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Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Diarrhoea'. | Disseminated peritoneal coccidioidomycosis in pregnancy following fertility treatment: A case report and literature review.
Disseminated peritoneal coccidioidomycosis in the setting of early pregnancy after fertility treatment is rare and can present as a diagnostic challenge. A 39-year-old underwent ovarian stimulation with clomiphene citrate followed by HCG trigger and intrauterine insemination. She developed persistent abdominal pain, ascites and episodes of fever in early pregnancy, and eventually underwent a diagnostic laparoscopy for worsening clinical presentation. Operative findings were notable for peritoneal studding, infracolic omentum inflammation, bowel adhesions to the abdominal wall and normal-appearing uterus and adnexa. The pathology results indicated peritoneal Coccidioides immitis infection. Hormonal changes associated with fertility treatment and immune tolerance in pregnancy may increase the risk for disseminated peritoneal coccidioidomycosis. A high index of suspicion and a multidisciplinary team are important for the diagnostic workup and treatment plan of disseminated peritoneal coccidioidomycosis.
1 Introduction
Coccidioidomycosis is a fungal infection that results primarily in pulmonary disease and is endemic to the Southwest United States, Mexico and South America [1]. Extrapulmonary dissemination occurs in 1% of cases, usually in patients with risk factors like male sex, African ancestry, immunosuppression and pregnancy [[2], [3], [4]]. Prior data have shown that disseminated disease occurs in 23% of pregnant patients in the first trimester [5]. Extrapulmonary disease occurs most commonly in soft tissue, skin, joints and brain [6]. In contrast, peritoneum dissemination is rare, occurring through hematogenous spread or swallowing pulmonary secretions [7]. Disseminated cocciodiodes, like tuberculosis, is a great mimicker and can be challenging to diagnose. For example, early infection may present with persistently negative antibodies, especially in patients who are immunosuppressed or immune tolerant, as observed in pregnant women [3]. Additionally, there is a wide sensitivity and specificity of the enzyme immunoassay test, depending on lab assay [3].
To our knowledge, there are no reported cases of disseminated peritoneal coccidioidomycosis in the setting of early pregnancy following fertility treatment. We present the case of a 39-year-old woman with an early pregnancy resulting from ovarian stimulation with clomiphene citrate and intrauterine insemination who developed episodes of fever, ascites and abdominal pain ultimately requiring an exploratory laparotomy leading to a diagnosis of disseminated peritoneal Coccidioides immitis.
2 Case Presentation
A 39-year-old woman presented to an infertility clinic. She was diagnosed with unexplained secondary infertility associated with male factor. Her workup showed normal day 3 laboratory results (FSH 7.0 mIU/mL, estradiol 35 pg/mL), TSH 2.8 mcIU/mL, normal hysterosalpingogram, antral follicle count of 32 and semen analysis with mild oligoteratospermia. The couple had negative infectious disease screening, including hepatitis B and C, HIV, syphilis and HTLV 1–2. She underwent her first clomiphene citrate 50 mg cycle and developed two dominant follicles. Ovulation was triggered using 250 μg of HCG subcutaneously. She underwent an uncomplicated intrauterine insemination with 24 million fresh, motile washed sperm.
She began experiencing intermittent fevers and abdominal pain 8 days after insemination. She was seen by her primary care physician, who noted normal temperature, mild tenderness on exam and negative pregnancy test. She was counseled that her symptoms may be secondary to early pregnancy or mild gastritis. Three days later, she re-presented with a mild leukocytosis, serum beta-hCG 84 mIU/ml and normal electrolytes. Pelvic ultrasound showed moderate free fluid with echogenic debris, two left ovarian corpus lutea and an unremarkable appendix (Fig. 1). Consistent with early gestation, no pregnancy was identified, and suspected diagnosis was ruptured hemorrhagic cyst. However, her symptoms continued to worsen, with increasing ascites and distension, persistent fevers, mild increase in liver enzymes (AST 96 U/L, ALT 93 U/L]) and leukocytosis (15 K/uL), and she was sent to the emergency room at 4 weeks 1 day.Fig. 1 A. Large amount of free fluid in pouch of Douglas. B. Left ovary with corpus lutea.
Fig. 1
She had her first documented fever (38.2 °C), up-trending leukocytosis (17 K/uL), mild increase in liver enzymes (AST 50 U/L, ALT 80 U/L), beta-hCG of 127 mIU/ml, normal electrolytes and negative blood cultures. Abdominal ultrasound showed free fluid throughout the abdomen, thickened endometrial lining and a normal appendix. In addition to abdominal distension, the patient developed diarrhea and nausea. Given early gestation and goal to avoid CT radiation, a non-contrast MRI was performed, which showed significant free fluid, two ovarian cysts, likely corpus lutea, and inability to visualize the appendix. There was low suspicion for ovarian hyperstimulation syndrome given clomiphene citrate use for stimulation, two dominant follicles at trigger, normal electrolytes and absence of enlarged ovaries.
She was admitted for IV antibiotics for suspected bacterial peritonitis. Infectious disease was consulted. Ceftriaxone, flagyl and vancomycin were used for genitourinary coverage given fertility treatments. The patient was originally from Tanzania, which made the team suspicious for tuberculosis despite lack of clinical history and x-ray showing small pleural effusions.
By hospital day (HD) 3, she was clinically worsening, with fevers (39.4 °C), rising leukocytosis (23 K/uL) and abdominal distention. CT of the abdomen with contrast showed moderate ascites, omental nodularity and caking, not previously seen on MRI, concerning for malignancy or non-malignant causes, including tuberculosis. Gynecology oncology was consulted and the tumor markers CA-125, CA19-9, CEA, CA 15-3, CA 27.29, AFP were normal. Coccidioidomycosis IgM, IgG, and complement fixation titers were negative and <1:2 respectively. In terms of her pregnancy of unknown location, beta-HCGs were abnormally rising and trended every 48 h (126 mIU/ml, 180 mIU/ml, 395 mIU/ml).
On HD 5, paracentesis drained 800 l of fluid and interventional radiology-guided omental biopsies resulted in fat necrosis and granulomatous inflammation. Both peritoneal fluid and tissue biopsies were negative for neoplastic cells, CEA, acid-fast bacilli, fungal, bacterial, non-tuberculosis mycobacterium DNA and Mycobacterium tuberculosis (MTB) PCR. The only pertinent test was an indeterminate serum quantiferon gold; however, peritoneal fluid adenosine deaminase and negative MTB PCR were not consistent with tuberculosis. With progressively worsening symptoms and lack of diagnosis, the decision was made to proceed with laparoscopy for tissue diagnosis. Given abnormally rising beta-HCGs, pregnancy was likely non-viable, thus she elected for termination.
She underwent a diagnostic laparoscopy, omentectomy, lysis of adhesions and suction curettage on HD 8 with gynecology oncology, given CT results concerning for malignancy. Laparoscopy was converted to mini laparotomy due to significant adhesions and inability to obtain adequate biopsies for tissue diagnosis. Operative findings included extensive studding of peritoneum, infracolic omentum inflammation, bowel adhesions to abdominal wall, normal-appearing uterus and adnexa with 3.5 l of ascites (Fig. 2). Curettage showed decidualized endometrium without chorionic villi or coccidiodes. Beta-HCG down-trended to zero post-operatively consistent with successful surgical abortion.Fig. 2 A. Bowel attached to abdominal wall upon entry. B. Laparoscopic view of uterus, adnexa and ascites. C. “Caked omentum”, pathologic specimen.
Fig. 2
Post-operatively her fevers continued despite antibiotics. Surgical omental biopsy cultures resulted as Coccidioides immitis on postoperative day 11. Her only notable travel history was to Palm Springs, California, and visiting construction sites in the past two years, locations known to harbor coccidioidomycosis. After significant improvement on oral antifungal therapy, she was discharged on HD 15 with fluconazole 400 mg daily. She was followed by the multidisciplinary team as an outpatient. Coccidioides antibody complement fixation (titer 1:4) turned positive one month after her admission date.
3 Discussion
This is a unique case describing disseminated peritoneal coccidioidomycosis in a newly pregnant patient following fertility treatment with insemination. Peritoneal coccidioidomycosis is a challenging diagnosis as there are only 34 published cases [8]. Most patients with isolated peritoneal involvement and negative serology titers are immunosuppressed patients [3,9]. It is therefore possible that our pregnant patient had falsely negative titers due to the immune tolerance of pregnancy.
Most patients with disseminated coccidioidomycosis present gradually with abdominal distension and ascites occurring months to years after infection [2]. In our patient's case, it is possible that the immune-tolerance effects of pregnancy or the hormonal effects of ovarian stimulation may have contributed to her acute presentation. Prior data report pregnant women experience disseminated disease 100 times more frequently [2,6].
Our case highlights a possible association between hormonal changes with fertility treatment, immune tolerance in pregnancy, and risk for peritoneal coccidioidomycosis. Studies show that elevated serum levels of 17-beta-estradiol and progesterone in vitro increase coccidioidomycosis growth, contributing to dissemination [10]. Our patient received clomiphene citrate and was newly pregnant, thereby raising estradiol and progesterone levels. From an immunologic standpoint, pregnancy is a state of decreased cell-mediated immunity, which explains why coccidioidomycosis disseminates more commonly in pregnancy [4,11]. Evidence shows that pregnancy increases the risk of dissemination in proportion to gestational age, with greatest risk in the third trimester, thus our patient's presentation in early gestation was unusual [4,11]. In addition to pregnancy and presumably elevated hormones levels, African ancestry is another risk factor for disseminated disease in our case [11].
The timing and source of initial infection in our patient is unclear. Coccidioidomycosis was likely contracted years prior to presentation through environmental exposure. Even in dissemination, the usual source of initial infection is the pulmonary tract [1]. It is unusual for disseminated disease to involve the female genital tract, thus the insemination procedure or specimen are unlikely to be a cause for initial infection [12]. In concordance, endometrial tissue was negative for coccidioidomycosis. In the only other report of disseminated coccidioidomycosis in a woman who underwent ovarian stimulation with clomiphene citrate and insemination, presentation was several years after fertility treatment [10].
There is limited evidence on how to treat isolated peritoneal coccidioidomycosis. Management is typically fluconazole 400 mg daily for 6–12 months with duration guided by clinical, laboratory, and radiographic response [3]. Unlike other sites of dissemination, mortality is rare with isolated peritoneal coccidioidomycosis [13]. Going forward, our patient may have a small but increased risk of disease reactivation in future pregnancies. There is a lack of literature guiding reproductive patients for timing and risk of future conception [6,14]. According to the Infectious Disease Society of America guidelines, risk of reactivation in pregnancy is low in women who have completed therapy [3]. Once pregnant, the current recommendation is coccidioidal serologic testing every 6–12 weeks [3].
4 Conclusion
We believe this is the only published case of isolated peritoneal coccidioidomycosis in early pregnancy. The diagnosis of peritoneal coccidioidomycosis was particularly challenging given our patient's negative infectious workup and granulomatous tissue on initial omental biopsy. This case demonstrates the importance of a multidisciplinary team. Our patient was originally from Tanzania, which prompted us to consider tuberculosis as the etiology of her disease. Ultimately, local factors like living in California, rather than global factors, were the cause of her disease.
Contributors
Abigail Armstrong contributed to conception/design and drafting of the article.
Mika Watanabe contributed to conception/design and editing of the article.
Debika Bhattacharya was the infectious disease physician on the case and contributed to review and revision of the manuscript.
Mae Zakhour performed the surgery and contributed to review and revision of the manuscript.
Lindsay Kroener was the reproductive endocrinologist on the case and contributed to review and revision of the manuscript.
Conflict of Interest
The authors declare that they have no conflict of interest regarding the publication of this case report.
Funding
No funding from an external source supported the publication of this case report.
Patient Consent
Obtained.
Provenance and Peer Review
This case report was peer reviewed. | CEFTRIAXONE, CLOMIPHENE, GONADOTROPHIN, CHORIONIC, METRONIDAZOLE\METRONIDAZOLE HYDROCHLORIDE, VANCOMYCIN | DrugsGivenReaction | CC BY | 33665141 | 19,006,800 | 2021-04 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Leukocytosis'. | Disseminated peritoneal coccidioidomycosis in pregnancy following fertility treatment: A case report and literature review.
Disseminated peritoneal coccidioidomycosis in the setting of early pregnancy after fertility treatment is rare and can present as a diagnostic challenge. A 39-year-old underwent ovarian stimulation with clomiphene citrate followed by HCG trigger and intrauterine insemination. She developed persistent abdominal pain, ascites and episodes of fever in early pregnancy, and eventually underwent a diagnostic laparoscopy for worsening clinical presentation. Operative findings were notable for peritoneal studding, infracolic omentum inflammation, bowel adhesions to the abdominal wall and normal-appearing uterus and adnexa. The pathology results indicated peritoneal Coccidioides immitis infection. Hormonal changes associated with fertility treatment and immune tolerance in pregnancy may increase the risk for disseminated peritoneal coccidioidomycosis. A high index of suspicion and a multidisciplinary team are important for the diagnostic workup and treatment plan of disseminated peritoneal coccidioidomycosis.
1 Introduction
Coccidioidomycosis is a fungal infection that results primarily in pulmonary disease and is endemic to the Southwest United States, Mexico and South America [1]. Extrapulmonary dissemination occurs in 1% of cases, usually in patients with risk factors like male sex, African ancestry, immunosuppression and pregnancy [[2], [3], [4]]. Prior data have shown that disseminated disease occurs in 23% of pregnant patients in the first trimester [5]. Extrapulmonary disease occurs most commonly in soft tissue, skin, joints and brain [6]. In contrast, peritoneum dissemination is rare, occurring through hematogenous spread or swallowing pulmonary secretions [7]. Disseminated cocciodiodes, like tuberculosis, is a great mimicker and can be challenging to diagnose. For example, early infection may present with persistently negative antibodies, especially in patients who are immunosuppressed or immune tolerant, as observed in pregnant women [3]. Additionally, there is a wide sensitivity and specificity of the enzyme immunoassay test, depending on lab assay [3].
To our knowledge, there are no reported cases of disseminated peritoneal coccidioidomycosis in the setting of early pregnancy following fertility treatment. We present the case of a 39-year-old woman with an early pregnancy resulting from ovarian stimulation with clomiphene citrate and intrauterine insemination who developed episodes of fever, ascites and abdominal pain ultimately requiring an exploratory laparotomy leading to a diagnosis of disseminated peritoneal Coccidioides immitis.
2 Case Presentation
A 39-year-old woman presented to an infertility clinic. She was diagnosed with unexplained secondary infertility associated with male factor. Her workup showed normal day 3 laboratory results (FSH 7.0 mIU/mL, estradiol 35 pg/mL), TSH 2.8 mcIU/mL, normal hysterosalpingogram, antral follicle count of 32 and semen analysis with mild oligoteratospermia. The couple had negative infectious disease screening, including hepatitis B and C, HIV, syphilis and HTLV 1–2. She underwent her first clomiphene citrate 50 mg cycle and developed two dominant follicles. Ovulation was triggered using 250 μg of HCG subcutaneously. She underwent an uncomplicated intrauterine insemination with 24 million fresh, motile washed sperm.
She began experiencing intermittent fevers and abdominal pain 8 days after insemination. She was seen by her primary care physician, who noted normal temperature, mild tenderness on exam and negative pregnancy test. She was counseled that her symptoms may be secondary to early pregnancy or mild gastritis. Three days later, she re-presented with a mild leukocytosis, serum beta-hCG 84 mIU/ml and normal electrolytes. Pelvic ultrasound showed moderate free fluid with echogenic debris, two left ovarian corpus lutea and an unremarkable appendix (Fig. 1). Consistent with early gestation, no pregnancy was identified, and suspected diagnosis was ruptured hemorrhagic cyst. However, her symptoms continued to worsen, with increasing ascites and distension, persistent fevers, mild increase in liver enzymes (AST 96 U/L, ALT 93 U/L]) and leukocytosis (15 K/uL), and she was sent to the emergency room at 4 weeks 1 day.Fig. 1 A. Large amount of free fluid in pouch of Douglas. B. Left ovary with corpus lutea.
Fig. 1
She had her first documented fever (38.2 °C), up-trending leukocytosis (17 K/uL), mild increase in liver enzymes (AST 50 U/L, ALT 80 U/L), beta-hCG of 127 mIU/ml, normal electrolytes and negative blood cultures. Abdominal ultrasound showed free fluid throughout the abdomen, thickened endometrial lining and a normal appendix. In addition to abdominal distension, the patient developed diarrhea and nausea. Given early gestation and goal to avoid CT radiation, a non-contrast MRI was performed, which showed significant free fluid, two ovarian cysts, likely corpus lutea, and inability to visualize the appendix. There was low suspicion for ovarian hyperstimulation syndrome given clomiphene citrate use for stimulation, two dominant follicles at trigger, normal electrolytes and absence of enlarged ovaries.
She was admitted for IV antibiotics for suspected bacterial peritonitis. Infectious disease was consulted. Ceftriaxone, flagyl and vancomycin were used for genitourinary coverage given fertility treatments. The patient was originally from Tanzania, which made the team suspicious for tuberculosis despite lack of clinical history and x-ray showing small pleural effusions.
By hospital day (HD) 3, she was clinically worsening, with fevers (39.4 °C), rising leukocytosis (23 K/uL) and abdominal distention. CT of the abdomen with contrast showed moderate ascites, omental nodularity and caking, not previously seen on MRI, concerning for malignancy or non-malignant causes, including tuberculosis. Gynecology oncology was consulted and the tumor markers CA-125, CA19-9, CEA, CA 15-3, CA 27.29, AFP were normal. Coccidioidomycosis IgM, IgG, and complement fixation titers were negative and <1:2 respectively. In terms of her pregnancy of unknown location, beta-HCGs were abnormally rising and trended every 48 h (126 mIU/ml, 180 mIU/ml, 395 mIU/ml).
On HD 5, paracentesis drained 800 l of fluid and interventional radiology-guided omental biopsies resulted in fat necrosis and granulomatous inflammation. Both peritoneal fluid and tissue biopsies were negative for neoplastic cells, CEA, acid-fast bacilli, fungal, bacterial, non-tuberculosis mycobacterium DNA and Mycobacterium tuberculosis (MTB) PCR. The only pertinent test was an indeterminate serum quantiferon gold; however, peritoneal fluid adenosine deaminase and negative MTB PCR were not consistent with tuberculosis. With progressively worsening symptoms and lack of diagnosis, the decision was made to proceed with laparoscopy for tissue diagnosis. Given abnormally rising beta-HCGs, pregnancy was likely non-viable, thus she elected for termination.
She underwent a diagnostic laparoscopy, omentectomy, lysis of adhesions and suction curettage on HD 8 with gynecology oncology, given CT results concerning for malignancy. Laparoscopy was converted to mini laparotomy due to significant adhesions and inability to obtain adequate biopsies for tissue diagnosis. Operative findings included extensive studding of peritoneum, infracolic omentum inflammation, bowel adhesions to abdominal wall, normal-appearing uterus and adnexa with 3.5 l of ascites (Fig. 2). Curettage showed decidualized endometrium without chorionic villi or coccidiodes. Beta-HCG down-trended to zero post-operatively consistent with successful surgical abortion.Fig. 2 A. Bowel attached to abdominal wall upon entry. B. Laparoscopic view of uterus, adnexa and ascites. C. “Caked omentum”, pathologic specimen.
Fig. 2
Post-operatively her fevers continued despite antibiotics. Surgical omental biopsy cultures resulted as Coccidioides immitis on postoperative day 11. Her only notable travel history was to Palm Springs, California, and visiting construction sites in the past two years, locations known to harbor coccidioidomycosis. After significant improvement on oral antifungal therapy, she was discharged on HD 15 with fluconazole 400 mg daily. She was followed by the multidisciplinary team as an outpatient. Coccidioides antibody complement fixation (titer 1:4) turned positive one month after her admission date.
3 Discussion
This is a unique case describing disseminated peritoneal coccidioidomycosis in a newly pregnant patient following fertility treatment with insemination. Peritoneal coccidioidomycosis is a challenging diagnosis as there are only 34 published cases [8]. Most patients with isolated peritoneal involvement and negative serology titers are immunosuppressed patients [3,9]. It is therefore possible that our pregnant patient had falsely negative titers due to the immune tolerance of pregnancy.
Most patients with disseminated coccidioidomycosis present gradually with abdominal distension and ascites occurring months to years after infection [2]. In our patient's case, it is possible that the immune-tolerance effects of pregnancy or the hormonal effects of ovarian stimulation may have contributed to her acute presentation. Prior data report pregnant women experience disseminated disease 100 times more frequently [2,6].
Our case highlights a possible association between hormonal changes with fertility treatment, immune tolerance in pregnancy, and risk for peritoneal coccidioidomycosis. Studies show that elevated serum levels of 17-beta-estradiol and progesterone in vitro increase coccidioidomycosis growth, contributing to dissemination [10]. Our patient received clomiphene citrate and was newly pregnant, thereby raising estradiol and progesterone levels. From an immunologic standpoint, pregnancy is a state of decreased cell-mediated immunity, which explains why coccidioidomycosis disseminates more commonly in pregnancy [4,11]. Evidence shows that pregnancy increases the risk of dissemination in proportion to gestational age, with greatest risk in the third trimester, thus our patient's presentation in early gestation was unusual [4,11]. In addition to pregnancy and presumably elevated hormones levels, African ancestry is another risk factor for disseminated disease in our case [11].
The timing and source of initial infection in our patient is unclear. Coccidioidomycosis was likely contracted years prior to presentation through environmental exposure. Even in dissemination, the usual source of initial infection is the pulmonary tract [1]. It is unusual for disseminated disease to involve the female genital tract, thus the insemination procedure or specimen are unlikely to be a cause for initial infection [12]. In concordance, endometrial tissue was negative for coccidioidomycosis. In the only other report of disseminated coccidioidomycosis in a woman who underwent ovarian stimulation with clomiphene citrate and insemination, presentation was several years after fertility treatment [10].
There is limited evidence on how to treat isolated peritoneal coccidioidomycosis. Management is typically fluconazole 400 mg daily for 6–12 months with duration guided by clinical, laboratory, and radiographic response [3]. Unlike other sites of dissemination, mortality is rare with isolated peritoneal coccidioidomycosis [13]. Going forward, our patient may have a small but increased risk of disease reactivation in future pregnancies. There is a lack of literature guiding reproductive patients for timing and risk of future conception [6,14]. According to the Infectious Disease Society of America guidelines, risk of reactivation in pregnancy is low in women who have completed therapy [3]. Once pregnant, the current recommendation is coccidioidal serologic testing every 6–12 weeks [3].
4 Conclusion
We believe this is the only published case of isolated peritoneal coccidioidomycosis in early pregnancy. The diagnosis of peritoneal coccidioidomycosis was particularly challenging given our patient's negative infectious workup and granulomatous tissue on initial omental biopsy. This case demonstrates the importance of a multidisciplinary team. Our patient was originally from Tanzania, which prompted us to consider tuberculosis as the etiology of her disease. Ultimately, local factors like living in California, rather than global factors, were the cause of her disease.
Contributors
Abigail Armstrong contributed to conception/design and drafting of the article.
Mika Watanabe contributed to conception/design and editing of the article.
Debika Bhattacharya was the infectious disease physician on the case and contributed to review and revision of the manuscript.
Mae Zakhour performed the surgery and contributed to review and revision of the manuscript.
Lindsay Kroener was the reproductive endocrinologist on the case and contributed to review and revision of the manuscript.
Conflict of Interest
The authors declare that they have no conflict of interest regarding the publication of this case report.
Funding
No funding from an external source supported the publication of this case report.
Patient Consent
Obtained.
Provenance and Peer Review
This case report was peer reviewed. | CEFTRIAXONE, CLOMIPHENE, GONADOTROPHIN, CHORIONIC, METRONIDAZOLE\METRONIDAZOLE HYDROCHLORIDE, VANCOMYCIN | DrugsGivenReaction | CC BY | 33665141 | 19,006,800 | 2021-04 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Maternal exposure before pregnancy'. | Disseminated peritoneal coccidioidomycosis in pregnancy following fertility treatment: A case report and literature review.
Disseminated peritoneal coccidioidomycosis in the setting of early pregnancy after fertility treatment is rare and can present as a diagnostic challenge. A 39-year-old underwent ovarian stimulation with clomiphene citrate followed by HCG trigger and intrauterine insemination. She developed persistent abdominal pain, ascites and episodes of fever in early pregnancy, and eventually underwent a diagnostic laparoscopy for worsening clinical presentation. Operative findings were notable for peritoneal studding, infracolic omentum inflammation, bowel adhesions to the abdominal wall and normal-appearing uterus and adnexa. The pathology results indicated peritoneal Coccidioides immitis infection. Hormonal changes associated with fertility treatment and immune tolerance in pregnancy may increase the risk for disseminated peritoneal coccidioidomycosis. A high index of suspicion and a multidisciplinary team are important for the diagnostic workup and treatment plan of disseminated peritoneal coccidioidomycosis.
1 Introduction
Coccidioidomycosis is a fungal infection that results primarily in pulmonary disease and is endemic to the Southwest United States, Mexico and South America [1]. Extrapulmonary dissemination occurs in 1% of cases, usually in patients with risk factors like male sex, African ancestry, immunosuppression and pregnancy [[2], [3], [4]]. Prior data have shown that disseminated disease occurs in 23% of pregnant patients in the first trimester [5]. Extrapulmonary disease occurs most commonly in soft tissue, skin, joints and brain [6]. In contrast, peritoneum dissemination is rare, occurring through hematogenous spread or swallowing pulmonary secretions [7]. Disseminated cocciodiodes, like tuberculosis, is a great mimicker and can be challenging to diagnose. For example, early infection may present with persistently negative antibodies, especially in patients who are immunosuppressed or immune tolerant, as observed in pregnant women [3]. Additionally, there is a wide sensitivity and specificity of the enzyme immunoassay test, depending on lab assay [3].
To our knowledge, there are no reported cases of disseminated peritoneal coccidioidomycosis in the setting of early pregnancy following fertility treatment. We present the case of a 39-year-old woman with an early pregnancy resulting from ovarian stimulation with clomiphene citrate and intrauterine insemination who developed episodes of fever, ascites and abdominal pain ultimately requiring an exploratory laparotomy leading to a diagnosis of disseminated peritoneal Coccidioides immitis.
2 Case Presentation
A 39-year-old woman presented to an infertility clinic. She was diagnosed with unexplained secondary infertility associated with male factor. Her workup showed normal day 3 laboratory results (FSH 7.0 mIU/mL, estradiol 35 pg/mL), TSH 2.8 mcIU/mL, normal hysterosalpingogram, antral follicle count of 32 and semen analysis with mild oligoteratospermia. The couple had negative infectious disease screening, including hepatitis B and C, HIV, syphilis and HTLV 1–2. She underwent her first clomiphene citrate 50 mg cycle and developed two dominant follicles. Ovulation was triggered using 250 μg of HCG subcutaneously. She underwent an uncomplicated intrauterine insemination with 24 million fresh, motile washed sperm.
She began experiencing intermittent fevers and abdominal pain 8 days after insemination. She was seen by her primary care physician, who noted normal temperature, mild tenderness on exam and negative pregnancy test. She was counseled that her symptoms may be secondary to early pregnancy or mild gastritis. Three days later, she re-presented with a mild leukocytosis, serum beta-hCG 84 mIU/ml and normal electrolytes. Pelvic ultrasound showed moderate free fluid with echogenic debris, two left ovarian corpus lutea and an unremarkable appendix (Fig. 1). Consistent with early gestation, no pregnancy was identified, and suspected diagnosis was ruptured hemorrhagic cyst. However, her symptoms continued to worsen, with increasing ascites and distension, persistent fevers, mild increase in liver enzymes (AST 96 U/L, ALT 93 U/L]) and leukocytosis (15 K/uL), and she was sent to the emergency room at 4 weeks 1 day.Fig. 1 A. Large amount of free fluid in pouch of Douglas. B. Left ovary with corpus lutea.
Fig. 1
She had her first documented fever (38.2 °C), up-trending leukocytosis (17 K/uL), mild increase in liver enzymes (AST 50 U/L, ALT 80 U/L), beta-hCG of 127 mIU/ml, normal electrolytes and negative blood cultures. Abdominal ultrasound showed free fluid throughout the abdomen, thickened endometrial lining and a normal appendix. In addition to abdominal distension, the patient developed diarrhea and nausea. Given early gestation and goal to avoid CT radiation, a non-contrast MRI was performed, which showed significant free fluid, two ovarian cysts, likely corpus lutea, and inability to visualize the appendix. There was low suspicion for ovarian hyperstimulation syndrome given clomiphene citrate use for stimulation, two dominant follicles at trigger, normal electrolytes and absence of enlarged ovaries.
She was admitted for IV antibiotics for suspected bacterial peritonitis. Infectious disease was consulted. Ceftriaxone, flagyl and vancomycin were used for genitourinary coverage given fertility treatments. The patient was originally from Tanzania, which made the team suspicious for tuberculosis despite lack of clinical history and x-ray showing small pleural effusions.
By hospital day (HD) 3, she was clinically worsening, with fevers (39.4 °C), rising leukocytosis (23 K/uL) and abdominal distention. CT of the abdomen with contrast showed moderate ascites, omental nodularity and caking, not previously seen on MRI, concerning for malignancy or non-malignant causes, including tuberculosis. Gynecology oncology was consulted and the tumor markers CA-125, CA19-9, CEA, CA 15-3, CA 27.29, AFP were normal. Coccidioidomycosis IgM, IgG, and complement fixation titers were negative and <1:2 respectively. In terms of her pregnancy of unknown location, beta-HCGs were abnormally rising and trended every 48 h (126 mIU/ml, 180 mIU/ml, 395 mIU/ml).
On HD 5, paracentesis drained 800 l of fluid and interventional radiology-guided omental biopsies resulted in fat necrosis and granulomatous inflammation. Both peritoneal fluid and tissue biopsies were negative for neoplastic cells, CEA, acid-fast bacilli, fungal, bacterial, non-tuberculosis mycobacterium DNA and Mycobacterium tuberculosis (MTB) PCR. The only pertinent test was an indeterminate serum quantiferon gold; however, peritoneal fluid adenosine deaminase and negative MTB PCR were not consistent with tuberculosis. With progressively worsening symptoms and lack of diagnosis, the decision was made to proceed with laparoscopy for tissue diagnosis. Given abnormally rising beta-HCGs, pregnancy was likely non-viable, thus she elected for termination.
She underwent a diagnostic laparoscopy, omentectomy, lysis of adhesions and suction curettage on HD 8 with gynecology oncology, given CT results concerning for malignancy. Laparoscopy was converted to mini laparotomy due to significant adhesions and inability to obtain adequate biopsies for tissue diagnosis. Operative findings included extensive studding of peritoneum, infracolic omentum inflammation, bowel adhesions to abdominal wall, normal-appearing uterus and adnexa with 3.5 l of ascites (Fig. 2). Curettage showed decidualized endometrium without chorionic villi or coccidiodes. Beta-HCG down-trended to zero post-operatively consistent with successful surgical abortion.Fig. 2 A. Bowel attached to abdominal wall upon entry. B. Laparoscopic view of uterus, adnexa and ascites. C. “Caked omentum”, pathologic specimen.
Fig. 2
Post-operatively her fevers continued despite antibiotics. Surgical omental biopsy cultures resulted as Coccidioides immitis on postoperative day 11. Her only notable travel history was to Palm Springs, California, and visiting construction sites in the past two years, locations known to harbor coccidioidomycosis. After significant improvement on oral antifungal therapy, she was discharged on HD 15 with fluconazole 400 mg daily. She was followed by the multidisciplinary team as an outpatient. Coccidioides antibody complement fixation (titer 1:4) turned positive one month after her admission date.
3 Discussion
This is a unique case describing disseminated peritoneal coccidioidomycosis in a newly pregnant patient following fertility treatment with insemination. Peritoneal coccidioidomycosis is a challenging diagnosis as there are only 34 published cases [8]. Most patients with isolated peritoneal involvement and negative serology titers are immunosuppressed patients [3,9]. It is therefore possible that our pregnant patient had falsely negative titers due to the immune tolerance of pregnancy.
Most patients with disseminated coccidioidomycosis present gradually with abdominal distension and ascites occurring months to years after infection [2]. In our patient's case, it is possible that the immune-tolerance effects of pregnancy or the hormonal effects of ovarian stimulation may have contributed to her acute presentation. Prior data report pregnant women experience disseminated disease 100 times more frequently [2,6].
Our case highlights a possible association between hormonal changes with fertility treatment, immune tolerance in pregnancy, and risk for peritoneal coccidioidomycosis. Studies show that elevated serum levels of 17-beta-estradiol and progesterone in vitro increase coccidioidomycosis growth, contributing to dissemination [10]. Our patient received clomiphene citrate and was newly pregnant, thereby raising estradiol and progesterone levels. From an immunologic standpoint, pregnancy is a state of decreased cell-mediated immunity, which explains why coccidioidomycosis disseminates more commonly in pregnancy [4,11]. Evidence shows that pregnancy increases the risk of dissemination in proportion to gestational age, with greatest risk in the third trimester, thus our patient's presentation in early gestation was unusual [4,11]. In addition to pregnancy and presumably elevated hormones levels, African ancestry is another risk factor for disseminated disease in our case [11].
The timing and source of initial infection in our patient is unclear. Coccidioidomycosis was likely contracted years prior to presentation through environmental exposure. Even in dissemination, the usual source of initial infection is the pulmonary tract [1]. It is unusual for disseminated disease to involve the female genital tract, thus the insemination procedure or specimen are unlikely to be a cause for initial infection [12]. In concordance, endometrial tissue was negative for coccidioidomycosis. In the only other report of disseminated coccidioidomycosis in a woman who underwent ovarian stimulation with clomiphene citrate and insemination, presentation was several years after fertility treatment [10].
There is limited evidence on how to treat isolated peritoneal coccidioidomycosis. Management is typically fluconazole 400 mg daily for 6–12 months with duration guided by clinical, laboratory, and radiographic response [3]. Unlike other sites of dissemination, mortality is rare with isolated peritoneal coccidioidomycosis [13]. Going forward, our patient may have a small but increased risk of disease reactivation in future pregnancies. There is a lack of literature guiding reproductive patients for timing and risk of future conception [6,14]. According to the Infectious Disease Society of America guidelines, risk of reactivation in pregnancy is low in women who have completed therapy [3]. Once pregnant, the current recommendation is coccidioidal serologic testing every 6–12 weeks [3].
4 Conclusion
We believe this is the only published case of isolated peritoneal coccidioidomycosis in early pregnancy. The diagnosis of peritoneal coccidioidomycosis was particularly challenging given our patient's negative infectious workup and granulomatous tissue on initial omental biopsy. This case demonstrates the importance of a multidisciplinary team. Our patient was originally from Tanzania, which prompted us to consider tuberculosis as the etiology of her disease. Ultimately, local factors like living in California, rather than global factors, were the cause of her disease.
Contributors
Abigail Armstrong contributed to conception/design and drafting of the article.
Mika Watanabe contributed to conception/design and editing of the article.
Debika Bhattacharya was the infectious disease physician on the case and contributed to review and revision of the manuscript.
Mae Zakhour performed the surgery and contributed to review and revision of the manuscript.
Lindsay Kroener was the reproductive endocrinologist on the case and contributed to review and revision of the manuscript.
Conflict of Interest
The authors declare that they have no conflict of interest regarding the publication of this case report.
Funding
No funding from an external source supported the publication of this case report.
Patient Consent
Obtained.
Provenance and Peer Review
This case report was peer reviewed. | CHORIOGONADOTROPIN ALFA, CLOMIPHENE CITRATE | DrugsGivenReaction | CC BY | 33665141 | 19,111,009 | 2021-04 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Nausea'. | Disseminated peritoneal coccidioidomycosis in pregnancy following fertility treatment: A case report and literature review.
Disseminated peritoneal coccidioidomycosis in the setting of early pregnancy after fertility treatment is rare and can present as a diagnostic challenge. A 39-year-old underwent ovarian stimulation with clomiphene citrate followed by HCG trigger and intrauterine insemination. She developed persistent abdominal pain, ascites and episodes of fever in early pregnancy, and eventually underwent a diagnostic laparoscopy for worsening clinical presentation. Operative findings were notable for peritoneal studding, infracolic omentum inflammation, bowel adhesions to the abdominal wall and normal-appearing uterus and adnexa. The pathology results indicated peritoneal Coccidioides immitis infection. Hormonal changes associated with fertility treatment and immune tolerance in pregnancy may increase the risk for disseminated peritoneal coccidioidomycosis. A high index of suspicion and a multidisciplinary team are important for the diagnostic workup and treatment plan of disseminated peritoneal coccidioidomycosis.
1 Introduction
Coccidioidomycosis is a fungal infection that results primarily in pulmonary disease and is endemic to the Southwest United States, Mexico and South America [1]. Extrapulmonary dissemination occurs in 1% of cases, usually in patients with risk factors like male sex, African ancestry, immunosuppression and pregnancy [[2], [3], [4]]. Prior data have shown that disseminated disease occurs in 23% of pregnant patients in the first trimester [5]. Extrapulmonary disease occurs most commonly in soft tissue, skin, joints and brain [6]. In contrast, peritoneum dissemination is rare, occurring through hematogenous spread or swallowing pulmonary secretions [7]. Disseminated cocciodiodes, like tuberculosis, is a great mimicker and can be challenging to diagnose. For example, early infection may present with persistently negative antibodies, especially in patients who are immunosuppressed or immune tolerant, as observed in pregnant women [3]. Additionally, there is a wide sensitivity and specificity of the enzyme immunoassay test, depending on lab assay [3].
To our knowledge, there are no reported cases of disseminated peritoneal coccidioidomycosis in the setting of early pregnancy following fertility treatment. We present the case of a 39-year-old woman with an early pregnancy resulting from ovarian stimulation with clomiphene citrate and intrauterine insemination who developed episodes of fever, ascites and abdominal pain ultimately requiring an exploratory laparotomy leading to a diagnosis of disseminated peritoneal Coccidioides immitis.
2 Case Presentation
A 39-year-old woman presented to an infertility clinic. She was diagnosed with unexplained secondary infertility associated with male factor. Her workup showed normal day 3 laboratory results (FSH 7.0 mIU/mL, estradiol 35 pg/mL), TSH 2.8 mcIU/mL, normal hysterosalpingogram, antral follicle count of 32 and semen analysis with mild oligoteratospermia. The couple had negative infectious disease screening, including hepatitis B and C, HIV, syphilis and HTLV 1–2. She underwent her first clomiphene citrate 50 mg cycle and developed two dominant follicles. Ovulation was triggered using 250 μg of HCG subcutaneously. She underwent an uncomplicated intrauterine insemination with 24 million fresh, motile washed sperm.
She began experiencing intermittent fevers and abdominal pain 8 days after insemination. She was seen by her primary care physician, who noted normal temperature, mild tenderness on exam and negative pregnancy test. She was counseled that her symptoms may be secondary to early pregnancy or mild gastritis. Three days later, she re-presented with a mild leukocytosis, serum beta-hCG 84 mIU/ml and normal electrolytes. Pelvic ultrasound showed moderate free fluid with echogenic debris, two left ovarian corpus lutea and an unremarkable appendix (Fig. 1). Consistent with early gestation, no pregnancy was identified, and suspected diagnosis was ruptured hemorrhagic cyst. However, her symptoms continued to worsen, with increasing ascites and distension, persistent fevers, mild increase in liver enzymes (AST 96 U/L, ALT 93 U/L]) and leukocytosis (15 K/uL), and she was sent to the emergency room at 4 weeks 1 day.Fig. 1 A. Large amount of free fluid in pouch of Douglas. B. Left ovary with corpus lutea.
Fig. 1
She had her first documented fever (38.2 °C), up-trending leukocytosis (17 K/uL), mild increase in liver enzymes (AST 50 U/L, ALT 80 U/L), beta-hCG of 127 mIU/ml, normal electrolytes and negative blood cultures. Abdominal ultrasound showed free fluid throughout the abdomen, thickened endometrial lining and a normal appendix. In addition to abdominal distension, the patient developed diarrhea and nausea. Given early gestation and goal to avoid CT radiation, a non-contrast MRI was performed, which showed significant free fluid, two ovarian cysts, likely corpus lutea, and inability to visualize the appendix. There was low suspicion for ovarian hyperstimulation syndrome given clomiphene citrate use for stimulation, two dominant follicles at trigger, normal electrolytes and absence of enlarged ovaries.
She was admitted for IV antibiotics for suspected bacterial peritonitis. Infectious disease was consulted. Ceftriaxone, flagyl and vancomycin were used for genitourinary coverage given fertility treatments. The patient was originally from Tanzania, which made the team suspicious for tuberculosis despite lack of clinical history and x-ray showing small pleural effusions.
By hospital day (HD) 3, she was clinically worsening, with fevers (39.4 °C), rising leukocytosis (23 K/uL) and abdominal distention. CT of the abdomen with contrast showed moderate ascites, omental nodularity and caking, not previously seen on MRI, concerning for malignancy or non-malignant causes, including tuberculosis. Gynecology oncology was consulted and the tumor markers CA-125, CA19-9, CEA, CA 15-3, CA 27.29, AFP were normal. Coccidioidomycosis IgM, IgG, and complement fixation titers were negative and <1:2 respectively. In terms of her pregnancy of unknown location, beta-HCGs were abnormally rising and trended every 48 h (126 mIU/ml, 180 mIU/ml, 395 mIU/ml).
On HD 5, paracentesis drained 800 l of fluid and interventional radiology-guided omental biopsies resulted in fat necrosis and granulomatous inflammation. Both peritoneal fluid and tissue biopsies were negative for neoplastic cells, CEA, acid-fast bacilli, fungal, bacterial, non-tuberculosis mycobacterium DNA and Mycobacterium tuberculosis (MTB) PCR. The only pertinent test was an indeterminate serum quantiferon gold; however, peritoneal fluid adenosine deaminase and negative MTB PCR were not consistent with tuberculosis. With progressively worsening symptoms and lack of diagnosis, the decision was made to proceed with laparoscopy for tissue diagnosis. Given abnormally rising beta-HCGs, pregnancy was likely non-viable, thus she elected for termination.
She underwent a diagnostic laparoscopy, omentectomy, lysis of adhesions and suction curettage on HD 8 with gynecology oncology, given CT results concerning for malignancy. Laparoscopy was converted to mini laparotomy due to significant adhesions and inability to obtain adequate biopsies for tissue diagnosis. Operative findings included extensive studding of peritoneum, infracolic omentum inflammation, bowel adhesions to abdominal wall, normal-appearing uterus and adnexa with 3.5 l of ascites (Fig. 2). Curettage showed decidualized endometrium without chorionic villi or coccidiodes. Beta-HCG down-trended to zero post-operatively consistent with successful surgical abortion.Fig. 2 A. Bowel attached to abdominal wall upon entry. B. Laparoscopic view of uterus, adnexa and ascites. C. “Caked omentum”, pathologic specimen.
Fig. 2
Post-operatively her fevers continued despite antibiotics. Surgical omental biopsy cultures resulted as Coccidioides immitis on postoperative day 11. Her only notable travel history was to Palm Springs, California, and visiting construction sites in the past two years, locations known to harbor coccidioidomycosis. After significant improvement on oral antifungal therapy, she was discharged on HD 15 with fluconazole 400 mg daily. She was followed by the multidisciplinary team as an outpatient. Coccidioides antibody complement fixation (titer 1:4) turned positive one month after her admission date.
3 Discussion
This is a unique case describing disseminated peritoneal coccidioidomycosis in a newly pregnant patient following fertility treatment with insemination. Peritoneal coccidioidomycosis is a challenging diagnosis as there are only 34 published cases [8]. Most patients with isolated peritoneal involvement and negative serology titers are immunosuppressed patients [3,9]. It is therefore possible that our pregnant patient had falsely negative titers due to the immune tolerance of pregnancy.
Most patients with disseminated coccidioidomycosis present gradually with abdominal distension and ascites occurring months to years after infection [2]. In our patient's case, it is possible that the immune-tolerance effects of pregnancy or the hormonal effects of ovarian stimulation may have contributed to her acute presentation. Prior data report pregnant women experience disseminated disease 100 times more frequently [2,6].
Our case highlights a possible association between hormonal changes with fertility treatment, immune tolerance in pregnancy, and risk for peritoneal coccidioidomycosis. Studies show that elevated serum levels of 17-beta-estradiol and progesterone in vitro increase coccidioidomycosis growth, contributing to dissemination [10]. Our patient received clomiphene citrate and was newly pregnant, thereby raising estradiol and progesterone levels. From an immunologic standpoint, pregnancy is a state of decreased cell-mediated immunity, which explains why coccidioidomycosis disseminates more commonly in pregnancy [4,11]. Evidence shows that pregnancy increases the risk of dissemination in proportion to gestational age, with greatest risk in the third trimester, thus our patient's presentation in early gestation was unusual [4,11]. In addition to pregnancy and presumably elevated hormones levels, African ancestry is another risk factor for disseminated disease in our case [11].
The timing and source of initial infection in our patient is unclear. Coccidioidomycosis was likely contracted years prior to presentation through environmental exposure. Even in dissemination, the usual source of initial infection is the pulmonary tract [1]. It is unusual for disseminated disease to involve the female genital tract, thus the insemination procedure or specimen are unlikely to be a cause for initial infection [12]. In concordance, endometrial tissue was negative for coccidioidomycosis. In the only other report of disseminated coccidioidomycosis in a woman who underwent ovarian stimulation with clomiphene citrate and insemination, presentation was several years after fertility treatment [10].
There is limited evidence on how to treat isolated peritoneal coccidioidomycosis. Management is typically fluconazole 400 mg daily for 6–12 months with duration guided by clinical, laboratory, and radiographic response [3]. Unlike other sites of dissemination, mortality is rare with isolated peritoneal coccidioidomycosis [13]. Going forward, our patient may have a small but increased risk of disease reactivation in future pregnancies. There is a lack of literature guiding reproductive patients for timing and risk of future conception [6,14]. According to the Infectious Disease Society of America guidelines, risk of reactivation in pregnancy is low in women who have completed therapy [3]. Once pregnant, the current recommendation is coccidioidal serologic testing every 6–12 weeks [3].
4 Conclusion
We believe this is the only published case of isolated peritoneal coccidioidomycosis in early pregnancy. The diagnosis of peritoneal coccidioidomycosis was particularly challenging given our patient's negative infectious workup and granulomatous tissue on initial omental biopsy. This case demonstrates the importance of a multidisciplinary team. Our patient was originally from Tanzania, which prompted us to consider tuberculosis as the etiology of her disease. Ultimately, local factors like living in California, rather than global factors, were the cause of her disease.
Contributors
Abigail Armstrong contributed to conception/design and drafting of the article.
Mika Watanabe contributed to conception/design and editing of the article.
Debika Bhattacharya was the infectious disease physician on the case and contributed to review and revision of the manuscript.
Mae Zakhour performed the surgery and contributed to review and revision of the manuscript.
Lindsay Kroener was the reproductive endocrinologist on the case and contributed to review and revision of the manuscript.
Conflict of Interest
The authors declare that they have no conflict of interest regarding the publication of this case report.
Funding
No funding from an external source supported the publication of this case report.
Patient Consent
Obtained.
Provenance and Peer Review
This case report was peer reviewed. | CEFTRIAXONE, CLOMIPHENE, GONADOTROPHIN, CHORIONIC, METRONIDAZOLE\METRONIDAZOLE HYDROCHLORIDE, VANCOMYCIN | DrugsGivenReaction | CC BY | 33665141 | 19,006,800 | 2021-04 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Pyrexia'. | Disseminated peritoneal coccidioidomycosis in pregnancy following fertility treatment: A case report and literature review.
Disseminated peritoneal coccidioidomycosis in the setting of early pregnancy after fertility treatment is rare and can present as a diagnostic challenge. A 39-year-old underwent ovarian stimulation with clomiphene citrate followed by HCG trigger and intrauterine insemination. She developed persistent abdominal pain, ascites and episodes of fever in early pregnancy, and eventually underwent a diagnostic laparoscopy for worsening clinical presentation. Operative findings were notable for peritoneal studding, infracolic omentum inflammation, bowel adhesions to the abdominal wall and normal-appearing uterus and adnexa. The pathology results indicated peritoneal Coccidioides immitis infection. Hormonal changes associated with fertility treatment and immune tolerance in pregnancy may increase the risk for disseminated peritoneal coccidioidomycosis. A high index of suspicion and a multidisciplinary team are important for the diagnostic workup and treatment plan of disseminated peritoneal coccidioidomycosis.
1 Introduction
Coccidioidomycosis is a fungal infection that results primarily in pulmonary disease and is endemic to the Southwest United States, Mexico and South America [1]. Extrapulmonary dissemination occurs in 1% of cases, usually in patients with risk factors like male sex, African ancestry, immunosuppression and pregnancy [[2], [3], [4]]. Prior data have shown that disseminated disease occurs in 23% of pregnant patients in the first trimester [5]. Extrapulmonary disease occurs most commonly in soft tissue, skin, joints and brain [6]. In contrast, peritoneum dissemination is rare, occurring through hematogenous spread or swallowing pulmonary secretions [7]. Disseminated cocciodiodes, like tuberculosis, is a great mimicker and can be challenging to diagnose. For example, early infection may present with persistently negative antibodies, especially in patients who are immunosuppressed or immune tolerant, as observed in pregnant women [3]. Additionally, there is a wide sensitivity and specificity of the enzyme immunoassay test, depending on lab assay [3].
To our knowledge, there are no reported cases of disseminated peritoneal coccidioidomycosis in the setting of early pregnancy following fertility treatment. We present the case of a 39-year-old woman with an early pregnancy resulting from ovarian stimulation with clomiphene citrate and intrauterine insemination who developed episodes of fever, ascites and abdominal pain ultimately requiring an exploratory laparotomy leading to a diagnosis of disseminated peritoneal Coccidioides immitis.
2 Case Presentation
A 39-year-old woman presented to an infertility clinic. She was diagnosed with unexplained secondary infertility associated with male factor. Her workup showed normal day 3 laboratory results (FSH 7.0 mIU/mL, estradiol 35 pg/mL), TSH 2.8 mcIU/mL, normal hysterosalpingogram, antral follicle count of 32 and semen analysis with mild oligoteratospermia. The couple had negative infectious disease screening, including hepatitis B and C, HIV, syphilis and HTLV 1–2. She underwent her first clomiphene citrate 50 mg cycle and developed two dominant follicles. Ovulation was triggered using 250 μg of HCG subcutaneously. She underwent an uncomplicated intrauterine insemination with 24 million fresh, motile washed sperm.
She began experiencing intermittent fevers and abdominal pain 8 days after insemination. She was seen by her primary care physician, who noted normal temperature, mild tenderness on exam and negative pregnancy test. She was counseled that her symptoms may be secondary to early pregnancy or mild gastritis. Three days later, she re-presented with a mild leukocytosis, serum beta-hCG 84 mIU/ml and normal electrolytes. Pelvic ultrasound showed moderate free fluid with echogenic debris, two left ovarian corpus lutea and an unremarkable appendix (Fig. 1). Consistent with early gestation, no pregnancy was identified, and suspected diagnosis was ruptured hemorrhagic cyst. However, her symptoms continued to worsen, with increasing ascites and distension, persistent fevers, mild increase in liver enzymes (AST 96 U/L, ALT 93 U/L]) and leukocytosis (15 K/uL), and she was sent to the emergency room at 4 weeks 1 day.Fig. 1 A. Large amount of free fluid in pouch of Douglas. B. Left ovary with corpus lutea.
Fig. 1
She had her first documented fever (38.2 °C), up-trending leukocytosis (17 K/uL), mild increase in liver enzymes (AST 50 U/L, ALT 80 U/L), beta-hCG of 127 mIU/ml, normal electrolytes and negative blood cultures. Abdominal ultrasound showed free fluid throughout the abdomen, thickened endometrial lining and a normal appendix. In addition to abdominal distension, the patient developed diarrhea and nausea. Given early gestation and goal to avoid CT radiation, a non-contrast MRI was performed, which showed significant free fluid, two ovarian cysts, likely corpus lutea, and inability to visualize the appendix. There was low suspicion for ovarian hyperstimulation syndrome given clomiphene citrate use for stimulation, two dominant follicles at trigger, normal electrolytes and absence of enlarged ovaries.
She was admitted for IV antibiotics for suspected bacterial peritonitis. Infectious disease was consulted. Ceftriaxone, flagyl and vancomycin were used for genitourinary coverage given fertility treatments. The patient was originally from Tanzania, which made the team suspicious for tuberculosis despite lack of clinical history and x-ray showing small pleural effusions.
By hospital day (HD) 3, she was clinically worsening, with fevers (39.4 °C), rising leukocytosis (23 K/uL) and abdominal distention. CT of the abdomen with contrast showed moderate ascites, omental nodularity and caking, not previously seen on MRI, concerning for malignancy or non-malignant causes, including tuberculosis. Gynecology oncology was consulted and the tumor markers CA-125, CA19-9, CEA, CA 15-3, CA 27.29, AFP were normal. Coccidioidomycosis IgM, IgG, and complement fixation titers were negative and <1:2 respectively. In terms of her pregnancy of unknown location, beta-HCGs were abnormally rising and trended every 48 h (126 mIU/ml, 180 mIU/ml, 395 mIU/ml).
On HD 5, paracentesis drained 800 l of fluid and interventional radiology-guided omental biopsies resulted in fat necrosis and granulomatous inflammation. Both peritoneal fluid and tissue biopsies were negative for neoplastic cells, CEA, acid-fast bacilli, fungal, bacterial, non-tuberculosis mycobacterium DNA and Mycobacterium tuberculosis (MTB) PCR. The only pertinent test was an indeterminate serum quantiferon gold; however, peritoneal fluid adenosine deaminase and negative MTB PCR were not consistent with tuberculosis. With progressively worsening symptoms and lack of diagnosis, the decision was made to proceed with laparoscopy for tissue diagnosis. Given abnormally rising beta-HCGs, pregnancy was likely non-viable, thus she elected for termination.
She underwent a diagnostic laparoscopy, omentectomy, lysis of adhesions and suction curettage on HD 8 with gynecology oncology, given CT results concerning for malignancy. Laparoscopy was converted to mini laparotomy due to significant adhesions and inability to obtain adequate biopsies for tissue diagnosis. Operative findings included extensive studding of peritoneum, infracolic omentum inflammation, bowel adhesions to abdominal wall, normal-appearing uterus and adnexa with 3.5 l of ascites (Fig. 2). Curettage showed decidualized endometrium without chorionic villi or coccidiodes. Beta-HCG down-trended to zero post-operatively consistent with successful surgical abortion.Fig. 2 A. Bowel attached to abdominal wall upon entry. B. Laparoscopic view of uterus, adnexa and ascites. C. “Caked omentum”, pathologic specimen.
Fig. 2
Post-operatively her fevers continued despite antibiotics. Surgical omental biopsy cultures resulted as Coccidioides immitis on postoperative day 11. Her only notable travel history was to Palm Springs, California, and visiting construction sites in the past two years, locations known to harbor coccidioidomycosis. After significant improvement on oral antifungal therapy, she was discharged on HD 15 with fluconazole 400 mg daily. She was followed by the multidisciplinary team as an outpatient. Coccidioides antibody complement fixation (titer 1:4) turned positive one month after her admission date.
3 Discussion
This is a unique case describing disseminated peritoneal coccidioidomycosis in a newly pregnant patient following fertility treatment with insemination. Peritoneal coccidioidomycosis is a challenging diagnosis as there are only 34 published cases [8]. Most patients with isolated peritoneal involvement and negative serology titers are immunosuppressed patients [3,9]. It is therefore possible that our pregnant patient had falsely negative titers due to the immune tolerance of pregnancy.
Most patients with disseminated coccidioidomycosis present gradually with abdominal distension and ascites occurring months to years after infection [2]. In our patient's case, it is possible that the immune-tolerance effects of pregnancy or the hormonal effects of ovarian stimulation may have contributed to her acute presentation. Prior data report pregnant women experience disseminated disease 100 times more frequently [2,6].
Our case highlights a possible association between hormonal changes with fertility treatment, immune tolerance in pregnancy, and risk for peritoneal coccidioidomycosis. Studies show that elevated serum levels of 17-beta-estradiol and progesterone in vitro increase coccidioidomycosis growth, contributing to dissemination [10]. Our patient received clomiphene citrate and was newly pregnant, thereby raising estradiol and progesterone levels. From an immunologic standpoint, pregnancy is a state of decreased cell-mediated immunity, which explains why coccidioidomycosis disseminates more commonly in pregnancy [4,11]. Evidence shows that pregnancy increases the risk of dissemination in proportion to gestational age, with greatest risk in the third trimester, thus our patient's presentation in early gestation was unusual [4,11]. In addition to pregnancy and presumably elevated hormones levels, African ancestry is another risk factor for disseminated disease in our case [11].
The timing and source of initial infection in our patient is unclear. Coccidioidomycosis was likely contracted years prior to presentation through environmental exposure. Even in dissemination, the usual source of initial infection is the pulmonary tract [1]. It is unusual for disseminated disease to involve the female genital tract, thus the insemination procedure or specimen are unlikely to be a cause for initial infection [12]. In concordance, endometrial tissue was negative for coccidioidomycosis. In the only other report of disseminated coccidioidomycosis in a woman who underwent ovarian stimulation with clomiphene citrate and insemination, presentation was several years after fertility treatment [10].
There is limited evidence on how to treat isolated peritoneal coccidioidomycosis. Management is typically fluconazole 400 mg daily for 6–12 months with duration guided by clinical, laboratory, and radiographic response [3]. Unlike other sites of dissemination, mortality is rare with isolated peritoneal coccidioidomycosis [13]. Going forward, our patient may have a small but increased risk of disease reactivation in future pregnancies. There is a lack of literature guiding reproductive patients for timing and risk of future conception [6,14]. According to the Infectious Disease Society of America guidelines, risk of reactivation in pregnancy is low in women who have completed therapy [3]. Once pregnant, the current recommendation is coccidioidal serologic testing every 6–12 weeks [3].
4 Conclusion
We believe this is the only published case of isolated peritoneal coccidioidomycosis in early pregnancy. The diagnosis of peritoneal coccidioidomycosis was particularly challenging given our patient's negative infectious workup and granulomatous tissue on initial omental biopsy. This case demonstrates the importance of a multidisciplinary team. Our patient was originally from Tanzania, which prompted us to consider tuberculosis as the etiology of her disease. Ultimately, local factors like living in California, rather than global factors, were the cause of her disease.
Contributors
Abigail Armstrong contributed to conception/design and drafting of the article.
Mika Watanabe contributed to conception/design and editing of the article.
Debika Bhattacharya was the infectious disease physician on the case and contributed to review and revision of the manuscript.
Mae Zakhour performed the surgery and contributed to review and revision of the manuscript.
Lindsay Kroener was the reproductive endocrinologist on the case and contributed to review and revision of the manuscript.
Conflict of Interest
The authors declare that they have no conflict of interest regarding the publication of this case report.
Funding
No funding from an external source supported the publication of this case report.
Patient Consent
Obtained.
Provenance and Peer Review
This case report was peer reviewed. | CEFTRIAXONE, CLOMIPHENE, GONADOTROPHIN, CHORIONIC, METRONIDAZOLE\METRONIDAZOLE HYDROCHLORIDE, VANCOMYCIN | DrugsGivenReaction | CC BY | 33665141 | 19,006,800 | 2021-04 |
What was the administration route of drug 'CHORIOGONADOTROPIN ALFA'? | Disseminated peritoneal coccidioidomycosis in pregnancy following fertility treatment: A case report and literature review.
Disseminated peritoneal coccidioidomycosis in the setting of early pregnancy after fertility treatment is rare and can present as a diagnostic challenge. A 39-year-old underwent ovarian stimulation with clomiphene citrate followed by HCG trigger and intrauterine insemination. She developed persistent abdominal pain, ascites and episodes of fever in early pregnancy, and eventually underwent a diagnostic laparoscopy for worsening clinical presentation. Operative findings were notable for peritoneal studding, infracolic omentum inflammation, bowel adhesions to the abdominal wall and normal-appearing uterus and adnexa. The pathology results indicated peritoneal Coccidioides immitis infection. Hormonal changes associated with fertility treatment and immune tolerance in pregnancy may increase the risk for disseminated peritoneal coccidioidomycosis. A high index of suspicion and a multidisciplinary team are important for the diagnostic workup and treatment plan of disseminated peritoneal coccidioidomycosis.
1 Introduction
Coccidioidomycosis is a fungal infection that results primarily in pulmonary disease and is endemic to the Southwest United States, Mexico and South America [1]. Extrapulmonary dissemination occurs in 1% of cases, usually in patients with risk factors like male sex, African ancestry, immunosuppression and pregnancy [[2], [3], [4]]. Prior data have shown that disseminated disease occurs in 23% of pregnant patients in the first trimester [5]. Extrapulmonary disease occurs most commonly in soft tissue, skin, joints and brain [6]. In contrast, peritoneum dissemination is rare, occurring through hematogenous spread or swallowing pulmonary secretions [7]. Disseminated cocciodiodes, like tuberculosis, is a great mimicker and can be challenging to diagnose. For example, early infection may present with persistently negative antibodies, especially in patients who are immunosuppressed or immune tolerant, as observed in pregnant women [3]. Additionally, there is a wide sensitivity and specificity of the enzyme immunoassay test, depending on lab assay [3].
To our knowledge, there are no reported cases of disseminated peritoneal coccidioidomycosis in the setting of early pregnancy following fertility treatment. We present the case of a 39-year-old woman with an early pregnancy resulting from ovarian stimulation with clomiphene citrate and intrauterine insemination who developed episodes of fever, ascites and abdominal pain ultimately requiring an exploratory laparotomy leading to a diagnosis of disseminated peritoneal Coccidioides immitis.
2 Case Presentation
A 39-year-old woman presented to an infertility clinic. She was diagnosed with unexplained secondary infertility associated with male factor. Her workup showed normal day 3 laboratory results (FSH 7.0 mIU/mL, estradiol 35 pg/mL), TSH 2.8 mcIU/mL, normal hysterosalpingogram, antral follicle count of 32 and semen analysis with mild oligoteratospermia. The couple had negative infectious disease screening, including hepatitis B and C, HIV, syphilis and HTLV 1–2. She underwent her first clomiphene citrate 50 mg cycle and developed two dominant follicles. Ovulation was triggered using 250 μg of HCG subcutaneously. She underwent an uncomplicated intrauterine insemination with 24 million fresh, motile washed sperm.
She began experiencing intermittent fevers and abdominal pain 8 days after insemination. She was seen by her primary care physician, who noted normal temperature, mild tenderness on exam and negative pregnancy test. She was counseled that her symptoms may be secondary to early pregnancy or mild gastritis. Three days later, she re-presented with a mild leukocytosis, serum beta-hCG 84 mIU/ml and normal electrolytes. Pelvic ultrasound showed moderate free fluid with echogenic debris, two left ovarian corpus lutea and an unremarkable appendix (Fig. 1). Consistent with early gestation, no pregnancy was identified, and suspected diagnosis was ruptured hemorrhagic cyst. However, her symptoms continued to worsen, with increasing ascites and distension, persistent fevers, mild increase in liver enzymes (AST 96 U/L, ALT 93 U/L]) and leukocytosis (15 K/uL), and she was sent to the emergency room at 4 weeks 1 day.Fig. 1 A. Large amount of free fluid in pouch of Douglas. B. Left ovary with corpus lutea.
Fig. 1
She had her first documented fever (38.2 °C), up-trending leukocytosis (17 K/uL), mild increase in liver enzymes (AST 50 U/L, ALT 80 U/L), beta-hCG of 127 mIU/ml, normal electrolytes and negative blood cultures. Abdominal ultrasound showed free fluid throughout the abdomen, thickened endometrial lining and a normal appendix. In addition to abdominal distension, the patient developed diarrhea and nausea. Given early gestation and goal to avoid CT radiation, a non-contrast MRI was performed, which showed significant free fluid, two ovarian cysts, likely corpus lutea, and inability to visualize the appendix. There was low suspicion for ovarian hyperstimulation syndrome given clomiphene citrate use for stimulation, two dominant follicles at trigger, normal electrolytes and absence of enlarged ovaries.
She was admitted for IV antibiotics for suspected bacterial peritonitis. Infectious disease was consulted. Ceftriaxone, flagyl and vancomycin were used for genitourinary coverage given fertility treatments. The patient was originally from Tanzania, which made the team suspicious for tuberculosis despite lack of clinical history and x-ray showing small pleural effusions.
By hospital day (HD) 3, she was clinically worsening, with fevers (39.4 °C), rising leukocytosis (23 K/uL) and abdominal distention. CT of the abdomen with contrast showed moderate ascites, omental nodularity and caking, not previously seen on MRI, concerning for malignancy or non-malignant causes, including tuberculosis. Gynecology oncology was consulted and the tumor markers CA-125, CA19-9, CEA, CA 15-3, CA 27.29, AFP were normal. Coccidioidomycosis IgM, IgG, and complement fixation titers were negative and <1:2 respectively. In terms of her pregnancy of unknown location, beta-HCGs were abnormally rising and trended every 48 h (126 mIU/ml, 180 mIU/ml, 395 mIU/ml).
On HD 5, paracentesis drained 800 l of fluid and interventional radiology-guided omental biopsies resulted in fat necrosis and granulomatous inflammation. Both peritoneal fluid and tissue biopsies were negative for neoplastic cells, CEA, acid-fast bacilli, fungal, bacterial, non-tuberculosis mycobacterium DNA and Mycobacterium tuberculosis (MTB) PCR. The only pertinent test was an indeterminate serum quantiferon gold; however, peritoneal fluid adenosine deaminase and negative MTB PCR were not consistent with tuberculosis. With progressively worsening symptoms and lack of diagnosis, the decision was made to proceed with laparoscopy for tissue diagnosis. Given abnormally rising beta-HCGs, pregnancy was likely non-viable, thus she elected for termination.
She underwent a diagnostic laparoscopy, omentectomy, lysis of adhesions and suction curettage on HD 8 with gynecology oncology, given CT results concerning for malignancy. Laparoscopy was converted to mini laparotomy due to significant adhesions and inability to obtain adequate biopsies for tissue diagnosis. Operative findings included extensive studding of peritoneum, infracolic omentum inflammation, bowel adhesions to abdominal wall, normal-appearing uterus and adnexa with 3.5 l of ascites (Fig. 2). Curettage showed decidualized endometrium without chorionic villi or coccidiodes. Beta-HCG down-trended to zero post-operatively consistent with successful surgical abortion.Fig. 2 A. Bowel attached to abdominal wall upon entry. B. Laparoscopic view of uterus, adnexa and ascites. C. “Caked omentum”, pathologic specimen.
Fig. 2
Post-operatively her fevers continued despite antibiotics. Surgical omental biopsy cultures resulted as Coccidioides immitis on postoperative day 11. Her only notable travel history was to Palm Springs, California, and visiting construction sites in the past two years, locations known to harbor coccidioidomycosis. After significant improvement on oral antifungal therapy, she was discharged on HD 15 with fluconazole 400 mg daily. She was followed by the multidisciplinary team as an outpatient. Coccidioides antibody complement fixation (titer 1:4) turned positive one month after her admission date.
3 Discussion
This is a unique case describing disseminated peritoneal coccidioidomycosis in a newly pregnant patient following fertility treatment with insemination. Peritoneal coccidioidomycosis is a challenging diagnosis as there are only 34 published cases [8]. Most patients with isolated peritoneal involvement and negative serology titers are immunosuppressed patients [3,9]. It is therefore possible that our pregnant patient had falsely negative titers due to the immune tolerance of pregnancy.
Most patients with disseminated coccidioidomycosis present gradually with abdominal distension and ascites occurring months to years after infection [2]. In our patient's case, it is possible that the immune-tolerance effects of pregnancy or the hormonal effects of ovarian stimulation may have contributed to her acute presentation. Prior data report pregnant women experience disseminated disease 100 times more frequently [2,6].
Our case highlights a possible association between hormonal changes with fertility treatment, immune tolerance in pregnancy, and risk for peritoneal coccidioidomycosis. Studies show that elevated serum levels of 17-beta-estradiol and progesterone in vitro increase coccidioidomycosis growth, contributing to dissemination [10]. Our patient received clomiphene citrate and was newly pregnant, thereby raising estradiol and progesterone levels. From an immunologic standpoint, pregnancy is a state of decreased cell-mediated immunity, which explains why coccidioidomycosis disseminates more commonly in pregnancy [4,11]. Evidence shows that pregnancy increases the risk of dissemination in proportion to gestational age, with greatest risk in the third trimester, thus our patient's presentation in early gestation was unusual [4,11]. In addition to pregnancy and presumably elevated hormones levels, African ancestry is another risk factor for disseminated disease in our case [11].
The timing and source of initial infection in our patient is unclear. Coccidioidomycosis was likely contracted years prior to presentation through environmental exposure. Even in dissemination, the usual source of initial infection is the pulmonary tract [1]. It is unusual for disseminated disease to involve the female genital tract, thus the insemination procedure or specimen are unlikely to be a cause for initial infection [12]. In concordance, endometrial tissue was negative for coccidioidomycosis. In the only other report of disseminated coccidioidomycosis in a woman who underwent ovarian stimulation with clomiphene citrate and insemination, presentation was several years after fertility treatment [10].
There is limited evidence on how to treat isolated peritoneal coccidioidomycosis. Management is typically fluconazole 400 mg daily for 6–12 months with duration guided by clinical, laboratory, and radiographic response [3]. Unlike other sites of dissemination, mortality is rare with isolated peritoneal coccidioidomycosis [13]. Going forward, our patient may have a small but increased risk of disease reactivation in future pregnancies. There is a lack of literature guiding reproductive patients for timing and risk of future conception [6,14]. According to the Infectious Disease Society of America guidelines, risk of reactivation in pregnancy is low in women who have completed therapy [3]. Once pregnant, the current recommendation is coccidioidal serologic testing every 6–12 weeks [3].
4 Conclusion
We believe this is the only published case of isolated peritoneal coccidioidomycosis in early pregnancy. The diagnosis of peritoneal coccidioidomycosis was particularly challenging given our patient's negative infectious workup and granulomatous tissue on initial omental biopsy. This case demonstrates the importance of a multidisciplinary team. Our patient was originally from Tanzania, which prompted us to consider tuberculosis as the etiology of her disease. Ultimately, local factors like living in California, rather than global factors, were the cause of her disease.
Contributors
Abigail Armstrong contributed to conception/design and drafting of the article.
Mika Watanabe contributed to conception/design and editing of the article.
Debika Bhattacharya was the infectious disease physician on the case and contributed to review and revision of the manuscript.
Mae Zakhour performed the surgery and contributed to review and revision of the manuscript.
Lindsay Kroener was the reproductive endocrinologist on the case and contributed to review and revision of the manuscript.
Conflict of Interest
The authors declare that they have no conflict of interest regarding the publication of this case report.
Funding
No funding from an external source supported the publication of this case report.
Patient Consent
Obtained.
Provenance and Peer Review
This case report was peer reviewed. | Subcutaneous | DrugAdministrationRoute | CC BY | 33665141 | 19,111,009 | 2021-04 |
What was the administration route of drug 'GONADOTROPHIN, CHORIONIC'? | Disseminated peritoneal coccidioidomycosis in pregnancy following fertility treatment: A case report and literature review.
Disseminated peritoneal coccidioidomycosis in the setting of early pregnancy after fertility treatment is rare and can present as a diagnostic challenge. A 39-year-old underwent ovarian stimulation with clomiphene citrate followed by HCG trigger and intrauterine insemination. She developed persistent abdominal pain, ascites and episodes of fever in early pregnancy, and eventually underwent a diagnostic laparoscopy for worsening clinical presentation. Operative findings were notable for peritoneal studding, infracolic omentum inflammation, bowel adhesions to the abdominal wall and normal-appearing uterus and adnexa. The pathology results indicated peritoneal Coccidioides immitis infection. Hormonal changes associated with fertility treatment and immune tolerance in pregnancy may increase the risk for disseminated peritoneal coccidioidomycosis. A high index of suspicion and a multidisciplinary team are important for the diagnostic workup and treatment plan of disseminated peritoneal coccidioidomycosis.
1 Introduction
Coccidioidomycosis is a fungal infection that results primarily in pulmonary disease and is endemic to the Southwest United States, Mexico and South America [1]. Extrapulmonary dissemination occurs in 1% of cases, usually in patients with risk factors like male sex, African ancestry, immunosuppression and pregnancy [[2], [3], [4]]. Prior data have shown that disseminated disease occurs in 23% of pregnant patients in the first trimester [5]. Extrapulmonary disease occurs most commonly in soft tissue, skin, joints and brain [6]. In contrast, peritoneum dissemination is rare, occurring through hematogenous spread or swallowing pulmonary secretions [7]. Disseminated cocciodiodes, like tuberculosis, is a great mimicker and can be challenging to diagnose. For example, early infection may present with persistently negative antibodies, especially in patients who are immunosuppressed or immune tolerant, as observed in pregnant women [3]. Additionally, there is a wide sensitivity and specificity of the enzyme immunoassay test, depending on lab assay [3].
To our knowledge, there are no reported cases of disseminated peritoneal coccidioidomycosis in the setting of early pregnancy following fertility treatment. We present the case of a 39-year-old woman with an early pregnancy resulting from ovarian stimulation with clomiphene citrate and intrauterine insemination who developed episodes of fever, ascites and abdominal pain ultimately requiring an exploratory laparotomy leading to a diagnosis of disseminated peritoneal Coccidioides immitis.
2 Case Presentation
A 39-year-old woman presented to an infertility clinic. She was diagnosed with unexplained secondary infertility associated with male factor. Her workup showed normal day 3 laboratory results (FSH 7.0 mIU/mL, estradiol 35 pg/mL), TSH 2.8 mcIU/mL, normal hysterosalpingogram, antral follicle count of 32 and semen analysis with mild oligoteratospermia. The couple had negative infectious disease screening, including hepatitis B and C, HIV, syphilis and HTLV 1–2. She underwent her first clomiphene citrate 50 mg cycle and developed two dominant follicles. Ovulation was triggered using 250 μg of HCG subcutaneously. She underwent an uncomplicated intrauterine insemination with 24 million fresh, motile washed sperm.
She began experiencing intermittent fevers and abdominal pain 8 days after insemination. She was seen by her primary care physician, who noted normal temperature, mild tenderness on exam and negative pregnancy test. She was counseled that her symptoms may be secondary to early pregnancy or mild gastritis. Three days later, she re-presented with a mild leukocytosis, serum beta-hCG 84 mIU/ml and normal electrolytes. Pelvic ultrasound showed moderate free fluid with echogenic debris, two left ovarian corpus lutea and an unremarkable appendix (Fig. 1). Consistent with early gestation, no pregnancy was identified, and suspected diagnosis was ruptured hemorrhagic cyst. However, her symptoms continued to worsen, with increasing ascites and distension, persistent fevers, mild increase in liver enzymes (AST 96 U/L, ALT 93 U/L]) and leukocytosis (15 K/uL), and she was sent to the emergency room at 4 weeks 1 day.Fig. 1 A. Large amount of free fluid in pouch of Douglas. B. Left ovary with corpus lutea.
Fig. 1
She had her first documented fever (38.2 °C), up-trending leukocytosis (17 K/uL), mild increase in liver enzymes (AST 50 U/L, ALT 80 U/L), beta-hCG of 127 mIU/ml, normal electrolytes and negative blood cultures. Abdominal ultrasound showed free fluid throughout the abdomen, thickened endometrial lining and a normal appendix. In addition to abdominal distension, the patient developed diarrhea and nausea. Given early gestation and goal to avoid CT radiation, a non-contrast MRI was performed, which showed significant free fluid, two ovarian cysts, likely corpus lutea, and inability to visualize the appendix. There was low suspicion for ovarian hyperstimulation syndrome given clomiphene citrate use for stimulation, two dominant follicles at trigger, normal electrolytes and absence of enlarged ovaries.
