most common symptoms being cranial allodynia (n = 15), photophobia (n = 15), nausea (n = 11) and phonophobia (n = 10).
Non-headache attack symptoms
The majority reported non-headache symptoms in the lead up to their spontaneous cluster headache attacks (n = 27, 82%), with the commonest symptoms being concentration difficulties (n = 18), mood changes (n = 15), neck stiffness (n = 13) and yawning (n = 8). The median onset time of symptoms was 10 minutes (IQR 2–30) before the onset of pain. Although most symptoms start before the onset of pain, five subjects only reported developing the symptoms during the attack.
Twenty-eight subjects reported non-headache symptoms following their cluster headache attacks (85%), the commonest symptoms being tiredness (n = 27), mood changes (n = 13), concentration difficulties (n = 12), and neck stiffness (n = 7). The median duration of symptoms was 120 minutes (IQR 53–315).
Attack triggers
The most commonly reported triggers for spontaneous attacks were alcohol ingestion (n = 22), followed by changes in temperature (n = 12), strong smells such as from nail varnish, paint (n = 11) followed by disrupted sleep (n = 4) and exercise (n = 3). Other triggers mentioned were stress (n = 2), caffeine (n = 2), changing time zones (n = 1), let down from stress (n = 1), being in a pressurised cabin on an airplane (n = 1), vardenafil (n = 1), and dehydration (n = 1). All subjects reported attacks within a few hours of alcohol ingestion, no one reported a next-day effect.
Clinical phenotyping of open NTG visit
NTG triggered cluster headache-like attacks (n = 26, 79%), CAS (n = 31, 94%) and agitation (n = 24, 73%) during the open unblinded NTG visit. In the episodic cluster headache group, 16 out of 19 developed an NTG-induced attack (mean, 84%; 95% CI, 66–100%) and in the chronic cluster headache group, 11 out of 14 developed an NTG-induced attack (79%, 54–100%). Five out of the 31 subjects developed CAS, but did not develop an attack; of these subjects, three developed mild generalised pain, one developed restless legs, and one developed CAS on the contralateral side to the subject’s spontaneous attack phenotype, with a generalised headache. These cases were excluded.
The median onset time for CAS to develop from the start of the NTG infusion was 31 minutes (IQR 13–46). The median onset for an NTG-induced attack was 30 minutes (IQR 20–39) and the median time to maximum pain, if reached, was 51 minutes (IQR 39–70). The most common first cranial autonomic symptoms brought on by NTG infusion were nasal congestion (n = 10), conjunctival injection (n = 5), lacrimation (n = 4) and periorbital oedema (n = 3).
Clinical phenotyping of single-blinded NTG and placebo visit
During the single-blinded visits, NTG induced attacks in 19 subjects (76%); three subjects did not have an attack (12%), two subjects developed migraine-like headache (8%) and one subject developed unilateral mild pain without CAS or agitation (4%) (Table 3). In the placebo group, only one developed an attack (4%), two subjects developed unilateral mild pain without CAS or agitation (8%) and two subjects experienced short-lived unilateral CAS (8%). Of the subjects receiving NTG, eight out of 13 ECH (mean, 62%; 95% CI, 31%-92%) and 11 out of 12 CCH (92%, 73–100%) developed NTG-induced attacks (Figure 4(a)).
Table 3. Subject characteristics and comparison between spontaneous attack and triggered attack from single-blinded nitroglycerin visit, M = male, F = female, ECH = episodic cluster headache, CCH = chronic cluster headache, L = Left, R = Right, Y = Yes, N = No, VRS = verbal rating scale, mod = moderate, O2 = high flow oxygen via non-rebreather mask, suma = sumatriptan.
Subject Age Sex Subtype Migraine Verapamil (total daily dose in mg) Spontaneous attack Triggered attack- single-blinded NTG visit
Laterality Severity CAS Agitation Laterality Severity/VRS CAS Agitation Feels like spontaneous attack Treatment Last spontaneous attack (days)
1 55 M CCH N 480 R 9/10 Conjunctival injection, nasal congestion, lacrimation. 3 months of R Horner’s syndrome in 2007, now resolved Y R 10/10
VRS 3 Conjunctival injection, nasal congestion, lacrimation, periorbital oedema Y Y O2 158
2 28 F CCH Y
– R 10/10 Periorbital oedema/ptosis, nasal congestion, dry eye then lacrimation Y R 10/10
VRS 3 Periorbital oedema, nasal congestion, facial flushing Y Y O2 128
3 40 M ECH N – R 10/10 Lacrimation, rhinorrhoea, ptosis Y R 10/10
VRS 3 Lacrimation, conjunctival injection, periorbital oedema, nasal congestion, aural fullness and facial droop Y Y Suma 1
4 38 F ECH Y – L 10/10 Lacrimation, conjunctival injection, periorbital oedema, nasal congestion, ptosis, facial flushing Y No attack, developed generalised pain 4/10 Y N N/A 1
5 53 M CCH N 960 L 10/10 Rhinorrhoea, ptosis Y L 10/10
VRS 3 Conjunctival injection, eye grittiness, lacrimation Y Y O2 4
6 48 M ECH N
480 L 8/10 Nasal congestion, lacrimation Y Did not attend
7 23 M ECH Y – L 10/10 Lacrimation, conjunctival injection, nasal congestion, ptosis, facial flushing Y Did not attend
8 43 M CCH N – R 10/10 Nasal congestion, rhinorrhoea, lacrimation, facial flushing Y R 10/10
VRS 3 Nasal congestion, conjunctival injection, eye grittiness Y Y Suma <1
9 43 M ECH N 240 R 10/10 Lacrimation, conjunctival injection, facial flushing, ptosis, facial droop Y Did not attend
10 44 M ECH N – R 10/10 Nasal congestion, ptosis, periorbital oedema, lacrimation, flushing Y No attack, L mild hangover like headache, with nasal congestion.
After study visit felt nauseous and vomited, then slept, headache free at 7pm N N O2- no response <1
11 47 M ECH N – R Severe attacks 10/10 Nasal congestion, aural fullness Y R 7/10
VRS 2/3 moderate/
severe Nasal congestion, conjunctival injection, aural fullness Y Y Suma 13
12 48 M ECH N 560 L 10/10 Lacrimation, nasal congestion, periorbital oedema Y Did not attend
13 40 M ECH Y – R 10/10 Nasal congestion, ptosis, conjunctival injection, lacrimation, throat tightness, rhinorrhoea Y No attack, bilateral mild headache 4/10 with nasal congestion Y, brief (7 mins) N N/A 19
14 50 M ECH Y – R 10/10
Lacrimation, periorbital oedema, nasal congestion, rhinorrhoea Y Did not attend
15 56 M ECH Y – R 10/10 Lacrimation, rhinorrhoea, facial flushing, gritty eyes, conjunctival injection Y with severe attacks Did not attend
16 35 M ECH Y 240 L 10/10 Nasal congestion, conjunctival injection, ptosis, lacrimation, rhinorrhoea Y Not attack, milder than a shadow and no CAS N N N/A 16
17 58 M ECH Y – L 10/10 Nasal congestion, rhinorrhoea, lacrimation, aural fullness, throat swelling Y L 7/10
VRS 2–3 (mod-severe) Nasal congestion, rhinorrhoea, voice change, lacrimation Y Y Suma 1
18 43 M CCH Y – L (70%) Mild 6/10, severe 10/10 Nasal congestion, periorbital oedema, aural fullness, facial flushing Y L Mild,
VRS 1 Nasal congestion Y Y- shadow O2 7
19 32 M ECH Y 600 L 10/10 Lacrimation, conjunctival injection, facial flushing Y L 7–8/10
VRS 2–3
(mod-severe) Lacrimation, eye grittiness, nasal congestion, facial flushing Y Y O2 <1
20 49 F ECH Y – R 10/10 Ptosis, periorbital oedema, lacrimation, nasal congestion, rhinorrhoea, (aural fullness with severe attacks) Y R 6–7/10
VRS 2 mod Nasal congestion, periorbital oedema, lacrimation, conjunctival injection Y Y O2 7
21 49 M CCH Y – R 4–10/10 Facial flushing, nasal congestion, ptosis, lacrimation, rhinorrhoea, conjunctival injection Y L 8/10
VRS 2–3
(mod-severe)
Facial flushing, lacrimation, periorbital oedema, conjunctival injection Y Y, but on L rather than R Suma <1
22 57 M CCH N – R 10/10 Lacrimation, conjunctival injection, nasal congestion, rhinorrhoea Y No attack, no pain and no CAS N N N/A 26
23 40 F CCH Y 640 L 10/10
Lacrimation, conjunctival injection, periorbital oedema, rhinorrhoea, ptosis, aural fullness Y Did not attend
24 44 M CCH N 720 R 10/10 Lacrimation, conjunctival injection, periorbital oedema, facial flushing Y Did not attend
25 23 F ECH Y – R 6–10/10 Nasal congestion, lacrimation, periorbital oedema. Rhinorrhoea and facial flushing with severe attacks Y R 7/10
VRS 2
(moderate) Nasal congestion, periorbital oedema Y Y O2 3
26 40 M CCH Y – L Shadow 4/10, daytime attacks 6–7/10, full attack 10/10 Ptosis, aural fullness, lacrimation, conjunctival injection, periorbital oedema, nasal congestion Y L 8.5–9/10
VRS 3 severe Nasal congestion, periorbital oedema, lacrimation Y Y Suma 3
27 20 F CCH N – R 8–9/10 Nasal congestion, lacrimation, rhinorrhoea, ptosis, aural fullness Y R 8/10
VRS 3
severe Nasal congestion, periorbital oedema Y Y O2 <1
28 31 F ECH Y – R 10/10 Nasal congestion, periorbital oedema, rhinorrhoea, ptosis, aural fullness Y R 2/10
VRS 1 (mild) Nasal congestion, facial swelling Y Y, but milder Suma 3
29 35 M ECH N – L Max pain 10/10 Nasal congestion, periorbital oedema, lacrimation, voice change (croaky). Facial flushing with severe attacks and rhinorrhoea after attack Y L 6–7/10
VRS 2 (moderate) Nasal congestion, lacrimation, conjunctival injection, voice change Y Y Suma <1
30 38 F CCH Y 240 L 4–10/10 Lacrimation, rhinorrhoea, conjunctival injection, facial flushing. Ptosis with severe attacks Y L 6–7/10
VRS 2 (moderate) Aural fullness Y Y Suma 1
31 49 M ECH Y 400 L 10/10 Nasal congestion, lacrimation, conjunctival injection, rhinorrhoea, ptosis, aural fullness. Prominent miosis after attack Y No attack, whole head felt heavy N N N/A 10
32 35 F CCH N 600 L 4/10 (on verapamil),
7/10 average Periorbital oedema, eye grittiness, facial flushing, lacrimation Y L 7/10
VRS 2–3
(mod-severe) Nasal congestion, conjunctival injection, facial flushing, lacrimation Y Y Suma 1
33 32 M CCH Y – L Severe attacks 10/10 Lacrimation, ptosis, nasal congestion, conjunctival injection, ptosis, facial flushing, eye grittiness Y L 6/10
VRS 2 (mod-severe) Lacrimation, nasal congestion, ptosis Y Y Suma <1
Figure 4. (a) Kaplan-Meier graph comparing time until cluster headache attack between the eight episodic cluster headache (ECH) and the 11 chronic cluster headache (CCH) subjects during single-blinded nitroglycerin (NTG) infusion, from the start of the infusion in minutes, log-rank P = 0.534. (b) Kaplan-Meier graph comparing time until cluster headache attack onset between the open unblinded (n = 33) and single-blinded (n =25) nitroglycerin (NTG) infusions with single-blinded placebo infusions (n = 24). Log-rank P = 0.000.