She was admitted for IV antibiotics for suspected bacterial peritonitis. Infectious disease was consulted. Ceftriaxone, flagyl and vancomycin were used for genitourinary coverage given fertility treatments. The patient was originally from Tanzania, which made the team suspicious for tuberculosis despite lack of clinical history and x-ray showing small pleural effusions.
By hospital day (HD) 3, she was clinically worsening, with fevers (39.4 °C), rising leukocytosis (23 K/uL) and abdominal distention. CT of the abdomen with contrast showed moderate ascites, omental nodularity and caking, not previously seen on MRI, concerning for malignancy or non-malignant causes, including tuberculosis. Gynecology oncology was consulted and the tumor markers CA-125, CA19-9, CEA, CA 15-3, CA 27.29, AFP were normal. Coccidioidomycosis IgM, IgG, and complement fixation titers were negative and <1:2 respectively. In terms of her pregnancy of unknown location, beta-HCGs were abnormally rising and trended every 48 h (126 mIU/ml, 180 mIU/ml, 395 mIU/ml).
On HD 5, paracentesis drained 800 l of fluid and interventional radiology-guided omental biopsies resulted in fat necrosis and granulomatous inflammation. Both peritoneal fluid and tissue biopsies were negative for neoplastic cells, CEA, acid-fast bacilli, fungal, bacterial, non-tuberculosis mycobacterium DNA and Mycobacterium tuberculosis (MTB) PCR. The only pertinent test was an indeterminate serum quantiferon gold; however, peritoneal fluid adenosine deaminase and negative MTB PCR were not consistent with tuberculosis. With progressively worsening symptoms and lack of diagnosis, the decision was made to proceed with laparoscopy for tissue diagnosis. Given abnormally rising beta-HCGs, pregnancy was likely non-viable, thus she elected for termination.
She underwent a diagnostic laparoscopy, omentectomy, lysis of adhesions and suction curettage on HD 8 with gynecology oncology, given CT results concerning for malignancy. Laparoscopy was converted to mini laparotomy due to significant adhesions and inability to obtain adequate biopsies for tissue diagnosis. Operative findings included extensive studding of peritoneum, infracolic omentum inflammation, bowel adhesions to abdominal wall, normal-appearing uterus and adnexa with 3.5 l of ascites (Fig. 2). Curettage showed decidualized endometrium without chorionic villi or coccidiodes. Beta-HCG down-trended to zero post-operatively consistent with successful surgical abortion.Fig. 2 A. Bowel attached to abdominal wall upon entry. B. Laparoscopic view of uterus, adnexa and ascites. C. “Caked omentum”, pathologic specimen.
Fig. 2
Post-operatively her fevers continued despite antibiotics. Surgical omental biopsy cultures resulted as Coccidioides immitis on postoperative day 11. Her only notable travel history was to Palm Springs, California, and visiting construction sites in the past two years, locations known to harbor coccidioidomycosis. After significant improvement on oral antifungal therapy, she was discharged on HD 15 with fluconazole 400 mg daily. She was followed by the multidisciplinary team as an outpatient. Coccidioides antibody complement fixation (titer 1:4) turned positive one month after her admission date.
3 Discussion
This is a unique case describing disseminated peritoneal coccidioidomycosis in a newly pregnant patient following fertility treatment with insemination. Peritoneal coccidioidomycosis is a challenging diagnosis as there are only 34 published cases [8]. Most patients with isolated peritoneal involvement and negative serology titers are immunosuppressed patients [3,9]. It is therefore possible that our pregnant patient had falsely negative titers due to the immune tolerance of pregnancy.
Most patients with disseminated coccidioidomycosis present gradually with abdominal distension and ascites occurring months to years after infection [2]. In our patient's case, it is possible that the immune-tolerance effects of pregnancy or the hormonal effects of ovarian stimulation may have contributed to her acute presentation. Prior data report pregnant women experience disseminated disease 100 times more frequently [2,6].
Our case highlights a possible association between hormonal changes with fertility treatment, immune tolerance in pregnancy, and risk for peritoneal coccidioidomycosis. Studies show that elevated serum levels of 17-beta-estradiol and progesterone in vitro increase coccidioidomycosis growth, contributing to dissemination [10]. Our patient received clomiphene citrate and was newly pregnant, thereby raising estradiol and progesterone levels. From an immunologic standpoint, pregnancy is a state of decreased cell-mediated immunity, which explains why coccidioidomycosis disseminates more commonly in pregnancy [4,11]. Evidence shows that pregnancy increases the risk of dissemination in proportion to gestational age, with greatest risk in the third trimester, thus our patient's presentation in early gestation was unusual [4,11]. In addition to pregnancy and presumably elevated hormones levels, African ancestry is another risk factor for disseminated disease in our case [11].
The timing and source of initial infection in our patient is unclear. Coccidioidomycosis was likely contracted years prior to presentation through environmental exposure. Even in dissemination, the usual source of initial infection is the pulmonary tract [1]. It is unusual for disseminated disease to involve the female genital tract, thus the insemination procedure or specimen are unlikely to be a cause for initial infection [12]. In concordance, endometrial tissue was negative for coccidioidomycosis. In the only other report of disseminated coccidioidomycosis in a woman who underwent ovarian stimulation with clomiphene citrate and insemination, presentation was several years after fertility treatment [10].
There is limited evidence on how to treat isolated peritoneal coccidioidomycosis. Management is typically fluconazole 400 mg daily for 6–12 months with duration guided by clinical, laboratory, and radiographic response [3]. Unlike other sites of dissemination, mortality is rare with isolated peritoneal coccidioidomycosis [13]. Going forward, our patient may have a small but increased risk of disease reactivation in future pregnancies. There is a lack of literature guiding reproductive patients for timing and risk of future conception [6,14]. According to the Infectious Disease Society of America guidelines, risk of reactivation in pregnancy is low in women who have completed therapy [3]. Once pregnant, the current recommendation is coccidioidal serologic testing every 6–12 weeks [3].
4 Conclusion
We believe this is the only published case of isolated peritoneal coccidioidomycosis in early pregnancy. The diagnosis of peritoneal coccidioidomycosis was particularly challenging given our patient's negative infectious workup and granulomatous tissue on initial omental biopsy. This case demonstrates the importance of a multidisciplinary team. Our patient was originally from Tanzania, which prompted us to consider tuberculosis as the etiology of her disease. Ultimately, local factors like living in California, rather than global factors, were the cause of her disease.
Contributors
Abigail Armstrong contributed to conception/design and drafting of the article.
Mika Watanabe contributed to conception/design and editing of the article.
Debika Bhattacharya was the infectious disease physician on the case and contributed to review and revision of the manuscript.
Mae Zakhour performed the surgery and contributed to review and revision of the manuscript.
Lindsay Kroener was the reproductive endocrinologist on the case and contributed to review and revision of the manuscript.
Conflict of Interest
The authors declare that they have no conflict of interest regarding the publication of this case report.
Funding
No funding from an external source supported the publication of this case report.
Patient Consent
Obtained.
Provenance and Peer Review
This case report was peer reviewed. | Subcutaneous | DrugAdministrationRoute | CC BY | 33665141 | 20,876,580 | 2021-04 |
What was the outcome of reaction 'Abdominal distension'? | Disseminated peritoneal coccidioidomycosis in pregnancy following fertility treatment: A case report and literature review.
Disseminated peritoneal coccidioidomycosis in the setting of early pregnancy after fertility treatment is rare and can present as a diagnostic challenge. A 39-year-old underwent ovarian stimulation with clomiphene citrate followed by HCG trigger and intrauterine insemination. She developed persistent abdominal pain, ascites and episodes of fever in early pregnancy, and eventually underwent a diagnostic laparoscopy for worsening clinical presentation. Operative findings were notable for peritoneal studding, infracolic omentum inflammation, bowel adhesions to the abdominal wall and normal-appearing uterus and adnexa. The pathology results indicated peritoneal Coccidioides immitis infection. Hormonal changes associated with fertility treatment and immune tolerance in pregnancy may increase the risk for disseminated peritoneal coccidioidomycosis. A high index of suspicion and a multidisciplinary team are important for the diagnostic workup and treatment plan of disseminated peritoneal coccidioidomycosis.
1 Introduction
Coccidioidomycosis is a fungal infection that results primarily in pulmonary disease and is endemic to the Southwest United States, Mexico and South America [1]. Extrapulmonary dissemination occurs in 1% of cases, usually in patients with risk factors like male sex, African ancestry, immunosuppression and pregnancy [[2], [3], [4]]. Prior data have shown that disseminated disease occurs in 23% of pregnant patients in the first trimester [5]. Extrapulmonary disease occurs most commonly in soft tissue, skin, joints and brain [6]. In contrast, peritoneum dissemination is rare, occurring through hematogenous spread or swallowing pulmonary secretions [7]. Disseminated cocciodiodes, like tuberculosis, is a great mimicker and can be challenging to diagnose. For example, early infection may present with persistently negative antibodies, especially in patients who are immunosuppressed or immune tolerant, as observed in pregnant women [3]. Additionally, there is a wide sensitivity and specificity of the enzyme immunoassay test, depending on lab assay [3].
To our knowledge, there are no reported cases of disseminated peritoneal coccidioidomycosis in the setting of early pregnancy following fertility treatment. We present the case of a 39-year-old woman with an early pregnancy resulting from ovarian stimulation with clomiphene citrate and intrauterine insemination who developed episodes of fever, ascites and abdominal pain ultimately requiring an exploratory laparotomy leading to a diagnosis of disseminated peritoneal Coccidioides immitis.
2 Case Presentation
A 39-year-old woman presented to an infertility clinic. She was diagnosed with unexplained secondary infertility associated with male factor. Her workup showed normal day 3 laboratory results (FSH 7.0 mIU/mL, estradiol 35 pg/mL), TSH 2.8 mcIU/mL, normal hysterosalpingogram, antral follicle count of 32 and semen analysis with mild oligoteratospermia. The couple had negative infectious disease screening, including hepatitis B and C, HIV, syphilis and HTLV 1–2. She underwent her first clomiphene citrate 50 mg cycle and developed two dominant follicles. Ovulation was triggered using 250 μg of HCG subcutaneously. She underwent an uncomplicated intrauterine insemination with 24 million fresh, motile washed sperm.
She began experiencing intermittent fevers and abdominal pain 8 days after insemination. She was seen by her primary care physician, who noted normal temperature, mild tenderness on exam and negative pregnancy test. She was counseled that her symptoms may be secondary to early pregnancy or mild gastritis. Three days later, she re-presented with a mild leukocytosis, serum beta-hCG 84 mIU/ml and normal electrolytes. Pelvic ultrasound showed moderate free fluid with echogenic debris, two left ovarian corpus lutea and an unremarkable appendix (Fig. 1). Consistent with early gestation, no pregnancy was identified, and suspected diagnosis was ruptured hemorrhagic cyst. However, her symptoms continued to worsen, with increasing ascites and distension, persistent fevers, mild increase in liver enzymes (AST 96 U/L, ALT 93 U/L]) and leukocytosis (15 K/uL), and she was sent to the emergency room at 4 weeks 1 day.Fig. 1 A. Large amount of free fluid in pouch of Douglas. B. Left ovary with corpus lutea.
Fig. 1
She had her first documented fever (38.2 °C), up-trending leukocytosis (17 K/uL), mild increase in liver enzymes (AST 50 U/L, ALT 80 U/L), beta-hCG of 127 mIU/ml, normal electrolytes and negative blood cultures. Abdominal ultrasound showed free fluid throughout the abdomen, thickened endometrial lining and a normal appendix. In addition to abdominal distension, the patient developed diarrhea and nausea. Given early gestation and goal to avoid CT radiation, a non-contrast MRI was performed, which showed significant free fluid, two ovarian cysts, likely corpus lutea, and inability to visualize the appendix. There was low suspicion for ovarian hyperstimulation syndrome given clomiphene citrate use for stimulation, two dominant follicles at trigger, normal electrolytes and absence of enlarged ovaries.
She was admitted for IV antibiotics for suspected bacterial peritonitis. Infectious disease was consulted. Ceftriaxone, flagyl and vancomycin were used for genitourinary coverage given fertility treatments. The patient was originally from Tanzania, which made the team suspicious for tuberculosis despite lack of clinical history and x-ray showing small pleural effusions.
By hospital day (HD) 3, she was clinically worsening, with fevers (39.4 °C), rising leukocytosis (23 K/uL) and abdominal distention. CT of the abdomen with contrast showed moderate ascites, omental nodularity and caking, not previously seen on MRI, concerning for malignancy or non-malignant causes, including tuberculosis. Gynecology oncology was consulted and the tumor markers CA-125, CA19-9, CEA, CA 15-3, CA 27.29, AFP were normal. Coccidioidomycosis IgM, IgG, and complement fixation titers were negative and <1:2 respectively. In terms of her pregnancy of unknown location, beta-HCGs were abnormally rising and trended every 48 h (126 mIU/ml, 180 mIU/ml, 395 mIU/ml).
On HD 5, paracentesis drained 800 l of fluid and interventional radiology-guided omental biopsies resulted in fat necrosis and granulomatous inflammation. Both peritoneal fluid and tissue biopsies were negative for neoplastic cells, CEA, acid-fast bacilli, fungal, bacterial, non-tuberculosis mycobacterium DNA and Mycobacterium tuberculosis (MTB) PCR. The only pertinent test was an indeterminate serum quantiferon gold; however, peritoneal fluid adenosine deaminase and negative MTB PCR were not consistent with tuberculosis. With progressively worsening symptoms and lack of diagnosis, the decision was made to proceed with laparoscopy for tissue diagnosis. Given abnormally rising beta-HCGs, pregnancy was likely non-viable, thus she elected for termination.
She underwent a diagnostic laparoscopy, omentectomy, lysis of adhesions and suction curettage on HD 8 with gynecology oncology, given CT results concerning for malignancy. Laparoscopy was converted to mini laparotomy due to significant adhesions and inability to obtain adequate biopsies for tissue diagnosis. Operative findings included extensive studding of peritoneum, infracolic omentum inflammation, bowel adhesions to abdominal wall, normal-appearing uterus and adnexa with 3.5 l of ascites (Fig. 2). Curettage showed decidualized endometrium without chorionic villi or coccidiodes. Beta-HCG down-trended to zero post-operatively consistent with successful surgical abortion.Fig. 2 A. Bowel attached to abdominal wall upon entry. B. Laparoscopic view of uterus, adnexa and ascites. C. “Caked omentum”, pathologic specimen.
Fig. 2
Post-operatively her fevers continued despite antibiotics. Surgical omental biopsy cultures resulted as Coccidioides immitis on postoperative day 11. Her only notable travel history was to Palm Springs, California, and visiting construction sites in the past two years, locations known to harbor coccidioidomycosis. After significant improvement on oral antifungal therapy, she was discharged on HD 15 with fluconazole 400 mg daily. She was followed by the multidisciplinary team as an outpatient. Coccidioides antibody complement fixation (titer 1:4) turned positive one month after her admission date.
3 Discussion
This is a unique case describing disseminated peritoneal coccidioidomycosis in a newly pregnant patient following fertility treatment with insemination. Peritoneal coccidioidomycosis is a challenging diagnosis as there are only 34 published cases [8]. Most patients with isolated peritoneal involvement and negative serology titers are immunosuppressed patients [3,9]. It is therefore possible that our pregnant patient had falsely negative titers due to the immune tolerance of pregnancy.
Most patients with disseminated coccidioidomycosis present gradually with abdominal distension and ascites occurring months to years after infection [2]. In our patient's case, it is possible that the immune-tolerance effects of pregnancy or the hormonal effects of ovarian stimulation may have contributed to her acute presentation. Prior data report pregnant women experience disseminated disease 100 times more frequently [2,6].
Our case highlights a possible association between hormonal changes with fertility treatment, immune tolerance in pregnancy, and risk for peritoneal coccidioidomycosis. Studies show that elevated serum levels of 17-beta-estradiol and progesterone in vitro increase coccidioidomycosis growth, contributing to dissemination [10]. Our patient received clomiphene citrate and was newly pregnant, thereby raising estradiol and progesterone levels. From an immunologic standpoint, pregnancy is a state of decreased cell-mediated immunity, which explains why coccidioidomycosis disseminates more commonly in pregnancy [4,11]. Evidence shows that pregnancy increases the risk of dissemination in proportion to gestational age, with greatest risk in the third trimester, thus our patient's presentation in early gestation was unusual [4,11]. In addition to pregnancy and presumably elevated hormones levels, African ancestry is another risk factor for disseminated disease in our case [11].
The timing and source of initial infection in our patient is unclear. Coccidioidomycosis was likely contracted years prior to presentation through environmental exposure. Even in dissemination, the usual source of initial infection is the pulmonary tract [1]. It is unusual for disseminated disease to involve the female genital tract, thus the insemination procedure or specimen are unlikely to be a cause for initial infection [12]. In concordance, endometrial tissue was negative for coccidioidomycosis. In the only other report of disseminated coccidioidomycosis in a woman who underwent ovarian stimulation with clomiphene citrate and insemination, presentation was several years after fertility treatment [10].
There is limited evidence on how to treat isolated peritoneal coccidioidomycosis. Management is typically fluconazole 400 mg daily for 6–12 months with duration guided by clinical, laboratory, and radiographic response [3]. Unlike other sites of dissemination, mortality is rare with isolated peritoneal coccidioidomycosis [13]. Going forward, our patient may have a small but increased risk of disease reactivation in future pregnancies. There is a lack of literature guiding reproductive patients for timing and risk of future conception [6,14]. According to the Infectious Disease Society of America guidelines, risk of reactivation in pregnancy is low in women who have completed therapy [3]. Once pregnant, the current recommendation is coccidioidal serologic testing every 6–12 weeks [3].
4 Conclusion
We believe this is the only published case of isolated peritoneal coccidioidomycosis in early pregnancy. The diagnosis of peritoneal coccidioidomycosis was particularly challenging given our patient's negative infectious workup and granulomatous tissue on initial omental biopsy. This case demonstrates the importance of a multidisciplinary team. Our patient was originally from Tanzania, which prompted us to consider tuberculosis as the etiology of her disease. Ultimately, local factors like living in California, rather than global factors, were the cause of her disease.
Contributors
Abigail Armstrong contributed to conception/design and drafting of the article.
Mika Watanabe contributed to conception/design and editing of the article.
Debika Bhattacharya was the infectious disease physician on the case and contributed to review and revision of the manuscript.
Mae Zakhour performed the surgery and contributed to review and revision of the manuscript.
Lindsay Kroener was the reproductive endocrinologist on the case and contributed to review and revision of the manuscript.
Conflict of Interest
The authors declare that they have no conflict of interest regarding the publication of this case report.
Funding
No funding from an external source supported the publication of this case report.
Patient Consent
Obtained.
Provenance and Peer Review
This case report was peer reviewed. | Recovering | ReactionOutcome | CC BY | 33665141 | 19,006,800 | 2021-04 |
What was the outcome of reaction 'Abdominal pain'? | Disseminated peritoneal coccidioidomycosis in pregnancy following fertility treatment: A case report and literature review.
Disseminated peritoneal coccidioidomycosis in the setting of early pregnancy after fertility treatment is rare and can present as a diagnostic challenge. A 39-year-old underwent ovarian stimulation with clomiphene citrate followed by HCG trigger and intrauterine insemination. She developed persistent abdominal pain, ascites and episodes of fever in early pregnancy, and eventually underwent a diagnostic laparoscopy for worsening clinical presentation. Operative findings were notable for peritoneal studding, infracolic omentum inflammation, bowel adhesions to the abdominal wall and normal-appearing uterus and adnexa. The pathology results indicated peritoneal Coccidioides immitis infection. Hormonal changes associated with fertility treatment and immune tolerance in pregnancy may increase the risk for disseminated peritoneal coccidioidomycosis. A high index of suspicion and a multidisciplinary team are important for the diagnostic workup and treatment plan of disseminated peritoneal coccidioidomycosis.
1 Introduction
Coccidioidomycosis is a fungal infection that results primarily in pulmonary disease and is endemic to the Southwest United States, Mexico and South America [1]. Extrapulmonary dissemination occurs in 1% of cases, usually in patients with risk factors like male sex, African ancestry, immunosuppression and pregnancy [[2], [3], [4]]. Prior data have shown that disseminated disease occurs in 23% of pregnant patients in the first trimester [5]. Extrapulmonary disease occurs most commonly in soft tissue, skin, joints and brain [6]. In contrast, peritoneum dissemination is rare, occurring through hematogenous spread or swallowing pulmonary secretions [7]. Disseminated cocciodiodes, like tuberculosis, is a great mimicker and can be challenging to diagnose. For example, early infection may present with persistently negative antibodies, especially in patients who are immunosuppressed or immune tolerant, as observed in pregnant women [3]. Additionally, there is a wide sensitivity and specificity of the enzyme immunoassay test, depending on lab assay [3].
To our knowledge, there are no reported cases of disseminated peritoneal coccidioidomycosis in the setting of early pregnancy following fertility treatment. We present the case of a 39-year-old woman with an early pregnancy resulting from ovarian stimulation with clomiphene citrate and intrauterine insemination who developed episodes of fever, ascites and abdominal pain ultimately requiring an exploratory laparotomy leading to a diagnosis of disseminated peritoneal Coccidioides immitis.
2 Case Presentation
A 39-year-old woman presented to an infertility clinic. She was diagnosed with unexplained secondary infertility associated with male factor. Her workup showed normal day 3 laboratory results (FSH 7.0 mIU/mL, estradiol 35 pg/mL), TSH 2.8 mcIU/mL, normal hysterosalpingogram, antral follicle count of 32 and semen analysis with mild oligoteratospermia. The couple had negative infectious disease screening, including hepatitis B and C, HIV, syphilis and HTLV 1–2. She underwent her first clomiphene citrate 50 mg cycle and developed two dominant follicles. Ovulation was triggered using 250 μg of HCG subcutaneously. She underwent an uncomplicated intrauterine insemination with 24 million fresh, motile washed sperm.
She began experiencing intermittent fevers and abdominal pain 8 days after insemination. She was seen by her primary care physician, who noted normal temperature, mild tenderness on exam and negative pregnancy test. She was counseled that her symptoms may be secondary to early pregnancy or mild gastritis. Three days later, she re-presented with a mild leukocytosis, serum beta-hCG 84 mIU/ml and normal electrolytes. Pelvic ultrasound showed moderate free fluid with echogenic debris, two left ovarian corpus lutea and an unremarkable appendix (Fig. 1). Consistent with early gestation, no pregnancy was identified, and suspected diagnosis was ruptured hemorrhagic cyst. However, her symptoms continued to worsen, with increasing ascites and distension, persistent fevers, mild increase in liver enzymes (AST 96 U/L, ALT 93 U/L]) and leukocytosis (15 K/uL), and she was sent to the emergency room at 4 weeks 1 day.Fig. 1 A. Large amount of free fluid in pouch of Douglas. B. Left ovary with corpus lutea.
Fig. 1
She had her first documented fever (38.2 °C), up-trending leukocytosis (17 K/uL), mild increase in liver enzymes (AST 50 U/L, ALT 80 U/L), beta-hCG of 127 mIU/ml, normal electrolytes and negative blood cultures. Abdominal ultrasound showed free fluid throughout the abdomen, thickened endometrial lining and a normal appendix. In addition to abdominal distension, the patient developed diarrhea and nausea. Given early gestation and goal to avoid CT radiation, a non-contrast MRI was performed, which showed significant free fluid, two ovarian cysts, likely corpus lutea, and inability to visualize the appendix. There was low suspicion for ovarian hyperstimulation syndrome given clomiphene citrate use for stimulation, two dominant follicles at trigger, normal electrolytes and absence of enlarged ovaries.
She was admitted for IV antibiotics for suspected bacterial peritonitis. Infectious disease was consulted. Ceftriaxone, flagyl and vancomycin were used for genitourinary coverage given fertility treatments. The patient was originally from Tanzania, which made the team suspicious for tuberculosis despite lack of clinical history and x-ray showing small pleural effusions.
By hospital day (HD) 3, she was clinically worsening, with fevers (39.4 °C), rising leukocytosis (23 K/uL) and abdominal distention. CT of the abdomen with contrast showed moderate ascites, omental nodularity and caking, not previously seen on MRI, concerning for malignancy or non-malignant causes, including tuberculosis. Gynecology oncology was consulted and the tumor markers CA-125, CA19-9, CEA, CA 15-3, CA 27.29, AFP were normal. Coccidioidomycosis IgM, IgG, and complement fixation titers were negative and <1:2 respectively. In terms of her pregnancy of unknown location, beta-HCGs were abnormally rising and trended every 48 h (126 mIU/ml, 180 mIU/ml, 395 mIU/ml).
On HD 5, paracentesis drained 800 l of fluid and interventional radiology-guided omental biopsies resulted in fat necrosis and granulomatous inflammation. Both peritoneal fluid and tissue biopsies were negative for neoplastic cells, CEA, acid-fast bacilli, fungal, bacterial, non-tuberculosis mycobacterium DNA and Mycobacterium tuberculosis (MTB) PCR. The only pertinent test was an indeterminate serum quantiferon gold; however, peritoneal fluid adenosine deaminase and negative MTB PCR were not consistent with tuberculosis. With progressively worsening symptoms and lack of diagnosis, the decision was made to proceed with laparoscopy for tissue diagnosis. Given abnormally rising beta-HCGs, pregnancy was likely non-viable, thus she elected for termination.
She underwent a diagnostic laparoscopy, omentectomy, lysis of adhesions and suction curettage on HD 8 with gynecology oncology, given CT results concerning for malignancy. Laparoscopy was converted to mini laparotomy due to significant adhesions and inability to obtain adequate biopsies for tissue diagnosis. Operative findings included extensive studding of peritoneum, infracolic omentum inflammation, bowel adhesions to abdominal wall, normal-appearing uterus and adnexa with 3.5 l of ascites (Fig. 2). Curettage showed decidualized endometrium without chorionic villi or coccidiodes. Beta-HCG down-trended to zero post-operatively consistent with successful surgical abortion.Fig. 2 A. Bowel attached to abdominal wall upon entry. B. Laparoscopic view of uterus, adnexa and ascites. C. “Caked omentum”, pathologic specimen.
Fig. 2
Post-operatively her fevers continued despite antibiotics. Surgical omental biopsy cultures resulted as Coccidioides immitis on postoperative day 11. Her only notable travel history was to Palm Springs, California, and visiting construction sites in the past two years, locations known to harbor coccidioidomycosis. After significant improvement on oral antifungal therapy, she was discharged on HD 15 with fluconazole 400 mg daily. She was followed by the multidisciplinary team as an outpatient. Coccidioides antibody complement fixation (titer 1:4) turned positive one month after her admission date.
3 Discussion
This is a unique case describing disseminated peritoneal coccidioidomycosis in a newly pregnant patient following fertility treatment with insemination. Peritoneal coccidioidomycosis is a challenging diagnosis as there are only 34 published cases [8]. Most patients with isolated peritoneal involvement and negative serology titers are immunosuppressed patients [3,9]. It is therefore possible that our pregnant patient had falsely negative titers due to the immune tolerance of pregnancy.
Most patients with disseminated coccidioidomycosis present gradually with abdominal distension and ascites occurring months to years after infection [2]. In our patient's case, it is possible that the immune-tolerance effects of pregnancy or the hormonal effects of ovarian stimulation may have contributed to her acute presentation. Prior data report pregnant women experience disseminated disease 100 times more frequently [2,6].
Our case highlights a possible association between hormonal changes with fertility treatment, immune tolerance in pregnancy, and risk for peritoneal coccidioidomycosis. Studies show that elevated serum levels of 17-beta-estradiol and progesterone in vitro increase coccidioidomycosis growth, contributing to dissemination [10]. Our patient received clomiphene citrate and was newly pregnant, thereby raising estradiol and progesterone levels. From an immunologic standpoint, pregnancy is a state of decreased cell-mediated immunity, which explains why coccidioidomycosis disseminates more commonly in pregnancy [4,11]. Evidence shows that pregnancy increases the risk of dissemination in proportion to gestational age, with greatest risk in the third trimester, thus our patient's presentation in early gestation was unusual [4,11]. In addition to pregnancy and presumably elevated hormones levels, African ancestry is another risk factor for disseminated disease in our case [11].
The timing and source of initial infection in our patient is unclear. Coccidioidomycosis was likely contracted years prior to presentation through environmental exposure. Even in dissemination, the usual source of initial infection is the pulmonary tract [1]. It is unusual for disseminated disease to involve the female genital tract, thus the insemination procedure or specimen are unlikely to be a cause for initial infection [12]. In concordance, endometrial tissue was negative for coccidioidomycosis. In the only other report of disseminated coccidioidomycosis in a woman who underwent ovarian stimulation with clomiphene citrate and insemination, presentation was several years after fertility treatment [10].
There is limited evidence on how to treat isolated peritoneal coccidioidomycosis. Management is typically fluconazole 400 mg daily for 6–12 months with duration guided by clinical, laboratory, and radiographic response [3]. Unlike other sites of dissemination, mortality is rare with isolated peritoneal coccidioidomycosis [13]. Going forward, our patient may have a small but increased risk of disease reactivation in future pregnancies. There is a lack of literature guiding reproductive patients for timing and risk of future conception [6,14]. According to the Infectious Disease Society of America guidelines, risk of reactivation in pregnancy is low in women who have completed therapy [3]. Once pregnant, the current recommendation is coccidioidal serologic testing every 6–12 weeks [3].
4 Conclusion
We believe this is the only published case of isolated peritoneal coccidioidomycosis in early pregnancy. The diagnosis of peritoneal coccidioidomycosis was particularly challenging given our patient's negative infectious workup and granulomatous tissue on initial omental biopsy. This case demonstrates the importance of a multidisciplinary team. Our patient was originally from Tanzania, which prompted us to consider tuberculosis as the etiology of her disease. Ultimately, local factors like living in California, rather than global factors, were the cause of her disease.
Contributors
Abigail Armstrong contributed to conception/design and drafting of the article.
Mika Watanabe contributed to conception/design and editing of the article.
Debika Bhattacharya was the infectious disease physician on the case and contributed to review and revision of the manuscript.
Mae Zakhour performed the surgery and contributed to review and revision of the manuscript.
Lindsay Kroener was the reproductive endocrinologist on the case and contributed to review and revision of the manuscript.
Conflict of Interest
The authors declare that they have no conflict of interest regarding the publication of this case report.
Funding
No funding from an external source supported the publication of this case report.
Patient Consent
Obtained.
Provenance and Peer Review
This case report was peer reviewed. | Recovering | ReactionOutcome | CC BY | 33665141 | 19,006,800 | 2021-04 |
What was the outcome of reaction 'Ascites'? | Disseminated peritoneal coccidioidomycosis in pregnancy following fertility treatment: A case report and literature review.
Disseminated peritoneal coccidioidomycosis in the setting of early pregnancy after fertility treatment is rare and can present as a diagnostic challenge. A 39-year-old underwent ovarian stimulation with clomiphene citrate followed by HCG trigger and intrauterine insemination. She developed persistent abdominal pain, ascites and episodes of fever in early pregnancy, and eventually underwent a diagnostic laparoscopy for worsening clinical presentation. Operative findings were notable for peritoneal studding, infracolic omentum inflammation, bowel adhesions to the abdominal wall and normal-appearing uterus and adnexa. The pathology results indicated peritoneal Coccidioides immitis infection. Hormonal changes associated with fertility treatment and immune tolerance in pregnancy may increase the risk for disseminated peritoneal coccidioidomycosis. A high index of suspicion and a multidisciplinary team are important for the diagnostic workup and treatment plan of disseminated peritoneal coccidioidomycosis.
1 Introduction
Coccidioidomycosis is a fungal infection that results primarily in pulmonary disease and is endemic to the Southwest United States, Mexico and South America [1]. Extrapulmonary dissemination occurs in 1% of cases, usually in patients with risk factors like male sex, African ancestry, immunosuppression and pregnancy [[2], [3], [4]]. Prior data have shown that disseminated disease occurs in 23% of pregnant patients in the first trimester [5]. Extrapulmonary disease occurs most commonly in soft tissue, skin, joints and brain [6]. In contrast, peritoneum dissemination is rare, occurring through hematogenous spread or swallowing pulmonary secretions [7]. Disseminated cocciodiodes, like tuberculosis, is a great mimicker and can be challenging to diagnose. For example, early infection may present with persistently negative antibodies, especially in patients who are immunosuppressed or immune tolerant, as observed in pregnant women [3]. Additionally, there is a wide sensitivity and specificity of the enzyme immunoassay test, depending on lab assay [3].
To our knowledge, there are no reported cases of disseminated peritoneal coccidioidomycosis in the setting of early pregnancy following fertility treatment. We present the case of a 39-year-old woman with an early pregnancy resulting from ovarian stimulation with clomiphene citrate and intrauterine insemination who developed episodes of fever, ascites and abdominal pain ultimately requiring an exploratory laparotomy leading to a diagnosis of disseminated peritoneal Coccidioides immitis.
2 Case Presentation
A 39-year-old woman presented to an infertility clinic. She was diagnosed with unexplained secondary infertility associated with male factor. Her workup showed normal day 3 laboratory results (FSH 7.0 mIU/mL, estradiol 35 pg/mL), TSH 2.8 mcIU/mL, normal hysterosalpingogram, antral follicle count of 32 and semen analysis with mild oligoteratospermia. The couple had negative infectious disease screening, including hepatitis B and C, HIV, syphilis and HTLV 1–2. She underwent her first clomiphene citrate 50 mg cycle and developed two dominant follicles. Ovulation was triggered using 250 μg of HCG subcutaneously. She underwent an uncomplicated intrauterine insemination with 24 million fresh, motile washed sperm.
She began experiencing intermittent fevers and abdominal pain 8 days after insemination. She was seen by her primary care physician, who noted normal temperature, mild tenderness on exam and negative pregnancy test. She was counseled that her symptoms may be secondary to early pregnancy or mild gastritis. Three days later, she re-presented with a mild leukocytosis, serum beta-hCG 84 mIU/ml and normal electrolytes. Pelvic ultrasound showed moderate free fluid with echogenic debris, two left ovarian corpus lutea and an unremarkable appendix (Fig. 1). Consistent with early gestation, no pregnancy was identified, and suspected diagnosis was ruptured hemorrhagic cyst. However, her symptoms continued to worsen, with increasing ascites and distension, persistent fevers, mild increase in liver enzymes (AST 96 U/L, ALT 93 U/L]) and leukocytosis (15 K/uL), and she was sent to the emergency room at 4 weeks 1 day.Fig. 1 A. Large amount of free fluid in pouch of Douglas. B. Left ovary with corpus lutea.
Fig. 1
She had her first documented fever (38.2 °C), up-trending leukocytosis (17 K/uL), mild increase in liver enzymes (AST 50 U/L, ALT 80 U/L), beta-hCG of 127 mIU/ml, normal electrolytes and negative blood cultures. Abdominal ultrasound showed free fluid throughout the abdomen, thickened endometrial lining and a normal appendix. In addition to abdominal distension, the patient developed diarrhea and nausea. Given early gestation and goal to avoid CT radiation, a non-contrast MRI was performed, which showed significant free fluid, two ovarian cysts, likely corpus lutea, and inability to visualize the appendix. There was low suspicion for ovarian hyperstimulation syndrome given clomiphene citrate use for stimulation, two dominant follicles at trigger, normal electrolytes and absence of enlarged ovaries.
She was admitted for IV antibiotics for suspected bacterial peritonitis. Infectious disease was consulted. Ceftriaxone, flagyl and vancomycin were used for genitourinary coverage given fertility treatments. The patient was originally from Tanzania, which made the team suspicious for tuberculosis despite lack of clinical history and x-ray showing small pleural effusions.
By hospital day (HD) 3, she was clinically worsening, with fevers (39.4 °C), rising leukocytosis (23 K/uL) and abdominal distention. CT of the abdomen with contrast showed moderate ascites, omental nodularity and caking, not previously seen on MRI, concerning for malignancy or non-malignant causes, including tuberculosis. Gynecology oncology was consulted and the tumor markers CA-125, CA19-9, CEA, CA 15-3, CA 27.29, AFP were normal. Coccidioidomycosis IgM, IgG, and complement fixation titers were negative and <1:2 respectively. In terms of her pregnancy of unknown location, beta-HCGs were abnormally rising and trended every 48 h (126 mIU/ml, 180 mIU/ml, 395 mIU/ml).
On HD 5, paracentesis drained 800 l of fluid and interventional radiology-guided omental biopsies resulted in fat necrosis and granulomatous inflammation. Both peritoneal fluid and tissue biopsies were negative for neoplastic cells, CEA, acid-fast bacilli, fungal, bacterial, non-tuberculosis mycobacterium DNA and Mycobacterium tuberculosis (MTB) PCR. The only pertinent test was an indeterminate serum quantiferon gold; however, peritoneal fluid adenosine deaminase and negative MTB PCR were not consistent with tuberculosis. With progressively worsening symptoms and lack of diagnosis, the decision was made to proceed with laparoscopy for tissue diagnosis. Given abnormally rising beta-HCGs, pregnancy was likely non-viable, thus she elected for termination.
She underwent a diagnostic laparoscopy, omentectomy, lysis of adhesions and suction curettage on HD 8 with gynecology oncology, given CT results concerning for malignancy. Laparoscopy was converted to mini laparotomy due to significant adhesions and inability to obtain adequate biopsies for tissue diagnosis. Operative findings included extensive studding of peritoneum, infracolic omentum inflammation, bowel adhesions to abdominal wall, normal-appearing uterus and adnexa with 3.5 l of ascites (Fig. 2). Curettage showed decidualized endometrium without chorionic villi or coccidiodes. Beta-HCG down-trended to zero post-operatively consistent with successful surgical abortion.Fig. 2 A. Bowel attached to abdominal wall upon entry. B. Laparoscopic view of uterus, adnexa and ascites. C. “Caked omentum”, pathologic specimen.
Fig. 2
Post-operatively her fevers continued despite antibiotics. Surgical omental biopsy cultures resulted as Coccidioides immitis on postoperative day 11. Her only notable travel history was to Palm Springs, California, and visiting construction sites in the past two years, locations known to harbor coccidioidomycosis. After significant improvement on oral antifungal therapy, she was discharged on HD 15 with fluconazole 400 mg daily. She was followed by the multidisciplinary team as an outpatient. Coccidioides antibody complement fixation (titer 1:4) turned positive one month after her admission date.
3 Discussion
This is a unique case describing disseminated peritoneal coccidioidomycosis in a newly pregnant patient following fertility treatment with insemination. Peritoneal coccidioidomycosis is a challenging diagnosis as there are only 34 published cases [8]. Most patients with isolated peritoneal involvement and negative serology titers are immunosuppressed patients [3,9]. It is therefore possible that our pregnant patient had falsely negative titers due to the immune tolerance of pregnancy.
Most patients with disseminated coccidioidomycosis present gradually with abdominal distension and ascites occurring months to years after infection [2]. In our patient's case, it is possible that the immune-tolerance effects of pregnancy or the hormonal effects of ovarian stimulation may have contributed to her acute presentation. Prior data report pregnant women experience disseminated disease 100 times more frequently [2,6].
Our case highlights a possible association between hormonal changes with fertility treatment, immune tolerance in pregnancy, and risk for peritoneal coccidioidomycosis. Studies show that elevated serum levels of 17-beta-estradiol and progesterone in vitro increase coccidioidomycosis growth, contributing to dissemination [10]. Our patient received clomiphene citrate and was newly pregnant, thereby raising estradiol and progesterone levels. From an immunologic standpoint, pregnancy is a state of decreased cell-mediated immunity, which explains why coccidioidomycosis disseminates more commonly in pregnancy [4,11]. Evidence shows that pregnancy increases the risk of dissemination in proportion to gestational age, with greatest risk in the third trimester, thus our patient's presentation in early gestation was unusual [4,11]. In addition to pregnancy and presumably elevated hormones levels, African ancestry is another risk factor for disseminated disease in our case [11].
The timing and source of initial infection in our patient is unclear. Coccidioidomycosis was likely contracted years prior to presentation through environmental exposure. Even in dissemination, the usual source of initial infection is the pulmonary tract [1]. It is unusual for disseminated disease to involve the female genital tract, thus the insemination procedure or specimen are unlikely to be a cause for initial infection [12]. In concordance, endometrial tissue was negative for coccidioidomycosis. In the only other report of disseminated coccidioidomycosis in a woman who underwent ovarian stimulation with clomiphene citrate and insemination, presentation was several years after fertility treatment [10].
There is limited evidence on how to treat isolated peritoneal coccidioidomycosis. Management is typically fluconazole 400 mg daily for 6–12 months with duration guided by clinical, laboratory, and radiographic response [3]. Unlike other sites of dissemination, mortality is rare with isolated peritoneal coccidioidomycosis [13]. Going forward, our patient may have a small but increased risk of disease reactivation in future pregnancies. There is a lack of literature guiding reproductive patients for timing and risk of future conception [6,14]. According to the Infectious Disease Society of America guidelines, risk of reactivation in pregnancy is low in women who have completed therapy [3]. Once pregnant, the current recommendation is coccidioidal serologic testing every 6–12 weeks [3].
4 Conclusion
We believe this is the only published case of isolated peritoneal coccidioidomycosis in early pregnancy. The diagnosis of peritoneal coccidioidomycosis was particularly challenging given our patient's negative infectious workup and granulomatous tissue on initial omental biopsy. This case demonstrates the importance of a multidisciplinary team. Our patient was originally from Tanzania, which prompted us to consider tuberculosis as the etiology of her disease. Ultimately, local factors like living in California, rather than global factors, were the cause of her disease.
Contributors
Abigail Armstrong contributed to conception/design and drafting of the article.
Mika Watanabe contributed to conception/design and editing of the article.
Debika Bhattacharya was the infectious disease physician on the case and contributed to review and revision of the manuscript.
Mae Zakhour performed the surgery and contributed to review and revision of the manuscript.
Lindsay Kroener was the reproductive endocrinologist on the case and contributed to review and revision of the manuscript.
Conflict of Interest
The authors declare that they have no conflict of interest regarding the publication of this case report.
Funding
No funding from an external source supported the publication of this case report.
Patient Consent
Obtained.
Provenance and Peer Review
This case report was peer reviewed. | Recovering | ReactionOutcome | CC BY | 33665141 | 19,006,800 | 2021-04 |
What was the outcome of reaction 'Diarrhoea'? | Disseminated peritoneal coccidioidomycosis in pregnancy following fertility treatment: A case report and literature review.
Disseminated peritoneal coccidioidomycosis in the setting of early pregnancy after fertility treatment is rare and can present as a diagnostic challenge. A 39-year-old underwent ovarian stimulation with clomiphene citrate followed by HCG trigger and intrauterine insemination. She developed persistent abdominal pain, ascites and episodes of fever in early pregnancy, and eventually underwent a diagnostic laparoscopy for worsening clinical presentation. Operative findings were notable for peritoneal studding, infracolic omentum inflammation, bowel adhesions to the abdominal wall and normal-appearing uterus and adnexa. The pathology results indicated peritoneal Coccidioides immitis infection. Hormonal changes associated with fertility treatment and immune tolerance in pregnancy may increase the risk for disseminated peritoneal coccidioidomycosis. A high index of suspicion and a multidisciplinary team are important for the diagnostic workup and treatment plan of disseminated peritoneal coccidioidomycosis.
1 Introduction
Coccidioidomycosis is a fungal infection that results primarily in pulmonary disease and is endemic to the Southwest United States, Mexico and South America [1]. Extrapulmonary dissemination occurs in 1% of cases, usually in patients with risk factors like male sex, African ancestry, immunosuppression and pregnancy [[2], [3], [4]]. Prior data have shown that disseminated disease occurs in 23% of pregnant patients in the first trimester [5]. Extrapulmonary disease occurs most commonly in soft tissue, skin, joints and brain [6]. In contrast, peritoneum dissemination is rare, occurring through hematogenous spread or swallowing pulmonary secretions [7]. Disseminated cocciodiodes, like tuberculosis, is a great mimicker and can be challenging to diagnose. For example, early infection may present with persistently negative antibodies, especially in patients who are immunosuppressed or immune tolerant, as observed in pregnant women [3]. Additionally, there is a wide sensitivity and specificity of the enzyme immunoassay test, depending on lab assay [3].
To our knowledge, there are no reported cases of disseminated peritoneal coccidioidomycosis in the setting of early pregnancy following fertility treatment. We present the case of a 39-year-old woman with an early pregnancy resulting from ovarian stimulation with clomiphene citrate and intrauterine insemination who developed episodes of fever, ascites and abdominal pain ultimately requiring an exploratory laparotomy leading to a diagnosis of disseminated peritoneal Coccidioides immitis.
2 Case Presentation
A 39-year-old woman presented to an infertility clinic. She was diagnosed with unexplained secondary infertility associated with male factor. Her workup showed normal day 3 laboratory results (FSH 7.0 mIU/mL, estradiol 35 pg/mL), TSH 2.8 mcIU/mL, normal hysterosalpingogram, antral follicle count of 32 and semen analysis with mild oligoteratospermia. The couple had negative infectious disease screening, including hepatitis B and C, HIV, syphilis and HTLV 1–2. She underwent her first clomiphene citrate 50 mg cycle and developed two dominant follicles. Ovulation was triggered using 250 μg of HCG subcutaneously. She underwent an uncomplicated intrauterine insemination with 24 million fresh, motile washed sperm.
She began experiencing intermittent fevers and abdominal pain 8 days after insemination. She was seen by her primary care physician, who noted normal temperature, mild tenderness on exam and negative pregnancy test. She was counseled that her symptoms may be secondary to early pregnancy or mild gastritis. Three days later, she re-presented with a mild leukocytosis, serum beta-hCG 84 mIU/ml and normal electrolytes. Pelvic ultrasound showed moderate free fluid with echogenic debris, two left ovarian corpus lutea and an unremarkable appendix (Fig. 1). Consistent with early gestation, no pregnancy was identified, and suspected diagnosis was ruptured hemorrhagic cyst. However, her symptoms continued to worsen, with increasing ascites and distension, persistent fevers, mild increase in liver enzymes (AST 96 U/L, ALT 93 U/L]) and leukocytosis (15 K/uL), and she was sent to the emergency room at 4 weeks 1 day.Fig. 1 A. Large amount of free fluid in pouch of Douglas. B. Left ovary with corpus lutea.
Fig. 1
She had her first documented fever (38.2 °C), up-trending leukocytosis (17 K/uL), mild increase in liver enzymes (AST 50 U/L, ALT 80 U/L), beta-hCG of 127 mIU/ml, normal electrolytes and negative blood cultures. Abdominal ultrasound showed free fluid throughout the abdomen, thickened endometrial lining and a normal appendix. In addition to abdominal distension, the patient developed diarrhea and nausea. Given early gestation and goal to avoid CT radiation, a non-contrast MRI was performed, which showed significant free fluid, two ovarian cysts, likely corpus lutea, and inability to visualize the appendix. There was low suspicion for ovarian hyperstimulation syndrome given clomiphene citrate use for stimulation, two dominant follicles at trigger, normal electrolytes and absence of enlarged ovaries.
She was admitted for IV antibiotics for suspected bacterial peritonitis. Infectious disease was consulted. Ceftriaxone, flagyl and vancomycin were used for genitourinary coverage given fertility treatments. The patient was originally from Tanzania, which made the team suspicious for tuberculosis despite lack of clinical history and x-ray showing small pleural effusions.
By hospital day (HD) 3, she was clinically worsening, with fevers (39.4 °C), rising leukocytosis (23 K/uL) and abdominal distention. CT of the abdomen with contrast showed moderate ascites, omental nodularity and caking, not previously seen on MRI, concerning for malignancy or non-malignant causes, including tuberculosis. Gynecology oncology was consulted and the tumor markers CA-125, CA19-9, CEA, CA 15-3, CA 27.29, AFP were normal. Coccidioidomycosis IgM, IgG, and complement fixation titers were negative and <1:2 respectively. In terms of her pregnancy of unknown location, beta-HCGs were abnormally rising and trended every 48 h (126 mIU/ml, 180 mIU/ml, 395 mIU/ml).
On HD 5, paracentesis drained 800 l of fluid and interventional radiology-guided omental biopsies resulted in fat necrosis and granulomatous inflammation. Both peritoneal fluid and tissue biopsies were negative for neoplastic cells, CEA, acid-fast bacilli, fungal, bacterial, non-tuberculosis mycobacterium DNA and Mycobacterium tuberculosis (MTB) PCR. The only pertinent test was an indeterminate serum quantiferon gold; however, peritoneal fluid adenosine deaminase and negative MTB PCR were not consistent with tuberculosis. With progressively worsening symptoms and lack of diagnosis, the decision was made to proceed with laparoscopy for tissue diagnosis. Given abnormally rising beta-HCGs, pregnancy was likely non-viable, thus she elected for termination.
She underwent a diagnostic laparoscopy, omentectomy, lysis of adhesions and suction curettage on HD 8 with gynecology oncology, given CT results concerning for malignancy. Laparoscopy was converted to mini laparotomy due to significant adhesions and inability to obtain adequate biopsies for tissue diagnosis. Operative findings included extensive studding of peritoneum, infracolic omentum inflammation, bowel adhesions to abdominal wall, normal-appearing uterus and adnexa with 3.5 l of ascites (Fig. 2). Curettage showed decidualized endometrium without chorionic villi or coccidiodes. Beta-HCG down-trended to zero post-operatively consistent with successful surgical abortion.Fig. 2 A. Bowel attached to abdominal wall upon entry. B. Laparoscopic view of uterus, adnexa and ascites. C. “Caked omentum”, pathologic specimen.
Fig. 2
Post-operatively her fevers continued despite antibiotics. Surgical omental biopsy cultures resulted as Coccidioides immitis on postoperative day 11. Her only notable travel history was to Palm Springs, California, and visiting construction sites in the past two years, locations known to harbor coccidioidomycosis. After significant improvement on oral antifungal therapy, she was discharged on HD 15 with fluconazole 400 mg daily. She was followed by the multidisciplinary team as an outpatient. Coccidioides antibody complement fixation (titer 1:4) turned positive one month after her admission date.
3 Discussion
This is a unique case describing disseminated peritoneal coccidioidomycosis in a newly pregnant patient following fertility treatment with insemination. Peritoneal coccidioidomycosis is a challenging diagnosis as there are only 34 published cases [8]. Most patients with isolated peritoneal involvement and negative serology titers are immunosuppressed patients [3,9]. It is therefore possible that our pregnant patient had falsely negative titers due to the immune tolerance of pregnancy.
Most patients with disseminated coccidioidomycosis present gradually with abdominal distension and ascites occurring months to years after infection [2]. In our patient's case, it is possible that the immune-tolerance effects of pregnancy or the hormonal effects of ovarian stimulation may have contributed to her acute presentation. Prior data report pregnant women experience disseminated disease 100 times more frequently [2,6].
Our case highlights a possible association between hormonal changes with fertility treatment, immune tolerance in pregnancy, and risk for peritoneal coccidioidomycosis. Studies show that elevated serum levels of 17-beta-estradiol and progesterone in vitro increase coccidioidomycosis growth, contributing to dissemination [10]. Our patient received clomiphene citrate and was newly pregnant, thereby raising estradiol and progesterone levels. From an immunologic standpoint, pregnancy is a state of decreased cell-mediated immunity, which explains why coccidioidomycosis disseminates more commonly in pregnancy [4,11]. Evidence shows that pregnancy increases the risk of dissemination in proportion to gestational age, with greatest risk in the third trimester, thus our patient's presentation in early gestation was unusual [4,11]. In addition to pregnancy and presumably elevated hormones levels, African ancestry is another risk factor for disseminated disease in our case [11].
The timing and source of initial infection in our patient is unclear. Coccidioidomycosis was likely contracted years prior to presentation through environmental exposure. Even in dissemination, the usual source of initial infection is the pulmonary tract [1]. It is unusual for disseminated disease to involve the female genital tract, thus the insemination procedure or specimen are unlikely to be a cause for initial infection [12]. In concordance, endometrial tissue was negative for coccidioidomycosis. In the only other report of disseminated coccidioidomycosis in a woman who underwent ovarian stimulation with clomiphene citrate and insemination, presentation was several years after fertility treatment [10].
There is limited evidence on how to treat isolated peritoneal coccidioidomycosis. Management is typically fluconazole 400 mg daily for 6–12 months with duration guided by clinical, laboratory, and radiographic response [3]. Unlike other sites of dissemination, mortality is rare with isolated peritoneal coccidioidomycosis [13]. Going forward, our patient may have a small but increased risk of disease reactivation in future pregnancies. There is a lack of literature guiding reproductive patients for timing and risk of future conception [6,14]. According to the Infectious Disease Society of America guidelines, risk of reactivation in pregnancy is low in women who have completed therapy [3]. Once pregnant, the current recommendation is coccidioidal serologic testing every 6–12 weeks [3].
4 Conclusion
We believe this is the only published case of isolated peritoneal coccidioidomycosis in early pregnancy. The diagnosis of peritoneal coccidioidomycosis was particularly challenging given our patient's negative infectious workup and granulomatous tissue on initial omental biopsy. This case demonstrates the importance of a multidisciplinary team. Our patient was originally from Tanzania, which prompted us to consider tuberculosis as the etiology of her disease. Ultimately, local factors like living in California, rather than global factors, were the cause of her disease.
Contributors
Abigail Armstrong contributed to conception/design and drafting of the article.
Mika Watanabe contributed to conception/design and editing of the article.
Debika Bhattacharya was the infectious disease physician on the case and contributed to review and revision of the manuscript.
Mae Zakhour performed the surgery and contributed to review and revision of the manuscript.
Lindsay Kroener was the reproductive endocrinologist on the case and contributed to review and revision of the manuscript.
Conflict of Interest
The authors declare that they have no conflict of interest regarding the publication of this case report.
Funding
No funding from an external source supported the publication of this case report.
Patient Consent
Obtained.
Provenance and Peer Review
This case report was peer reviewed. | Recovering | ReactionOutcome | CC BY | 33665141 | 19,006,800 | 2021-04 |
What was the outcome of reaction 'Leukocytosis'? | Disseminated peritoneal coccidioidomycosis in pregnancy following fertility treatment: A case report and literature review.
Disseminated peritoneal coccidioidomycosis in the setting of early pregnancy after fertility treatment is rare and can present as a diagnostic challenge. A 39-year-old underwent ovarian stimulation with clomiphene citrate followed by HCG trigger and intrauterine insemination. She developed persistent abdominal pain, ascites and episodes of fever in early pregnancy, and eventually underwent a diagnostic laparoscopy for worsening clinical presentation. Operative findings were notable for peritoneal studding, infracolic omentum inflammation, bowel adhesions to the abdominal wall and normal-appearing uterus and adnexa. The pathology results indicated peritoneal Coccidioides immitis infection. Hormonal changes associated with fertility treatment and immune tolerance in pregnancy may increase the risk for disseminated peritoneal coccidioidomycosis. A high index of suspicion and a multidisciplinary team are important for the diagnostic workup and treatment plan of disseminated peritoneal coccidioidomycosis.
1 Introduction
Coccidioidomycosis is a fungal infection that results primarily in pulmonary disease and is endemic to the Southwest United States, Mexico and South America [1]. Extrapulmonary dissemination occurs in 1% of cases, usually in patients with risk factors like male sex, African ancestry, immunosuppression and pregnancy [[2], [3], [4]]. Prior data have shown that disseminated disease occurs in 23% of pregnant patients in the first trimester [5]. Extrapulmonary disease occurs most commonly in soft tissue, skin, joints and brain [6]. In contrast, peritoneum dissemination is rare, occurring through hematogenous spread or swallowing pulmonary secretions [7]. Disseminated cocciodiodes, like tuberculosis, is a great mimicker and can be challenging to diagnose. For example, early infection may present with persistently negative antibodies, especially in patients who are immunosuppressed or immune tolerant, as observed in pregnant women [3]. Additionally, there is a wide sensitivity and specificity of the enzyme immunoassay test, depending on lab assay [3].
To our knowledge, there are no reported cases of disseminated peritoneal coccidioidomycosis in the setting of early pregnancy following fertility treatment. We present the case of a 39-year-old woman with an early pregnancy resulting from ovarian stimulation with clomiphene citrate and intrauterine insemination who developed episodes of fever, ascites and abdominal pain ultimately requiring an exploratory laparotomy leading to a diagnosis of disseminated peritoneal Coccidioides immitis.
2 Case Presentation
A 39-year-old woman presented to an infertility clinic. She was diagnosed with unexplained secondary infertility associated with male factor. Her workup showed normal day 3 laboratory results (FSH 7.0 mIU/mL, estradiol 35 pg/mL), TSH 2.8 mcIU/mL, normal hysterosalpingogram, antral follicle count of 32 and semen analysis with mild oligoteratospermia. The couple had negative infectious disease screening, including hepatitis B and C, HIV, syphilis and HTLV 1–2. She underwent her first clomiphene citrate 50 mg cycle and developed two dominant follicles. Ovulation was triggered using 250 μg of HCG subcutaneously. She underwent an uncomplicated intrauterine insemination with 24 million fresh, motile washed sperm.
She began experiencing intermittent fevers and abdominal pain 8 days after insemination. She was seen by her primary care physician, who noted normal temperature, mild tenderness on exam and negative pregnancy test. She was counseled that her symptoms may be secondary to early pregnancy or mild gastritis. Three days later, she re-presented with a mild leukocytosis, serum beta-hCG 84 mIU/ml and normal electrolytes. Pelvic ultrasound showed moderate free fluid with echogenic debris, two left ovarian corpus lutea and an unremarkable appendix (Fig. 1). Consistent with early gestation, no pregnancy was identified, and suspected diagnosis was ruptured hemorrhagic cyst. However, her symptoms continued to worsen, with increasing ascites and distension, persistent fevers, mild increase in liver enzymes (AST 96 U/L, ALT 93 U/L]) and leukocytosis (15 K/uL), and she was sent to the emergency room at 4 weeks 1 day.Fig. 1 A. Large amount of free fluid in pouch of Douglas. B. Left ovary with corpus lutea.
Fig. 1
She had her first documented fever (38.2 °C), up-trending leukocytosis (17 K/uL), mild increase in liver enzymes (AST 50 U/L, ALT 80 U/L), beta-hCG of 127 mIU/ml, normal electrolytes and negative blood cultures. Abdominal ultrasound showed free fluid throughout the abdomen, thickened endometrial lining and a normal appendix. In addition to abdominal distension, the patient developed diarrhea and nausea. Given early gestation and goal to avoid CT radiation, a non-contrast MRI was performed, which showed significant free fluid, two ovarian cysts, likely corpus lutea, and inability to visualize the appendix. There was low suspicion for ovarian hyperstimulation syndrome given clomiphene citrate use for stimulation, two dominant follicles at trigger, normal electrolytes and absence of enlarged ovaries.
She was admitted for IV antibiotics for suspected bacterial peritonitis. Infectious disease was consulted. Ceftriaxone, flagyl and vancomycin were used for genitourinary coverage given fertility treatments. The patient was originally from Tanzania, which made the team suspicious for tuberculosis despite lack of clinical history and x-ray showing small pleural effusions.
By hospital day (HD) 3, she was clinically worsening, with fevers (39.4 °C), rising leukocytosis (23 K/uL) and abdominal distention. CT of the abdomen with contrast showed moderate ascites, omental nodularity and caking, not previously seen on MRI, concerning for malignancy or non-malignant causes, including tuberculosis. Gynecology oncology was consulted and the tumor markers CA-125, CA19-9, CEA, CA 15-3, CA 27.29, AFP were normal. Coccidioidomycosis IgM, IgG, and complement fixation titers were negative and <1:2 respectively. In terms of her pregnancy of unknown location, beta-HCGs were abnormally rising and trended every 48 h (126 mIU/ml, 180 mIU/ml, 395 mIU/ml).
On HD 5, paracentesis drained 800 l of fluid and interventional radiology-guided omental biopsies resulted in fat necrosis and granulomatous inflammation. Both peritoneal fluid and tissue biopsies were negative for neoplastic cells, CEA, acid-fast bacilli, fungal, bacterial, non-tuberculosis mycobacterium DNA and Mycobacterium tuberculosis (MTB) PCR. The only pertinent test was an indeterminate serum quantiferon gold; however, peritoneal fluid adenosine deaminase and negative MTB PCR were not consistent with tuberculosis. With progressively worsening symptoms and lack of diagnosis, the decision was made to proceed with laparoscopy for tissue diagnosis. Given abnormally rising beta-HCGs, pregnancy was likely non-viable, thus she elected for termination.
She underwent a diagnostic laparoscopy, omentectomy, lysis of adhesions and suction curettage on HD 8 with gynecology oncology, given CT results concerning for malignancy. Laparoscopy was converted to mini laparotomy due to significant adhesions and inability to obtain adequate biopsies for tissue diagnosis. Operative findings included extensive studding of peritoneum, infracolic omentum inflammation, bowel adhesions to abdominal wall, normal-appearing uterus and adnexa with 3.5 l of ascites (Fig. 2). Curettage showed decidualized endometrium without chorionic villi or coccidiodes. Beta-HCG down-trended to zero post-operatively consistent with successful surgical abortion.Fig. 2 A. Bowel attached to abdominal wall upon entry. B. Laparoscopic view of uterus, adnexa and ascites. C. “Caked omentum”, pathologic specimen.
Fig. 2
Post-operatively her fevers continued despite antibiotics. Surgical omental biopsy cultures resulted as Coccidioides immitis on postoperative day 11. Her only notable travel history was to Palm Springs, California, and visiting construction sites in the past two years, locations known to harbor coccidioidomycosis. After significant improvement on oral antifungal therapy, she was discharged on HD 15 with fluconazole 400 mg daily. She was followed by the multidisciplinary team as an outpatient. Coccidioides antibody complement fixation (titer 1:4) turned positive one month after her admission date.
3 Discussion
This is a unique case describing disseminated peritoneal coccidioidomycosis in a newly pregnant patient following fertility treatment with insemination. Peritoneal coccidioidomycosis is a challenging diagnosis as there are only 34 published cases [8]. Most patients with isolated peritoneal involvement and negative serology titers are immunosuppressed patients [3,9]. It is therefore possible that our pregnant patient had falsely negative titers due to the immune tolerance of pregnancy.
Most patients with disseminated coccidioidomycosis present gradually with abdominal distension and ascites occurring months to years after infection [2]. In our patient's case, it is possible that the immune-tolerance effects of pregnancy or the hormonal effects of ovarian stimulation may have contributed to her acute presentation. Prior data report pregnant women experience disseminated disease 100 times more frequently [2,6].
Our case highlights a possible association between hormonal changes with fertility treatment, immune tolerance in pregnancy, and risk for peritoneal coccidioidomycosis. Studies show that elevated serum levels of 17-beta-estradiol and progesterone in vitro increase coccidioidomycosis growth, contributing to dissemination [10]. Our patient received clomiphene citrate and was newly pregnant, thereby raising estradiol and progesterone levels. From an immunologic standpoint, pregnancy is a state of decreased cell-mediated immunity, which explains why coccidioidomycosis disseminates more commonly in pregnancy [4,11]. Evidence shows that pregnancy increases the risk of dissemination in proportion to gestational age, with greatest risk in the third trimester, thus our patient's presentation in early gestation was unusual [4,11]. In addition to pregnancy and presumably elevated hormones levels, African ancestry is another risk factor for disseminated disease in our case [11].
The timing and source of initial infection in our patient is unclear. Coccidioidomycosis was likely contracted years prior to presentation through environmental exposure. Even in dissemination, the usual source of initial infection is the pulmonary tract [1]. It is unusual for disseminated disease to involve the female genital tract, thus the insemination procedure or specimen are unlikely to be a cause for initial infection [12]. In concordance, endometrial tissue was negative for coccidioidomycosis. In the only other report of disseminated coccidioidomycosis in a woman who underwent ovarian stimulation with clomiphene citrate and insemination, presentation was several years after fertility treatment [10].
There is limited evidence on how to treat isolated peritoneal coccidioidomycosis. Management is typically fluconazole 400 mg daily for 6–12 months with duration guided by clinical, laboratory, and radiographic response [3]. Unlike other sites of dissemination, mortality is rare with isolated peritoneal coccidioidomycosis [13]. Going forward, our patient may have a small but increased risk of disease reactivation in future pregnancies. There is a lack of literature guiding reproductive patients for timing and risk of future conception [6,14]. According to the Infectious Disease Society of America guidelines, risk of reactivation in pregnancy is low in women who have completed therapy [3]. Once pregnant, the current recommendation is coccidioidal serologic testing every 6–12 weeks [3].
4 Conclusion
We believe this is the only published case of isolated peritoneal coccidioidomycosis in early pregnancy. The diagnosis of peritoneal coccidioidomycosis was particularly challenging given our patient's negative infectious workup and granulomatous tissue on initial omental biopsy. This case demonstrates the importance of a multidisciplinary team. Our patient was originally from Tanzania, which prompted us to consider tuberculosis as the etiology of her disease. Ultimately, local factors like living in California, rather than global factors, were the cause of her disease.
Contributors
Abigail Armstrong contributed to conception/design and drafting of the article.
Mika Watanabe contributed to conception/design and editing of the article.
Debika Bhattacharya was the infectious disease physician on the case and contributed to review and revision of the manuscript.
Mae Zakhour performed the surgery and contributed to review and revision of the manuscript.
Lindsay Kroener was the reproductive endocrinologist on the case and contributed to review and revision of the manuscript.
Conflict of Interest
The authors declare that they have no conflict of interest regarding the publication of this case report.
Funding
No funding from an external source supported the publication of this case report.
Patient Consent
Obtained.
Provenance and Peer Review
This case report was peer reviewed. | Recovering | ReactionOutcome | CC BY | 33665141 | 19,006,800 | 2021-04 |
What was the outcome of reaction 'Maternal exposure before pregnancy'? | Disseminated peritoneal coccidioidomycosis in pregnancy following fertility treatment: A case report and literature review.
Disseminated peritoneal coccidioidomycosis in the setting of early pregnancy after fertility treatment is rare and can present as a diagnostic challenge. A 39-year-old underwent ovarian stimulation with clomiphene citrate followed by HCG trigger and intrauterine insemination. She developed persistent abdominal pain, ascites and episodes of fever in early pregnancy, and eventually underwent a diagnostic laparoscopy for worsening clinical presentation. Operative findings were notable for peritoneal studding, infracolic omentum inflammation, bowel adhesions to the abdominal wall and normal-appearing uterus and adnexa. The pathology results indicated peritoneal Coccidioides immitis infection. Hormonal changes associated with fertility treatment and immune tolerance in pregnancy may increase the risk for disseminated peritoneal coccidioidomycosis. A high index of suspicion and a multidisciplinary team are important for the diagnostic workup and treatment plan of disseminated peritoneal coccidioidomycosis.
1 Introduction
Coccidioidomycosis is a fungal infection that results primarily in pulmonary disease and is endemic to the Southwest United States, Mexico and South America [1]. Extrapulmonary dissemination occurs in 1% of cases, usually in patients with risk factors like male sex, African ancestry, immunosuppression and pregnancy [[2], [3], [4]]. Prior data have shown that disseminated disease occurs in 23% of pregnant patients in the first trimester [5]. Extrapulmonary disease occurs most commonly in soft tissue, skin, joints and brain [6]. In contrast, peritoneum dissemination is rare, occurring through hematogenous spread or swallowing pulmonary secretions [7]. Disseminated cocciodiodes, like tuberculosis, is a great mimicker and can be challenging to diagnose. For example, early infection may present with persistently negative antibodies, especially in patients who are immunosuppressed or immune tolerant, as observed in pregnant women [3]. Additionally, there is a wide sensitivity and specificity of the enzyme immunoassay test, depending on lab assay [3].
To our knowledge, there are no reported cases of disseminated peritoneal coccidioidomycosis in the setting of early pregnancy following fertility treatment. We present the case of a 39-year-old woman with an early pregnancy resulting from ovarian stimulation with clomiphene citrate and intrauterine insemination who developed episodes of fever, ascites and abdominal pain ultimately requiring an exploratory laparotomy leading to a diagnosis of disseminated peritoneal Coccidioides immitis.
2 Case Presentation
A 39-year-old woman presented to an infertility clinic. She was diagnosed with unexplained secondary infertility associated with male factor. Her workup showed normal day 3 laboratory results (FSH 7.0 mIU/mL, estradiol 35 pg/mL), TSH 2.8 mcIU/mL, normal hysterosalpingogram, antral follicle count of 32 and semen analysis with mild oligoteratospermia. The couple had negative infectious disease screening, including hepatitis B and C, HIV, syphilis and HTLV 1–2. She underwent her first clomiphene citrate 50 mg cycle and developed two dominant follicles. Ovulation was triggered using 250 μg of HCG subcutaneously. She underwent an uncomplicated intrauterine insemination with 24 million fresh, motile washed sperm.
She began experiencing intermittent fevers and abdominal pain 8 days after insemination. She was seen by her primary care physician, who noted normal temperature, mild tenderness on exam and negative pregnancy test. She was counseled that her symptoms may be secondary to early pregnancy or mild gastritis. Three days later, she re-presented with a mild leukocytosis, serum beta-hCG 84 mIU/ml and normal electrolytes. Pelvic ultrasound showed moderate free fluid with echogenic debris, two left ovarian corpus lutea and an unremarkable appendix (Fig. 1). Consistent with early gestation, no pregnancy was identified, and suspected diagnosis was ruptured hemorrhagic cyst. However, her symptoms continued to worsen, with increasing ascites and distension, persistent fevers, mild increase in liver enzymes (AST 96 U/L, ALT 93 U/L]) and leukocytosis (15 K/uL), and she was sent to the emergency room at 4 weeks 1 day.Fig. 1 A. Large amount of free fluid in pouch of Douglas. B. Left ovary with corpus lutea.
Fig. 1
She had her first documented fever (38.2 °C), up-trending leukocytosis (17 K/uL), mild increase in liver enzymes (AST 50 U/L, ALT 80 U/L), beta-hCG of 127 mIU/ml, normal electrolytes and negative blood cultures. Abdominal ultrasound showed free fluid throughout the abdomen, thickened endometrial lining and a normal appendix. In addition to abdominal distension, the patient developed diarrhea and nausea. Given early gestation and goal to avoid CT radiation, a non-contrast MRI was performed, which showed significant free fluid, two ovarian cysts, likely corpus lutea, and inability to visualize the appendix. There was low suspicion for ovarian hyperstimulation syndrome given clomiphene citrate use for stimulation, two dominant follicles at trigger, normal electrolytes and absence of enlarged ovaries.
She was admitted for IV antibiotics for suspected bacterial peritonitis. Infectious disease was consulted. Ceftriaxone, flagyl and vancomycin were used for genitourinary coverage given fertility treatments. The patient was originally from Tanzania, which made the team suspicious for tuberculosis despite lack of clinical history and x-ray showing small pleural effusions.
By hospital day (HD) 3, she was clinically worsening, with fevers (39.4 °C), rising leukocytosis (23 K/uL) and abdominal distention. CT of the abdomen with contrast showed moderate ascites, omental nodularity and caking, not previously seen on MRI, concerning for malignancy or non-malignant causes, including tuberculosis. Gynecology oncology was consulted and the tumor markers CA-125, CA19-9, CEA, CA 15-3, CA 27.29, AFP were normal. Coccidioidomycosis IgM, IgG, and complement fixation titers were negative and <1:2 respectively. In terms of her pregnancy of unknown location, beta-HCGs were abnormally rising and trended every 48 h (126 mIU/ml, 180 mIU/ml, 395 mIU/ml).
On HD 5, paracentesis drained 800 l of fluid and interventional radiology-guided omental biopsies resulted in fat necrosis and granulomatous inflammation. Both peritoneal fluid and tissue biopsies were negative for neoplastic cells, CEA, acid-fast bacilli, fungal, bacterial, non-tuberculosis mycobacterium DNA and Mycobacterium tuberculosis (MTB) PCR. The only pertinent test was an indeterminate serum quantiferon gold; however, peritoneal fluid adenosine deaminase and negative MTB PCR were not consistent with tuberculosis. With progressively worsening symptoms and lack of diagnosis, the decision was made to proceed with laparoscopy for tissue diagnosis. Given abnormally rising beta-HCGs, pregnancy was likely non-viable, thus she elected for termination.
She underwent a diagnostic laparoscopy, omentectomy, lysis of adhesions and suction curettage on HD 8 with gynecology oncology, given CT results concerning for malignancy. Laparoscopy was converted to mini laparotomy due to significant adhesions and inability to obtain adequate biopsies for tissue diagnosis. Operative findings included extensive studding of peritoneum, infracolic omentum inflammation, bowel adhesions to abdominal wall, normal-appearing uterus and adnexa with 3.5 l of ascites (Fig. 2). Curettage showed decidualized endometrium without chorionic villi or coccidiodes. Beta-HCG down-trended to zero post-operatively consistent with successful surgical abortion.Fig. 2 A. Bowel attached to abdominal wall upon entry. B. Laparoscopic view of uterus, adnexa and ascites. C. “Caked omentum”, pathologic specimen.
Fig. 2
Post-operatively her fevers continued despite antibiotics. Surgical omental biopsy cultures resulted as Coccidioides immitis on postoperative day 11. Her only notable travel history was to Palm Springs, California, and visiting construction sites in the past two years, locations known to harbor coccidioidomycosis. After significant improvement on oral antifungal therapy, she was discharged on HD 15 with fluconazole 400 mg daily. She was followed by the multidisciplinary team as an outpatient. Coccidioides antibody complement fixation (titer 1:4) turned positive one month after her admission date.
3 Discussion
This is a unique case describing disseminated peritoneal coccidioidomycosis in a newly pregnant patient following fertility treatment with insemination. Peritoneal coccidioidomycosis is a challenging diagnosis as there are only 34 published cases [8]. Most patients with isolated peritoneal involvement and negative serology titers are immunosuppressed patients [3,9]. It is therefore possible that our pregnant patient had falsely negative titers due to the immune tolerance of pregnancy.
Most patients with disseminated coccidioidomycosis present gradually with abdominal distension and ascites occurring months to years after infection [2]. In our patient's case, it is possible that the immune-tolerance effects of pregnancy or the hormonal effects of ovarian stimulation may have contributed to her acute presentation. Prior data report pregnant women experience disseminated disease 100 times more frequently [2,6].
Our case highlights a possible association between hormonal changes with fertility treatment, immune tolerance in pregnancy, and risk for peritoneal coccidioidomycosis. Studies show that elevated serum levels of 17-beta-estradiol and progesterone in vitro increase coccidioidomycosis growth, contributing to dissemination [10]. Our patient received clomiphene citrate and was newly pregnant, thereby raising estradiol and progesterone levels. From an immunologic standpoint, pregnancy is a state of decreased cell-mediated immunity, which explains why coccidioidomycosis disseminates more commonly in pregnancy [4,11]. Evidence shows that pregnancy increases the risk of dissemination in proportion to gestational age, with greatest risk in the third trimester, thus our patient's presentation in early gestation was unusual [4,11]. In addition to pregnancy and presumably elevated hormones levels, African ancestry is another risk factor for disseminated disease in our case [11].
The timing and source of initial infection in our patient is unclear. Coccidioidomycosis was likely contracted years prior to presentation through environmental exposure. Even in dissemination, the usual source of initial infection is the pulmonary tract [1]. It is unusual for disseminated disease to involve the female genital tract, thus the insemination procedure or specimen are unlikely to be a cause for initial infection [12]. In concordance, endometrial tissue was negative for coccidioidomycosis. In the only other report of disseminated coccidioidomycosis in a woman who underwent ovarian stimulation with clomiphene citrate and insemination, presentation was several years after fertility treatment [10].
There is limited evidence on how to treat isolated peritoneal coccidioidomycosis. Management is typically fluconazole 400 mg daily for 6–12 months with duration guided by clinical, laboratory, and radiographic response [3]. Unlike other sites of dissemination, mortality is rare with isolated peritoneal coccidioidomycosis [13]. Going forward, our patient may have a small but increased risk of disease reactivation in future pregnancies. There is a lack of literature guiding reproductive patients for timing and risk of future conception [6,14]. According to the Infectious Disease Society of America guidelines, risk of reactivation in pregnancy is low in women who have completed therapy [3]. Once pregnant, the current recommendation is coccidioidal serologic testing every 6–12 weeks [3].
4 Conclusion
We believe this is the only published case of isolated peritoneal coccidioidomycosis in early pregnancy. The diagnosis of peritoneal coccidioidomycosis was particularly challenging given our patient's negative infectious workup and granulomatous tissue on initial omental biopsy. This case demonstrates the importance of a multidisciplinary team. Our patient was originally from Tanzania, which prompted us to consider tuberculosis as the etiology of her disease. Ultimately, local factors like living in California, rather than global factors, were the cause of her disease.
Contributors
Abigail Armstrong contributed to conception/design and drafting of the article.
Mika Watanabe contributed to conception/design and editing of the article.
Debika Bhattacharya was the infectious disease physician on the case and contributed to review and revision of the manuscript.
Mae Zakhour performed the surgery and contributed to review and revision of the manuscript.
Lindsay Kroener was the reproductive endocrinologist on the case and contributed to review and revision of the manuscript.
Conflict of Interest
The authors declare that they have no conflict of interest regarding the publication of this case report.
Funding
No funding from an external source supported the publication of this case report.
Patient Consent
Obtained.
Provenance and Peer Review
This case report was peer reviewed. | Recovered | ReactionOutcome | CC BY | 33665141 | 19,111,009 | 2021-04 |
What was the outcome of reaction 'Nausea'? | Disseminated peritoneal coccidioidomycosis in pregnancy following fertility treatment: A case report and literature review.
Disseminated peritoneal coccidioidomycosis in the setting of early pregnancy after fertility treatment is rare and can present as a diagnostic challenge. A 39-year-old underwent ovarian stimulation with clomiphene citrate followed by HCG trigger and intrauterine insemination. She developed persistent abdominal pain, ascites and episodes of fever in early pregnancy, and eventually underwent a diagnostic laparoscopy for worsening clinical presentation. Operative findings were notable for peritoneal studding, infracolic omentum inflammation, bowel adhesions to the abdominal wall and normal-appearing uterus and adnexa. The pathology results indicated peritoneal Coccidioides immitis infection. Hormonal changes associated with fertility treatment and immune tolerance in pregnancy may increase the risk for disseminated peritoneal coccidioidomycosis. A high index of suspicion and a multidisciplinary team are important for the diagnostic workup and treatment plan of disseminated peritoneal coccidioidomycosis.
1 Introduction
Coccidioidomycosis is a fungal infection that results primarily in pulmonary disease and is endemic to the Southwest United States, Mexico and South America [1]. Extrapulmonary dissemination occurs in 1% of cases, usually in patients with risk factors like male sex, African ancestry, immunosuppression and pregnancy [[2], [3], [4]]. Prior data have shown that disseminated disease occurs in 23% of pregnant patients in the first trimester [5]. Extrapulmonary disease occurs most commonly in soft tissue, skin, joints and brain [6]. In contrast, peritoneum dissemination is rare, occurring through hematogenous spread or swallowing pulmonary secretions [7]. Disseminated cocciodiodes, like tuberculosis, is a great mimicker and can be challenging to diagnose. For example, early infection may present with persistently negative antibodies, especially in patients who are immunosuppressed or immune tolerant, as observed in pregnant women [3]. Additionally, there is a wide sensitivity and specificity of the enzyme immunoassay test, depending on lab assay [3].
To our knowledge, there are no reported cases of disseminated peritoneal coccidioidomycosis in the setting of early pregnancy following fertility treatment. We present the case of a 39-year-old woman with an early pregnancy resulting from ovarian stimulation with clomiphene citrate and intrauterine insemination who developed episodes of fever, ascites and abdominal pain ultimately requiring an exploratory laparotomy leading to a diagnosis of disseminated peritoneal Coccidioides immitis.
2 Case Presentation
A 39-year-old woman presented to an infertility clinic. She was diagnosed with unexplained secondary infertility associated with male factor. Her workup showed normal day 3 laboratory results (FSH 7.0 mIU/mL, estradiol 35 pg/mL), TSH 2.8 mcIU/mL, normal hysterosalpingogram, antral follicle count of 32 and semen analysis with mild oligoteratospermia. The couple had negative infectious disease screening, including hepatitis B and C, HIV, syphilis and HTLV 1–2. She underwent her first clomiphene citrate 50 mg cycle and developed two dominant follicles. Ovulation was triggered using 250 μg of HCG subcutaneously. She underwent an uncomplicated intrauterine insemination with 24 million fresh, motile washed sperm.
She began experiencing intermittent fevers and abdominal pain 8 days after insemination. She was seen by her primary care physician, who noted normal temperature, mild tenderness on exam and negative pregnancy test. She was counseled that her symptoms may be secondary to early pregnancy or mild gastritis. Three days later, she re-presented with a mild leukocytosis, serum beta-hCG 84 mIU/ml and normal electrolytes. Pelvic ultrasound showed moderate free fluid with echogenic debris, two left ovarian corpus lutea and an unremarkable appendix (Fig. 1). Consistent with early gestation, no pregnancy was identified, and suspected diagnosis was ruptured hemorrhagic cyst. However, her symptoms continued to worsen, with increasing ascites and distension, persistent fevers, mild increase in liver enzymes (AST 96 U/L, ALT 93 U/L]) and leukocytosis (15 K/uL), and she was sent to the emergency room at 4 weeks 1 day.Fig. 1 A. Large amount of free fluid in pouch of Douglas. B. Left ovary with corpus lutea.
Fig. 1
She had her first documented fever (38.2 °C), up-trending leukocytosis (17 K/uL), mild increase in liver enzymes (AST 50 U/L, ALT 80 U/L), beta-hCG of 127 mIU/ml, normal electrolytes and negative blood cultures. Abdominal ultrasound showed free fluid throughout the abdomen, thickened endometrial lining and a normal appendix. In addition to abdominal distension, the patient developed diarrhea and nausea. Given early gestation and goal to avoid CT radiation, a non-contrast MRI was performed, which showed significant free fluid, two ovarian cysts, likely corpus lutea, and inability to visualize the appendix. There was low suspicion for ovarian hyperstimulation syndrome given clomiphene citrate use for stimulation, two dominant follicles at trigger, normal electrolytes and absence of enlarged ovaries.
She was admitted for IV antibiotics for suspected bacterial peritonitis. Infectious disease was consulted. Ceftriaxone, flagyl and vancomycin were used for genitourinary coverage given fertility treatments. The patient was originally from Tanzania, which made the team suspicious for tuberculosis despite lack of clinical history and x-ray showing small pleural effusions.
By hospital day (HD) 3, she was clinically worsening, with fevers (39.4 °C), rising leukocytosis (23 K/uL) and abdominal distention. CT of the abdomen with contrast showed moderate ascites, omental nodularity and caking, not previously seen on MRI, concerning for malignancy or non-malignant causes, including tuberculosis. Gynecology oncology was consulted and the tumor markers CA-125, CA19-9, CEA, CA 15-3, CA 27.29, AFP were normal. Coccidioidomycosis IgM, IgG, and complement fixation titers were negative and <1:2 respectively. In terms of her pregnancy of unknown location, beta-HCGs were abnormally rising and trended every 48 h (126 mIU/ml, 180 mIU/ml, 395 mIU/ml).
On HD 5, paracentesis drained 800 l of fluid and interventional radiology-guided omental biopsies resulted in fat necrosis and granulomatous inflammation. Both peritoneal fluid and tissue biopsies were negative for neoplastic cells, CEA, acid-fast bacilli, fungal, bacterial, non-tuberculosis mycobacterium DNA and Mycobacterium tuberculosis (MTB) PCR. The only pertinent test was an indeterminate serum quantiferon gold; however, peritoneal fluid adenosine deaminase and negative MTB PCR were not consistent with tuberculosis. With progressively worsening symptoms and lack of diagnosis, the decision was made to proceed with laparoscopy for tissue diagnosis. Given abnormally rising beta-HCGs, pregnancy was likely non-viable, thus she elected for termination.
She underwent a diagnostic laparoscopy, omentectomy, lysis of adhesions and suction curettage on HD 8 with gynecology oncology, given CT results concerning for malignancy. Laparoscopy was converted to mini laparotomy due to significant adhesions and inability to obtain adequate biopsies for tissue diagnosis. Operative findings included extensive studding of peritoneum, infracolic omentum inflammation, bowel adhesions to abdominal wall, normal-appearing uterus and adnexa with 3.5 l of ascites (Fig. 2). Curettage showed decidualized endometrium without chorionic villi or coccidiodes. Beta-HCG down-trended to zero post-operatively consistent with successful surgical abortion.Fig. 2 A. Bowel attached to abdominal wall upon entry. B. Laparoscopic view of uterus, adnexa and ascites. C. “Caked omentum”, pathologic specimen.
Fig. 2
Post-operatively her fevers continued despite antibiotics. Surgical omental biopsy cultures resulted as Coccidioides immitis on postoperative day 11. Her only notable travel history was to Palm Springs, California, and visiting construction sites in the past two years, locations known to harbor coccidioidomycosis. After significant improvement on oral antifungal therapy, she was discharged on HD 15 with fluconazole 400 mg daily. She was followed by the multidisciplinary team as an outpatient. Coccidioides antibody complement fixation (titer 1:4) turned positive one month after her admission date.
3 Discussion
This is a unique case describing disseminated peritoneal coccidioidomycosis in a newly pregnant patient following fertility treatment with insemination. Peritoneal coccidioidomycosis is a challenging diagnosis as there are only 34 published cases [8]. Most patients with isolated peritoneal involvement and negative serology titers are immunosuppressed patients [3,9]. It is therefore possible that our pregnant patient had falsely negative titers due to the immune tolerance of pregnancy.
Most patients with disseminated coccidioidomycosis present gradually with abdominal distension and ascites occurring months to years after infection [2]. In our patient's case, it is possible that the immune-tolerance effects of pregnancy or the hormonal effects of ovarian stimulation may have contributed to her acute presentation. Prior data report pregnant women experience disseminated disease 100 times more frequently [2,6].
Our case highlights a possible association between hormonal changes with fertility treatment, immune tolerance in pregnancy, and risk for peritoneal coccidioidomycosis. Studies show that elevated serum levels of 17-beta-estradiol and progesterone in vitro increase coccidioidomycosis growth, contributing to dissemination [10]. Our patient received clomiphene citrate and was newly pregnant, thereby raising estradiol and progesterone levels. From an immunologic standpoint, pregnancy is a state of decreased cell-mediated immunity, which explains why coccidioidomycosis disseminates more commonly in pregnancy [4,11]. Evidence shows that pregnancy increases the risk of dissemination in proportion to gestational age, with greatest risk in the third trimester, thus our patient's presentation in early gestation was unusual [4,11]. In addition to pregnancy and presumably elevated hormones levels, African ancestry is another risk factor for disseminated disease in our case [11].
The timing and source of initial infection in our patient is unclear. Coccidioidomycosis was likely contracted years prior to presentation through environmental exposure. Even in dissemination, the usual source of initial infection is the pulmonary tract [1]. It is unusual for disseminated disease to involve the female genital tract, thus the insemination procedure or specimen are unlikely to be a cause for initial infection [12]. In concordance, endometrial tissue was negative for coccidioidomycosis. In the only other report of disseminated coccidioidomycosis in a woman who underwent ovarian stimulation with clomiphene citrate and insemination, presentation was several years after fertility treatment [10].
There is limited evidence on how to treat isolated peritoneal coccidioidomycosis. Management is typically fluconazole 400 mg daily for 6–12 months with duration guided by clinical, laboratory, and radiographic response [3]. Unlike other sites of dissemination, mortality is rare with isolated peritoneal coccidioidomycosis [13]. Going forward, our patient may have a small but increased risk of disease reactivation in future pregnancies. There is a lack of literature guiding reproductive patients for timing and risk of future conception [6,14]. According to the Infectious Disease Society of America guidelines, risk of reactivation in pregnancy is low in women who have completed therapy [3]. Once pregnant, the current recommendation is coccidioidal serologic testing every 6–12 weeks [3].
4 Conclusion
We believe this is the only published case of isolated peritoneal coccidioidomycosis in early pregnancy. The diagnosis of peritoneal coccidioidomycosis was particularly challenging given our patient's negative infectious workup and granulomatous tissue on initial omental biopsy. This case demonstrates the importance of a multidisciplinary team. Our patient was originally from Tanzania, which prompted us to consider tuberculosis as the etiology of her disease. Ultimately, local factors like living in California, rather than global factors, were the cause of her disease.
Contributors
Abigail Armstrong contributed to conception/design and drafting of the article.
Mika Watanabe contributed to conception/design and editing of the article.
Debika Bhattacharya was the infectious disease physician on the case and contributed to review and revision of the manuscript.
Mae Zakhour performed the surgery and contributed to review and revision of the manuscript.
Lindsay Kroener was the reproductive endocrinologist on the case and contributed to review and revision of the manuscript.
Conflict of Interest
The authors declare that they have no conflict of interest regarding the publication of this case report.
Funding
No funding from an external source supported the publication of this case report.
Patient Consent
Obtained.
Provenance and Peer Review
This case report was peer reviewed. | Recovering | ReactionOutcome | CC BY | 33665141 | 19,006,800 | 2021-04 |
What was the outcome of reaction 'Pyrexia'? | Disseminated peritoneal coccidioidomycosis in pregnancy following fertility treatment: A case report and literature review.
Disseminated peritoneal coccidioidomycosis in the setting of early pregnancy after fertility treatment is rare and can present as a diagnostic challenge. A 39-year-old underwent ovarian stimulation with clomiphene citrate followed by HCG trigger and intrauterine insemination. She developed persistent abdominal pain, ascites and episodes of fever in early pregnancy, and eventually underwent a diagnostic laparoscopy for worsening clinical presentation. Operative findings were notable for peritoneal studding, infracolic omentum inflammation, bowel adhesions to the abdominal wall and normal-appearing uterus and adnexa. The pathology results indicated peritoneal Coccidioides immitis infection. Hormonal changes associated with fertility treatment and immune tolerance in pregnancy may increase the risk for disseminated peritoneal coccidioidomycosis. A high index of suspicion and a multidisciplinary team are important for the diagnostic workup and treatment plan of disseminated peritoneal coccidioidomycosis.
1 Introduction
Coccidioidomycosis is a fungal infection that results primarily in pulmonary disease and is endemic to the Southwest United States, Mexico and South America [1]. Extrapulmonary dissemination occurs in 1% of cases, usually in patients with risk factors like male sex, African ancestry, immunosuppression and pregnancy [[2], [3], [4]]. Prior data have shown that disseminated disease occurs in 23% of pregnant patients in the first trimester [5]. Extrapulmonary disease occurs most commonly in soft tissue, skin, joints and brain [6]. In contrast, peritoneum dissemination is rare, occurring through hematogenous spread or swallowing pulmonary secretions [7]. Disseminated cocciodiodes, like tuberculosis, is a great mimicker and can be challenging to diagnose. For example, early infection may present with persistently negative antibodies, especially in patients who are immunosuppressed or immune tolerant, as observed in pregnant women [3]. Additionally, there is a wide sensitivity and specificity of the enzyme immunoassay test, depending on lab assay [3].
To our knowledge, there are no reported cases of disseminated peritoneal coccidioidomycosis in the setting of early pregnancy following fertility treatment. We present the case of a 39-year-old woman with an early pregnancy resulting from ovarian stimulation with clomiphene citrate and intrauterine insemination who developed episodes of fever, ascites and abdominal pain ultimately requiring an exploratory laparotomy leading to a diagnosis of disseminated peritoneal Coccidioides immitis.
2 Case Presentation
A 39-year-old woman presented to an infertility clinic. She was diagnosed with unexplained secondary infertility associated with male factor. Her workup showed normal day 3 laboratory results (FSH 7.0 mIU/mL, estradiol 35 pg/mL), TSH 2.8 mcIU/mL, normal hysterosalpingogram, antral follicle count of 32 and semen analysis with mild oligoteratospermia. The couple had negative infectious disease screening, including hepatitis B and C, HIV, syphilis and HTLV 1–2. She underwent her first clomiphene citrate 50 mg cycle and developed two dominant follicles. Ovulation was triggered using 250 μg of HCG subcutaneously. She underwent an uncomplicated intrauterine insemination with 24 million fresh, motile washed sperm.
She began experiencing intermittent fevers and abdominal pain 8 days after insemination. She was seen by her primary care physician, who noted normal temperature, mild tenderness on exam and negative pregnancy test. She was counseled that her symptoms may be secondary to early pregnancy or mild gastritis. Three days later, she re-presented with a mild leukocytosis, serum beta-hCG 84 mIU/ml and normal electrolytes. Pelvic ultrasound showed moderate free fluid with echogenic debris, two left ovarian corpus lutea and an unremarkable appendix (Fig. 1). Consistent with early gestation, no pregnancy was identified, and suspected diagnosis was ruptured hemorrhagic cyst. However, her symptoms continued to worsen, with increasing ascites and distension, persistent fevers, mild increase in liver enzymes (AST 96 U/L, ALT 93 U/L]) and leukocytosis (15 K/uL), and she was sent to the emergency room at 4 weeks 1 day.Fig. 1 A. Large amount of free fluid in pouch of Douglas. B. Left ovary with corpus lutea.
Fig. 1
She had her first documented fever (38.2 °C), up-trending leukocytosis (17 K/uL), mild increase in liver enzymes (AST 50 U/L, ALT 80 U/L), beta-hCG of 127 mIU/ml, normal electrolytes and negative blood cultures. Abdominal ultrasound showed free fluid throughout the abdomen, thickened endometrial lining and a normal appendix. In addition to abdominal distension, the patient developed diarrhea and nausea. Given early gestation and goal to avoid CT radiation, a non-contrast MRI was performed, which showed significant free fluid, two ovarian cysts, likely corpus lutea, and inability to visualize the appendix. There was low suspicion for ovarian hyperstimulation syndrome given clomiphene citrate use for stimulation, two dominant follicles at trigger, normal electrolytes and absence of enlarged ovaries.
She was admitted for IV antibiotics for suspected bacterial peritonitis. Infectious disease was consulted. Ceftriaxone, flagyl and vancomycin were used for genitourinary coverage given fertility treatments. The patient was originally from Tanzania, which made the team suspicious for tuberculosis despite lack of clinical history and x-ray showing small pleural effusions.
By hospital day (HD) 3, she was clinically worsening, with fevers (39.4 °C), rising leukocytosis (23 K/uL) and abdominal distention. CT of the abdomen with contrast showed moderate ascites, omental nodularity and caking, not previously seen on MRI, concerning for malignancy or non-malignant causes, including tuberculosis. Gynecology oncology was consulted and the tumor markers CA-125, CA19-9, CEA, CA 15-3, CA 27.29, AFP were normal. Coccidioidomycosis IgM, IgG, and complement fixation titers were negative and <1:2 respectively. In terms of her pregnancy of unknown location, beta-HCGs were abnormally rising and trended every 48 h (126 mIU/ml, 180 mIU/ml, 395 mIU/ml).
On HD 5, paracentesis drained 800 l of fluid and interventional radiology-guided omental biopsies resulted in fat necrosis and granulomatous inflammation. Both peritoneal fluid and tissue biopsies were negative for neoplastic cells, CEA, acid-fast bacilli, fungal, bacterial, non-tuberculosis mycobacterium DNA and Mycobacterium tuberculosis (MTB) PCR. The only pertinent test was an indeterminate serum quantiferon gold; however, peritoneal fluid adenosine deaminase and negative MTB PCR were not consistent with tuberculosis. With progressively worsening symptoms and lack of diagnosis, the decision was made to proceed with laparoscopy for tissue diagnosis. Given abnormally rising beta-HCGs, pregnancy was likely non-viable, thus she elected for termination.
She underwent a diagnostic laparoscopy, omentectomy, lysis of adhesions and suction curettage on HD 8 with gynecology oncology, given CT results concerning for malignancy. Laparoscopy was converted to mini laparotomy due to significant adhesions and inability to obtain adequate biopsies for tissue diagnosis. Operative findings included extensive studding of peritoneum, infracolic omentum inflammation, bowel adhesions to abdominal wall, normal-appearing uterus and adnexa with 3.5 l of ascites (Fig. 2). Curettage showed decidualized endometrium without chorionic villi or coccidiodes. Beta-HCG down-trended to zero post-operatively consistent with successful surgical abortion.Fig. 2 A. Bowel attached to abdominal wall upon entry. B. Laparoscopic view of uterus, adnexa and ascites. C. “Caked omentum”, pathologic specimen.
Fig. 2
Post-operatively her fevers continued despite antibiotics. Surgical omental biopsy cultures resulted as Coccidioides immitis on postoperative day 11. Her only notable travel history was to Palm Springs, California, and visiting construction sites in the past two years, locations known to harbor coccidioidomycosis. After significant improvement on oral antifungal therapy, she was discharged on HD 15 with fluconazole 400 mg daily. She was followed by the multidisciplinary team as an outpatient. Coccidioides antibody complement fixation (titer 1:4) turned positive one month after her admission date.
3 Discussion
This is a unique case describing disseminated peritoneal coccidioidomycosis in a newly pregnant patient following fertility treatment with insemination. Peritoneal coccidioidomycosis is a challenging diagnosis as there are only 34 published cases [8]. Most patients with isolated peritoneal involvement and negative serology titers are immunosuppressed patients [3,9]. It is therefore possible that our pregnant patient had falsely negative titers due to the immune tolerance of pregnancy.
Most patients with disseminated coccidioidomycosis present gradually with abdominal distension and ascites occurring months to years after infection [2]. In our patient's case, it is possible that the immune-tolerance effects of pregnancy or the hormonal effects of ovarian stimulation may have contributed to her acute presentation. Prior data report pregnant women experience disseminated disease 100 times more frequently [2,6].
Our case highlights a possible association between hormonal changes with fertility treatment, immune tolerance in pregnancy, and risk for peritoneal coccidioidomycosis. Studies show that elevated serum levels of 17-beta-estradiol and progesterone in vitro increase coccidioidomycosis growth, contributing to dissemination [10]. Our patient received clomiphene citrate and was newly pregnant, thereby raising estradiol and progesterone levels. From an immunologic standpoint, pregnancy is a state of decreased cell-mediated immunity, which explains why coccidioidomycosis disseminates more commonly in pregnancy [4,11]. Evidence shows that pregnancy increases the risk of dissemination in proportion to gestational age, with greatest risk in the third trimester, thus our patient's presentation in early gestation was unusual [4,11]. In addition to pregnancy and presumably elevated hormones levels, African ancestry is another risk factor for disseminated disease in our case [11].
The timing and source of initial infection in our patient is unclear. Coccidioidomycosis was likely contracted years prior to presentation through environmental exposure. Even in dissemination, the usual source of initial infection is the pulmonary tract [1]. It is unusual for disseminated disease to involve the female genital tract, thus the insemination procedure or specimen are unlikely to be a cause for initial infection [12]. In concordance, endometrial tissue was negative for coccidioidomycosis. In the only other report of disseminated coccidioidomycosis in a woman who underwent ovarian stimulation with clomiphene citrate and insemination, presentation was several years after fertility treatment [10].
There is limited evidence on how to treat isolated peritoneal coccidioidomycosis. Management is typically fluconazole 400 mg daily for 6–12 months with duration guided by clinical, laboratory, and radiographic response [3]. Unlike other sites of dissemination, mortality is rare with isolated peritoneal coccidioidomycosis [13]. Going forward, our patient may have a small but increased risk of disease reactivation in future pregnancies. There is a lack of literature guiding reproductive patients for timing and risk of future conception [6,14]. According to the Infectious Disease Society of America guidelines, risk of reactivation in pregnancy is low in women who have completed therapy [3]. Once pregnant, the current recommendation is coccidioidal serologic testing every 6–12 weeks [3].
4 Conclusion
We believe this is the only published case of isolated peritoneal coccidioidomycosis in early pregnancy. The diagnosis of peritoneal coccidioidomycosis was particularly challenging given our patient's negative infectious workup and granulomatous tissue on initial omental biopsy. This case demonstrates the importance of a multidisciplinary team. Our patient was originally from Tanzania, which prompted us to consider tuberculosis as the etiology of her disease. Ultimately, local factors like living in California, rather than global factors, were the cause of her disease.
Contributors
Abigail Armstrong contributed to conception/design and drafting of the article.
Mika Watanabe contributed to conception/design and editing of the article.
Debika Bhattacharya was the infectious disease physician on the case and contributed to review and revision of the manuscript.
Mae Zakhour performed the surgery and contributed to review and revision of the manuscript.
Lindsay Kroener was the reproductive endocrinologist on the case and contributed to review and revision of the manuscript.
Conflict of Interest
The authors declare that they have no conflict of interest regarding the publication of this case report.
Funding
No funding from an external source supported the publication of this case report.
Patient Consent
Obtained.
Provenance and Peer Review
This case report was peer reviewed. | Recovering | ReactionOutcome | CC BY | 33665141 | 19,006,800 | 2021-04 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Anastomotic leak'. | A Retrospective Study of Lung Transplantation in Patients With Lymphangioleiomyomatosis: Challenges and Outcomes.
Background: Lymphangioleiomyomatosis (LAM) is a rare systemic disease that generally leads to a progressive decline in pulmonary function. Experience, especially from the Asian population, including combined drug therapy before and after lung transplantation (LT) in LAM, is still limited. This study aimed to summarize the clinical data from patients with pulmonary LAM who underwent LT at centers in China. Methods: A retrospective review of all patients with LAM undergoing LT at the two largest centers in China between 2010 and 2018 was conducted. Pre- and posttransplant data were assessed and analyzed. Results: Overall, 25 patients with LAM underwent bilateral LT. The mean age was 35.0 ± 8.6 years at diagnosis and 36.8 ± 9.3 years at the time of transplant. Before LT, only six patients could complete pulmonary function test; the reachable mean forced expiratory volume in one second (FEV1) before LT was 15.9 ± 6.9%. Twenty-one patients (84%) had a recurrent pneumothorax, four (16.0%) of which required pleurodesis. Eight patients (32%) were treated with sirolimus pretransplant for 3.9 years (1-9 years). The average intra-surgery bleeding volume was 1,280 ± 730 ml in need of a transfusion of 1,316 ± 874 ml due to moderate-to-severe adhesion and pretransplant pleurodesis. The causes of death of four patients (16%) included primary graft dysfunction, bronchial dehiscence with long-term use of sirolimus, and uncontrollable infections. The median follow-up time from LT was 41.1 ± 25.0 months. Conclusions: LT for LAM patients from the Asian population has been reinforced from the data that we presented. Peri-transplantation use of sirolimus and LAM-related complications should be further defined and under constant surveillance.
Introduction
Lymphangioleiomyomatosis (LAM) is a rare disease characterized by the proliferation of abnormal smooth muscle-like cells (LAM cells), leading to diffuse pulmonary cyst formation, chylous pleural effusions, and the formation of lymphangioleiomyomas (1). LAM occurs sporadically (S-LAM) or as a pulmonary manifestation related to tuberous sclerosis complex (TSC-LAM) carrying mutations in TSC1 or TSC2 genes (2).
It generally affects women of reproductive age and presents a variable course, including indolent lung cysts, progressive dyspnea on exertion, recurrent pneumothorax, and thoracic lymphadenopathy, ultimately leading to respiratory failure, renal angiomyolipoma, and chylous effusions, as extrapulmonary manifestations. However, 30–40% of women with tuberous sclerosis complex developed pulmonary LAM (3). The inhibitors of the mechanistic target of rapamycin (mTOR) sirolimus have demonstrated treatment benefit in LAM (4–6).
When all medical therapies are exhausted, end-stage patients should be considered for lung transplantation (LT) (7), which is a definitive treatment option evidenced by increasing survival benefit and improvement in the quality of life (5, 8–17). The first LT was performed for LAM in 1984 (18). From 1987 to 2002, LAM accounted for only approximately 1% of all causes for LT, according to the data from the United Network for Organ Sharing (19). The survival rate seemed to be comparable with that of patients undergoing LT for other forms of end-stage lung diseases (1, 20). The results from the United States (19), Brazil (21), and France (12) have shown a preference for bilateral lung transplantation (BLT). More patients received BLT compared with single lung transplantation (SLT) between January 1995 and June 2014, according to the registry of the International Society for Heart and Lung Transplantation (ISHLT). However, a report from Japan chose SLT considering donor sharing; more than 80% of lung transplant recipients with LAM underwent SLT during 2000–2016 (22).
Moreover, limited published data are available regarding patients' clinical pretransplant status, types of procedure, posttransplant complications, and LAM-related morbidity in the current era. The primary aim of this study was to summarize the clinical data from patients with pulmonary LAM who underwent LT at centers in China, particularly documenting pretransplant features, posttransplant morbidity, and outcomes.
Methods
Study Cohorts and Data Collection
The institutional ethics committees of Wuxi People's Hospital and China–Japan Friendship Hospital approved the study, including the present retrospective review, verbal consent procedure, and analysis of data. All patient data were anonymous. Written informed consent was obtained from the patients or their next of kin. The study was conducted in accordance with the 2000 Declaration of Helsinki and the Declaration of Istanbul 2008. None of the transplant donors were from a vulnerable population, and all donors or next of kin provided written informed consent that was freely given.
Patients undergoing LT for end-stage pulmonary LAM from 2010 to 2018 were identified and reviewed. LAM diagnosis was based on the 2010 guidelines of the European Respiratory Society (1). All pretransplant diagnoses of pulmonary LAM were confirmed in the explants. All patients with LAM had undergone a systematic assessment. The first was to assess the ABO type, human leukocyte antigen type, and donor-specific human leukocyte antigen antibodies (DSA) of our patients. The second was to assess the function of target organs, involving lung function test, blood gas analysis, 6-min walk test (6MWT), and chest computed tomography (CT). The third concerned the function of other organs, including liver and kidney functions, coagulation function, bone marrow function, and heart function (electrocardiogram, echocardiography, and coronary CT angiography if necessary). The fourth was the exclusion of cancer, including blood cancer marker level, whole-body CT examination, and positron emission tomography-CT if necessary. The fifth related to whether LAM was associated with other organs, involving CT of the head, chest, and whole abdomen and B-ultrasound of the uterus and its accessories. The last concerned the preoperative infection status and the immunity level of patients. Preoperative discussions were conducted with multidisciplinary experts to determine whether the patient would be included in the waiting list for LT, including LT doctors, respiratory physicians, cardiologists, thoracic surgeons, anesthesiologists, emergency doctors, intensive care unit doctors, rehabilitation doctors, nutritionists, and ethics committee members. The surgical indications of patients with LAM at the center referred to the 2006 guidelines of ISHLT (23).
The ABO blood groups of the donors and recipients were identical before the surgery. The preoperative chest X-ray or chest CT examination did not find any pulmonary infection or other pulmonary diseases in the donors, with the oxygenation index reaching above 300 mmHg. Pretransplant demographics of recipients, clinical history, diagnostic methods to confirm LAM diagnosis, medical treatments, surgical characteristics, complications, morbidity, mortality, survival rate after LT, and use of sirolimus after transplantation were reviewed in all patients. The patients were followed up every 3 months during the first year after LT, 6 months after 1–3 years, and once annually after 3 years. The review covered the target organ and other organ functions and the immunity level and infection status of patients.
Statistical Analysis
Descriptive statistics were used to analyze patient characteristics. Normally distributed continuous data were described as mean ± standard deviation. Categorical variables were presented as percentages. Medians and ranges were presented for skewed data. Survival was estimated by Kaplan–Meier analysis. All calculations and comparisons were performed using SPSS version 16 (SPSS Inc., IL, USA) and GraphPad Prism 7 (GraphPad Software Inc., CA, USA). A P-value of <0.05 was considered significant.
Results
Study Population and Establishment of Lymphangioleiomyomatosis Diagnosis
From January 2010 to December 2018, 25 female patients with sporadic LAM underwent sequential BLT at the centers. The main clinical characteristics before LT are described in Table 1. The mean ages at diagnosis and while undergoing LT were 35.0 ± 8.6 years and 36.8 ± 9.3 years, respectively.
Table 1 Clinical characteristics of LAM patients (n = 25) at registration for LT.
Variable Value
Female (n,%) 25 (100)
Age at diagnosis (years) 35.0 ± 8.6
Age at transplantation (years) 36.8 ± 9.3
Pregnancy history (n, %) 19 (76)
Clinical features
Patients with lung involvement alone (n, %) 15 (60)
Patients with extrapulmonary manifestation (n, %) 10 (40)
Renal angiomyolipoma (n, %) 6 (24)
Mediastinal lymphadenopathy (n, %) 2 (8)
Retroperitoneal lymphangioleiomyoma (n, %) 2 (8)
Pelvic lymphangioleiomyoma (n, %) 5 (20)
Pneumothorax (n, %) 21 (84)
Pleurodesis (n, %) 4 (16)
Chylous effusion (n, %) 3 (12)
Chylothorax (n, %) 3 (12)
Ascites (n, %) 1 (4)
Supplemental oxygen therapy (n, %) 25 (100)
Oxygenation index 168.1 ± 52.0
Use of sirolimus (n, %) 8 (32)
Use of sirolimus until lung transplantation (n, %) 8 (32)
Pulmonary function test (n, %) 6 (24)
FEV1 (%predicted) 15.9 ± 6.9
FVC (%predicted) 33.7 ± 19.6
6-min walk test 5 (20)
Distance (m) 85.4 ± 46.0
Minimum SpO2 (%) 81.8 ± 4.3
Clinical and Radiologic Findings Before Transplantation
Twenty-one (84%) recipients had a history of pneumothorax, which was the most common pretransplant symptom, and four patients (16%) had been treated by pleurodesis. Ten patients (40%) presented with extrapulmonary manifestations of LAM (Table 1), involving the kidney, pelvic, mediastinal, and retroperitoneal regions. Three patients (12%) had chylothorax. The most common radiologic features on chest CT were diffuse, cystic lung disease consistent with LAM, further confirmed in the explants of all patients.
All the patients had severe hypoxia and required continuous oxygen before surgery; seven patients (28%) required mechanical ventilation before transplantation, and one patient (4%) received a tracheotomy. Due to the critical status, six (24%) patients completed the pulmonary function test, which showed FEV1 15.9 ± 6.9% of predicted and FVC 33.7 ± 19.6% of predicted. All patients used supplemental oxygen before transplant with a concentration of 29–53% and an oxygenation index of 168.1 ± 52.0. Five (20%) patients completed 6MWT. The mean distance walked was 85.4 ± 46 m, and the minimum SpO2 at the end of the test was 81.8 ± 4.32%. The last pulmonary function test and 6MWT results before LT are summarized in Table 1.
Medical and Surgical Interventions Before Transplantation
Eight (32%) patients received sirolimus before transplantation, for an average time of 3.9 years (range 1–9 years). One patient repeatedly had a bilateral pneumothorax, atelectasis, intractable chylothorax, abdominal chylous fluid, and a uterine muscle lipoma. She received pleural and peritoneal drainage, followed by right middle lobe wedge resection with lung repair. A uterus lymphatic smooth muscle tumor was resected. Then, she received thoracic duct ligation and bilateral pleurodesis treatment. The postoperative histological examination confirmed lung and uterine LAM. Another four patients (16%) received pleurodesis due to recurrent pneumothorax and/or chylothorax. Moreover, 19 patients (76%) had a history of pregnancy, and 6 patients (24%) had a recent history of pregnancy (within 1 year of pregnancy, including abortion or production).
Lung Transplantation and Posttransplantation Outcomes
No significant intraoperative complications were reported, although two patients (8%) required intraoperative extracorporeal membrane oxygenation support. The average volume of intraoperative blood loss was 1,280 ±730 ml, and the mean blood transfusion was 1,316 ± 874 ml. One patient (4%) experienced intraoperative blood loss of up to 4,000 ml due to extensive pleural adhesions in the thoracic cavity regarding pretransplant bilateral pleurodesis.
The complications after the surgery included the disturbance of anastomotic integrity. One patient developed anastomotic stenosis after anastomotic infection in the early stage after LT. The condition of anastomotic stenosis improved after antibiotics and balloon dilatation treatment. However, another patient died due to anastomotic leakage. After the surgery, 45% of the patients developed an infection, and two patients died of tuberculosis infection. One patient died of primary graft dysfunction during the early postoperative period. Bronchiolitis obliterans syndrome was diagnosed in one patient (4%) 48 months after LT. The postoperative details are described in Table 2. Twenty-one (84%) patients received triple-drug maintenance immunosuppressive therapy (tacrolimus, mycophenolate, and prednisone) after transplantation. Four patients (16%) temporarily received tacrolimus and prednisone treatment because of infection in an early stage after the surgery. One patient received sirolimus (maintained serum level 8–10 ng/ml) instead of tacrolimus 3 months after transplantation when anastomosis completely healed, but meanwhile, a retroperitoneal mass was suspected.
Table 2 Intra- and posttransplantation data (n = 25).
Variable Value
Follow-up (months) 41.1 ± 25.0
Immunosuppression
Tacrolimus + mycophenolate + prednisone (n, %) 21 (84)
Tacrolimus + prednisone (n, %) 4 (16)
Complications
Neoplasm or lymphoproliferative disease (n, %) 0 (0)
Chylothorax (n, %) 1 (4)
Recurrence of LAM (n, %) 0 (0)
Pulmonary retransplantation (n, %) 0 (0)
Intraoperative bleeding (n, %) 1 (4)
Anastomotic complications (n, %) 2 (8)
Anastomotic leakage (n, %) 1 (4)
Anastomotic stenosis (n, %) 1 (4)
Bronchiolitis obliterans syndrome (n, %) 1 (4)
Recurrence of LAM (n, %) 0 (0)
Primary graft dysfunction (n, %) 1 (4)
Infection (n, %) 12 (48)
Tuberculosis infection 3 (12)
Aspergillus 3 (12)
Acinetobacter baumannii 4 (16)
Other infection 2 (8)
Cause of death
Primary graft dysfunction (n, %) 1 (4)
Anastomotic leakage (n, %) 1 (4)
Infection (n, %) 2 (8)
The median follow-up of this group of patients was 41.1 ± 25.0 months. The range of follow-up from LT to either death or closing date was 0.5–84 months. Four deaths (16%) occurred during the study. One patient (4%) died of primary graft dysfunction 30 days after the surgery. Two patients died of uncontrollable infections 2 and 13 months after the surgery. Another patient (4%) died of anastomotic leakage 12 days after the surgery. The patient had been on oral sirolimus for 9 years and until transplantation.
No LAM recurrence was observed, no patient developed the malignant proliferative disease after the procedure, and no patient underwent pulmonary re-transplantation. The estimated 1- and 2-year posttransplant survival rates were 88 and 84%, respectively (Figure 1).
Figure 1 Kaplan–Meier survival analysis after lung transplantation in 25 patients with LAM.
Discussion
This study demonstrated a favorable outcome for LT in LAM patients similar to that published in a USA report from actuarial Kaplan–Meier survival for LAM was 85% at 1 year, and 76% at 3 years (19). Despite three (12%) early deaths (<3 months after transplantation), the survival rate of the present cohort was more favorable than that of patients with other indications (24) and Japan's data, as well as the 1-year survival of 78–81% in the report of ISHLT registry (25). The estimated survival rates from a Brazilian cohort have been shown to be 90% after 1 year, 90% after 3 years, and 77% after 5 years, which were greater than those observed in previous studies (15–20). The long-term survival was also promising, attributing to the fact that it often involved younger patients without any extrapulmonary organ dysfunction (11).
A newly adopted lung allocation scoring system based on disease severity in the USA since 2005 (26) has categorized LAM with chronic obstructive pulmonary disease and other obstructive diseases, giving a lower priority to patients with idiopathic pulmonary fibrosis when allocating donor lungs. Thus, a longer waiting time for patients with LAM should be optimized. Recently, BLT has been performed with a higher frequency compared with SLT for LAM (13, 15, 27). BLT could achieve a better long-term outcome (28) due to lower incidence of bronchiolitis obliterans syndrome, reducing the rate of complications such as pneumothorax, chylothorax, and recurrence of LAM following LT, together with better pulmonary function tests. Hence, BLT is recommended if donor lungs are available.
Recurrent pneumothorax and chylothorax requiring surgical or chemical pleurodesis are common in patients with LAM. The average lifetime pneumothorax-related burden for patients with LAM is a high in-patient cost (29). The upmost challenge for LT in patients with LAM would be to minimize the risk of severe hemorrhage in patients who had pretransplant pleurodesis for pneumothorax or chylothorax, which is a serious triggering factor for excessive bleeding by dissection of the adhesions. According to the previous reports, the pretransplant rates of pleurodesis and pleurectomy ranged from 18 to 100% and from 21 to 43%, respectively, whereas the rate of intraoperative complications varied from 25 to 71% (11–17) (Table 3). However, in the present cohort with a pleurodesis rate of 16%, the rate of intraoperative complications was only 4%.
Table 3 Summaries of studies on LT for LAM.
Study No. of LT Age at LT (years) FEV1% FEV1/FVC Pre-LT complications Intra-surgery Main Post-LT complications 30 days of mortality 1-year survival
Boehler et al. (9) 34 40 ± 9 24 ± 12 38 ± 12 Pleural effusion 16%
Pleurodesis 18% Adhesions 54%
Hemorrhage 12% Bronchial stenosis
or dehiscence 18% 15% 69%
Urban et al. (10) 13 - FEV1 0.57 ± 0.15 L - Pleurodesis 58% (in total) - - 8% 69%
Pechet et al. (11) 14 41.8 ± 6.8 20 ± 8 - Pleural effusion 7.1%
Pleurodesis 00% Adhesions 71.4%
Hemorrhage 50% Sepsis 21.4%
Dehiscence 14.3%
Chylothorax 28.6% 0% 100%
KpodonuJ et al. (19) 79 41.1 ± 8.3 - - - - Fungal infection 2.5% 5% 86%
Reynaud-Gauber et al. (12) 45 41 ± 10 Obstructive 26.4 ± 14.1
Combined19.7 ± 7.2 Combined 47.4 ± 12.3 Pleural effusion 13.3%
Pleurodesis 48.8% Adhesions 46.6%
Hemorrhage 46.6% Bronchial stenosis or dehiscence 15.6% - 80%
Benden et al. (13) 61 41.3 ± 9.1 27 ± 14 - Pleural effusion 14%
Pleurodesis 54.1% Adhesions 57.4%
Hemorrhage 33.3% Respiratory tract infection 59% 5% 79%
Machuca et al. (14) 10 43.8 ± 6.7 Mean 32.9 - Pleural effusion 0%
Pleurodesis 100% Hemorrhage (>1,000 ml) 30% Infections 30% 10% 90%
Nakagirin et al. (16) 13 42 ± 4.6 - - Pleural effusion 30.7%
Pleurodesis 53.8% - - - -
Ando et al. (17) 57 39.5 ± 7.3 32.8 ± 17 40.2 ± 15.2 Pleural effusion 21%
Pleurodesis 53.8% - Bronchial stenosis or dehiscence 0% 93.5%
Bruno et al. (21) 11 43 ± 7 28 ± 14 45 ± 16 Pleurodesis 9% - Stenosis 9%
Pulmonary infections 55% 90%
Oishi et al. (22) 29 45.3 ± 8.4 - - Pleural effusion 6.9%
Pleurodesis 31% Adhesions 31%
Hemorrhage
(>2,000 ml) 13.8% Chylothorax 20.7% 0% 83.3%
Khawar et al. (30) 138 45 (38–52) 23 (17.0–33.3) - - - - - 94%
Salman et al. (31) 25 50 ± 9 22 ± 10 - - - Dialysis (32%) 0% 92%
Kurosaki et al. (32) 12 32 ± 7.3 FEV1 0.7 ± 0.4 Pleurodesis (58%) Chylothorax 50%
Acute rejection 42% 0 100%
Previous studies showed that almost all patients with LAM died 10 years after the start of symptoms (33, 34). The guideline for LAM recipients from ISHLT suggested that the New York Heart Association functional class III or IV, severe impairment of lung function, and poor exercise tolerance should be considered for LT (23). When determined to perform LT, severe obstruction, compromised gas exchange impairing quality of life, and progressive respiratory failure are among the most important factors for evaluation (35). How to refine the specific timing of LT is very difficult. The poor prognostic factors included decreased FEV1/FVC, decreased total lung capacity, and cystic lesions. In the published reports of cohorts, the age at onset, diagnosis, diffusing capacity for carbon monoxide (DLCO)% predicted, PaO2, and 6MWT at registration were quite similar. However, FEV1% predicted at registration and during the waiting period have been shown to be worthy of special note. In the present cohort, most of the patients in the present study had end-stage respiratory failure and required oxygen or even high-flow oxygen to extend their life before the surgery. Most of them could not complete the pulmonary function test. As few as six patients could complete the necessary ventilatory function test as required but were unable to undergo the diffusion function test, as well as 6MWT. The pretransplant FEV1% was 15.9 ± 6.9% of predicted and obviously lower than that found in most previous reports, ranging from 19 ± 11% to 32.8 ± 17% (11–17). This signified the difficulties related to patient management at the centers to perform BLT. Although pleural intervention is not seen as a contraindication to transplant, it would become a contributor to both intra-surgery and post-surgery morbidities.
In the present cohort, the waiting time of patients seemed relatively shorter than the Japanese center's interval, partly due to the donation volume and the endurance of the patients (17). The time to choose LT for patients with LAM was also crucial for long-term survival. With the delay in choosing LT, intractable chylothorax or metastatic LAM lesions could be seen. If patients received LT in a later phase, critical status, high cost, and risk of retransplant were implicated. More assessment tools are needed in the future to fully evaluate the timing and benefit of LT in patients with LAM.
Infections are a major complication after LT in LAM. The frequency of respiratory infections ranged from 10 to 59%, with heterogeneous etiology such as cytomegalovirus, Aspergillus sp., and bacterial pathogens (11–16). Two patients died of uncontrollable infections pathologically confirmed as tuberculosis infection. Another surviving patient also had a relapsed tuberculosis infection 6 months after the surgery. This patient recovered well after antituberculosis treatment. Hence, patients with LAM undergoing LT are recommended to receive conventional inhalation isoniazid to prevent tuberculosis infection. Immunosuppression use after LT is also a risk factor.
For patients with LAM, the use of mTOR inhibitors is a topic with special interest. As a conventional immunosuppressant in organ transplantation (36), sirolimus has been proved in vitro and in preclinical models for stabilizing lung function in LAM and treating extrapulmonary manifestations, such as renal angiomyolipoma, by inhibiting T- and B-lymphocyte activation via the IL-2 signaling pathway (3, 37). mTOR inhibitors are appealing to physicians in decreasing the rate of cytomegalovirus infection (38) and effective for post-surgery chylous pleural and peritoneal effusions (3). A significant concern regarding the use of mTOR inhibitors is that these drugs interfere with wound healing corresponding to the suppression of fibroblast proliferation and angiogenesis, which is related to the increased rate of bronchial anastomotic integrity disorder (39). In the present cohort, one patient died of anastomotic leakage 12 days after the surgery. She had received sirolimus for 9 years before the surgery and did not stop treatment before the surgery. No anastomotic leakage was observed in the other seven patients treated with sirolimus medication for 1–6 years. Whether it is necessary to stop the drug before the surgery and when need to be confirmed by further exploration. Some centers suggest initiating mTOR inhibitors only after confirming complete bronchial anastomotic healing, 3 months (12) after LT or even waiting up to 9 months. A high incidence of airway dehiscence occurred when sirolimus was begun immediately after transplantation (40).
Previous studies found the predominance of LAM in women of reproductive age. Pregnancy worsened the disease (41), and menopause caused disease remission (42). Patients enrolled in the present cohort seemed to be younger and mainly sporadic LAM dominant compared with clinical analysis findings from the Chinese mainland (43) and the American National Heart, Lung and Blood Institute (2, 35). Exploring whether the younger age of female patients to undergo LT can improve their life expectations, including pregnancy demanding, can be highly challenging.
This study had certain limitations because of the paucity of available knowledge regarding the pathophysiology and treatment of LAM. Small sample size and its retrospective heterogeneous characteristic were the main factors to be considered as insufficiencies similar to previous reports due to the rarity of LAM and a high requirement of the large-center qualification. The condition of patients was quite serious in the present study, and most patients could not complete the preoperative lung function and 6MWT, resulting in incomplete data. Hence, large-scale clinical research is needed in the future. For the surveillance of the posttransplantation course, convincing evidence of maintenance therapeutic agents and improvements in patients with LAM undergoing transplantation with regard to their posttransplant survival will be the key points to explore in future studies.
Conclusions
The present study reinforced the role of LT for patients with end-stage LAM. Favorable survival and quality of life were demonstrated. Nevertheless, the occurrence of LAM-related and transplant-related complications should be monitored continuously. Pre- and posttransplantation immunosuppressive approaches confer a special interest in further demystifying LAM via coordination of medical therapy providers and transplant surgeons, thus allowing for the optimization of recipients both while waiting and after the surgery.
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
The studies involving human participants were reviewed and approved by The Institutional Ethics Committees of Wuxi People's Hospital The Institutional Ethics Committees of China-Japan Friendship Hospital. The patients/participants provided their written informed consent to participate in this study.
Author Contributions
JZ and JC take full responsibility for the content of this manuscript, including its data and analysis. DL, BY, LB, MZ, HW, JL, BW, and K-FX made substantial contributions to the conception and design of the study. JZ and WC made substantial contributions to the analysis and interpretation of data. JZ drafted the initial 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. The National Key Research and Development Program of China No. 2016YFC0901502. | SIROLIMUS | DrugsGivenReaction | CC BY | 33665195 | 19,030,548 | 2021 |
What was the administration route of drug 'SIROLIMUS'? | A Retrospective Study of Lung Transplantation in Patients With Lymphangioleiomyomatosis: Challenges and Outcomes.
Background: Lymphangioleiomyomatosis (LAM) is a rare systemic disease that generally leads to a progressive decline in pulmonary function. Experience, especially from the Asian population, including combined drug therapy before and after lung transplantation (LT) in LAM, is still limited. This study aimed to summarize the clinical data from patients with pulmonary LAM who underwent LT at centers in China. Methods: A retrospective review of all patients with LAM undergoing LT at the two largest centers in China between 2010 and 2018 was conducted. Pre- and posttransplant data were assessed and analyzed. Results: Overall, 25 patients with LAM underwent bilateral LT. The mean age was 35.0 ± 8.6 years at diagnosis and 36.8 ± 9.3 years at the time of transplant. Before LT, only six patients could complete pulmonary function test; the reachable mean forced expiratory volume in one second (FEV1) before LT was 15.9 ± 6.9%. Twenty-one patients (84%) had a recurrent pneumothorax, four (16.0%) of which required pleurodesis. Eight patients (32%) were treated with sirolimus pretransplant for 3.9 years (1-9 years). The average intra-surgery bleeding volume was 1,280 ± 730 ml in need of a transfusion of 1,316 ± 874 ml due to moderate-to-severe adhesion and pretransplant pleurodesis. The causes of death of four patients (16%) included primary graft dysfunction, bronchial dehiscence with long-term use of sirolimus, and uncontrollable infections. The median follow-up time from LT was 41.1 ± 25.0 months. Conclusions: LT for LAM patients from the Asian population has been reinforced from the data that we presented. Peri-transplantation use of sirolimus and LAM-related complications should be further defined and under constant surveillance.
Introduction
Lymphangioleiomyomatosis (LAM) is a rare disease characterized by the proliferation of abnormal smooth muscle-like cells (LAM cells), leading to diffuse pulmonary cyst formation, chylous pleural effusions, and the formation of lymphangioleiomyomas (1). LAM occurs sporadically (S-LAM) or as a pulmonary manifestation related to tuberous sclerosis complex (TSC-LAM) carrying mutations in TSC1 or TSC2 genes (2).
It generally affects women of reproductive age and presents a variable course, including indolent lung cysts, progressive dyspnea on exertion, recurrent pneumothorax, and thoracic lymphadenopathy, ultimately leading to respiratory failure, renal angiomyolipoma, and chylous effusions, as extrapulmonary manifestations. However, 30–40% of women with tuberous sclerosis complex developed pulmonary LAM (3). The inhibitors of the mechanistic target of rapamycin (mTOR) sirolimus have demonstrated treatment benefit in LAM (4–6).
When all medical therapies are exhausted, end-stage patients should be considered for lung transplantation (LT) (7), which is a definitive treatment option evidenced by increasing survival benefit and improvement in the quality of life (5, 8–17). The first LT was performed for LAM in 1984 (18). From 1987 to 2002, LAM accounted for only approximately 1% of all causes for LT, according to the data from the United Network for Organ Sharing (19). The survival rate seemed to be comparable with that of patients undergoing LT for other forms of end-stage lung diseases (1, 20). The results from the United States (19), Brazil (21), and France (12) have shown a preference for bilateral lung transplantation (BLT). More patients received BLT compared with single lung transplantation (SLT) between January 1995 and June 2014, according to the registry of the International Society for Heart and Lung Transplantation (ISHLT). However, a report from Japan chose SLT considering donor sharing; more than 80% of lung transplant recipients with LAM underwent SLT during 2000–2016 (22).
Moreover, limited published data are available regarding patients' clinical pretransplant status, types of procedure, posttransplant complications, and LAM-related morbidity in the current era. The primary aim of this study was to summarize the clinical data from patients with pulmonary LAM who underwent LT at centers in China, particularly documenting pretransplant features, posttransplant morbidity, and outcomes.
Methods
Study Cohorts and Data Collection
The institutional ethics committees of Wuxi People's Hospital and China–Japan Friendship Hospital approved the study, including the present retrospective review, verbal consent procedure, and analysis of data. All patient data were anonymous. Written informed consent was obtained from the patients or their next of kin. The study was conducted in accordance with the 2000 Declaration of Helsinki and the Declaration of Istanbul 2008. None of the transplant donors were from a vulnerable population, and all donors or next of kin provided written informed consent that was freely given.
Patients undergoing LT for end-stage pulmonary LAM from 2010 to 2018 were identified and reviewed. LAM diagnosis was based on the 2010 guidelines of the European Respiratory Society (1). All pretransplant diagnoses of pulmonary LAM were confirmed in the explants. All patients with LAM had undergone a systematic assessment. The first was to assess the ABO type, human leukocyte antigen type, and donor-specific human leukocyte antigen antibodies (DSA) of our patients. The second was to assess the function of target organs, involving lung function test, blood gas analysis, 6-min walk test (6MWT), and chest computed tomography (CT). The third concerned the function of other organs, including liver and kidney functions, coagulation function, bone marrow function, and heart function (electrocardiogram, echocardiography, and coronary CT angiography if necessary). The fourth was the exclusion of cancer, including blood cancer marker level, whole-body CT examination, and positron emission tomography-CT if necessary. The fifth related to whether LAM was associated with other organs, involving CT of the head, chest, and whole abdomen and B-ultrasound of the uterus and its accessories. The last concerned the preoperative infection status and the immunity level of patients. Preoperative discussions were conducted with multidisciplinary experts to determine whether the patient would be included in the waiting list for LT, including LT doctors, respiratory physicians, cardiologists, thoracic surgeons, anesthesiologists, emergency doctors, intensive care unit doctors, rehabilitation doctors, nutritionists, and ethics committee members. The surgical indications of patients with LAM at the center referred to the 2006 guidelines of ISHLT (23).
The ABO blood groups of the donors and recipients were identical before the surgery. The preoperative chest X-ray or chest CT examination did not find any pulmonary infection or other pulmonary diseases in the donors, with the oxygenation index reaching above 300 mmHg. Pretransplant demographics of recipients, clinical history, diagnostic methods to confirm LAM diagnosis, medical treatments, surgical characteristics, complications, morbidity, mortality, survival rate after LT, and use of sirolimus after transplantation were reviewed in all patients. The patients were followed up every 3 months during the first year after LT, 6 months after 1–3 years, and once annually after 3 years. The review covered the target organ and other organ functions and the immunity level and infection status of patients.
Statistical Analysis
Descriptive statistics were used to analyze patient characteristics. Normally distributed continuous data were described as mean ± standard deviation. Categorical variables were presented as percentages. Medians and ranges were presented for skewed data. Survival was estimated by Kaplan–Meier analysis. All calculations and comparisons were performed using SPSS version 16 (SPSS Inc., IL, USA) and GraphPad Prism 7 (GraphPad Software Inc., CA, USA). A P-value of <0.05 was considered significant.
Results
Study Population and Establishment of Lymphangioleiomyomatosis Diagnosis
From January 2010 to December 2018, 25 female patients with sporadic LAM underwent sequential BLT at the centers. The main clinical characteristics before LT are described in Table 1. The mean ages at diagnosis and while undergoing LT were 35.0 ± 8.6 years and 36.8 ± 9.3 years, respectively.
Table 1 Clinical characteristics of LAM patients (n = 25) at registration for LT.
Variable Value
Female (n,%) 25 (100)
Age at diagnosis (years) 35.0 ± 8.6
Age at transplantation (years) 36.8 ± 9.3
Pregnancy history (n, %) 19 (76)
Clinical features
Patients with lung involvement alone (n, %) 15 (60)
Patients with extrapulmonary manifestation (n, %) 10 (40)
Renal angiomyolipoma (n, %) 6 (24)
Mediastinal lymphadenopathy (n, %) 2 (8)
Retroperitoneal lymphangioleiomyoma (n, %) 2 (8)
Pelvic lymphangioleiomyoma (n, %) 5 (20)
Pneumothorax (n, %) 21 (84)
Pleurodesis (n, %) 4 (16)
Chylous effusion (n, %) 3 (12)
Chylothorax (n, %) 3 (12)
Ascites (n, %) 1 (4)
Supplemental oxygen therapy (n, %) 25 (100)
Oxygenation index 168.1 ± 52.0
Use of sirolimus (n, %) 8 (32)
Use of sirolimus until lung transplantation (n, %) 8 (32)
Pulmonary function test (n, %) 6 (24)
FEV1 (%predicted) 15.9 ± 6.9
FVC (%predicted) 33.7 ± 19.6
6-min walk test 5 (20)
Distance (m) 85.4 ± 46.0
Minimum SpO2 (%) 81.8 ± 4.3
Clinical and Radiologic Findings Before Transplantation
Twenty-one (84%) recipients had a history of pneumothorax, which was the most common pretransplant symptom, and four patients (16%) had been treated by pleurodesis. Ten patients (40%) presented with extrapulmonary manifestations of LAM (Table 1), involving the kidney, pelvic, mediastinal, and retroperitoneal regions. Three patients (12%) had chylothorax. The most common radiologic features on chest CT were diffuse, cystic lung disease consistent with LAM, further confirmed in the explants of all patients.
All the patients had severe hypoxia and required continuous oxygen before surgery; seven patients (28%) required mechanical ventilation before transplantation, and one patient (4%) received a tracheotomy. Due to the critical status, six (24%) patients completed the pulmonary function test, which showed FEV1 15.9 ± 6.9% of predicted and FVC 33.7 ± 19.6% of predicted. All patients used supplemental oxygen before transplant with a concentration of 29–53% and an oxygenation index of 168.1 ± 52.0. Five (20%) patients completed 6MWT. The mean distance walked was 85.4 ± 46 m, and the minimum SpO2 at the end of the test was 81.8 ± 4.32%. The last pulmonary function test and 6MWT results before LT are summarized in Table 1.
Medical and Surgical Interventions Before Transplantation
Eight (32%) patients received sirolimus before transplantation, for an average time of 3.9 years (range 1–9 years). One patient repeatedly had a bilateral pneumothorax, atelectasis, intractable chylothorax, abdominal chylous fluid, and a uterine muscle lipoma. She received pleural and peritoneal drainage, followed by right middle lobe wedge resection with lung repair. A uterus lymphatic smooth muscle tumor was resected. Then, she received thoracic duct ligation and bilateral pleurodesis treatment. The postoperative histological examination confirmed lung and uterine LAM. Another four patients (16%) received pleurodesis due to recurrent pneumothorax and/or chylothorax. Moreover, 19 patients (76%) had a history of pregnancy, and 6 patients (24%) had a recent history of pregnancy (within 1 year of pregnancy, including abortion or production).
Lung Transplantation and Posttransplantation Outcomes
No significant intraoperative complications were reported, although two patients (8%) required intraoperative extracorporeal membrane oxygenation support. The average volume of intraoperative blood loss was 1,280 ±730 ml, and the mean blood transfusion was 1,316 ± 874 ml. One patient (4%) experienced intraoperative blood loss of up to 4,000 ml due to extensive pleural adhesions in the thoracic cavity regarding pretransplant bilateral pleurodesis.
The complications after the surgery included the disturbance of anastomotic integrity. One patient developed anastomotic stenosis after anastomotic infection in the early stage after LT. The condition of anastomotic stenosis improved after antibiotics and balloon dilatation treatment. However, another patient died due to anastomotic leakage. After the surgery, 45% of the patients developed an infection, and two patients died of tuberculosis infection. One patient died of primary graft dysfunction during the early postoperative period. Bronchiolitis obliterans syndrome was diagnosed in one patient (4%) 48 months after LT. The postoperative details are described in Table 2. Twenty-one (84%) patients received triple-drug maintenance immunosuppressive therapy (tacrolimus, mycophenolate, and prednisone) after transplantation. Four patients (16%) temporarily received tacrolimus and prednisone treatment because of infection in an early stage after the surgery. One patient received sirolimus (maintained serum level 8–10 ng/ml) instead of tacrolimus 3 months after transplantation when anastomosis completely healed, but meanwhile, a retroperitoneal mass was suspected.
Table 2 Intra- and posttransplantation data (n = 25).
Variable Value
Follow-up (months) 41.1 ± 25.0
Immunosuppression
Tacrolimus + mycophenolate + prednisone (n, %) 21 (84)
Tacrolimus + prednisone (n, %) 4 (16)
Complications
Neoplasm or lymphoproliferative disease (n, %) 0 (0)
Chylothorax (n, %) 1 (4)
Recurrence of LAM (n, %) 0 (0)
Pulmonary retransplantation (n, %) 0 (0)
Intraoperative bleeding (n, %) 1 (4)
Anastomotic complications (n, %) 2 (8)
Anastomotic leakage (n, %) 1 (4)
Anastomotic stenosis (n, %) 1 (4)
Bronchiolitis obliterans syndrome (n, %) 1 (4)
Recurrence of LAM (n, %) 0 (0)
Primary graft dysfunction (n, %) 1 (4)
Infection (n, %) 12 (48)
Tuberculosis infection 3 (12)
Aspergillus 3 (12)
Acinetobacter baumannii 4 (16)
Other infection 2 (8)
Cause of death
Primary graft dysfunction (n, %) 1 (4)
Anastomotic leakage (n, %) 1 (4)
Infection (n, %) 2 (8)
The median follow-up of this group of patients was 41.1 ± 25.0 months. The range of follow-up from LT to either death or closing date was 0.5–84 months. Four deaths (16%) occurred during the study. One patient (4%) died of primary graft dysfunction 30 days after the surgery. Two patients died of uncontrollable infections 2 and 13 months after the surgery. Another patient (4%) died of anastomotic leakage 12 days after the surgery. The patient had been on oral sirolimus for 9 years and until transplantation.
No LAM recurrence was observed, no patient developed the malignant proliferative disease after the procedure, and no patient underwent pulmonary re-transplantation. The estimated 1- and 2-year posttransplant survival rates were 88 and 84%, respectively (Figure 1).
Figure 1 Kaplan–Meier survival analysis after lung transplantation in 25 patients with LAM.
Discussion
This study demonstrated a favorable outcome for LT in LAM patients similar to that published in a USA report from actuarial Kaplan–Meier survival for LAM was 85% at 1 year, and 76% at 3 years (19). Despite three (12%) early deaths (<3 months after transplantation), the survival rate of the present cohort was more favorable than that of patients with other indications (24) and Japan's data, as well as the 1-year survival of 78–81% in the report of ISHLT registry (25). The estimated survival rates from a Brazilian cohort have been shown to be 90% after 1 year, 90% after 3 years, and 77% after 5 years, which were greater than those observed in previous studies (15–20). The long-term survival was also promising, attributing to the fact that it often involved younger patients without any extrapulmonary organ dysfunction (11).
A newly adopted lung allocation scoring system based on disease severity in the USA since 2005 (26) has categorized LAM with chronic obstructive pulmonary disease and other obstructive diseases, giving a lower priority to patients with idiopathic pulmonary fibrosis when allocating donor lungs. Thus, a longer waiting time for patients with LAM should be optimized. Recently, BLT has been performed with a higher frequency compared with SLT for LAM (13, 15, 27). BLT could achieve a better long-term outcome (28) due to lower incidence of bronchiolitis obliterans syndrome, reducing the rate of complications such as pneumothorax, chylothorax, and recurrence of LAM following LT, together with better pulmonary function tests. Hence, BLT is recommended if donor lungs are available.
Recurrent pneumothorax and chylothorax requiring surgical or chemical pleurodesis are common in patients with LAM. The average lifetime pneumothorax-related burden for patients with LAM is a high in-patient cost (29). The upmost challenge for LT in patients with LAM would be to minimize the risk of severe hemorrhage in patients who had pretransplant pleurodesis for pneumothorax or chylothorax, which is a serious triggering factor for excessive bleeding by dissection of the adhesions. According to the previous reports, the pretransplant rates of pleurodesis and pleurectomy ranged from 18 to 100% and from 21 to 43%, respectively, whereas the rate of intraoperative complications varied from 25 to 71% (11–17) (Table 3). However, in the present cohort with a pleurodesis rate of 16%, the rate of intraoperative complications was only 4%.
Table 3 Summaries of studies on LT for LAM.
Study No. of LT Age at LT (years) FEV1% FEV1/FVC Pre-LT complications Intra-surgery Main Post-LT complications 30 days of mortality 1-year survival
Boehler et al. (9) 34 40 ± 9 24 ± 12 38 ± 12 Pleural effusion 16%
Pleurodesis 18% Adhesions 54%
Hemorrhage 12% Bronchial stenosis
or dehiscence 18% 15% 69%
Urban et al. (10) 13 - FEV1 0.57 ± 0.15 L - Pleurodesis 58% (in total) - - 8% 69%
Pechet et al. (11) 14 41.8 ± 6.8 20 ± 8 - Pleural effusion 7.1%
Pleurodesis 00% Adhesions 71.4%
Hemorrhage 50% Sepsis 21.4%
Dehiscence 14.3%
Chylothorax 28.6% 0% 100%
KpodonuJ et al. (19) 79 41.1 ± 8.3 - - - - Fungal infection 2.5% 5% 86%
Reynaud-Gauber et al. (12) 45 41 ± 10 Obstructive 26.4 ± 14.1
Combined19.7 ± 7.2 Combined 47.4 ± 12.3 Pleural effusion 13.3%
Pleurodesis 48.8% Adhesions 46.6%
Hemorrhage 46.6% Bronchial stenosis or dehiscence 15.6% - 80%
Benden et al. (13) 61 41.3 ± 9.1 27 ± 14 - Pleural effusion 14%
Pleurodesis 54.1% Adhesions 57.4%
Hemorrhage 33.3% Respiratory tract infection 59% 5% 79%
Machuca et al. (14) 10 43.8 ± 6.7 Mean 32.9 - Pleural effusion 0%
Pleurodesis 100% Hemorrhage (>1,000 ml) 30% Infections 30% 10% 90%
Nakagirin et al. (16) 13 42 ± 4.6 - - Pleural effusion 30.7%
Pleurodesis 53.8% - - - -
Ando et al. (17) 57 39.5 ± 7.3 32.8 ± 17 40.2 ± 15.2 Pleural effusion 21%
Pleurodesis 53.8% - Bronchial stenosis or dehiscence 0% 93.5%
Bruno et al. (21) 11 43 ± 7 28 ± 14 45 ± 16 Pleurodesis 9% - Stenosis 9%
Pulmonary infections 55% 90%
Oishi et al. (22) 29 45.3 ± 8.4 - - Pleural effusion 6.9%
Pleurodesis 31% Adhesions 31%
Hemorrhage
(>2,000 ml) 13.8% Chylothorax 20.7% 0% 83.3%
Khawar et al. (30) 138 45 (38–52) 23 (17.0–33.3) - - - - - 94%
Salman et al. (31) 25 50 ± 9 22 ± 10 - - - Dialysis (32%) 0% 92%
Kurosaki et al. (32) 12 32 ± 7.3 FEV1 0.7 ± 0.4 Pleurodesis (58%) Chylothorax 50%
Acute rejection 42% 0 100%
Previous studies showed that almost all patients with LAM died 10 years after the start of symptoms (33, 34). The guideline for LAM recipients from ISHLT suggested that the New York Heart Association functional class III or IV, severe impairment of lung function, and poor exercise tolerance should be considered for LT (23). When determined to perform LT, severe obstruction, compromised gas exchange impairing quality of life, and progressive respiratory failure are among the most important factors for evaluation (35). How to refine the specific timing of LT is very difficult. The poor prognostic factors included decreased FEV1/FVC, decreased total lung capacity, and cystic lesions. In the published reports of cohorts, the age at onset, diagnosis, diffusing capacity for carbon monoxide (DLCO)% predicted, PaO2, and 6MWT at registration were quite similar. However, FEV1% predicted at registration and during the waiting period have been shown to be worthy of special note. In the present cohort, most of the patients in the present study had end-stage respiratory failure and required oxygen or even high-flow oxygen to extend their life before the surgery. Most of them could not complete the pulmonary function test. As few as six patients could complete the necessary ventilatory function test as required but were unable to undergo the diffusion function test, as well as 6MWT. The pretransplant FEV1% was 15.9 ± 6.9% of predicted and obviously lower than that found in most previous reports, ranging from 19 ± 11% to 32.8 ± 17% (11–17). This signified the difficulties related to patient management at the centers to perform BLT. Although pleural intervention is not seen as a contraindication to transplant, it would become a contributor to both intra-surgery and post-surgery morbidities.
In the present cohort, the waiting time of patients seemed relatively shorter than the Japanese center's interval, partly due to the donation volume and the endurance of the patients (17). The time to choose LT for patients with LAM was also crucial for long-term survival. With the delay in choosing LT, intractable chylothorax or metastatic LAM lesions could be seen. If patients received LT in a later phase, critical status, high cost, and risk of retransplant were implicated. More assessment tools are needed in the future to fully evaluate the timing and benefit of LT in patients with LAM.
Infections are a major complication after LT in LAM. The frequency of respiratory infections ranged from 10 to 59%, with heterogeneous etiology such as cytomegalovirus, Aspergillus sp., and bacterial pathogens (11–16). Two patients died of uncontrollable infections pathologically confirmed as tuberculosis infection. Another surviving patient also had a relapsed tuberculosis infection 6 months after the surgery. This patient recovered well after antituberculosis treatment. Hence, patients with LAM undergoing LT are recommended to receive conventional inhalation isoniazid to prevent tuberculosis infection. Immunosuppression use after LT is also a risk factor.
For patients with LAM, the use of mTOR inhibitors is a topic with special interest. As a conventional immunosuppressant in organ transplantation (36), sirolimus has been proved in vitro and in preclinical models for stabilizing lung function in LAM and treating extrapulmonary manifestations, such as renal angiomyolipoma, by inhibiting T- and B-lymphocyte activation via the IL-2 signaling pathway (3, 37). mTOR inhibitors are appealing to physicians in decreasing the rate of cytomegalovirus infection (38) and effective for post-surgery chylous pleural and peritoneal effusions (3). A significant concern regarding the use of mTOR inhibitors is that these drugs interfere with wound healing corresponding to the suppression of fibroblast proliferation and angiogenesis, which is related to the increased rate of bronchial anastomotic integrity disorder (39). In the present cohort, one patient died of anastomotic leakage 12 days after the surgery. She had received sirolimus for 9 years before the surgery and did not stop treatment before the surgery. No anastomotic leakage was observed in the other seven patients treated with sirolimus medication for 1–6 years. Whether it is necessary to stop the drug before the surgery and when need to be confirmed by further exploration. Some centers suggest initiating mTOR inhibitors only after confirming complete bronchial anastomotic healing, 3 months (12) after LT or even waiting up to 9 months. A high incidence of airway dehiscence occurred when sirolimus was begun immediately after transplantation (40).
Previous studies found the predominance of LAM in women of reproductive age. Pregnancy worsened the disease (41), and menopause caused disease remission (42). Patients enrolled in the present cohort seemed to be younger and mainly sporadic LAM dominant compared with clinical analysis findings from the Chinese mainland (43) and the American National Heart, Lung and Blood Institute (2, 35). Exploring whether the younger age of female patients to undergo LT can improve their life expectations, including pregnancy demanding, can be highly challenging.
This study had certain limitations because of the paucity of available knowledge regarding the pathophysiology and treatment of LAM. Small sample size and its retrospective heterogeneous characteristic were the main factors to be considered as insufficiencies similar to previous reports due to the rarity of LAM and a high requirement of the large-center qualification. The condition of patients was quite serious in the present study, and most patients could not complete the preoperative lung function and 6MWT, resulting in incomplete data. Hence, large-scale clinical research is needed in the future. For the surveillance of the posttransplantation course, convincing evidence of maintenance therapeutic agents and improvements in patients with LAM undergoing transplantation with regard to their posttransplant survival will be the key points to explore in future studies.
Conclusions
The present study reinforced the role of LT for patients with end-stage LAM. Favorable survival and quality of life were demonstrated. Nevertheless, the occurrence of LAM-related and transplant-related complications should be monitored continuously. Pre- and posttransplantation immunosuppressive approaches confer a special interest in further demystifying LAM via coordination of medical therapy providers and transplant surgeons, thus allowing for the optimization of recipients both while waiting and after the surgery.
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
The studies involving human participants were reviewed and approved by The Institutional Ethics Committees of Wuxi People's Hospital The Institutional Ethics Committees of China-Japan Friendship Hospital. The patients/participants provided their written informed consent to participate in this study.
Author Contributions
JZ and JC take full responsibility for the content of this manuscript, including its data and analysis. DL, BY, LB, MZ, HW, JL, BW, and K-FX made substantial contributions to the conception and design of the study. JZ and WC made substantial contributions to the analysis and interpretation of data. JZ drafted the initial 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. The National Key Research and Development Program of China No. 2016YFC0901502. | Oral | DrugAdministrationRoute | CC BY | 33665195 | 19,030,548 | 2021 |
What was the outcome of reaction 'Anastomotic leak'? | A Retrospective Study of Lung Transplantation in Patients With Lymphangioleiomyomatosis: Challenges and Outcomes.
Background: Lymphangioleiomyomatosis (LAM) is a rare systemic disease that generally leads to a progressive decline in pulmonary function. Experience, especially from the Asian population, including combined drug therapy before and after lung transplantation (LT) in LAM, is still limited. This study aimed to summarize the clinical data from patients with pulmonary LAM who underwent LT at centers in China. Methods: A retrospective review of all patients with LAM undergoing LT at the two largest centers in China between 2010 and 2018 was conducted. Pre- and posttransplant data were assessed and analyzed. Results: Overall, 25 patients with LAM underwent bilateral LT. The mean age was 35.0 ± 8.6 years at diagnosis and 36.8 ± 9.3 years at the time of transplant. Before LT, only six patients could complete pulmonary function test; the reachable mean forced expiratory volume in one second (FEV1) before LT was 15.9 ± 6.9%. Twenty-one patients (84%) had a recurrent pneumothorax, four (16.0%) of which required pleurodesis. Eight patients (32%) were treated with sirolimus pretransplant for 3.9 years (1-9 years). The average intra-surgery bleeding volume was 1,280 ± 730 ml in need of a transfusion of 1,316 ± 874 ml due to moderate-to-severe adhesion and pretransplant pleurodesis. The causes of death of four patients (16%) included primary graft dysfunction, bronchial dehiscence with long-term use of sirolimus, and uncontrollable infections. The median follow-up time from LT was 41.1 ± 25.0 months. Conclusions: LT for LAM patients from the Asian population has been reinforced from the data that we presented. Peri-transplantation use of sirolimus and LAM-related complications should be further defined and under constant surveillance.
Introduction
Lymphangioleiomyomatosis (LAM) is a rare disease characterized by the proliferation of abnormal smooth muscle-like cells (LAM cells), leading to diffuse pulmonary cyst formation, chylous pleural effusions, and the formation of lymphangioleiomyomas (1). LAM occurs sporadically (S-LAM) or as a pulmonary manifestation related to tuberous sclerosis complex (TSC-LAM) carrying mutations in TSC1 or TSC2 genes (2).