The median onset time to an induced attack was 33 minutes (IQR 15–42) from the start of the single-blinded NTG infusion, and in the single-blinded placebo visit only one subject developed an attack; the onset time was 10 minutes. On comparison of the attack onset time for the unblinded NTG, single-blinded NTG and single-blinded placebo visits, there was a difference between the placebo and NTG visits (P = 0.000, Figure 4(b)).
NTG headache
The majority of subjects developed an NTG headache (n = 28, 85%) following the NTG infusion in the unblinded open visit, of which 27 subjects had a migraine diagnosis (n = 18), had migraine markers (n = 10) and a family history of migraine (n = 18); only one subject did not have migraine, migraine markers or a family history of migraine. The median time from the start of NTG infusion was 3 minutes (IQR 2–6), and the median duration of NTG headache was 26 minutes (IQR 14–41).
Of the 25 subjects that went on to the single-blinded NTG visits, 18 (72%) developed NTG headache following NTG infusion, of which all had either migraine (n = 11), migraine markers (n = 7) or family history (n = 10). The median time of NTG headache onset from the start of NTG infusion in the blinded visit was 4 minutes (IQR 3–8), with a median duration of 26 minutes (IQR 9–45).
In the placebo visit, three of the 24 subjects (13%) developed NTG headache, median onset time was 13 minutes (range 1–18), and the median duration was 10 minutes (range 3–16).
Non-headache symptoms
The majority of subjects reported non-headache symptoms in both the open unblinded NTG visit (n = 30, 91%) and the single-blinded NTG visit (n = 21, 84%) visits. In the single-blinded placebo visit, eight subjects (33%) reported non-headache symptoms. The most common non-headache symptoms from the open unblinded NTG visit were neck stiffness, photophobia, thirst and allodynia. The most common non-headache symptoms from the single-blinded NTG visit were neck stiffness, yawning, thirst and photophobia (Table 4). The median number of non-headache symptoms reported in the open unblinded NTG visit was three (IQR 2–5), and from the single-blinded NTG visit was three (IQR 2–6), compared with two (IQR 2–3) on-headache symptoms in the single-blinded placebo group.
Table 4. Frequencies of non-headache symptoms reported during each visit.
Non-headache symptom Open unblinded NTG visit (n = 33) Single-blinded NTG visit
(n = 25) Single-blinded placebo visit
(n = 24)
Thirst 15 10 3
Craving 0 0 0
Yawning 8 12 4
Tiredness 4 3 0
Mood changes 5 4 1
Visual blurring 4 3 1
Neck stiffness 21 15 3
Irritability 3 3 0
Photophobia 18 10 1
Concentration difficulties 6 4 1
Phonophobia 4 6 0
Urinary symptoms 0 0 0
Speech disturbances 0 0 0
Nausea 6 3 0
Gastrointestinal discomfort 0 0 0
Movement sensitivity 5 5 1
Allodynia 9 8 2
In the open unblinded NTG visit, the median onset time of non-headache symptoms from the start of the infusion was 9 minutes (IQR 4–17) with the median maximum duration of the symptoms being 50 minutes (IQR 24–64), the duration is calculated from the first symptom until the end of the last symptom. In the single-blinded NTG visit, the median onset time was 5 minutes (IQR 3–9) from the start of the infusion, and the median maximum duration of symptoms was 59 minutes (IQR 35–76). The outlier was a subject who developed allodynia and neck stiffness during their attack. For those that developed non-headache symptoms during the single-blinded placebo visit, the median onset time was 9 minutes (IQR 2–9), with a median duration of 16 minutes (IQR 6–34).
Cranial autonomic symptoms
NTG triggered CAS in the majority of the subjects during the open unblinded NTG visit (n = 31, 94%). In all, five subjects out of the 31 (19%) developed unilateral CAS; however, they did not have a cluster headache attack. Two subjects had CAS with generalised headache, one had CAS without any pain, one subject developed CAS on the contralateral side to their attacks with mild generalised pain, and one subject with CAS developed restless leg symptoms, but no cluster headache attack. Of the subjects who developed unilateral CAS and cluster headache attack (n = 26, 79%), the median number of CAS was four (IQR 2–5), with the most common CAS being nasal congestion (n = 21), lacrimation (n = 16) and periorbital oedema (n = 15) (Table 5).
Table 5. Frequencies of cranial autonomic symptoms reported in subjects who had attacks following NTG infusion.
Cranial autonomicsymptoms Open unblinded NTG visit, total number of attacks (n = 26) Single-blinded NTG visit, total number of attacks (n = 19)
Lacrimation 16 11
Conjunctival injection 12 9
Periorbital oedema 15 8
Eye grittiness/itchiness 3 3
Nasal congestion 21 16
Rhinorrhoea 2 1
Ptosis 4 1
Aural fullness 5 2
Facial flushing 7 4
Sialorrhoea 1 0
Throat swelling 2 0
Voice change 4 2
Facial swelling 3 1
Similarly, NTG brought on CAS in the majority of subjects during the single-blinded NTG visit (n = 21, 84%), of which two were not accompanied by a cluster headache attack, compared with four out of 24 in the single-blinded placebo group developing CAS (Figure 5(a)). One of the subjects from the single-blinded NTG group had a generalised headache similar to a hangover headache with unilateral CAS, and the other subject had a migraine-like headache with CAS. Of the 19 subjects (76%) that had unilateral CAS and a cluster headache attack, the median number of symptoms was three (IQR 2–4) and the most frequent symptoms were nasal congestion (n = 16), lacrimation ( n = 11) and conjunctival injection (n = 9) (Table 5). In comparing the time until all CAS onset between ECH and CCH after blinded NTG infusion, there was no difference between the two groups (log-rank P = 0.740; Figure 5(b)).
Figure 5. (a) Kaplan-Meier graph showing time until onset of cranial autonomic symptoms (CAS) following open unblinded (n = 33) and single-blinded NTG (n = 25) infusions compared with the single-blinded placebo infusion (n = 24). Log-rank P = 0.000. (b) Kaplan-Meier graph showing the time until CAS onset in the single-blinded NTG visit, comparing episodic cluster headache (ECH) with chronic cluster headache (CCH). Log-rank P = 0.740.
The median time until CAS onset for those that developed cluster headache attacks was 31 min (IQR 13–46) in the open unblinded NTG visit and 12 min (IQR 6–30) in the single-blinded NTG visit. Subjects sequentially reported CAS development.
During the single-blinded placebo visit, four subjects (17%) developed unilateral CAS, of which one subject developed a spontaneous attack, and three developed CAS but no pain. The median number of symptoms reported in the placebo group was two (IQR 1–2) and the symptoms reported were nasal congestion (n = 2), conjunctival injection (n = 1), periorbital swelling (n = 1), rhinorrhoea (n = 1) and aural fullness (n = 1).
Agitation
Nitroglycerin brought on agitation in the majority of subjects, open unblinded NTG visit (n = 24, 73%) and single-blinded NTG visit (n= 20, 80%), compared with none in the single-blinded placebo visit.
Non-headache symptoms post-attack
The non-headache symptoms were not studied here, as all attacks were treated with sumatriptan or oxygen after 20 minutes, thus altering the natural progression and development of symptoms.
Episodic cluster headache compared with chronic cluster headache
For the subjects that developed an NTG-induced attack following the single-blinded NTG infusion, the time until NTG-induced attack was shorter in the episodic cluster headache group compared with the chronic cluster headache group (U = 15, z = −2.399, P = 0.016). The time until CAS onset, in the subjects that developed CAS following single-blinded NTG infusion was not different between episodic cluster headache and chronic cluster headache groups (U = 38, z = −1.2000, P = 0.230).
Effect of verapamil on NTG triggering
There were seven subjects on verapamil that attended the single-blinded NTG visits, of which two did not develop NTG-triggered cluster headache attacks (29%). Using χ2, there was no difference between verapamil and NTG triggering (χ2 (df = 1) = 0.111, P = 0.739).
Effect of migraine on NTG-triggered attacks
Within the cohort that attended the single-blinded NTG visits, 15 had migraine (60%). There was no difference between the number of non-headache symptoms (U = 67, z = −0.449, P = 0.654) or number of CAS (U = 57, z = −1.019, P = 0.308), between the subjects with migraine and those without migraine. Furthermore, there was no association between subjects with migraine and NTG triggering (χ2 (df = 1) = 0.146, P = 0.702); similarly, there was no association between subjects with migraine and development of NTG headache (χ2 (df = 1) = 0.033, P = 0.856).
Discussion
This study demonstrates that weight-calculated intravenous NTG effectively triggers cluster headache attacks in both chronic cluster headache and episodic cluster headache subjects within bout when compared with placebo. The approach is reliable in terms of triggering a fully-featured attack that allows careful observation of symptoms and their development during acute attacks of cluster headache.
The benefit of weight-calculated intravenous NTG compared to intranasal and sublingual administration is that this is more reliable and has more stable bioavailability. The median time until cluster headache attack onset was 30 minutes (open unblinded NTG visit) and 33 minutes (single-blinded NTG visit), with the overall maximum onset time of 81 minutes. Subjects who did not develop an attack during the 140 minutes of observation were asked to report if they developed an attack later on that day, and none did. The median onset time is similar to the reported latency period reported in the literature (Table 1). The minimum onset time for NTG-induced attacks was 2 minutes, and this is less than reported from the sublingual route, where the shortest time until onset time was 9 minutes (8); this is expected, given the intravenous route has a half-life of 2.3–2.8 minutes (30,31). Two subjects started experiencing mild attack pain before the start of the NTG infusion, and within the placebo group we observed one subject who developed a spontaneous attack. Spontaneous attacks could be anticipated given the subjects are within bout; there were three subjects with only short-lasting CAS symptoms and two subjects who experienced a mild pain without CAS, similar to a shadow.
This study delineates the development of the various stages of an NTG-induced cluster headache attack, including the non-headache symptoms and CAS (Figure 6). The majority of subjects developed NTG headache shortly after the infusion started. This headache was generalised, mild and progressive in nature, predominantly in the bi-occipital and bi-temporal regions. Subjects described it as pressure-like or band-like ache, and they reported it to be distinct from their cluster headache attacks; if there were an overlap, the cluster headache attack would clearly ramp up and supersede the NTG headache. It is difficult to disentangle whether NTG headache developed because there was a high proportion of subjects with either a migraine diagnosis, migraine marker or family history of migraine. However, from a previous study with 25 healthy volunteers without a migraine diagnosis, 16 (64%) developed NTG headache following 0.5 mg NTG sublingual administration (32).
Figure 6. Violin plots of the stages of cluster headache attack from the 19 subjects that developed cluster headache attacks and subdivided by chronicity. The timeline starts with 20 minutes of single-blinded nitroglycerin (NTG) infusion, followed by 120 minutes of post-infusion observation. CAS = cranial autonomic symptoms.
Following the NTG headache, the majority of subjects reported non-headache symptoms in the lead-up to the onset of the pain from the attack and in some subjects, non-headache symptoms accompanied their attacks. The non-headache symptoms included homeostatic symptoms (thirst, cravings, yawning, frequency of urination), fatigue/cognitive symptoms (concentration difficulty, fatigue, memory impairment, mood changes, irritability) and sensitised sensory symptoms (neck stiffness, photophobia, phonophobia, osmophobia, nausea), as are reported in the premonitory phase of migraine (33). The most common symptoms were neck stiffness, photophobia and thirst. During their spontaneous attacks, subjects reported that non-headache symptoms would precede the attack at a median of 10 minutes (IQR 2–30) before the onset of pain, although it is known that there are discrepancies between retrospective and prospective reporting (25). Comparing the symptoms observed from NTG-induced attacks in this study with the prospective observational questionnaire study (24), the most reported general symptoms in the pre-pain phase in this study were concentration difficulties, photophobia and mood changes. Patients in the observational study also reported general symptoms during their attacks and postictal symptoms similar to the symptoms seen during the NTG-induced attacks and the reported symptoms by the subjects in this study during the postdrome phase of their spontaneous attacks. Non-headache symptoms such as photophobia, phonophobia, and localised allodynia were often reported during the attacks, as has been reported previously (21,34). In one semi-structured questionnaire study, they found a high proportion of cluster headache patients (73.2%) reported phonophobia or photophobia with their attacks (35), cluster headache patients with migraine did not more frequently report these symptoms compared with those without co-existing migraine. Furthermore, allodynia was more often reported in cluster headache patients with migraine. From pre-clinical studies, high dose NTG causes a sustained increase in spontaneous firing of Aδ and C-fibre trigeminal neurons (36), which migraine biology may unmask.