It generally affects women of reproductive age and presents a variable course, including indolent lung cysts, progressive dyspnea on exertion, recurrent pneumothorax, and thoracic lymphadenopathy, ultimately leading to respiratory failure, renal angiomyolipoma, and chylous effusions, as extrapulmonary manifestations. However, 30–40% of women with tuberous sclerosis complex developed pulmonary LAM (3). The inhibitors of the mechanistic target of rapamycin (mTOR) sirolimus have demonstrated treatment benefit in LAM (4–6).
When all medical therapies are exhausted, end-stage patients should be considered for lung transplantation (LT) (7), which is a definitive treatment option evidenced by increasing survival benefit and improvement in the quality of life (5, 8–17). The first LT was performed for LAM in 1984 (18). From 1987 to 2002, LAM accounted for only approximately 1% of all causes for LT, according to the data from the United Network for Organ Sharing (19). The survival rate seemed to be comparable with that of patients undergoing LT for other forms of end-stage lung diseases (1, 20). The results from the United States (19), Brazil (21), and France (12) have shown a preference for bilateral lung transplantation (BLT). More patients received BLT compared with single lung transplantation (SLT) between January 1995 and June 2014, according to the registry of the International Society for Heart and Lung Transplantation (ISHLT). However, a report from Japan chose SLT considering donor sharing; more than 80% of lung transplant recipients with LAM underwent SLT during 2000–2016 (22).
Moreover, limited published data are available regarding patients' clinical pretransplant status, types of procedure, posttransplant complications, and LAM-related morbidity in the current era. The primary aim of this study was to summarize the clinical data from patients with pulmonary LAM who underwent LT at centers in China, particularly documenting pretransplant features, posttransplant morbidity, and outcomes.
Methods
Study Cohorts and Data Collection
The institutional ethics committees of Wuxi People's Hospital and China–Japan Friendship Hospital approved the study, including the present retrospective review, verbal consent procedure, and analysis of data. All patient data were anonymous. Written informed consent was obtained from the patients or their next of kin. The study was conducted in accordance with the 2000 Declaration of Helsinki and the Declaration of Istanbul 2008. None of the transplant donors were from a vulnerable population, and all donors or next of kin provided written informed consent that was freely given.
Patients undergoing LT for end-stage pulmonary LAM from 2010 to 2018 were identified and reviewed. LAM diagnosis was based on the 2010 guidelines of the European Respiratory Society (1). All pretransplant diagnoses of pulmonary LAM were confirmed in the explants. All patients with LAM had undergone a systematic assessment. The first was to assess the ABO type, human leukocyte antigen type, and donor-specific human leukocyte antigen antibodies (DSA) of our patients. The second was to assess the function of target organs, involving lung function test, blood gas analysis, 6-min walk test (6MWT), and chest computed tomography (CT). The third concerned the function of other organs, including liver and kidney functions, coagulation function, bone marrow function, and heart function (electrocardiogram, echocardiography, and coronary CT angiography if necessary). The fourth was the exclusion of cancer, including blood cancer marker level, whole-body CT examination, and positron emission tomography-CT if necessary. The fifth related to whether LAM was associated with other organs, involving CT of the head, chest, and whole abdomen and B-ultrasound of the uterus and its accessories. The last concerned the preoperative infection status and the immunity level of patients. Preoperative discussions were conducted with multidisciplinary experts to determine whether the patient would be included in the waiting list for LT, including LT doctors, respiratory physicians, cardiologists, thoracic surgeons, anesthesiologists, emergency doctors, intensive care unit doctors, rehabilitation doctors, nutritionists, and ethics committee members. The surgical indications of patients with LAM at the center referred to the 2006 guidelines of ISHLT (23).
The ABO blood groups of the donors and recipients were identical before the surgery. The preoperative chest X-ray or chest CT examination did not find any pulmonary infection or other pulmonary diseases in the donors, with the oxygenation index reaching above 300 mmHg. Pretransplant demographics of recipients, clinical history, diagnostic methods to confirm LAM diagnosis, medical treatments, surgical characteristics, complications, morbidity, mortality, survival rate after LT, and use of sirolimus after transplantation were reviewed in all patients. The patients were followed up every 3 months during the first year after LT, 6 months after 1–3 years, and once annually after 3 years. The review covered the target organ and other organ functions and the immunity level and infection status of patients.
Statistical Analysis
Descriptive statistics were used to analyze patient characteristics. Normally distributed continuous data were described as mean ± standard deviation. Categorical variables were presented as percentages. Medians and ranges were presented for skewed data. Survival was estimated by Kaplan–Meier analysis. All calculations and comparisons were performed using SPSS version 16 (SPSS Inc., IL, USA) and GraphPad Prism 7 (GraphPad Software Inc., CA, USA). A P-value of <0.05 was considered significant.
Results
Study Population and Establishment of Lymphangioleiomyomatosis Diagnosis
From January 2010 to December 2018, 25 female patients with sporadic LAM underwent sequential BLT at the centers. The main clinical characteristics before LT are described in Table 1. The mean ages at diagnosis and while undergoing LT were 35.0 ± 8.6 years and 36.8 ± 9.3 years, respectively.
Table 1 Clinical characteristics of LAM patients (n = 25) at registration for LT.
Variable Value
Female (n,%) 25 (100)
Age at diagnosis (years) 35.0 ± 8.6
Age at transplantation (years) 36.8 ± 9.3
Pregnancy history (n, %) 19 (76)
Clinical features
Patients with lung involvement alone (n, %) 15 (60)
Patients with extrapulmonary manifestation (n, %) 10 (40)
Renal angiomyolipoma (n, %) 6 (24)
Mediastinal lymphadenopathy (n, %) 2 (8)
Retroperitoneal lymphangioleiomyoma (n, %) 2 (8)
Pelvic lymphangioleiomyoma (n, %) 5 (20)
Pneumothorax (n, %) 21 (84)
Pleurodesis (n, %) 4 (16)
Chylous effusion (n, %) 3 (12)
Chylothorax (n, %) 3 (12)
Ascites (n, %) 1 (4)
Supplemental oxygen therapy (n, %) 25 (100)
Oxygenation index 168.1 ± 52.0
Use of sirolimus (n, %) 8 (32)
Use of sirolimus until lung transplantation (n, %) 8 (32)
Pulmonary function test (n, %) 6 (24)
FEV1 (%predicted) 15.9 ± 6.9
FVC (%predicted) 33.7 ± 19.6
6-min walk test 5 (20)
Distance (m) 85.4 ± 46.0
Minimum SpO2 (%) 81.8 ± 4.3
Clinical and Radiologic Findings Before Transplantation
Twenty-one (84%) recipients had a history of pneumothorax, which was the most common pretransplant symptom, and four patients (16%) had been treated by pleurodesis. Ten patients (40%) presented with extrapulmonary manifestations of LAM (Table 1), involving the kidney, pelvic, mediastinal, and retroperitoneal regions. Three patients (12%) had chylothorax. The most common radiologic features on chest CT were diffuse, cystic lung disease consistent with LAM, further confirmed in the explants of all patients.
All the patients had severe hypoxia and required continuous oxygen before surgery; seven patients (28%) required mechanical ventilation before transplantation, and one patient (4%) received a tracheotomy. Due to the critical status, six (24%) patients completed the pulmonary function test, which showed FEV1 15.9 ± 6.9% of predicted and FVC 33.7 ± 19.6% of predicted. All patients used supplemental oxygen before transplant with a concentration of 29–53% and an oxygenation index of 168.1 ± 52.0. Five (20%) patients completed 6MWT. The mean distance walked was 85.4 ± 46 m, and the minimum SpO2 at the end of the test was 81.8 ± 4.32%. The last pulmonary function test and 6MWT results before LT are summarized in Table 1.
Medical and Surgical Interventions Before Transplantation
Eight (32%) patients received sirolimus before transplantation, for an average time of 3.9 years (range 1–9 years). One patient repeatedly had a bilateral pneumothorax, atelectasis, intractable chylothorax, abdominal chylous fluid, and a uterine muscle lipoma. She received pleural and peritoneal drainage, followed by right middle lobe wedge resection with lung repair. A uterus lymphatic smooth muscle tumor was resected. Then, she received thoracic duct ligation and bilateral pleurodesis treatment. The postoperative histological examination confirmed lung and uterine LAM. Another four patients (16%) received pleurodesis due to recurrent pneumothorax and/or chylothorax. Moreover, 19 patients (76%) had a history of pregnancy, and 6 patients (24%) had a recent history of pregnancy (within 1 year of pregnancy, including abortion or production).
Lung Transplantation and Posttransplantation Outcomes
No significant intraoperative complications were reported, although two patients (8%) required intraoperative extracorporeal membrane oxygenation support. The average volume of intraoperative blood loss was 1,280 ±730 ml, and the mean blood transfusion was 1,316 ± 874 ml. One patient (4%) experienced intraoperative blood loss of up to 4,000 ml due to extensive pleural adhesions in the thoracic cavity regarding pretransplant bilateral pleurodesis.
The complications after the surgery included the disturbance of anastomotic integrity. One patient developed anastomotic stenosis after anastomotic infection in the early stage after LT. The condition of anastomotic stenosis improved after antibiotics and balloon dilatation treatment. However, another patient died due to anastomotic leakage. After the surgery, 45% of the patients developed an infection, and two patients died of tuberculosis infection. One patient died of primary graft dysfunction during the early postoperative period. Bronchiolitis obliterans syndrome was diagnosed in one patient (4%) 48 months after LT. The postoperative details are described in Table 2. Twenty-one (84%) patients received triple-drug maintenance immunosuppressive therapy (tacrolimus, mycophenolate, and prednisone) after transplantation. Four patients (16%) temporarily received tacrolimus and prednisone treatment because of infection in an early stage after the surgery. One patient received sirolimus (maintained serum level 8–10 ng/ml) instead of tacrolimus 3 months after transplantation when anastomosis completely healed, but meanwhile, a retroperitoneal mass was suspected.
Table 2 Intra- and posttransplantation data (n = 25).
Variable Value
Follow-up (months) 41.1 ± 25.0
Immunosuppression
Tacrolimus + mycophenolate + prednisone (n, %) 21 (84)
Tacrolimus + prednisone (n, %) 4 (16)
Complications
Neoplasm or lymphoproliferative disease (n, %) 0 (0)
Chylothorax (n, %) 1 (4)
Recurrence of LAM (n, %) 0 (0)
Pulmonary retransplantation (n, %) 0 (0)
Intraoperative bleeding (n, %) 1 (4)
Anastomotic complications (n, %) 2 (8)
Anastomotic leakage (n, %) 1 (4)
Anastomotic stenosis (n, %) 1 (4)
Bronchiolitis obliterans syndrome (n, %) 1 (4)
Recurrence of LAM (n, %) 0 (0)
Primary graft dysfunction (n, %) 1 (4)
Infection (n, %) 12 (48)
Tuberculosis infection 3 (12)
Aspergillus 3 (12)
Acinetobacter baumannii 4 (16)
Other infection 2 (8)
Cause of death
Primary graft dysfunction (n, %) 1 (4)
Anastomotic leakage (n, %) 1 (4)
Infection (n, %) 2 (8)
The median follow-up of this group of patients was 41.1 ± 25.0 months. The range of follow-up from LT to either death or closing date was 0.5–84 months. Four deaths (16%) occurred during the study. One patient (4%) died of primary graft dysfunction 30 days after the surgery. Two patients died of uncontrollable infections 2 and 13 months after the surgery. Another patient (4%) died of anastomotic leakage 12 days after the surgery. The patient had been on oral sirolimus for 9 years and until transplantation.
No LAM recurrence was observed, no patient developed the malignant proliferative disease after the procedure, and no patient underwent pulmonary re-transplantation. The estimated 1- and 2-year posttransplant survival rates were 88 and 84%, respectively (Figure 1).
Figure 1 Kaplan–Meier survival analysis after lung transplantation in 25 patients with LAM.
Discussion
This study demonstrated a favorable outcome for LT in LAM patients similar to that published in a USA report from actuarial Kaplan–Meier survival for LAM was 85% at 1 year, and 76% at 3 years (19). Despite three (12%) early deaths (<3 months after transplantation), the survival rate of the present cohort was more favorable than that of patients with other indications (24) and Japan's data, as well as the 1-year survival of 78–81% in the report of ISHLT registry (25). The estimated survival rates from a Brazilian cohort have been shown to be 90% after 1 year, 90% after 3 years, and 77% after 5 years, which were greater than those observed in previous studies (15–20). The long-term survival was also promising, attributing to the fact that it often involved younger patients without any extrapulmonary organ dysfunction (11).
A newly adopted lung allocation scoring system based on disease severity in the USA since 2005 (26) has categorized LAM with chronic obstructive pulmonary disease and other obstructive diseases, giving a lower priority to patients with idiopathic pulmonary fibrosis when allocating donor lungs. Thus, a longer waiting time for patients with LAM should be optimized. Recently, BLT has been performed with a higher frequency compared with SLT for LAM (13, 15, 27). BLT could achieve a better long-term outcome (28) due to lower incidence of bronchiolitis obliterans syndrome, reducing the rate of complications such as pneumothorax, chylothorax, and recurrence of LAM following LT, together with better pulmonary function tests. Hence, BLT is recommended if donor lungs are available.
Recurrent pneumothorax and chylothorax requiring surgical or chemical pleurodesis are common in patients with LAM. The average lifetime pneumothorax-related burden for patients with LAM is a high in-patient cost (29). The upmost challenge for LT in patients with LAM would be to minimize the risk of severe hemorrhage in patients who had pretransplant pleurodesis for pneumothorax or chylothorax, which is a serious triggering factor for excessive bleeding by dissection of the adhesions. According to the previous reports, the pretransplant rates of pleurodesis and pleurectomy ranged from 18 to 100% and from 21 to 43%, respectively, whereas the rate of intraoperative complications varied from 25 to 71% (11–17) (Table 3). However, in the present cohort with a pleurodesis rate of 16%, the rate of intraoperative complications was only 4%.
Table 3 Summaries of studies on LT for LAM.
Study No. of LT Age at LT (years) FEV1% FEV1/FVC Pre-LT complications Intra-surgery Main Post-LT complications 30 days of mortality 1-year survival
Boehler et al. (9) 34 40 ± 9 24 ± 12 38 ± 12 Pleural effusion 16%
Pleurodesis 18% Adhesions 54%
Hemorrhage 12% Bronchial stenosis
or dehiscence 18% 15% 69%
Urban et al. (10) 13 - FEV1 0.57 ± 0.15 L - Pleurodesis 58% (in total) - - 8% 69%
Pechet et al. (11) 14 41.8 ± 6.8 20 ± 8 - Pleural effusion 7.1%
Pleurodesis 00% Adhesions 71.4%
Hemorrhage 50% Sepsis 21.4%
Dehiscence 14.3%
Chylothorax 28.6% 0% 100%
KpodonuJ et al. (19) 79 41.1 ± 8.3 - - - - Fungal infection 2.5% 5% 86%
Reynaud-Gauber et al. (12) 45 41 ± 10 Obstructive 26.4 ± 14.1
Combined19.7 ± 7.2 Combined 47.4 ± 12.3 Pleural effusion 13.3%
Pleurodesis 48.8% Adhesions 46.6%
Hemorrhage 46.6% Bronchial stenosis or dehiscence 15.6% - 80%
Benden et al. (13) 61 41.3 ± 9.1 27 ± 14 - Pleural effusion 14%
Pleurodesis 54.1% Adhesions 57.4%
Hemorrhage 33.3% Respiratory tract infection 59% 5% 79%
Machuca et al. (14) 10 43.8 ± 6.7 Mean 32.9 - Pleural effusion 0%
Pleurodesis 100% Hemorrhage (>1,000 ml) 30% Infections 30% 10% 90%
Nakagirin et al. (16) 13 42 ± 4.6 - - Pleural effusion 30.7%
Pleurodesis 53.8% - - - -
Ando et al. (17) 57 39.5 ± 7.3 32.8 ± 17 40.2 ± 15.2 Pleural effusion 21%
Pleurodesis 53.8% - Bronchial stenosis or dehiscence 0% 93.5%
Bruno et al. (21) 11 43 ± 7 28 ± 14 45 ± 16 Pleurodesis 9% - Stenosis 9%
Pulmonary infections 55% 90%
Oishi et al. (22) 29 45.3 ± 8.4 - - Pleural effusion 6.9%
Pleurodesis 31% Adhesions 31%
Hemorrhage
(>2,000 ml) 13.8% Chylothorax 20.7% 0% 83.3%
Khawar et al. (30) 138 45 (38–52) 23 (17.0–33.3) - - - - - 94%
Salman et al. (31) 25 50 ± 9 22 ± 10 - - - Dialysis (32%) 0% 92%
Kurosaki et al. (32) 12 32 ± 7.3 FEV1 0.7 ± 0.4 Pleurodesis (58%) Chylothorax 50%
Acute rejection 42% 0 100%
Previous studies showed that almost all patients with LAM died 10 years after the start of symptoms (33, 34). The guideline for LAM recipients from ISHLT suggested that the New York Heart Association functional class III or IV, severe impairment of lung function, and poor exercise tolerance should be considered for LT (23). When determined to perform LT, severe obstruction, compromised gas exchange impairing quality of life, and progressive respiratory failure are among the most important factors for evaluation (35). How to refine the specific timing of LT is very difficult. The poor prognostic factors included decreased FEV1/FVC, decreased total lung capacity, and cystic lesions. In the published reports of cohorts, the age at onset, diagnosis, diffusing capacity for carbon monoxide (DLCO)% predicted, PaO2, and 6MWT at registration were quite similar. However, FEV1% predicted at registration and during the waiting period have been shown to be worthy of special note. In the present cohort, most of the patients in the present study had end-stage respiratory failure and required oxygen or even high-flow oxygen to extend their life before the surgery. Most of them could not complete the pulmonary function test. As few as six patients could complete the necessary ventilatory function test as required but were unable to undergo the diffusion function test, as well as 6MWT. The pretransplant FEV1% was 15.9 ± 6.9% of predicted and obviously lower than that found in most previous reports, ranging from 19 ± 11% to 32.8 ± 17% (11–17). This signified the difficulties related to patient management at the centers to perform BLT. Although pleural intervention is not seen as a contraindication to transplant, it would become a contributor to both intra-surgery and post-surgery morbidities.
In the present cohort, the waiting time of patients seemed relatively shorter than the Japanese center's interval, partly due to the donation volume and the endurance of the patients (17). The time to choose LT for patients with LAM was also crucial for long-term survival. With the delay in choosing LT, intractable chylothorax or metastatic LAM lesions could be seen. If patients received LT in a later phase, critical status, high cost, and risk of retransplant were implicated. More assessment tools are needed in the future to fully evaluate the timing and benefit of LT in patients with LAM.
Infections are a major complication after LT in LAM. The frequency of respiratory infections ranged from 10 to 59%, with heterogeneous etiology such as cytomegalovirus, Aspergillus sp., and bacterial pathogens (11–16). Two patients died of uncontrollable infections pathologically confirmed as tuberculosis infection. Another surviving patient also had a relapsed tuberculosis infection 6 months after the surgery. This patient recovered well after antituberculosis treatment. Hence, patients with LAM undergoing LT are recommended to receive conventional inhalation isoniazid to prevent tuberculosis infection. Immunosuppression use after LT is also a risk factor.
For patients with LAM, the use of mTOR inhibitors is a topic with special interest. As a conventional immunosuppressant in organ transplantation (36), sirolimus has been proved in vitro and in preclinical models for stabilizing lung function in LAM and treating extrapulmonary manifestations, such as renal angiomyolipoma, by inhibiting T- and B-lymphocyte activation via the IL-2 signaling pathway (3, 37). mTOR inhibitors are appealing to physicians in decreasing the rate of cytomegalovirus infection (38) and effective for post-surgery chylous pleural and peritoneal effusions (3). A significant concern regarding the use of mTOR inhibitors is that these drugs interfere with wound healing corresponding to the suppression of fibroblast proliferation and angiogenesis, which is related to the increased rate of bronchial anastomotic integrity disorder (39). In the present cohort, one patient died of anastomotic leakage 12 days after the surgery. She had received sirolimus for 9 years before the surgery and did not stop treatment before the surgery. No anastomotic leakage was observed in the other seven patients treated with sirolimus medication for 1–6 years. Whether it is necessary to stop the drug before the surgery and when need to be confirmed by further exploration. Some centers suggest initiating mTOR inhibitors only after confirming complete bronchial anastomotic healing, 3 months (12) after LT or even waiting up to 9 months. A high incidence of airway dehiscence occurred when sirolimus was begun immediately after transplantation (40).
Previous studies found the predominance of LAM in women of reproductive age. Pregnancy worsened the disease (41), and menopause caused disease remission (42). Patients enrolled in the present cohort seemed to be younger and mainly sporadic LAM dominant compared with clinical analysis findings from the Chinese mainland (43) and the American National Heart, Lung and Blood Institute (2, 35). Exploring whether the younger age of female patients to undergo LT can improve their life expectations, including pregnancy demanding, can be highly challenging.
This study had certain limitations because of the paucity of available knowledge regarding the pathophysiology and treatment of LAM. Small sample size and its retrospective heterogeneous characteristic were the main factors to be considered as insufficiencies similar to previous reports due to the rarity of LAM and a high requirement of the large-center qualification. The condition of patients was quite serious in the present study, and most patients could not complete the preoperative lung function and 6MWT, resulting in incomplete data. Hence, large-scale clinical research is needed in the future. For the surveillance of the posttransplantation course, convincing evidence of maintenance therapeutic agents and improvements in patients with LAM undergoing transplantation with regard to their posttransplant survival will be the key points to explore in future studies.
Conclusions
The present study reinforced the role of LT for patients with end-stage LAM. Favorable survival and quality of life were demonstrated. Nevertheless, the occurrence of LAM-related and transplant-related complications should be monitored continuously. Pre- and posttransplantation immunosuppressive approaches confer a special interest in further demystifying LAM via coordination of medical therapy providers and transplant surgeons, thus allowing for the optimization of recipients both while waiting and after the surgery.
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
The studies involving human participants were reviewed and approved by The Institutional Ethics Committees of Wuxi People's Hospital The Institutional Ethics Committees of China-Japan Friendship Hospital. The patients/participants provided their written informed consent to participate in this study.
Author Contributions
JZ and JC take full responsibility for the content of this manuscript, including its data and analysis. DL, BY, LB, MZ, HW, JL, BW, and K-FX made substantial contributions to the conception and design of the study. JZ and WC made substantial contributions to the analysis and interpretation of data. JZ drafted the initial 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. The National Key Research and Development Program of China No. 2016YFC0901502. | Fatal | ReactionOutcome | CC BY | 33665195 | 19,030,548 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Drug ineffective'. | Difficult reversal of dabigatran with idarucizumab in a multiple-trauma patient: A question of dose?
Dabigatran is an oral anticoagulant directly acting as thrombin inhibitor. The monoclonal antibody idarucizumab was developed to reverse its anticoagulatory effects after application of a standardized dose. Following administration, dabigatran plasma level rebounds have been reported but its consequences are not fully understood. We report a case of a multiple-trauma patient under dabigatran treatment suffering from secondary bleeding relapse after initially successful reversal with idarucizumab. Stabilisation of the patient's coagulopathy and subsequent bleeding was not achieved until application of an additional dose of idarucizumab. We conclude that patients treated with dabigatran and presenting with active bleeding require close attention to its reversal with standard doses of idarucizumab. Screening for thrombin time was shown beneficial in early detection of dabigatran rebound in this case.
Introduction
Dabigatran, a direct thrombin inhibitor, is primarily eliminated in the urine with a terminal half-life of 12–17 h in healthy patients. Its anticoagulatory effects can be rapidly reversed with idarucizumab which binds both free and thrombin-bound dabigatran (two bolus injections of 2.5 g reduce dabigatran plasma concentrations >99% [1]) [2]. The terminal half-life of idarucizumab is 10.3 h. The REVERSE-AD trial reported a dabigatran plasma level rebound in 23% of all cases resulting in 2% bleeding relapse following idarucizumab treatment [2]. Other case reports have described dabigatran rebound 7 to 61 h after initial idarucizumab administration requiring repeated dosage [2,3]. Being a hydrophilic molecule, dabigatran can easily move between intra- and extravascular compartments and it is thought that a variable intravascular concentration may account for rebound bleeding accompanied by fluctuating coagulation parameters. Therefore, a single dose of idarucizumab might not be sufficient to completely neutralise dabigatran's effects [4].
Case
We report our experience with a poly-trauma patient whose medical management was likely compromised by severe coagulopathy secondary to dabigatran. This 83-year-old Caucasian male (83 kg, 180 cm) fell from a ladder and suffered multiple injuries resulting in an injury severity score of 34. He had been prescribed dabigatran 110 mg bid since 2011 for atrial fibrillation, recurrent pulmonary embolism (2003 and 2011) and transient ischemic attacks (2018). The last dose of dabigatran was 9 h prior to trauma. Blood creatinine was 1.5 mg/dl. Other medications included bisoprolol 1.25 mg qd, lisinopril 10 mg qd, simvastatin 40 mg qd, pantoprazole 40 mg qd and allopurinol 300 mg qd. Further comorbidities were hypertension, hyperlipidaemia, gout and an inguinal hernia. No allergies were reported, and the patient did not have a history of easy bleeding/bruising prior to dabigatran treatment. INR prior to trauma was between 1.4 and 2.3 (0.8–1.3).
The patient was initially treated in the ER of a county hospital. An arterial and central venous line were placed, the patient was intubated and ventilated. The contrast-enhanced whole-body CT indicated a subarachnoid 9 mm bleeding, bilateral haematopneumothoraces with lung contusions, left sided rib fractures II-XII, bilateral clavicular fractures, I-III lumbar fracture, minor spleen lesion and a psoas hematoma. Both thoracic cavities were drained. The patient was transfused with 1500 ml balanced crystalloids (ELO-MEL®, Fresenius, Germany), 500 ml succinylated gelatine (Gelofusin®, BBraun, Germany) and 2 units of packed red blood cells (PRBCs) and required intravenous administration of norepinephrine (>0.25 μg kg-1 min-1) to maintain stable hemodynamic parameters (Table 1). Blood work indicated a prolonged aPTT (activated partial thromboplastin time) and elevated INR (international normalised ratio; Table 1). Medical treatment included administration of fibrinogen concentrate 2 g (Haemocomplettan®, CSL Behring, Germany), tranexamic acid 1 g and idarucizumab 5 g, as recommended. The bleeding situation improved markedly. Due to injury severity the patient was transferred to our Level I trauma centre. On arrival, blood work showed only slightly prolonged aPTT and TT (thrombin time). Coagulation tests used, were Pathromtin SL assay® for aPTT, Thromborel S assay® for PT, BC Thrombin assay® for TT and Multifibren U (Clauss) assay® for fibrinogen, all Siemens, Marburg, Germany. Lowered fibrinogen was substituted with another dose of 2 g. Fluid resuscitation included administration of 500 ml of crystalloids, 500 ml of succinylated gelatine, and one unit of PRBC.Table 1 Timeline of treatment, blood samples and patient condition.
Table 1 Time of accident Arrival minor trauma Center Arrival major trauma Center Arrival ICU department
Day 1 Day 2
16:00 17:30 18:00 21:00 21:25 22:30 23:19 00:16 00:51 01:19 05:23 13:53
Blood values
Thrombin time (sec, 15–21) 28 89 29 26 20
aPTT (sec, 26–37) 60 49 185 57 49 46
INR (PT) 1.7 1.6 2.0 1.6 1.5 1.4
Fibrinogen (mg/ dl, 210–400) 75 103 208 220 242
Plt (g l−1, 150–380) 148 94 79 84 73 65
Hgb (g dl−1, 13.0–17.7) 12.7 11.2 8.1 8.1 9.2 9.7
FXIII (%, 70–140) 61 52 57 71 55
Lactate (mmol l−1, 0.63–2.44) 1.77 2.44 2.33 1.11 3.55 1.88
Dabigatran (ng ml−1) <20
ROTEM
INTEM CT (s, 100–240) 192 172 169 172
CFT (s, 30–110) 223 174 138 133
MCF (mm, 50–72) 50 53 54 53
LI30 (%, 94–100) 100 100 100 100
LI60 (%, 85–100) 100 100 99 98
A10 (mm, 44–66) 35 39 41 43
EXTEM CT (s, 38–79) 83 61 57 50
CFT (s, 34–159) 178 159 131 117
MCF (mm, 50–72) 52 54 56 58
LI30 (%, 94–100) 100 100 100 100
LI60 (%, 85–100) 100 100 100 99
A10 (mm, 43–65) 39 41 44 47
FIBTEM MCF (mm, 9–25) 4 9 16 16
A10 (mm, 7–23) 4 7 13 14
Treatment
Crystalloids (ml) 1500 500
Colloids (ml) 500 500 500 500 500 500
PRBC 2 1 3
PC 1
Fibrinogen Concentrate (g) 2 2 4
4F-PCC (IE) 1200
Factor XIII Concentrate 1250
Tranexamic Acid (g) 1 1
Idarucizumab (g) 5 2.5
Norepinephrine (µg kg−1 min−1) 0.25 0.3 0.4 0.4 0.4 0.4 0.3 0.3 0.25 0.1 0.1 0.1
Chest drain effusion (ml) ~1000 150 300 650
aPTT = activated Partial Thromboplastin Time, INR = International Normalised Ratio; Plt = Platelets, Hgb = Haemoglobin, ROTEM = rotational thromboelastometry; CT = Clotting Time; CFT = Clot Forming Time; MCF = Maximum Clot Firmness; LI30 = Lysis Index 30 min; LI60 = Lysis Index 60 min; A10 = Amplitude 10 min; PRBC = packed red blood cell; PC = platelet concentrate; 4F-PCC = 4-factor prothrombin complex concentrate.
About 5 h after recommended dosage of idarucizumab, blood work indicated a relapse in prolongation of aPTT and TT. Blood loss through the chest drains increased from zero up to 1100 ml in 90 min (Table 1). Intravenous norepinephrine and fluid requirements increased. One unit of platelet concentrate (PC), three units of PRBCs, fibrinogen concentrate 4 g, 4F-PCC 1200 IU (Prothromplex Total®, Baxter, Vienna), Factor XIII concentrate 1250 IU (Fibrogammin®, CSL Behring, Germany), and tranexamic acid 1 g were administered primarily suspecting traumatic bleeding. Despite this intensive medical management following the European trauma guidelines, stabilisation was not achieved [5,6]. Finally, another half-dose of idarucizumab (2.5 g) was given, to treat the possibility of incomplete reversal of dabigatran-induced coagulopathy. Hereafter, the patient's condition stabilised promptly. With decreased catecholamine requirement and bleeding cessation we resigned from completing to a second full-dose of 5 g [7]. Laboratory work-up showed almost normal aPTT and TT values, further improving over the next 12 h (Table 1). Dabigatran plasma levels 12 h after 7.5 g of idarucizumab were beneath detectability, indicating sufficient long-term reversal. The patient was referred back to the county hospital after 17 days with subsequent transfer to a rehabilitation facility two weeks later.
Discussion
In this case, dabigatran serum levels were not measured sequentially. The link to ongoing bleeding and abnormal coagulation values is therefor made more difficult. Although plasma level concentrations of dabigatran may not be useful for measuring the antagonistic effects of idarucizumab [3] they can be used to predict possible dabigatran rebound when measured prior to administration [8]. Bleeding-related coagulopathy was treated according to the rotational thrombelastometry results (ROTEMdelta®, Instrumentation Laboratory, Bedford MA, USA). While ROTEM maximal clot firmness stays unaffected, other haemostatic tests relying on thrombin (e.g. aPTT, TT, fibrinogen) are inaccurate in the presence of high dabigatran levels due to thrombin inactivation [4]. Other considerable factors maybe contributing to the coagulopathic state of this patient include dilutional coagulopathy, disseminated intravascular coagulation and trauma-related coagulopathy. They can be excluded by the ROTEM findings or missing triggers. Factor-specific inheritable deficiencies and liver or renal failure are not supported by history or laboratory values. Finally, our suspicion was confirmed by prompt cessation of bleeding as well as hemodynamic stabilisation after another half-dose of idarucizumab.
Conclusion
We conclude that a dabigatran-related coagulopathy contributed to massive bleeding in a multiple traumatised patient. An increasing number of patients admitted to the ER are treated with directly acting oral thrombin inhibitors. In the absence of feasible plasma level testing, screening for aPTT and TT can be beneficial for identifying patients at risk but can also support early detection of non-responders to antidote therapy. Patients treated with dabigatran and presenting with active bleeding require close attention to its reversal with standard doses of idarucizumab.
CRediT authorship contribution statement
MS designed the study, collected and interpreted the data and drafted the article. CR and SS contributed to data collection and drafted the article. DF and EO revised the article and contributed to the final article.
Patient consent
The patient in this manuscript has given written informed consent to publication of his case details.
Assistance with the article
None.
Financial support and sponsorship
This research received no specific grant / financial support or sponsorship from any funding agency in the public, commercial or not-for-profit sectors.
Declaration of competing interest
MS, CR, SS and EO none. DF has received personal fees for lectures or similar in the past, independent of the presented manuscript. DF has received personal fees from 10.13039/100008322CSL Behring GmbH, from LFB, and BBraun and non-financial support from TEM International, outside the submitted work. | CALCIUM CHLORIDE\MAGNESIUM CHLORIDE\POTASSIUM CHLORIDE\SODIUM ACETATE\SODIUM CHLORIDE, COAGULATION FACTOR IX HUMAN\COAGULATION FACTOR VII HUMAN\COAGULATION FACTOR X HUMAN\PROTEIN C\PROTHR, DABIGATRAN, FACTOR XIII CONCENTRATE (HUMAN), FIBRINOGEN HUMAN, GELATIN\POTASSIUM CHLORIDE\SODIUM CHLORIDE, IDARUCIZUMAB, NOREPINEPHRINE, TRANEXAMIC ACID | DrugsGivenReaction | CC BY | 33665315 | 20,038,151 | 2021-04 |
What is the weight of the patient? | Difficult reversal of dabigatran with idarucizumab in a multiple-trauma patient: A question of dose?
Dabigatran is an oral anticoagulant directly acting as thrombin inhibitor. The monoclonal antibody idarucizumab was developed to reverse its anticoagulatory effects after application of a standardized dose. Following administration, dabigatran plasma level rebounds have been reported but its consequences are not fully understood. We report a case of a multiple-trauma patient under dabigatran treatment suffering from secondary bleeding relapse after initially successful reversal with idarucizumab. Stabilisation of the patient's coagulopathy and subsequent bleeding was not achieved until application of an additional dose of idarucizumab. We conclude that patients treated with dabigatran and presenting with active bleeding require close attention to its reversal with standard doses of idarucizumab. Screening for thrombin time was shown beneficial in early detection of dabigatran rebound in this case.
Introduction
Dabigatran, a direct thrombin inhibitor, is primarily eliminated in the urine with a terminal half-life of 12–17 h in healthy patients. Its anticoagulatory effects can be rapidly reversed with idarucizumab which binds both free and thrombin-bound dabigatran (two bolus injections of 2.5 g reduce dabigatran plasma concentrations >99% [1]) [2]. The terminal half-life of idarucizumab is 10.3 h. The REVERSE-AD trial reported a dabigatran plasma level rebound in 23% of all cases resulting in 2% bleeding relapse following idarucizumab treatment [2]. Other case reports have described dabigatran rebound 7 to 61 h after initial idarucizumab administration requiring repeated dosage [2,3]. Being a hydrophilic molecule, dabigatran can easily move between intra- and extravascular compartments and it is thought that a variable intravascular concentration may account for rebound bleeding accompanied by fluctuating coagulation parameters. Therefore, a single dose of idarucizumab might not be sufficient to completely neutralise dabigatran's effects [4].
Case
We report our experience with a poly-trauma patient whose medical management was likely compromised by severe coagulopathy secondary to dabigatran. This 83-year-old Caucasian male (83 kg, 180 cm) fell from a ladder and suffered multiple injuries resulting in an injury severity score of 34. He had been prescribed dabigatran 110 mg bid since 2011 for atrial fibrillation, recurrent pulmonary embolism (2003 and 2011) and transient ischemic attacks (2018). The last dose of dabigatran was 9 h prior to trauma. Blood creatinine was 1.5 mg/dl. Other medications included bisoprolol 1.25 mg qd, lisinopril 10 mg qd, simvastatin 40 mg qd, pantoprazole 40 mg qd and allopurinol 300 mg qd. Further comorbidities were hypertension, hyperlipidaemia, gout and an inguinal hernia. No allergies were reported, and the patient did not have a history of easy bleeding/bruising prior to dabigatran treatment. INR prior to trauma was between 1.4 and 2.3 (0.8–1.3).
The patient was initially treated in the ER of a county hospital. An arterial and central venous line were placed, the patient was intubated and ventilated. The contrast-enhanced whole-body CT indicated a subarachnoid 9 mm bleeding, bilateral haematopneumothoraces with lung contusions, left sided rib fractures II-XII, bilateral clavicular fractures, I-III lumbar fracture, minor spleen lesion and a psoas hematoma. Both thoracic cavities were drained. The patient was transfused with 1500 ml balanced crystalloids (ELO-MEL®, Fresenius, Germany), 500 ml succinylated gelatine (Gelofusin®, BBraun, Germany) and 2 units of packed red blood cells (PRBCs) and required intravenous administration of norepinephrine (>0.25 μg kg-1 min-1) to maintain stable hemodynamic parameters (Table 1). Blood work indicated a prolonged aPTT (activated partial thromboplastin time) and elevated INR (international normalised ratio; Table 1). Medical treatment included administration of fibrinogen concentrate 2 g (Haemocomplettan®, CSL Behring, Germany), tranexamic acid 1 g and idarucizumab 5 g, as recommended. The bleeding situation improved markedly. Due to injury severity the patient was transferred to our Level I trauma centre. On arrival, blood work showed only slightly prolonged aPTT and TT (thrombin time). Coagulation tests used, were Pathromtin SL assay® for aPTT, Thromborel S assay® for PT, BC Thrombin assay® for TT and Multifibren U (Clauss) assay® for fibrinogen, all Siemens, Marburg, Germany. Lowered fibrinogen was substituted with another dose of 2 g. Fluid resuscitation included administration of 500 ml of crystalloids, 500 ml of succinylated gelatine, and one unit of PRBC.Table 1 Timeline of treatment, blood samples and patient condition.
Table 1 Time of accident Arrival minor trauma Center Arrival major trauma Center Arrival ICU department
Day 1 Day 2
16:00 17:30 18:00 21:00 21:25 22:30 23:19 00:16 00:51 01:19 05:23 13:53
Blood values
Thrombin time (sec, 15–21) 28 89 29 26 20
aPTT (sec, 26–37) 60 49 185 57 49 46
INR (PT) 1.7 1.6 2.0 1.6 1.5 1.4
Fibrinogen (mg/ dl, 210–400) 75 103 208 220 242
Plt (g l−1, 150–380) 148 94 79 84 73 65
Hgb (g dl−1, 13.0–17.7) 12.7 11.2 8.1 8.1 9.2 9.7
FXIII (%, 70–140) 61 52 57 71 55
Lactate (mmol l−1, 0.63–2.44) 1.77 2.44 2.33 1.11 3.55 1.88
Dabigatran (ng ml−1) <20
ROTEM
INTEM CT (s, 100–240) 192 172 169 172
CFT (s, 30–110) 223 174 138 133
MCF (mm, 50–72) 50 53 54 53
LI30 (%, 94–100) 100 100 100 100
LI60 (%, 85–100) 100 100 99 98
A10 (mm, 44–66) 35 39 41 43
EXTEM CT (s, 38–79) 83 61 57 50
CFT (s, 34–159) 178 159 131 117
MCF (mm, 50–72) 52 54 56 58
LI30 (%, 94–100) 100 100 100 100
LI60 (%, 85–100) 100 100 100 99
A10 (mm, 43–65) 39 41 44 47
FIBTEM MCF (mm, 9–25) 4 9 16 16
A10 (mm, 7–23) 4 7 13 14
Treatment
Crystalloids (ml) 1500 500
Colloids (ml) 500 500 500 500 500 500
PRBC 2 1 3
PC 1
Fibrinogen Concentrate (g) 2 2 4
4F-PCC (IE) 1200
Factor XIII Concentrate 1250
Tranexamic Acid (g) 1 1
Idarucizumab (g) 5 2.5
Norepinephrine (µg kg−1 min−1) 0.25 0.3 0.4 0.4 0.4 0.4 0.3 0.3 0.25 0.1 0.1 0.1
Chest drain effusion (ml) ~1000 150 300 650
aPTT = activated Partial Thromboplastin Time, INR = International Normalised Ratio; Plt = Platelets, Hgb = Haemoglobin, ROTEM = rotational thromboelastometry; CT = Clotting Time; CFT = Clot Forming Time; MCF = Maximum Clot Firmness; LI30 = Lysis Index 30 min; LI60 = Lysis Index 60 min; A10 = Amplitude 10 min; PRBC = packed red blood cell; PC = platelet concentrate; 4F-PCC = 4-factor prothrombin complex concentrate.
About 5 h after recommended dosage of idarucizumab, blood work indicated a relapse in prolongation of aPTT and TT. Blood loss through the chest drains increased from zero up to 1100 ml in 90 min (Table 1). Intravenous norepinephrine and fluid requirements increased. One unit of platelet concentrate (PC), three units of PRBCs, fibrinogen concentrate 4 g, 4F-PCC 1200 IU (Prothromplex Total®, Baxter, Vienna), Factor XIII concentrate 1250 IU (Fibrogammin®, CSL Behring, Germany), and tranexamic acid 1 g were administered primarily suspecting traumatic bleeding. Despite this intensive medical management following the European trauma guidelines, stabilisation was not achieved [5,6]. Finally, another half-dose of idarucizumab (2.5 g) was given, to treat the possibility of incomplete reversal of dabigatran-induced coagulopathy. Hereafter, the patient's condition stabilised promptly. With decreased catecholamine requirement and bleeding cessation we resigned from completing to a second full-dose of 5 g [7]. Laboratory work-up showed almost normal aPTT and TT values, further improving over the next 12 h (Table 1). Dabigatran plasma levels 12 h after 7.5 g of idarucizumab were beneath detectability, indicating sufficient long-term reversal. The patient was referred back to the county hospital after 17 days with subsequent transfer to a rehabilitation facility two weeks later.
Discussion
In this case, dabigatran serum levels were not measured sequentially. The link to ongoing bleeding and abnormal coagulation values is therefor made more difficult. Although plasma level concentrations of dabigatran may not be useful for measuring the antagonistic effects of idarucizumab [3] they can be used to predict possible dabigatran rebound when measured prior to administration [8]. Bleeding-related coagulopathy was treated according to the rotational thrombelastometry results (ROTEMdelta®, Instrumentation Laboratory, Bedford MA, USA). While ROTEM maximal clot firmness stays unaffected, other haemostatic tests relying on thrombin (e.g. aPTT, TT, fibrinogen) are inaccurate in the presence of high dabigatran levels due to thrombin inactivation [4]. Other considerable factors maybe contributing to the coagulopathic state of this patient include dilutional coagulopathy, disseminated intravascular coagulation and trauma-related coagulopathy. They can be excluded by the ROTEM findings or missing triggers. Factor-specific inheritable deficiencies and liver or renal failure are not supported by history or laboratory values. Finally, our suspicion was confirmed by prompt cessation of bleeding as well as hemodynamic stabilisation after another half-dose of idarucizumab.
Conclusion
We conclude that a dabigatran-related coagulopathy contributed to massive bleeding in a multiple traumatised patient. An increasing number of patients admitted to the ER are treated with directly acting oral thrombin inhibitors. In the absence of feasible plasma level testing, screening for aPTT and TT can be beneficial for identifying patients at risk but can also support early detection of non-responders to antidote therapy. Patients treated with dabigatran and presenting with active bleeding require close attention to its reversal with standard doses of idarucizumab.
CRediT authorship contribution statement
MS designed the study, collected and interpreted the data and drafted the article. CR and SS contributed to data collection and drafted the article. DF and EO revised the article and contributed to the final article.
Patient consent
The patient in this manuscript has given written informed consent to publication of his case details.
Assistance with the article
None.
Financial support and sponsorship
This research received no specific grant / financial support or sponsorship from any funding agency in the public, commercial or not-for-profit sectors.
Declaration of competing interest
MS, CR, SS and EO none. DF has received personal fees for lectures or similar in the past, independent of the presented manuscript. DF has received personal fees from 10.13039/100008322CSL Behring GmbH, from LFB, and BBraun and non-financial support from TEM International, outside the submitted work. | 83 kg. | Weight | CC BY | 33665315 | 20,038,151 | 2021-04 |
What was the administration route of drug 'NOREPINEPHRINE'? | Difficult reversal of dabigatran with idarucizumab in a multiple-trauma patient: A question of dose?
Dabigatran is an oral anticoagulant directly acting as thrombin inhibitor. The monoclonal antibody idarucizumab was developed to reverse its anticoagulatory effects after application of a standardized dose. Following administration, dabigatran plasma level rebounds have been reported but its consequences are not fully understood. We report a case of a multiple-trauma patient under dabigatran treatment suffering from secondary bleeding relapse after initially successful reversal with idarucizumab. Stabilisation of the patient's coagulopathy and subsequent bleeding was not achieved until application of an additional dose of idarucizumab. We conclude that patients treated with dabigatran and presenting with active bleeding require close attention to its reversal with standard doses of idarucizumab. Screening for thrombin time was shown beneficial in early detection of dabigatran rebound in this case.
Introduction
Dabigatran, a direct thrombin inhibitor, is primarily eliminated in the urine with a terminal half-life of 12–17 h in healthy patients. Its anticoagulatory effects can be rapidly reversed with idarucizumab which binds both free and thrombin-bound dabigatran (two bolus injections of 2.5 g reduce dabigatran plasma concentrations >99% [1]) [2]. The terminal half-life of idarucizumab is 10.3 h. The REVERSE-AD trial reported a dabigatran plasma level rebound in 23% of all cases resulting in 2% bleeding relapse following idarucizumab treatment [2]. Other case reports have described dabigatran rebound 7 to 61 h after initial idarucizumab administration requiring repeated dosage [2,3]. Being a hydrophilic molecule, dabigatran can easily move between intra- and extravascular compartments and it is thought that a variable intravascular concentration may account for rebound bleeding accompanied by fluctuating coagulation parameters. Therefore, a single dose of idarucizumab might not be sufficient to completely neutralise dabigatran's effects [4].
Case
We report our experience with a poly-trauma patient whose medical management was likely compromised by severe coagulopathy secondary to dabigatran. This 83-year-old Caucasian male (83 kg, 180 cm) fell from a ladder and suffered multiple injuries resulting in an injury severity score of 34. He had been prescribed dabigatran 110 mg bid since 2011 for atrial fibrillation, recurrent pulmonary embolism (2003 and 2011) and transient ischemic attacks (2018). The last dose of dabigatran was 9 h prior to trauma. Blood creatinine was 1.5 mg/dl. Other medications included bisoprolol 1.25 mg qd, lisinopril 10 mg qd, simvastatin 40 mg qd, pantoprazole 40 mg qd and allopurinol 300 mg qd. Further comorbidities were hypertension, hyperlipidaemia, gout and an inguinal hernia. No allergies were reported, and the patient did not have a history of easy bleeding/bruising prior to dabigatran treatment. INR prior to trauma was between 1.4 and 2.3 (0.8–1.3).
The patient was initially treated in the ER of a county hospital. An arterial and central venous line were placed, the patient was intubated and ventilated. The contrast-enhanced whole-body CT indicated a subarachnoid 9 mm bleeding, bilateral haematopneumothoraces with lung contusions, left sided rib fractures II-XII, bilateral clavicular fractures, I-III lumbar fracture, minor spleen lesion and a psoas hematoma. Both thoracic cavities were drained. The patient was transfused with 1500 ml balanced crystalloids (ELO-MEL®, Fresenius, Germany), 500 ml succinylated gelatine (Gelofusin®, BBraun, Germany) and 2 units of packed red blood cells (PRBCs) and required intravenous administration of norepinephrine (>0.25 μg kg-1 min-1) to maintain stable hemodynamic parameters (Table 1). Blood work indicated a prolonged aPTT (activated partial thromboplastin time) and elevated INR (international normalised ratio; Table 1). Medical treatment included administration of fibrinogen concentrate 2 g (Haemocomplettan®, CSL Behring, Germany), tranexamic acid 1 g and idarucizumab 5 g, as recommended. The bleeding situation improved markedly. Due to injury severity the patient was transferred to our Level I trauma centre. On arrival, blood work showed only slightly prolonged aPTT and TT (thrombin time). Coagulation tests used, were Pathromtin SL assay® for aPTT, Thromborel S assay® for PT, BC Thrombin assay® for TT and Multifibren U (Clauss) assay® for fibrinogen, all Siemens, Marburg, Germany. Lowered fibrinogen was substituted with another dose of 2 g. Fluid resuscitation included administration of 500 ml of crystalloids, 500 ml of succinylated gelatine, and one unit of PRBC.Table 1 Timeline of treatment, blood samples and patient condition.
Table 1 Time of accident Arrival minor trauma Center Arrival major trauma Center Arrival ICU department
Day 1 Day 2
16:00 17:30 18:00 21:00 21:25 22:30 23:19 00:16 00:51 01:19 05:23 13:53
Blood values
Thrombin time (sec, 15–21) 28 89 29 26 20
aPTT (sec, 26–37) 60 49 185 57 49 46
INR (PT) 1.7 1.6 2.0 1.6 1.5 1.4
Fibrinogen (mg/ dl, 210–400) 75 103 208 220 242
Plt (g l−1, 150–380) 148 94 79 84 73 65
Hgb (g dl−1, 13.0–17.7) 12.7 11.2 8.1 8.1 9.2 9.7
FXIII (%, 70–140) 61 52 57 71 55
Lactate (mmol l−1, 0.63–2.44) 1.77 2.44 2.33 1.11 3.55 1.88
Dabigatran (ng ml−1) <20
ROTEM
INTEM CT (s, 100–240) 192 172 169 172
CFT (s, 30–110) 223 174 138 133
MCF (mm, 50–72) 50 53 54 53
LI30 (%, 94–100) 100 100 100 100
LI60 (%, 85–100) 100 100 99 98
A10 (mm, 44–66) 35 39 41 43
EXTEM CT (s, 38–79) 83 61 57 50
CFT (s, 34–159) 178 159 131 117
MCF (mm, 50–72) 52 54 56 58
LI30 (%, 94–100) 100 100 100 100
LI60 (%, 85–100) 100 100 100 99
A10 (mm, 43–65) 39 41 44 47
FIBTEM MCF (mm, 9–25) 4 9 16 16
A10 (mm, 7–23) 4 7 13 14
Treatment
Crystalloids (ml) 1500 500
Colloids (ml) 500 500 500 500 500 500
PRBC 2 1 3
PC 1
Fibrinogen Concentrate (g) 2 2 4
4F-PCC (IE) 1200
Factor XIII Concentrate 1250
Tranexamic Acid (g) 1 1
Idarucizumab (g) 5 2.5
Norepinephrine (µg kg−1 min−1) 0.25 0.3 0.4 0.4 0.4 0.4 0.3 0.3 0.25 0.1 0.1 0.1
Chest drain effusion (ml) ~1000 150 300 650
aPTT = activated Partial Thromboplastin Time, INR = International Normalised Ratio; Plt = Platelets, Hgb = Haemoglobin, ROTEM = rotational thromboelastometry; CT = Clotting Time; CFT = Clot Forming Time; MCF = Maximum Clot Firmness; LI30 = Lysis Index 30 min; LI60 = Lysis Index 60 min; A10 = Amplitude 10 min; PRBC = packed red blood cell; PC = platelet concentrate; 4F-PCC = 4-factor prothrombin complex concentrate.
About 5 h after recommended dosage of idarucizumab, blood work indicated a relapse in prolongation of aPTT and TT. Blood loss through the chest drains increased from zero up to 1100 ml in 90 min (Table 1). Intravenous norepinephrine and fluid requirements increased. One unit of platelet concentrate (PC), three units of PRBCs, fibrinogen concentrate 4 g, 4F-PCC 1200 IU (Prothromplex Total®, Baxter, Vienna), Factor XIII concentrate 1250 IU (Fibrogammin®, CSL Behring, Germany), and tranexamic acid 1 g were administered primarily suspecting traumatic bleeding. Despite this intensive medical management following the European trauma guidelines, stabilisation was not achieved [5,6]. Finally, another half-dose of idarucizumab (2.5 g) was given, to treat the possibility of incomplete reversal of dabigatran-induced coagulopathy. Hereafter, the patient's condition stabilised promptly. With decreased catecholamine requirement and bleeding cessation we resigned from completing to a second full-dose of 5 g [7]. Laboratory work-up showed almost normal aPTT and TT values, further improving over the next 12 h (Table 1). Dabigatran plasma levels 12 h after 7.5 g of idarucizumab were beneath detectability, indicating sufficient long-term reversal. The patient was referred back to the county hospital after 17 days with subsequent transfer to a rehabilitation facility two weeks later.
Discussion
In this case, dabigatran serum levels were not measured sequentially. The link to ongoing bleeding and abnormal coagulation values is therefor made more difficult. Although plasma level concentrations of dabigatran may not be useful for measuring the antagonistic effects of idarucizumab [3] they can be used to predict possible dabigatran rebound when measured prior to administration [8]. Bleeding-related coagulopathy was treated according to the rotational thrombelastometry results (ROTEMdelta®, Instrumentation Laboratory, Bedford MA, USA). While ROTEM maximal clot firmness stays unaffected, other haemostatic tests relying on thrombin (e.g. aPTT, TT, fibrinogen) are inaccurate in the presence of high dabigatran levels due to thrombin inactivation [4]. Other considerable factors maybe contributing to the coagulopathic state of this patient include dilutional coagulopathy, disseminated intravascular coagulation and trauma-related coagulopathy. They can be excluded by the ROTEM findings or missing triggers. Factor-specific inheritable deficiencies and liver or renal failure are not supported by history or laboratory values. Finally, our suspicion was confirmed by prompt cessation of bleeding as well as hemodynamic stabilisation after another half-dose of idarucizumab.
Conclusion
We conclude that a dabigatran-related coagulopathy contributed to massive bleeding in a multiple traumatised patient. An increasing number of patients admitted to the ER are treated with directly acting oral thrombin inhibitors. In the absence of feasible plasma level testing, screening for aPTT and TT can be beneficial for identifying patients at risk but can also support early detection of non-responders to antidote therapy. Patients treated with dabigatran and presenting with active bleeding require close attention to its reversal with standard doses of idarucizumab.
CRediT authorship contribution statement
MS designed the study, collected and interpreted the data and drafted the article. CR and SS contributed to data collection and drafted the article. DF and EO revised the article and contributed to the final article.
Patient consent
The patient in this manuscript has given written informed consent to publication of his case details.
Assistance with the article
None.
Financial support and sponsorship
This research received no specific grant / financial support or sponsorship from any funding agency in the public, commercial or not-for-profit sectors.
Declaration of competing interest
MS, CR, SS and EO none. DF has received personal fees for lectures or similar in the past, independent of the presented manuscript. DF has received personal fees from 10.13039/100008322CSL Behring GmbH, from LFB, and BBraun and non-financial support from TEM International, outside the submitted work. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY | 33665315 | 20,038,151 | 2021-04 |
What was the dosage of drug 'COAGULATION FACTOR IX HUMAN\COAGULATION FACTOR VII HUMAN\COAGULATION FACTOR X HUMAN\PROTEIN C\PROTHR'? | Difficult reversal of dabigatran with idarucizumab in a multiple-trauma patient: A question of dose?
Dabigatran is an oral anticoagulant directly acting as thrombin inhibitor. The monoclonal antibody idarucizumab was developed to reverse its anticoagulatory effects after application of a standardized dose. Following administration, dabigatran plasma level rebounds have been reported but its consequences are not fully understood. We report a case of a multiple-trauma patient under dabigatran treatment suffering from secondary bleeding relapse after initially successful reversal with idarucizumab. Stabilisation of the patient's coagulopathy and subsequent bleeding was not achieved until application of an additional dose of idarucizumab. We conclude that patients treated with dabigatran and presenting with active bleeding require close attention to its reversal with standard doses of idarucizumab. Screening for thrombin time was shown beneficial in early detection of dabigatran rebound in this case.
Introduction
Dabigatran, a direct thrombin inhibitor, is primarily eliminated in the urine with a terminal half-life of 12–17 h in healthy patients. Its anticoagulatory effects can be rapidly reversed with idarucizumab which binds both free and thrombin-bound dabigatran (two bolus injections of 2.5 g reduce dabigatran plasma concentrations >99% [1]) [2]. The terminal half-life of idarucizumab is 10.3 h. The REVERSE-AD trial reported a dabigatran plasma level rebound in 23% of all cases resulting in 2% bleeding relapse following idarucizumab treatment [2]. Other case reports have described dabigatran rebound 7 to 61 h after initial idarucizumab administration requiring repeated dosage [2,3]. Being a hydrophilic molecule, dabigatran can easily move between intra- and extravascular compartments and it is thought that a variable intravascular concentration may account for rebound bleeding accompanied by fluctuating coagulation parameters. Therefore, a single dose of idarucizumab might not be sufficient to completely neutralise dabigatran's effects [4].
Case
We report our experience with a poly-trauma patient whose medical management was likely compromised by severe coagulopathy secondary to dabigatran. This 83-year-old Caucasian male (83 kg, 180 cm) fell from a ladder and suffered multiple injuries resulting in an injury severity score of 34. He had been prescribed dabigatran 110 mg bid since 2011 for atrial fibrillation, recurrent pulmonary embolism (2003 and 2011) and transient ischemic attacks (2018). The last dose of dabigatran was 9 h prior to trauma. Blood creatinine was 1.5 mg/dl. Other medications included bisoprolol 1.25 mg qd, lisinopril 10 mg qd, simvastatin 40 mg qd, pantoprazole 40 mg qd and allopurinol 300 mg qd. Further comorbidities were hypertension, hyperlipidaemia, gout and an inguinal hernia. No allergies were reported, and the patient did not have a history of easy bleeding/bruising prior to dabigatran treatment. INR prior to trauma was between 1.4 and 2.3 (0.8–1.3).
The patient was initially treated in the ER of a county hospital. An arterial and central venous line were placed, the patient was intubated and ventilated. The contrast-enhanced whole-body CT indicated a subarachnoid 9 mm bleeding, bilateral haematopneumothoraces with lung contusions, left sided rib fractures II-XII, bilateral clavicular fractures, I-III lumbar fracture, minor spleen lesion and a psoas hematoma. Both thoracic cavities were drained. The patient was transfused with 1500 ml balanced crystalloids (ELO-MEL®, Fresenius, Germany), 500 ml succinylated gelatine (Gelofusin®, BBraun, Germany) and 2 units of packed red blood cells (PRBCs) and required intravenous administration of norepinephrine (>0.25 μg kg-1 min-1) to maintain stable hemodynamic parameters (Table 1). Blood work indicated a prolonged aPTT (activated partial thromboplastin time) and elevated INR (international normalised ratio; Table 1). Medical treatment included administration of fibrinogen concentrate 2 g (Haemocomplettan®, CSL Behring, Germany), tranexamic acid 1 g and idarucizumab 5 g, as recommended. The bleeding situation improved markedly. Due to injury severity the patient was transferred to our Level I trauma centre. On arrival, blood work showed only slightly prolonged aPTT and TT (thrombin time). Coagulation tests used, were Pathromtin SL assay® for aPTT, Thromborel S assay® for PT, BC Thrombin assay® for TT and Multifibren U (Clauss) assay® for fibrinogen, all Siemens, Marburg, Germany. Lowered fibrinogen was substituted with another dose of 2 g. Fluid resuscitation included administration of 500 ml of crystalloids, 500 ml of succinylated gelatine, and one unit of PRBC.Table 1 Timeline of treatment, blood samples and patient condition.
Table 1 Time of accident Arrival minor trauma Center Arrival major trauma Center Arrival ICU department
Day 1 Day 2
16:00 17:30 18:00 21:00 21:25 22:30 23:19 00:16 00:51 01:19 05:23 13:53
Blood values
Thrombin time (sec, 15–21) 28 89 29 26 20
aPTT (sec, 26–37) 60 49 185 57 49 46
INR (PT) 1.7 1.6 2.0 1.6 1.5 1.4
Fibrinogen (mg/ dl, 210–400) 75 103 208 220 242
Plt (g l−1, 150–380) 148 94 79 84 73 65
Hgb (g dl−1, 13.0–17.7) 12.7 11.2 8.1 8.1 9.2 9.7
FXIII (%, 70–140) 61 52 57 71 55
Lactate (mmol l−1, 0.63–2.44) 1.77 2.44 2.33 1.11 3.55 1.88
Dabigatran (ng ml−1) <20
ROTEM
INTEM CT (s, 100–240) 192 172 169 172
CFT (s, 30–110) 223 174 138 133
MCF (mm, 50–72) 50 53 54 53
LI30 (%, 94–100) 100 100 100 100
LI60 (%, 85–100) 100 100 99 98
A10 (mm, 44–66) 35 39 41 43
EXTEM CT (s, 38–79) 83 61 57 50
CFT (s, 34–159) 178 159 131 117
MCF (mm, 50–72) 52 54 56 58
LI30 (%, 94–100) 100 100 100 100
LI60 (%, 85–100) 100 100 100 99
A10 (mm, 43–65) 39 41 44 47
FIBTEM MCF (mm, 9–25) 4 9 16 16
A10 (mm, 7–23) 4 7 13 14
Treatment
Crystalloids (ml) 1500 500
Colloids (ml) 500 500 500 500 500 500
PRBC 2 1 3
PC 1
Fibrinogen Concentrate (g) 2 2 4
4F-PCC (IE) 1200
Factor XIII Concentrate 1250
Tranexamic Acid (g) 1 1
Idarucizumab (g) 5 2.5
Norepinephrine (µg kg−1 min−1) 0.25 0.3 0.4 0.4 0.4 0.4 0.3 0.3 0.25 0.1 0.1 0.1
Chest drain effusion (ml) ~1000 150 300 650
aPTT = activated Partial Thromboplastin Time, INR = International Normalised Ratio; Plt = Platelets, Hgb = Haemoglobin, ROTEM = rotational thromboelastometry; CT = Clotting Time; CFT = Clot Forming Time; MCF = Maximum Clot Firmness; LI30 = Lysis Index 30 min; LI60 = Lysis Index 60 min; A10 = Amplitude 10 min; PRBC = packed red blood cell; PC = platelet concentrate; 4F-PCC = 4-factor prothrombin complex concentrate.
About 5 h after recommended dosage of idarucizumab, blood work indicated a relapse in prolongation of aPTT and TT. Blood loss through the chest drains increased from zero up to 1100 ml in 90 min (Table 1). Intravenous norepinephrine and fluid requirements increased. One unit of platelet concentrate (PC), three units of PRBCs, fibrinogen concentrate 4 g, 4F-PCC 1200 IU (Prothromplex Total®, Baxter, Vienna), Factor XIII concentrate 1250 IU (Fibrogammin®, CSL Behring, Germany), and tranexamic acid 1 g were administered primarily suspecting traumatic bleeding. Despite this intensive medical management following the European trauma guidelines, stabilisation was not achieved [5,6]. Finally, another half-dose of idarucizumab (2.5 g) was given, to treat the possibility of incomplete reversal of dabigatran-induced coagulopathy. Hereafter, the patient's condition stabilised promptly. With decreased catecholamine requirement and bleeding cessation we resigned from completing to a second full-dose of 5 g [7]. Laboratory work-up showed almost normal aPTT and TT values, further improving over the next 12 h (Table 1). Dabigatran plasma levels 12 h after 7.5 g of idarucizumab were beneath detectability, indicating sufficient long-term reversal. The patient was referred back to the county hospital after 17 days with subsequent transfer to a rehabilitation facility two weeks later.
Discussion
In this case, dabigatran serum levels were not measured sequentially. The link to ongoing bleeding and abnormal coagulation values is therefor made more difficult. Although plasma level concentrations of dabigatran may not be useful for measuring the antagonistic effects of idarucizumab [3] they can be used to predict possible dabigatran rebound when measured prior to administration [8]. Bleeding-related coagulopathy was treated according to the rotational thrombelastometry results (ROTEMdelta®, Instrumentation Laboratory, Bedford MA, USA). While ROTEM maximal clot firmness stays unaffected, other haemostatic tests relying on thrombin (e.g. aPTT, TT, fibrinogen) are inaccurate in the presence of high dabigatran levels due to thrombin inactivation [4]. Other considerable factors maybe contributing to the coagulopathic state of this patient include dilutional coagulopathy, disseminated intravascular coagulation and trauma-related coagulopathy. They can be excluded by the ROTEM findings or missing triggers. Factor-specific inheritable deficiencies and liver or renal failure are not supported by history or laboratory values. Finally, our suspicion was confirmed by prompt cessation of bleeding as well as hemodynamic stabilisation after another half-dose of idarucizumab.
Conclusion
We conclude that a dabigatran-related coagulopathy contributed to massive bleeding in a multiple traumatised patient. An increasing number of patients admitted to the ER are treated with directly acting oral thrombin inhibitors. In the absence of feasible plasma level testing, screening for aPTT and TT can be beneficial for identifying patients at risk but can also support early detection of non-responders to antidote therapy. Patients treated with dabigatran and presenting with active bleeding require close attention to its reversal with standard doses of idarucizumab.
CRediT authorship contribution statement
MS designed the study, collected and interpreted the data and drafted the article. CR and SS contributed to data collection and drafted the article. DF and EO revised the article and contributed to the final article.
Patient consent
The patient in this manuscript has given written informed consent to publication of his case details.
Assistance with the article
None.
Financial support and sponsorship
This research received no specific grant / financial support or sponsorship from any funding agency in the public, commercial or not-for-profit sectors.
Declaration of competing interest
MS, CR, SS and EO none. DF has received personal fees for lectures or similar in the past, independent of the presented manuscript. DF has received personal fees from 10.13039/100008322CSL Behring GmbH, from LFB, and BBraun and non-financial support from TEM International, outside the submitted work. | 1250 INTERNATIONAL UNIT | DrugDosageText | CC BY | 33665315 | 20,038,151 | 2021-04 |
What was the dosage of drug 'DABIGATRAN'? | Difficult reversal of dabigatran with idarucizumab in a multiple-trauma patient: A question of dose?
Dabigatran is an oral anticoagulant directly acting as thrombin inhibitor. The monoclonal antibody idarucizumab was developed to reverse its anticoagulatory effects after application of a standardized dose. Following administration, dabigatran plasma level rebounds have been reported but its consequences are not fully understood. We report a case of a multiple-trauma patient under dabigatran treatment suffering from secondary bleeding relapse after initially successful reversal with idarucizumab. Stabilisation of the patient's coagulopathy and subsequent bleeding was not achieved until application of an additional dose of idarucizumab. We conclude that patients treated with dabigatran and presenting with active bleeding require close attention to its reversal with standard doses of idarucizumab. Screening for thrombin time was shown beneficial in early detection of dabigatran rebound in this case.
Introduction
Dabigatran, a direct thrombin inhibitor, is primarily eliminated in the urine with a terminal half-life of 12–17 h in healthy patients. Its anticoagulatory effects can be rapidly reversed with idarucizumab which binds both free and thrombin-bound dabigatran (two bolus injections of 2.5 g reduce dabigatran plasma concentrations >99% [1]) [2]. The terminal half-life of idarucizumab is 10.3 h. The REVERSE-AD trial reported a dabigatran plasma level rebound in 23% of all cases resulting in 2% bleeding relapse following idarucizumab treatment [2]. Other case reports have described dabigatran rebound 7 to 61 h after initial idarucizumab administration requiring repeated dosage [2,3]. Being a hydrophilic molecule, dabigatran can easily move between intra- and extravascular compartments and it is thought that a variable intravascular concentration may account for rebound bleeding accompanied by fluctuating coagulation parameters. Therefore, a single dose of idarucizumab might not be sufficient to completely neutralise dabigatran's effects [4].
Case
We report our experience with a poly-trauma patient whose medical management was likely compromised by severe coagulopathy secondary to dabigatran. This 83-year-old Caucasian male (83 kg, 180 cm) fell from a ladder and suffered multiple injuries resulting in an injury severity score of 34. He had been prescribed dabigatran 110 mg bid since 2011 for atrial fibrillation, recurrent pulmonary embolism (2003 and 2011) and transient ischemic attacks (2018). The last dose of dabigatran was 9 h prior to trauma. Blood creatinine was 1.5 mg/dl. Other medications included bisoprolol 1.25 mg qd, lisinopril 10 mg qd, simvastatin 40 mg qd, pantoprazole 40 mg qd and allopurinol 300 mg qd. Further comorbidities were hypertension, hyperlipidaemia, gout and an inguinal hernia. No allergies were reported, and the patient did not have a history of easy bleeding/bruising prior to dabigatran treatment. INR prior to trauma was between 1.4 and 2.3 (0.8–1.3).
The patient was initially treated in the ER of a county hospital. An arterial and central venous line were placed, the patient was intubated and ventilated. The contrast-enhanced whole-body CT indicated a subarachnoid 9 mm bleeding, bilateral haematopneumothoraces with lung contusions, left sided rib fractures II-XII, bilateral clavicular fractures, I-III lumbar fracture, minor spleen lesion and a psoas hematoma. Both thoracic cavities were drained. The patient was transfused with 1500 ml balanced crystalloids (ELO-MEL®, Fresenius, Germany), 500 ml succinylated gelatine (Gelofusin®, BBraun, Germany) and 2 units of packed red blood cells (PRBCs) and required intravenous administration of norepinephrine (>0.25 μg kg-1 min-1) to maintain stable hemodynamic parameters (Table 1). Blood work indicated a prolonged aPTT (activated partial thromboplastin time) and elevated INR (international normalised ratio; Table 1). Medical treatment included administration of fibrinogen concentrate 2 g (Haemocomplettan®, CSL Behring, Germany), tranexamic acid 1 g and idarucizumab 5 g, as recommended. The bleeding situation improved markedly. Due to injury severity the patient was transferred to our Level I trauma centre. On arrival, blood work showed only slightly prolonged aPTT and TT (thrombin time). Coagulation tests used, were Pathromtin SL assay® for aPTT, Thromborel S assay® for PT, BC Thrombin assay® for TT and Multifibren U (Clauss) assay® for fibrinogen, all Siemens, Marburg, Germany. Lowered fibrinogen was substituted with another dose of 2 g. Fluid resuscitation included administration of 500 ml of crystalloids, 500 ml of succinylated gelatine, and one unit of PRBC.Table 1 Timeline of treatment, blood samples and patient condition.
Table 1 Time of accident Arrival minor trauma Center Arrival major trauma Center Arrival ICU department
Day 1 Day 2
16:00 17:30 18:00 21:00 21:25 22:30 23:19 00:16 00:51 01:19 05:23 13:53
Blood values
Thrombin time (sec, 15–21) 28 89 29 26 20
aPTT (sec, 26–37) 60 49 185 57 49 46
INR (PT) 1.7 1.6 2.0 1.6 1.5 1.4
Fibrinogen (mg/ dl, 210–400) 75 103 208 220 242
Plt (g l−1, 150–380) 148 94 79 84 73 65
Hgb (g dl−1, 13.0–17.7) 12.7 11.2 8.1 8.1 9.2 9.7
FXIII (%, 70–140) 61 52 57 71 55
Lactate (mmol l−1, 0.63–2.44) 1.77 2.44 2.33 1.11 3.55 1.88
Dabigatran (ng ml−1) <20
ROTEM
INTEM CT (s, 100–240) 192 172 169 172
CFT (s, 30–110) 223 174 138 133
MCF (mm, 50–72) 50 53 54 53
LI30 (%, 94–100) 100 100 100 100
LI60 (%, 85–100) 100 100 99 98
A10 (mm, 44–66) 35 39 41 43
EXTEM CT (s, 38–79) 83 61 57 50
CFT (s, 34–159) 178 159 131 117
MCF (mm, 50–72) 52 54 56 58
LI30 (%, 94–100) 100 100 100 100
LI60 (%, 85–100) 100 100 100 99
A10 (mm, 43–65) 39 41 44 47
FIBTEM MCF (mm, 9–25) 4 9 16 16
A10 (mm, 7–23) 4 7 13 14
Treatment
Crystalloids (ml) 1500 500
Colloids (ml) 500 500 500 500 500 500
PRBC 2 1 3
PC 1
Fibrinogen Concentrate (g) 2 2 4
4F-PCC (IE) 1200
Factor XIII Concentrate 1250
Tranexamic Acid (g) 1 1
Idarucizumab (g) 5 2.5
Norepinephrine (µg kg−1 min−1) 0.25 0.3 0.4 0.4 0.4 0.4 0.3 0.3 0.25 0.1 0.1 0.1
Chest drain effusion (ml) ~1000 150 300 650
aPTT = activated Partial Thromboplastin Time, INR = International Normalised Ratio; Plt = Platelets, Hgb = Haemoglobin, ROTEM = rotational thromboelastometry; CT = Clotting Time; CFT = Clot Forming Time; MCF = Maximum Clot Firmness; LI30 = Lysis Index 30 min; LI60 = Lysis Index 60 min; A10 = Amplitude 10 min; PRBC = packed red blood cell; PC = platelet concentrate; 4F-PCC = 4-factor prothrombin complex concentrate.
About 5 h after recommended dosage of idarucizumab, blood work indicated a relapse in prolongation of aPTT and TT. Blood loss through the chest drains increased from zero up to 1100 ml in 90 min (Table 1). Intravenous norepinephrine and fluid requirements increased. One unit of platelet concentrate (PC), three units of PRBCs, fibrinogen concentrate 4 g, 4F-PCC 1200 IU (Prothromplex Total®, Baxter, Vienna), Factor XIII concentrate 1250 IU (Fibrogammin®, CSL Behring, Germany), and tranexamic acid 1 g were administered primarily suspecting traumatic bleeding. Despite this intensive medical management following the European trauma guidelines, stabilisation was not achieved [5,6]. Finally, another half-dose of idarucizumab (2.5 g) was given, to treat the possibility of incomplete reversal of dabigatran-induced coagulopathy. Hereafter, the patient's condition stabilised promptly. With decreased catecholamine requirement and bleeding cessation we resigned from completing to a second full-dose of 5 g [7]. Laboratory work-up showed almost normal aPTT and TT values, further improving over the next 12 h (Table 1). Dabigatran plasma levels 12 h after 7.5 g of idarucizumab were beneath detectability, indicating sufficient long-term reversal. The patient was referred back to the county hospital after 17 days with subsequent transfer to a rehabilitation facility two weeks later.
Discussion
In this case, dabigatran serum levels were not measured sequentially. The link to ongoing bleeding and abnormal coagulation values is therefor made more difficult. Although plasma level concentrations of dabigatran may not be useful for measuring the antagonistic effects of idarucizumab [3] they can be used to predict possible dabigatran rebound when measured prior to administration [8]. Bleeding-related coagulopathy was treated according to the rotational thrombelastometry results (ROTEMdelta®, Instrumentation Laboratory, Bedford MA, USA). While ROTEM maximal clot firmness stays unaffected, other haemostatic tests relying on thrombin (e.g. aPTT, TT, fibrinogen) are inaccurate in the presence of high dabigatran levels due to thrombin inactivation [4]. Other considerable factors maybe contributing to the coagulopathic state of this patient include dilutional coagulopathy, disseminated intravascular coagulation and trauma-related coagulopathy. They can be excluded by the ROTEM findings or missing triggers. Factor-specific inheritable deficiencies and liver or renal failure are not supported by history or laboratory values. Finally, our suspicion was confirmed by prompt cessation of bleeding as well as hemodynamic stabilisation after another half-dose of idarucizumab.
Conclusion
We conclude that a dabigatran-related coagulopathy contributed to massive bleeding in a multiple traumatised patient. An increasing number of patients admitted to the ER are treated with directly acting oral thrombin inhibitors. In the absence of feasible plasma level testing, screening for aPTT and TT can be beneficial for identifying patients at risk but can also support early detection of non-responders to antidote therapy. Patients treated with dabigatran and presenting with active bleeding require close attention to its reversal with standard doses of idarucizumab.