Similar to the prospective questionnaire study by Snoer and colleagues (24), in some subjects CAS presented before the onset of the attack pain (Figure 6). In this study, the median onset time for CAS was 31 minutes (IQR 13–46) in the open unblinded NTG visit and 12 minutes (IQR 6–30) in the single-blinded NTG visit, whereas the onset of NTG-induced attack was 30 minutes (IQR 20–39) in the open unblinded visit and 33 minutes (IQR 15–42) in the single-blinded NTG visit. From the open unblinded NTG visit, 38% presented with CAS before the attack, 15% presented with CAS with the onset of the attack, and from the single-blinded NTG visit, 58% presented with CAS before the attack and 16% presented with CAS with the onset of the attack.
Vollesen and colleagues used calcitonin gene-related peptide (CGRP) infusion to trigger cluster headache attacks, finding CGRP induced 50% of subjects with CCH and 89% for ECH subjects in bout (4). In our study, NTG induced attacks in 79% of the CCH subjects and 84% in ECH subjects in bout, in the open unblinded NTG visits, and 92% CCH and 62% ECH in bout in the single-blinded NTG visits. There are some differences in the number of chronic cluster headache subjects on verapamil between the studies; in this study, 33% of CCH subjects were on verapamil and in the study by Vollesen and colleagues, 57% of CCH subjects were on verapamil (of which one was on both verapamil and lithium) and one was on 4 mg melatonin. Vollesen and colleagues proposed that the CCH patients who did not develop an attack following CGRP infusion had a lower median attack frequency in the preceding 30 days prior to the study compared to the CCH patients that did develop an attack. However, in this study, subjects reported having their last attack as long ago as 128 and 158 days and still had NTG-induced attacks (Table 3).
NTG is a pro-drug of nitric oxide (NO) and has effects on blood vessel dilation through mechanisms of the NO-cyclic guanylate phosphate (cGMP) pathway (27). However, the vasodilatory effects of NTG are not sufficient to explain the cluster headache attack that occurs after a latency and the central features associated with the attack. Indeed, experimental studies demonstrate that NTG has central effects (37,38). Interestingly, in studies where NO donors were administered in vivo and in vitro, there was a local release of CGRP (39–42). The difference in the rate of cluster headache attacks induced by NTG and CGRP in ECH and CCH subjects could reflect in part the underlying biological processes and systems that are more active in the different subtypes of cluster headache. The difference between ECH and CCH is also suggested by the treatment response to a CGRP monoclonal antibody, galcanezumab (43,44), and non-invasive vagal nerve stimulator (45,46).
Limitations
The main limitations to the study were the recruitment of eligible subjects and the dropout rate at each stage due to the nature of the condition. Therefore, a pragmatic approach was taken with the study design regarding randomisation. Although there was a randomisation sequence, this was modified by the investigator if deemed necessary. This would be in the case of episodic cluster headache patients that were near the end of their bout missing the NTG visit if they followed the randomised sequence. For this reason, it was designed to be a single-blind cross-over study and not a double-blind and randomised study. Expectation bias was reduced by maintaining blinding of the subjects until the end of the study and having both infusions identical in volume, appearance and duration of infusion. Furthermore, given the stark difference between placebo and NTG, there was no difference between attack onset in the open unblinded compared with the single-blinded NTG visits (Figure 4(b)), is an indication that randomisation was not a factor in this study.
Conclusion
We present the results of the first placebo-controlled study using intravenous NTG administration to systematically study NTG-induced cluster headache attacks. We have shown that NTG can reliably bring on cluster headache attacks as well as the development of non-headache symptoms and CAS. This study highlights differences between NTG-induced attack onset times between the ECH and CCH subjects. Understanding the stages of cluster headache is essential; by recognising the non-headache symptoms in the lead up to the onset of pain and the underlying pathogenesis of this, we may be able to uncover new therapeutic targets to abort attacks before the onset of the severe and devastating pain experienced by our cluster headache patients.
Article highlights
Weight-calculated standardised intravenous nitroglycerin administration is a reliable method to induce cluster headache attacks, cranial autonomic symptoms and non-headache symptoms that accompany cluster headache attacks.
Accompanying non-headache symptoms in cluster headache attacks are important to recognise for both clinical and research purposes.
There may be inherent differences between episodic cluster headache and chronic cluster headache.
Acknowledgement
This study would not have been possible without the support of OUCH(UK), all the cluster headache patients who were interested in helping us with this study and all the subjects who took part in this study.
Ethics or Institutional Review Board approval: This study 16/LO/0693 obtained approval from the London, City & East NHS Research Ethics Committee on 23 June 2016. This study was carried out in accordance with the World Medical Association Declaration of Helsinki (1964), the Research Governance Framework for Health and Social Care (2nd edition, 2005), the Data Protection Act (1998) and the Principles of Good Clinical Practice (GCP); all subjects gave informed consent before taking part.
Declaration of conflicting interests: The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: DYW no reported competing interests. PJG reports, over the last 36 months, grants and personal fees from Amgen and Eli-Lilly and Company, grant from Celegene, and personal fees from Alder Biopharmaceuticals, Aeon Biopharma, Allergan, Biohaven Pharmaceuticals Inc., Clexio, Electrocore LLC, eNeura, Epalex, GlaxoSmithKline, Impel Neuropharma, MundiPharma, Novartis, Pfizer, Praxis, Sanofi, Santara Therapeutics Satsuma, Teva Pharmaceuticals, Trigemina Inc., WL Gore, and personal fees from MedicoLegal work, Massachusetts Medical Society, Up-to-Date, Oxford University Press, and Wolters Kluwer; and a patent magnetic stimulation for headache assigned to eNeura without fee.
Funding: The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study is part-funded by the National Institute for Health Research (NIHR) Maudsley Biomedical Research Centre at South London Maudsley Foundation Trust and King’s College London. The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care.
ORCID iDs: Diana Y Wei https://orcid.org/0000-0003-0644-7172
Peter J Goadsby https://orcid.org/0000-0003-3260-5904 | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY | 33615843 | 19,017,453 | 2021-07 |
What was the dosage of drug 'NITROGLYCERIN'? | Comprehensive clinical phenotyping of nitroglycerin infusion induced cluster headache attacks.
Nitroglycerin administration allows the study of cluster headache attacks in their entirety in a standardised way.
A single-blind, placebo-controlled, cross-over study using weight-calculated intravenous nitroglycerin administration at 0.5 µg/kg/min over 20 minutes to study cluster headache attacks, including accompanying non-headache symptoms and cranial autonomic symptoms.
Thirty-three subjects with cluster headache were included in the study; 24 completed all three study visits. Nitroglycerin-induced attacks developed in 26 out of 33 subjects (79%) receiving unblinded nitroglycerin infusion, and in 19 out of 25 subjects (76%) receiving single-blinded nitroglycerin infusion, compared with one out of 24 subjects (4%) receiving single-blinded placebo infusion. Episodic cluster headache subjects had a shorter latency period to a nitroglycerin-induced attack compared to the chronic cluster headache (CCH) subjects (U = 15, z = -2.399, p = 0.016). Sixteen of nineteen episodic cluster headache (mean, 84%; 95% confidence interval, 66-100%) and 11 of 14 chronic cluster headache subjects developed a nitroglycerin-induced attack (79%, 54-100%) following the unblinded nitroglycerin infusion. Following the single-blinded nitroglycerin infusion, eight out of 13 episodic cluster headache (62%, 31-92%) and 11 out of 12 chronic cluster headache (92%, 73-100%) subjects developed nitroglycerin-induced attacks. Nitroglycerin induced non-headache symptoms in the majority of subjects receiving it: 91% in the open unblinded nitroglycerin visit and 84% in the single-blinded nitroglycerin visits, compared with 33% in the single-blinded placebo visit. Cranial autonomic symptoms were induced by nitroglycerin infusion, 94% in the open unblinded nitroglycerin visit and 84% in the single-blinded nitroglycerin visit, compared with 17% in the single-blinded placebo visit.
Intravenous weight-adjusted nitroglycerin administration in both episodic cluster headache in bout and chronic cluster headache is effective and reliable in inducing cluster headache attacks, cranial autonomic symptoms and non-headache symptoms.
Introduction
Due to the episodic nature of acute attacks of cluster headache, a standardised and reliable method for triggering attacks is necessary for their complete study. There have been several substances used to trigger attacks, including histamine (1,2), meta-chloro-phenylpiperazine (mCPP) (3) and more recently calcitonin gene-related peptide (CGRP) (4). Nitroglycerin (NTG) is the most frequently employed substance in human experimental modelling of cluster headache attacks, being used since 1953 (2) (Table 1).
Table 1. Review of studies using nitroglycerin to induce cluster headache attacks.
Study Number of CH patients NTG dose and route Control Placebo Rate of induced CH attack Latency period before onset of headache
(range in minutes)
Peters 1953 (2) 14 1.3 mg sublingual No, but compared with migraine, combination of CH and migraine, vasodilating head pain and tension headache No, but compared with histamine and nicotinic acid 78.6% Not reported
Ekbom 1968 (5) 38 ECH: 28 in bout, 15 out of bout (of which five were tested in bout as well) 1 mg sublingual No No In bout ECH 100% (n = 28)
Out of bout 0% (n = 15) 12–72
Barre 1982 (6) 10 CH: two CCH, nine ECH in bout 1 mg sublingual No No 100% 34–52
Mean 45.9
Drummond et al. 1984 (7) 29 CH 0.9 mg sublingual No No 76% Within 90 min
Drummond et al. 1985 (8) 22 CH: 10 CCH, 12 ECH in bout
0.9 mg sublingual Yes, 10 in the control group without headache No ECH 75% (n = 9)
CCH 60% (n = 6) 9–90
Mean 44
Bogucki 1990 (9) 21 ECH in bout 1 mg sublingual No No 67% (n = 14)
30–65
Dahl et al. 1990 (10) 15 ECH in bout 1 mg sublingual 10 healthy controls No 53% (n = 8)
Controls: not reported 30–65
Hannerz et al. 1992 (11) Eight ECH: five in bout and three out of bout 1 mg sublingual No No In bout ECH 100% (n = 5) Not reported
Fanciullacci et al. 1995 (12) 18 in bout ECH, 12 out of bout ECH 0.9 mg sublingual No No In bout ECH 100% (n = 18)
Out of bout ECH 0% (n = 12) 39–86
Fanciullacci et al. 1997 (13) 11 in bout ECH, eight out of bout ECH 0.9 mg sublingual No No In bout ECH 100% (n = 11)
Out of bout ECH 0% (n = 8) 18–50
Hsieh et al. 1996 (14) Seven ECH: four in bout ECH, three out of bout 1 mg sublingual No No In bout ECH 100%
Out of bout ECH 0% 18–35
May et al. 1998 (15) Nine CCH, eight out of bout ECH 1.0–1.2 mg spray No No CCH 100%
Out of bout ECH 0% Not reported
Costa et al. 2000 (16) 15 CH: Six ECH, nine CCH 0.9 mg sublingual No No ECH 33% (n = 2)
CCH 78% (n = 7) 19–41
Costa et al. 2003 (17) 18 ECH in bout 0.9 mg sublingual Yes, 12 healthy sex and age-matched No ECH 67% (n = 12)
Controls 0% 19–41
Sances et al. 2004 (18) 42 CH: 29 ECH (11 out of bout), 13 CCH 0.9 mg sublingual Yes, 53 healthy controls No In bout ECH and CCH 81% (n = 25 out of 31)
Controls 7.5% developed headache in 7-hour post-NTG Mean onset latency of 65.4 ± 54.7
Cluster headache patients suffer from recurrent episodes of severe unilateral pain in the trigeminal region; therefore, historically, the main emphasis has been centred around the pain onset of a cluster headache, and indeed this is often used as the indicator of the start of the attack. However, from clinical practice, there has been growing awareness of nonpainful symptoms preceding the onset of pain (19,20) and in recent years, the clinical phenotype of cluster headache has been further characterised by retrospective accounts (21–23) and prospective diaries (24,25).
The most frequent route of administration of NTG has been sublingual; however, the bioavailability of sublingual NTG is extremely variable (26). Therefore, we used a weight-calculated dose for intravenous infusion in a standardised single-blind, placebo-controlled study. NTG is a pro-drug of nitric oxide, with predominant actions on the cyclic guanylate phosphate (cGMP) pathway (27), and from pre-clinical studies there are indications of neural actions more centrally. This study is the first single-blind, placebo-controlled cross-over study using a weight-adjusted dose of nitroglycerin administered intravenously in cluster headache patients, thereby allowing comprehensive investigation of the various stages of the acute attack of cluster headache.
Methods
Subject selection and recruitment
The study was advertised on the UK cluster headache patient website OUCH (UK) (Organisation for the Understanding of Cluster Headache UK) (https://ouchuk.org/research/research-volunteers-needed) and in the tertiary Headache centre in King’s College Hospital, London. Subjects interested in participating would make contact via a dedicated research email. Subjects would then be screened for eligibility for the study via emails and a telephone call; those who met the criteria and were interested in participating were invited to attend the study visit. The study was approved by the London, City & East Research Ethics Committee (Ref Number 16/LO/0693). Data were collected from August 2016 until January 2019.
The subjects enrolled fulfilled the ICHD-3 beta criteria for cluster headache (28), and were between the ages of 18 and 60, with no significant previous medical history and no previous syncope or history of autonomic dysfunction. They had had a reliable response to high flow oxygen and/or subcutaneous sumatriptan during spontaneous attacks and normal brain neuroimaging. Women in child-bearing age were required to use reliable contraceptive methods during the study. Subjects were excluded if they were pregnant or breastfeeding, and who had any significant psychiatric disease, diagnosis of another primary headache type (other than migraine) or chronic pain syndrome, any medical history that would have contraindications to receiving NTG, use of preventive medication other than verapamil, or taking indomethacin for any reason, allergies to the medications used in the study or intolerance to high flow oxygen, and use of illicit drugs during the study.
Study visits
The study comprised of three visits in total, with each visit separated by a minimum of 1 week. During the first visit, subjects consented and a full headache history with a physical examination of the neurological and cardiovascular systems was performed, along with recordings of the baseline blood pressure, lying and standing blood pressure, heart rate, oxygen saturation, weight and electrocardiogram. Female subjects were required to have a urinary pregnancy test before the start of the infusion.
Open NTG infusion
If deemed eligible, subjects received an intravenous infusion of nitroglycerin at 0.5 µg/kg/min over 20 minutes. Subjects remained recumbent for 30 minutes before the infusion, and after the NTG infusion, subjects received 250 mL of 0.9% sodium chloride intravenously. The blood pressure and pulse were checked at the start of the infusion, and every 5 min during the infusion.
Phenotypic characterisation
Every 5 minutes, subjects were asked to rate their pain level from a scale from no pain, mild, moderate to severe, where severe equates to their most severe attack, and they were asked a questionnaire of non-headache symptoms and cranial autonomic symptoms (CAS) (Figure 1). If the subject experienced pain, further details were obtained regarding the location and characteristic. Beyond the cluster headache attack, subjects were asked to report any other headache types and in particular NTG headache, which has been well described from migraine studies (29). The NTG headache was assessed for severity, phenotype, accompanying non-headache symptoms and duration. Subjects were actively encouraged to report any symptoms as and when they developed. Following the infusion, at 10 minute intervals, any developments in pain, non-headache symptoms and CAS were recorded for a total of 120 minutes after the infusion, based on the latency period reported from previous studies (Table 1).
Figure 1. Questionnaire for non-headache and cranial autonomic symptoms.
B: bilateral; R: right-sided; L: left-sided.
Single-blinded NTG and placebo infusions
During the two single-blinded visits, subjects either received intravenous nitroglycerin at 0.5 µg/kg/min over 20 minutes or an equal volume of 0.9% sodium chloride at the same rate over 20 minutes, followed by the same 120 minutes of observations (Figure 2). The sequence was pre-determined using the randomise function in Excel; however, the investigator was able to amend this in certain situations if the subject was episodic and due to finish their bout.
Figure 2. Outline of events from open unblinded nitroglycerin visit.
BP: blood pressure; CAS: cranial autonomic symptoms; NTG: nitroglycerin; IV: intravenous.
Treatment of acute attacks
Acute treatment was administered at 20 minutes from the start of attack either with sumatriptan 6 mg subcutaneous injection (Imigran 6 mg/0.5 ml solution for injection pre-filled syringes, GlaxoSmithKline UK Ltd, or sumatriptan 6 mg/0.5 ml solution for injection pre-filled pens, Sun Pharmaceuticals Industries Europe B.V.) or with 15 L/min oxygen via a non-rebreather mask (O2Star™ non-rebreather oxygen mask M/L, Dräger). The visit was concluded only when the subject was pain free.
Statistical analysis
The data was tabulated (Excel for Mac v 16.30), and descriptive statistics were performed to summarise data (SPSS Statistics version 26 for Mac and Excel). Mann-Whitney tests were performed on time until attack onset and time until CAS onset for those that developed NTG-triggered cluster headache attacks and CAS, comparing the differences in ECH with CCH subgroups. Kaplan-Meier survival graphs were used to examine the time until onset of event; that is, survival of no cluster headache attack status, or absence of CAS after NTG infusion for 140 minutes (20 minutes of infusion and 120 minutes of post-infusion observation), with log-rank statistical testing; P < 0.05 was considered significant. Graphs were made using SPSS and violin plots were made using GraphPad Prism 8 for Mac OS.
Results
Demography
A total of 229 subjects were contacted to check for eligibility, of which 33 were included in the study; 24 completed all three study visits (Figure 3). All patients fulfilled the ICHD-3 beta criteria for cluster headache, 19 episodic cluster headache in bout (58%) and 14 chronic cluster headache (42%) (Table 2). The majority were male (n = 24, 73%) with a male: female ratio of 3:1. The average age was 41 (SD 10), with the mean age of females (34 years, SD 9) younger than in males (44 years, SD 9) in this cohort. Subjects had had the condition for a median of 9 years (IQR 5–16).
Figure 3. Subject numbers throughout the study.
Table 2. Subject characteristics.
Subject Age Sex Subtype Side of attacks Time since first attack (years) Average attack frequency (per day) Average attack duration when untreated (mins) Average bout duration (weeks) Verapamil (total daily dose in mg)
1 55 M Chronic Right 5 2 45 – 480
2 28 F Chronic Right 12 7 150 – –
3 40 M Episodic Right 20 3 150 8 –
4 38 F Episodic Left 12 2 120 4 –
5 53 M Chronic Left 15 4 35 – 960
6 48 M Episodic Left 25 5 52.5 5 480
7 23 M Episodic Left 8 2 120 10 –
8 43 M Chronic Right 9 1 40 – –
9 43 M Episodic Right 13 3 60 5 240
10 44 M Episodic Right 27 6 45 6 –
11 47 M Episodic Right 3 1 105 20 –
12 48 M Episodic Left 26 3 180 10 560
13 40 M Episodic Right 5 3 60 8 –
14 50 M Episodic Right 10 2 105 8 –
15 56 M Episodic* Right 24 1 45 – –
16 35 M Episodic Left 7 2 150 6 240
17 58 M Episodic Left 3 1 135 24 –
18 43 M Chronic Left 4 2 60 – –
19 32 M Episodic Left 3 3 50 12 600
20 49 F Episodic Right 8 5 50 9 –
21 49 M Chronic Right 35 2 90 – –
22 57 M Chronic Right 20 5 65 –
23 40 F Chronic Left 4 1.5 120 – 640
24 44 M Chronic Right 6 2 90 – 720
25 23 F Episodic Right 9 2.5 90 6 –
26 40 M Chronic Left 17 1.5 180 – –
27 20 F Chronic Right 6 1.5 150 – –
28 31 F Episodic Right 14 2 75 11 –
29 35 M Episodic Left 9 2 90 3 –
30 38 F Chronic Left 6 1.5 180 – 240
31 49 M Episodic Left 0.5 1.5 37.5 21 400
32 35 F Chronic Left 4 0.3 30 – 600
33 32 M Chronic Left 10 6 60 – –
M: male; F: female.
*Subject was chronic but became episodic during study with no attacks in 6 months.
Clinical phenotyping of subjects by history
Pain features
There was a near-equal split between the laterality of attacks; 17 subjects had right-sided attacks (52%), and 16 subjects had left-sided attacks (49%). The median number of attacks per day was two (IQR 1.5–3) lasting a median of 90 minutes (IQR 50–128). Verapamil was the only preventive allowed on the study; 12 subjects (36%) were on verapamil ranging from 240 mg to 960 mg per day.
Migraine, accompanying features and non-headache symptoms in spontaneous attacks
In this cohort, 58% (n = 19) had a concurrent migraine (28): five had migraine with aura, of which four had visual aura and one had facial sensory aura. Of the subjects who did not meet the diagnostic criteria for migraine (28) (n = 14, 42%), the majority had either migraine markers and/or a family history of migraine. Migraine markers were defined if subjects experienced: childhood cyclic nausea and vomiting, motion sickness, cold stimulus-induced headache, hangover headache and jetlag. Four subjects did not have migraine markers, and three subjects (9%) did not have either migraine marker or a family history of migraine. Subjects (n = 24, 73%) reported accompanying symptoms with their spontaneous attacks, the most common symptoms being cranial allodynia (n = 15), photophobia (n = 15), nausea (n = 11) and phonophobia (n = 10).
Non-headache attack symptoms
The majority reported non-headache symptoms in the lead up to their spontaneous cluster headache attacks (n = 27, 82%), with the commonest symptoms being concentration difficulties (n = 18), mood changes (n = 15), neck stiffness (n = 13) and yawning (n = 8). The median onset time of symptoms was 10 minutes (IQR 2–30) before the onset of pain. Although most symptoms start before the onset of pain, five subjects only reported developing the symptoms during the attack.
Twenty-eight subjects reported non-headache symptoms following their cluster headache attacks (85%), the commonest symptoms being tiredness (n = 27), mood changes (n = 13), concentration difficulties (n = 12), and neck stiffness (n = 7). The median duration of symptoms was 120 minutes (IQR 53–315).
Attack triggers
The most commonly reported triggers for spontaneous attacks were alcohol ingestion (n = 22), followed by changes in temperature (n = 12), strong smells such as from nail varnish, paint (n = 11) followed by disrupted sleep (n = 4) and exercise (n = 3). Other triggers mentioned were stress (n = 2), caffeine (n = 2), changing time zones (n = 1), let down from stress (n = 1), being in a pressurised cabin on an airplane (n = 1), vardenafil (n = 1), and dehydration (n = 1). All subjects reported attacks within a few hours of alcohol ingestion, no one reported a next-day effect.
Clinical phenotyping of open NTG visit
NTG triggered cluster headache-like attacks (n = 26, 79%), CAS (n = 31, 94%) and agitation (n = 24, 73%) during the open unblinded NTG visit. In the episodic cluster headache group, 16 out of 19 developed an NTG-induced attack (mean, 84%; 95% CI, 66–100%) and in the chronic cluster headache group, 11 out of 14 developed an NTG-induced attack (79%, 54–100%). Five out of the 31 subjects developed CAS, but did not develop an attack; of these subjects, three developed mild generalised pain, one developed restless legs, and one developed CAS on the contralateral side to the subject’s spontaneous attack phenotype, with a generalised headache. These cases were excluded.