CRediT authorship contribution statement
MS designed the study, collected and interpreted the data and drafted the article. CR and SS contributed to data collection and drafted the article. DF and EO revised the article and contributed to the final article.
Patient consent
The patient in this manuscript has given written informed consent to publication of his case details.
Assistance with the article
None.
Financial support and sponsorship
This research received no specific grant / financial support or sponsorship from any funding agency in the public, commercial or not-for-profit sectors.
Declaration of competing interest
MS, CR, SS and EO none. DF has received personal fees for lectures or similar in the past, independent of the presented manuscript. DF has received personal fees from 10.13039/100008322CSL Behring GmbH, from LFB, and BBraun and non-financial support from TEM International, outside the submitted work. | 220 MILLIGRAM, QD (110 MILLIGRAM, BID) | DrugDosageText | CC BY | 33665315 | 20,038,151 | 2021-04 |
What was the dosage of drug 'FACTOR XIII CONCENTRATE (HUMAN)'? | Difficult reversal of dabigatran with idarucizumab in a multiple-trauma patient: A question of dose?
Dabigatran is an oral anticoagulant directly acting as thrombin inhibitor. The monoclonal antibody idarucizumab was developed to reverse its anticoagulatory effects after application of a standardized dose. Following administration, dabigatran plasma level rebounds have been reported but its consequences are not fully understood. We report a case of a multiple-trauma patient under dabigatran treatment suffering from secondary bleeding relapse after initially successful reversal with idarucizumab. Stabilisation of the patient's coagulopathy and subsequent bleeding was not achieved until application of an additional dose of idarucizumab. We conclude that patients treated with dabigatran and presenting with active bleeding require close attention to its reversal with standard doses of idarucizumab. Screening for thrombin time was shown beneficial in early detection of dabigatran rebound in this case.
Introduction
Dabigatran, a direct thrombin inhibitor, is primarily eliminated in the urine with a terminal half-life of 12–17 h in healthy patients. Its anticoagulatory effects can be rapidly reversed with idarucizumab which binds both free and thrombin-bound dabigatran (two bolus injections of 2.5 g reduce dabigatran plasma concentrations >99% [1]) [2]. The terminal half-life of idarucizumab is 10.3 h. The REVERSE-AD trial reported a dabigatran plasma level rebound in 23% of all cases resulting in 2% bleeding relapse following idarucizumab treatment [2]. Other case reports have described dabigatran rebound 7 to 61 h after initial idarucizumab administration requiring repeated dosage [2,3]. Being a hydrophilic molecule, dabigatran can easily move between intra- and extravascular compartments and it is thought that a variable intravascular concentration may account for rebound bleeding accompanied by fluctuating coagulation parameters. Therefore, a single dose of idarucizumab might not be sufficient to completely neutralise dabigatran's effects [4].
Case
We report our experience with a poly-trauma patient whose medical management was likely compromised by severe coagulopathy secondary to dabigatran. This 83-year-old Caucasian male (83 kg, 180 cm) fell from a ladder and suffered multiple injuries resulting in an injury severity score of 34. He had been prescribed dabigatran 110 mg bid since 2011 for atrial fibrillation, recurrent pulmonary embolism (2003 and 2011) and transient ischemic attacks (2018). The last dose of dabigatran was 9 h prior to trauma. Blood creatinine was 1.5 mg/dl. Other medications included bisoprolol 1.25 mg qd, lisinopril 10 mg qd, simvastatin 40 mg qd, pantoprazole 40 mg qd and allopurinol 300 mg qd. Further comorbidities were hypertension, hyperlipidaemia, gout and an inguinal hernia. No allergies were reported, and the patient did not have a history of easy bleeding/bruising prior to dabigatran treatment. INR prior to trauma was between 1.4 and 2.3 (0.8–1.3).
The patient was initially treated in the ER of a county hospital. An arterial and central venous line were placed, the patient was intubated and ventilated. The contrast-enhanced whole-body CT indicated a subarachnoid 9 mm bleeding, bilateral haematopneumothoraces with lung contusions, left sided rib fractures II-XII, bilateral clavicular fractures, I-III lumbar fracture, minor spleen lesion and a psoas hematoma. Both thoracic cavities were drained. The patient was transfused with 1500 ml balanced crystalloids (ELO-MEL®, Fresenius, Germany), 500 ml succinylated gelatine (Gelofusin®, BBraun, Germany) and 2 units of packed red blood cells (PRBCs) and required intravenous administration of norepinephrine (>0.25 μg kg-1 min-1) to maintain stable hemodynamic parameters (Table 1). Blood work indicated a prolonged aPTT (activated partial thromboplastin time) and elevated INR (international normalised ratio; Table 1). Medical treatment included administration of fibrinogen concentrate 2 g (Haemocomplettan®, CSL Behring, Germany), tranexamic acid 1 g and idarucizumab 5 g, as recommended. The bleeding situation improved markedly. Due to injury severity the patient was transferred to our Level I trauma centre. On arrival, blood work showed only slightly prolonged aPTT and TT (thrombin time). Coagulation tests used, were Pathromtin SL assay® for aPTT, Thromborel S assay® for PT, BC Thrombin assay® for TT and Multifibren U (Clauss) assay® for fibrinogen, all Siemens, Marburg, Germany. Lowered fibrinogen was substituted with another dose of 2 g. Fluid resuscitation included administration of 500 ml of crystalloids, 500 ml of succinylated gelatine, and one unit of PRBC.Table 1 Timeline of treatment, blood samples and patient condition.
Table 1 Time of accident Arrival minor trauma Center Arrival major trauma Center Arrival ICU department
Day 1 Day 2
16:00 17:30 18:00 21:00 21:25 22:30 23:19 00:16 00:51 01:19 05:23 13:53
Blood values
Thrombin time (sec, 15–21) 28 89 29 26 20
aPTT (sec, 26–37) 60 49 185 57 49 46
INR (PT) 1.7 1.6 2.0 1.6 1.5 1.4
Fibrinogen (mg/ dl, 210–400) 75 103 208 220 242
Plt (g l−1, 150–380) 148 94 79 84 73 65
Hgb (g dl−1, 13.0–17.7) 12.7 11.2 8.1 8.1 9.2 9.7
FXIII (%, 70–140) 61 52 57 71 55
Lactate (mmol l−1, 0.63–2.44) 1.77 2.44 2.33 1.11 3.55 1.88
Dabigatran (ng ml−1) <20
ROTEM
INTEM CT (s, 100–240) 192 172 169 172
CFT (s, 30–110) 223 174 138 133
MCF (mm, 50–72) 50 53 54 53
LI30 (%, 94–100) 100 100 100 100
LI60 (%, 85–100) 100 100 99 98
A10 (mm, 44–66) 35 39 41 43
EXTEM CT (s, 38–79) 83 61 57 50
CFT (s, 34–159) 178 159 131 117
MCF (mm, 50–72) 52 54 56 58
LI30 (%, 94–100) 100 100 100 100
LI60 (%, 85–100) 100 100 100 99
A10 (mm, 43–65) 39 41 44 47
FIBTEM MCF (mm, 9–25) 4 9 16 16
A10 (mm, 7–23) 4 7 13 14
Treatment
Crystalloids (ml) 1500 500
Colloids (ml) 500 500 500 500 500 500
PRBC 2 1 3
PC 1
Fibrinogen Concentrate (g) 2 2 4
4F-PCC (IE) 1200
Factor XIII Concentrate 1250
Tranexamic Acid (g) 1 1
Idarucizumab (g) 5 2.5
Norepinephrine (µg kg−1 min−1) 0.25 0.3 0.4 0.4 0.4 0.4 0.3 0.3 0.25 0.1 0.1 0.1
Chest drain effusion (ml) ~1000 150 300 650
aPTT = activated Partial Thromboplastin Time, INR = International Normalised Ratio; Plt = Platelets, Hgb = Haemoglobin, ROTEM = rotational thromboelastometry; CT = Clotting Time; CFT = Clot Forming Time; MCF = Maximum Clot Firmness; LI30 = Lysis Index 30 min; LI60 = Lysis Index 60 min; A10 = Amplitude 10 min; PRBC = packed red blood cell; PC = platelet concentrate; 4F-PCC = 4-factor prothrombin complex concentrate.
About 5 h after recommended dosage of idarucizumab, blood work indicated a relapse in prolongation of aPTT and TT. Blood loss through the chest drains increased from zero up to 1100 ml in 90 min (Table 1). Intravenous norepinephrine and fluid requirements increased. One unit of platelet concentrate (PC), three units of PRBCs, fibrinogen concentrate 4 g, 4F-PCC 1200 IU (Prothromplex Total®, Baxter, Vienna), Factor XIII concentrate 1250 IU (Fibrogammin®, CSL Behring, Germany), and tranexamic acid 1 g were administered primarily suspecting traumatic bleeding. Despite this intensive medical management following the European trauma guidelines, stabilisation was not achieved [5,6]. Finally, another half-dose of idarucizumab (2.5 g) was given, to treat the possibility of incomplete reversal of dabigatran-induced coagulopathy. Hereafter, the patient's condition stabilised promptly. With decreased catecholamine requirement and bleeding cessation we resigned from completing to a second full-dose of 5 g [7]. Laboratory work-up showed almost normal aPTT and TT values, further improving over the next 12 h (Table 1). Dabigatran plasma levels 12 h after 7.5 g of idarucizumab were beneath detectability, indicating sufficient long-term reversal. The patient was referred back to the county hospital after 17 days with subsequent transfer to a rehabilitation facility two weeks later.
Discussion
In this case, dabigatran serum levels were not measured sequentially. The link to ongoing bleeding and abnormal coagulation values is therefor made more difficult. Although plasma level concentrations of dabigatran may not be useful for measuring the antagonistic effects of idarucizumab [3] they can be used to predict possible dabigatran rebound when measured prior to administration [8]. Bleeding-related coagulopathy was treated according to the rotational thrombelastometry results (ROTEMdelta®, Instrumentation Laboratory, Bedford MA, USA). While ROTEM maximal clot firmness stays unaffected, other haemostatic tests relying on thrombin (e.g. aPTT, TT, fibrinogen) are inaccurate in the presence of high dabigatran levels due to thrombin inactivation [4]. Other considerable factors maybe contributing to the coagulopathic state of this patient include dilutional coagulopathy, disseminated intravascular coagulation and trauma-related coagulopathy. They can be excluded by the ROTEM findings or missing triggers. Factor-specific inheritable deficiencies and liver or renal failure are not supported by history or laboratory values. Finally, our suspicion was confirmed by prompt cessation of bleeding as well as hemodynamic stabilisation after another half-dose of idarucizumab.
Conclusion
We conclude that a dabigatran-related coagulopathy contributed to massive bleeding in a multiple traumatised patient. An increasing number of patients admitted to the ER are treated with directly acting oral thrombin inhibitors. In the absence of feasible plasma level testing, screening for aPTT and TT can be beneficial for identifying patients at risk but can also support early detection of non-responders to antidote therapy. Patients treated with dabigatran and presenting with active bleeding require close attention to its reversal with standard doses of idarucizumab.
CRediT authorship contribution statement
MS designed the study, collected and interpreted the data and drafted the article. CR and SS contributed to data collection and drafted the article. DF and EO revised the article and contributed to the final article.
Patient consent
The patient in this manuscript has given written informed consent to publication of his case details.
Assistance with the article
None.
Financial support and sponsorship
This research received no specific grant / financial support or sponsorship from any funding agency in the public, commercial or not-for-profit sectors.
Declaration of competing interest
MS, CR, SS and EO none. DF has received personal fees for lectures or similar in the past, independent of the presented manuscript. DF has received personal fees from 10.13039/100008322CSL Behring GmbH, from LFB, and BBraun and non-financial support from TEM International, outside the submitted work. | 1250 INTERNATIONAL UNIT, TOTAL (1250 INTERNATIONAL UNIT, TOT) | DrugDosageText | CC BY | 33665315 | 20,038,151 | 2021-04 |
What was the dosage of drug 'TRANEXAMIC ACID'? | Difficult reversal of dabigatran with idarucizumab in a multiple-trauma patient: A question of dose?
Dabigatran is an oral anticoagulant directly acting as thrombin inhibitor. The monoclonal antibody idarucizumab was developed to reverse its anticoagulatory effects after application of a standardized dose. Following administration, dabigatran plasma level rebounds have been reported but its consequences are not fully understood. We report a case of a multiple-trauma patient under dabigatran treatment suffering from secondary bleeding relapse after initially successful reversal with idarucizumab. Stabilisation of the patient's coagulopathy and subsequent bleeding was not achieved until application of an additional dose of idarucizumab. We conclude that patients treated with dabigatran and presenting with active bleeding require close attention to its reversal with standard doses of idarucizumab. Screening for thrombin time was shown beneficial in early detection of dabigatran rebound in this case.
Introduction
Dabigatran, a direct thrombin inhibitor, is primarily eliminated in the urine with a terminal half-life of 12–17 h in healthy patients. Its anticoagulatory effects can be rapidly reversed with idarucizumab which binds both free and thrombin-bound dabigatran (two bolus injections of 2.5 g reduce dabigatran plasma concentrations >99% [1]) [2]. The terminal half-life of idarucizumab is 10.3 h. The REVERSE-AD trial reported a dabigatran plasma level rebound in 23% of all cases resulting in 2% bleeding relapse following idarucizumab treatment [2]. Other case reports have described dabigatran rebound 7 to 61 h after initial idarucizumab administration requiring repeated dosage [2,3]. Being a hydrophilic molecule, dabigatran can easily move between intra- and extravascular compartments and it is thought that a variable intravascular concentration may account for rebound bleeding accompanied by fluctuating coagulation parameters. Therefore, a single dose of idarucizumab might not be sufficient to completely neutralise dabigatran's effects [4].
Case
We report our experience with a poly-trauma patient whose medical management was likely compromised by severe coagulopathy secondary to dabigatran. This 83-year-old Caucasian male (83 kg, 180 cm) fell from a ladder and suffered multiple injuries resulting in an injury severity score of 34. He had been prescribed dabigatran 110 mg bid since 2011 for atrial fibrillation, recurrent pulmonary embolism (2003 and 2011) and transient ischemic attacks (2018). The last dose of dabigatran was 9 h prior to trauma. Blood creatinine was 1.5 mg/dl. Other medications included bisoprolol 1.25 mg qd, lisinopril 10 mg qd, simvastatin 40 mg qd, pantoprazole 40 mg qd and allopurinol 300 mg qd. Further comorbidities were hypertension, hyperlipidaemia, gout and an inguinal hernia. No allergies were reported, and the patient did not have a history of easy bleeding/bruising prior to dabigatran treatment. INR prior to trauma was between 1.4 and 2.3 (0.8–1.3).
The patient was initially treated in the ER of a county hospital. An arterial and central venous line were placed, the patient was intubated and ventilated. The contrast-enhanced whole-body CT indicated a subarachnoid 9 mm bleeding, bilateral haematopneumothoraces with lung contusions, left sided rib fractures II-XII, bilateral clavicular fractures, I-III lumbar fracture, minor spleen lesion and a psoas hematoma. Both thoracic cavities were drained. The patient was transfused with 1500 ml balanced crystalloids (ELO-MEL®, Fresenius, Germany), 500 ml succinylated gelatine (Gelofusin®, BBraun, Germany) and 2 units of packed red blood cells (PRBCs) and required intravenous administration of norepinephrine (>0.25 μg kg-1 min-1) to maintain stable hemodynamic parameters (Table 1). Blood work indicated a prolonged aPTT (activated partial thromboplastin time) and elevated INR (international normalised ratio; Table 1). Medical treatment included administration of fibrinogen concentrate 2 g (Haemocomplettan®, CSL Behring, Germany), tranexamic acid 1 g and idarucizumab 5 g, as recommended. The bleeding situation improved markedly. Due to injury severity the patient was transferred to our Level I trauma centre. On arrival, blood work showed only slightly prolonged aPTT and TT (thrombin time). Coagulation tests used, were Pathromtin SL assay® for aPTT, Thromborel S assay® for PT, BC Thrombin assay® for TT and Multifibren U (Clauss) assay® for fibrinogen, all Siemens, Marburg, Germany. Lowered fibrinogen was substituted with another dose of 2 g. Fluid resuscitation included administration of 500 ml of crystalloids, 500 ml of succinylated gelatine, and one unit of PRBC.Table 1 Timeline of treatment, blood samples and patient condition.
Table 1 Time of accident Arrival minor trauma Center Arrival major trauma Center Arrival ICU department
Day 1 Day 2
16:00 17:30 18:00 21:00 21:25 22:30 23:19 00:16 00:51 01:19 05:23 13:53
Blood values
Thrombin time (sec, 15–21) 28 89 29 26 20
aPTT (sec, 26–37) 60 49 185 57 49 46
INR (PT) 1.7 1.6 2.0 1.6 1.5 1.4
Fibrinogen (mg/ dl, 210–400) 75 103 208 220 242
Plt (g l−1, 150–380) 148 94 79 84 73 65
Hgb (g dl−1, 13.0–17.7) 12.7 11.2 8.1 8.1 9.2 9.7
FXIII (%, 70–140) 61 52 57 71 55
Lactate (mmol l−1, 0.63–2.44) 1.77 2.44 2.33 1.11 3.55 1.88
Dabigatran (ng ml−1) <20
ROTEM
INTEM CT (s, 100–240) 192 172 169 172
CFT (s, 30–110) 223 174 138 133
MCF (mm, 50–72) 50 53 54 53
LI30 (%, 94–100) 100 100 100 100
LI60 (%, 85–100) 100 100 99 98
A10 (mm, 44–66) 35 39 41 43
EXTEM CT (s, 38–79) 83 61 57 50
CFT (s, 34–159) 178 159 131 117
MCF (mm, 50–72) 52 54 56 58
LI30 (%, 94–100) 100 100 100 100
LI60 (%, 85–100) 100 100 100 99
A10 (mm, 43–65) 39 41 44 47
FIBTEM MCF (mm, 9–25) 4 9 16 16
A10 (mm, 7–23) 4 7 13 14
Treatment
Crystalloids (ml) 1500 500
Colloids (ml) 500 500 500 500 500 500
PRBC 2 1 3
PC 1
Fibrinogen Concentrate (g) 2 2 4
4F-PCC (IE) 1200
Factor XIII Concentrate 1250
Tranexamic Acid (g) 1 1
Idarucizumab (g) 5 2.5
Norepinephrine (µg kg−1 min−1) 0.25 0.3 0.4 0.4 0.4 0.4 0.3 0.3 0.25 0.1 0.1 0.1
Chest drain effusion (ml) ~1000 150 300 650
aPTT = activated Partial Thromboplastin Time, INR = International Normalised Ratio; Plt = Platelets, Hgb = Haemoglobin, ROTEM = rotational thromboelastometry; CT = Clotting Time; CFT = Clot Forming Time; MCF = Maximum Clot Firmness; LI30 = Lysis Index 30 min; LI60 = Lysis Index 60 min; A10 = Amplitude 10 min; PRBC = packed red blood cell; PC = platelet concentrate; 4F-PCC = 4-factor prothrombin complex concentrate.
About 5 h after recommended dosage of idarucizumab, blood work indicated a relapse in prolongation of aPTT and TT. Blood loss through the chest drains increased from zero up to 1100 ml in 90 min (Table 1). Intravenous norepinephrine and fluid requirements increased. One unit of platelet concentrate (PC), three units of PRBCs, fibrinogen concentrate 4 g, 4F-PCC 1200 IU (Prothromplex Total®, Baxter, Vienna), Factor XIII concentrate 1250 IU (Fibrogammin®, CSL Behring, Germany), and tranexamic acid 1 g were administered primarily suspecting traumatic bleeding. Despite this intensive medical management following the European trauma guidelines, stabilisation was not achieved [5,6]. Finally, another half-dose of idarucizumab (2.5 g) was given, to treat the possibility of incomplete reversal of dabigatran-induced coagulopathy. Hereafter, the patient's condition stabilised promptly. With decreased catecholamine requirement and bleeding cessation we resigned from completing to a second full-dose of 5 g [7]. Laboratory work-up showed almost normal aPTT and TT values, further improving over the next 12 h (Table 1). Dabigatran plasma levels 12 h after 7.5 g of idarucizumab were beneath detectability, indicating sufficient long-term reversal. The patient was referred back to the county hospital after 17 days with subsequent transfer to a rehabilitation facility two weeks later.
Discussion
In this case, dabigatran serum levels were not measured sequentially. The link to ongoing bleeding and abnormal coagulation values is therefor made more difficult. Although plasma level concentrations of dabigatran may not be useful for measuring the antagonistic effects of idarucizumab [3] they can be used to predict possible dabigatran rebound when measured prior to administration [8]. Bleeding-related coagulopathy was treated according to the rotational thrombelastometry results (ROTEMdelta®, Instrumentation Laboratory, Bedford MA, USA). While ROTEM maximal clot firmness stays unaffected, other haemostatic tests relying on thrombin (e.g. aPTT, TT, fibrinogen) are inaccurate in the presence of high dabigatran levels due to thrombin inactivation [4]. Other considerable factors maybe contributing to the coagulopathic state of this patient include dilutional coagulopathy, disseminated intravascular coagulation and trauma-related coagulopathy. They can be excluded by the ROTEM findings or missing triggers. Factor-specific inheritable deficiencies and liver or renal failure are not supported by history or laboratory values. Finally, our suspicion was confirmed by prompt cessation of bleeding as well as hemodynamic stabilisation after another half-dose of idarucizumab.
Conclusion
We conclude that a dabigatran-related coagulopathy contributed to massive bleeding in a multiple traumatised patient. An increasing number of patients admitted to the ER are treated with directly acting oral thrombin inhibitors. In the absence of feasible plasma level testing, screening for aPTT and TT can be beneficial for identifying patients at risk but can also support early detection of non-responders to antidote therapy. Patients treated with dabigatran and presenting with active bleeding require close attention to its reversal with standard doses of idarucizumab.
CRediT authorship contribution statement
MS designed the study, collected and interpreted the data and drafted the article. CR and SS contributed to data collection and drafted the article. DF and EO revised the article and contributed to the final article.
Patient consent
The patient in this manuscript has given written informed consent to publication of his case details.
Assistance with the article
None.
Financial support and sponsorship
This research received no specific grant / financial support or sponsorship from any funding agency in the public, commercial or not-for-profit sectors.
Declaration of competing interest
MS, CR, SS and EO none. DF has received personal fees for lectures or similar in the past, independent of the presented manuscript. DF has received personal fees from 10.13039/100008322CSL Behring GmbH, from LFB, and BBraun and non-financial support from TEM International, outside the submitted work. | 1 GRAM, TOTAL | DrugDosageText | CC BY | 33665315 | 20,038,151 | 2021-04 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Fall'. | "Ciprofloxacin-induced" bilateral quadriceps tendon rupture: A case report and conclusions of the recent literature.
The potential risk of fluoroquinolones on the musculoskeletal tissue, and tendinous structures in particular, has been known since its introduction in the 1980s. Following reports of serious and persistent side effects in their national registry, the German medicines authority (BfArM) has requested the European Medicines Agency (EMA) to conclude a safety review focusing on long-lasting effects mainly affecting the musculoskeletal and nervous systems. This review, published in early 2019, led to restriction of the usage of fluoroquinolones due to the risk of disabling and potentially long-term side effects. Furthermore, there have been a number of meta-analyses published in the recent years, which brought more clarity to the extent of fluoroquinolones' possible side effects. With this case report followed by an overview of the latest evidence, we would like to highlight these latest efforts in the quest to prescribe fluoroquinolones cautiously and sensitize physicians to this topic.
Case history
A 59-year old male teacher, with no pre-existing medical comorbidities other than hyperplasia of the prostate, presented to our emergency department with inability to walk and pain on the upper margins of his patella on both sides. He reported playing football with some friends, as he suddenly slumped to the ground while trying to pass the ball without any adversary contact. He didn't describe any pain located around his knees before the incident and has neither been treated for any disease nor trauma on his lower limbs. Other than tamsulosin for his prostate hyperplasia, he was on no regular medication. His medical history was significant only for completing a 24-day course of ciprofloxacin for a prostate infection a year before the incident.
On physical examination, swelling was recognized as well as dimples during palpation on top of both kneecaps. He was unable to extend both knees and a positive leg raise test was seen bilaterally. There were no other deficits in power, sensation or proprioception in either lower limb. Knee x-rays showed an unusual contour of the suprapatellar soft tissue bilaterally, with a sagging of both suprapatellar regions, radiographically indicating bilateral quadriceps tendon rupture (Fig. 1). On the right knee, a CT-scan was performed to rule out any osseous lesion, whereby the suspicion of a quadriceps rupture became more concrete. Due to the distinctive clinical presentation of complete tendon rupture bilaterally, no further diagnostics were initiated, and the patient was treated operatively the next day.Fig. 1 Bilateral Knee x-rays on the day of the incident.
Fig. 1
Intraoperatively, the clinical findings of complete tears of the quadriceps tendon on both sides were verified. The tear on the left side showed hardly any signs of a fresh tear, but a largely degenerated quadriceps tendon with fraying and fatty streaks within the tendon. No inserting fibers were left at the proximal pole of the patella, which led to the assumption that a degenerative, partial tear might have already existed prior to the incident. Also, the proximal part of the ruptured tendon on the right side showed degenerative signs with fraying and fatty strikes, but there were signs of a complete fresh tear with a few freshly ruptured fibers inserting at the proximal pole of the patella. Both tendons were readapted by a hybrid of suture anchors and transosseous tunnel repair technique.
Postoperatively, the patient remained full weight-bearing in extension for six weeks. Unfortunately, within the six weeks postoperatively our patient had an incident in which he slipped away with his right leg on the wet floor of his bathroom. For a couple of days, he felt self-limiting pain in the right leg. On clinical examination 6 weeks postoperatively, a well healing left lower limb could be seen with no extension lag. On the right side, a dimple could be palpated proximal to the patella around the scar, as well as diminished quadriceps contraction was observed. In the subsequently initiated magnetic resonance imaging (MRI) of the right knee, the clinical suspicion of a re-ruptured quadriceps tendon was confirmed.
In the operative revision of the re-ruptured right quadriceps tendon, a torn central suture was seen with a central defect of around 3 cm width and dehiscence of 2 cm. Due to the retraction and impaired quality of the quadriceps tendon, a V—Y plasty was performed with subsequent adaption to the patella by a hybrid of suture anchors and transosseous tunnel repair technique. Postoperative conventional radiographical and computer tomographic findings showed the medial anchor to be placed subchondral, which needed another operative revision with replacement of the aforesaid anchor. Postoperatively, full weight-bearing in extension for six weeks was initiated again.
In the latest outpatient consultation 10 months after surgical treatment on the left and 8 months after the revision surgery on the right quadriceps tendon, a well healing left knee could be observed with normal extension motor strength levels, as well as increasing range of motion (Flexion/Extension 130/0/0°) and no extension-lag. The right knee showed good range of motion (Flexion/Extension 120/0/0°) as well as close to normal extension motor strength levels without any extension-lag, but a persistent dent could be seen and palpated on the superior margin of the patella. The patient described to possess good stability and strength in the left leg, but persistent limited strength levels during climbing stairs and longer walks as well as faster exhaustion with consequent rare instability and giving-way symptomatic on the right side. In regard to these restrictions and the observed suprapatellar dimple, another MRI examination of the right knee was undertaken to assess the integrity of the quadriceps tendon. This MRI showed an intact right quadriceps tendon with elongated and persistent edematous alteration (Fig. 2). In order to address the persistent impaired strength and stability intensive muscular strength-training has been continued.Fig. 2 MRI examination of the right knee 8 months after surgical revision.
Fig. 2
Discussion
The toxicity of fluoroquinolones on musculoskeletal tissue has been acknowledged since its introduction in the 1980s. In the late 20th and the beginning of the 21st century, there has been a rising number of reported cases of tendon-related issues with this drug class, which has led the Food and Drug Administration (FDA) to add a ‘black box’ warning to fluoroquinolone antibiotics in 2008 – the most stringent warning there is [1]. Following reports of serious persistent side effects mainly affecting muscles, joints and the nervous system, recently, also the European Medicines Agency (EMA) concluded a safety review of fluoroquinolone antibiotics, which led to restriction of its use due to the risk of disabling and potentially long-term side effects (see Table 1) [2]. Tendinopathy and tendon ruptures after treatment with fluoroquinolones are almost exclusively seen in Achilles tendons [3]. Quadriceps tendon tears associated with fluoroquinolone therapy are hardly ever seen and we only found one other case report about this rare incident [4].Table 1 Recommendations endorsed by the EMA's human medicines committee (CHMP) on the use of fluoroquinolone antibiotics [4].
Table 1Restrictions on the use of fluoroquinolone antibiotics will mean that they should not be used:
• to treat infections that might get better without treatment or are not severe (such as throat infections).
• to treat non-bacterial infections, e.g. non-bacterial (chronic) prostatitis.
• for preventing traveler's diarrhea or recurring lower urinary tract infections (urine infections that do not extend beyond the bladder).
• to treat mild or moderate bacterial infections unless other antibacterial medicines commonly recommended for these infections cannot be used.
Acute quadriceps tendon rupture is a relatively rare injury (incidence 1.37/100′000), usually seen in middle-aged men [5]. The typical mechanism of injury is an indirect trauma with a violent contraction of the quadriceps muscle with the foot planted on the ground and the knee partially bent [6]. Besides fluoroquinolones, several pre-existing conditions increase the risk of quadriceps rupture such as obesity, systemic lupus erythematosus, rheumatoid arthritis, chronic renal failure, gout, hyperparathyroidism and corticosteroid intake [7]. Shah concludes in his risk analysis of 66 simultaneous, bilateral quadriceps tendon ruptures that younger patients with this injury should be evaluated for any underlying medical condition [8].
In our case, no other risk factor than the intake of ciprofloxacin a year before the incident was apparent. Besides, the relative atraumatic nature of the injury and the intraoperative findings of largely degenerated tendons on both sides imply ciprofloxacin to be the causative agent. The mechanism for fluoroquinolone-induced tendon rupture remains poorly understood but has been linked to the degradation of Type I collagen following alterations in the regulation of matrix metalloproteinases [9]. The resulting symptoms, such as sudden pain, tenderness to palpation, edema and difficulty with movement of the involved area, may appear as soon as 2 hours after first dose of fluoroquinolone. On average, the duration of fluoroquinolone therapy before the onset of tendon injury is 8 days [3]. However, as seen in our case and also stated by the EMA, they can cause long-lasting and potentially permanent side effects involving tendons, muscles and joints [2].
A number of recently published systematic reviews on this topic have underlined the increased risk of tendon injuries associated with fluoroquinolones. While generally spoken the odds ratio for any tendon disorder is roughly doubled after the intake of a fluoroquinolone therapy in the general population, it is of particular interest to identify high-risk populations, as they are at a substantially higher risk for tendon associated disabilities [10,11]. When one is trying to distinguish what patient is at particular risk, three criteria appear to possess a major role: age (>60 years), concomitant intake of corticosteroids and duration of the antibiotic therapy. In absolute measures, for a person under the age of 60 years who is prescribed to 5 days of a fluoroquinolone therapy a number needed to treat (NNT) to cause one additional tendon rupture of 1:521,429 (CI 405,556–730,000) results. Whereas for a person over the age of 60 years with a therapy duration of 28 days and concomitant corticosteroid intake the NNT to cause one additional tendon rupture increases to 1:6651 (CI 5173–8690) [12].
According to the FDA, the possible serious side effects of fluoroquinolones (incl. tendinous disorders) generally outweigh the benefits for patients with milder infections (for example acute bacterial sinusitis, acute bacterial exacerbation of chronic bronchitis, and uncomplicated urinary tract infections). Hence, fluoroquinolones should be reserved for these conditions only if no alternative treatment option exists [13]. Despite the aforementioned elevated risk for developing a tendinous disorder, fluoroquinolones are still commonly prescribed for treating milder infections [14].
In conclusion, in keeping with the warnings from the FDA and EMA, we strongly suggest that fluoroquinolones should only be prescribed after careful consideration for alternative treatment options, especially in patients with preexisting risk factors for developing tendinopathy. Furthermore, careful patient instruction regarding possible signs of tendon damage should be carried out when prescribing fluroquinolones.
CRediT authorship contribution statement
All authors contributed to the idea to report the case and had full access to all of the data in the study and take responsibility for the integrity of the data. All authors contributed to patient management. Acquisition, analysis, or interpretation of data: All authors. Drafting of the manuscript: CS and RT. Critical revision of the manuscript for important intellectual content: All authors. Clinical case presentation and management undertaken at Zuger Kantonsspital, Baar, Switzerland.
Declaration of competing interest
None.
Acknowledgements
We thank Paul Lauber for revising the manuscript. | CIPROFLOXACIN, TAMSULOSIN | DrugsGivenReaction | CC BY-NC-ND | 33665316 | 19,063,502 | 2021-04 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Gait inability'. | "Ciprofloxacin-induced" bilateral quadriceps tendon rupture: A case report and conclusions of the recent literature.
The potential risk of fluoroquinolones on the musculoskeletal tissue, and tendinous structures in particular, has been known since its introduction in the 1980s. Following reports of serious and persistent side effects in their national registry, the German medicines authority (BfArM) has requested the European Medicines Agency (EMA) to conclude a safety review focusing on long-lasting effects mainly affecting the musculoskeletal and nervous systems. This review, published in early 2019, led to restriction of the usage of fluoroquinolones due to the risk of disabling and potentially long-term side effects. Furthermore, there have been a number of meta-analyses published in the recent years, which brought more clarity to the extent of fluoroquinolones' possible side effects. With this case report followed by an overview of the latest evidence, we would like to highlight these latest efforts in the quest to prescribe fluoroquinolones cautiously and sensitize physicians to this topic.
Case history
A 59-year old male teacher, with no pre-existing medical comorbidities other than hyperplasia of the prostate, presented to our emergency department with inability to walk and pain on the upper margins of his patella on both sides. He reported playing football with some friends, as he suddenly slumped to the ground while trying to pass the ball without any adversary contact. He didn't describe any pain located around his knees before the incident and has neither been treated for any disease nor trauma on his lower limbs. Other than tamsulosin for his prostate hyperplasia, he was on no regular medication. His medical history was significant only for completing a 24-day course of ciprofloxacin for a prostate infection a year before the incident.
On physical examination, swelling was recognized as well as dimples during palpation on top of both kneecaps. He was unable to extend both knees and a positive leg raise test was seen bilaterally. There were no other deficits in power, sensation or proprioception in either lower limb. Knee x-rays showed an unusual contour of the suprapatellar soft tissue bilaterally, with a sagging of both suprapatellar regions, radiographically indicating bilateral quadriceps tendon rupture (Fig. 1). On the right knee, a CT-scan was performed to rule out any osseous lesion, whereby the suspicion of a quadriceps rupture became more concrete. Due to the distinctive clinical presentation of complete tendon rupture bilaterally, no further diagnostics were initiated, and the patient was treated operatively the next day.Fig. 1 Bilateral Knee x-rays on the day of the incident.
Fig. 1
Intraoperatively, the clinical findings of complete tears of the quadriceps tendon on both sides were verified. The tear on the left side showed hardly any signs of a fresh tear, but a largely degenerated quadriceps tendon with fraying and fatty streaks within the tendon. No inserting fibers were left at the proximal pole of the patella, which led to the assumption that a degenerative, partial tear might have already existed prior to the incident. Also, the proximal part of the ruptured tendon on the right side showed degenerative signs with fraying and fatty strikes, but there were signs of a complete fresh tear with a few freshly ruptured fibers inserting at the proximal pole of the patella. Both tendons were readapted by a hybrid of suture anchors and transosseous tunnel repair technique.
Postoperatively, the patient remained full weight-bearing in extension for six weeks. Unfortunately, within the six weeks postoperatively our patient had an incident in which he slipped away with his right leg on the wet floor of his bathroom. For a couple of days, he felt self-limiting pain in the right leg. On clinical examination 6 weeks postoperatively, a well healing left lower limb could be seen with no extension lag. On the right side, a dimple could be palpated proximal to the patella around the scar, as well as diminished quadriceps contraction was observed. In the subsequently initiated magnetic resonance imaging (MRI) of the right knee, the clinical suspicion of a re-ruptured quadriceps tendon was confirmed.
In the operative revision of the re-ruptured right quadriceps tendon, a torn central suture was seen with a central defect of around 3 cm width and dehiscence of 2 cm. Due to the retraction and impaired quality of the quadriceps tendon, a V—Y plasty was performed with subsequent adaption to the patella by a hybrid of suture anchors and transosseous tunnel repair technique. Postoperative conventional radiographical and computer tomographic findings showed the medial anchor to be placed subchondral, which needed another operative revision with replacement of the aforesaid anchor. Postoperatively, full weight-bearing in extension for six weeks was initiated again.
In the latest outpatient consultation 10 months after surgical treatment on the left and 8 months after the revision surgery on the right quadriceps tendon, a well healing left knee could be observed with normal extension motor strength levels, as well as increasing range of motion (Flexion/Extension 130/0/0°) and no extension-lag. The right knee showed good range of motion (Flexion/Extension 120/0/0°) as well as close to normal extension motor strength levels without any extension-lag, but a persistent dent could be seen and palpated on the superior margin of the patella. The patient described to possess good stability and strength in the left leg, but persistent limited strength levels during climbing stairs and longer walks as well as faster exhaustion with consequent rare instability and giving-way symptomatic on the right side. In regard to these restrictions and the observed suprapatellar dimple, another MRI examination of the right knee was undertaken to assess the integrity of the quadriceps tendon. This MRI showed an intact right quadriceps tendon with elongated and persistent edematous alteration (Fig. 2). In order to address the persistent impaired strength and stability intensive muscular strength-training has been continued.Fig. 2 MRI examination of the right knee 8 months after surgical revision.
Fig. 2
Discussion
The toxicity of fluoroquinolones on musculoskeletal tissue has been acknowledged since its introduction in the 1980s. In the late 20th and the beginning of the 21st century, there has been a rising number of reported cases of tendon-related issues with this drug class, which has led the Food and Drug Administration (FDA) to add a ‘black box’ warning to fluoroquinolone antibiotics in 2008 – the most stringent warning there is [1]. Following reports of serious persistent side effects mainly affecting muscles, joints and the nervous system, recently, also the European Medicines Agency (EMA) concluded a safety review of fluoroquinolone antibiotics, which led to restriction of its use due to the risk of disabling and potentially long-term side effects (see Table 1) [2]. Tendinopathy and tendon ruptures after treatment with fluoroquinolones are almost exclusively seen in Achilles tendons [3]. Quadriceps tendon tears associated with fluoroquinolone therapy are hardly ever seen and we only found one other case report about this rare incident [4].Table 1 Recommendations endorsed by the EMA's human medicines committee (CHMP) on the use of fluoroquinolone antibiotics [4].
Table 1Restrictions on the use of fluoroquinolone antibiotics will mean that they should not be used:
• to treat infections that might get better without treatment or are not severe (such as throat infections).
• to treat non-bacterial infections, e.g. non-bacterial (chronic) prostatitis.
• for preventing traveler's diarrhea or recurring lower urinary tract infections (urine infections that do not extend beyond the bladder).
• to treat mild or moderate bacterial infections unless other antibacterial medicines commonly recommended for these infections cannot be used.
Acute quadriceps tendon rupture is a relatively rare injury (incidence 1.37/100′000), usually seen in middle-aged men [5]. The typical mechanism of injury is an indirect trauma with a violent contraction of the quadriceps muscle with the foot planted on the ground and the knee partially bent [6]. Besides fluoroquinolones, several pre-existing conditions increase the risk of quadriceps rupture such as obesity, systemic lupus erythematosus, rheumatoid arthritis, chronic renal failure, gout, hyperparathyroidism and corticosteroid intake [7]. Shah concludes in his risk analysis of 66 simultaneous, bilateral quadriceps tendon ruptures that younger patients with this injury should be evaluated for any underlying medical condition [8].
In our case, no other risk factor than the intake of ciprofloxacin a year before the incident was apparent. Besides, the relative atraumatic nature of the injury and the intraoperative findings of largely degenerated tendons on both sides imply ciprofloxacin to be the causative agent. The mechanism for fluoroquinolone-induced tendon rupture remains poorly understood but has been linked to the degradation of Type I collagen following alterations in the regulation of matrix metalloproteinases [9]. The resulting symptoms, such as sudden pain, tenderness to palpation, edema and difficulty with movement of the involved area, may appear as soon as 2 hours after first dose of fluoroquinolone. On average, the duration of fluoroquinolone therapy before the onset of tendon injury is 8 days [3]. However, as seen in our case and also stated by the EMA, they can cause long-lasting and potentially permanent side effects involving tendons, muscles and joints [2].
A number of recently published systematic reviews on this topic have underlined the increased risk of tendon injuries associated with fluoroquinolones. While generally spoken the odds ratio for any tendon disorder is roughly doubled after the intake of a fluoroquinolone therapy in the general population, it is of particular interest to identify high-risk populations, as they are at a substantially higher risk for tendon associated disabilities [10,11]. When one is trying to distinguish what patient is at particular risk, three criteria appear to possess a major role: age (>60 years), concomitant intake of corticosteroids and duration of the antibiotic therapy. In absolute measures, for a person under the age of 60 years who is prescribed to 5 days of a fluoroquinolone therapy a number needed to treat (NNT) to cause one additional tendon rupture of 1:521,429 (CI 405,556–730,000) results. Whereas for a person over the age of 60 years with a therapy duration of 28 days and concomitant corticosteroid intake the NNT to cause one additional tendon rupture increases to 1:6651 (CI 5173–8690) [12].
According to the FDA, the possible serious side effects of fluoroquinolones (incl. tendinous disorders) generally outweigh the benefits for patients with milder infections (for example acute bacterial sinusitis, acute bacterial exacerbation of chronic bronchitis, and uncomplicated urinary tract infections). Hence, fluoroquinolones should be reserved for these conditions only if no alternative treatment option exists [13]. Despite the aforementioned elevated risk for developing a tendinous disorder, fluoroquinolones are still commonly prescribed for treating milder infections [14].
In conclusion, in keeping with the warnings from the FDA and EMA, we strongly suggest that fluoroquinolones should only be prescribed after careful consideration for alternative treatment options, especially in patients with preexisting risk factors for developing tendinopathy. Furthermore, careful patient instruction regarding possible signs of tendon damage should be carried out when prescribing fluroquinolones.
CRediT authorship contribution statement
All authors contributed to the idea to report the case and had full access to all of the data in the study and take responsibility for the integrity of the data. All authors contributed to patient management. Acquisition, analysis, or interpretation of data: All authors. Drafting of the manuscript: CS and RT. Critical revision of the manuscript for important intellectual content: All authors. Clinical case presentation and management undertaken at Zuger Kantonsspital, Baar, Switzerland.
Declaration of competing interest
None.
Acknowledgements
We thank Paul Lauber for revising the manuscript. | CIPROFLOXACIN, TAMSULOSIN | DrugsGivenReaction | CC BY-NC-ND | 33665316 | 19,063,502 | 2021-04 |
What was the outcome of reaction 'Fall'? | "Ciprofloxacin-induced" bilateral quadriceps tendon rupture: A case report and conclusions of the recent literature.
The potential risk of fluoroquinolones on the musculoskeletal tissue, and tendinous structures in particular, has been known since its introduction in the 1980s. Following reports of serious and persistent side effects in their national registry, the German medicines authority (BfArM) has requested the European Medicines Agency (EMA) to conclude a safety review focusing on long-lasting effects mainly affecting the musculoskeletal and nervous systems. This review, published in early 2019, led to restriction of the usage of fluoroquinolones due to the risk of disabling and potentially long-term side effects. Furthermore, there have been a number of meta-analyses published in the recent years, which brought more clarity to the extent of fluoroquinolones' possible side effects. With this case report followed by an overview of the latest evidence, we would like to highlight these latest efforts in the quest to prescribe fluoroquinolones cautiously and sensitize physicians to this topic.
Case history
A 59-year old male teacher, with no pre-existing medical comorbidities other than hyperplasia of the prostate, presented to our emergency department with inability to walk and pain on the upper margins of his patella on both sides. He reported playing football with some friends, as he suddenly slumped to the ground while trying to pass the ball without any adversary contact. He didn't describe any pain located around his knees before the incident and has neither been treated for any disease nor trauma on his lower limbs. Other than tamsulosin for his prostate hyperplasia, he was on no regular medication. His medical history was significant only for completing a 24-day course of ciprofloxacin for a prostate infection a year before the incident.
On physical examination, swelling was recognized as well as dimples during palpation on top of both kneecaps. He was unable to extend both knees and a positive leg raise test was seen bilaterally. There were no other deficits in power, sensation or proprioception in either lower limb. Knee x-rays showed an unusual contour of the suprapatellar soft tissue bilaterally, with a sagging of both suprapatellar regions, radiographically indicating bilateral quadriceps tendon rupture (Fig. 1). On the right knee, a CT-scan was performed to rule out any osseous lesion, whereby the suspicion of a quadriceps rupture became more concrete. Due to the distinctive clinical presentation of complete tendon rupture bilaterally, no further diagnostics were initiated, and the patient was treated operatively the next day.Fig. 1 Bilateral Knee x-rays on the day of the incident.
Fig. 1
Intraoperatively, the clinical findings of complete tears of the quadriceps tendon on both sides were verified. The tear on the left side showed hardly any signs of a fresh tear, but a largely degenerated quadriceps tendon with fraying and fatty streaks within the tendon. No inserting fibers were left at the proximal pole of the patella, which led to the assumption that a degenerative, partial tear might have already existed prior to the incident. Also, the proximal part of the ruptured tendon on the right side showed degenerative signs with fraying and fatty strikes, but there were signs of a complete fresh tear with a few freshly ruptured fibers inserting at the proximal pole of the patella. Both tendons were readapted by a hybrid of suture anchors and transosseous tunnel repair technique.
Postoperatively, the patient remained full weight-bearing in extension for six weeks. Unfortunately, within the six weeks postoperatively our patient had an incident in which he slipped away with his right leg on the wet floor of his bathroom. For a couple of days, he felt self-limiting pain in the right leg. On clinical examination 6 weeks postoperatively, a well healing left lower limb could be seen with no extension lag. On the right side, a dimple could be palpated proximal to the patella around the scar, as well as diminished quadriceps contraction was observed. In the subsequently initiated magnetic resonance imaging (MRI) of the right knee, the clinical suspicion of a re-ruptured quadriceps tendon was confirmed.
In the operative revision of the re-ruptured right quadriceps tendon, a torn central suture was seen with a central defect of around 3 cm width and dehiscence of 2 cm. Due to the retraction and impaired quality of the quadriceps tendon, a V—Y plasty was performed with subsequent adaption to the patella by a hybrid of suture anchors and transosseous tunnel repair technique. Postoperative conventional radiographical and computer tomographic findings showed the medial anchor to be placed subchondral, which needed another operative revision with replacement of the aforesaid anchor. Postoperatively, full weight-bearing in extension for six weeks was initiated again.
In the latest outpatient consultation 10 months after surgical treatment on the left and 8 months after the revision surgery on the right quadriceps tendon, a well healing left knee could be observed with normal extension motor strength levels, as well as increasing range of motion (Flexion/Extension 130/0/0°) and no extension-lag. The right knee showed good range of motion (Flexion/Extension 120/0/0°) as well as close to normal extension motor strength levels without any extension-lag, but a persistent dent could be seen and palpated on the superior margin of the patella. The patient described to possess good stability and strength in the left leg, but persistent limited strength levels during climbing stairs and longer walks as well as faster exhaustion with consequent rare instability and giving-way symptomatic on the right side. In regard to these restrictions and the observed suprapatellar dimple, another MRI examination of the right knee was undertaken to assess the integrity of the quadriceps tendon. This MRI showed an intact right quadriceps tendon with elongated and persistent edematous alteration (Fig. 2). In order to address the persistent impaired strength and stability intensive muscular strength-training has been continued.Fig. 2 MRI examination of the right knee 8 months after surgical revision.
Fig. 2
Discussion
The toxicity of fluoroquinolones on musculoskeletal tissue has been acknowledged since its introduction in the 1980s. In the late 20th and the beginning of the 21st century, there has been a rising number of reported cases of tendon-related issues with this drug class, which has led the Food and Drug Administration (FDA) to add a ‘black box’ warning to fluoroquinolone antibiotics in 2008 – the most stringent warning there is [1]. Following reports of serious persistent side effects mainly affecting muscles, joints and the nervous system, recently, also the European Medicines Agency (EMA) concluded a safety review of fluoroquinolone antibiotics, which led to restriction of its use due to the risk of disabling and potentially long-term side effects (see Table 1) [2]. Tendinopathy and tendon ruptures after treatment with fluoroquinolones are almost exclusively seen in Achilles tendons [3]. Quadriceps tendon tears associated with fluoroquinolone therapy are hardly ever seen and we only found one other case report about this rare incident [4].Table 1 Recommendations endorsed by the EMA's human medicines committee (CHMP) on the use of fluoroquinolone antibiotics [4].
Table 1Restrictions on the use of fluoroquinolone antibiotics will mean that they should not be used:
• to treat infections that might get better without treatment or are not severe (such as throat infections).
• to treat non-bacterial infections, e.g. non-bacterial (chronic) prostatitis.
• for preventing traveler's diarrhea or recurring lower urinary tract infections (urine infections that do not extend beyond the bladder).
• to treat mild or moderate bacterial infections unless other antibacterial medicines commonly recommended for these infections cannot be used.
Acute quadriceps tendon rupture is a relatively rare injury (incidence 1.37/100′000), usually seen in middle-aged men [5]. The typical mechanism of injury is an indirect trauma with a violent contraction of the quadriceps muscle with the foot planted on the ground and the knee partially bent [6]. Besides fluoroquinolones, several pre-existing conditions increase the risk of quadriceps rupture such as obesity, systemic lupus erythematosus, rheumatoid arthritis, chronic renal failure, gout, hyperparathyroidism and corticosteroid intake [7]. Shah concludes in his risk analysis of 66 simultaneous, bilateral quadriceps tendon ruptures that younger patients with this injury should be evaluated for any underlying medical condition [8].
In our case, no other risk factor than the intake of ciprofloxacin a year before the incident was apparent. Besides, the relative atraumatic nature of the injury and the intraoperative findings of largely degenerated tendons on both sides imply ciprofloxacin to be the causative agent. The mechanism for fluoroquinolone-induced tendon rupture remains poorly understood but has been linked to the degradation of Type I collagen following alterations in the regulation of matrix metalloproteinases [9]. The resulting symptoms, such as sudden pain, tenderness to palpation, edema and difficulty with movement of the involved area, may appear as soon as 2 hours after first dose of fluoroquinolone. On average, the duration of fluoroquinolone therapy before the onset of tendon injury is 8 days [3]. However, as seen in our case and also stated by the EMA, they can cause long-lasting and potentially permanent side effects involving tendons, muscles and joints [2].
A number of recently published systematic reviews on this topic have underlined the increased risk of tendon injuries associated with fluoroquinolones. While generally spoken the odds ratio for any tendon disorder is roughly doubled after the intake of a fluoroquinolone therapy in the general population, it is of particular interest to identify high-risk populations, as they are at a substantially higher risk for tendon associated disabilities [10,11]. When one is trying to distinguish what patient is at particular risk, three criteria appear to possess a major role: age (>60 years), concomitant intake of corticosteroids and duration of the antibiotic therapy. In absolute measures, for a person under the age of 60 years who is prescribed to 5 days of a fluoroquinolone therapy a number needed to treat (NNT) to cause one additional tendon rupture of 1:521,429 (CI 405,556–730,000) results. Whereas for a person over the age of 60 years with a therapy duration of 28 days and concomitant corticosteroid intake the NNT to cause one additional tendon rupture increases to 1:6651 (CI 5173–8690) [12].
According to the FDA, the possible serious side effects of fluoroquinolones (incl. tendinous disorders) generally outweigh the benefits for patients with milder infections (for example acute bacterial sinusitis, acute bacterial exacerbation of chronic bronchitis, and uncomplicated urinary tract infections). Hence, fluoroquinolones should be reserved for these conditions only if no alternative treatment option exists [13]. Despite the aforementioned elevated risk for developing a tendinous disorder, fluoroquinolones are still commonly prescribed for treating milder infections [14].
In conclusion, in keeping with the warnings from the FDA and EMA, we strongly suggest that fluoroquinolones should only be prescribed after careful consideration for alternative treatment options, especially in patients with preexisting risk factors for developing tendinopathy. Furthermore, careful patient instruction regarding possible signs of tendon damage should be carried out when prescribing fluroquinolones.
CRediT authorship contribution statement
All authors contributed to the idea to report the case and had full access to all of the data in the study and take responsibility for the integrity of the data. All authors contributed to patient management. Acquisition, analysis, or interpretation of data: All authors. Drafting of the manuscript: CS and RT. Critical revision of the manuscript for important intellectual content: All authors. Clinical case presentation and management undertaken at Zuger Kantonsspital, Baar, Switzerland.
Declaration of competing interest
None.
Acknowledgements
We thank Paul Lauber for revising the manuscript. | Recovering | ReactionOutcome | CC BY-NC-ND | 33665316 | 19,063,502 | 2021-04 |
What was the outcome of reaction 'Gait inability'? | "Ciprofloxacin-induced" bilateral quadriceps tendon rupture: A case report and conclusions of the recent literature.
The potential risk of fluoroquinolones on the musculoskeletal tissue, and tendinous structures in particular, has been known since its introduction in the 1980s. Following reports of serious and persistent side effects in their national registry, the German medicines authority (BfArM) has requested the European Medicines Agency (EMA) to conclude a safety review focusing on long-lasting effects mainly affecting the musculoskeletal and nervous systems. This review, published in early 2019, led to restriction of the usage of fluoroquinolones due to the risk of disabling and potentially long-term side effects. Furthermore, there have been a number of meta-analyses published in the recent years, which brought more clarity to the extent of fluoroquinolones' possible side effects. With this case report followed by an overview of the latest evidence, we would like to highlight these latest efforts in the quest to prescribe fluoroquinolones cautiously and sensitize physicians to this topic.
Case history
A 59-year old male teacher, with no pre-existing medical comorbidities other than hyperplasia of the prostate, presented to our emergency department with inability to walk and pain on the upper margins of his patella on both sides. He reported playing football with some friends, as he suddenly slumped to the ground while trying to pass the ball without any adversary contact. He didn't describe any pain located around his knees before the incident and has neither been treated for any disease nor trauma on his lower limbs. Other than tamsulosin for his prostate hyperplasia, he was on no regular medication. His medical history was significant only for completing a 24-day course of ciprofloxacin for a prostate infection a year before the incident.
On physical examination, swelling was recognized as well as dimples during palpation on top of both kneecaps. He was unable to extend both knees and a positive leg raise test was seen bilaterally. There were no other deficits in power, sensation or proprioception in either lower limb. Knee x-rays showed an unusual contour of the suprapatellar soft tissue bilaterally, with a sagging of both suprapatellar regions, radiographically indicating bilateral quadriceps tendon rupture (Fig. 1). On the right knee, a CT-scan was performed to rule out any osseous lesion, whereby the suspicion of a quadriceps rupture became more concrete. Due to the distinctive clinical presentation of complete tendon rupture bilaterally, no further diagnostics were initiated, and the patient was treated operatively the next day.Fig. 1 Bilateral Knee x-rays on the day of the incident.
Fig. 1
Intraoperatively, the clinical findings of complete tears of the quadriceps tendon on both sides were verified. The tear on the left side showed hardly any signs of a fresh tear, but a largely degenerated quadriceps tendon with fraying and fatty streaks within the tendon. No inserting fibers were left at the proximal pole of the patella, which led to the assumption that a degenerative, partial tear might have already existed prior to the incident. Also, the proximal part of the ruptured tendon on the right side showed degenerative signs with fraying and fatty strikes, but there were signs of a complete fresh tear with a few freshly ruptured fibers inserting at the proximal pole of the patella. Both tendons were readapted by a hybrid of suture anchors and transosseous tunnel repair technique.
Postoperatively, the patient remained full weight-bearing in extension for six weeks. Unfortunately, within the six weeks postoperatively our patient had an incident in which he slipped away with his right leg on the wet floor of his bathroom. For a couple of days, he felt self-limiting pain in the right leg. On clinical examination 6 weeks postoperatively, a well healing left lower limb could be seen with no extension lag. On the right side, a dimple could be palpated proximal to the patella around the scar, as well as diminished quadriceps contraction was observed. In the subsequently initiated magnetic resonance imaging (MRI) of the right knee, the clinical suspicion of a re-ruptured quadriceps tendon was confirmed.
In the operative revision of the re-ruptured right quadriceps tendon, a torn central suture was seen with a central defect of around 3 cm width and dehiscence of 2 cm. Due to the retraction and impaired quality of the quadriceps tendon, a V—Y plasty was performed with subsequent adaption to the patella by a hybrid of suture anchors and transosseous tunnel repair technique. Postoperative conventional radiographical and computer tomographic findings showed the medial anchor to be placed subchondral, which needed another operative revision with replacement of the aforesaid anchor. Postoperatively, full weight-bearing in extension for six weeks was initiated again.
In the latest outpatient consultation 10 months after surgical treatment on the left and 8 months after the revision surgery on the right quadriceps tendon, a well healing left knee could be observed with normal extension motor strength levels, as well as increasing range of motion (Flexion/Extension 130/0/0°) and no extension-lag. The right knee showed good range of motion (Flexion/Extension 120/0/0°) as well as close to normal extension motor strength levels without any extension-lag, but a persistent dent could be seen and palpated on the superior margin of the patella. The patient described to possess good stability and strength in the left leg, but persistent limited strength levels during climbing stairs and longer walks as well as faster exhaustion with consequent rare instability and giving-way symptomatic on the right side. In regard to these restrictions and the observed suprapatellar dimple, another MRI examination of the right knee was undertaken to assess the integrity of the quadriceps tendon. This MRI showed an intact right quadriceps tendon with elongated and persistent edematous alteration (Fig. 2). In order to address the persistent impaired strength and stability intensive muscular strength-training has been continued.Fig. 2 MRI examination of the right knee 8 months after surgical revision.
Fig. 2
Discussion
The toxicity of fluoroquinolones on musculoskeletal tissue has been acknowledged since its introduction in the 1980s. In the late 20th and the beginning of the 21st century, there has been a rising number of reported cases of tendon-related issues with this drug class, which has led the Food and Drug Administration (FDA) to add a ‘black box’ warning to fluoroquinolone antibiotics in 2008 – the most stringent warning there is [1]. Following reports of serious persistent side effects mainly affecting muscles, joints and the nervous system, recently, also the European Medicines Agency (EMA) concluded a safety review of fluoroquinolone antibiotics, which led to restriction of its use due to the risk of disabling and potentially long-term side effects (see Table 1) [2]. Tendinopathy and tendon ruptures after treatment with fluoroquinolones are almost exclusively seen in Achilles tendons [3]. Quadriceps tendon tears associated with fluoroquinolone therapy are hardly ever seen and we only found one other case report about this rare incident [4].Table 1 Recommendations endorsed by the EMA's human medicines committee (CHMP) on the use of fluoroquinolone antibiotics [4].
Table 1Restrictions on the use of fluoroquinolone antibiotics will mean that they should not be used:
• to treat infections that might get better without treatment or are not severe (such as throat infections).
• to treat non-bacterial infections, e.g. non-bacterial (chronic) prostatitis.
• for preventing traveler's diarrhea or recurring lower urinary tract infections (urine infections that do not extend beyond the bladder).
• to treat mild or moderate bacterial infections unless other antibacterial medicines commonly recommended for these infections cannot be used.
Acute quadriceps tendon rupture is a relatively rare injury (incidence 1.37/100′000), usually seen in middle-aged men [5]. The typical mechanism of injury is an indirect trauma with a violent contraction of the quadriceps muscle with the foot planted on the ground and the knee partially bent [6]. Besides fluoroquinolones, several pre-existing conditions increase the risk of quadriceps rupture such as obesity, systemic lupus erythematosus, rheumatoid arthritis, chronic renal failure, gout, hyperparathyroidism and corticosteroid intake [7]. Shah concludes in his risk analysis of 66 simultaneous, bilateral quadriceps tendon ruptures that younger patients with this injury should be evaluated for any underlying medical condition [8].
In our case, no other risk factor than the intake of ciprofloxacin a year before the incident was apparent. Besides, the relative atraumatic nature of the injury and the intraoperative findings of largely degenerated tendons on both sides imply ciprofloxacin to be the causative agent. The mechanism for fluoroquinolone-induced tendon rupture remains poorly understood but has been linked to the degradation of Type I collagen following alterations in the regulation of matrix metalloproteinases [9]. The resulting symptoms, such as sudden pain, tenderness to palpation, edema and difficulty with movement of the involved area, may appear as soon as 2 hours after first dose of fluoroquinolone. On average, the duration of fluoroquinolone therapy before the onset of tendon injury is 8 days [3]. However, as seen in our case and also stated by the EMA, they can cause long-lasting and potentially permanent side effects involving tendons, muscles and joints [2].
A number of recently published systematic reviews on this topic have underlined the increased risk of tendon injuries associated with fluoroquinolones. While generally spoken the odds ratio for any tendon disorder is roughly doubled after the intake of a fluoroquinolone therapy in the general population, it is of particular interest to identify high-risk populations, as they are at a substantially higher risk for tendon associated disabilities [10,11]. When one is trying to distinguish what patient is at particular risk, three criteria appear to possess a major role: age (>60 years), concomitant intake of corticosteroids and duration of the antibiotic therapy. In absolute measures, for a person under the age of 60 years who is prescribed to 5 days of a fluoroquinolone therapy a number needed to treat (NNT) to cause one additional tendon rupture of 1:521,429 (CI 405,556–730,000) results. Whereas for a person over the age of 60 years with a therapy duration of 28 days and concomitant corticosteroid intake the NNT to cause one additional tendon rupture increases to 1:6651 (CI 5173–8690) [12].
According to the FDA, the possible serious side effects of fluoroquinolones (incl. tendinous disorders) generally outweigh the benefits for patients with milder infections (for example acute bacterial sinusitis, acute bacterial exacerbation of chronic bronchitis, and uncomplicated urinary tract infections). Hence, fluoroquinolones should be reserved for these conditions only if no alternative treatment option exists [13]. Despite the aforementioned elevated risk for developing a tendinous disorder, fluoroquinolones are still commonly prescribed for treating milder infections [14].
In conclusion, in keeping with the warnings from the FDA and EMA, we strongly suggest that fluoroquinolones should only be prescribed after careful consideration for alternative treatment options, especially in patients with preexisting risk factors for developing tendinopathy. Furthermore, careful patient instruction regarding possible signs of tendon damage should be carried out when prescribing fluroquinolones.
CRediT authorship contribution statement
All authors contributed to the idea to report the case and had full access to all of the data in the study and take responsibility for the integrity of the data. All authors contributed to patient management. Acquisition, analysis, or interpretation of data: All authors. Drafting of the manuscript: CS and RT. Critical revision of the manuscript for important intellectual content: All authors. Clinical case presentation and management undertaken at Zuger Kantonsspital, Baar, Switzerland.
Declaration of competing interest
None.
Acknowledgements
We thank Paul Lauber for revising the manuscript. | Recovered | ReactionOutcome | CC BY-NC-ND | 33665316 | 19,063,502 | 2021-04 |
What was the outcome of reaction 'Tendon rupture'? | "Ciprofloxacin-induced" bilateral quadriceps tendon rupture: A case report and conclusions of the recent literature.
The potential risk of fluoroquinolones on the musculoskeletal tissue, and tendinous structures in particular, has been known since its introduction in the 1980s. Following reports of serious and persistent side effects in their national registry, the German medicines authority (BfArM) has requested the European Medicines Agency (EMA) to conclude a safety review focusing on long-lasting effects mainly affecting the musculoskeletal and nervous systems. This review, published in early 2019, led to restriction of the usage of fluoroquinolones due to the risk of disabling and potentially long-term side effects. Furthermore, there have been a number of meta-analyses published in the recent years, which brought more clarity to the extent of fluoroquinolones' possible side effects. With this case report followed by an overview of the latest evidence, we would like to highlight these latest efforts in the quest to prescribe fluoroquinolones cautiously and sensitize physicians to this topic.
Case history
A 59-year old male teacher, with no pre-existing medical comorbidities other than hyperplasia of the prostate, presented to our emergency department with inability to walk and pain on the upper margins of his patella on both sides. He reported playing football with some friends, as he suddenly slumped to the ground while trying to pass the ball without any adversary contact. He didn't describe any pain located around his knees before the incident and has neither been treated for any disease nor trauma on his lower limbs. Other than tamsulosin for his prostate hyperplasia, he was on no regular medication. His medical history was significant only for completing a 24-day course of ciprofloxacin for a prostate infection a year before the incident.
On physical examination, swelling was recognized as well as dimples during palpation on top of both kneecaps. He was unable to extend both knees and a positive leg raise test was seen bilaterally. There were no other deficits in power, sensation or proprioception in either lower limb. Knee x-rays showed an unusual contour of the suprapatellar soft tissue bilaterally, with a sagging of both suprapatellar regions, radiographically indicating bilateral quadriceps tendon rupture (Fig. 1). On the right knee, a CT-scan was performed to rule out any osseous lesion, whereby the suspicion of a quadriceps rupture became more concrete. Due to the distinctive clinical presentation of complete tendon rupture bilaterally, no further diagnostics were initiated, and the patient was treated operatively the next day.Fig. 1 Bilateral Knee x-rays on the day of the incident.
Fig. 1
Intraoperatively, the clinical findings of complete tears of the quadriceps tendon on both sides were verified. The tear on the left side showed hardly any signs of a fresh tear, but a largely degenerated quadriceps tendon with fraying and fatty streaks within the tendon. No inserting fibers were left at the proximal pole of the patella, which led to the assumption that a degenerative, partial tear might have already existed prior to the incident. Also, the proximal part of the ruptured tendon on the right side showed degenerative signs with fraying and fatty strikes, but there were signs of a complete fresh tear with a few freshly ruptured fibers inserting at the proximal pole of the patella. Both tendons were readapted by a hybrid of suture anchors and transosseous tunnel repair technique.
Postoperatively, the patient remained full weight-bearing in extension for six weeks. Unfortunately, within the six weeks postoperatively our patient had an incident in which he slipped away with his right leg on the wet floor of his bathroom. For a couple of days, he felt self-limiting pain in the right leg. On clinical examination 6 weeks postoperatively, a well healing left lower limb could be seen with no extension lag. On the right side, a dimple could be palpated proximal to the patella around the scar, as well as diminished quadriceps contraction was observed. In the subsequently initiated magnetic resonance imaging (MRI) of the right knee, the clinical suspicion of a re-ruptured quadriceps tendon was confirmed.
In the operative revision of the re-ruptured right quadriceps tendon, a torn central suture was seen with a central defect of around 3 cm width and dehiscence of 2 cm. Due to the retraction and impaired quality of the quadriceps tendon, a V—Y plasty was performed with subsequent adaption to the patella by a hybrid of suture anchors and transosseous tunnel repair technique. Postoperative conventional radiographical and computer tomographic findings showed the medial anchor to be placed subchondral, which needed another operative revision with replacement of the aforesaid anchor. Postoperatively, full weight-bearing in extension for six weeks was initiated again.
In the latest outpatient consultation 10 months after surgical treatment on the left and 8 months after the revision surgery on the right quadriceps tendon, a well healing left knee could be observed with normal extension motor strength levels, as well as increasing range of motion (Flexion/Extension 130/0/0°) and no extension-lag. The right knee showed good range of motion (Flexion/Extension 120/0/0°) as well as close to normal extension motor strength levels without any extension-lag, but a persistent dent could be seen and palpated on the superior margin of the patella. The patient described to possess good stability and strength in the left leg, but persistent limited strength levels during climbing stairs and longer walks as well as faster exhaustion with consequent rare instability and giving-way symptomatic on the right side. In regard to these restrictions and the observed suprapatellar dimple, another MRI examination of the right knee was undertaken to assess the integrity of the quadriceps tendon. This MRI showed an intact right quadriceps tendon with elongated and persistent edematous alteration (Fig. 2). In order to address the persistent impaired strength and stability intensive muscular strength-training has been continued.Fig. 2 MRI examination of the right knee 8 months after surgical revision.
Fig. 2
Discussion
The toxicity of fluoroquinolones on musculoskeletal tissue has been acknowledged since its introduction in the 1980s. In the late 20th and the beginning of the 21st century, there has been a rising number of reported cases of tendon-related issues with this drug class, which has led the Food and Drug Administration (FDA) to add a ‘black box’ warning to fluoroquinolone antibiotics in 2008 – the most stringent warning there is [1]. Following reports of serious persistent side effects mainly affecting muscles, joints and the nervous system, recently, also the European Medicines Agency (EMA) concluded a safety review of fluoroquinolone antibiotics, which led to restriction of its use due to the risk of disabling and potentially long-term side effects (see Table 1) [2]. Tendinopathy and tendon ruptures after treatment with fluoroquinolones are almost exclusively seen in Achilles tendons [3]. Quadriceps tendon tears associated with fluoroquinolone therapy are hardly ever seen and we only found one other case report about this rare incident [4].Table 1 Recommendations endorsed by the EMA's human medicines committee (CHMP) on the use of fluoroquinolone antibiotics [4].
Table 1Restrictions on the use of fluoroquinolone antibiotics will mean that they should not be used:
• to treat infections that might get better without treatment or are not severe (such as throat infections).
• to treat non-bacterial infections, e.g. non-bacterial (chronic) prostatitis.
• for preventing traveler's diarrhea or recurring lower urinary tract infections (urine infections that do not extend beyond the bladder).
• to treat mild or moderate bacterial infections unless other antibacterial medicines commonly recommended for these infections cannot be used.
Acute quadriceps tendon rupture is a relatively rare injury (incidence 1.37/100′000), usually seen in middle-aged men [5]. The typical mechanism of injury is an indirect trauma with a violent contraction of the quadriceps muscle with the foot planted on the ground and the knee partially bent [6]. Besides fluoroquinolones, several pre-existing conditions increase the risk of quadriceps rupture such as obesity, systemic lupus erythematosus, rheumatoid arthritis, chronic renal failure, gout, hyperparathyroidism and corticosteroid intake [7]. Shah concludes in his risk analysis of 66 simultaneous, bilateral quadriceps tendon ruptures that younger patients with this injury should be evaluated for any underlying medical condition [8].
In our case, no other risk factor than the intake of ciprofloxacin a year before the incident was apparent. Besides, the relative atraumatic nature of the injury and the intraoperative findings of largely degenerated tendons on both sides imply ciprofloxacin to be the causative agent. The mechanism for fluoroquinolone-induced tendon rupture remains poorly understood but has been linked to the degradation of Type I collagen following alterations in the regulation of matrix metalloproteinases [9]. The resulting symptoms, such as sudden pain, tenderness to palpation, edema and difficulty with movement of the involved area, may appear as soon as 2 hours after first dose of fluoroquinolone. On average, the duration of fluoroquinolone therapy before the onset of tendon injury is 8 days [3]. However, as seen in our case and also stated by the EMA, they can cause long-lasting and potentially permanent side effects involving tendons, muscles and joints [2].
A number of recently published systematic reviews on this topic have underlined the increased risk of tendon injuries associated with fluoroquinolones. While generally spoken the odds ratio for any tendon disorder is roughly doubled after the intake of a fluoroquinolone therapy in the general population, it is of particular interest to identify high-risk populations, as they are at a substantially higher risk for tendon associated disabilities [10,11]. When one is trying to distinguish what patient is at particular risk, three criteria appear to possess a major role: age (>60 years), concomitant intake of corticosteroids and duration of the antibiotic therapy. In absolute measures, for a person under the age of 60 years who is prescribed to 5 days of a fluoroquinolone therapy a number needed to treat (NNT) to cause one additional tendon rupture of 1:521,429 (CI 405,556–730,000) results. Whereas for a person over the age of 60 years with a therapy duration of 28 days and concomitant corticosteroid intake the NNT to cause one additional tendon rupture increases to 1:6651 (CI 5173–8690) [12].
According to the FDA, the possible serious side effects of fluoroquinolones (incl. tendinous disorders) generally outweigh the benefits for patients with milder infections (for example acute bacterial sinusitis, acute bacterial exacerbation of chronic bronchitis, and uncomplicated urinary tract infections). Hence, fluoroquinolones should be reserved for these conditions only if no alternative treatment option exists [13]. Despite the aforementioned elevated risk for developing a tendinous disorder, fluoroquinolones are still commonly prescribed for treating milder infections [14].
In conclusion, in keeping with the warnings from the FDA and EMA, we strongly suggest that fluoroquinolones should only be prescribed after careful consideration for alternative treatment options, especially in patients with preexisting risk factors for developing tendinopathy. Furthermore, careful patient instruction regarding possible signs of tendon damage should be carried out when prescribing fluroquinolones.
CRediT authorship contribution statement
All authors contributed to the idea to report the case and had full access to all of the data in the study and take responsibility for the integrity of the data. All authors contributed to patient management. Acquisition, analysis, or interpretation of data: All authors. Drafting of the manuscript: CS and RT. Critical revision of the manuscript for important intellectual content: All authors. Clinical case presentation and management undertaken at Zuger Kantonsspital, Baar, Switzerland.
Declaration of competing interest
None.
Acknowledgements
We thank Paul Lauber for revising the manuscript. | Recovering | ReactionOutcome | CC BY-NC-ND | 33665316 | 19,063,502 | 2021-04 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Corneal abrasion'. | Nocardia keratitis mimicking superior limbic keratoconjunctivitis and herpes simplex virus.
Nocardia keratitis is a rare type of infectious keratitis and may mimic other corneal diseases and lead to delay in diagnosis. This case illustrates how Nocardia often escapes accurate diagnosis due to its insidious onset, variable clinical manifestations, and unusual characteristics on cultures.
The patient presented with an epithelial defect and superior pannus and scarring, which was misdiagnosed as superior limbic keratoconjunctivitis (SLK) and herpes simplex virus (HSV) keratitis. Repeat corneal scraping cultures, smears, and conjunctival biopsy were necessary to elucidate the diagnosis. It can be effectively treated with the intravenous preparation of trimethoprim-sulfamethoxazole 80 mg/mL (brand name SEPTRA) used topically as eye drops.
The diagnosis of Nocardia keratitis relies on a high clinical suspicion and a prompt corneal scraping with culture. Due to its potential for rapid resolution with early therapy, it is important to isolate Nocardia early in its disease course.
Topical amikacin had been the standard of care for Nocardia keratitis for many years. However, recently there is increasing resistance of Nocardia to amikacin. SEPTRA offers an alternative therapy. Nocardia keratitis mimics other infectious and inflammatory etiologies so rapid diagnosis and treatment is critical in the prevention of long-term complications.
1 Introduction
Nocardia are a group of aerobic, gram-positive, and catalase-positive bacteria in the shape of long, thin, and branching filaments that stain weakly acid-fast on Ziehl-Neelsen1.
Nocardia asteroides is the most commonly reported species to cause Nocardia keratitis. It is classically described with an appearance of stromal infiltrates in a wreath-like pattern and may be associated with tiny epithelial calcifications often near the limbus adjacent to pannus-like areas of increased vascularity.2,3 Culture on blood agar may occasionally lead to a consideration of contamination due to the tendency for prominent areas of calcification on the agar.2
Nocardia keratitis is seen more frequently in young males, especially those who live in rural areas.3,4 As Nocardia is the most common bacteria found in soil, corneal trauma and contact with soil predispose those in rural areas to infection. Other risk factors for Nocardia keratitis include contact lens wear, ophthalmic surgery, and topical corticosteroids.5, 6, 7, 8
This unique case of Nocardia keratitis focuses attention on the variability of presentation and the possibility of a prolonged clinical course over months. The multiple misdiagnoses suffered by this patient highlight how this pathogen is elusive and often discovered late in the clinical course leading to permanent ocular sequelae.