The median onset time for CAS to develop from the start of the NTG infusion was 31 minutes (IQR 13–46). The median onset for an NTG-induced attack was 30 minutes (IQR 20–39) and the median time to maximum pain, if reached, was 51 minutes (IQR 39–70). The most common first cranial autonomic symptoms brought on by NTG infusion were nasal congestion (n = 10), conjunctival injection (n = 5), lacrimation (n = 4) and periorbital oedema (n = 3).
Clinical phenotyping of single-blinded NTG and placebo visit
During the single-blinded visits, NTG induced attacks in 19 subjects (76%); three subjects did not have an attack (12%), two subjects developed migraine-like headache (8%) and one subject developed unilateral mild pain without CAS or agitation (4%) (Table 3). In the placebo group, only one developed an attack (4%), two subjects developed unilateral mild pain without CAS or agitation (8%) and two subjects experienced short-lived unilateral CAS (8%). Of the subjects receiving NTG, eight out of 13 ECH (mean, 62%; 95% CI, 31%-92%) and 11 out of 12 CCH (92%, 73–100%) developed NTG-induced attacks (Figure 4(a)).
Table 3. Subject characteristics and comparison between spontaneous attack and triggered attack from single-blinded nitroglycerin visit, M = male, F = female, ECH = episodic cluster headache, CCH = chronic cluster headache, L = Left, R = Right, Y = Yes, N = No, VRS = verbal rating scale, mod = moderate, O2 = high flow oxygen via non-rebreather mask, suma = sumatriptan.
Subject Age Sex Subtype Migraine Verapamil (total daily dose in mg) Spontaneous attack Triggered attack- single-blinded NTG visit
Laterality Severity CAS Agitation Laterality Severity/VRS CAS Agitation Feels like spontaneous attack Treatment Last spontaneous attack (days)
1 55 M CCH N 480 R 9/10 Conjunctival injection, nasal congestion, lacrimation. 3 months of R Horner’s syndrome in 2007, now resolved Y R 10/10
VRS 3 Conjunctival injection, nasal congestion, lacrimation, periorbital oedema Y Y O2 158
2 28 F CCH Y
– R 10/10 Periorbital oedema/ptosis, nasal congestion, dry eye then lacrimation Y R 10/10
VRS 3 Periorbital oedema, nasal congestion, facial flushing Y Y O2 128
3 40 M ECH N – R 10/10 Lacrimation, rhinorrhoea, ptosis Y R 10/10
VRS 3 Lacrimation, conjunctival injection, periorbital oedema, nasal congestion, aural fullness and facial droop Y Y Suma 1
4 38 F ECH Y – L 10/10 Lacrimation, conjunctival injection, periorbital oedema, nasal congestion, ptosis, facial flushing Y No attack, developed generalised pain 4/10 Y N N/A 1
5 53 M CCH N 960 L 10/10 Rhinorrhoea, ptosis Y L 10/10
VRS 3 Conjunctival injection, eye grittiness, lacrimation Y Y O2 4
6 48 M ECH N
480 L 8/10 Nasal congestion, lacrimation Y Did not attend
7 23 M ECH Y – L 10/10 Lacrimation, conjunctival injection, nasal congestion, ptosis, facial flushing Y Did not attend
8 43 M CCH N – R 10/10 Nasal congestion, rhinorrhoea, lacrimation, facial flushing Y R 10/10
VRS 3 Nasal congestion, conjunctival injection, eye grittiness Y Y Suma <1
9 43 M ECH N 240 R 10/10 Lacrimation, conjunctival injection, facial flushing, ptosis, facial droop Y Did not attend
10 44 M ECH N – R 10/10 Nasal congestion, ptosis, periorbital oedema, lacrimation, flushing Y No attack, L mild hangover like headache, with nasal congestion.
After study visit felt nauseous and vomited, then slept, headache free at 7pm N N O2- no response <1
11 47 M ECH N – R Severe attacks 10/10 Nasal congestion, aural fullness Y R 7/10
VRS 2/3 moderate/
severe Nasal congestion, conjunctival injection, aural fullness Y Y Suma 13
12 48 M ECH N 560 L 10/10 Lacrimation, nasal congestion, periorbital oedema Y Did not attend
13 40 M ECH Y – R 10/10 Nasal congestion, ptosis, conjunctival injection, lacrimation, throat tightness, rhinorrhoea Y No attack, bilateral mild headache 4/10 with nasal congestion Y, brief (7 mins) N N/A 19
14 50 M ECH Y – R 10/10
Lacrimation, periorbital oedema, nasal congestion, rhinorrhoea Y Did not attend
15 56 M ECH Y – R 10/10 Lacrimation, rhinorrhoea, facial flushing, gritty eyes, conjunctival injection Y with severe attacks Did not attend
16 35 M ECH Y 240 L 10/10 Nasal congestion, conjunctival injection, ptosis, lacrimation, rhinorrhoea Y Not attack, milder than a shadow and no CAS N N N/A 16
17 58 M ECH Y – L 10/10 Nasal congestion, rhinorrhoea, lacrimation, aural fullness, throat swelling Y L 7/10
VRS 2–3 (mod-severe) Nasal congestion, rhinorrhoea, voice change, lacrimation Y Y Suma 1
18 43 M CCH Y – L (70%) Mild 6/10, severe 10/10 Nasal congestion, periorbital oedema, aural fullness, facial flushing Y L Mild,
VRS 1 Nasal congestion Y Y- shadow O2 7
19 32 M ECH Y 600 L 10/10 Lacrimation, conjunctival injection, facial flushing Y L 7–8/10
VRS 2–3
(mod-severe) Lacrimation, eye grittiness, nasal congestion, facial flushing Y Y O2 <1
20 49 F ECH Y – R 10/10 Ptosis, periorbital oedema, lacrimation, nasal congestion, rhinorrhoea, (aural fullness with severe attacks) Y R 6–7/10
VRS 2 mod Nasal congestion, periorbital oedema, lacrimation, conjunctival injection Y Y O2 7
21 49 M CCH Y – R 4–10/10 Facial flushing, nasal congestion, ptosis, lacrimation, rhinorrhoea, conjunctival injection Y L 8/10
VRS 2–3
(mod-severe)
Facial flushing, lacrimation, periorbital oedema, conjunctival injection Y Y, but on L rather than R Suma <1
22 57 M CCH N – R 10/10 Lacrimation, conjunctival injection, nasal congestion, rhinorrhoea Y No attack, no pain and no CAS N N N/A 26
23 40 F CCH Y 640 L 10/10
Lacrimation, conjunctival injection, periorbital oedema, rhinorrhoea, ptosis, aural fullness Y Did not attend
24 44 M CCH N 720 R 10/10 Lacrimation, conjunctival injection, periorbital oedema, facial flushing Y Did not attend
25 23 F ECH Y – R 6–10/10 Nasal congestion, lacrimation, periorbital oedema. Rhinorrhoea and facial flushing with severe attacks Y R 7/10
VRS 2
(moderate) Nasal congestion, periorbital oedema Y Y O2 3
26 40 M CCH Y – L Shadow 4/10, daytime attacks 6–7/10, full attack 10/10 Ptosis, aural fullness, lacrimation, conjunctival injection, periorbital oedema, nasal congestion Y L 8.5–9/10
VRS 3 severe Nasal congestion, periorbital oedema, lacrimation Y Y Suma 3
27 20 F CCH N – R 8–9/10 Nasal congestion, lacrimation, rhinorrhoea, ptosis, aural fullness Y R 8/10
VRS 3
severe Nasal congestion, periorbital oedema Y Y O2 <1
28 31 F ECH Y – R 10/10 Nasal congestion, periorbital oedema, rhinorrhoea, ptosis, aural fullness Y R 2/10
VRS 1 (mild) Nasal congestion, facial swelling Y Y, but milder Suma 3
29 35 M ECH N – L Max pain 10/10 Nasal congestion, periorbital oedema, lacrimation, voice change (croaky). Facial flushing with severe attacks and rhinorrhoea after attack Y L 6–7/10
VRS 2 (moderate) Nasal congestion, lacrimation, conjunctival injection, voice change Y Y Suma <1
30 38 F CCH Y 240 L 4–10/10 Lacrimation, rhinorrhoea, conjunctival injection, facial flushing. Ptosis with severe attacks Y L 6–7/10
VRS 2 (moderate) Aural fullness Y Y Suma 1
31 49 M ECH Y 400 L 10/10 Nasal congestion, lacrimation, conjunctival injection, rhinorrhoea, ptosis, aural fullness. Prominent miosis after attack Y No attack, whole head felt heavy N N N/A 10
32 35 F CCH N 600 L 4/10 (on verapamil),
7/10 average Periorbital oedema, eye grittiness, facial flushing, lacrimation Y L 7/10
VRS 2–3
(mod-severe) Nasal congestion, conjunctival injection, facial flushing, lacrimation Y Y Suma 1
33 32 M CCH Y – L Severe attacks 10/10 Lacrimation, ptosis, nasal congestion, conjunctival injection, ptosis, facial flushing, eye grittiness Y L 6/10
VRS 2 (mod-severe) Lacrimation, nasal congestion, ptosis Y Y Suma <1
Figure 4. (a) Kaplan-Meier graph comparing time until cluster headache attack between the eight episodic cluster headache (ECH) and the 11 chronic cluster headache (CCH) subjects during single-blinded nitroglycerin (NTG) infusion, from the start of the infusion in minutes, log-rank P = 0.534. (b) Kaplan-Meier graph comparing time until cluster headache attack onset between the open unblinded (n = 33) and single-blinded (n =25) nitroglycerin (NTG) infusions with single-blinded placebo infusions (n = 24). Log-rank P = 0.000.
The median onset time to an induced attack was 33 minutes (IQR 15–42) from the start of the single-blinded NTG infusion, and in the single-blinded placebo visit only one subject developed an attack; the onset time was 10 minutes. On comparison of the attack onset time for the unblinded NTG, single-blinded NTG and single-blinded placebo visits, there was a difference between the placebo and NTG visits (P = 0.000, Figure 4(b)).
NTG headache
The majority of subjects developed an NTG headache (n = 28, 85%) following the NTG infusion in the unblinded open visit, of which 27 subjects had a migraine diagnosis (n = 18), had migraine markers (n = 10) and a family history of migraine (n = 18); only one subject did not have migraine, migraine markers or a family history of migraine. The median time from the start of NTG infusion was 3 minutes (IQR 2–6), and the median duration of NTG headache was 26 minutes (IQR 14–41).
Of the 25 subjects that went on to the single-blinded NTG visits, 18 (72%) developed NTG headache following NTG infusion, of which all had either migraine (n = 11), migraine markers (n = 7) or family history (n = 10). The median time of NTG headache onset from the start of NTG infusion in the blinded visit was 4 minutes (IQR 3–8), with a median duration of 26 minutes (IQR 9–45).
In the placebo visit, three of the 24 subjects (13%) developed NTG headache, median onset time was 13 minutes (range 1–18), and the median duration was 10 minutes (range 3–16).
Non-headache symptoms
The majority of subjects reported non-headache symptoms in both the open unblinded NTG visit (n = 30, 91%) and the single-blinded NTG visit (n = 21, 84%) visits. In the single-blinded placebo visit, eight subjects (33%) reported non-headache symptoms. The most common non-headache symptoms from the open unblinded NTG visit were neck stiffness, photophobia, thirst and allodynia. The most common non-headache symptoms from the single-blinded NTG visit were neck stiffness, yawning, thirst and photophobia (Table 4). The median number of non-headache symptoms reported in the open unblinded NTG visit was three (IQR 2–5), and from the single-blinded NTG visit was three (IQR 2–6), compared with two (IQR 2–3) on-headache symptoms in the single-blinded placebo group.
Table 4. Frequencies of non-headache symptoms reported during each visit.
Non-headache symptom Open unblinded NTG visit (n = 33) Single-blinded NTG visit
(n = 25) Single-blinded placebo visit
(n = 24)
Thirst 15 10 3
Craving 0 0 0
Yawning 8 12 4
Tiredness 4 3 0
Mood changes 5 4 1
Visual blurring 4 3 1
Neck stiffness 21 15 3
Irritability 3 3 0
Photophobia 18 10 1
Concentration difficulties 6 4 1
Phonophobia 4 6 0
Urinary symptoms 0 0 0
Speech disturbances 0 0 0
Nausea 6 3 0
Gastrointestinal discomfort 0 0 0
Movement sensitivity 5 5 1
Allodynia 9 8 2
In the open unblinded NTG visit, the median onset time of non-headache symptoms from the start of the infusion was 9 minutes (IQR 4–17) with the median maximum duration of the symptoms being 50 minutes (IQR 24–64), the duration is calculated from the first symptom until the end of the last symptom. In the single-blinded NTG visit, the median onset time was 5 minutes (IQR 3–9) from the start of the infusion, and the median maximum duration of symptoms was 59 minutes (IQR 35–76). The outlier was a subject who developed allodynia and neck stiffness during their attack. For those that developed non-headache symptoms during the single-blinded placebo visit, the median onset time was 9 minutes (IQR 2–9), with a median duration of 16 minutes (IQR 6–34).
Cranial autonomic symptoms
NTG triggered CAS in the majority of the subjects during the open unblinded NTG visit (n = 31, 94%). In all, five subjects out of the 31 (19%) developed unilateral CAS; however, they did not have a cluster headache attack. Two subjects had CAS with generalised headache, one had CAS without any pain, one subject developed CAS on the contralateral side to their attacks with mild generalised pain, and one subject with CAS developed restless leg symptoms, but no cluster headache attack. Of the subjects who developed unilateral CAS and cluster headache attack (n = 26, 79%), the median number of CAS was four (IQR 2–5), with the most common CAS being nasal congestion (n = 21), lacrimation (n = 16) and periorbital oedema (n = 15) (Table 5).
Table 5. Frequencies of cranial autonomic symptoms reported in subjects who had attacks following NTG infusion.
Cranial autonomicsymptoms Open unblinded NTG visit, total number of attacks (n = 26) Single-blinded NTG visit, total number of attacks (n = 19)
Lacrimation 16 11
Conjunctival injection 12 9
Periorbital oedema 15 8
Eye grittiness/itchiness 3 3
Nasal congestion 21 16
Rhinorrhoea 2 1
Ptosis 4 1
Aural fullness 5 2
Facial flushing 7 4
Sialorrhoea 1 0
Throat swelling 2 0
Voice change 4 2
Facial swelling 3 1
Similarly, NTG brought on CAS in the majority of subjects during the single-blinded NTG visit (n = 21, 84%), of which two were not accompanied by a cluster headache attack, compared with four out of 24 in the single-blinded placebo group developing CAS (Figure 5(a)). One of the subjects from the single-blinded NTG group had a generalised headache similar to a hangover headache with unilateral CAS, and the other subject had a migraine-like headache with CAS. Of the 19 subjects (76%) that had unilateral CAS and a cluster headache attack, the median number of symptoms was three (IQR 2–4) and the most frequent symptoms were nasal congestion (n = 16), lacrimation ( n = 11) and conjunctival injection (n = 9) (Table 5). In comparing the time until all CAS onset between ECH and CCH after blinded NTG infusion, there was no difference between the two groups (log-rank P = 0.740; Figure 5(b)).
Figure 5. (a) Kaplan-Meier graph showing time until onset of cranial autonomic symptoms (CAS) following open unblinded (n = 33) and single-blinded NTG (n = 25) infusions compared with the single-blinded placebo infusion (n = 24). Log-rank P = 0.000. (b) Kaplan-Meier graph showing the time until CAS onset in the single-blinded NTG visit, comparing episodic cluster headache (ECH) with chronic cluster headache (CCH). Log-rank P = 0.740.
The median time until CAS onset for those that developed cluster headache attacks was 31 min (IQR 13–46) in the open unblinded NTG visit and 12 min (IQR 6–30) in the single-blinded NTG visit. Subjects sequentially reported CAS development.
During the single-blinded placebo visit, four subjects (17%) developed unilateral CAS, of which one subject developed a spontaneous attack, and three developed CAS but no pain. The median number of symptoms reported in the placebo group was two (IQR 1–2) and the symptoms reported were nasal congestion (n = 2), conjunctival injection (n = 1), periorbital swelling (n = 1), rhinorrhoea (n = 1) and aural fullness (n = 1).
Agitation
Nitroglycerin brought on agitation in the majority of subjects, open unblinded NTG visit (n = 24, 73%) and single-blinded NTG visit (n= 20, 80%), compared with none in the single-blinded placebo visit.
Non-headache symptoms post-attack
The non-headache symptoms were not studied here, as all attacks were treated with sumatriptan or oxygen after 20 minutes, thus altering the natural progression and development of symptoms.
Episodic cluster headache compared with chronic cluster headache
For the subjects that developed an NTG-induced attack following the single-blinded NTG infusion, the time until NTG-induced attack was shorter in the episodic cluster headache group compared with the chronic cluster headache group (U = 15, z = −2.399, P = 0.016). The time until CAS onset, in the subjects that developed CAS following single-blinded NTG infusion was not different between episodic cluster headache and chronic cluster headache groups (U = 38, z = −1.2000, P = 0.230).
Effect of verapamil on NTG triggering
There were seven subjects on verapamil that attended the single-blinded NTG visits, of which two did not develop NTG-triggered cluster headache attacks (29%). Using χ2, there was no difference between verapamil and NTG triggering (χ2 (df = 1) = 0.111, P = 0.739).
Effect of migraine on NTG-triggered attacks
Within the cohort that attended the single-blinded NTG visits, 15 had migraine (60%). There was no difference between the number of non-headache symptoms (U = 67, z = −0.449, P = 0.654) or number of CAS (U = 57, z = −1.019, P = 0.308), between the subjects with migraine and those without migraine. Furthermore, there was no association between subjects with migraine and NTG triggering (χ2 (df = 1) = 0.146, P = 0.702); similarly, there was no association between subjects with migraine and development of NTG headache (χ2 (df = 1) = 0.033, P = 0.856).
Discussion
This study demonstrates that weight-calculated intravenous NTG effectively triggers cluster headache attacks in both chronic cluster headache and episodic cluster headache subjects within bout when compared with placebo. The approach is reliable in terms of triggering a fully-featured attack that allows careful observation of symptoms and their development during acute attacks of cluster headache.
The benefit of weight-calculated intravenous NTG compared to intranasal and sublingual administration is that this is more reliable and has more stable bioavailability. The median time until cluster headache attack onset was 30 minutes (open unblinded NTG visit) and 33 minutes (single-blinded NTG visit), with the overall maximum onset time of 81 minutes. Subjects who did not develop an attack during the 140 minutes of observation were asked to report if they developed an attack later on that day, and none did. The median onset time is similar to the reported latency period reported in the literature (Table 1). The minimum onset time for NTG-induced attacks was 2 minutes, and this is less than reported from the sublingual route, where the shortest time until onset time was 9 minutes (8); this is expected, given the intravenous route has a half-life of 2.3–2.8 minutes (30,31). Two subjects started experiencing mild attack pain before the start of the NTG infusion, and within the placebo group we observed one subject who developed a spontaneous attack. Spontaneous attacks could be anticipated given the subjects are within bout; there were three subjects with only short-lasting CAS symptoms and two subjects who experienced a mild pain without CAS, similar to a shadow.
This study delineates the development of the various stages of an NTG-induced cluster headache attack, including the non-headache symptoms and CAS (Figure 6). The majority of subjects developed NTG headache shortly after the infusion started. This headache was generalised, mild and progressive in nature, predominantly in the bi-occipital and bi-temporal regions. Subjects described it as pressure-like or band-like ache, and they reported it to be distinct from their cluster headache attacks; if there were an overlap, the cluster headache attack would clearly ramp up and supersede the NTG headache. It is difficult to disentangle whether NTG headache developed because there was a high proportion of subjects with either a migraine diagnosis, migraine marker or family history of migraine. However, from a previous study with 25 healthy volunteers without a migraine diagnosis, 16 (64%) developed NTG headache following 0.5 mg NTG sublingual administration (32).
Figure 6. Violin plots of the stages of cluster headache attack from the 19 subjects that developed cluster headache attacks and subdivided by chronicity. The timeline starts with 20 minutes of single-blinded nitroglycerin (NTG) infusion, followed by 120 minutes of post-infusion observation. CAS = cranial autonomic symptoms.
Following the NTG headache, the majority of subjects reported non-headache symptoms in the lead-up to the onset of the pain from the attack and in some subjects, non-headache symptoms accompanied their attacks. The non-headache symptoms included homeostatic symptoms (thirst, cravings, yawning, frequency of urination), fatigue/cognitive symptoms (concentration difficulty, fatigue, memory impairment, mood changes, irritability) and sensitised sensory symptoms (neck stiffness, photophobia, phonophobia, osmophobia, nausea), as are reported in the premonitory phase of migraine (33). The most common symptoms were neck stiffness, photophobia and thirst. During their spontaneous attacks, subjects reported that non-headache symptoms would precede the attack at a median of 10 minutes (IQR 2–30) before the onset of pain, although it is known that there are discrepancies between retrospective and prospective reporting (25). Comparing the symptoms observed from NTG-induced attacks in this study with the prospective observational questionnaire study (24), the most reported general symptoms in the pre-pain phase in this study were concentration difficulties, photophobia and mood changes. Patients in the observational study also reported general symptoms during their attacks and postictal symptoms similar to the symptoms seen during the NTG-induced attacks and the reported symptoms by the subjects in this study during the postdrome phase of their spontaneous attacks. Non-headache symptoms such as photophobia, phonophobia, and localised allodynia were often reported during the attacks, as has been reported previously (21,34). In one semi-structured questionnaire study, they found a high proportion of cluster headache patients (73.2%) reported phonophobia or photophobia with their attacks (35), cluster headache patients with migraine did not more frequently report these symptoms compared with those without co-existing migraine. Furthermore, allodynia was more often reported in cluster headache patients with migraine. From pre-clinical studies, high dose NTG causes a sustained increase in spontaneous firing of Aδ and C-fibre trigeminal neurons (36), which migraine biology may unmask.
Similar to the prospective questionnaire study by Snoer and colleagues (24), in some subjects CAS presented before the onset of the attack pain (Figure 6). In this study, the median onset time for CAS was 31 minutes (IQR 13–46) in the open unblinded NTG visit and 12 minutes (IQR 6–30) in the single-blinded NTG visit, whereas the onset of NTG-induced attack was 30 minutes (IQR 20–39) in the open unblinded visit and 33 minutes (IQR 15–42) in the single-blinded NTG visit. From the open unblinded NTG visit, 38% presented with CAS before the attack, 15% presented with CAS with the onset of the attack, and from the single-blinded NTG visit, 58% presented with CAS before the attack and 16% presented with CAS with the onset of the attack.
Vollesen and colleagues used calcitonin gene-related peptide (CGRP) infusion to trigger cluster headache attacks, finding CGRP induced 50% of subjects with CCH and 89% for ECH subjects in bout (4). In our study, NTG induced attacks in 79% of the CCH subjects and 84% in ECH subjects in bout, in the open unblinded NTG visits, and 92% CCH and 62% ECH in bout in the single-blinded NTG visits. There are some differences in the number of chronic cluster headache subjects on verapamil between the studies; in this study, 33% of CCH subjects were on verapamil and in the study by Vollesen and colleagues, 57% of CCH subjects were on verapamil (of which one was on both verapamil and lithium) and one was on 4 mg melatonin. Vollesen and colleagues proposed that the CCH patients who did not develop an attack following CGRP infusion had a lower median attack frequency in the preceding 30 days prior to the study compared to the CCH patients that did develop an attack. However, in this study, subjects reported having their last attack as long ago as 128 and 158 days and still had NTG-induced attacks (Table 3).