2 Case presentation
A 41-year-old male contact lens user without history of corneal trauma or soil contact presented with a three-week history of pruritus, photophobia, and excessive tearing of the right eye. He was initially found to have a corneal abrasion and started on topical tobramycin 0.3% QID, which aggravated his symptoms. The patient was then referred to an ophthalmologist who added loteprednol 0.5% daily. The patient failed to respond to this therapy and was sent to a corneal specialist. On initial presentation, the patient's best-corrected visual acuity (BCVA) in the right eye was 20/20–3. Anterior segment exam was significant for bilateral blepharitis, right floppy eyelid, right trace perilimbal injection, 2+ superior palpebral conjunctival injection, and a new right corneal scar with irregular epithelium lacking definitive boundaries superiorly at 12 o'clock. Given the pattern of injection, recurrent discomfort, and subjective complaint of itchiness, superior limbic keratoconjunctivitis (SLK) was considered. The corneal specialist trialed a course of ofloxacin 0.3% and then increased loteprednol 0.5% to BID dosing.
On two-week follow-up, the patient displayed symptomatic improvement. However, the clinical exam demonstrated new dendritiform lesions developing at the peripheral edge of the corneal scar. Treatment for presumed herpes simplex keratitis (HSV) was initiated with a course of oral valacyclovir TID and topical ganciclovir 0.15% QID. Additionally, the patient was sent for corneal cultures to rule out fungal keratitis. Follow-up results were negative for fungi.
The patient returned in one month with worsening symptoms. At this time, his corneal scar displayed anterior stromal scarring with new overlying neovascularization and an advancing edge of irregular epithelium (Fig. 1). Keratic precipitates and anterior chamber inflammation were absent. At this point, the diagnosis of HSV interstitial keratitis was considered. The topical medications were switched from loteprednol to difluprednate 0.05% QID; the patient was restarted on valacyclovir TID.Fig. 1 Clinical photograph of the patient's right eye on initial presentation to second corneal specialist (3 months from first symptoms) demonstrating superior pannus, anterior stromal scarring, conjunctival injection, and floppy eyelids.
Fig. 1
After returning from vacation overseas, the patient followed up with the corneal specialist with minimal improvement. Given the failure to respond to herpetic treatment, a superior conjunctival resection for presumed SLK and corneal scrapings were taken from the right eye where the cornea was abnormal. A ProKera Slim™ amniotic membrane was placed over the defect and prophylactic ophthalmic antibiotics were started. The patient was maintained on oral valacyclovir TID, topical difluprednate 0.05% BID, and topical ofloxacin 0.3% as antibiotic prophylaxis for a few days. Corneal scrapings did not reveal findings suggestive of SLK or microbial keratitis when evaluated.
One week later, the patient reported dramatically decreased vision with severe photophobia and difficulty opening the right eye. Visual acuity was 20/400 with the ProKera Slim™. At this point, the corneal scraping was 95% healed so the ProKera Slim™ was removed. No further stromal infiltrates were noted. All medications were discontinued except bacitracin-polymyxin B. On subsequent follow-up one week later, the patient was referred to another corneal specialist for consultation. At this visit, a repeat corneal Gram stain and a Papinicolau stain were positive for filamentous rods and Nocardia was suspected (Fig. 2). Therapy was initiated with trimethroprim-sulfamethaxazole (SEPTRA) 80 mg/mL in the right eye every 2 hours. One week later, cultural identification was confirmed for Nocardia asteroides and sensitivities showed resistance to amikacin. After three months of unabated progression of his signs and symptoms, the patient showed clinical improvement in three days. However given the prolonged course, he required an additional month of therapy. The patient healed with a subepithelial scar and neovascularization. At this point, SEPTRA was discontinued. The final visual acuity of the right eye was 20/30. Interestingly, the conjunctival biopsy was revisited and showed no signs of Nocardia.Fig. 2 Papinicolau stain magnified 400X of corneal scraping demonstrating branching filaments characteristic of Nocardia asteroides.
Fig. 2
3 Discussion
The usual presenting symptoms of Nocardia keratitis include pain, photophobia, blepharospasm, and lid swelling. Nocardia keratitis frequently runs a protracted benign course, but acute severe cases have been seen.9, 10, 11 Superficial granular infiltrates coalesce into a white plaque of variable size over time and result in corneal ulceration that is often superior in location. In addition to the classic finding of patchy wreath-like anterior stromal infiltrates, other presenting features include pseudodendritic epithelial defect, subepithelial infiltrate, persistent epithelial defect, and/or neovascularization into the cornea.2,10
Diagnosis of Nocardia keratitis is often delayed due to several factors. First, symptoms can have an insidious onset and patients may not initially seek medical care. The variable clinical presentations can mimic other forms of keratitis, such as mycotic or atypical mycobacterial infection.12 The clinician needs to have a high clinical suspicion as Nocardia grows slowly on culture. A prompt corneal scraping and culture should be performed with clinical suspicion. However, this may yield negative results as in this case. Nocardia corneal scrapings are positive for gram-positive, branching filaments that stain weakly acid-fast on Ziehl-Neelsen and black on Gomori methenamine silver.1
Nocardia keratitis can be misdiagnosed as superior limbic keratoconjunctivitis if the disease is located in the superior cornea, as in this case. SLK is characterized by inflammation of the superior bulbar and tarsal conjunctiva in addition to superior corneal vascularization that may appear as a pannus.13 SLK will often demonstrate punctate staining with fluorescein and/or rose Bengal. There can also be localized filamentary keratopathy in one-third of cases. Diagnosis involves obtaining a corneal scraping for Giemsa stain, which typically shows enhanced keratinization, poor nuclei, and hyalinized cytoplasm. Corneal scrapings from this case were not diagnostic for SLK. Treatment modalities include use of topical silver nitrate 1%, anti-inflammatory agents, and conjunctival resection.14,15
Another confounder for Nocardia may be HSV as in this case. At one point in the presentation, a dendritiform lesion was noted suggesting HSV epitheliopathy. A few weeks later, corneal neovascularization and haze developed which appeared clinically as an HSV interstitial keratitis. This clinical picture of apparent recurrence can be quite convincing for herpetic interstitial keratitis. However, the steroid treatment may have exacerbated the Nocardia infection.
Nocardia keratitis is most effectively treated with trimethoprim-sulfamethoxazole or amikacin; the latter is considered the drug of choice for all species of Nocardia.16 However, resistance to amikacin, as in this case, has been previously described.17 The intravenous preparation of trimethoprim-sulfamethoxazole can be used directly as eye drops, typically in a dosing of 16 mg/mL trimethoprim and 80 mg/mL sulfamethoxazole. Amikacin is typically used in the concentration of 2.5% and is prepared by adding 8 mL of artificial tears to 2 mL of the intravenous preparation of 125 mg/mL amikacin.6 Of note, systemic antibiotics do not add benefit to the clinical outcome of Nocardia keratitis. Steroids worsen the symptoms of Nocardia keratitis, potentially leading to complications such as corneal perforation, scleritis, and endophthalmitis. Thus, it is critically important to identify the causative organism early as routine steroid use for falsely suspected viral keratitis and SLK exacerbates the underlying condition.
Nocardia keratitis responds well to medical therapy. If treatment is started early in the course, the corneal ulcer tends to heal rapidly with mild peripheral vascularization. The infiltrate resolves with minimal scarring and forms a fine superficial nebular opacity. Visual acuity improves rapidly and the end result is a barely visible residual stromal haze.
4 Conclusions
Nocardia are a rare cause of infectious keratitis. Early diagnosis and treatment of Nocardia keratitis are difficult because of its infrequent occurrence and variable clinical manifestations. We describe a case of Nocardia keratitis that was initially misdiagnosed and treated with multiple antibacterial, antiviral, and anti-inflammatory agents. Due to its superior location, SLK was considered and prompted a superior conjunctival resection that disproved the diagnosis. Of note, the initial cultures were negative and it was only after a second corneal scraping that Nocardia was correctly identified by cytology and confirmed by cultures. Once diagnosed, this case of Nocardia keratitis responded effectively to treatment with trimethoprim-sulfamethoxazole (SEPTRA) in the setting of amikacin resistance.
Patient consent
The patient consented to publication of the case in writing and orally.
CRediT authorship contribution statement
Eileen L. Chang: Project administration, Writing - original draft, Writing - review & editing. Rachel L. Chu: Writing - original draft. John R. Wittpenn: Investigation, Writing - review & editing. Henry D. Perry: Supervision, Conceptualization, Investigation, Writing - review & editing.
Acknowledgments and Disclosures
No funding or grant support. There are no conflicts of interest or financial disclosures for any of the authors listed. All authors attest that they meet the current ICMJE criteria for Authorship. | TOBRAMYCIN | DrugsGivenReaction | CC BY-NC-ND | 33665477 | 19,295,206 | 2021-06 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Eye disorder'. | Nocardia keratitis mimicking superior limbic keratoconjunctivitis and herpes simplex virus.
Nocardia keratitis is a rare type of infectious keratitis and may mimic other corneal diseases and lead to delay in diagnosis. This case illustrates how Nocardia often escapes accurate diagnosis due to its insidious onset, variable clinical manifestations, and unusual characteristics on cultures.
The patient presented with an epithelial defect and superior pannus and scarring, which was misdiagnosed as superior limbic keratoconjunctivitis (SLK) and herpes simplex virus (HSV) keratitis. Repeat corneal scraping cultures, smears, and conjunctival biopsy were necessary to elucidate the diagnosis. It can be effectively treated with the intravenous preparation of trimethoprim-sulfamethoxazole 80 mg/mL (brand name SEPTRA) used topically as eye drops.
The diagnosis of Nocardia keratitis relies on a high clinical suspicion and a prompt corneal scraping with culture. Due to its potential for rapid resolution with early therapy, it is important to isolate Nocardia early in its disease course.
Topical amikacin had been the standard of care for Nocardia keratitis for many years. However, recently there is increasing resistance of Nocardia to amikacin. SEPTRA offers an alternative therapy. Nocardia keratitis mimics other infectious and inflammatory etiologies so rapid diagnosis and treatment is critical in the prevention of long-term complications.
1 Introduction
Nocardia are a group of aerobic, gram-positive, and catalase-positive bacteria in the shape of long, thin, and branching filaments that stain weakly acid-fast on Ziehl-Neelsen1.
Nocardia asteroides is the most commonly reported species to cause Nocardia keratitis. It is classically described with an appearance of stromal infiltrates in a wreath-like pattern and may be associated with tiny epithelial calcifications often near the limbus adjacent to pannus-like areas of increased vascularity.2,3 Culture on blood agar may occasionally lead to a consideration of contamination due to the tendency for prominent areas of calcification on the agar.2
Nocardia keratitis is seen more frequently in young males, especially those who live in rural areas.3,4 As Nocardia is the most common bacteria found in soil, corneal trauma and contact with soil predispose those in rural areas to infection. Other risk factors for Nocardia keratitis include contact lens wear, ophthalmic surgery, and topical corticosteroids.5, 6, 7, 8
This unique case of Nocardia keratitis focuses attention on the variability of presentation and the possibility of a prolonged clinical course over months. The multiple misdiagnoses suffered by this patient highlight how this pathogen is elusive and often discovered late in the clinical course leading to permanent ocular sequelae.
2 Case presentation
A 41-year-old male contact lens user without history of corneal trauma or soil contact presented with a three-week history of pruritus, photophobia, and excessive tearing of the right eye. He was initially found to have a corneal abrasion and started on topical tobramycin 0.3% QID, which aggravated his symptoms. The patient was then referred to an ophthalmologist who added loteprednol 0.5% daily. The patient failed to respond to this therapy and was sent to a corneal specialist. On initial presentation, the patient's best-corrected visual acuity (BCVA) in the right eye was 20/20–3. Anterior segment exam was significant for bilateral blepharitis, right floppy eyelid, right trace perilimbal injection, 2+ superior palpebral conjunctival injection, and a new right corneal scar with irregular epithelium lacking definitive boundaries superiorly at 12 o'clock. Given the pattern of injection, recurrent discomfort, and subjective complaint of itchiness, superior limbic keratoconjunctivitis (SLK) was considered. The corneal specialist trialed a course of ofloxacin 0.3% and then increased loteprednol 0.5% to BID dosing.
On two-week follow-up, the patient displayed symptomatic improvement. However, the clinical exam demonstrated new dendritiform lesions developing at the peripheral edge of the corneal scar. Treatment for presumed herpes simplex keratitis (HSV) was initiated with a course of oral valacyclovir TID and topical ganciclovir 0.15% QID. Additionally, the patient was sent for corneal cultures to rule out fungal keratitis. Follow-up results were negative for fungi.
The patient returned in one month with worsening symptoms. At this time, his corneal scar displayed anterior stromal scarring with new overlying neovascularization and an advancing edge of irregular epithelium (Fig. 1). Keratic precipitates and anterior chamber inflammation were absent. At this point, the diagnosis of HSV interstitial keratitis was considered. The topical medications were switched from loteprednol to difluprednate 0.05% QID; the patient was restarted on valacyclovir TID.Fig. 1 Clinical photograph of the patient's right eye on initial presentation to second corneal specialist (3 months from first symptoms) demonstrating superior pannus, anterior stromal scarring, conjunctival injection, and floppy eyelids.
Fig. 1
After returning from vacation overseas, the patient followed up with the corneal specialist with minimal improvement. Given the failure to respond to herpetic treatment, a superior conjunctival resection for presumed SLK and corneal scrapings were taken from the right eye where the cornea was abnormal. A ProKera Slim™ amniotic membrane was placed over the defect and prophylactic ophthalmic antibiotics were started. The patient was maintained on oral valacyclovir TID, topical difluprednate 0.05% BID, and topical ofloxacin 0.3% as antibiotic prophylaxis for a few days. Corneal scrapings did not reveal findings suggestive of SLK or microbial keratitis when evaluated.
One week later, the patient reported dramatically decreased vision with severe photophobia and difficulty opening the right eye. Visual acuity was 20/400 with the ProKera Slim™. At this point, the corneal scraping was 95% healed so the ProKera Slim™ was removed. No further stromal infiltrates were noted. All medications were discontinued except bacitracin-polymyxin B. On subsequent follow-up one week later, the patient was referred to another corneal specialist for consultation. At this visit, a repeat corneal Gram stain and a Papinicolau stain were positive for filamentous rods and Nocardia was suspected (Fig. 2). Therapy was initiated with trimethroprim-sulfamethaxazole (SEPTRA) 80 mg/mL in the right eye every 2 hours. One week later, cultural identification was confirmed for Nocardia asteroides and sensitivities showed resistance to amikacin. After three months of unabated progression of his signs and symptoms, the patient showed clinical improvement in three days. However given the prolonged course, he required an additional month of therapy. The patient healed with a subepithelial scar and neovascularization. At this point, SEPTRA was discontinued. The final visual acuity of the right eye was 20/30. Interestingly, the conjunctival biopsy was revisited and showed no signs of Nocardia.Fig. 2 Papinicolau stain magnified 400X of corneal scraping demonstrating branching filaments characteristic of Nocardia asteroides.
Fig. 2
3 Discussion
The usual presenting symptoms of Nocardia keratitis include pain, photophobia, blepharospasm, and lid swelling. Nocardia keratitis frequently runs a protracted benign course, but acute severe cases have been seen.9, 10, 11 Superficial granular infiltrates coalesce into a white plaque of variable size over time and result in corneal ulceration that is often superior in location. In addition to the classic finding of patchy wreath-like anterior stromal infiltrates, other presenting features include pseudodendritic epithelial defect, subepithelial infiltrate, persistent epithelial defect, and/or neovascularization into the cornea.2,10
Diagnosis of Nocardia keratitis is often delayed due to several factors. First, symptoms can have an insidious onset and patients may not initially seek medical care. The variable clinical presentations can mimic other forms of keratitis, such as mycotic or atypical mycobacterial infection.12 The clinician needs to have a high clinical suspicion as Nocardia grows slowly on culture. A prompt corneal scraping and culture should be performed with clinical suspicion. However, this may yield negative results as in this case. Nocardia corneal scrapings are positive for gram-positive, branching filaments that stain weakly acid-fast on Ziehl-Neelsen and black on Gomori methenamine silver.1
Nocardia keratitis can be misdiagnosed as superior limbic keratoconjunctivitis if the disease is located in the superior cornea, as in this case. SLK is characterized by inflammation of the superior bulbar and tarsal conjunctiva in addition to superior corneal vascularization that may appear as a pannus.13 SLK will often demonstrate punctate staining with fluorescein and/or rose Bengal. There can also be localized filamentary keratopathy in one-third of cases. Diagnosis involves obtaining a corneal scraping for Giemsa stain, which typically shows enhanced keratinization, poor nuclei, and hyalinized cytoplasm. Corneal scrapings from this case were not diagnostic for SLK. Treatment modalities include use of topical silver nitrate 1%, anti-inflammatory agents, and conjunctival resection.14,15
Another confounder for Nocardia may be HSV as in this case. At one point in the presentation, a dendritiform lesion was noted suggesting HSV epitheliopathy. A few weeks later, corneal neovascularization and haze developed which appeared clinically as an HSV interstitial keratitis. This clinical picture of apparent recurrence can be quite convincing for herpetic interstitial keratitis. However, the steroid treatment may have exacerbated the Nocardia infection.
Nocardia keratitis is most effectively treated with trimethoprim-sulfamethoxazole or amikacin; the latter is considered the drug of choice for all species of Nocardia.16 However, resistance to amikacin, as in this case, has been previously described.17 The intravenous preparation of trimethoprim-sulfamethoxazole can be used directly as eye drops, typically in a dosing of 16 mg/mL trimethoprim and 80 mg/mL sulfamethoxazole. Amikacin is typically used in the concentration of 2.5% and is prepared by adding 8 mL of artificial tears to 2 mL of the intravenous preparation of 125 mg/mL amikacin.6 Of note, systemic antibiotics do not add benefit to the clinical outcome of Nocardia keratitis. Steroids worsen the symptoms of Nocardia keratitis, potentially leading to complications such as corneal perforation, scleritis, and endophthalmitis. Thus, it is critically important to identify the causative organism early as routine steroid use for falsely suspected viral keratitis and SLK exacerbates the underlying condition.
Nocardia keratitis responds well to medical therapy. If treatment is started early in the course, the corneal ulcer tends to heal rapidly with mild peripheral vascularization. The infiltrate resolves with minimal scarring and forms a fine superficial nebular opacity. Visual acuity improves rapidly and the end result is a barely visible residual stromal haze.
4 Conclusions
Nocardia are a rare cause of infectious keratitis. Early diagnosis and treatment of Nocardia keratitis are difficult because of its infrequent occurrence and variable clinical manifestations. We describe a case of Nocardia keratitis that was initially misdiagnosed and treated with multiple antibacterial, antiviral, and anti-inflammatory agents. Due to its superior location, SLK was considered and prompted a superior conjunctival resection that disproved the diagnosis. Of note, the initial cultures were negative and it was only after a second corneal scraping that Nocardia was correctly identified by cytology and confirmed by cultures. Once diagnosed, this case of Nocardia keratitis responded effectively to treatment with trimethoprim-sulfamethoxazole (SEPTRA) in the setting of amikacin resistance.
Patient consent
The patient consented to publication of the case in writing and orally.
CRediT authorship contribution statement
Eileen L. Chang: Project administration, Writing - original draft, Writing - review & editing. Rachel L. Chu: Writing - original draft. John R. Wittpenn: Investigation, Writing - review & editing. Henry D. Perry: Supervision, Conceptualization, Investigation, Writing - review & editing.
Acknowledgments and Disclosures
No funding or grant support. There are no conflicts of interest or financial disclosures for any of the authors listed. All authors attest that they meet the current ICMJE criteria for Authorship. | DIFLUPREDNATE, OFLOXACIN, VALACYCLOVIR HYDROCHLORIDE | DrugsGivenReaction | CC BY-NC-ND | 33665477 | 19,356,229 | 2021-06 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Keratitis bacterial'. | Nocardia keratitis mimicking superior limbic keratoconjunctivitis and herpes simplex virus.
Nocardia keratitis is a rare type of infectious keratitis and may mimic other corneal diseases and lead to delay in diagnosis. This case illustrates how Nocardia often escapes accurate diagnosis due to its insidious onset, variable clinical manifestations, and unusual characteristics on cultures.
The patient presented with an epithelial defect and superior pannus and scarring, which was misdiagnosed as superior limbic keratoconjunctivitis (SLK) and herpes simplex virus (HSV) keratitis. Repeat corneal scraping cultures, smears, and conjunctival biopsy were necessary to elucidate the diagnosis. It can be effectively treated with the intravenous preparation of trimethoprim-sulfamethoxazole 80 mg/mL (brand name SEPTRA) used topically as eye drops.
The diagnosis of Nocardia keratitis relies on a high clinical suspicion and a prompt corneal scraping with culture. Due to its potential for rapid resolution with early therapy, it is important to isolate Nocardia early in its disease course.
Topical amikacin had been the standard of care for Nocardia keratitis for many years. However, recently there is increasing resistance of Nocardia to amikacin. SEPTRA offers an alternative therapy. Nocardia keratitis mimics other infectious and inflammatory etiologies so rapid diagnosis and treatment is critical in the prevention of long-term complications.
1 Introduction
Nocardia are a group of aerobic, gram-positive, and catalase-positive bacteria in the shape of long, thin, and branching filaments that stain weakly acid-fast on Ziehl-Neelsen1.
Nocardia asteroides is the most commonly reported species to cause Nocardia keratitis. It is classically described with an appearance of stromal infiltrates in a wreath-like pattern and may be associated with tiny epithelial calcifications often near the limbus adjacent to pannus-like areas of increased vascularity.2,3 Culture on blood agar may occasionally lead to a consideration of contamination due to the tendency for prominent areas of calcification on the agar.2
Nocardia keratitis is seen more frequently in young males, especially those who live in rural areas.3,4 As Nocardia is the most common bacteria found in soil, corneal trauma and contact with soil predispose those in rural areas to infection. Other risk factors for Nocardia keratitis include contact lens wear, ophthalmic surgery, and topical corticosteroids.5, 6, 7, 8
This unique case of Nocardia keratitis focuses attention on the variability of presentation and the possibility of a prolonged clinical course over months. The multiple misdiagnoses suffered by this patient highlight how this pathogen is elusive and often discovered late in the clinical course leading to permanent ocular sequelae.
2 Case presentation
A 41-year-old male contact lens user without history of corneal trauma or soil contact presented with a three-week history of pruritus, photophobia, and excessive tearing of the right eye. He was initially found to have a corneal abrasion and started on topical tobramycin 0.3% QID, which aggravated his symptoms. The patient was then referred to an ophthalmologist who added loteprednol 0.5% daily. The patient failed to respond to this therapy and was sent to a corneal specialist. On initial presentation, the patient's best-corrected visual acuity (BCVA) in the right eye was 20/20–3. Anterior segment exam was significant for bilateral blepharitis, right floppy eyelid, right trace perilimbal injection, 2+ superior palpebral conjunctival injection, and a new right corneal scar with irregular epithelium lacking definitive boundaries superiorly at 12 o'clock. Given the pattern of injection, recurrent discomfort, and subjective complaint of itchiness, superior limbic keratoconjunctivitis (SLK) was considered. The corneal specialist trialed a course of ofloxacin 0.3% and then increased loteprednol 0.5% to BID dosing.
On two-week follow-up, the patient displayed symptomatic improvement. However, the clinical exam demonstrated new dendritiform lesions developing at the peripheral edge of the corneal scar. Treatment for presumed herpes simplex keratitis (HSV) was initiated with a course of oral valacyclovir TID and topical ganciclovir 0.15% QID. Additionally, the patient was sent for corneal cultures to rule out fungal keratitis. Follow-up results were negative for fungi.
The patient returned in one month with worsening symptoms. At this time, his corneal scar displayed anterior stromal scarring with new overlying neovascularization and an advancing edge of irregular epithelium (Fig. 1). Keratic precipitates and anterior chamber inflammation were absent. At this point, the diagnosis of HSV interstitial keratitis was considered. The topical medications were switched from loteprednol to difluprednate 0.05% QID; the patient was restarted on valacyclovir TID.Fig. 1 Clinical photograph of the patient's right eye on initial presentation to second corneal specialist (3 months from first symptoms) demonstrating superior pannus, anterior stromal scarring, conjunctival injection, and floppy eyelids.
Fig. 1
After returning from vacation overseas, the patient followed up with the corneal specialist with minimal improvement. Given the failure to respond to herpetic treatment, a superior conjunctival resection for presumed SLK and corneal scrapings were taken from the right eye where the cornea was abnormal. A ProKera Slim™ amniotic membrane was placed over the defect and prophylactic ophthalmic antibiotics were started. The patient was maintained on oral valacyclovir TID, topical difluprednate 0.05% BID, and topical ofloxacin 0.3% as antibiotic prophylaxis for a few days. Corneal scrapings did not reveal findings suggestive of SLK or microbial keratitis when evaluated.
One week later, the patient reported dramatically decreased vision with severe photophobia and difficulty opening the right eye. Visual acuity was 20/400 with the ProKera Slim™. At this point, the corneal scraping was 95% healed so the ProKera Slim™ was removed. No further stromal infiltrates were noted. All medications were discontinued except bacitracin-polymyxin B. On subsequent follow-up one week later, the patient was referred to another corneal specialist for consultation. At this visit, a repeat corneal Gram stain and a Papinicolau stain were positive for filamentous rods and Nocardia was suspected (Fig. 2). Therapy was initiated with trimethroprim-sulfamethaxazole (SEPTRA) 80 mg/mL in the right eye every 2 hours. One week later, cultural identification was confirmed for Nocardia asteroides and sensitivities showed resistance to amikacin. After three months of unabated progression of his signs and symptoms, the patient showed clinical improvement in three days. However given the prolonged course, he required an additional month of therapy. The patient healed with a subepithelial scar and neovascularization. At this point, SEPTRA was discontinued. The final visual acuity of the right eye was 20/30. Interestingly, the conjunctival biopsy was revisited and showed no signs of Nocardia.Fig. 2 Papinicolau stain magnified 400X of corneal scraping demonstrating branching filaments characteristic of Nocardia asteroides.
Fig. 2
3 Discussion
The usual presenting symptoms of Nocardia keratitis include pain, photophobia, blepharospasm, and lid swelling. Nocardia keratitis frequently runs a protracted benign course, but acute severe cases have been seen.9, 10, 11 Superficial granular infiltrates coalesce into a white plaque of variable size over time and result in corneal ulceration that is often superior in location. In addition to the classic finding of patchy wreath-like anterior stromal infiltrates, other presenting features include pseudodendritic epithelial defect, subepithelial infiltrate, persistent epithelial defect, and/or neovascularization into the cornea.2,10
Diagnosis of Nocardia keratitis is often delayed due to several factors. First, symptoms can have an insidious onset and patients may not initially seek medical care. The variable clinical presentations can mimic other forms of keratitis, such as mycotic or atypical mycobacterial infection.12 The clinician needs to have a high clinical suspicion as Nocardia grows slowly on culture. A prompt corneal scraping and culture should be performed with clinical suspicion. However, this may yield negative results as in this case. Nocardia corneal scrapings are positive for gram-positive, branching filaments that stain weakly acid-fast on Ziehl-Neelsen and black on Gomori methenamine silver.1
Nocardia keratitis can be misdiagnosed as superior limbic keratoconjunctivitis if the disease is located in the superior cornea, as in this case. SLK is characterized by inflammation of the superior bulbar and tarsal conjunctiva in addition to superior corneal vascularization that may appear as a pannus.13 SLK will often demonstrate punctate staining with fluorescein and/or rose Bengal. There can also be localized filamentary keratopathy in one-third of cases. Diagnosis involves obtaining a corneal scraping for Giemsa stain, which typically shows enhanced keratinization, poor nuclei, and hyalinized cytoplasm. Corneal scrapings from this case were not diagnostic for SLK. Treatment modalities include use of topical silver nitrate 1%, anti-inflammatory agents, and conjunctival resection.14,15
Another confounder for Nocardia may be HSV as in this case. At one point in the presentation, a dendritiform lesion was noted suggesting HSV epitheliopathy. A few weeks later, corneal neovascularization and haze developed which appeared clinically as an HSV interstitial keratitis. This clinical picture of apparent recurrence can be quite convincing for herpetic interstitial keratitis. However, the steroid treatment may have exacerbated the Nocardia infection.
Nocardia keratitis is most effectively treated with trimethoprim-sulfamethoxazole or amikacin; the latter is considered the drug of choice for all species of Nocardia.16 However, resistance to amikacin, as in this case, has been previously described.17 The intravenous preparation of trimethoprim-sulfamethoxazole can be used directly as eye drops, typically in a dosing of 16 mg/mL trimethoprim and 80 mg/mL sulfamethoxazole. Amikacin is typically used in the concentration of 2.5% and is prepared by adding 8 mL of artificial tears to 2 mL of the intravenous preparation of 125 mg/mL amikacin.6 Of note, systemic antibiotics do not add benefit to the clinical outcome of Nocardia keratitis. Steroids worsen the symptoms of Nocardia keratitis, potentially leading to complications such as corneal perforation, scleritis, and endophthalmitis. Thus, it is critically important to identify the causative organism early as routine steroid use for falsely suspected viral keratitis and SLK exacerbates the underlying condition.
Nocardia keratitis responds well to medical therapy. If treatment is started early in the course, the corneal ulcer tends to heal rapidly with mild peripheral vascularization. The infiltrate resolves with minimal scarring and forms a fine superficial nebular opacity. Visual acuity improves rapidly and the end result is a barely visible residual stromal haze.
4 Conclusions
Nocardia are a rare cause of infectious keratitis. Early diagnosis and treatment of Nocardia keratitis are difficult because of its infrequent occurrence and variable clinical manifestations. We describe a case of Nocardia keratitis that was initially misdiagnosed and treated with multiple antibacterial, antiviral, and anti-inflammatory agents. Due to its superior location, SLK was considered and prompted a superior conjunctival resection that disproved the diagnosis. Of note, the initial cultures were negative and it was only after a second corneal scraping that Nocardia was correctly identified by cytology and confirmed by cultures. Once diagnosed, this case of Nocardia keratitis responded effectively to treatment with trimethoprim-sulfamethoxazole (SEPTRA) in the setting of amikacin resistance.
Patient consent
The patient consented to publication of the case in writing and orally.
CRediT authorship contribution statement
Eileen L. Chang: Project administration, Writing - original draft, Writing - review & editing. Rachel L. Chu: Writing - original draft. John R. Wittpenn: Investigation, Writing - review & editing. Henry D. Perry: Supervision, Conceptualization, Investigation, Writing - review & editing.
Acknowledgments and Disclosures
No funding or grant support. There are no conflicts of interest or financial disclosures for any of the authors listed. All authors attest that they meet the current ICMJE criteria for Authorship. | LOTEPREDNOL, TOBRAMYCIN | DrugsGivenReaction | CC BY-NC-ND | 33665477 | 19,283,167 | 2021-06 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Nocardiosis'. | Nocardia keratitis mimicking superior limbic keratoconjunctivitis and herpes simplex virus.
Nocardia keratitis is a rare type of infectious keratitis and may mimic other corneal diseases and lead to delay in diagnosis. This case illustrates how Nocardia often escapes accurate diagnosis due to its insidious onset, variable clinical manifestations, and unusual characteristics on cultures.
The patient presented with an epithelial defect and superior pannus and scarring, which was misdiagnosed as superior limbic keratoconjunctivitis (SLK) and herpes simplex virus (HSV) keratitis. Repeat corneal scraping cultures, smears, and conjunctival biopsy were necessary to elucidate the diagnosis. It can be effectively treated with the intravenous preparation of trimethoprim-sulfamethoxazole 80 mg/mL (brand name SEPTRA) used topically as eye drops.
The diagnosis of Nocardia keratitis relies on a high clinical suspicion and a prompt corneal scraping with culture. Due to its potential for rapid resolution with early therapy, it is important to isolate Nocardia early in its disease course.
Topical amikacin had been the standard of care for Nocardia keratitis for many years. However, recently there is increasing resistance of Nocardia to amikacin. SEPTRA offers an alternative therapy. Nocardia keratitis mimics other infectious and inflammatory etiologies so rapid diagnosis and treatment is critical in the prevention of long-term complications.
1 Introduction
Nocardia are a group of aerobic, gram-positive, and catalase-positive bacteria in the shape of long, thin, and branching filaments that stain weakly acid-fast on Ziehl-Neelsen1.
Nocardia asteroides is the most commonly reported species to cause Nocardia keratitis. It is classically described with an appearance of stromal infiltrates in a wreath-like pattern and may be associated with tiny epithelial calcifications often near the limbus adjacent to pannus-like areas of increased vascularity.2,3 Culture on blood agar may occasionally lead to a consideration of contamination due to the tendency for prominent areas of calcification on the agar.2
Nocardia keratitis is seen more frequently in young males, especially those who live in rural areas.3,4 As Nocardia is the most common bacteria found in soil, corneal trauma and contact with soil predispose those in rural areas to infection. Other risk factors for Nocardia keratitis include contact lens wear, ophthalmic surgery, and topical corticosteroids.5, 6, 7, 8
This unique case of Nocardia keratitis focuses attention on the variability of presentation and the possibility of a prolonged clinical course over months. The multiple misdiagnoses suffered by this patient highlight how this pathogen is elusive and often discovered late in the clinical course leading to permanent ocular sequelae.
2 Case presentation
A 41-year-old male contact lens user without history of corneal trauma or soil contact presented with a three-week history of pruritus, photophobia, and excessive tearing of the right eye. He was initially found to have a corneal abrasion and started on topical tobramycin 0.3% QID, which aggravated his symptoms. The patient was then referred to an ophthalmologist who added loteprednol 0.5% daily. The patient failed to respond to this therapy and was sent to a corneal specialist. On initial presentation, the patient's best-corrected visual acuity (BCVA) in the right eye was 20/20–3. Anterior segment exam was significant for bilateral blepharitis, right floppy eyelid, right trace perilimbal injection, 2+ superior palpebral conjunctival injection, and a new right corneal scar with irregular epithelium lacking definitive boundaries superiorly at 12 o'clock. Given the pattern of injection, recurrent discomfort, and subjective complaint of itchiness, superior limbic keratoconjunctivitis (SLK) was considered. The corneal specialist trialed a course of ofloxacin 0.3% and then increased loteprednol 0.5% to BID dosing.
On two-week follow-up, the patient displayed symptomatic improvement. However, the clinical exam demonstrated new dendritiform lesions developing at the peripheral edge of the corneal scar. Treatment for presumed herpes simplex keratitis (HSV) was initiated with a course of oral valacyclovir TID and topical ganciclovir 0.15% QID. Additionally, the patient was sent for corneal cultures to rule out fungal keratitis. Follow-up results were negative for fungi.
The patient returned in one month with worsening symptoms. At this time, his corneal scar displayed anterior stromal scarring with new overlying neovascularization and an advancing edge of irregular epithelium (Fig. 1). Keratic precipitates and anterior chamber inflammation were absent. At this point, the diagnosis of HSV interstitial keratitis was considered. The topical medications were switched from loteprednol to difluprednate 0.05% QID; the patient was restarted on valacyclovir TID.Fig. 1 Clinical photograph of the patient's right eye on initial presentation to second corneal specialist (3 months from first symptoms) demonstrating superior pannus, anterior stromal scarring, conjunctival injection, and floppy eyelids.
Fig. 1
After returning from vacation overseas, the patient followed up with the corneal specialist with minimal improvement. Given the failure to respond to herpetic treatment, a superior conjunctival resection for presumed SLK and corneal scrapings were taken from the right eye where the cornea was abnormal. A ProKera Slim™ amniotic membrane was placed over the defect and prophylactic ophthalmic antibiotics were started. The patient was maintained on oral valacyclovir TID, topical difluprednate 0.05% BID, and topical ofloxacin 0.3% as antibiotic prophylaxis for a few days. Corneal scrapings did not reveal findings suggestive of SLK or microbial keratitis when evaluated.
One week later, the patient reported dramatically decreased vision with severe photophobia and difficulty opening the right eye. Visual acuity was 20/400 with the ProKera Slim™. At this point, the corneal scraping was 95% healed so the ProKera Slim™ was removed. No further stromal infiltrates were noted. All medications were discontinued except bacitracin-polymyxin B. On subsequent follow-up one week later, the patient was referred to another corneal specialist for consultation. At this visit, a repeat corneal Gram stain and a Papinicolau stain were positive for filamentous rods and Nocardia was suspected (Fig. 2). Therapy was initiated with trimethroprim-sulfamethaxazole (SEPTRA) 80 mg/mL in the right eye every 2 hours. One week later, cultural identification was confirmed for Nocardia asteroides and sensitivities showed resistance to amikacin. After three months of unabated progression of his signs and symptoms, the patient showed clinical improvement in three days. However given the prolonged course, he required an additional month of therapy. The patient healed with a subepithelial scar and neovascularization. At this point, SEPTRA was discontinued. The final visual acuity of the right eye was 20/30. Interestingly, the conjunctival biopsy was revisited and showed no signs of Nocardia.Fig. 2 Papinicolau stain magnified 400X of corneal scraping demonstrating branching filaments characteristic of Nocardia asteroides.
Fig. 2
3 Discussion
The usual presenting symptoms of Nocardia keratitis include pain, photophobia, blepharospasm, and lid swelling. Nocardia keratitis frequently runs a protracted benign course, but acute severe cases have been seen.9, 10, 11 Superficial granular infiltrates coalesce into a white plaque of variable size over time and result in corneal ulceration that is often superior in location. In addition to the classic finding of patchy wreath-like anterior stromal infiltrates, other presenting features include pseudodendritic epithelial defect, subepithelial infiltrate, persistent epithelial defect, and/or neovascularization into the cornea.2,10
Diagnosis of Nocardia keratitis is often delayed due to several factors. First, symptoms can have an insidious onset and patients may not initially seek medical care. The variable clinical presentations can mimic other forms of keratitis, such as mycotic or atypical mycobacterial infection.12 The clinician needs to have a high clinical suspicion as Nocardia grows slowly on culture. A prompt corneal scraping and culture should be performed with clinical suspicion. However, this may yield negative results as in this case. Nocardia corneal scrapings are positive for gram-positive, branching filaments that stain weakly acid-fast on Ziehl-Neelsen and black on Gomori methenamine silver.1
Nocardia keratitis can be misdiagnosed as superior limbic keratoconjunctivitis if the disease is located in the superior cornea, as in this case. SLK is characterized by inflammation of the superior bulbar and tarsal conjunctiva in addition to superior corneal vascularization that may appear as a pannus.13 SLK will often demonstrate punctate staining with fluorescein and/or rose Bengal. There can also be localized filamentary keratopathy in one-third of cases. Diagnosis involves obtaining a corneal scraping for Giemsa stain, which typically shows enhanced keratinization, poor nuclei, and hyalinized cytoplasm. Corneal scrapings from this case were not diagnostic for SLK. Treatment modalities include use of topical silver nitrate 1%, anti-inflammatory agents, and conjunctival resection.14,15
Another confounder for Nocardia may be HSV as in this case. At one point in the presentation, a dendritiform lesion was noted suggesting HSV epitheliopathy. A few weeks later, corneal neovascularization and haze developed which appeared clinically as an HSV interstitial keratitis. This clinical picture of apparent recurrence can be quite convincing for herpetic interstitial keratitis. However, the steroid treatment may have exacerbated the Nocardia infection.
Nocardia keratitis is most effectively treated with trimethoprim-sulfamethoxazole or amikacin; the latter is considered the drug of choice for all species of Nocardia.16 However, resistance to amikacin, as in this case, has been previously described.17 The intravenous preparation of trimethoprim-sulfamethoxazole can be used directly as eye drops, typically in a dosing of 16 mg/mL trimethoprim and 80 mg/mL sulfamethoxazole. Amikacin is typically used in the concentration of 2.5% and is prepared by adding 8 mL of artificial tears to 2 mL of the intravenous preparation of 125 mg/mL amikacin.6 Of note, systemic antibiotics do not add benefit to the clinical outcome of Nocardia keratitis. Steroids worsen the symptoms of Nocardia keratitis, potentially leading to complications such as corneal perforation, scleritis, and endophthalmitis. Thus, it is critically important to identify the causative organism early as routine steroid use for falsely suspected viral keratitis and SLK exacerbates the underlying condition.
Nocardia keratitis responds well to medical therapy. If treatment is started early in the course, the corneal ulcer tends to heal rapidly with mild peripheral vascularization. The infiltrate resolves with minimal scarring and forms a fine superficial nebular opacity. Visual acuity improves rapidly and the end result is a barely visible residual stromal haze.
4 Conclusions
Nocardia are a rare cause of infectious keratitis. Early diagnosis and treatment of Nocardia keratitis are difficult because of its infrequent occurrence and variable clinical manifestations. We describe a case of Nocardia keratitis that was initially misdiagnosed and treated with multiple antibacterial, antiviral, and anti-inflammatory agents. Due to its superior location, SLK was considered and prompted a superior conjunctival resection that disproved the diagnosis. Of note, the initial cultures were negative and it was only after a second corneal scraping that Nocardia was correctly identified by cytology and confirmed by cultures. Once diagnosed, this case of Nocardia keratitis responded effectively to treatment with trimethoprim-sulfamethoxazole (SEPTRA) in the setting of amikacin resistance.
Patient consent
The patient consented to publication of the case in writing and orally.
CRediT authorship contribution statement
Eileen L. Chang: Project administration, Writing - original draft, Writing - review & editing. Rachel L. Chu: Writing - original draft. John R. Wittpenn: Investigation, Writing - review & editing. Henry D. Perry: Supervision, Conceptualization, Investigation, Writing - review & editing.
Acknowledgments and Disclosures
No funding or grant support. There are no conflicts of interest or financial disclosures for any of the authors listed. All authors attest that they meet the current ICMJE criteria for Authorship. | LOTEPREDNOL, TOBRAMYCIN | DrugsGivenReaction | CC BY-NC-ND | 33665477 | 19,283,167 | 2021-06 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Off label use'. | Nocardia keratitis mimicking superior limbic keratoconjunctivitis and herpes simplex virus.
Nocardia keratitis is a rare type of infectious keratitis and may mimic other corneal diseases and lead to delay in diagnosis. This case illustrates how Nocardia often escapes accurate diagnosis due to its insidious onset, variable clinical manifestations, and unusual characteristics on cultures.
The patient presented with an epithelial defect and superior pannus and scarring, which was misdiagnosed as superior limbic keratoconjunctivitis (SLK) and herpes simplex virus (HSV) keratitis. Repeat corneal scraping cultures, smears, and conjunctival biopsy were necessary to elucidate the diagnosis. It can be effectively treated with the intravenous preparation of trimethoprim-sulfamethoxazole 80 mg/mL (brand name SEPTRA) used topically as eye drops.
The diagnosis of Nocardia keratitis relies on a high clinical suspicion and a prompt corneal scraping with culture. Due to its potential for rapid resolution with early therapy, it is important to isolate Nocardia early in its disease course.
Topical amikacin had been the standard of care for Nocardia keratitis for many years. However, recently there is increasing resistance of Nocardia to amikacin. SEPTRA offers an alternative therapy. Nocardia keratitis mimics other infectious and inflammatory etiologies so rapid diagnosis and treatment is critical in the prevention of long-term complications.
1 Introduction
Nocardia are a group of aerobic, gram-positive, and catalase-positive bacteria in the shape of long, thin, and branching filaments that stain weakly acid-fast on Ziehl-Neelsen1.
Nocardia asteroides is the most commonly reported species to cause Nocardia keratitis. It is classically described with an appearance of stromal infiltrates in a wreath-like pattern and may be associated with tiny epithelial calcifications often near the limbus adjacent to pannus-like areas of increased vascularity.2,3 Culture on blood agar may occasionally lead to a consideration of contamination due to the tendency for prominent areas of calcification on the agar.2
Nocardia keratitis is seen more frequently in young males, especially those who live in rural areas.3,4 As Nocardia is the most common bacteria found in soil, corneal trauma and contact with soil predispose those in rural areas to infection. Other risk factors for Nocardia keratitis include contact lens wear, ophthalmic surgery, and topical corticosteroids.5, 6, 7, 8
This unique case of Nocardia keratitis focuses attention on the variability of presentation and the possibility of a prolonged clinical course over months. The multiple misdiagnoses suffered by this patient highlight how this pathogen is elusive and often discovered late in the clinical course leading to permanent ocular sequelae.
2 Case presentation
A 41-year-old male contact lens user without history of corneal trauma or soil contact presented with a three-week history of pruritus, photophobia, and excessive tearing of the right eye. He was initially found to have a corneal abrasion and started on topical tobramycin 0.3% QID, which aggravated his symptoms. The patient was then referred to an ophthalmologist who added loteprednol 0.5% daily. The patient failed to respond to this therapy and was sent to a corneal specialist. On initial presentation, the patient's best-corrected visual acuity (BCVA) in the right eye was 20/20–3. Anterior segment exam was significant for bilateral blepharitis, right floppy eyelid, right trace perilimbal injection, 2+ superior palpebral conjunctival injection, and a new right corneal scar with irregular epithelium lacking definitive boundaries superiorly at 12 o'clock. Given the pattern of injection, recurrent discomfort, and subjective complaint of itchiness, superior limbic keratoconjunctivitis (SLK) was considered. The corneal specialist trialed a course of ofloxacin 0.3% and then increased loteprednol 0.5% to BID dosing.
On two-week follow-up, the patient displayed symptomatic improvement. However, the clinical exam demonstrated new dendritiform lesions developing at the peripheral edge of the corneal scar. Treatment for presumed herpes simplex keratitis (HSV) was initiated with a course of oral valacyclovir TID and topical ganciclovir 0.15% QID. Additionally, the patient was sent for corneal cultures to rule out fungal keratitis. Follow-up results were negative for fungi.
The patient returned in one month with worsening symptoms. At this time, his corneal scar displayed anterior stromal scarring with new overlying neovascularization and an advancing edge of irregular epithelium (Fig. 1). Keratic precipitates and anterior chamber inflammation were absent. At this point, the diagnosis of HSV interstitial keratitis was considered. The topical medications were switched from loteprednol to difluprednate 0.05% QID; the patient was restarted on valacyclovir TID.Fig. 1 Clinical photograph of the patient's right eye on initial presentation to second corneal specialist (3 months from first symptoms) demonstrating superior pannus, anterior stromal scarring, conjunctival injection, and floppy eyelids.
Fig. 1
After returning from vacation overseas, the patient followed up with the corneal specialist with minimal improvement. Given the failure to respond to herpetic treatment, a superior conjunctival resection for presumed SLK and corneal scrapings were taken from the right eye where the cornea was abnormal. A ProKera Slim™ amniotic membrane was placed over the defect and prophylactic ophthalmic antibiotics were started. The patient was maintained on oral valacyclovir TID, topical difluprednate 0.05% BID, and topical ofloxacin 0.3% as antibiotic prophylaxis for a few days. Corneal scrapings did not reveal findings suggestive of SLK or microbial keratitis when evaluated.
One week later, the patient reported dramatically decreased vision with severe photophobia and difficulty opening the right eye. Visual acuity was 20/400 with the ProKera Slim™. At this point, the corneal scraping was 95% healed so the ProKera Slim™ was removed. No further stromal infiltrates were noted. All medications were discontinued except bacitracin-polymyxin B. On subsequent follow-up one week later, the patient was referred to another corneal specialist for consultation. At this visit, a repeat corneal Gram stain and a Papinicolau stain were positive for filamentous rods and Nocardia was suspected (Fig. 2). Therapy was initiated with trimethroprim-sulfamethaxazole (SEPTRA) 80 mg/mL in the right eye every 2 hours. One week later, cultural identification was confirmed for Nocardia asteroides and sensitivities showed resistance to amikacin. After three months of unabated progression of his signs and symptoms, the patient showed clinical improvement in three days. However given the prolonged course, he required an additional month of therapy. The patient healed with a subepithelial scar and neovascularization. At this point, SEPTRA was discontinued. The final visual acuity of the right eye was 20/30. Interestingly, the conjunctival biopsy was revisited and showed no signs of Nocardia.Fig. 2 Papinicolau stain magnified 400X of corneal scraping demonstrating branching filaments characteristic of Nocardia asteroides.
Fig. 2
3 Discussion
The usual presenting symptoms of Nocardia keratitis include pain, photophobia, blepharospasm, and lid swelling. Nocardia keratitis frequently runs a protracted benign course, but acute severe cases have been seen.9, 10, 11 Superficial granular infiltrates coalesce into a white plaque of variable size over time and result in corneal ulceration that is often superior in location. In addition to the classic finding of patchy wreath-like anterior stromal infiltrates, other presenting features include pseudodendritic epithelial defect, subepithelial infiltrate, persistent epithelial defect, and/or neovascularization into the cornea.2,10
Diagnosis of Nocardia keratitis is often delayed due to several factors. First, symptoms can have an insidious onset and patients may not initially seek medical care. The variable clinical presentations can mimic other forms of keratitis, such as mycotic or atypical mycobacterial infection.12 The clinician needs to have a high clinical suspicion as Nocardia grows slowly on culture. A prompt corneal scraping and culture should be performed with clinical suspicion. However, this may yield negative results as in this case. Nocardia corneal scrapings are positive for gram-positive, branching filaments that stain weakly acid-fast on Ziehl-Neelsen and black on Gomori methenamine silver.1
Nocardia keratitis can be misdiagnosed as superior limbic keratoconjunctivitis if the disease is located in the superior cornea, as in this case. SLK is characterized by inflammation of the superior bulbar and tarsal conjunctiva in addition to superior corneal vascularization that may appear as a pannus.13 SLK will often demonstrate punctate staining with fluorescein and/or rose Bengal. There can also be localized filamentary keratopathy in one-third of cases. Diagnosis involves obtaining a corneal scraping for Giemsa stain, which typically shows enhanced keratinization, poor nuclei, and hyalinized cytoplasm. Corneal scrapings from this case were not diagnostic for SLK. Treatment modalities include use of topical silver nitrate 1%, anti-inflammatory agents, and conjunctival resection.14,15
Another confounder for Nocardia may be HSV as in this case. At one point in the presentation, a dendritiform lesion was noted suggesting HSV epitheliopathy. A few weeks later, corneal neovascularization and haze developed which appeared clinically as an HSV interstitial keratitis. This clinical picture of apparent recurrence can be quite convincing for herpetic interstitial keratitis. However, the steroid treatment may have exacerbated the Nocardia infection.
Nocardia keratitis is most effectively treated with trimethoprim-sulfamethoxazole or amikacin; the latter is considered the drug of choice for all species of Nocardia.16 However, resistance to amikacin, as in this case, has been previously described.17 The intravenous preparation of trimethoprim-sulfamethoxazole can be used directly as eye drops, typically in a dosing of 16 mg/mL trimethoprim and 80 mg/mL sulfamethoxazole. Amikacin is typically used in the concentration of 2.5% and is prepared by adding 8 mL of artificial tears to 2 mL of the intravenous preparation of 125 mg/mL amikacin.6 Of note, systemic antibiotics do not add benefit to the clinical outcome of Nocardia keratitis. Steroids worsen the symptoms of Nocardia keratitis, potentially leading to complications such as corneal perforation, scleritis, and endophthalmitis. Thus, it is critically important to identify the causative organism early as routine steroid use for falsely suspected viral keratitis and SLK exacerbates the underlying condition.
Nocardia keratitis responds well to medical therapy. If treatment is started early in the course, the corneal ulcer tends to heal rapidly with mild peripheral vascularization. The infiltrate resolves with minimal scarring and forms a fine superficial nebular opacity. Visual acuity improves rapidly and the end result is a barely visible residual stromal haze.
4 Conclusions
Nocardia are a rare cause of infectious keratitis. Early diagnosis and treatment of Nocardia keratitis are difficult because of its infrequent occurrence and variable clinical manifestations. We describe a case of Nocardia keratitis that was initially misdiagnosed and treated with multiple antibacterial, antiviral, and anti-inflammatory agents. Due to its superior location, SLK was considered and prompted a superior conjunctival resection that disproved the diagnosis. Of note, the initial cultures were negative and it was only after a second corneal scraping that Nocardia was correctly identified by cytology and confirmed by cultures. Once diagnosed, this case of Nocardia keratitis responded effectively to treatment with trimethoprim-sulfamethoxazole (SEPTRA) in the setting of amikacin resistance.
Patient consent
The patient consented to publication of the case in writing and orally.
CRediT authorship contribution statement
Eileen L. Chang: Project administration, Writing - original draft, Writing - review & editing. Rachel L. Chu: Writing - original draft. John R. Wittpenn: Investigation, Writing - review & editing. Henry D. Perry: Supervision, Conceptualization, Investigation, Writing - review & editing.
Acknowledgments and Disclosures
No funding or grant support. There are no conflicts of interest or financial disclosures for any of the authors listed. All authors attest that they meet the current ICMJE criteria for Authorship. | TOBRAMYCIN | DrugsGivenReaction | CC BY-NC-ND | 33665477 | 19,295,206 | 2021-06 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Photophobia'. | Nocardia keratitis mimicking superior limbic keratoconjunctivitis and herpes simplex virus.
Nocardia keratitis is a rare type of infectious keratitis and may mimic other corneal diseases and lead to delay in diagnosis. This case illustrates how Nocardia often escapes accurate diagnosis due to its insidious onset, variable clinical manifestations, and unusual characteristics on cultures.
The patient presented with an epithelial defect and superior pannus and scarring, which was misdiagnosed as superior limbic keratoconjunctivitis (SLK) and herpes simplex virus (HSV) keratitis. Repeat corneal scraping cultures, smears, and conjunctival biopsy were necessary to elucidate the diagnosis. It can be effectively treated with the intravenous preparation of trimethoprim-sulfamethoxazole 80 mg/mL (brand name SEPTRA) used topically as eye drops.
The diagnosis of Nocardia keratitis relies on a high clinical suspicion and a prompt corneal scraping with culture. Due to its potential for rapid resolution with early therapy, it is important to isolate Nocardia early in its disease course.
Topical amikacin had been the standard of care for Nocardia keratitis for many years. However, recently there is increasing resistance of Nocardia to amikacin. SEPTRA offers an alternative therapy. Nocardia keratitis mimics other infectious and inflammatory etiologies so rapid diagnosis and treatment is critical in the prevention of long-term complications.
1 Introduction
Nocardia are a group of aerobic, gram-positive, and catalase-positive bacteria in the shape of long, thin, and branching filaments that stain weakly acid-fast on Ziehl-Neelsen1.
Nocardia asteroides is the most commonly reported species to cause Nocardia keratitis. It is classically described with an appearance of stromal infiltrates in a wreath-like pattern and may be associated with tiny epithelial calcifications often near the limbus adjacent to pannus-like areas of increased vascularity.2,3 Culture on blood agar may occasionally lead to a consideration of contamination due to the tendency for prominent areas of calcification on the agar.2
Nocardia keratitis is seen more frequently in young males, especially those who live in rural areas.3,4 As Nocardia is the most common bacteria found in soil, corneal trauma and contact with soil predispose those in rural areas to infection. Other risk factors for Nocardia keratitis include contact lens wear, ophthalmic surgery, and topical corticosteroids.5, 6, 7, 8
This unique case of Nocardia keratitis focuses attention on the variability of presentation and the possibility of a prolonged clinical course over months. The multiple misdiagnoses suffered by this patient highlight how this pathogen is elusive and often discovered late in the clinical course leading to permanent ocular sequelae.
2 Case presentation
A 41-year-old male contact lens user without history of corneal trauma or soil contact presented with a three-week history of pruritus, photophobia, and excessive tearing of the right eye. He was initially found to have a corneal abrasion and started on topical tobramycin 0.3% QID, which aggravated his symptoms. The patient was then referred to an ophthalmologist who added loteprednol 0.5% daily. The patient failed to respond to this therapy and was sent to a corneal specialist. On initial presentation, the patient's best-corrected visual acuity (BCVA) in the right eye was 20/20–3. Anterior segment exam was significant for bilateral blepharitis, right floppy eyelid, right trace perilimbal injection, 2+ superior palpebral conjunctival injection, and a new right corneal scar with irregular epithelium lacking definitive boundaries superiorly at 12 o'clock. Given the pattern of injection, recurrent discomfort, and subjective complaint of itchiness, superior limbic keratoconjunctivitis (SLK) was considered. The corneal specialist trialed a course of ofloxacin 0.3% and then increased loteprednol 0.5% to BID dosing.
On two-week follow-up, the patient displayed symptomatic improvement. However, the clinical exam demonstrated new dendritiform lesions developing at the peripheral edge of the corneal scar. Treatment for presumed herpes simplex keratitis (HSV) was initiated with a course of oral valacyclovir TID and topical ganciclovir 0.15% QID. Additionally, the patient was sent for corneal cultures to rule out fungal keratitis. Follow-up results were negative for fungi.
The patient returned in one month with worsening symptoms. At this time, his corneal scar displayed anterior stromal scarring with new overlying neovascularization and an advancing edge of irregular epithelium (Fig. 1). Keratic precipitates and anterior chamber inflammation were absent. At this point, the diagnosis of HSV interstitial keratitis was considered. The topical medications were switched from loteprednol to difluprednate 0.05% QID; the patient was restarted on valacyclovir TID.Fig. 1 Clinical photograph of the patient's right eye on initial presentation to second corneal specialist (3 months from first symptoms) demonstrating superior pannus, anterior stromal scarring, conjunctival injection, and floppy eyelids.
Fig. 1
After returning from vacation overseas, the patient followed up with the corneal specialist with minimal improvement. Given the failure to respond to herpetic treatment, a superior conjunctival resection for presumed SLK and corneal scrapings were taken from the right eye where the cornea was abnormal. A ProKera Slim™ amniotic membrane was placed over the defect and prophylactic ophthalmic antibiotics were started. The patient was maintained on oral valacyclovir TID, topical difluprednate 0.05% BID, and topical ofloxacin 0.3% as antibiotic prophylaxis for a few days. Corneal scrapings did not reveal findings suggestive of SLK or microbial keratitis when evaluated.
One week later, the patient reported dramatically decreased vision with severe photophobia and difficulty opening the right eye. Visual acuity was 20/400 with the ProKera Slim™. At this point, the corneal scraping was 95% healed so the ProKera Slim™ was removed. No further stromal infiltrates were noted. All medications were discontinued except bacitracin-polymyxin B. On subsequent follow-up one week later, the patient was referred to another corneal specialist for consultation. At this visit, a repeat corneal Gram stain and a Papinicolau stain were positive for filamentous rods and Nocardia was suspected (Fig. 2). Therapy was initiated with trimethroprim-sulfamethaxazole (SEPTRA) 80 mg/mL in the right eye every 2 hours. One week later, cultural identification was confirmed for Nocardia asteroides and sensitivities showed resistance to amikacin. After three months of unabated progression of his signs and symptoms, the patient showed clinical improvement in three days. However given the prolonged course, he required an additional month of therapy. The patient healed with a subepithelial scar and neovascularization. At this point, SEPTRA was discontinued. The final visual acuity of the right eye was 20/30. Interestingly, the conjunctival biopsy was revisited and showed no signs of Nocardia.Fig. 2 Papinicolau stain magnified 400X of corneal scraping demonstrating branching filaments characteristic of Nocardia asteroides.
Fig. 2
3 Discussion
The usual presenting symptoms of Nocardia keratitis include pain, photophobia, blepharospasm, and lid swelling. Nocardia keratitis frequently runs a protracted benign course, but acute severe cases have been seen.9, 10, 11 Superficial granular infiltrates coalesce into a white plaque of variable size over time and result in corneal ulceration that is often superior in location. In addition to the classic finding of patchy wreath-like anterior stromal infiltrates, other presenting features include pseudodendritic epithelial defect, subepithelial infiltrate, persistent epithelial defect, and/or neovascularization into the cornea.2,10
Diagnosis of Nocardia keratitis is often delayed due to several factors. First, symptoms can have an insidious onset and patients may not initially seek medical care. The variable clinical presentations can mimic other forms of keratitis, such as mycotic or atypical mycobacterial infection.12 The clinician needs to have a high clinical suspicion as Nocardia grows slowly on culture. A prompt corneal scraping and culture should be performed with clinical suspicion. However, this may yield negative results as in this case. Nocardia corneal scrapings are positive for gram-positive, branching filaments that stain weakly acid-fast on Ziehl-Neelsen and black on Gomori methenamine silver.1
Nocardia keratitis can be misdiagnosed as superior limbic keratoconjunctivitis if the disease is located in the superior cornea, as in this case. SLK is characterized by inflammation of the superior bulbar and tarsal conjunctiva in addition to superior corneal vascularization that may appear as a pannus.13 SLK will often demonstrate punctate staining with fluorescein and/or rose Bengal. There can also be localized filamentary keratopathy in one-third of cases. Diagnosis involves obtaining a corneal scraping for Giemsa stain, which typically shows enhanced keratinization, poor nuclei, and hyalinized cytoplasm. Corneal scrapings from this case were not diagnostic for SLK. Treatment modalities include use of topical silver nitrate 1%, anti-inflammatory agents, and conjunctival resection.14,15
Another confounder for Nocardia may be HSV as in this case. At one point in the presentation, a dendritiform lesion was noted suggesting HSV epitheliopathy. A few weeks later, corneal neovascularization and haze developed which appeared clinically as an HSV interstitial keratitis. This clinical picture of apparent recurrence can be quite convincing for herpetic interstitial keratitis. However, the steroid treatment may have exacerbated the Nocardia infection.
Nocardia keratitis is most effectively treated with trimethoprim-sulfamethoxazole or amikacin; the latter is considered the drug of choice for all species of Nocardia.16 However, resistance to amikacin, as in this case, has been previously described.17 The intravenous preparation of trimethoprim-sulfamethoxazole can be used directly as eye drops, typically in a dosing of 16 mg/mL trimethoprim and 80 mg/mL sulfamethoxazole. Amikacin is typically used in the concentration of 2.5% and is prepared by adding 8 mL of artificial tears to 2 mL of the intravenous preparation of 125 mg/mL amikacin.6 Of note, systemic antibiotics do not add benefit to the clinical outcome of Nocardia keratitis. Steroids worsen the symptoms of Nocardia keratitis, potentially leading to complications such as corneal perforation, scleritis, and endophthalmitis. Thus, it is critically important to identify the causative organism early as routine steroid use for falsely suspected viral keratitis and SLK exacerbates the underlying condition.
Nocardia keratitis responds well to medical therapy. If treatment is started early in the course, the corneal ulcer tends to heal rapidly with mild peripheral vascularization. The infiltrate resolves with minimal scarring and forms a fine superficial nebular opacity. Visual acuity improves rapidly and the end result is a barely visible residual stromal haze.
4 Conclusions
Nocardia are a rare cause of infectious keratitis. Early diagnosis and treatment of Nocardia keratitis are difficult because of its infrequent occurrence and variable clinical manifestations. We describe a case of Nocardia keratitis that was initially misdiagnosed and treated with multiple antibacterial, antiviral, and anti-inflammatory agents. Due to its superior location, SLK was considered and prompted a superior conjunctival resection that disproved the diagnosis. Of note, the initial cultures were negative and it was only after a second corneal scraping that Nocardia was correctly identified by cytology and confirmed by cultures. Once diagnosed, this case of Nocardia keratitis responded effectively to treatment with trimethoprim-sulfamethoxazole (SEPTRA) in the setting of amikacin resistance.
Patient consent
The patient consented to publication of the case in writing and orally.
CRediT authorship contribution statement
Eileen L. Chang: Project administration, Writing - original draft, Writing - review & editing. Rachel L. Chu: Writing - original draft. John R. Wittpenn: Investigation, Writing - review & editing. Henry D. Perry: Supervision, Conceptualization, Investigation, Writing - review & editing.
Acknowledgments and Disclosures
No funding or grant support. There are no conflicts of interest or financial disclosures for any of the authors listed. All authors attest that they meet the current ICMJE criteria for Authorship. | DIFLUPREDNATE, OFLOXACIN, VALACYCLOVIR HYDROCHLORIDE | DrugsGivenReaction | CC BY-NC-ND | 33665477 | 19,356,229 | 2021-06 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Therapy non-responder'. | Nocardia keratitis mimicking superior limbic keratoconjunctivitis and herpes simplex virus.
Nocardia keratitis is a rare type of infectious keratitis and may mimic other corneal diseases and lead to delay in diagnosis. This case illustrates how Nocardia often escapes accurate diagnosis due to its insidious onset, variable clinical manifestations, and unusual characteristics on cultures.
The patient presented with an epithelial defect and superior pannus and scarring, which was misdiagnosed as superior limbic keratoconjunctivitis (SLK) and herpes simplex virus (HSV) keratitis. Repeat corneal scraping cultures, smears, and conjunctival biopsy were necessary to elucidate the diagnosis. It can be effectively treated with the intravenous preparation of trimethoprim-sulfamethoxazole 80 mg/mL (brand name SEPTRA) used topically as eye drops.
The diagnosis of Nocardia keratitis relies on a high clinical suspicion and a prompt corneal scraping with culture. Due to its potential for rapid resolution with early therapy, it is important to isolate Nocardia early in its disease course.
Topical amikacin had been the standard of care for Nocardia keratitis for many years. However, recently there is increasing resistance of Nocardia to amikacin. SEPTRA offers an alternative therapy. Nocardia keratitis mimics other infectious and inflammatory etiologies so rapid diagnosis and treatment is critical in the prevention of long-term complications.
1 Introduction
Nocardia are a group of aerobic, gram-positive, and catalase-positive bacteria in the shape of long, thin, and branching filaments that stain weakly acid-fast on Ziehl-Neelsen1.
Nocardia asteroides is the most commonly reported species to cause Nocardia keratitis. It is classically described with an appearance of stromal infiltrates in a wreath-like pattern and may be associated with tiny epithelial calcifications often near the limbus adjacent to pannus-like areas of increased vascularity.2,3 Culture on blood agar may occasionally lead to a consideration of contamination due to the tendency for prominent areas of calcification on the agar.2
Nocardia keratitis is seen more frequently in young males, especially those who live in rural areas.3,4 As Nocardia is the most common bacteria found in soil, corneal trauma and contact with soil predispose those in rural areas to infection. Other risk factors for Nocardia keratitis include contact lens wear, ophthalmic surgery, and topical corticosteroids.5, 6, 7, 8
This unique case of Nocardia keratitis focuses attention on the variability of presentation and the possibility of a prolonged clinical course over months. The multiple misdiagnoses suffered by this patient highlight how this pathogen is elusive and often discovered late in the clinical course leading to permanent ocular sequelae.
2 Case presentation
A 41-year-old male contact lens user without history of corneal trauma or soil contact presented with a three-week history of pruritus, photophobia, and excessive tearing of the right eye. He was initially found to have a corneal abrasion and started on topical tobramycin 0.3% QID, which aggravated his symptoms. The patient was then referred to an ophthalmologist who added loteprednol 0.5% daily. The patient failed to respond to this therapy and was sent to a corneal specialist. On initial presentation, the patient's best-corrected visual acuity (BCVA) in the right eye was 20/20–3. Anterior segment exam was significant for bilateral blepharitis, right floppy eyelid, right trace perilimbal injection, 2+ superior palpebral conjunctival injection, and a new right corneal scar with irregular epithelium lacking definitive boundaries superiorly at 12 o'clock. Given the pattern of injection, recurrent discomfort, and subjective complaint of itchiness, superior limbic keratoconjunctivitis (SLK) was considered. The corneal specialist trialed a course of ofloxacin 0.3% and then increased loteprednol 0.5% to BID dosing.
On two-week follow-up, the patient displayed symptomatic improvement. However, the clinical exam demonstrated new dendritiform lesions developing at the peripheral edge of the corneal scar. Treatment for presumed herpes simplex keratitis (HSV) was initiated with a course of oral valacyclovir TID and topical ganciclovir 0.15% QID. Additionally, the patient was sent for corneal cultures to rule out fungal keratitis. Follow-up results were negative for fungi.
The patient returned in one month with worsening symptoms. At this time, his corneal scar displayed anterior stromal scarring with new overlying neovascularization and an advancing edge of irregular epithelium (Fig. 1). Keratic precipitates and anterior chamber inflammation were absent. At this point, the diagnosis of HSV interstitial keratitis was considered. The topical medications were switched from loteprednol to difluprednate 0.05% QID; the patient was restarted on valacyclovir TID.Fig. 1 Clinical photograph of the patient's right eye on initial presentation to second corneal specialist (3 months from first symptoms) demonstrating superior pannus, anterior stromal scarring, conjunctival injection, and floppy eyelids.
Fig. 1
After returning from vacation overseas, the patient followed up with the corneal specialist with minimal improvement. Given the failure to respond to herpetic treatment, a superior conjunctival resection for presumed SLK and corneal scrapings were taken from the right eye where the cornea was abnormal. A ProKera Slim™ amniotic membrane was placed over the defect and prophylactic ophthalmic antibiotics were started. The patient was maintained on oral valacyclovir TID, topical difluprednate 0.05% BID, and topical ofloxacin 0.3% as antibiotic prophylaxis for a few days. Corneal scrapings did not reveal findings suggestive of SLK or microbial keratitis when evaluated.
One week later, the patient reported dramatically decreased vision with severe photophobia and difficulty opening the right eye. Visual acuity was 20/400 with the ProKera Slim™. At this point, the corneal scraping was 95% healed so the ProKera Slim™ was removed. No further stromal infiltrates were noted. All medications were discontinued except bacitracin-polymyxin B. On subsequent follow-up one week later, the patient was referred to another corneal specialist for consultation. At this visit, a repeat corneal Gram stain and a Papinicolau stain were positive for filamentous rods and Nocardia was suspected (Fig. 2). Therapy was initiated with trimethroprim-sulfamethaxazole (SEPTRA) 80 mg/mL in the right eye every 2 hours. One week later, cultural identification was confirmed for Nocardia asteroides and sensitivities showed resistance to amikacin. After three months of unabated progression of his signs and symptoms, the patient showed clinical improvement in three days. However given the prolonged course, he required an additional month of therapy. The patient healed with a subepithelial scar and neovascularization. At this point, SEPTRA was discontinued. The final visual acuity of the right eye was 20/30. Interestingly, the conjunctival biopsy was revisited and showed no signs of Nocardia.Fig. 2 Papinicolau stain magnified 400X of corneal scraping demonstrating branching filaments characteristic of Nocardia asteroides.
Fig. 2
3 Discussion
The usual presenting symptoms of Nocardia keratitis include pain, photophobia, blepharospasm, and lid swelling. Nocardia keratitis frequently runs a protracted benign course, but acute severe cases have been seen.9, 10, 11 Superficial granular infiltrates coalesce into a white plaque of variable size over time and result in corneal ulceration that is often superior in location. In addition to the classic finding of patchy wreath-like anterior stromal infiltrates, other presenting features include pseudodendritic epithelial defect, subepithelial infiltrate, persistent epithelial defect, and/or neovascularization into the cornea.2,10
Diagnosis of Nocardia keratitis is often delayed due to several factors. First, symptoms can have an insidious onset and patients may not initially seek medical care. The variable clinical presentations can mimic other forms of keratitis, such as mycotic or atypical mycobacterial infection.12 The clinician needs to have a high clinical suspicion as Nocardia grows slowly on culture. A prompt corneal scraping and culture should be performed with clinical suspicion. However, this may yield negative results as in this case. Nocardia corneal scrapings are positive for gram-positive, branching filaments that stain weakly acid-fast on Ziehl-Neelsen and black on Gomori methenamine silver.1
Nocardia keratitis can be misdiagnosed as superior limbic keratoconjunctivitis if the disease is located in the superior cornea, as in this case. SLK is characterized by inflammation of the superior bulbar and tarsal conjunctiva in addition to superior corneal vascularization that may appear as a pannus.13 SLK will often demonstrate punctate staining with fluorescein and/or rose Bengal. There can also be localized filamentary keratopathy in one-third of cases. Diagnosis involves obtaining a corneal scraping for Giemsa stain, which typically shows enhanced keratinization, poor nuclei, and hyalinized cytoplasm. Corneal scrapings from this case were not diagnostic for SLK. Treatment modalities include use of topical silver nitrate 1%, anti-inflammatory agents, and conjunctival resection.14,15
Another confounder for Nocardia may be HSV as in this case. At one point in the presentation, a dendritiform lesion was noted suggesting HSV epitheliopathy. A few weeks later, corneal neovascularization and haze developed which appeared clinically as an HSV interstitial keratitis. This clinical picture of apparent recurrence can be quite convincing for herpetic interstitial keratitis. However, the steroid treatment may have exacerbated the Nocardia infection.
Nocardia keratitis is most effectively treated with trimethoprim-sulfamethoxazole or amikacin; the latter is considered the drug of choice for all species of Nocardia.16 However, resistance to amikacin, as in this case, has been previously described.17 The intravenous preparation of trimethoprim-sulfamethoxazole can be used directly as eye drops, typically in a dosing of 16 mg/mL trimethoprim and 80 mg/mL sulfamethoxazole. Amikacin is typically used in the concentration of 2.5% and is prepared by adding 8 mL of artificial tears to 2 mL of the intravenous preparation of 125 mg/mL amikacin.6 Of note, systemic antibiotics do not add benefit to the clinical outcome of Nocardia keratitis. Steroids worsen the symptoms of Nocardia keratitis, potentially leading to complications such as corneal perforation, scleritis, and endophthalmitis. Thus, it is critically important to identify the causative organism early as routine steroid use for falsely suspected viral keratitis and SLK exacerbates the underlying condition.
Nocardia keratitis responds well to medical therapy. If treatment is started early in the course, the corneal ulcer tends to heal rapidly with mild peripheral vascularization. The infiltrate resolves with minimal scarring and forms a fine superficial nebular opacity. Visual acuity improves rapidly and the end result is a barely visible residual stromal haze.
4 Conclusions
Nocardia are a rare cause of infectious keratitis. Early diagnosis and treatment of Nocardia keratitis are difficult because of its infrequent occurrence and variable clinical manifestations. We describe a case of Nocardia keratitis that was initially misdiagnosed and treated with multiple antibacterial, antiviral, and anti-inflammatory agents. Due to its superior location, SLK was considered and prompted a superior conjunctival resection that disproved the diagnosis. Of note, the initial cultures were negative and it was only after a second corneal scraping that Nocardia was correctly identified by cytology and confirmed by cultures. Once diagnosed, this case of Nocardia keratitis responded effectively to treatment with trimethoprim-sulfamethoxazole (SEPTRA) in the setting of amikacin resistance.
Patient consent
The patient consented to publication of the case in writing and orally.
CRediT authorship contribution statement
Eileen L. Chang: Project administration, Writing - original draft, Writing - review & editing. Rachel L. Chu: Writing - original draft. John R. Wittpenn: Investigation, Writing - review & editing. Henry D. Perry: Supervision, Conceptualization, Investigation, Writing - review & editing.
Acknowledgments and Disclosures
No funding or grant support. There are no conflicts of interest or financial disclosures for any of the authors listed. All authors attest that they meet the current ICMJE criteria for Authorship. | LOTEPREDNOL, TOBRAMYCIN | DrugsGivenReaction | CC BY-NC-ND | 33665477 | 19,283,167 | 2021-06 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Visual impairment'. | Nocardia keratitis mimicking superior limbic keratoconjunctivitis and herpes simplex virus.
Nocardia keratitis is a rare type of infectious keratitis and may mimic other corneal diseases and lead to delay in diagnosis. This case illustrates how Nocardia often escapes accurate diagnosis due to its insidious onset, variable clinical manifestations, and unusual characteristics on cultures.
The patient presented with an epithelial defect and superior pannus and scarring, which was misdiagnosed as superior limbic keratoconjunctivitis (SLK) and herpes simplex virus (HSV) keratitis. Repeat corneal scraping cultures, smears, and conjunctival biopsy were necessary to elucidate the diagnosis. It can be effectively treated with the intravenous preparation of trimethoprim-sulfamethoxazole 80 mg/mL (brand name SEPTRA) used topically as eye drops.
The diagnosis of Nocardia keratitis relies on a high clinical suspicion and a prompt corneal scraping with culture. Due to its potential for rapid resolution with early therapy, it is important to isolate Nocardia early in its disease course.
Topical amikacin had been the standard of care for Nocardia keratitis for many years. However, recently there is increasing resistance of Nocardia to amikacin. SEPTRA offers an alternative therapy. Nocardia keratitis mimics other infectious and inflammatory etiologies so rapid diagnosis and treatment is critical in the prevention of long-term complications.