NTG is a pro-drug of nitric oxide (NO) and has effects on blood vessel dilation through mechanisms of the NO-cyclic guanylate phosphate (cGMP) pathway (27). However, the vasodilatory effects of NTG are not sufficient to explain the cluster headache attack that occurs after a latency and the central features associated with the attack. Indeed, experimental studies demonstrate that NTG has central effects (37,38). Interestingly, in studies where NO donors were administered in vivo and in vitro, there was a local release of CGRP (39–42). The difference in the rate of cluster headache attacks induced by NTG and CGRP in ECH and CCH subjects could reflect in part the underlying biological processes and systems that are more active in the different subtypes of cluster headache. The difference between ECH and CCH is also suggested by the treatment response to a CGRP monoclonal antibody, galcanezumab (43,44), and non-invasive vagal nerve stimulator (45,46).
Limitations
The main limitations to the study were the recruitment of eligible subjects and the dropout rate at each stage due to the nature of the condition. Therefore, a pragmatic approach was taken with the study design regarding randomisation. Although there was a randomisation sequence, this was modified by the investigator if deemed necessary. This would be in the case of episodic cluster headache patients that were near the end of their bout missing the NTG visit if they followed the randomised sequence. For this reason, it was designed to be a single-blind cross-over study and not a double-blind and randomised study. Expectation bias was reduced by maintaining blinding of the subjects until the end of the study and having both infusions identical in volume, appearance and duration of infusion. Furthermore, given the stark difference between placebo and NTG, there was no difference between attack onset in the open unblinded compared with the single-blinded NTG visits (Figure 4(b)), is an indication that randomisation was not a factor in this study.
Conclusion
We present the results of the first placebo-controlled study using intravenous NTG administration to systematically study NTG-induced cluster headache attacks. We have shown that NTG can reliably bring on cluster headache attacks as well as the development of non-headache symptoms and CAS. This study highlights differences between NTG-induced attack onset times between the ECH and CCH subjects. Understanding the stages of cluster headache is essential; by recognising the non-headache symptoms in the lead up to the onset of pain and the underlying pathogenesis of this, we may be able to uncover new therapeutic targets to abort attacks before the onset of the severe and devastating pain experienced by our cluster headache patients.
Article highlights
Weight-calculated standardised intravenous nitroglycerin administration is a reliable method to induce cluster headache attacks, cranial autonomic symptoms and non-headache symptoms that accompany cluster headache attacks.
Accompanying non-headache symptoms in cluster headache attacks are important to recognise for both clinical and research purposes.
There may be inherent differences between episodic cluster headache and chronic cluster headache.
Acknowledgement
This study would not have been possible without the support of OUCH(UK), all the cluster headache patients who were interested in helping us with this study and all the subjects who took part in this study.
Ethics or Institutional Review Board approval: This study 16/LO/0693 obtained approval from the London, City & East NHS Research Ethics Committee on 23 June 2016. This study was carried out in accordance with the World Medical Association Declaration of Helsinki (1964), the Research Governance Framework for Health and Social Care (2nd edition, 2005), the Data Protection Act (1998) and the Principles of Good Clinical Practice (GCP); all subjects gave informed consent before taking part.
Declaration of conflicting interests: The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: DYW no reported competing interests. PJG reports, over the last 36 months, grants and personal fees from Amgen and Eli-Lilly and Company, grant from Celegene, and personal fees from Alder Biopharmaceuticals, Aeon Biopharma, Allergan, Biohaven Pharmaceuticals Inc., Clexio, Electrocore LLC, eNeura, Epalex, GlaxoSmithKline, Impel Neuropharma, MundiPharma, Novartis, Pfizer, Praxis, Sanofi, Santara Therapeutics Satsuma, Teva Pharmaceuticals, Trigemina Inc., WL Gore, and personal fees from MedicoLegal work, Massachusetts Medical Society, Up-to-Date, Oxford University Press, and Wolters Kluwer; and a patent magnetic stimulation for headache assigned to eNeura without fee.
Funding: The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study is part-funded by the National Institute for Health Research (NIHR) Maudsley Biomedical Research Centre at South London Maudsley Foundation Trust and King’s College London. The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care.
ORCID iDs: Diana Y Wei https://orcid.org/0000-0003-0644-7172
Peter J Goadsby https://orcid.org/0000-0003-3260-5904 | 0.5 MCG/KG/MIN (OVER 20 MINUTES) | DrugDosageText | CC BY | 33615843 | 19,017,453 | 2021-07 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Pneumocephalus'. | Chemical meningitis after cervical transforaminal epidural steroid injection: a case report.
We herein report a case of chemical meningitis that developed after cervical transforaminal steroid injection. A 49-year-old man presented with symptoms of meningitis (severe headache and neck stiffness) after cervical transforaminal steroid injection at the right C5-6 level. The injection solution was a mixture of lidocaine (0.3 mL), hyaluronidase (1 mL), placenta hydrolysate (2 mL), and normal saline (1 mL). The patient developed symptoms of meningitis 2.5 hours after the cervical epidural injection. Cerebrospinal fluid (CSF) analysis was performed 1 day after the injection, and the results showed an elevated white blood cell count at 7106 cells/µL. The patient's CSF analysis findings and symptoms did not differ from those of bacterial meningitis. However, considering that his symptoms developed 2.5 hours after the epidural injection, we believe that the patient developed chemical meningitis; therefore, he was symptomatically treated with an analgesic. Three days after the cervical transforaminal epidural injection, the patient experienced complete relief from the headache and neck stiffness. A Gram stain of the CSF revealed no organisms. Hence, the diagnosis of chemical meningitis was confirmed. Clinicians should be knowledgeable about the risk of this complication.
Introduction
In pain clinics, epidural injection is widely used to manage axial neck and back pain and radicular pain.1,2 Previous studies have shown that epidural injection is effective for treatment of radicular pain or axial pain induced by spinal stenosis or herniated discs.1,2 However, adverse effects such as neural injury, infection, cord or cerebral infarction, hematoma, and lidocaine-induced seizure can occasionally occur.3–5 Moreover, chemical meningitis is a potential adverse effect of epidural injection.6–8 This condition can cause several symptoms, such as headache, neck stiffness, fever, nausea/vomiting, and an altered mental status.6–8 In all reported cases, chemical meningitis occurred after interlaminar lumbar epidural injection.
We herein describe a patient who developed chemical meningitis after cervical transforaminal epidural steroid injection (TFESI).
Case report
A 49-year-old man underwent TFESI in the right C6 nerve root under C-arm fluoroscopic guidance for control of radicular pain induced by right C5–6 foraminal stenosis due to spondylosis in a local pain clinic. The injected solution was a mixture of lidocaine (0.3 mL), hyaluronidase (1 mL), placenta hydrolysate (2 mL), and normal saline (1 mL). Prior to the TFESI, 0.3 mL of contrast medium had been injected to determine whether the needle tip was placed at the proper location. The patient had a history of avascular necrosis of both femoral heads. In addition, he had undergone left total hip replacement for avascular necrosis of the left femoral head 3 years previously. He had undergone a single TFESI procedure of the right C6 nerve root with the same injection material 3 months previously. However, he developed no adverse effects after the previous TFESI.
About 2 hours 30 minutes after the cervical TFESI, the patient developed a severe headache. He visited the emergency department of a university hospital around 2:00 am the day after the epidural injection. Upon arrival, the patient’s body temperature was 37.7°C, and his blood pressure, pulse rate, and respiratory rate were normal. Laboratory tests showed that his white blood cell (WBC) count was elevated to 18,390 cells/µL (reference range, 4,000–10,000 cells/µL) with a neutrophil count of 80.8%, and his C-reactive protein level was elevated to 0.897 mg/dL (reference range, 0.0–0.5 mg/dL). The patient was admitted at the physical medicine and rehabilitation department. Using a numeric rating scale (0 indicating no pain and 10 indicating the worst pain imaginable), the patient gave a rating of 9 for his headache, which was aggravated in the supine position and relieved in the sitting and standing positions. The patient had also developed neck stiffness. His mental status was normal, and no motor or sensory deficits were observed. The deep tendon reflexes in the bilateral upper and lower limbs were normal. Brudzinski’s and Kernig’s signs were negative. Brain computed tomography (CT) and magnetic resonance imaging revealed no abnormalities (Figure 1). In addition, cervical spine magnetic resonance imaging revealed no specific abnormal findings other than right C5–6 foraminal stenosis. Considering the patient’s history, symptoms, and physical examination and imaging findings, we believe that he developed meningitis. Cerebrospinal fluid (CSF) analysis was performed around 1:00 pm (about 11 hours after arriving at the emergency room), revealing an elevated WBC count at 7106 cells/μL (polymorphonuclear cells, 93%; lymphocytes, 6%). Moreover, the patient’s protein and glucose concentrations were 293.95 mg/dL (reference range, 15–45 mg/dL) and 52 mg/dL (reference range, 40–70 mg/dL), respectively. The CSF was cloudy. The patient’s CSF analysis findings and symptoms did not differ from those of bacterial meningitis. However, considering that the symptoms developed 2.5 hours after the epidural injection, we believe that the patient most likely developed chemical meningitis. Dexamethasone was not administered for the treatment of chemical meningitis because the patient had a history of avascular necrosis of the femoral head; instead, only intravenous propacetamol (1 mg) was administered every 4 to 6 hours for 2 days for symptomatic treatment. If the symptoms became aggravated, we planned to start intravenous antibiotic treatment. However, the symptoms were gradually relieved. Three days after the cervical TFESI, the patient experienced complete relief from the headache and neck stiffness. A Gram stain of the CSF revealed no organisms. Additionally, fungal infection was ruled out by the CSF culture result. A follow-up CSF evaluation was conducted 6 days after the epidural injection. The following results were obtained: WBC count, 193 cells/μL (polymorphonuclear cells, 3%; lymphocytes, 73%); protein concentration, 65.38 mg/dL; and glucose concentration, 53 mg/dL. Based on the course of the patient’s symptoms and the CSF analysis findings, the diagnosis of chemical meningitis due to cervical TFESI was confirmed. The patient was discharged on the seventh day after the epidural injection.
Figure 1. Non-contrast brain computed tomography revealed no abnormalities.
Discussion
We have herein described a patient who developed chemical meningitis after TFESI. Although dexamethasone and antibiotics were not administered for treatment of the meningitis, the patient experienced complete relief from the symptoms of meningitis 3 days after the epidural injection.
The mechanism underlying the occurrence of chemical meningitis has not been clearly elucidated. However, it might be caused by allergic or hypersensitivity reactions.9 Although several reports have described chemical meningitis caused by local anesthetics after spinal anesthesia or intrathecal anesthetics and/or steroid injection,10–13 only three cases of chemical meningitis after epidural injection for pain management have been reported.6–8 In 1987, Gutknecht6 reported a case of chemical meningitis after interlaminar epidural injection at the L12–1, L4–5, and L5–S1 levels with methylprednisolone for treatment of lower back pain and lumbar radicular pain. The patient’s symptoms developed 4 hours after the epidural injection, and brain CT revealed air droplets in the subarachnoid space. In 2016, Shah et al.8 reported a case of chemical meningitis with pneumocephalus. The symptoms developed 1.5 hours after the epidural injection of lidocaine, methylprednisolone, and betamethasone. The patient’s symptoms completely resolved 48 hours after the onset of meningitis symptoms. In 2020, Koo and Cho7 reported a case of chemical meningitis with pneumocephalus. The symptoms developed 30 minutes after lumbar interlaminar epidural injection with mepivacaine and dexamethasone. Brain CT revealed multiple small foci of air in the subarachnoid space and ventricle. Two days after initiating symptomatic treatment, the patient’s symptoms completely resolved. Because pneumocephalus was observed in these three cases,6–8 inadvertent dural puncture might have occurred during the procedure. Although there were no findings indicative of pneumocephalus in our case, there was a high risk of unintended intrathecal entry of the injected solution. In addition, a mixture of lidocaine, hyaluronidase, and placenta hydrolysate was used for cervical TFESI. Therefore, which component of the injected solution induced the chemical meningitis remains unclear.
Chemical and bacterial meningitis cannot be easily differentiated because their symptoms and laboratory findings are similar. Moreover, the CSF culture results are available after a few days.14 A previous study showed that the symptoms of bacterial meningitis usually develop 2 to 10 days after the procedure, and those of chemical meningitis develop within a few hours.15 The only significant difference between the two disorders is the duration from epidural injection to onset of symptoms. In our case, because the patient’s meningitis symptoms appeared about 2 hours 30 minutes after the cervical TFESI, we considered that our patient had chemical meningitis and therefore did not administer antibiotics. However, because the course of each disorder is not fully elucidated, clinicians should initiate empirical treatment with broad-spectrum antibiotics until the CSF culture results are available.8
In summary, we have herein reported a case of chemical meningitis that developed after TFESI. Intrathecal injection might have been conducted inadvertently. Hence, clinicians should be knowledgeable about the risk of this complication. In addition, the sensitivity and specificity of physical signs of meningeal inflammation, such as Brudzinski’s and Kernig’s signs, are not high enough to accurately rule in or rule out meningitis. Therefore, when patients complain of meningitis symptoms such as headache, neck stiffness, and nausea/vomiting after epidural injection, the occurrence of chemical meningitis should be considered even in the absence of physical signs of meningeal irritation, and CSF analysis with empirical antibiotic treatment should be initiated as soon as possible.
Ethics: The study protocol was approved by the Institutional Review Board of Yeungnam University Hospital. The patient provided written informed consent.
Declaration of conflicting interest: The authors declare that there is no conflict of interest.
Funding: This work was supported by a National Research Foundation of Korea grant funded by the Korean government (grant no. NRF-2019M3E5D1A02068106).
ORCID iD: Min Cheol Chang https://orcid.org/0000-0002-7629-7213 | BETAMETHASONE, LIDOCAINE, METHYLPREDNISOLONE SODIUM SUCCINATE | DrugsGivenReaction | CC BY-NC | 33616459 | 19,014,130 | 2021-02 |
What was the administration route of drug 'BETAMETHASONE'? | Chemical meningitis after cervical transforaminal epidural steroid injection: a case report.
We herein report a case of chemical meningitis that developed after cervical transforaminal steroid injection. A 49-year-old man presented with symptoms of meningitis (severe headache and neck stiffness) after cervical transforaminal steroid injection at the right C5-6 level. The injection solution was a mixture of lidocaine (0.3 mL), hyaluronidase (1 mL), placenta hydrolysate (2 mL), and normal saline (1 mL). The patient developed symptoms of meningitis 2.5 hours after the cervical epidural injection. Cerebrospinal fluid (CSF) analysis was performed 1 day after the injection, and the results showed an elevated white blood cell count at 7106 cells/µL. The patient's CSF analysis findings and symptoms did not differ from those of bacterial meningitis. However, considering that his symptoms developed 2.5 hours after the epidural injection, we believe that the patient developed chemical meningitis; therefore, he was symptomatically treated with an analgesic. Three days after the cervical transforaminal epidural injection, the patient experienced complete relief from the headache and neck stiffness. A Gram stain of the CSF revealed no organisms. Hence, the diagnosis of chemical meningitis was confirmed. Clinicians should be knowledgeable about the risk of this complication.
Introduction
In pain clinics, epidural injection is widely used to manage axial neck and back pain and radicular pain.1,2 Previous studies have shown that epidural injection is effective for treatment of radicular pain or axial pain induced by spinal stenosis or herniated discs.1,2 However, adverse effects such as neural injury, infection, cord or cerebral infarction, hematoma, and lidocaine-induced seizure can occasionally occur.3–5 Moreover, chemical meningitis is a potential adverse effect of epidural injection.6–8 This condition can cause several symptoms, such as headache, neck stiffness, fever, nausea/vomiting, and an altered mental status.6–8 In all reported cases, chemical meningitis occurred after interlaminar lumbar epidural injection.
We herein describe a patient who developed chemical meningitis after cervical transforaminal epidural steroid injection (TFESI).
Case report
A 49-year-old man underwent TFESI in the right C6 nerve root under C-arm fluoroscopic guidance for control of radicular pain induced by right C5–6 foraminal stenosis due to spondylosis in a local pain clinic. The injected solution was a mixture of lidocaine (0.3 mL), hyaluronidase (1 mL), placenta hydrolysate (2 mL), and normal saline (1 mL). Prior to the TFESI, 0.3 mL of contrast medium had been injected to determine whether the needle tip was placed at the proper location. The patient had a history of avascular necrosis of both femoral heads. In addition, he had undergone left total hip replacement for avascular necrosis of the left femoral head 3 years previously. He had undergone a single TFESI procedure of the right C6 nerve root with the same injection material 3 months previously. However, he developed no adverse effects after the previous TFESI.
About 2 hours 30 minutes after the cervical TFESI, the patient developed a severe headache. He visited the emergency department of a university hospital around 2:00 am the day after the epidural injection. Upon arrival, the patient’s body temperature was 37.7°C, and his blood pressure, pulse rate, and respiratory rate were normal. Laboratory tests showed that his white blood cell (WBC) count was elevated to 18,390 cells/µL (reference range, 4,000–10,000 cells/µL) with a neutrophil count of 80.8%, and his C-reactive protein level was elevated to 0.897 mg/dL (reference range, 0.0–0.5 mg/dL). The patient was admitted at the physical medicine and rehabilitation department. Using a numeric rating scale (0 indicating no pain and 10 indicating the worst pain imaginable), the patient gave a rating of 9 for his headache, which was aggravated in the supine position and relieved in the sitting and standing positions. The patient had also developed neck stiffness. His mental status was normal, and no motor or sensory deficits were observed. The deep tendon reflexes in the bilateral upper and lower limbs were normal. Brudzinski’s and Kernig’s signs were negative. Brain computed tomography (CT) and magnetic resonance imaging revealed no abnormalities (Figure 1). In addition, cervical spine magnetic resonance imaging revealed no specific abnormal findings other than right C5–6 foraminal stenosis. Considering the patient’s history, symptoms, and physical examination and imaging findings, we believe that he developed meningitis. Cerebrospinal fluid (CSF) analysis was performed around 1:00 pm (about 11 hours after arriving at the emergency room), revealing an elevated WBC count at 7106 cells/μL (polymorphonuclear cells, 93%; lymphocytes, 6%). Moreover, the patient’s protein and glucose concentrations were 293.95 mg/dL (reference range, 15–45 mg/dL) and 52 mg/dL (reference range, 40–70 mg/dL), respectively. The CSF was cloudy. The patient’s CSF analysis findings and symptoms did not differ from those of bacterial meningitis. However, considering that the symptoms developed 2.5 hours after the epidural injection, we believe that the patient most likely developed chemical meningitis. Dexamethasone was not administered for the treatment of chemical meningitis because the patient had a history of avascular necrosis of the femoral head; instead, only intravenous propacetamol (1 mg) was administered every 4 to 6 hours for 2 days for symptomatic treatment. If the symptoms became aggravated, we planned to start intravenous antibiotic treatment. However, the symptoms were gradually relieved. Three days after the cervical TFESI, the patient experienced complete relief from the headache and neck stiffness. A Gram stain of the CSF revealed no organisms. Additionally, fungal infection was ruled out by the CSF culture result. A follow-up CSF evaluation was conducted 6 days after the epidural injection. The following results were obtained: WBC count, 193 cells/μL (polymorphonuclear cells, 3%; lymphocytes, 73%); protein concentration, 65.38 mg/dL; and glucose concentration, 53 mg/dL. Based on the course of the patient’s symptoms and the CSF analysis findings, the diagnosis of chemical meningitis due to cervical TFESI was confirmed. The patient was discharged on the seventh day after the epidural injection.
Figure 1. Non-contrast brain computed tomography revealed no abnormalities.
Discussion
We have herein described a patient who developed chemical meningitis after TFESI. Although dexamethasone and antibiotics were not administered for treatment of the meningitis, the patient experienced complete relief from the symptoms of meningitis 3 days after the epidural injection.
The mechanism underlying the occurrence of chemical meningitis has not been clearly elucidated. However, it might be caused by allergic or hypersensitivity reactions.9 Although several reports have described chemical meningitis caused by local anesthetics after spinal anesthesia or intrathecal anesthetics and/or steroid injection,10–13 only three cases of chemical meningitis after epidural injection for pain management have been reported.6–8 In 1987, Gutknecht6 reported a case of chemical meningitis after interlaminar epidural injection at the L12–1, L4–5, and L5–S1 levels with methylprednisolone for treatment of lower back pain and lumbar radicular pain. The patient’s symptoms developed 4 hours after the epidural injection, and brain CT revealed air droplets in the subarachnoid space. In 2016, Shah et al.8 reported a case of chemical meningitis with pneumocephalus. The symptoms developed 1.5 hours after the epidural injection of lidocaine, methylprednisolone, and betamethasone. The patient’s symptoms completely resolved 48 hours after the onset of meningitis symptoms. In 2020, Koo and Cho7 reported a case of chemical meningitis with pneumocephalus. The symptoms developed 30 minutes after lumbar interlaminar epidural injection with mepivacaine and dexamethasone. Brain CT revealed multiple small foci of air in the subarachnoid space and ventricle. Two days after initiating symptomatic treatment, the patient’s symptoms completely resolved. Because pneumocephalus was observed in these three cases,6–8 inadvertent dural puncture might have occurred during the procedure. Although there were no findings indicative of pneumocephalus in our case, there was a high risk of unintended intrathecal entry of the injected solution. In addition, a mixture of lidocaine, hyaluronidase, and placenta hydrolysate was used for cervical TFESI. Therefore, which component of the injected solution induced the chemical meningitis remains unclear.
Chemical and bacterial meningitis cannot be easily differentiated because their symptoms and laboratory findings are similar. Moreover, the CSF culture results are available after a few days.14 A previous study showed that the symptoms of bacterial meningitis usually develop 2 to 10 days after the procedure, and those of chemical meningitis develop within a few hours.15 The only significant difference between the two disorders is the duration from epidural injection to onset of symptoms. In our case, because the patient’s meningitis symptoms appeared about 2 hours 30 minutes after the cervical TFESI, we considered that our patient had chemical meningitis and therefore did not administer antibiotics. However, because the course of each disorder is not fully elucidated, clinicians should initiate empirical treatment with broad-spectrum antibiotics until the CSF culture results are available.8
In summary, we have herein reported a case of chemical meningitis that developed after TFESI. Intrathecal injection might have been conducted inadvertently. Hence, clinicians should be knowledgeable about the risk of this complication. In addition, the sensitivity and specificity of physical signs of meningeal inflammation, such as Brudzinski’s and Kernig’s signs, are not high enough to accurately rule in or rule out meningitis. Therefore, when patients complain of meningitis symptoms such as headache, neck stiffness, and nausea/vomiting after epidural injection, the occurrence of chemical meningitis should be considered even in the absence of physical signs of meningeal irritation, and CSF analysis with empirical antibiotic treatment should be initiated as soon as possible.
Ethics: The study protocol was approved by the Institutional Review Board of Yeungnam University Hospital. The patient provided written informed consent.
Declaration of conflicting interest: The authors declare that there is no conflict of interest.
Funding: This work was supported by a National Research Foundation of Korea grant funded by the Korean government (grant no. NRF-2019M3E5D1A02068106).
ORCID iD: Min Cheol Chang https://orcid.org/0000-0002-7629-7213 | Epidural | DrugAdministrationRoute | CC BY-NC | 33616459 | 19,014,130 | 2021-02 |
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