1 Introduction
Nocardia are a group of aerobic, gram-positive, and catalase-positive bacteria in the shape of long, thin, and branching filaments that stain weakly acid-fast on Ziehl-Neelsen1.
Nocardia asteroides is the most commonly reported species to cause Nocardia keratitis. It is classically described with an appearance of stromal infiltrates in a wreath-like pattern and may be associated with tiny epithelial calcifications often near the limbus adjacent to pannus-like areas of increased vascularity.2,3 Culture on blood agar may occasionally lead to a consideration of contamination due to the tendency for prominent areas of calcification on the agar.2
Nocardia keratitis is seen more frequently in young males, especially those who live in rural areas.3,4 As Nocardia is the most common bacteria found in soil, corneal trauma and contact with soil predispose those in rural areas to infection. Other risk factors for Nocardia keratitis include contact lens wear, ophthalmic surgery, and topical corticosteroids.5, 6, 7, 8
This unique case of Nocardia keratitis focuses attention on the variability of presentation and the possibility of a prolonged clinical course over months. The multiple misdiagnoses suffered by this patient highlight how this pathogen is elusive and often discovered late in the clinical course leading to permanent ocular sequelae.
2 Case presentation
A 41-year-old male contact lens user without history of corneal trauma or soil contact presented with a three-week history of pruritus, photophobia, and excessive tearing of the right eye. He was initially found to have a corneal abrasion and started on topical tobramycin 0.3% QID, which aggravated his symptoms. The patient was then referred to an ophthalmologist who added loteprednol 0.5% daily. The patient failed to respond to this therapy and was sent to a corneal specialist. On initial presentation, the patient's best-corrected visual acuity (BCVA) in the right eye was 20/20–3. Anterior segment exam was significant for bilateral blepharitis, right floppy eyelid, right trace perilimbal injection, 2+ superior palpebral conjunctival injection, and a new right corneal scar with irregular epithelium lacking definitive boundaries superiorly at 12 o'clock. Given the pattern of injection, recurrent discomfort, and subjective complaint of itchiness, superior limbic keratoconjunctivitis (SLK) was considered. The corneal specialist trialed a course of ofloxacin 0.3% and then increased loteprednol 0.5% to BID dosing.
On two-week follow-up, the patient displayed symptomatic improvement. However, the clinical exam demonstrated new dendritiform lesions developing at the peripheral edge of the corneal scar. Treatment for presumed herpes simplex keratitis (HSV) was initiated with a course of oral valacyclovir TID and topical ganciclovir 0.15% QID. Additionally, the patient was sent for corneal cultures to rule out fungal keratitis. Follow-up results were negative for fungi.
The patient returned in one month with worsening symptoms. At this time, his corneal scar displayed anterior stromal scarring with new overlying neovascularization and an advancing edge of irregular epithelium (Fig. 1). Keratic precipitates and anterior chamber inflammation were absent. At this point, the diagnosis of HSV interstitial keratitis was considered. The topical medications were switched from loteprednol to difluprednate 0.05% QID; the patient was restarted on valacyclovir TID.Fig. 1 Clinical photograph of the patient's right eye on initial presentation to second corneal specialist (3 months from first symptoms) demonstrating superior pannus, anterior stromal scarring, conjunctival injection, and floppy eyelids.
Fig. 1
After returning from vacation overseas, the patient followed up with the corneal specialist with minimal improvement. Given the failure to respond to herpetic treatment, a superior conjunctival resection for presumed SLK and corneal scrapings were taken from the right eye where the cornea was abnormal. A ProKera Slim™ amniotic membrane was placed over the defect and prophylactic ophthalmic antibiotics were started. The patient was maintained on oral valacyclovir TID, topical difluprednate 0.05% BID, and topical ofloxacin 0.3% as antibiotic prophylaxis for a few days. Corneal scrapings did not reveal findings suggestive of SLK or microbial keratitis when evaluated.
One week later, the patient reported dramatically decreased vision with severe photophobia and difficulty opening the right eye. Visual acuity was 20/400 with the ProKera Slim™. At this point, the corneal scraping was 95% healed so the ProKera Slim™ was removed. No further stromal infiltrates were noted. All medications were discontinued except bacitracin-polymyxin B. On subsequent follow-up one week later, the patient was referred to another corneal specialist for consultation. At this visit, a repeat corneal Gram stain and a Papinicolau stain were positive for filamentous rods and Nocardia was suspected (Fig. 2). Therapy was initiated with trimethroprim-sulfamethaxazole (SEPTRA) 80 mg/mL in the right eye every 2 hours. One week later, cultural identification was confirmed for Nocardia asteroides and sensitivities showed resistance to amikacin. After three months of unabated progression of his signs and symptoms, the patient showed clinical improvement in three days. However given the prolonged course, he required an additional month of therapy. The patient healed with a subepithelial scar and neovascularization. At this point, SEPTRA was discontinued. The final visual acuity of the right eye was 20/30. Interestingly, the conjunctival biopsy was revisited and showed no signs of Nocardia.Fig. 2 Papinicolau stain magnified 400X of corneal scraping demonstrating branching filaments characteristic of Nocardia asteroides.
Fig. 2
3 Discussion
The usual presenting symptoms of Nocardia keratitis include pain, photophobia, blepharospasm, and lid swelling. Nocardia keratitis frequently runs a protracted benign course, but acute severe cases have been seen.9, 10, 11 Superficial granular infiltrates coalesce into a white plaque of variable size over time and result in corneal ulceration that is often superior in location. In addition to the classic finding of patchy wreath-like anterior stromal infiltrates, other presenting features include pseudodendritic epithelial defect, subepithelial infiltrate, persistent epithelial defect, and/or neovascularization into the cornea.2,10
Diagnosis of Nocardia keratitis is often delayed due to several factors. First, symptoms can have an insidious onset and patients may not initially seek medical care. The variable clinical presentations can mimic other forms of keratitis, such as mycotic or atypical mycobacterial infection.12 The clinician needs to have a high clinical suspicion as Nocardia grows slowly on culture. A prompt corneal scraping and culture should be performed with clinical suspicion. However, this may yield negative results as in this case. Nocardia corneal scrapings are positive for gram-positive, branching filaments that stain weakly acid-fast on Ziehl-Neelsen and black on Gomori methenamine silver.1
Nocardia keratitis can be misdiagnosed as superior limbic keratoconjunctivitis if the disease is located in the superior cornea, as in this case. SLK is characterized by inflammation of the superior bulbar and tarsal conjunctiva in addition to superior corneal vascularization that may appear as a pannus.13 SLK will often demonstrate punctate staining with fluorescein and/or rose Bengal. There can also be localized filamentary keratopathy in one-third of cases. Diagnosis involves obtaining a corneal scraping for Giemsa stain, which typically shows enhanced keratinization, poor nuclei, and hyalinized cytoplasm. Corneal scrapings from this case were not diagnostic for SLK. Treatment modalities include use of topical silver nitrate 1%, anti-inflammatory agents, and conjunctival resection.14,15
Another confounder for Nocardia may be HSV as in this case. At one point in the presentation, a dendritiform lesion was noted suggesting HSV epitheliopathy. A few weeks later, corneal neovascularization and haze developed which appeared clinically as an HSV interstitial keratitis. This clinical picture of apparent recurrence can be quite convincing for herpetic interstitial keratitis. However, the steroid treatment may have exacerbated the Nocardia infection.
Nocardia keratitis is most effectively treated with trimethoprim-sulfamethoxazole or amikacin; the latter is considered the drug of choice for all species of Nocardia.16 However, resistance to amikacin, as in this case, has been previously described.17 The intravenous preparation of trimethoprim-sulfamethoxazole can be used directly as eye drops, typically in a dosing of 16 mg/mL trimethoprim and 80 mg/mL sulfamethoxazole. Amikacin is typically used in the concentration of 2.5% and is prepared by adding 8 mL of artificial tears to 2 mL of the intravenous preparation of 125 mg/mL amikacin.6 Of note, systemic antibiotics do not add benefit to the clinical outcome of Nocardia keratitis. Steroids worsen the symptoms of Nocardia keratitis, potentially leading to complications such as corneal perforation, scleritis, and endophthalmitis. Thus, it is critically important to identify the causative organism early as routine steroid use for falsely suspected viral keratitis and SLK exacerbates the underlying condition.
Nocardia keratitis responds well to medical therapy. If treatment is started early in the course, the corneal ulcer tends to heal rapidly with mild peripheral vascularization. The infiltrate resolves with minimal scarring and forms a fine superficial nebular opacity. Visual acuity improves rapidly and the end result is a barely visible residual stromal haze.
4 Conclusions
Nocardia are a rare cause of infectious keratitis. Early diagnosis and treatment of Nocardia keratitis are difficult because of its infrequent occurrence and variable clinical manifestations. We describe a case of Nocardia keratitis that was initially misdiagnosed and treated with multiple antibacterial, antiviral, and anti-inflammatory agents. Due to its superior location, SLK was considered and prompted a superior conjunctival resection that disproved the diagnosis. Of note, the initial cultures were negative and it was only after a second corneal scraping that Nocardia was correctly identified by cytology and confirmed by cultures. Once diagnosed, this case of Nocardia keratitis responded effectively to treatment with trimethoprim-sulfamethoxazole (SEPTRA) in the setting of amikacin resistance.
Patient consent
The patient consented to publication of the case in writing and orally.
CRediT authorship contribution statement
Eileen L. Chang: Project administration, Writing - original draft, Writing - review & editing. Rachel L. Chu: Writing - original draft. John R. Wittpenn: Investigation, Writing - review & editing. Henry D. Perry: Supervision, Conceptualization, Investigation, Writing - review & editing.
Acknowledgments and Disclosures
No funding or grant support. There are no conflicts of interest or financial disclosures for any of the authors listed. All authors attest that they meet the current ICMJE criteria for Authorship. | DIFLUPREDNATE, OFLOXACIN, VALACYCLOVIR HYDROCHLORIDE | DrugsGivenReaction | CC BY-NC-ND | 33665477 | 19,356,229 | 2021-06 |
What was the administration route of drug 'DIFLUPREDNATE'? | Nocardia keratitis mimicking superior limbic keratoconjunctivitis and herpes simplex virus.
Nocardia keratitis is a rare type of infectious keratitis and may mimic other corneal diseases and lead to delay in diagnosis. This case illustrates how Nocardia often escapes accurate diagnosis due to its insidious onset, variable clinical manifestations, and unusual characteristics on cultures.
The patient presented with an epithelial defect and superior pannus and scarring, which was misdiagnosed as superior limbic keratoconjunctivitis (SLK) and herpes simplex virus (HSV) keratitis. Repeat corneal scraping cultures, smears, and conjunctival biopsy were necessary to elucidate the diagnosis. It can be effectively treated with the intravenous preparation of trimethoprim-sulfamethoxazole 80 mg/mL (brand name SEPTRA) used topically as eye drops.
The diagnosis of Nocardia keratitis relies on a high clinical suspicion and a prompt corneal scraping with culture. Due to its potential for rapid resolution with early therapy, it is important to isolate Nocardia early in its disease course.
Topical amikacin had been the standard of care for Nocardia keratitis for many years. However, recently there is increasing resistance of Nocardia to amikacin. SEPTRA offers an alternative therapy. Nocardia keratitis mimics other infectious and inflammatory etiologies so rapid diagnosis and treatment is critical in the prevention of long-term complications.
1 Introduction
Nocardia are a group of aerobic, gram-positive, and catalase-positive bacteria in the shape of long, thin, and branching filaments that stain weakly acid-fast on Ziehl-Neelsen1.
Nocardia asteroides is the most commonly reported species to cause Nocardia keratitis. It is classically described with an appearance of stromal infiltrates in a wreath-like pattern and may be associated with tiny epithelial calcifications often near the limbus adjacent to pannus-like areas of increased vascularity.2,3 Culture on blood agar may occasionally lead to a consideration of contamination due to the tendency for prominent areas of calcification on the agar.2
Nocardia keratitis is seen more frequently in young males, especially those who live in rural areas.3,4 As Nocardia is the most common bacteria found in soil, corneal trauma and contact with soil predispose those in rural areas to infection. Other risk factors for Nocardia keratitis include contact lens wear, ophthalmic surgery, and topical corticosteroids.5, 6, 7, 8
This unique case of Nocardia keratitis focuses attention on the variability of presentation and the possibility of a prolonged clinical course over months. The multiple misdiagnoses suffered by this patient highlight how this pathogen is elusive and often discovered late in the clinical course leading to permanent ocular sequelae.
2 Case presentation
A 41-year-old male contact lens user without history of corneal trauma or soil contact presented with a three-week history of pruritus, photophobia, and excessive tearing of the right eye. He was initially found to have a corneal abrasion and started on topical tobramycin 0.3% QID, which aggravated his symptoms. The patient was then referred to an ophthalmologist who added loteprednol 0.5% daily. The patient failed to respond to this therapy and was sent to a corneal specialist. On initial presentation, the patient's best-corrected visual acuity (BCVA) in the right eye was 20/20–3. Anterior segment exam was significant for bilateral blepharitis, right floppy eyelid, right trace perilimbal injection, 2+ superior palpebral conjunctival injection, and a new right corneal scar with irregular epithelium lacking definitive boundaries superiorly at 12 o'clock. Given the pattern of injection, recurrent discomfort, and subjective complaint of itchiness, superior limbic keratoconjunctivitis (SLK) was considered. The corneal specialist trialed a course of ofloxacin 0.3% and then increased loteprednol 0.5% to BID dosing.
On two-week follow-up, the patient displayed symptomatic improvement. However, the clinical exam demonstrated new dendritiform lesions developing at the peripheral edge of the corneal scar. Treatment for presumed herpes simplex keratitis (HSV) was initiated with a course of oral valacyclovir TID and topical ganciclovir 0.15% QID. Additionally, the patient was sent for corneal cultures to rule out fungal keratitis. Follow-up results were negative for fungi.
The patient returned in one month with worsening symptoms. At this time, his corneal scar displayed anterior stromal scarring with new overlying neovascularization and an advancing edge of irregular epithelium (Fig. 1). Keratic precipitates and anterior chamber inflammation were absent. At this point, the diagnosis of HSV interstitial keratitis was considered. The topical medications were switched from loteprednol to difluprednate 0.05% QID; the patient was restarted on valacyclovir TID.Fig. 1 Clinical photograph of the patient's right eye on initial presentation to second corneal specialist (3 months from first symptoms) demonstrating superior pannus, anterior stromal scarring, conjunctival injection, and floppy eyelids.
Fig. 1
After returning from vacation overseas, the patient followed up with the corneal specialist with minimal improvement. Given the failure to respond to herpetic treatment, a superior conjunctival resection for presumed SLK and corneal scrapings were taken from the right eye where the cornea was abnormal. A ProKera Slim™ amniotic membrane was placed over the defect and prophylactic ophthalmic antibiotics were started. The patient was maintained on oral valacyclovir TID, topical difluprednate 0.05% BID, and topical ofloxacin 0.3% as antibiotic prophylaxis for a few days. Corneal scrapings did not reveal findings suggestive of SLK or microbial keratitis when evaluated.
One week later, the patient reported dramatically decreased vision with severe photophobia and difficulty opening the right eye. Visual acuity was 20/400 with the ProKera Slim™. At this point, the corneal scraping was 95% healed so the ProKera Slim™ was removed. No further stromal infiltrates were noted. All medications were discontinued except bacitracin-polymyxin B. On subsequent follow-up one week later, the patient was referred to another corneal specialist for consultation. At this visit, a repeat corneal Gram stain and a Papinicolau stain were positive for filamentous rods and Nocardia was suspected (Fig. 2). Therapy was initiated with trimethroprim-sulfamethaxazole (SEPTRA) 80 mg/mL in the right eye every 2 hours. One week later, cultural identification was confirmed for Nocardia asteroides and sensitivities showed resistance to amikacin. After three months of unabated progression of his signs and symptoms, the patient showed clinical improvement in three days. However given the prolonged course, he required an additional month of therapy. The patient healed with a subepithelial scar and neovascularization. At this point, SEPTRA was discontinued. The final visual acuity of the right eye was 20/30. Interestingly, the conjunctival biopsy was revisited and showed no signs of Nocardia.Fig. 2 Papinicolau stain magnified 400X of corneal scraping demonstrating branching filaments characteristic of Nocardia asteroides.
Fig. 2
3 Discussion
The usual presenting symptoms of Nocardia keratitis include pain, photophobia, blepharospasm, and lid swelling. Nocardia keratitis frequently runs a protracted benign course, but acute severe cases have been seen.9, 10, 11 Superficial granular infiltrates coalesce into a white plaque of variable size over time and result in corneal ulceration that is often superior in location. In addition to the classic finding of patchy wreath-like anterior stromal infiltrates, other presenting features include pseudodendritic epithelial defect, subepithelial infiltrate, persistent epithelial defect, and/or neovascularization into the cornea.2,10
Diagnosis of Nocardia keratitis is often delayed due to several factors. First, symptoms can have an insidious onset and patients may not initially seek medical care. The variable clinical presentations can mimic other forms of keratitis, such as mycotic or atypical mycobacterial infection.12 The clinician needs to have a high clinical suspicion as Nocardia grows slowly on culture. A prompt corneal scraping and culture should be performed with clinical suspicion. However, this may yield negative results as in this case. Nocardia corneal scrapings are positive for gram-positive, branching filaments that stain weakly acid-fast on Ziehl-Neelsen and black on Gomori methenamine silver.1
Nocardia keratitis can be misdiagnosed as superior limbic keratoconjunctivitis if the disease is located in the superior cornea, as in this case. SLK is characterized by inflammation of the superior bulbar and tarsal conjunctiva in addition to superior corneal vascularization that may appear as a pannus.13 SLK will often demonstrate punctate staining with fluorescein and/or rose Bengal. There can also be localized filamentary keratopathy in one-third of cases. Diagnosis involves obtaining a corneal scraping for Giemsa stain, which typically shows enhanced keratinization, poor nuclei, and hyalinized cytoplasm. Corneal scrapings from this case were not diagnostic for SLK. Treatment modalities include use of topical silver nitrate 1%, anti-inflammatory agents, and conjunctival resection.14,15
Another confounder for Nocardia may be HSV as in this case. At one point in the presentation, a dendritiform lesion was noted suggesting HSV epitheliopathy. A few weeks later, corneal neovascularization and haze developed which appeared clinically as an HSV interstitial keratitis. This clinical picture of apparent recurrence can be quite convincing for herpetic interstitial keratitis. However, the steroid treatment may have exacerbated the Nocardia infection.
Nocardia keratitis is most effectively treated with trimethoprim-sulfamethoxazole or amikacin; the latter is considered the drug of choice for all species of Nocardia.16 However, resistance to amikacin, as in this case, has been previously described.17 The intravenous preparation of trimethoprim-sulfamethoxazole can be used directly as eye drops, typically in a dosing of 16 mg/mL trimethoprim and 80 mg/mL sulfamethoxazole. Amikacin is typically used in the concentration of 2.5% and is prepared by adding 8 mL of artificial tears to 2 mL of the intravenous preparation of 125 mg/mL amikacin.6 Of note, systemic antibiotics do not add benefit to the clinical outcome of Nocardia keratitis. Steroids worsen the symptoms of Nocardia keratitis, potentially leading to complications such as corneal perforation, scleritis, and endophthalmitis. Thus, it is critically important to identify the causative organism early as routine steroid use for falsely suspected viral keratitis and SLK exacerbates the underlying condition.
Nocardia keratitis responds well to medical therapy. If treatment is started early in the course, the corneal ulcer tends to heal rapidly with mild peripheral vascularization. The infiltrate resolves with minimal scarring and forms a fine superficial nebular opacity. Visual acuity improves rapidly and the end result is a barely visible residual stromal haze.
4 Conclusions
Nocardia are a rare cause of infectious keratitis. Early diagnosis and treatment of Nocardia keratitis are difficult because of its infrequent occurrence and variable clinical manifestations. We describe a case of Nocardia keratitis that was initially misdiagnosed and treated with multiple antibacterial, antiviral, and anti-inflammatory agents. Due to its superior location, SLK was considered and prompted a superior conjunctival resection that disproved the diagnosis. Of note, the initial cultures were negative and it was only after a second corneal scraping that Nocardia was correctly identified by cytology and confirmed by cultures. Once diagnosed, this case of Nocardia keratitis responded effectively to treatment with trimethoprim-sulfamethoxazole (SEPTRA) in the setting of amikacin resistance.
Patient consent
The patient consented to publication of the case in writing and orally.
CRediT authorship contribution statement
Eileen L. Chang: Project administration, Writing - original draft, Writing - review & editing. Rachel L. Chu: Writing - original draft. John R. Wittpenn: Investigation, Writing - review & editing. Henry D. Perry: Supervision, Conceptualization, Investigation, Writing - review & editing.
Acknowledgments and Disclosures
No funding or grant support. There are no conflicts of interest or financial disclosures for any of the authors listed. All authors attest that they meet the current ICMJE criteria for Authorship. | Topical | DrugAdministrationRoute | CC BY-NC-ND | 33665477 | 19,356,229 | 2021-06 |
What was the administration route of drug 'OFLOXACIN'? | Nocardia keratitis mimicking superior limbic keratoconjunctivitis and herpes simplex virus.
Nocardia keratitis is a rare type of infectious keratitis and may mimic other corneal diseases and lead to delay in diagnosis. This case illustrates how Nocardia often escapes accurate diagnosis due to its insidious onset, variable clinical manifestations, and unusual characteristics on cultures.
The patient presented with an epithelial defect and superior pannus and scarring, which was misdiagnosed as superior limbic keratoconjunctivitis (SLK) and herpes simplex virus (HSV) keratitis. Repeat corneal scraping cultures, smears, and conjunctival biopsy were necessary to elucidate the diagnosis. It can be effectively treated with the intravenous preparation of trimethoprim-sulfamethoxazole 80 mg/mL (brand name SEPTRA) used topically as eye drops.
The diagnosis of Nocardia keratitis relies on a high clinical suspicion and a prompt corneal scraping with culture. Due to its potential for rapid resolution with early therapy, it is important to isolate Nocardia early in its disease course.
Topical amikacin had been the standard of care for Nocardia keratitis for many years. However, recently there is increasing resistance of Nocardia to amikacin. SEPTRA offers an alternative therapy. Nocardia keratitis mimics other infectious and inflammatory etiologies so rapid diagnosis and treatment is critical in the prevention of long-term complications.
1 Introduction
Nocardia are a group of aerobic, gram-positive, and catalase-positive bacteria in the shape of long, thin, and branching filaments that stain weakly acid-fast on Ziehl-Neelsen1.
Nocardia asteroides is the most commonly reported species to cause Nocardia keratitis. It is classically described with an appearance of stromal infiltrates in a wreath-like pattern and may be associated with tiny epithelial calcifications often near the limbus adjacent to pannus-like areas of increased vascularity.2,3 Culture on blood agar may occasionally lead to a consideration of contamination due to the tendency for prominent areas of calcification on the agar.2
Nocardia keratitis is seen more frequently in young males, especially those who live in rural areas.3,4 As Nocardia is the most common bacteria found in soil, corneal trauma and contact with soil predispose those in rural areas to infection. Other risk factors for Nocardia keratitis include contact lens wear, ophthalmic surgery, and topical corticosteroids.5, 6, 7, 8
This unique case of Nocardia keratitis focuses attention on the variability of presentation and the possibility of a prolonged clinical course over months. The multiple misdiagnoses suffered by this patient highlight how this pathogen is elusive and often discovered late in the clinical course leading to permanent ocular sequelae.
2 Case presentation
A 41-year-old male contact lens user without history of corneal trauma or soil contact presented with a three-week history of pruritus, photophobia, and excessive tearing of the right eye. He was initially found to have a corneal abrasion and started on topical tobramycin 0.3% QID, which aggravated his symptoms. The patient was then referred to an ophthalmologist who added loteprednol 0.5% daily. The patient failed to respond to this therapy and was sent to a corneal specialist. On initial presentation, the patient's best-corrected visual acuity (BCVA) in the right eye was 20/20–3. Anterior segment exam was significant for bilateral blepharitis, right floppy eyelid, right trace perilimbal injection, 2+ superior palpebral conjunctival injection, and a new right corneal scar with irregular epithelium lacking definitive boundaries superiorly at 12 o'clock. Given the pattern of injection, recurrent discomfort, and subjective complaint of itchiness, superior limbic keratoconjunctivitis (SLK) was considered. The corneal specialist trialed a course of ofloxacin 0.3% and then increased loteprednol 0.5% to BID dosing.
On two-week follow-up, the patient displayed symptomatic improvement. However, the clinical exam demonstrated new dendritiform lesions developing at the peripheral edge of the corneal scar. Treatment for presumed herpes simplex keratitis (HSV) was initiated with a course of oral valacyclovir TID and topical ganciclovir 0.15% QID. Additionally, the patient was sent for corneal cultures to rule out fungal keratitis. Follow-up results were negative for fungi.
The patient returned in one month with worsening symptoms. At this time, his corneal scar displayed anterior stromal scarring with new overlying neovascularization and an advancing edge of irregular epithelium (Fig. 1). Keratic precipitates and anterior chamber inflammation were absent. At this point, the diagnosis of HSV interstitial keratitis was considered. The topical medications were switched from loteprednol to difluprednate 0.05% QID; the patient was restarted on valacyclovir TID.Fig. 1 Clinical photograph of the patient's right eye on initial presentation to second corneal specialist (3 months from first symptoms) demonstrating superior pannus, anterior stromal scarring, conjunctival injection, and floppy eyelids.
Fig. 1
After returning from vacation overseas, the patient followed up with the corneal specialist with minimal improvement. Given the failure to respond to herpetic treatment, a superior conjunctival resection for presumed SLK and corneal scrapings were taken from the right eye where the cornea was abnormal. A ProKera Slim™ amniotic membrane was placed over the defect and prophylactic ophthalmic antibiotics were started. The patient was maintained on oral valacyclovir TID, topical difluprednate 0.05% BID, and topical ofloxacin 0.3% as antibiotic prophylaxis for a few days. Corneal scrapings did not reveal findings suggestive of SLK or microbial keratitis when evaluated.
One week later, the patient reported dramatically decreased vision with severe photophobia and difficulty opening the right eye. Visual acuity was 20/400 with the ProKera Slim™. At this point, the corneal scraping was 95% healed so the ProKera Slim™ was removed. No further stromal infiltrates were noted. All medications were discontinued except bacitracin-polymyxin B. On subsequent follow-up one week later, the patient was referred to another corneal specialist for consultation. At this visit, a repeat corneal Gram stain and a Papinicolau stain were positive for filamentous rods and Nocardia was suspected (Fig. 2). Therapy was initiated with trimethroprim-sulfamethaxazole (SEPTRA) 80 mg/mL in the right eye every 2 hours. One week later, cultural identification was confirmed for Nocardia asteroides and sensitivities showed resistance to amikacin. After three months of unabated progression of his signs and symptoms, the patient showed clinical improvement in three days. However given the prolonged course, he required an additional month of therapy. The patient healed with a subepithelial scar and neovascularization. At this point, SEPTRA was discontinued. The final visual acuity of the right eye was 20/30. Interestingly, the conjunctival biopsy was revisited and showed no signs of Nocardia.Fig. 2 Papinicolau stain magnified 400X of corneal scraping demonstrating branching filaments characteristic of Nocardia asteroides.
Fig. 2
3 Discussion
The usual presenting symptoms of Nocardia keratitis include pain, photophobia, blepharospasm, and lid swelling. Nocardia keratitis frequently runs a protracted benign course, but acute severe cases have been seen.9, 10, 11 Superficial granular infiltrates coalesce into a white plaque of variable size over time and result in corneal ulceration that is often superior in location. In addition to the classic finding of patchy wreath-like anterior stromal infiltrates, other presenting features include pseudodendritic epithelial defect, subepithelial infiltrate, persistent epithelial defect, and/or neovascularization into the cornea.2,10
Diagnosis of Nocardia keratitis is often delayed due to several factors. First, symptoms can have an insidious onset and patients may not initially seek medical care. The variable clinical presentations can mimic other forms of keratitis, such as mycotic or atypical mycobacterial infection.12 The clinician needs to have a high clinical suspicion as Nocardia grows slowly on culture. A prompt corneal scraping and culture should be performed with clinical suspicion. However, this may yield negative results as in this case. Nocardia corneal scrapings are positive for gram-positive, branching filaments that stain weakly acid-fast on Ziehl-Neelsen and black on Gomori methenamine silver.1
Nocardia keratitis can be misdiagnosed as superior limbic keratoconjunctivitis if the disease is located in the superior cornea, as in this case. SLK is characterized by inflammation of the superior bulbar and tarsal conjunctiva in addition to superior corneal vascularization that may appear as a pannus.13 SLK will often demonstrate punctate staining with fluorescein and/or rose Bengal. There can also be localized filamentary keratopathy in one-third of cases. Diagnosis involves obtaining a corneal scraping for Giemsa stain, which typically shows enhanced keratinization, poor nuclei, and hyalinized cytoplasm. Corneal scrapings from this case were not diagnostic for SLK. Treatment modalities include use of topical silver nitrate 1%, anti-inflammatory agents, and conjunctival resection.14,15
Another confounder for Nocardia may be HSV as in this case. At one point in the presentation, a dendritiform lesion was noted suggesting HSV epitheliopathy. A few weeks later, corneal neovascularization and haze developed which appeared clinically as an HSV interstitial keratitis. This clinical picture of apparent recurrence can be quite convincing for herpetic interstitial keratitis. However, the steroid treatment may have exacerbated the Nocardia infection.
Nocardia keratitis is most effectively treated with trimethoprim-sulfamethoxazole or amikacin; the latter is considered the drug of choice for all species of Nocardia.16 However, resistance to amikacin, as in this case, has been previously described.17 The intravenous preparation of trimethoprim-sulfamethoxazole can be used directly as eye drops, typically in a dosing of 16 mg/mL trimethoprim and 80 mg/mL sulfamethoxazole. Amikacin is typically used in the concentration of 2.5% and is prepared by adding 8 mL of artificial tears to 2 mL of the intravenous preparation of 125 mg/mL amikacin.6 Of note, systemic antibiotics do not add benefit to the clinical outcome of Nocardia keratitis. Steroids worsen the symptoms of Nocardia keratitis, potentially leading to complications such as corneal perforation, scleritis, and endophthalmitis. Thus, it is critically important to identify the causative organism early as routine steroid use for falsely suspected viral keratitis and SLK exacerbates the underlying condition.
Nocardia keratitis responds well to medical therapy. If treatment is started early in the course, the corneal ulcer tends to heal rapidly with mild peripheral vascularization. The infiltrate resolves with minimal scarring and forms a fine superficial nebular opacity. Visual acuity improves rapidly and the end result is a barely visible residual stromal haze.
4 Conclusions
Nocardia are a rare cause of infectious keratitis. Early diagnosis and treatment of Nocardia keratitis are difficult because of its infrequent occurrence and variable clinical manifestations. We describe a case of Nocardia keratitis that was initially misdiagnosed and treated with multiple antibacterial, antiviral, and anti-inflammatory agents. Due to its superior location, SLK was considered and prompted a superior conjunctival resection that disproved the diagnosis. Of note, the initial cultures were negative and it was only after a second corneal scraping that Nocardia was correctly identified by cytology and confirmed by cultures. Once diagnosed, this case of Nocardia keratitis responded effectively to treatment with trimethoprim-sulfamethoxazole (SEPTRA) in the setting of amikacin resistance.
Patient consent
The patient consented to publication of the case in writing and orally.
CRediT authorship contribution statement
Eileen L. Chang: Project administration, Writing - original draft, Writing - review & editing. Rachel L. Chu: Writing - original draft. John R. Wittpenn: Investigation, Writing - review & editing. Henry D. Perry: Supervision, Conceptualization, Investigation, Writing - review & editing.
Acknowledgments and Disclosures
No funding or grant support. There are no conflicts of interest or financial disclosures for any of the authors listed. All authors attest that they meet the current ICMJE criteria for Authorship. | Topical | DrugAdministrationRoute | CC BY-NC-ND | 33665477 | 19,356,229 | 2021-06 |
What was the administration route of drug 'TOBRAMYCIN'? | Nocardia keratitis mimicking superior limbic keratoconjunctivitis and herpes simplex virus.
Nocardia keratitis is a rare type of infectious keratitis and may mimic other corneal diseases and lead to delay in diagnosis. This case illustrates how Nocardia often escapes accurate diagnosis due to its insidious onset, variable clinical manifestations, and unusual characteristics on cultures.
The patient presented with an epithelial defect and superior pannus and scarring, which was misdiagnosed as superior limbic keratoconjunctivitis (SLK) and herpes simplex virus (HSV) keratitis. Repeat corneal scraping cultures, smears, and conjunctival biopsy were necessary to elucidate the diagnosis. It can be effectively treated with the intravenous preparation of trimethoprim-sulfamethoxazole 80 mg/mL (brand name SEPTRA) used topically as eye drops.
The diagnosis of Nocardia keratitis relies on a high clinical suspicion and a prompt corneal scraping with culture. Due to its potential for rapid resolution with early therapy, it is important to isolate Nocardia early in its disease course.
Topical amikacin had been the standard of care for Nocardia keratitis for many years. However, recently there is increasing resistance of Nocardia to amikacin. SEPTRA offers an alternative therapy. Nocardia keratitis mimics other infectious and inflammatory etiologies so rapid diagnosis and treatment is critical in the prevention of long-term complications.
1 Introduction
Nocardia are a group of aerobic, gram-positive, and catalase-positive bacteria in the shape of long, thin, and branching filaments that stain weakly acid-fast on Ziehl-Neelsen1.
Nocardia asteroides is the most commonly reported species to cause Nocardia keratitis. It is classically described with an appearance of stromal infiltrates in a wreath-like pattern and may be associated with tiny epithelial calcifications often near the limbus adjacent to pannus-like areas of increased vascularity.2,3 Culture on blood agar may occasionally lead to a consideration of contamination due to the tendency for prominent areas of calcification on the agar.2
Nocardia keratitis is seen more frequently in young males, especially those who live in rural areas.3,4 As Nocardia is the most common bacteria found in soil, corneal trauma and contact with soil predispose those in rural areas to infection. Other risk factors for Nocardia keratitis include contact lens wear, ophthalmic surgery, and topical corticosteroids.5, 6, 7, 8
This unique case of Nocardia keratitis focuses attention on the variability of presentation and the possibility of a prolonged clinical course over months. The multiple misdiagnoses suffered by this patient highlight how this pathogen is elusive and often discovered late in the clinical course leading to permanent ocular sequelae.
2 Case presentation
A 41-year-old male contact lens user without history of corneal trauma or soil contact presented with a three-week history of pruritus, photophobia, and excessive tearing of the right eye. He was initially found to have a corneal abrasion and started on topical tobramycin 0.3% QID, which aggravated his symptoms. The patient was then referred to an ophthalmologist who added loteprednol 0.5% daily. The patient failed to respond to this therapy and was sent to a corneal specialist. On initial presentation, the patient's best-corrected visual acuity (BCVA) in the right eye was 20/20–3. Anterior segment exam was significant for bilateral blepharitis, right floppy eyelid, right trace perilimbal injection, 2+ superior palpebral conjunctival injection, and a new right corneal scar with irregular epithelium lacking definitive boundaries superiorly at 12 o'clock. Given the pattern of injection, recurrent discomfort, and subjective complaint of itchiness, superior limbic keratoconjunctivitis (SLK) was considered. The corneal specialist trialed a course of ofloxacin 0.3% and then increased loteprednol 0.5% to BID dosing.
On two-week follow-up, the patient displayed symptomatic improvement. However, the clinical exam demonstrated new dendritiform lesions developing at the peripheral edge of the corneal scar. Treatment for presumed herpes simplex keratitis (HSV) was initiated with a course of oral valacyclovir TID and topical ganciclovir 0.15% QID. Additionally, the patient was sent for corneal cultures to rule out fungal keratitis. Follow-up results were negative for fungi.
The patient returned in one month with worsening symptoms. At this time, his corneal scar displayed anterior stromal scarring with new overlying neovascularization and an advancing edge of irregular epithelium (Fig. 1). Keratic precipitates and anterior chamber inflammation were absent. At this point, the diagnosis of HSV interstitial keratitis was considered. The topical medications were switched from loteprednol to difluprednate 0.05% QID; the patient was restarted on valacyclovir TID.Fig. 1 Clinical photograph of the patient's right eye on initial presentation to second corneal specialist (3 months from first symptoms) demonstrating superior pannus, anterior stromal scarring, conjunctival injection, and floppy eyelids.
Fig. 1
After returning from vacation overseas, the patient followed up with the corneal specialist with minimal improvement. Given the failure to respond to herpetic treatment, a superior conjunctival resection for presumed SLK and corneal scrapings were taken from the right eye where the cornea was abnormal. A ProKera Slim™ amniotic membrane was placed over the defect and prophylactic ophthalmic antibiotics were started. The patient was maintained on oral valacyclovir TID, topical difluprednate 0.05% BID, and topical ofloxacin 0.3% as antibiotic prophylaxis for a few days. Corneal scrapings did not reveal findings suggestive of SLK or microbial keratitis when evaluated.
One week later, the patient reported dramatically decreased vision with severe photophobia and difficulty opening the right eye. Visual acuity was 20/400 with the ProKera Slim™. At this point, the corneal scraping was 95% healed so the ProKera Slim™ was removed. No further stromal infiltrates were noted. All medications were discontinued except bacitracin-polymyxin B. On subsequent follow-up one week later, the patient was referred to another corneal specialist for consultation. At this visit, a repeat corneal Gram stain and a Papinicolau stain were positive for filamentous rods and Nocardia was suspected (Fig. 2). Therapy was initiated with trimethroprim-sulfamethaxazole (SEPTRA) 80 mg/mL in the right eye every 2 hours. One week later, cultural identification was confirmed for Nocardia asteroides and sensitivities showed resistance to amikacin. After three months of unabated progression of his signs and symptoms, the patient showed clinical improvement in three days. However given the prolonged course, he required an additional month of therapy. The patient healed with a subepithelial scar and neovascularization. At this point, SEPTRA was discontinued. The final visual acuity of the right eye was 20/30. Interestingly, the conjunctival biopsy was revisited and showed no signs of Nocardia.Fig. 2 Papinicolau stain magnified 400X of corneal scraping demonstrating branching filaments characteristic of Nocardia asteroides.
Fig. 2
3 Discussion
The usual presenting symptoms of Nocardia keratitis include pain, photophobia, blepharospasm, and lid swelling. Nocardia keratitis frequently runs a protracted benign course, but acute severe cases have been seen.9, 10, 11 Superficial granular infiltrates coalesce into a white plaque of variable size over time and result in corneal ulceration that is often superior in location. In addition to the classic finding of patchy wreath-like anterior stromal infiltrates, other presenting features include pseudodendritic epithelial defect, subepithelial infiltrate, persistent epithelial defect, and/or neovascularization into the cornea.2,10
Diagnosis of Nocardia keratitis is often delayed due to several factors. First, symptoms can have an insidious onset and patients may not initially seek medical care. The variable clinical presentations can mimic other forms of keratitis, such as mycotic or atypical mycobacterial infection.12 The clinician needs to have a high clinical suspicion as Nocardia grows slowly on culture. A prompt corneal scraping and culture should be performed with clinical suspicion. However, this may yield negative results as in this case. Nocardia corneal scrapings are positive for gram-positive, branching filaments that stain weakly acid-fast on Ziehl-Neelsen and black on Gomori methenamine silver.1
Nocardia keratitis can be misdiagnosed as superior limbic keratoconjunctivitis if the disease is located in the superior cornea, as in this case. SLK is characterized by inflammation of the superior bulbar and tarsal conjunctiva in addition to superior corneal vascularization that may appear as a pannus.13 SLK will often demonstrate punctate staining with fluorescein and/or rose Bengal. There can also be localized filamentary keratopathy in one-third of cases. Diagnosis involves obtaining a corneal scraping for Giemsa stain, which typically shows enhanced keratinization, poor nuclei, and hyalinized cytoplasm. Corneal scrapings from this case were not diagnostic for SLK. Treatment modalities include use of topical silver nitrate 1%, anti-inflammatory agents, and conjunctival resection.14,15
Another confounder for Nocardia may be HSV as in this case. At one point in the presentation, a dendritiform lesion was noted suggesting HSV epitheliopathy. A few weeks later, corneal neovascularization and haze developed which appeared clinically as an HSV interstitial keratitis. This clinical picture of apparent recurrence can be quite convincing for herpetic interstitial keratitis. However, the steroid treatment may have exacerbated the Nocardia infection.
Nocardia keratitis is most effectively treated with trimethoprim-sulfamethoxazole or amikacin; the latter is considered the drug of choice for all species of Nocardia.16 However, resistance to amikacin, as in this case, has been previously described.17 The intravenous preparation of trimethoprim-sulfamethoxazole can be used directly as eye drops, typically in a dosing of 16 mg/mL trimethoprim and 80 mg/mL sulfamethoxazole. Amikacin is typically used in the concentration of 2.5% and is prepared by adding 8 mL of artificial tears to 2 mL of the intravenous preparation of 125 mg/mL amikacin.6 Of note, systemic antibiotics do not add benefit to the clinical outcome of Nocardia keratitis. Steroids worsen the symptoms of Nocardia keratitis, potentially leading to complications such as corneal perforation, scleritis, and endophthalmitis. Thus, it is critically important to identify the causative organism early as routine steroid use for falsely suspected viral keratitis and SLK exacerbates the underlying condition.
Nocardia keratitis responds well to medical therapy. If treatment is started early in the course, the corneal ulcer tends to heal rapidly with mild peripheral vascularization. The infiltrate resolves with minimal scarring and forms a fine superficial nebular opacity. Visual acuity improves rapidly and the end result is a barely visible residual stromal haze.
4 Conclusions
Nocardia are a rare cause of infectious keratitis. Early diagnosis and treatment of Nocardia keratitis are difficult because of its infrequent occurrence and variable clinical manifestations. We describe a case of Nocardia keratitis that was initially misdiagnosed and treated with multiple antibacterial, antiviral, and anti-inflammatory agents. Due to its superior location, SLK was considered and prompted a superior conjunctival resection that disproved the diagnosis. Of note, the initial cultures were negative and it was only after a second corneal scraping that Nocardia was correctly identified by cytology and confirmed by cultures. Once diagnosed, this case of Nocardia keratitis responded effectively to treatment with trimethoprim-sulfamethoxazole (SEPTRA) in the setting of amikacin resistance.
Patient consent
The patient consented to publication of the case in writing and orally.
CRediT authorship contribution statement
Eileen L. Chang: Project administration, Writing - original draft, Writing - review & editing. Rachel L. Chu: Writing - original draft. John R. Wittpenn: Investigation, Writing - review & editing. Henry D. Perry: Supervision, Conceptualization, Investigation, Writing - review & editing.
Acknowledgments and Disclosures
No funding or grant support. There are no conflicts of interest or financial disclosures for any of the authors listed. All authors attest that they meet the current ICMJE criteria for Authorship. | Topical | DrugAdministrationRoute | CC BY-NC-ND | 33665477 | 19,283,167 | 2021-06 |
What was the administration route of drug 'VALACYCLOVIR HYDROCHLORIDE'? | Nocardia keratitis mimicking superior limbic keratoconjunctivitis and herpes simplex virus.
Nocardia keratitis is a rare type of infectious keratitis and may mimic other corneal diseases and lead to delay in diagnosis. This case illustrates how Nocardia often escapes accurate diagnosis due to its insidious onset, variable clinical manifestations, and unusual characteristics on cultures.
The patient presented with an epithelial defect and superior pannus and scarring, which was misdiagnosed as superior limbic keratoconjunctivitis (SLK) and herpes simplex virus (HSV) keratitis. Repeat corneal scraping cultures, smears, and conjunctival biopsy were necessary to elucidate the diagnosis. It can be effectively treated with the intravenous preparation of trimethoprim-sulfamethoxazole 80 mg/mL (brand name SEPTRA) used topically as eye drops.
The diagnosis of Nocardia keratitis relies on a high clinical suspicion and a prompt corneal scraping with culture. Due to its potential for rapid resolution with early therapy, it is important to isolate Nocardia early in its disease course.
Topical amikacin had been the standard of care for Nocardia keratitis for many years. However, recently there is increasing resistance of Nocardia to amikacin. SEPTRA offers an alternative therapy. Nocardia keratitis mimics other infectious and inflammatory etiologies so rapid diagnosis and treatment is critical in the prevention of long-term complications.
1 Introduction
Nocardia are a group of aerobic, gram-positive, and catalase-positive bacteria in the shape of long, thin, and branching filaments that stain weakly acid-fast on Ziehl-Neelsen1.
Nocardia asteroides is the most commonly reported species to cause Nocardia keratitis. It is classically described with an appearance of stromal infiltrates in a wreath-like pattern and may be associated with tiny epithelial calcifications often near the limbus adjacent to pannus-like areas of increased vascularity.2,3 Culture on blood agar may occasionally lead to a consideration of contamination due to the tendency for prominent areas of calcification on the agar.2
Nocardia keratitis is seen more frequently in young males, especially those who live in rural areas.3,4 As Nocardia is the most common bacteria found in soil, corneal trauma and contact with soil predispose those in rural areas to infection. Other risk factors for Nocardia keratitis include contact lens wear, ophthalmic surgery, and topical corticosteroids.5, 6, 7, 8
This unique case of Nocardia keratitis focuses attention on the variability of presentation and the possibility of a prolonged clinical course over months. The multiple misdiagnoses suffered by this patient highlight how this pathogen is elusive and often discovered late in the clinical course leading to permanent ocular sequelae.
2 Case presentation
A 41-year-old male contact lens user without history of corneal trauma or soil contact presented with a three-week history of pruritus, photophobia, and excessive tearing of the right eye. He was initially found to have a corneal abrasion and started on topical tobramycin 0.3% QID, which aggravated his symptoms. The patient was then referred to an ophthalmologist who added loteprednol 0.5% daily. The patient failed to respond to this therapy and was sent to a corneal specialist. On initial presentation, the patient's best-corrected visual acuity (BCVA) in the right eye was 20/20–3. Anterior segment exam was significant for bilateral blepharitis, right floppy eyelid, right trace perilimbal injection, 2+ superior palpebral conjunctival injection, and a new right corneal scar with irregular epithelium lacking definitive boundaries superiorly at 12 o'clock. Given the pattern of injection, recurrent discomfort, and subjective complaint of itchiness, superior limbic keratoconjunctivitis (SLK) was considered. The corneal specialist trialed a course of ofloxacin 0.3% and then increased loteprednol 0.5% to BID dosing.
On two-week follow-up, the patient displayed symptomatic improvement. However, the clinical exam demonstrated new dendritiform lesions developing at the peripheral edge of the corneal scar. Treatment for presumed herpes simplex keratitis (HSV) was initiated with a course of oral valacyclovir TID and topical ganciclovir 0.15% QID. Additionally, the patient was sent for corneal cultures to rule out fungal keratitis. Follow-up results were negative for fungi.
The patient returned in one month with worsening symptoms. At this time, his corneal scar displayed anterior stromal scarring with new overlying neovascularization and an advancing edge of irregular epithelium (Fig. 1). Keratic precipitates and anterior chamber inflammation were absent. At this point, the diagnosis of HSV interstitial keratitis was considered. The topical medications were switched from loteprednol to difluprednate 0.05% QID; the patient was restarted on valacyclovir TID.Fig. 1 Clinical photograph of the patient's right eye on initial presentation to second corneal specialist (3 months from first symptoms) demonstrating superior pannus, anterior stromal scarring, conjunctival injection, and floppy eyelids.
Fig. 1
After returning from vacation overseas, the patient followed up with the corneal specialist with minimal improvement. Given the failure to respond to herpetic treatment, a superior conjunctival resection for presumed SLK and corneal scrapings were taken from the right eye where the cornea was abnormal. A ProKera Slim™ amniotic membrane was placed over the defect and prophylactic ophthalmic antibiotics were started. The patient was maintained on oral valacyclovir TID, topical difluprednate 0.05% BID, and topical ofloxacin 0.3% as antibiotic prophylaxis for a few days. Corneal scrapings did not reveal findings suggestive of SLK or microbial keratitis when evaluated.
One week later, the patient reported dramatically decreased vision with severe photophobia and difficulty opening the right eye. Visual acuity was 20/400 with the ProKera Slim™. At this point, the corneal scraping was 95% healed so the ProKera Slim™ was removed. No further stromal infiltrates were noted. All medications were discontinued except bacitracin-polymyxin B. On subsequent follow-up one week later, the patient was referred to another corneal specialist for consultation. At this visit, a repeat corneal Gram stain and a Papinicolau stain were positive for filamentous rods and Nocardia was suspected (Fig. 2). Therapy was initiated with trimethroprim-sulfamethaxazole (SEPTRA) 80 mg/mL in the right eye every 2 hours. One week later, cultural identification was confirmed for Nocardia asteroides and sensitivities showed resistance to amikacin. After three months of unabated progression of his signs and symptoms, the patient showed clinical improvement in three days. However given the prolonged course, he required an additional month of therapy. The patient healed with a subepithelial scar and neovascularization. At this point, SEPTRA was discontinued. The final visual acuity of the right eye was 20/30. Interestingly, the conjunctival biopsy was revisited and showed no signs of Nocardia.Fig. 2 Papinicolau stain magnified 400X of corneal scraping demonstrating branching filaments characteristic of Nocardia asteroides.
Fig. 2
3 Discussion
The usual presenting symptoms of Nocardia keratitis include pain, photophobia, blepharospasm, and lid swelling. Nocardia keratitis frequently runs a protracted benign course, but acute severe cases have been seen.9, 10, 11 Superficial granular infiltrates coalesce into a white plaque of variable size over time and result in corneal ulceration that is often superior in location. In addition to the classic finding of patchy wreath-like anterior stromal infiltrates, other presenting features include pseudodendritic epithelial defect, subepithelial infiltrate, persistent epithelial defect, and/or neovascularization into the cornea.2,10
Diagnosis of Nocardia keratitis is often delayed due to several factors. First, symptoms can have an insidious onset and patients may not initially seek medical care. The variable clinical presentations can mimic other forms of keratitis, such as mycotic or atypical mycobacterial infection.12 The clinician needs to have a high clinical suspicion as Nocardia grows slowly on culture. A prompt corneal scraping and culture should be performed with clinical suspicion. However, this may yield negative results as in this case. Nocardia corneal scrapings are positive for gram-positive, branching filaments that stain weakly acid-fast on Ziehl-Neelsen and black on Gomori methenamine silver.1
Nocardia keratitis can be misdiagnosed as superior limbic keratoconjunctivitis if the disease is located in the superior cornea, as in this case. SLK is characterized by inflammation of the superior bulbar and tarsal conjunctiva in addition to superior corneal vascularization that may appear as a pannus.13 SLK will often demonstrate punctate staining with fluorescein and/or rose Bengal. There can also be localized filamentary keratopathy in one-third of cases. Diagnosis involves obtaining a corneal scraping for Giemsa stain, which typically shows enhanced keratinization, poor nuclei, and hyalinized cytoplasm. Corneal scrapings from this case were not diagnostic for SLK. Treatment modalities include use of topical silver nitrate 1%, anti-inflammatory agents, and conjunctival resection.14,15
Another confounder for Nocardia may be HSV as in this case. At one point in the presentation, a dendritiform lesion was noted suggesting HSV epitheliopathy. A few weeks later, corneal neovascularization and haze developed which appeared clinically as an HSV interstitial keratitis. This clinical picture of apparent recurrence can be quite convincing for herpetic interstitial keratitis. However, the steroid treatment may have exacerbated the Nocardia infection.
Nocardia keratitis is most effectively treated with trimethoprim-sulfamethoxazole or amikacin; the latter is considered the drug of choice for all species of Nocardia.16 However, resistance to amikacin, as in this case, has been previously described.17 The intravenous preparation of trimethoprim-sulfamethoxazole can be used directly as eye drops, typically in a dosing of 16 mg/mL trimethoprim and 80 mg/mL sulfamethoxazole. Amikacin is typically used in the concentration of 2.5% and is prepared by adding 8 mL of artificial tears to 2 mL of the intravenous preparation of 125 mg/mL amikacin.6 Of note, systemic antibiotics do not add benefit to the clinical outcome of Nocardia keratitis. Steroids worsen the symptoms of Nocardia keratitis, potentially leading to complications such as corneal perforation, scleritis, and endophthalmitis. Thus, it is critically important to identify the causative organism early as routine steroid use for falsely suspected viral keratitis and SLK exacerbates the underlying condition.
Nocardia keratitis responds well to medical therapy. If treatment is started early in the course, the corneal ulcer tends to heal rapidly with mild peripheral vascularization. The infiltrate resolves with minimal scarring and forms a fine superficial nebular opacity. Visual acuity improves rapidly and the end result is a barely visible residual stromal haze.
4 Conclusions
Nocardia are a rare cause of infectious keratitis. Early diagnosis and treatment of Nocardia keratitis are difficult because of its infrequent occurrence and variable clinical manifestations. We describe a case of Nocardia keratitis that was initially misdiagnosed and treated with multiple antibacterial, antiviral, and anti-inflammatory agents. Due to its superior location, SLK was considered and prompted a superior conjunctival resection that disproved the diagnosis. Of note, the initial cultures were negative and it was only after a second corneal scraping that Nocardia was correctly identified by cytology and confirmed by cultures. Once diagnosed, this case of Nocardia keratitis responded effectively to treatment with trimethoprim-sulfamethoxazole (SEPTRA) in the setting of amikacin resistance.
Patient consent
The patient consented to publication of the case in writing and orally.
CRediT authorship contribution statement
Eileen L. Chang: Project administration, Writing - original draft, Writing - review & editing. Rachel L. Chu: Writing - original draft. John R. Wittpenn: Investigation, Writing - review & editing. Henry D. Perry: Supervision, Conceptualization, Investigation, Writing - review & editing.
Acknowledgments and Disclosures
No funding or grant support. There are no conflicts of interest or financial disclosures for any of the authors listed. All authors attest that they meet the current ICMJE criteria for Authorship. | Oral | DrugAdministrationRoute | CC BY-NC-ND | 33665477 | 19,356,229 | 2021-06 |
What was the dosage of drug 'DIFLUPREDNATE'? | Nocardia keratitis mimicking superior limbic keratoconjunctivitis and herpes simplex virus.
Nocardia keratitis is a rare type of infectious keratitis and may mimic other corneal diseases and lead to delay in diagnosis. This case illustrates how Nocardia often escapes accurate diagnosis due to its insidious onset, variable clinical manifestations, and unusual characteristics on cultures.
The patient presented with an epithelial defect and superior pannus and scarring, which was misdiagnosed as superior limbic keratoconjunctivitis (SLK) and herpes simplex virus (HSV) keratitis. Repeat corneal scraping cultures, smears, and conjunctival biopsy were necessary to elucidate the diagnosis. It can be effectively treated with the intravenous preparation of trimethoprim-sulfamethoxazole 80 mg/mL (brand name SEPTRA) used topically as eye drops.
The diagnosis of Nocardia keratitis relies on a high clinical suspicion and a prompt corneal scraping with culture. Due to its potential for rapid resolution with early therapy, it is important to isolate Nocardia early in its disease course.
Topical amikacin had been the standard of care for Nocardia keratitis for many years. However, recently there is increasing resistance of Nocardia to amikacin. SEPTRA offers an alternative therapy. Nocardia keratitis mimics other infectious and inflammatory etiologies so rapid diagnosis and treatment is critical in the prevention of long-term complications.
1 Introduction
Nocardia are a group of aerobic, gram-positive, and catalase-positive bacteria in the shape of long, thin, and branching filaments that stain weakly acid-fast on Ziehl-Neelsen1.
Nocardia asteroides is the most commonly reported species to cause Nocardia keratitis. It is classically described with an appearance of stromal infiltrates in a wreath-like pattern and may be associated with tiny epithelial calcifications often near the limbus adjacent to pannus-like areas of increased vascularity.2,3 Culture on blood agar may occasionally lead to a consideration of contamination due to the tendency for prominent areas of calcification on the agar.2
Nocardia keratitis is seen more frequently in young males, especially those who live in rural areas.3,4 As Nocardia is the most common bacteria found in soil, corneal trauma and contact with soil predispose those in rural areas to infection. Other risk factors for Nocardia keratitis include contact lens wear, ophthalmic surgery, and topical corticosteroids.5, 6, 7, 8
This unique case of Nocardia keratitis focuses attention on the variability of presentation and the possibility of a prolonged clinical course over months. The multiple misdiagnoses suffered by this patient highlight how this pathogen is elusive and often discovered late in the clinical course leading to permanent ocular sequelae.
2 Case presentation
A 41-year-old male contact lens user without history of corneal trauma or soil contact presented with a three-week history of pruritus, photophobia, and excessive tearing of the right eye. He was initially found to have a corneal abrasion and started on topical tobramycin 0.3% QID, which aggravated his symptoms. The patient was then referred to an ophthalmologist who added loteprednol 0.5% daily. The patient failed to respond to this therapy and was sent to a corneal specialist. On initial presentation, the patient's best-corrected visual acuity (BCVA) in the right eye was 20/20–3. Anterior segment exam was significant for bilateral blepharitis, right floppy eyelid, right trace perilimbal injection, 2+ superior palpebral conjunctival injection, and a new right corneal scar with irregular epithelium lacking definitive boundaries superiorly at 12 o'clock. Given the pattern of injection, recurrent discomfort, and subjective complaint of itchiness, superior limbic keratoconjunctivitis (SLK) was considered. The corneal specialist trialed a course of ofloxacin 0.3% and then increased loteprednol 0.5% to BID dosing.
On two-week follow-up, the patient displayed symptomatic improvement. However, the clinical exam demonstrated new dendritiform lesions developing at the peripheral edge of the corneal scar. Treatment for presumed herpes simplex keratitis (HSV) was initiated with a course of oral valacyclovir TID and topical ganciclovir 0.15% QID. Additionally, the patient was sent for corneal cultures to rule out fungal keratitis. Follow-up results were negative for fungi.
The patient returned in one month with worsening symptoms. At this time, his corneal scar displayed anterior stromal scarring with new overlying neovascularization and an advancing edge of irregular epithelium (Fig. 1). Keratic precipitates and anterior chamber inflammation were absent. At this point, the diagnosis of HSV interstitial keratitis was considered. The topical medications were switched from loteprednol to difluprednate 0.05% QID; the patient was restarted on valacyclovir TID.Fig. 1 Clinical photograph of the patient's right eye on initial presentation to second corneal specialist (3 months from first symptoms) demonstrating superior pannus, anterior stromal scarring, conjunctival injection, and floppy eyelids.
Fig. 1
After returning from vacation overseas, the patient followed up with the corneal specialist with minimal improvement. Given the failure to respond to herpetic treatment, a superior conjunctival resection for presumed SLK and corneal scrapings were taken from the right eye where the cornea was abnormal. A ProKera Slim™ amniotic membrane was placed over the defect and prophylactic ophthalmic antibiotics were started. The patient was maintained on oral valacyclovir TID, topical difluprednate 0.05% BID, and topical ofloxacin 0.3% as antibiotic prophylaxis for a few days. Corneal scrapings did not reveal findings suggestive of SLK or microbial keratitis when evaluated.
One week later, the patient reported dramatically decreased vision with severe photophobia and difficulty opening the right eye. Visual acuity was 20/400 with the ProKera Slim™. At this point, the corneal scraping was 95% healed so the ProKera Slim™ was removed. No further stromal infiltrates were noted. All medications were discontinued except bacitracin-polymyxin B. On subsequent follow-up one week later, the patient was referred to another corneal specialist for consultation. At this visit, a repeat corneal Gram stain and a Papinicolau stain were positive for filamentous rods and Nocardia was suspected (Fig. 2). Therapy was initiated with trimethroprim-sulfamethaxazole (SEPTRA) 80 mg/mL in the right eye every 2 hours. One week later, cultural identification was confirmed for Nocardia asteroides and sensitivities showed resistance to amikacin. After three months of unabated progression of his signs and symptoms, the patient showed clinical improvement in three days. However given the prolonged course, he required an additional month of therapy. The patient healed with a subepithelial scar and neovascularization. At this point, SEPTRA was discontinued. The final visual acuity of the right eye was 20/30. Interestingly, the conjunctival biopsy was revisited and showed no signs of Nocardia.Fig. 2 Papinicolau stain magnified 400X of corneal scraping demonstrating branching filaments characteristic of Nocardia asteroides.
Fig. 2
3 Discussion
The usual presenting symptoms of Nocardia keratitis include pain, photophobia, blepharospasm, and lid swelling. Nocardia keratitis frequently runs a protracted benign course, but acute severe cases have been seen.9, 10, 11 Superficial granular infiltrates coalesce into a white plaque of variable size over time and result in corneal ulceration that is often superior in location. In addition to the classic finding of patchy wreath-like anterior stromal infiltrates, other presenting features include pseudodendritic epithelial defect, subepithelial infiltrate, persistent epithelial defect, and/or neovascularization into the cornea.2,10
Diagnosis of Nocardia keratitis is often delayed due to several factors. First, symptoms can have an insidious onset and patients may not initially seek medical care. The variable clinical presentations can mimic other forms of keratitis, such as mycotic or atypical mycobacterial infection.12 The clinician needs to have a high clinical suspicion as Nocardia grows slowly on culture. A prompt corneal scraping and culture should be performed with clinical suspicion. However, this may yield negative results as in this case. Nocardia corneal scrapings are positive for gram-positive, branching filaments that stain weakly acid-fast on Ziehl-Neelsen and black on Gomori methenamine silver.1
Nocardia keratitis can be misdiagnosed as superior limbic keratoconjunctivitis if the disease is located in the superior cornea, as in this case. SLK is characterized by inflammation of the superior bulbar and tarsal conjunctiva in addition to superior corneal vascularization that may appear as a pannus.13 SLK will often demonstrate punctate staining with fluorescein and/or rose Bengal. There can also be localized filamentary keratopathy in one-third of cases. Diagnosis involves obtaining a corneal scraping for Giemsa stain, which typically shows enhanced keratinization, poor nuclei, and hyalinized cytoplasm. Corneal scrapings from this case were not diagnostic for SLK. Treatment modalities include use of topical silver nitrate 1%, anti-inflammatory agents, and conjunctival resection.14,15
Another confounder for Nocardia may be HSV as in this case. At one point in the presentation, a dendritiform lesion was noted suggesting HSV epitheliopathy. A few weeks later, corneal neovascularization and haze developed which appeared clinically as an HSV interstitial keratitis. This clinical picture of apparent recurrence can be quite convincing for herpetic interstitial keratitis. However, the steroid treatment may have exacerbated the Nocardia infection.
Nocardia keratitis is most effectively treated with trimethoprim-sulfamethoxazole or amikacin; the latter is considered the drug of choice for all species of Nocardia.16 However, resistance to amikacin, as in this case, has been previously described.17 The intravenous preparation of trimethoprim-sulfamethoxazole can be used directly as eye drops, typically in a dosing of 16 mg/mL trimethoprim and 80 mg/mL sulfamethoxazole. Amikacin is typically used in the concentration of 2.5% and is prepared by adding 8 mL of artificial tears to 2 mL of the intravenous preparation of 125 mg/mL amikacin.6 Of note, systemic antibiotics do not add benefit to the clinical outcome of Nocardia keratitis. Steroids worsen the symptoms of Nocardia keratitis, potentially leading to complications such as corneal perforation, scleritis, and endophthalmitis. Thus, it is critically important to identify the causative organism early as routine steroid use for falsely suspected viral keratitis and SLK exacerbates the underlying condition.
Nocardia keratitis responds well to medical therapy. If treatment is started early in the course, the corneal ulcer tends to heal rapidly with mild peripheral vascularization. The infiltrate resolves with minimal scarring and forms a fine superficial nebular opacity. Visual acuity improves rapidly and the end result is a barely visible residual stromal haze.
4 Conclusions
Nocardia are a rare cause of infectious keratitis. Early diagnosis and treatment of Nocardia keratitis are difficult because of its infrequent occurrence and variable clinical manifestations. We describe a case of Nocardia keratitis that was initially misdiagnosed and treated with multiple antibacterial, antiviral, and anti-inflammatory agents. Due to its superior location, SLK was considered and prompted a superior conjunctival resection that disproved the diagnosis. Of note, the initial cultures were negative and it was only after a second corneal scraping that Nocardia was correctly identified by cytology and confirmed by cultures. Once diagnosed, this case of Nocardia keratitis responded effectively to treatment with trimethoprim-sulfamethoxazole (SEPTRA) in the setting of amikacin resistance.
Patient consent
The patient consented to publication of the case in writing and orally.
CRediT authorship contribution statement
Eileen L. Chang: Project administration, Writing - original draft, Writing - review & editing. Rachel L. Chu: Writing - original draft. John R. Wittpenn: Investigation, Writing - review & editing. Henry D. Perry: Supervision, Conceptualization, Investigation, Writing - review & editing.
Acknowledgments and Disclosures
No funding or grant support. There are no conflicts of interest or financial disclosures for any of the authors listed. All authors attest that they meet the current ICMJE criteria for Authorship. | UNK, BID (0.05%) | DrugDosageText | CC BY-NC-ND | 33665477 | 19,356,229 | 2021-06 |
What was the dosage of drug 'OFLOXACIN'? | Nocardia keratitis mimicking superior limbic keratoconjunctivitis and herpes simplex virus.
Nocardia keratitis is a rare type of infectious keratitis and may mimic other corneal diseases and lead to delay in diagnosis. This case illustrates how Nocardia often escapes accurate diagnosis due to its insidious onset, variable clinical manifestations, and unusual characteristics on cultures.
The patient presented with an epithelial defect and superior pannus and scarring, which was misdiagnosed as superior limbic keratoconjunctivitis (SLK) and herpes simplex virus (HSV) keratitis. Repeat corneal scraping cultures, smears, and conjunctival biopsy were necessary to elucidate the diagnosis. It can be effectively treated with the intravenous preparation of trimethoprim-sulfamethoxazole 80 mg/mL (brand name SEPTRA) used topically as eye drops.
The diagnosis of Nocardia keratitis relies on a high clinical suspicion and a prompt corneal scraping with culture. Due to its potential for rapid resolution with early therapy, it is important to isolate Nocardia early in its disease course.
Topical amikacin had been the standard of care for Nocardia keratitis for many years. However, recently there is increasing resistance of Nocardia to amikacin. SEPTRA offers an alternative therapy. Nocardia keratitis mimics other infectious and inflammatory etiologies so rapid diagnosis and treatment is critical in the prevention of long-term complications.
1 Introduction
Nocardia are a group of aerobic, gram-positive, and catalase-positive bacteria in the shape of long, thin, and branching filaments that stain weakly acid-fast on Ziehl-Neelsen1.
Nocardia asteroides is the most commonly reported species to cause Nocardia keratitis. It is classically described with an appearance of stromal infiltrates in a wreath-like pattern and may be associated with tiny epithelial calcifications often near the limbus adjacent to pannus-like areas of increased vascularity.2,3 Culture on blood agar may occasionally lead to a consideration of contamination due to the tendency for prominent areas of calcification on the agar.2
Nocardia keratitis is seen more frequently in young males, especially those who live in rural areas.3,4 As Nocardia is the most common bacteria found in soil, corneal trauma and contact with soil predispose those in rural areas to infection. Other risk factors for Nocardia keratitis include contact lens wear, ophthalmic surgery, and topical corticosteroids.5, 6, 7, 8
This unique case of Nocardia keratitis focuses attention on the variability of presentation and the possibility of a prolonged clinical course over months. The multiple misdiagnoses suffered by this patient highlight how this pathogen is elusive and often discovered late in the clinical course leading to permanent ocular sequelae.
2 Case presentation
A 41-year-old male contact lens user without history of corneal trauma or soil contact presented with a three-week history of pruritus, photophobia, and excessive tearing of the right eye. He was initially found to have a corneal abrasion and started on topical tobramycin 0.3% QID, which aggravated his symptoms. The patient was then referred to an ophthalmologist who added loteprednol 0.5% daily. The patient failed to respond to this therapy and was sent to a corneal specialist. On initial presentation, the patient's best-corrected visual acuity (BCVA) in the right eye was 20/20–3. Anterior segment exam was significant for bilateral blepharitis, right floppy eyelid, right trace perilimbal injection, 2+ superior palpebral conjunctival injection, and a new right corneal scar with irregular epithelium lacking definitive boundaries superiorly at 12 o'clock. Given the pattern of injection, recurrent discomfort, and subjective complaint of itchiness, superior limbic keratoconjunctivitis (SLK) was considered. The corneal specialist trialed a course of ofloxacin 0.3% and then increased loteprednol 0.5% to BID dosing.
On two-week follow-up, the patient displayed symptomatic improvement. However, the clinical exam demonstrated new dendritiform lesions developing at the peripheral edge of the corneal scar. Treatment for presumed herpes simplex keratitis (HSV) was initiated with a course of oral valacyclovir TID and topical ganciclovir 0.15% QID. Additionally, the patient was sent for corneal cultures to rule out fungal keratitis. Follow-up results were negative for fungi.
The patient returned in one month with worsening symptoms. At this time, his corneal scar displayed anterior stromal scarring with new overlying neovascularization and an advancing edge of irregular epithelium (Fig. 1). Keratic precipitates and anterior chamber inflammation were absent. At this point, the diagnosis of HSV interstitial keratitis was considered. The topical medications were switched from loteprednol to difluprednate 0.05% QID; the patient was restarted on valacyclovir TID.Fig. 1 Clinical photograph of the patient's right eye on initial presentation to second corneal specialist (3 months from first symptoms) demonstrating superior pannus, anterior stromal scarring, conjunctival injection, and floppy eyelids.
Fig. 1
After returning from vacation overseas, the patient followed up with the corneal specialist with minimal improvement. Given the failure to respond to herpetic treatment, a superior conjunctival resection for presumed SLK and corneal scrapings were taken from the right eye where the cornea was abnormal. A ProKera Slim™ amniotic membrane was placed over the defect and prophylactic ophthalmic antibiotics were started. The patient was maintained on oral valacyclovir TID, topical difluprednate 0.05% BID, and topical ofloxacin 0.3% as antibiotic prophylaxis for a few days. Corneal scrapings did not reveal findings suggestive of SLK or microbial keratitis when evaluated.
One week later, the patient reported dramatically decreased vision with severe photophobia and difficulty opening the right eye. Visual acuity was 20/400 with the ProKera Slim™. At this point, the corneal scraping was 95% healed so the ProKera Slim™ was removed. No further stromal infiltrates were noted. All medications were discontinued except bacitracin-polymyxin B. On subsequent follow-up one week later, the patient was referred to another corneal specialist for consultation. At this visit, a repeat corneal Gram stain and a Papinicolau stain were positive for filamentous rods and Nocardia was suspected (Fig. 2). Therapy was initiated with trimethroprim-sulfamethaxazole (SEPTRA) 80 mg/mL in the right eye every 2 hours. One week later, cultural identification was confirmed for Nocardia asteroides and sensitivities showed resistance to amikacin. After three months of unabated progression of his signs and symptoms, the patient showed clinical improvement in three days. However given the prolonged course, he required an additional month of therapy. The patient healed with a subepithelial scar and neovascularization. At this point, SEPTRA was discontinued. The final visual acuity of the right eye was 20/30. Interestingly, the conjunctival biopsy was revisited and showed no signs of Nocardia.Fig. 2 Papinicolau stain magnified 400X of corneal scraping demonstrating branching filaments characteristic of Nocardia asteroides.
Fig. 2
3 Discussion
The usual presenting symptoms of Nocardia keratitis include pain, photophobia, blepharospasm, and lid swelling. Nocardia keratitis frequently runs a protracted benign course, but acute severe cases have been seen.9, 10, 11 Superficial granular infiltrates coalesce into a white plaque of variable size over time and result in corneal ulceration that is often superior in location. In addition to the classic finding of patchy wreath-like anterior stromal infiltrates, other presenting features include pseudodendritic epithelial defect, subepithelial infiltrate, persistent epithelial defect, and/or neovascularization into the cornea.2,10
Diagnosis of Nocardia keratitis is often delayed due to several factors. First, symptoms can have an insidious onset and patients may not initially seek medical care. The variable clinical presentations can mimic other forms of keratitis, such as mycotic or atypical mycobacterial infection.12 The clinician needs to have a high clinical suspicion as Nocardia grows slowly on culture. A prompt corneal scraping and culture should be performed with clinical suspicion. However, this may yield negative results as in this case. Nocardia corneal scrapings are positive for gram-positive, branching filaments that stain weakly acid-fast on Ziehl-Neelsen and black on Gomori methenamine silver.1
Nocardia keratitis can be misdiagnosed as superior limbic keratoconjunctivitis if the disease is located in the superior cornea, as in this case. SLK is characterized by inflammation of the superior bulbar and tarsal conjunctiva in addition to superior corneal vascularization that may appear as a pannus.13 SLK will often demonstrate punctate staining with fluorescein and/or rose Bengal. There can also be localized filamentary keratopathy in one-third of cases. Diagnosis involves obtaining a corneal scraping for Giemsa stain, which typically shows enhanced keratinization, poor nuclei, and hyalinized cytoplasm. Corneal scrapings from this case were not diagnostic for SLK. Treatment modalities include use of topical silver nitrate 1%, anti-inflammatory agents, and conjunctival resection.14,15
Another confounder for Nocardia may be HSV as in this case. At one point in the presentation, a dendritiform lesion was noted suggesting HSV epitheliopathy. A few weeks later, corneal neovascularization and haze developed which appeared clinically as an HSV interstitial keratitis. This clinical picture of apparent recurrence can be quite convincing for herpetic interstitial keratitis. However, the steroid treatment may have exacerbated the Nocardia infection.
Nocardia keratitis is most effectively treated with trimethoprim-sulfamethoxazole or amikacin; the latter is considered the drug of choice for all species of Nocardia.16 However, resistance to amikacin, as in this case, has been previously described.17 The intravenous preparation of trimethoprim-sulfamethoxazole can be used directly as eye drops, typically in a dosing of 16 mg/mL trimethoprim and 80 mg/mL sulfamethoxazole. Amikacin is typically used in the concentration of 2.5% and is prepared by adding 8 mL of artificial tears to 2 mL of the intravenous preparation of 125 mg/mL amikacin.6 Of note, systemic antibiotics do not add benefit to the clinical outcome of Nocardia keratitis. Steroids worsen the symptoms of Nocardia keratitis, potentially leading to complications such as corneal perforation, scleritis, and endophthalmitis. Thus, it is critically important to identify the causative organism early as routine steroid use for falsely suspected viral keratitis and SLK exacerbates the underlying condition.
Nocardia keratitis responds well to medical therapy. If treatment is started early in the course, the corneal ulcer tends to heal rapidly with mild peripheral vascularization. The infiltrate resolves with minimal scarring and forms a fine superficial nebular opacity. Visual acuity improves rapidly and the end result is a barely visible residual stromal haze.
4 Conclusions
Nocardia are a rare cause of infectious keratitis. Early diagnosis and treatment of Nocardia keratitis are difficult because of its infrequent occurrence and variable clinical manifestations. We describe a case of Nocardia keratitis that was initially misdiagnosed and treated with multiple antibacterial, antiviral, and anti-inflammatory agents. Due to its superior location, SLK was considered and prompted a superior conjunctival resection that disproved the diagnosis. Of note, the initial cultures were negative and it was only after a second corneal scraping that Nocardia was correctly identified by cytology and confirmed by cultures. Once diagnosed, this case of Nocardia keratitis responded effectively to treatment with trimethoprim-sulfamethoxazole (SEPTRA) in the setting of amikacin resistance.
Patient consent
The patient consented to publication of the case in writing and orally.
CRediT authorship contribution statement
Eileen L. Chang: Project administration, Writing - original draft, Writing - review & editing. Rachel L. Chu: Writing - original draft. John R. Wittpenn: Investigation, Writing - review & editing. Henry D. Perry: Supervision, Conceptualization, Investigation, Writing - review & editing.
Acknowledgments and Disclosures
No funding or grant support. There are no conflicts of interest or financial disclosures for any of the authors listed. All authors attest that they meet the current ICMJE criteria for Authorship. | UNK (0.3%) | DrugDosageText | CC BY-NC-ND | 33665477 | 19,356,229 | 2021-06 |
What was the dosage of drug 'TOBRAMYCIN'? | Nocardia keratitis mimicking superior limbic keratoconjunctivitis and herpes simplex virus.
Nocardia keratitis is a rare type of infectious keratitis and may mimic other corneal diseases and lead to delay in diagnosis. This case illustrates how Nocardia often escapes accurate diagnosis due to its insidious onset, variable clinical manifestations, and unusual characteristics on cultures.
The patient presented with an epithelial defect and superior pannus and scarring, which was misdiagnosed as superior limbic keratoconjunctivitis (SLK) and herpes simplex virus (HSV) keratitis. Repeat corneal scraping cultures, smears, and conjunctival biopsy were necessary to elucidate the diagnosis. It can be effectively treated with the intravenous preparation of trimethoprim-sulfamethoxazole 80 mg/mL (brand name SEPTRA) used topically as eye drops.
The diagnosis of Nocardia keratitis relies on a high clinical suspicion and a prompt corneal scraping with culture. Due to its potential for rapid resolution with early therapy, it is important to isolate Nocardia early in its disease course.
Topical amikacin had been the standard of care for Nocardia keratitis for many years. However, recently there is increasing resistance of Nocardia to amikacin. SEPTRA offers an alternative therapy. Nocardia keratitis mimics other infectious and inflammatory etiologies so rapid diagnosis and treatment is critical in the prevention of long-term complications.
1 Introduction
Nocardia are a group of aerobic, gram-positive, and catalase-positive bacteria in the shape of long, thin, and branching filaments that stain weakly acid-fast on Ziehl-Neelsen1.
Nocardia asteroides is the most commonly reported species to cause Nocardia keratitis. It is classically described with an appearance of stromal infiltrates in a wreath-like pattern and may be associated with tiny epithelial calcifications often near the limbus adjacent to pannus-like areas of increased vascularity.2,3 Culture on blood agar may occasionally lead to a consideration of contamination due to the tendency for prominent areas of calcification on the agar.2
Nocardia keratitis is seen more frequently in young males, especially those who live in rural areas.3,4 As Nocardia is the most common bacteria found in soil, corneal trauma and contact with soil predispose those in rural areas to infection. Other risk factors for Nocardia keratitis include contact lens wear, ophthalmic surgery, and topical corticosteroids.5, 6, 7, 8
This unique case of Nocardia keratitis focuses attention on the variability of presentation and the possibility of a prolonged clinical course over months. The multiple misdiagnoses suffered by this patient highlight how this pathogen is elusive and often discovered late in the clinical course leading to permanent ocular sequelae.
2 Case presentation
A 41-year-old male contact lens user without history of corneal trauma or soil contact presented with a three-week history of pruritus, photophobia, and excessive tearing of the right eye. He was initially found to have a corneal abrasion and started on topical tobramycin 0.3% QID, which aggravated his symptoms. The patient was then referred to an ophthalmologist who added loteprednol 0.5% daily. The patient failed to respond to this therapy and was sent to a corneal specialist. On initial presentation, the patient's best-corrected visual acuity (BCVA) in the right eye was 20/20–3. Anterior segment exam was significant for bilateral blepharitis, right floppy eyelid, right trace perilimbal injection, 2+ superior palpebral conjunctival injection, and a new right corneal scar with irregular epithelium lacking definitive boundaries superiorly at 12 o'clock. Given the pattern of injection, recurrent discomfort, and subjective complaint of itchiness, superior limbic keratoconjunctivitis (SLK) was considered. The corneal specialist trialed a course of ofloxacin 0.3% and then increased loteprednol 0.5% to BID dosing.
On two-week follow-up, the patient displayed symptomatic improvement. However, the clinical exam demonstrated new dendritiform lesions developing at the peripheral edge of the corneal scar. Treatment for presumed herpes simplex keratitis (HSV) was initiated with a course of oral valacyclovir TID and topical ganciclovir 0.15% QID. Additionally, the patient was sent for corneal cultures to rule out fungal keratitis. Follow-up results were negative for fungi.
The patient returned in one month with worsening symptoms. At this time, his corneal scar displayed anterior stromal scarring with new overlying neovascularization and an advancing edge of irregular epithelium (Fig. 1). Keratic precipitates and anterior chamber inflammation were absent. At this point, the diagnosis of HSV interstitial keratitis was considered. The topical medications were switched from loteprednol to difluprednate 0.05% QID; the patient was restarted on valacyclovir TID.Fig. 1 Clinical photograph of the patient's right eye on initial presentation to second corneal specialist (3 months from first symptoms) demonstrating superior pannus, anterior stromal scarring, conjunctival injection, and floppy eyelids.
Fig. 1
After returning from vacation overseas, the patient followed up with the corneal specialist with minimal improvement. Given the failure to respond to herpetic treatment, a superior conjunctival resection for presumed SLK and corneal scrapings were taken from the right eye where the cornea was abnormal. A ProKera Slim™ amniotic membrane was placed over the defect and prophylactic ophthalmic antibiotics were started. The patient was maintained on oral valacyclovir TID, topical difluprednate 0.05% BID, and topical ofloxacin 0.3% as antibiotic prophylaxis for a few days. Corneal scrapings did not reveal findings suggestive of SLK or microbial keratitis when evaluated.
One week later, the patient reported dramatically decreased vision with severe photophobia and difficulty opening the right eye. Visual acuity was 20/400 with the ProKera Slim™. At this point, the corneal scraping was 95% healed so the ProKera Slim™ was removed. No further stromal infiltrates were noted. All medications were discontinued except bacitracin-polymyxin B. On subsequent follow-up one week later, the patient was referred to another corneal specialist for consultation. At this visit, a repeat corneal Gram stain and a Papinicolau stain were positive for filamentous rods and Nocardia was suspected (Fig. 2). Therapy was initiated with trimethroprim-sulfamethaxazole (SEPTRA) 80 mg/mL in the right eye every 2 hours. One week later, cultural identification was confirmed for Nocardia asteroides and sensitivities showed resistance to amikacin. After three months of unabated progression of his signs and symptoms, the patient showed clinical improvement in three days. However given the prolonged course, he required an additional month of therapy. The patient healed with a subepithelial scar and neovascularization. At this point, SEPTRA was discontinued. The final visual acuity of the right eye was 20/30. Interestingly, the conjunctival biopsy was revisited and showed no signs of Nocardia.Fig. 2 Papinicolau stain magnified 400X of corneal scraping demonstrating branching filaments characteristic of Nocardia asteroides.
Fig. 2
3 Discussion
The usual presenting symptoms of Nocardia keratitis include pain, photophobia, blepharospasm, and lid swelling. Nocardia keratitis frequently runs a protracted benign course, but acute severe cases have been seen.9, 10, 11 Superficial granular infiltrates coalesce into a white plaque of variable size over time and result in corneal ulceration that is often superior in location. In addition to the classic finding of patchy wreath-like anterior stromal infiltrates, other presenting features include pseudodendritic epithelial defect, subepithelial infiltrate, persistent epithelial defect, and/or neovascularization into the cornea.2,10
Diagnosis of Nocardia keratitis is often delayed due to several factors. First, symptoms can have an insidious onset and patients may not initially seek medical care. The variable clinical presentations can mimic other forms of keratitis, such as mycotic or atypical mycobacterial infection.12 The clinician needs to have a high clinical suspicion as Nocardia grows slowly on culture. A prompt corneal scraping and culture should be performed with clinical suspicion. However, this may yield negative results as in this case. Nocardia corneal scrapings are positive for gram-positive, branching filaments that stain weakly acid-fast on Ziehl-Neelsen and black on Gomori methenamine silver.1
Nocardia keratitis can be misdiagnosed as superior limbic keratoconjunctivitis if the disease is located in the superior cornea, as in this case. SLK is characterized by inflammation of the superior bulbar and tarsal conjunctiva in addition to superior corneal vascularization that may appear as a pannus.13 SLK will often demonstrate punctate staining with fluorescein and/or rose Bengal. There can also be localized filamentary keratopathy in one-third of cases. Diagnosis involves obtaining a corneal scraping for Giemsa stain, which typically shows enhanced keratinization, poor nuclei, and hyalinized cytoplasm. Corneal scrapings from this case were not diagnostic for SLK. Treatment modalities include use of topical silver nitrate 1%, anti-inflammatory agents, and conjunctival resection.14,15
Another confounder for Nocardia may be HSV as in this case. At one point in the presentation, a dendritiform lesion was noted suggesting HSV epitheliopathy. A few weeks later, corneal neovascularization and haze developed which appeared clinically as an HSV interstitial keratitis. This clinical picture of apparent recurrence can be quite convincing for herpetic interstitial keratitis. However, the steroid treatment may have exacerbated the Nocardia infection.
Nocardia keratitis is most effectively treated with trimethoprim-sulfamethoxazole or amikacin; the latter is considered the drug of choice for all species of Nocardia.16 However, resistance to amikacin, as in this case, has been previously described.17 The intravenous preparation of trimethoprim-sulfamethoxazole can be used directly as eye drops, typically in a dosing of 16 mg/mL trimethoprim and 80 mg/mL sulfamethoxazole. Amikacin is typically used in the concentration of 2.5% and is prepared by adding 8 mL of artificial tears to 2 mL of the intravenous preparation of 125 mg/mL amikacin.6 Of note, systemic antibiotics do not add benefit to the clinical outcome of Nocardia keratitis. Steroids worsen the symptoms of Nocardia keratitis, potentially leading to complications such as corneal perforation, scleritis, and endophthalmitis. Thus, it is critically important to identify the causative organism early as routine steroid use for falsely suspected viral keratitis and SLK exacerbates the underlying condition.
Nocardia keratitis responds well to medical therapy. If treatment is started early in the course, the corneal ulcer tends to heal rapidly with mild peripheral vascularization. The infiltrate resolves with minimal scarring and forms a fine superficial nebular opacity. Visual acuity improves rapidly and the end result is a barely visible residual stromal haze.
4 Conclusions
Nocardia are a rare cause of infectious keratitis. Early diagnosis and treatment of Nocardia keratitis are difficult because of its infrequent occurrence and variable clinical manifestations. We describe a case of Nocardia keratitis that was initially misdiagnosed and treated with multiple antibacterial, antiviral, and anti-inflammatory agents. Due to its superior location, SLK was considered and prompted a superior conjunctival resection that disproved the diagnosis. Of note, the initial cultures were negative and it was only after a second corneal scraping that Nocardia was correctly identified by cytology and confirmed by cultures. Once diagnosed, this case of Nocardia keratitis responded effectively to treatment with trimethoprim-sulfamethoxazole (SEPTRA) in the setting of amikacin resistance.
Patient consent
The patient consented to publication of the case in writing and orally.
CRediT authorship contribution statement
Eileen L. Chang: Project administration, Writing - original draft, Writing - review & editing. Rachel L. Chu: Writing - original draft. John R. Wittpenn: Investigation, Writing - review & editing. Henry D. Perry: Supervision, Conceptualization, Investigation, Writing - review & editing.
Acknowledgments and Disclosures
No funding or grant support. There are no conflicts of interest or financial disclosures for any of the authors listed. All authors attest that they meet the current ICMJE criteria for Authorship. | UNK UNK, QID | DrugDosageText | CC BY-NC-ND | 33665477 | 19,295,206 | 2021-06 |
What was the dosage of drug 'VALACYCLOVIR HYDROCHLORIDE'? | Nocardia keratitis mimicking superior limbic keratoconjunctivitis and herpes simplex virus.
Nocardia keratitis is a rare type of infectious keratitis and may mimic other corneal diseases and lead to delay in diagnosis. This case illustrates how Nocardia often escapes accurate diagnosis due to its insidious onset, variable clinical manifestations, and unusual characteristics on cultures.
The patient presented with an epithelial defect and superior pannus and scarring, which was misdiagnosed as superior limbic keratoconjunctivitis (SLK) and herpes simplex virus (HSV) keratitis. Repeat corneal scraping cultures, smears, and conjunctival biopsy were necessary to elucidate the diagnosis. It can be effectively treated with the intravenous preparation of trimethoprim-sulfamethoxazole 80 mg/mL (brand name SEPTRA) used topically as eye drops.
The diagnosis of Nocardia keratitis relies on a high clinical suspicion and a prompt corneal scraping with culture. Due to its potential for rapid resolution with early therapy, it is important to isolate Nocardia early in its disease course.
Topical amikacin had been the standard of care for Nocardia keratitis for many years. However, recently there is increasing resistance of Nocardia to amikacin. SEPTRA offers an alternative therapy. Nocardia keratitis mimics other infectious and inflammatory etiologies so rapid diagnosis and treatment is critical in the prevention of long-term complications.
1 Introduction
Nocardia are a group of aerobic, gram-positive, and catalase-positive bacteria in the shape of long, thin, and branching filaments that stain weakly acid-fast on Ziehl-Neelsen1.
Nocardia asteroides is the most commonly reported species to cause Nocardia keratitis. It is classically described with an appearance of stromal infiltrates in a wreath-like pattern and may be associated with tiny epithelial calcifications often near the limbus adjacent to pannus-like areas of increased vascularity.2,3 Culture on blood agar may occasionally lead to a consideration of contamination due to the tendency for prominent areas of calcification on the agar.2
Nocardia keratitis is seen more frequently in young males, especially those who live in rural areas.3,4 As Nocardia is the most common bacteria found in soil, corneal trauma and contact with soil predispose those in rural areas to infection. Other risk factors for Nocardia keratitis include contact lens wear, ophthalmic surgery, and topical corticosteroids.5, 6, 7, 8
This unique case of Nocardia keratitis focuses attention on the variability of presentation and the possibility of a prolonged clinical course over months. The multiple misdiagnoses suffered by this patient highlight how this pathogen is elusive and often discovered late in the clinical course leading to permanent ocular sequelae.
2 Case presentation
A 41-year-old male contact lens user without history of corneal trauma or soil contact presented with a three-week history of pruritus, photophobia, and excessive tearing of the right eye. He was initially found to have a corneal abrasion and started on topical tobramycin 0.3% QID, which aggravated his symptoms. The patient was then referred to an ophthalmologist who added loteprednol 0.5% daily. The patient failed to respond to this therapy and was sent to a corneal specialist. On initial presentation, the patient's best-corrected visual acuity (BCVA) in the right eye was 20/20–3. Anterior segment exam was significant for bilateral blepharitis, right floppy eyelid, right trace perilimbal injection, 2+ superior palpebral conjunctival injection, and a new right corneal scar with irregular epithelium lacking definitive boundaries superiorly at 12 o'clock. Given the pattern of injection, recurrent discomfort, and subjective complaint of itchiness, superior limbic keratoconjunctivitis (SLK) was considered. The corneal specialist trialed a course of ofloxacin 0.3% and then increased loteprednol 0.5% to BID dosing.
On two-week follow-up, the patient displayed symptomatic improvement. However, the clinical exam demonstrated new dendritiform lesions developing at the peripheral edge of the corneal scar. Treatment for presumed herpes simplex keratitis (HSV) was initiated with a course of oral valacyclovir TID and topical ganciclovir 0.15% QID. Additionally, the patient was sent for corneal cultures to rule out fungal keratitis. Follow-up results were negative for fungi.
The patient returned in one month with worsening symptoms. At this time, his corneal scar displayed anterior stromal scarring with new overlying neovascularization and an advancing edge of irregular epithelium (Fig. 1). Keratic precipitates and anterior chamber inflammation were absent. At this point, the diagnosis of HSV interstitial keratitis was considered. The topical medications were switched from loteprednol to difluprednate 0.05% QID; the patient was restarted on valacyclovir TID.Fig. 1 Clinical photograph of the patient's right eye on initial presentation to second corneal specialist (3 months from first symptoms) demonstrating superior pannus, anterior stromal scarring, conjunctival injection, and floppy eyelids.
Fig. 1
After returning from vacation overseas, the patient followed up with the corneal specialist with minimal improvement. Given the failure to respond to herpetic treatment, a superior conjunctival resection for presumed SLK and corneal scrapings were taken from the right eye where the cornea was abnormal. A ProKera Slim™ amniotic membrane was placed over the defect and prophylactic ophthalmic antibiotics were started. The patient was maintained on oral valacyclovir TID, topical difluprednate 0.05% BID, and topical ofloxacin 0.3% as antibiotic prophylaxis for a few days. Corneal scrapings did not reveal findings suggestive of SLK or microbial keratitis when evaluated.
One week later, the patient reported dramatically decreased vision with severe photophobia and difficulty opening the right eye. Visual acuity was 20/400 with the ProKera Slim™. At this point, the corneal scraping was 95% healed so the ProKera Slim™ was removed. No further stromal infiltrates were noted. All medications were discontinued except bacitracin-polymyxin B. On subsequent follow-up one week later, the patient was referred to another corneal specialist for consultation. At this visit, a repeat corneal Gram stain and a Papinicolau stain were positive for filamentous rods and Nocardia was suspected (Fig. 2). Therapy was initiated with trimethroprim-sulfamethaxazole (SEPTRA) 80 mg/mL in the right eye every 2 hours. One week later, cultural identification was confirmed for Nocardia asteroides and sensitivities showed resistance to amikacin. After three months of unabated progression of his signs and symptoms, the patient showed clinical improvement in three days. However given the prolonged course, he required an additional month of therapy. The patient healed with a subepithelial scar and neovascularization. At this point, SEPTRA was discontinued. The final visual acuity of the right eye was 20/30. Interestingly, the conjunctival biopsy was revisited and showed no signs of Nocardia.Fig. 2 Papinicolau stain magnified 400X of corneal scraping demonstrating branching filaments characteristic of Nocardia asteroides.
Fig. 2
3 Discussion
The usual presenting symptoms of Nocardia keratitis include pain, photophobia, blepharospasm, and lid swelling. Nocardia keratitis frequently runs a protracted benign course, but acute severe cases have been seen.9, 10, 11 Superficial granular infiltrates coalesce into a white plaque of variable size over time and result in corneal ulceration that is often superior in location. In addition to the classic finding of patchy wreath-like anterior stromal infiltrates, other presenting features include pseudodendritic epithelial defect, subepithelial infiltrate, persistent epithelial defect, and/or neovascularization into the cornea.2,10
Diagnosis of Nocardia keratitis is often delayed due to several factors. First, symptoms can have an insidious onset and patients may not initially seek medical care. The variable clinical presentations can mimic other forms of keratitis, such as mycotic or atypical mycobacterial infection.12 The clinician needs to have a high clinical suspicion as Nocardia grows slowly on culture. A prompt corneal scraping and culture should be performed with clinical suspicion. However, this may yield negative results as in this case. Nocardia corneal scrapings are positive for gram-positive, branching filaments that stain weakly acid-fast on Ziehl-Neelsen and black on Gomori methenamine silver.1
Nocardia keratitis can be misdiagnosed as superior limbic keratoconjunctivitis if the disease is located in the superior cornea, as in this case. SLK is characterized by inflammation of the superior bulbar and tarsal conjunctiva in addition to superior corneal vascularization that may appear as a pannus.13 SLK will often demonstrate punctate staining with fluorescein and/or rose Bengal. There can also be localized filamentary keratopathy in one-third of cases. Diagnosis involves obtaining a corneal scraping for Giemsa stain, which typically shows enhanced keratinization, poor nuclei, and hyalinized cytoplasm. Corneal scrapings from this case were not diagnostic for SLK. Treatment modalities include use of topical silver nitrate 1%, anti-inflammatory agents, and conjunctival resection.14,15
Another confounder for Nocardia may be HSV as in this case. At one point in the presentation, a dendritiform lesion was noted suggesting HSV epitheliopathy. A few weeks later, corneal neovascularization and haze developed which appeared clinically as an HSV interstitial keratitis. This clinical picture of apparent recurrence can be quite convincing for herpetic interstitial keratitis. However, the steroid treatment may have exacerbated the Nocardia infection.
Nocardia keratitis is most effectively treated with trimethoprim-sulfamethoxazole or amikacin; the latter is considered the drug of choice for all species of Nocardia.16 However, resistance to amikacin, as in this case, has been previously described.17 The intravenous preparation of trimethoprim-sulfamethoxazole can be used directly as eye drops, typically in a dosing of 16 mg/mL trimethoprim and 80 mg/mL sulfamethoxazole. Amikacin is typically used in the concentration of 2.5% and is prepared by adding 8 mL of artificial tears to 2 mL of the intravenous preparation of 125 mg/mL amikacin.6 Of note, systemic antibiotics do not add benefit to the clinical outcome of Nocardia keratitis. Steroids worsen the symptoms of Nocardia keratitis, potentially leading to complications such as corneal perforation, scleritis, and endophthalmitis. Thus, it is critically important to identify the causative organism early as routine steroid use for falsely suspected viral keratitis and SLK exacerbates the underlying condition.
Nocardia keratitis responds well to medical therapy. If treatment is started early in the course, the corneal ulcer tends to heal rapidly with mild peripheral vascularization. The infiltrate resolves with minimal scarring and forms a fine superficial nebular opacity. Visual acuity improves rapidly and the end result is a barely visible residual stromal haze.
4 Conclusions
Nocardia are a rare cause of infectious keratitis. Early diagnosis and treatment of Nocardia keratitis are difficult because of its infrequent occurrence and variable clinical manifestations. We describe a case of Nocardia keratitis that was initially misdiagnosed and treated with multiple antibacterial, antiviral, and anti-inflammatory agents. Due to its superior location, SLK was considered and prompted a superior conjunctival resection that disproved the diagnosis. Of note, the initial cultures were negative and it was only after a second corneal scraping that Nocardia was correctly identified by cytology and confirmed by cultures. Once diagnosed, this case of Nocardia keratitis responded effectively to treatment with trimethoprim-sulfamethoxazole (SEPTRA) in the setting of amikacin resistance.
Patient consent
The patient consented to publication of the case in writing and orally.
CRediT authorship contribution statement
Eileen L. Chang: Project administration, Writing - original draft, Writing - review & editing. Rachel L. Chu: Writing - original draft. John R. Wittpenn: Investigation, Writing - review & editing. Henry D. Perry: Supervision, Conceptualization, Investigation, Writing - review & editing.
Acknowledgments and Disclosures
No funding or grant support. There are no conflicts of interest or financial disclosures for any of the authors listed. All authors attest that they meet the current ICMJE criteria for Authorship. | UNK, TID | DrugDosageText | CC BY-NC-ND | 33665477 | 19,356,229 | 2021-06 |
What was the outcome of reaction 'Condition aggravated'? | Nocardia keratitis mimicking superior limbic keratoconjunctivitis and herpes simplex virus.
Nocardia keratitis is a rare type of infectious keratitis and may mimic other corneal diseases and lead to delay in diagnosis. This case illustrates how Nocardia often escapes accurate diagnosis due to its insidious onset, variable clinical manifestations, and unusual characteristics on cultures.
The patient presented with an epithelial defect and superior pannus and scarring, which was misdiagnosed as superior limbic keratoconjunctivitis (SLK) and herpes simplex virus (HSV) keratitis. Repeat corneal scraping cultures, smears, and conjunctival biopsy were necessary to elucidate the diagnosis. It can be effectively treated with the intravenous preparation of trimethoprim-sulfamethoxazole 80 mg/mL (brand name SEPTRA) used topically as eye drops.
The diagnosis of Nocardia keratitis relies on a high clinical suspicion and a prompt corneal scraping with culture. Due to its potential for rapid resolution with early therapy, it is important to isolate Nocardia early in its disease course.
Topical amikacin had been the standard of care for Nocardia keratitis for many years. However, recently there is increasing resistance of Nocardia to amikacin. SEPTRA offers an alternative therapy. Nocardia keratitis mimics other infectious and inflammatory etiologies so rapid diagnosis and treatment is critical in the prevention of long-term complications.
1 Introduction
Nocardia are a group of aerobic, gram-positive, and catalase-positive bacteria in the shape of long, thin, and branching filaments that stain weakly acid-fast on Ziehl-Neelsen1.
Nocardia asteroides is the most commonly reported species to cause Nocardia keratitis. It is classically described with an appearance of stromal infiltrates in a wreath-like pattern and may be associated with tiny epithelial calcifications often near the limbus adjacent to pannus-like areas of increased vascularity.2,3 Culture on blood agar may occasionally lead to a consideration of contamination due to the tendency for prominent areas of calcification on the agar.2
Nocardia keratitis is seen more frequently in young males, especially those who live in rural areas.3,4 As Nocardia is the most common bacteria found in soil, corneal trauma and contact with soil predispose those in rural areas to infection. Other risk factors for Nocardia keratitis include contact lens wear, ophthalmic surgery, and topical corticosteroids.5, 6, 7, 8
This unique case of Nocardia keratitis focuses attention on the variability of presentation and the possibility of a prolonged clinical course over months. The multiple misdiagnoses suffered by this patient highlight how this pathogen is elusive and often discovered late in the clinical course leading to permanent ocular sequelae.
2 Case presentation
A 41-year-old male contact lens user without history of corneal trauma or soil contact presented with a three-week history of pruritus, photophobia, and excessive tearing of the right eye. He was initially found to have a corneal abrasion and started on topical tobramycin 0.3% QID, which aggravated his symptoms. The patient was then referred to an ophthalmologist who added loteprednol 0.5% daily. The patient failed to respond to this therapy and was sent to a corneal specialist. On initial presentation, the patient's best-corrected visual acuity (BCVA) in the right eye was 20/20–3. Anterior segment exam was significant for bilateral blepharitis, right floppy eyelid, right trace perilimbal injection, 2+ superior palpebral conjunctival injection, and a new right corneal scar with irregular epithelium lacking definitive boundaries superiorly at 12 o'clock. Given the pattern of injection, recurrent discomfort, and subjective complaint of itchiness, superior limbic keratoconjunctivitis (SLK) was considered. The corneal specialist trialed a course of ofloxacin 0.3% and then increased loteprednol 0.5% to BID dosing.
On two-week follow-up, the patient displayed symptomatic improvement. However, the clinical exam demonstrated new dendritiform lesions developing at the peripheral edge of the corneal scar. Treatment for presumed herpes simplex keratitis (HSV) was initiated with a course of oral valacyclovir TID and topical ganciclovir 0.15% QID. Additionally, the patient was sent for corneal cultures to rule out fungal keratitis. Follow-up results were negative for fungi.
The patient returned in one month with worsening symptoms. At this time, his corneal scar displayed anterior stromal scarring with new overlying neovascularization and an advancing edge of irregular epithelium (Fig. 1). Keratic precipitates and anterior chamber inflammation were absent. At this point, the diagnosis of HSV interstitial keratitis was considered. The topical medications were switched from loteprednol to difluprednate 0.05% QID; the patient was restarted on valacyclovir TID.Fig. 1 Clinical photograph of the patient's right eye on initial presentation to second corneal specialist (3 months from first symptoms) demonstrating superior pannus, anterior stromal scarring, conjunctival injection, and floppy eyelids.
Fig. 1
After returning from vacation overseas, the patient followed up with the corneal specialist with minimal improvement. Given the failure to respond to herpetic treatment, a superior conjunctival resection for presumed SLK and corneal scrapings were taken from the right eye where the cornea was abnormal. A ProKera Slim™ amniotic membrane was placed over the defect and prophylactic ophthalmic antibiotics were started. The patient was maintained on oral valacyclovir TID, topical difluprednate 0.05% BID, and topical ofloxacin 0.3% as antibiotic prophylaxis for a few days. Corneal scrapings did not reveal findings suggestive of SLK or microbial keratitis when evaluated.
One week later, the patient reported dramatically decreased vision with severe photophobia and difficulty opening the right eye. Visual acuity was 20/400 with the ProKera Slim™. At this point, the corneal scraping was 95% healed so the ProKera Slim™ was removed. No further stromal infiltrates were noted. All medications were discontinued except bacitracin-polymyxin B. On subsequent follow-up one week later, the patient was referred to another corneal specialist for consultation. At this visit, a repeat corneal Gram stain and a Papinicolau stain were positive for filamentous rods and Nocardia was suspected (Fig. 2). Therapy was initiated with trimethroprim-sulfamethaxazole (SEPTRA) 80 mg/mL in the right eye every 2 hours. One week later, cultural identification was confirmed for Nocardia asteroides and sensitivities showed resistance to amikacin. After three months of unabated progression of his signs and symptoms, the patient showed clinical improvement in three days. However given the prolonged course, he required an additional month of therapy. The patient healed with a subepithelial scar and neovascularization. At this point, SEPTRA was discontinued. The final visual acuity of the right eye was 20/30. Interestingly, the conjunctival biopsy was revisited and showed no signs of Nocardia.Fig. 2 Papinicolau stain magnified 400X of corneal scraping demonstrating branching filaments characteristic of Nocardia asteroides.
Fig. 2
3 Discussion
The usual presenting symptoms of Nocardia keratitis include pain, photophobia, blepharospasm, and lid swelling. Nocardia keratitis frequently runs a protracted benign course, but acute severe cases have been seen.9, 10, 11 Superficial granular infiltrates coalesce into a white plaque of variable size over time and result in corneal ulceration that is often superior in location. In addition to the classic finding of patchy wreath-like anterior stromal infiltrates, other presenting features include pseudodendritic epithelial defect, subepithelial infiltrate, persistent epithelial defect, and/or neovascularization into the cornea.2,10
Diagnosis of Nocardia keratitis is often delayed due to several factors. First, symptoms can have an insidious onset and patients may not initially seek medical care. The variable clinical presentations can mimic other forms of keratitis, such as mycotic or atypical mycobacterial infection.12 The clinician needs to have a high clinical suspicion as Nocardia grows slowly on culture. A prompt corneal scraping and culture should be performed with clinical suspicion. However, this may yield negative results as in this case. Nocardia corneal scrapings are positive for gram-positive, branching filaments that stain weakly acid-fast on Ziehl-Neelsen and black on Gomori methenamine silver.1
Nocardia keratitis can be misdiagnosed as superior limbic keratoconjunctivitis if the disease is located in the superior cornea, as in this case. SLK is characterized by inflammation of the superior bulbar and tarsal conjunctiva in addition to superior corneal vascularization that may appear as a pannus.13 SLK will often demonstrate punctate staining with fluorescein and/or rose Bengal. There can also be localized filamentary keratopathy in one-third of cases. Diagnosis involves obtaining a corneal scraping for Giemsa stain, which typically shows enhanced keratinization, poor nuclei, and hyalinized cytoplasm. Corneal scrapings from this case were not diagnostic for SLK. Treatment modalities include use of topical silver nitrate 1%, anti-inflammatory agents, and conjunctival resection.14,15
Another confounder for Nocardia may be HSV as in this case. At one point in the presentation, a dendritiform lesion was noted suggesting HSV epitheliopathy. A few weeks later, corneal neovascularization and haze developed which appeared clinically as an HSV interstitial keratitis. This clinical picture of apparent recurrence can be quite convincing for herpetic interstitial keratitis. However, the steroid treatment may have exacerbated the Nocardia infection.
Nocardia keratitis is most effectively treated with trimethoprim-sulfamethoxazole or amikacin; the latter is considered the drug of choice for all species of Nocardia.16 However, resistance to amikacin, as in this case, has been previously described.17 The intravenous preparation of trimethoprim-sulfamethoxazole can be used directly as eye drops, typically in a dosing of 16 mg/mL trimethoprim and 80 mg/mL sulfamethoxazole. Amikacin is typically used in the concentration of 2.5% and is prepared by adding 8 mL of artificial tears to 2 mL of the intravenous preparation of 125 mg/mL amikacin.6 Of note, systemic antibiotics do not add benefit to the clinical outcome of Nocardia keratitis. Steroids worsen the symptoms of Nocardia keratitis, potentially leading to complications such as corneal perforation, scleritis, and endophthalmitis. Thus, it is critically important to identify the causative organism early as routine steroid use for falsely suspected viral keratitis and SLK exacerbates the underlying condition.
Nocardia keratitis responds well to medical therapy. If treatment is started early in the course, the corneal ulcer tends to heal rapidly with mild peripheral vascularization. The infiltrate resolves with minimal scarring and forms a fine superficial nebular opacity. Visual acuity improves rapidly and the end result is a barely visible residual stromal haze.
4 Conclusions
Nocardia are a rare cause of infectious keratitis. Early diagnosis and treatment of Nocardia keratitis are difficult because of its infrequent occurrence and variable clinical manifestations. We describe a case of Nocardia keratitis that was initially misdiagnosed and treated with multiple antibacterial, antiviral, and anti-inflammatory agents. Due to its superior location, SLK was considered and prompted a superior conjunctival resection that disproved the diagnosis. Of note, the initial cultures were negative and it was only after a second corneal scraping that Nocardia was correctly identified by cytology and confirmed by cultures. Once diagnosed, this case of Nocardia keratitis responded effectively to treatment with trimethoprim-sulfamethoxazole (SEPTRA) in the setting of amikacin resistance.
Patient consent
The patient consented to publication of the case in writing and orally.
CRediT authorship contribution statement
Eileen L. Chang: Project administration, Writing - original draft, Writing - review & editing. Rachel L. Chu: Writing - original draft. John R. Wittpenn: Investigation, Writing - review & editing. Henry D. Perry: Supervision, Conceptualization, Investigation, Writing - review & editing.
Acknowledgments and Disclosures
No funding or grant support. There are no conflicts of interest or financial disclosures for any of the authors listed. All authors attest that they meet the current ICMJE criteria for Authorship. | Recovered | ReactionOutcome | CC BY-NC-ND | 33665477 | 19,283,167 | 2021-06 |
What was the outcome of reaction 'Corneal abrasion'? | Nocardia keratitis mimicking superior limbic keratoconjunctivitis and herpes simplex virus.
Nocardia keratitis is a rare type of infectious keratitis and may mimic other corneal diseases and lead to delay in diagnosis. This case illustrates how Nocardia often escapes accurate diagnosis due to its insidious onset, variable clinical manifestations, and unusual characteristics on cultures.
The patient presented with an epithelial defect and superior pannus and scarring, which was misdiagnosed as superior limbic keratoconjunctivitis (SLK) and herpes simplex virus (HSV) keratitis. Repeat corneal scraping cultures, smears, and conjunctival biopsy were necessary to elucidate the diagnosis. It can be effectively treated with the intravenous preparation of trimethoprim-sulfamethoxazole 80 mg/mL (brand name SEPTRA) used topically as eye drops.
The diagnosis of Nocardia keratitis relies on a high clinical suspicion and a prompt corneal scraping with culture. Due to its potential for rapid resolution with early therapy, it is important to isolate Nocardia early in its disease course.
Topical amikacin had been the standard of care for Nocardia keratitis for many years. However, recently there is increasing resistance of Nocardia to amikacin. SEPTRA offers an alternative therapy. Nocardia keratitis mimics other infectious and inflammatory etiologies so rapid diagnosis and treatment is critical in the prevention of long-term complications.
1 Introduction
Nocardia are a group of aerobic, gram-positive, and catalase-positive bacteria in the shape of long, thin, and branching filaments that stain weakly acid-fast on Ziehl-Neelsen1.
Nocardia asteroides is the most commonly reported species to cause Nocardia keratitis. It is classically described with an appearance of stromal infiltrates in a wreath-like pattern and may be associated with tiny epithelial calcifications often near the limbus adjacent to pannus-like areas of increased vascularity.2,3 Culture on blood agar may occasionally lead to a consideration of contamination due to the tendency for prominent areas of calcification on the agar.2
Nocardia keratitis is seen more frequently in young males, especially those who live in rural areas.3,4 As Nocardia is the most common bacteria found in soil, corneal trauma and contact with soil predispose those in rural areas to infection. Other risk factors for Nocardia keratitis include contact lens wear, ophthalmic surgery, and topical corticosteroids.5, 6, 7, 8
This unique case of Nocardia keratitis focuses attention on the variability of presentation and the possibility of a prolonged clinical course over months. The multiple misdiagnoses suffered by this patient highlight how this pathogen is elusive and often discovered late in the clinical course leading to permanent ocular sequelae.
2 Case presentation
A 41-year-old male contact lens user without history of corneal trauma or soil contact presented with a three-week history of pruritus, photophobia, and excessive tearing of the right eye. He was initially found to have a corneal abrasion and started on topical tobramycin 0.3% QID, which aggravated his symptoms. The patient was then referred to an ophthalmologist who added loteprednol 0.5% daily. The patient failed to respond to this therapy and was sent to a corneal specialist. On initial presentation, the patient's best-corrected visual acuity (BCVA) in the right eye was 20/20–3. Anterior segment exam was significant for bilateral blepharitis, right floppy eyelid, right trace perilimbal injection, 2+ superior palpebral conjunctival injection, and a new right corneal scar with irregular epithelium lacking definitive boundaries superiorly at 12 o'clock. Given the pattern of injection, recurrent discomfort, and subjective complaint of itchiness, superior limbic keratoconjunctivitis (SLK) was considered. The corneal specialist trialed a course of ofloxacin 0.3% and then increased loteprednol 0.5% to BID dosing.
On two-week follow-up, the patient displayed symptomatic improvement. However, the clinical exam demonstrated new dendritiform lesions developing at the peripheral edge of the corneal scar. Treatment for presumed herpes simplex keratitis (HSV) was initiated with a course of oral valacyclovir TID and topical ganciclovir 0.15% QID. Additionally, the patient was sent for corneal cultures to rule out fungal keratitis. Follow-up results were negative for fungi.
The patient returned in one month with worsening symptoms. At this time, his corneal scar displayed anterior stromal scarring with new overlying neovascularization and an advancing edge of irregular epithelium (Fig. 1). Keratic precipitates and anterior chamber inflammation were absent. At this point, the diagnosis of HSV interstitial keratitis was considered. The topical medications were switched from loteprednol to difluprednate 0.05% QID; the patient was restarted on valacyclovir TID.Fig. 1 Clinical photograph of the patient's right eye on initial presentation to second corneal specialist (3 months from first symptoms) demonstrating superior pannus, anterior stromal scarring, conjunctival injection, and floppy eyelids.
Fig. 1
After returning from vacation overseas, the patient followed up with the corneal specialist with minimal improvement. Given the failure to respond to herpetic treatment, a superior conjunctival resection for presumed SLK and corneal scrapings were taken from the right eye where the cornea was abnormal. A ProKera Slim™ amniotic membrane was placed over the defect and prophylactic ophthalmic antibiotics were started. The patient was maintained on oral valacyclovir TID, topical difluprednate 0.05% BID, and topical ofloxacin 0.3% as antibiotic prophylaxis for a few days. Corneal scrapings did not reveal findings suggestive of SLK or microbial keratitis when evaluated.
One week later, the patient reported dramatically decreased vision with severe photophobia and difficulty opening the right eye. Visual acuity was 20/400 with the ProKera Slim™. At this point, the corneal scraping was 95% healed so the ProKera Slim™ was removed. No further stromal infiltrates were noted. All medications were discontinued except bacitracin-polymyxin B. On subsequent follow-up one week later, the patient was referred to another corneal specialist for consultation. At this visit, a repeat corneal Gram stain and a Papinicolau stain were positive for filamentous rods and Nocardia was suspected (Fig. 2). Therapy was initiated with trimethroprim-sulfamethaxazole (SEPTRA) 80 mg/mL in the right eye every 2 hours. One week later, cultural identification was confirmed for Nocardia asteroides and sensitivities showed resistance to amikacin. After three months of unabated progression of his signs and symptoms, the patient showed clinical improvement in three days. However given the prolonged course, he required an additional month of therapy. The patient healed with a subepithelial scar and neovascularization. At this point, SEPTRA was discontinued. The final visual acuity of the right eye was 20/30. Interestingly, the conjunctival biopsy was revisited and showed no signs of Nocardia.Fig. 2 Papinicolau stain magnified 400X of corneal scraping demonstrating branching filaments characteristic of Nocardia asteroides.
Fig. 2
3 Discussion
The usual presenting symptoms of Nocardia keratitis include pain, photophobia, blepharospasm, and lid swelling. Nocardia keratitis frequently runs a protracted benign course, but acute severe cases have been seen.9, 10, 11 Superficial granular infiltrates coalesce into a white plaque of variable size over time and result in corneal ulceration that is often superior in location. In addition to the classic finding of patchy wreath-like anterior stromal infiltrates, other presenting features include pseudodendritic epithelial defect, subepithelial infiltrate, persistent epithelial defect, and/or neovascularization into the cornea.2,10
Diagnosis of Nocardia keratitis is often delayed due to several factors. First, symptoms can have an insidious onset and patients may not initially seek medical care. The variable clinical presentations can mimic other forms of keratitis, such as mycotic or atypical mycobacterial infection.12 The clinician needs to have a high clinical suspicion as Nocardia grows slowly on culture. A prompt corneal scraping and culture should be performed with clinical suspicion. However, this may yield negative results as in this case. Nocardia corneal scrapings are positive for gram-positive, branching filaments that stain weakly acid-fast on Ziehl-Neelsen and black on Gomori methenamine silver.1
Nocardia keratitis can be misdiagnosed as superior limbic keratoconjunctivitis if the disease is located in the superior cornea, as in this case. SLK is characterized by inflammation of the superior bulbar and tarsal conjunctiva in addition to superior corneal vascularization that may appear as a pannus.13 SLK will often demonstrate punctate staining with fluorescein and/or rose Bengal. There can also be localized filamentary keratopathy in one-third of cases. Diagnosis involves obtaining a corneal scraping for Giemsa stain, which typically shows enhanced keratinization, poor nuclei, and hyalinized cytoplasm. Corneal scrapings from this case were not diagnostic for SLK. Treatment modalities include use of topical silver nitrate 1%, anti-inflammatory agents, and conjunctival resection.14,15
Another confounder for Nocardia may be HSV as in this case. At one point in the presentation, a dendritiform lesion was noted suggesting HSV epitheliopathy. A few weeks later, corneal neovascularization and haze developed which appeared clinically as an HSV interstitial keratitis. This clinical picture of apparent recurrence can be quite convincing for herpetic interstitial keratitis. However, the steroid treatment may have exacerbated the Nocardia infection.
Nocardia keratitis is most effectively treated with trimethoprim-sulfamethoxazole or amikacin; the latter is considered the drug of choice for all species of Nocardia.16 However, resistance to amikacin, as in this case, has been previously described.17 The intravenous preparation of trimethoprim-sulfamethoxazole can be used directly as eye drops, typically in a dosing of 16 mg/mL trimethoprim and 80 mg/mL sulfamethoxazole. Amikacin is typically used in the concentration of 2.5% and is prepared by adding 8 mL of artificial tears to 2 mL of the intravenous preparation of 125 mg/mL amikacin.6 Of note, systemic antibiotics do not add benefit to the clinical outcome of Nocardia keratitis. Steroids worsen the symptoms of Nocardia keratitis, potentially leading to complications such as corneal perforation, scleritis, and endophthalmitis. Thus, it is critically important to identify the causative organism early as routine steroid use for falsely suspected viral keratitis and SLK exacerbates the underlying condition.
Nocardia keratitis responds well to medical therapy. If treatment is started early in the course, the corneal ulcer tends to heal rapidly with mild peripheral vascularization. The infiltrate resolves with minimal scarring and forms a fine superficial nebular opacity. Visual acuity improves rapidly and the end result is a barely visible residual stromal haze.
4 Conclusions
Nocardia are a rare cause of infectious keratitis. Early diagnosis and treatment of Nocardia keratitis are difficult because of its infrequent occurrence and variable clinical manifestations. We describe a case of Nocardia keratitis that was initially misdiagnosed and treated with multiple antibacterial, antiviral, and anti-inflammatory agents. Due to its superior location, SLK was considered and prompted a superior conjunctival resection that disproved the diagnosis. Of note, the initial cultures were negative and it was only after a second corneal scraping that Nocardia was correctly identified by cytology and confirmed by cultures. Once diagnosed, this case of Nocardia keratitis responded effectively to treatment with trimethoprim-sulfamethoxazole (SEPTRA) in the setting of amikacin resistance.
Patient consent
The patient consented to publication of the case in writing and orally.
CRediT authorship contribution statement
Eileen L. Chang: Project administration, Writing - original draft, Writing - review & editing. Rachel L. Chu: Writing - original draft. John R. Wittpenn: Investigation, Writing - review & editing. Henry D. Perry: Supervision, Conceptualization, Investigation, Writing - review & editing.
Acknowledgments and Disclosures
No funding or grant support. There are no conflicts of interest or financial disclosures for any of the authors listed. All authors attest that they meet the current ICMJE criteria for Authorship. | Recovered | ReactionOutcome | CC BY-NC-ND | 33665477 | 19,295,206 | 2021-06 |
What was the outcome of reaction 'Keratitis bacterial'? | Nocardia keratitis mimicking superior limbic keratoconjunctivitis and herpes simplex virus.
Nocardia keratitis is a rare type of infectious keratitis and may mimic other corneal diseases and lead to delay in diagnosis. This case illustrates how Nocardia often escapes accurate diagnosis due to its insidious onset, variable clinical manifestations, and unusual characteristics on cultures.
The patient presented with an epithelial defect and superior pannus and scarring, which was misdiagnosed as superior limbic keratoconjunctivitis (SLK) and herpes simplex virus (HSV) keratitis. Repeat corneal scraping cultures, smears, and conjunctival biopsy were necessary to elucidate the diagnosis. It can be effectively treated with the intravenous preparation of trimethoprim-sulfamethoxazole 80 mg/mL (brand name SEPTRA) used topically as eye drops.
The diagnosis of Nocardia keratitis relies on a high clinical suspicion and a prompt corneal scraping with culture. Due to its potential for rapid resolution with early therapy, it is important to isolate Nocardia early in its disease course.
Topical amikacin had been the standard of care for Nocardia keratitis for many years. However, recently there is increasing resistance of Nocardia to amikacin. SEPTRA offers an alternative therapy. Nocardia keratitis mimics other infectious and inflammatory etiologies so rapid diagnosis and treatment is critical in the prevention of long-term complications.
1 Introduction
Nocardia are a group of aerobic, gram-positive, and catalase-positive bacteria in the shape of long, thin, and branching filaments that stain weakly acid-fast on Ziehl-Neelsen1.
Nocardia asteroides is the most commonly reported species to cause Nocardia keratitis. It is classically described with an appearance of stromal infiltrates in a wreath-like pattern and may be associated with tiny epithelial calcifications often near the limbus adjacent to pannus-like areas of increased vascularity.2,3 Culture on blood agar may occasionally lead to a consideration of contamination due to the tendency for prominent areas of calcification on the agar.2
Nocardia keratitis is seen more frequently in young males, especially those who live in rural areas.3,4 As Nocardia is the most common bacteria found in soil, corneal trauma and contact with soil predispose those in rural areas to infection. Other risk factors for Nocardia keratitis include contact lens wear, ophthalmic surgery, and topical corticosteroids.5, 6, 7, 8
This unique case of Nocardia keratitis focuses attention on the variability of presentation and the possibility of a prolonged clinical course over months. The multiple misdiagnoses suffered by this patient highlight how this pathogen is elusive and often discovered late in the clinical course leading to permanent ocular sequelae.
2 Case presentation
A 41-year-old male contact lens user without history of corneal trauma or soil contact presented with a three-week history of pruritus, photophobia, and excessive tearing of the right eye. He was initially found to have a corneal abrasion and started on topical tobramycin 0.3% QID, which aggravated his symptoms. The patient was then referred to an ophthalmologist who added loteprednol 0.5% daily. The patient failed to respond to this therapy and was sent to a corneal specialist. On initial presentation, the patient's best-corrected visual acuity (BCVA) in the right eye was 20/20–3. Anterior segment exam was significant for bilateral blepharitis, right floppy eyelid, right trace perilimbal injection, 2+ superior palpebral conjunctival injection, and a new right corneal scar with irregular epithelium lacking definitive boundaries superiorly at 12 o'clock. Given the pattern of injection, recurrent discomfort, and subjective complaint of itchiness, superior limbic keratoconjunctivitis (SLK) was considered. The corneal specialist trialed a course of ofloxacin 0.3% and then increased loteprednol 0.5% to BID dosing.
On two-week follow-up, the patient displayed symptomatic improvement. However, the clinical exam demonstrated new dendritiform lesions developing at the peripheral edge of the corneal scar. Treatment for presumed herpes simplex keratitis (HSV) was initiated with a course of oral valacyclovir TID and topical ganciclovir 0.15% QID. Additionally, the patient was sent for corneal cultures to rule out fungal keratitis. Follow-up results were negative for fungi.
The patient returned in one month with worsening symptoms. At this time, his corneal scar displayed anterior stromal scarring with new overlying neovascularization and an advancing edge of irregular epithelium (Fig. 1). Keratic precipitates and anterior chamber inflammation were absent. At this point, the diagnosis of HSV interstitial keratitis was considered. The topical medications were switched from loteprednol to difluprednate 0.05% QID; the patient was restarted on valacyclovir TID.Fig. 1 Clinical photograph of the patient's right eye on initial presentation to second corneal specialist (3 months from first symptoms) demonstrating superior pannus, anterior stromal scarring, conjunctival injection, and floppy eyelids.
Fig. 1
After returning from vacation overseas, the patient followed up with the corneal specialist with minimal improvement. Given the failure to respond to herpetic treatment, a superior conjunctival resection for presumed SLK and corneal scrapings were taken from the right eye where the cornea was abnormal. A ProKera Slim™ amniotic membrane was placed over the defect and prophylactic ophthalmic antibiotics were started. The patient was maintained on oral valacyclovir TID, topical difluprednate 0.05% BID, and topical ofloxacin 0.3% as antibiotic prophylaxis for a few days. Corneal scrapings did not reveal findings suggestive of SLK or microbial keratitis when evaluated.
One week later, the patient reported dramatically decreased vision with severe photophobia and difficulty opening the right eye. Visual acuity was 20/400 with the ProKera Slim™. At this point, the corneal scraping was 95% healed so the ProKera Slim™ was removed. No further stromal infiltrates were noted. All medications were discontinued except bacitracin-polymyxin B. On subsequent follow-up one week later, the patient was referred to another corneal specialist for consultation. At this visit, a repeat corneal Gram stain and a Papinicolau stain were positive for filamentous rods and Nocardia was suspected (Fig. 2). Therapy was initiated with trimethroprim-sulfamethaxazole (SEPTRA) 80 mg/mL in the right eye every 2 hours. One week later, cultural identification was confirmed for Nocardia asteroides and sensitivities showed resistance to amikacin. After three months of unabated progression of his signs and symptoms, the patient showed clinical improvement in three days. However given the prolonged course, he required an additional month of therapy. The patient healed with a subepithelial scar and neovascularization. At this point, SEPTRA was discontinued. The final visual acuity of the right eye was 20/30. Interestingly, the conjunctival biopsy was revisited and showed no signs of Nocardia.Fig. 2 Papinicolau stain magnified 400X of corneal scraping demonstrating branching filaments characteristic of Nocardia asteroides.
Fig. 2
3 Discussion
The usual presenting symptoms of Nocardia keratitis include pain, photophobia, blepharospasm, and lid swelling. Nocardia keratitis frequently runs a protracted benign course, but acute severe cases have been seen.9, 10, 11 Superficial granular infiltrates coalesce into a white plaque of variable size over time and result in corneal ulceration that is often superior in location. In addition to the classic finding of patchy wreath-like anterior stromal infiltrates, other presenting features include pseudodendritic epithelial defect, subepithelial infiltrate, persistent epithelial defect, and/or neovascularization into the cornea.2,10
Diagnosis of Nocardia keratitis is often delayed due to several factors. First, symptoms can have an insidious onset and patients may not initially seek medical care. The variable clinical presentations can mimic other forms of keratitis, such as mycotic or atypical mycobacterial infection.12 The clinician needs to have a high clinical suspicion as Nocardia grows slowly on culture. A prompt corneal scraping and culture should be performed with clinical suspicion. However, this may yield negative results as in this case. Nocardia corneal scrapings are positive for gram-positive, branching filaments that stain weakly acid-fast on Ziehl-Neelsen and black on Gomori methenamine silver.1
Nocardia keratitis can be misdiagnosed as superior limbic keratoconjunctivitis if the disease is located in the superior cornea, as in this case. SLK is characterized by inflammation of the superior bulbar and tarsal conjunctiva in addition to superior corneal vascularization that may appear as a pannus.13 SLK will often demonstrate punctate staining with fluorescein and/or rose Bengal. There can also be localized filamentary keratopathy in one-third of cases. Diagnosis involves obtaining a corneal scraping for Giemsa stain, which typically shows enhanced keratinization, poor nuclei, and hyalinized cytoplasm. Corneal scrapings from this case were not diagnostic for SLK. Treatment modalities include use of topical silver nitrate 1%, anti-inflammatory agents, and conjunctival resection.14,15
Another confounder for Nocardia may be HSV as in this case. At one point in the presentation, a dendritiform lesion was noted suggesting HSV epitheliopathy. A few weeks later, corneal neovascularization and haze developed which appeared clinically as an HSV interstitial keratitis. This clinical picture of apparent recurrence can be quite convincing for herpetic interstitial keratitis. However, the steroid treatment may have exacerbated the Nocardia infection.
Nocardia keratitis is most effectively treated with trimethoprim-sulfamethoxazole or amikacin; the latter is considered the drug of choice for all species of Nocardia.16 However, resistance to amikacin, as in this case, has been previously described.17 The intravenous preparation of trimethoprim-sulfamethoxazole can be used directly as eye drops, typically in a dosing of 16 mg/mL trimethoprim and 80 mg/mL sulfamethoxazole. Amikacin is typically used in the concentration of 2.5% and is prepared by adding 8 mL of artificial tears to 2 mL of the intravenous preparation of 125 mg/mL amikacin.6 Of note, systemic antibiotics do not add benefit to the clinical outcome of Nocardia keratitis. Steroids worsen the symptoms of Nocardia keratitis, potentially leading to complications such as corneal perforation, scleritis, and endophthalmitis. Thus, it is critically important to identify the causative organism early as routine steroid use for falsely suspected viral keratitis and SLK exacerbates the underlying condition.
Nocardia keratitis responds well to medical therapy. If treatment is started early in the course, the corneal ulcer tends to heal rapidly with mild peripheral vascularization. The infiltrate resolves with minimal scarring and forms a fine superficial nebular opacity. Visual acuity improves rapidly and the end result is a barely visible residual stromal haze.
4 Conclusions
Nocardia are a rare cause of infectious keratitis. Early diagnosis and treatment of Nocardia keratitis are difficult because of its infrequent occurrence and variable clinical manifestations. We describe a case of Nocardia keratitis that was initially misdiagnosed and treated with multiple antibacterial, antiviral, and anti-inflammatory agents. Due to its superior location, SLK was considered and prompted a superior conjunctival resection that disproved the diagnosis. Of note, the initial cultures were negative and it was only after a second corneal scraping that Nocardia was correctly identified by cytology and confirmed by cultures. Once diagnosed, this case of Nocardia keratitis responded effectively to treatment with trimethoprim-sulfamethoxazole (SEPTRA) in the setting of amikacin resistance.
Patient consent
The patient consented to publication of the case in writing and orally.
CRediT authorship contribution statement
Eileen L. Chang: Project administration, Writing - original draft, Writing - review & editing. Rachel L. Chu: Writing - original draft. John R. Wittpenn: Investigation, Writing - review & editing. Henry D. Perry: Supervision, Conceptualization, Investigation, Writing - review & editing.
Acknowledgments and Disclosures
No funding or grant support. There are no conflicts of interest or financial disclosures for any of the authors listed. All authors attest that they meet the current ICMJE criteria for Authorship. | Recovered | ReactionOutcome | CC BY-NC-ND | 33665477 | 19,283,167 | 2021-06 |
What was the outcome of reaction 'Nocardiosis'? | Nocardia keratitis mimicking superior limbic keratoconjunctivitis and herpes simplex virus.
Nocardia keratitis is a rare type of infectious keratitis and may mimic other corneal diseases and lead to delay in diagnosis. This case illustrates how Nocardia often escapes accurate diagnosis due to its insidious onset, variable clinical manifestations, and unusual characteristics on cultures.
The patient presented with an epithelial defect and superior pannus and scarring, which was misdiagnosed as superior limbic keratoconjunctivitis (SLK) and herpes simplex virus (HSV) keratitis. Repeat corneal scraping cultures, smears, and conjunctival biopsy were necessary to elucidate the diagnosis. It can be effectively treated with the intravenous preparation of trimethoprim-sulfamethoxazole 80 mg/mL (brand name SEPTRA) used topically as eye drops.
The diagnosis of Nocardia keratitis relies on a high clinical suspicion and a prompt corneal scraping with culture. Due to its potential for rapid resolution with early therapy, it is important to isolate Nocardia early in its disease course.
Topical amikacin had been the standard of care for Nocardia keratitis for many years. However, recently there is increasing resistance of Nocardia to amikacin. SEPTRA offers an alternative therapy. Nocardia keratitis mimics other infectious and inflammatory etiologies so rapid diagnosis and treatment is critical in the prevention of long-term complications.
1 Introduction
Nocardia are a group of aerobic, gram-positive, and catalase-positive bacteria in the shape of long, thin, and branching filaments that stain weakly acid-fast on Ziehl-Neelsen1.
Nocardia asteroides is the most commonly reported species to cause Nocardia keratitis. It is classically described with an appearance of stromal infiltrates in a wreath-like pattern and may be associated with tiny epithelial calcifications often near the limbus adjacent to pannus-like areas of increased vascularity.2,3 Culture on blood agar may occasionally lead to a consideration of contamination due to the tendency for prominent areas of calcification on the agar.2
Nocardia keratitis is seen more frequently in young males, especially those who live in rural areas.3,4 As Nocardia is the most common bacteria found in soil, corneal trauma and contact with soil predispose those in rural areas to infection. Other risk factors for Nocardia keratitis include contact lens wear, ophthalmic surgery, and topical corticosteroids.5, 6, 7, 8
This unique case of Nocardia keratitis focuses attention on the variability of presentation and the possibility of a prolonged clinical course over months. The multiple misdiagnoses suffered by this patient highlight how this pathogen is elusive and often discovered late in the clinical course leading to permanent ocular sequelae.
2 Case presentation
A 41-year-old male contact lens user without history of corneal trauma or soil contact presented with a three-week history of pruritus, photophobia, and excessive tearing of the right eye. He was initially found to have a corneal abrasion and started on topical tobramycin 0.3% QID, which aggravated his symptoms. The patient was then referred to an ophthalmologist who added loteprednol 0.5% daily. The patient failed to respond to this therapy and was sent to a corneal specialist. On initial presentation, the patient's best-corrected visual acuity (BCVA) in the right eye was 20/20–3. Anterior segment exam was significant for bilateral blepharitis, right floppy eyelid, right trace perilimbal injection, 2+ superior palpebral conjunctival injection, and a new right corneal scar with irregular epithelium lacking definitive boundaries superiorly at 12 o'clock. Given the pattern of injection, recurrent discomfort, and subjective complaint of itchiness, superior limbic keratoconjunctivitis (SLK) was considered. The corneal specialist trialed a course of ofloxacin 0.3% and then increased loteprednol 0.5% to BID dosing.
On two-week follow-up, the patient displayed symptomatic improvement. However, the clinical exam demonstrated new dendritiform lesions developing at the peripheral edge of the corneal scar. Treatment for presumed herpes simplex keratitis (HSV) was initiated with a course of oral valacyclovir TID and topical ganciclovir 0.15% QID. Additionally, the patient was sent for corneal cultures to rule out fungal keratitis. Follow-up results were negative for fungi.
The patient returned in one month with worsening symptoms. At this time, his corneal scar displayed anterior stromal scarring with new overlying neovascularization and an advancing edge of irregular epithelium (Fig. 1). Keratic precipitates and anterior chamber inflammation were absent. At this point, the diagnosis of HSV interstitial keratitis was considered. The topical medications were switched from loteprednol to difluprednate 0.05% QID; the patient was restarted on valacyclovir TID.Fig. 1 Clinical photograph of the patient's right eye on initial presentation to second corneal specialist (3 months from first symptoms) demonstrating superior pannus, anterior stromal scarring, conjunctival injection, and floppy eyelids.
Fig. 1
After returning from vacation overseas, the patient followed up with the corneal specialist with minimal improvement. Given the failure to respond to herpetic treatment, a superior conjunctival resection for presumed SLK and corneal scrapings were taken from the right eye where the cornea was abnormal. A ProKera Slim™ amniotic membrane was placed over the defect and prophylactic ophthalmic antibiotics were started. The patient was maintained on oral valacyclovir TID, topical difluprednate 0.05% BID, and topical ofloxacin 0.3% as antibiotic prophylaxis for a few days. Corneal scrapings did not reveal findings suggestive of SLK or microbial keratitis when evaluated.
One week later, the patient reported dramatically decreased vision with severe photophobia and difficulty opening the right eye. Visual acuity was 20/400 with the ProKera Slim™. At this point, the corneal scraping was 95% healed so the ProKera Slim™ was removed. No further stromal infiltrates were noted. All medications were discontinued except bacitracin-polymyxin B. On subsequent follow-up one week later, the patient was referred to another corneal specialist for consultation. At this visit, a repeat corneal Gram stain and a Papinicolau stain were positive for filamentous rods and Nocardia was suspected (Fig. 2). Therapy was initiated with trimethroprim-sulfamethaxazole (SEPTRA) 80 mg/mL in the right eye every 2 hours. One week later, cultural identification was confirmed for Nocardia asteroides and sensitivities showed resistance to amikacin. After three months of unabated progression of his signs and symptoms, the patient showed clinical improvement in three days. However given the prolonged course, he required an additional month of therapy. The patient healed with a subepithelial scar and neovascularization. At this point, SEPTRA was discontinued. The final visual acuity of the right eye was 20/30. Interestingly, the conjunctival biopsy was revisited and showed no signs of Nocardia.Fig. 2 Papinicolau stain magnified 400X of corneal scraping demonstrating branching filaments characteristic of Nocardia asteroides.
Fig. 2
3 Discussion
The usual presenting symptoms of Nocardia keratitis include pain, photophobia, blepharospasm, and lid swelling. Nocardia keratitis frequently runs a protracted benign course, but acute severe cases have been seen.9, 10, 11 Superficial granular infiltrates coalesce into a white plaque of variable size over time and result in corneal ulceration that is often superior in location. In addition to the classic finding of patchy wreath-like anterior stromal infiltrates, other presenting features include pseudodendritic epithelial defect, subepithelial infiltrate, persistent epithelial defect, and/or neovascularization into the cornea.2,10
Diagnosis of Nocardia keratitis is often delayed due to several factors. First, symptoms can have an insidious onset and patients may not initially seek medical care. The variable clinical presentations can mimic other forms of keratitis, such as mycotic or atypical mycobacterial infection.12 The clinician needs to have a high clinical suspicion as Nocardia grows slowly on culture. A prompt corneal scraping and culture should be performed with clinical suspicion. However, this may yield negative results as in this case. Nocardia corneal scrapings are positive for gram-positive, branching filaments that stain weakly acid-fast on Ziehl-Neelsen and black on Gomori methenamine silver.1
Nocardia keratitis can be misdiagnosed as superior limbic keratoconjunctivitis if the disease is located in the superior cornea, as in this case. SLK is characterized by inflammation of the superior bulbar and tarsal conjunctiva in addition to superior corneal vascularization that may appear as a pannus.13 SLK will often demonstrate punctate staining with fluorescein and/or rose Bengal. There can also be localized filamentary keratopathy in one-third of cases. Diagnosis involves obtaining a corneal scraping for Giemsa stain, which typically shows enhanced keratinization, poor nuclei, and hyalinized cytoplasm. Corneal scrapings from this case were not diagnostic for SLK. Treatment modalities include use of topical silver nitrate 1%, anti-inflammatory agents, and conjunctival resection.14,15
Another confounder for Nocardia may be HSV as in this case. At one point in the presentation, a dendritiform lesion was noted suggesting HSV epitheliopathy. A few weeks later, corneal neovascularization and haze developed which appeared clinically as an HSV interstitial keratitis. This clinical picture of apparent recurrence can be quite convincing for herpetic interstitial keratitis. However, the steroid treatment may have exacerbated the Nocardia infection.
Nocardia keratitis is most effectively treated with trimethoprim-sulfamethoxazole or amikacin; the latter is considered the drug of choice for all species of Nocardia.16 However, resistance to amikacin, as in this case, has been previously described.17 The intravenous preparation of trimethoprim-sulfamethoxazole can be used directly as eye drops, typically in a dosing of 16 mg/mL trimethoprim and 80 mg/mL sulfamethoxazole. Amikacin is typically used in the concentration of 2.5% and is prepared by adding 8 mL of artificial tears to 2 mL of the intravenous preparation of 125 mg/mL amikacin.6 Of note, systemic antibiotics do not add benefit to the clinical outcome of Nocardia keratitis. Steroids worsen the symptoms of Nocardia keratitis, potentially leading to complications such as corneal perforation, scleritis, and endophthalmitis. Thus, it is critically important to identify the causative organism early as routine steroid use for falsely suspected viral keratitis and SLK exacerbates the underlying condition.
Nocardia keratitis responds well to medical therapy. If treatment is started early in the course, the corneal ulcer tends to heal rapidly with mild peripheral vascularization. The infiltrate resolves with minimal scarring and forms a fine superficial nebular opacity. Visual acuity improves rapidly and the end result is a barely visible residual stromal haze.
4 Conclusions
Nocardia are a rare cause of infectious keratitis. Early diagnosis and treatment of Nocardia keratitis are difficult because of its infrequent occurrence and variable clinical manifestations. We describe a case of Nocardia keratitis that was initially misdiagnosed and treated with multiple antibacterial, antiviral, and anti-inflammatory agents. Due to its superior location, SLK was considered and prompted a superior conjunctival resection that disproved the diagnosis. Of note, the initial cultures were negative and it was only after a second corneal scraping that Nocardia was correctly identified by cytology and confirmed by cultures. Once diagnosed, this case of Nocardia keratitis responded effectively to treatment with trimethoprim-sulfamethoxazole (SEPTRA) in the setting of amikacin resistance.
Patient consent
The patient consented to publication of the case in writing and orally.
CRediT authorship contribution statement
Eileen L. Chang: Project administration, Writing - original draft, Writing - review & editing. Rachel L. Chu: Writing - original draft. John R. Wittpenn: Investigation, Writing - review & editing. Henry D. Perry: Supervision, Conceptualization, Investigation, Writing - review & editing.
Acknowledgments and Disclosures
No funding or grant support. There are no conflicts of interest or financial disclosures for any of the authors listed. All authors attest that they meet the current ICMJE criteria for Authorship. | Recovered | ReactionOutcome | CC BY-NC-ND | 33665477 | 19,283,167 | 2021-06 |
What was the outcome of reaction 'Visual impairment'? | Nocardia keratitis mimicking superior limbic keratoconjunctivitis and herpes simplex virus.
Nocardia keratitis is a rare type of infectious keratitis and may mimic other corneal diseases and lead to delay in diagnosis. This case illustrates how Nocardia often escapes accurate diagnosis due to its insidious onset, variable clinical manifestations, and unusual characteristics on cultures.
The patient presented with an epithelial defect and superior pannus and scarring, which was misdiagnosed as superior limbic keratoconjunctivitis (SLK) and herpes simplex virus (HSV) keratitis. Repeat corneal scraping cultures, smears, and conjunctival biopsy were necessary to elucidate the diagnosis. It can be effectively treated with the intravenous preparation of trimethoprim-sulfamethoxazole 80 mg/mL (brand name SEPTRA) used topically as eye drops.
The diagnosis of Nocardia keratitis relies on a high clinical suspicion and a prompt corneal scraping with culture. Due to its potential for rapid resolution with early therapy, it is important to isolate Nocardia early in its disease course.
Topical amikacin had been the standard of care for Nocardia keratitis for many years. However, recently there is increasing resistance of Nocardia to amikacin. SEPTRA offers an alternative therapy. Nocardia keratitis mimics other infectious and inflammatory etiologies so rapid diagnosis and treatment is critical in the prevention of long-term complications.
1 Introduction
Nocardia are a group of aerobic, gram-positive, and catalase-positive bacteria in the shape of long, thin, and branching filaments that stain weakly acid-fast on Ziehl-Neelsen1.
Nocardia asteroides is the most commonly reported species to cause Nocardia keratitis. It is classically described with an appearance of stromal infiltrates in a wreath-like pattern and may be associated with tiny epithelial calcifications often near the limbus adjacent to pannus-like areas of increased vascularity.2,3 Culture on blood agar may occasionally lead to a consideration of contamination due to the tendency for prominent areas of calcification on the agar.2
Nocardia keratitis is seen more frequently in young males, especially those who live in rural areas.3,4 As Nocardia is the most common bacteria found in soil, corneal trauma and contact with soil predispose those in rural areas to infection. Other risk factors for Nocardia keratitis include contact lens wear, ophthalmic surgery, and topical corticosteroids.5, 6, 7, 8
This unique case of Nocardia keratitis focuses attention on the variability of presentation and the possibility of a prolonged clinical course over months. The multiple misdiagnoses suffered by this patient highlight how this pathogen is elusive and often discovered late in the clinical course leading to permanent ocular sequelae.
2 Case presentation
A 41-year-old male contact lens user without history of corneal trauma or soil contact presented with a three-week history of pruritus, photophobia, and excessive tearing of the right eye. He was initially found to have a corneal abrasion and started on topical tobramycin 0.3% QID, which aggravated his symptoms. The patient was then referred to an ophthalmologist who added loteprednol 0.5% daily. The patient failed to respond to this therapy and was sent to a corneal specialist. On initial presentation, the patient's best-corrected visual acuity (BCVA) in the right eye was 20/20–3. Anterior segment exam was significant for bilateral blepharitis, right floppy eyelid, right trace perilimbal injection, 2+ superior palpebral conjunctival injection, and a new right corneal scar with irregular epithelium lacking definitive boundaries superiorly at 12 o'clock. Given the pattern of injection, recurrent discomfort, and subjective complaint of itchiness, superior limbic keratoconjunctivitis (SLK) was considered. The corneal specialist trialed a course of ofloxacin 0.3% and then increased loteprednol 0.5% to BID dosing.
On two-week follow-up, the patient displayed symptomatic improvement. However, the clinical exam demonstrated new dendritiform lesions developing at the peripheral edge of the corneal scar. Treatment for presumed herpes simplex keratitis (HSV) was initiated with a course of oral valacyclovir TID and topical ganciclovir 0.15% QID. Additionally, the patient was sent for corneal cultures to rule out fungal keratitis. Follow-up results were negative for fungi.
The patient returned in one month with worsening symptoms. At this time, his corneal scar displayed anterior stromal scarring with new overlying neovascularization and an advancing edge of irregular epithelium (Fig. 1). Keratic precipitates and anterior chamber inflammation were absent. At this point, the diagnosis of HSV interstitial keratitis was considered. The topical medications were switched from loteprednol to difluprednate 0.05% QID; the patient was restarted on valacyclovir TID.Fig. 1 Clinical photograph of the patient's right eye on initial presentation to second corneal specialist (3 months from first symptoms) demonstrating superior pannus, anterior stromal scarring, conjunctival injection, and floppy eyelids.
Fig. 1
After returning from vacation overseas, the patient followed up with the corneal specialist with minimal improvement. Given the failure to respond to herpetic treatment, a superior conjunctival resection for presumed SLK and corneal scrapings were taken from the right eye where the cornea was abnormal. A ProKera Slim™ amniotic membrane was placed over the defect and prophylactic ophthalmic antibiotics were started. The patient was maintained on oral valacyclovir TID, topical difluprednate 0.05% BID, and topical ofloxacin 0.3% as antibiotic prophylaxis for a few days. Corneal scrapings did not reveal findings suggestive of SLK or microbial keratitis when evaluated.
One week later, the patient reported dramatically decreased vision with severe photophobia and difficulty opening the right eye. Visual acuity was 20/400 with the ProKera Slim™. At this point, the corneal scraping was 95% healed so the ProKera Slim™ was removed. No further stromal infiltrates were noted. All medications were discontinued except bacitracin-polymyxin B. On subsequent follow-up one week later, the patient was referred to another corneal specialist for consultation. At this visit, a repeat corneal Gram stain and a Papinicolau stain were positive for filamentous rods and Nocardia was suspected (Fig. 2). Therapy was initiated with trimethroprim-sulfamethaxazole (SEPTRA) 80 mg/mL in the right eye every 2 hours. One week later, cultural identification was confirmed for Nocardia asteroides and sensitivities showed resistance to amikacin. After three months of unabated progression of his signs and symptoms, the patient showed clinical improvement in three days. However given the prolonged course, he required an additional month of therapy. The patient healed with a subepithelial scar and neovascularization. At this point, SEPTRA was discontinued. The final visual acuity of the right eye was 20/30. Interestingly, the conjunctival biopsy was revisited and showed no signs of Nocardia.Fig. 2 Papinicolau stain magnified 400X of corneal scraping demonstrating branching filaments characteristic of Nocardia asteroides.
Fig. 2
3 Discussion
The usual presenting symptoms of Nocardia keratitis include pain, photophobia, blepharospasm, and lid swelling. Nocardia keratitis frequently runs a protracted benign course, but acute severe cases have been seen.9, 10, 11 Superficial granular infiltrates coalesce into a white plaque of variable size over time and result in corneal ulceration that is often superior in location. In addition to the classic finding of patchy wreath-like anterior stromal infiltrates, other presenting features include pseudodendritic epithelial defect, subepithelial infiltrate, persistent epithelial defect, and/or neovascularization into the cornea.2,10
Diagnosis of Nocardia keratitis is often delayed due to several factors. First, symptoms can have an insidious onset and patients may not initially seek medical care. The variable clinical presentations can mimic other forms of keratitis, such as mycotic or atypical mycobacterial infection.12 The clinician needs to have a high clinical suspicion as Nocardia grows slowly on culture. A prompt corneal scraping and culture should be performed with clinical suspicion. However, this may yield negative results as in this case. Nocardia corneal scrapings are positive for gram-positive, branching filaments that stain weakly acid-fast on Ziehl-Neelsen and black on Gomori methenamine silver.1
Nocardia keratitis can be misdiagnosed as superior limbic keratoconjunctivitis if the disease is located in the superior cornea, as in this case. SLK is characterized by inflammation of the superior bulbar and tarsal conjunctiva in addition to superior corneal vascularization that may appear as a pannus.13 SLK will often demonstrate punctate staining with fluorescein and/or rose Bengal. There can also be localized filamentary keratopathy in one-third of cases. Diagnosis involves obtaining a corneal scraping for Giemsa stain, which typically shows enhanced keratinization, poor nuclei, and hyalinized cytoplasm. Corneal scrapings from this case were not diagnostic for SLK. Treatment modalities include use of topical silver nitrate 1%, anti-inflammatory agents, and conjunctival resection.14,15
Another confounder for Nocardia may be HSV as in this case. At one point in the presentation, a dendritiform lesion was noted suggesting HSV epitheliopathy. A few weeks later, corneal neovascularization and haze developed which appeared clinically as an HSV interstitial keratitis. This clinical picture of apparent recurrence can be quite convincing for herpetic interstitial keratitis. However, the steroid treatment may have exacerbated the Nocardia infection.
Nocardia keratitis is most effectively treated with trimethoprim-sulfamethoxazole or amikacin; the latter is considered the drug of choice for all species of Nocardia.16 However, resistance to amikacin, as in this case, has been previously described.17 The intravenous preparation of trimethoprim-sulfamethoxazole can be used directly as eye drops, typically in a dosing of 16 mg/mL trimethoprim and 80 mg/mL sulfamethoxazole. Amikacin is typically used in the concentration of 2.5% and is prepared by adding 8 mL of artificial tears to 2 mL of the intravenous preparation of 125 mg/mL amikacin.6 Of note, systemic antibiotics do not add benefit to the clinical outcome of Nocardia keratitis. Steroids worsen the symptoms of Nocardia keratitis, potentially leading to complications such as corneal perforation, scleritis, and endophthalmitis. Thus, it is critically important to identify the causative organism early as routine steroid use for falsely suspected viral keratitis and SLK exacerbates the underlying condition.
Nocardia keratitis responds well to medical therapy. If treatment is started early in the course, the corneal ulcer tends to heal rapidly with mild peripheral vascularization. The infiltrate resolves with minimal scarring and forms a fine superficial nebular opacity. Visual acuity improves rapidly and the end result is a barely visible residual stromal haze.
4 Conclusions
Nocardia are a rare cause of infectious keratitis. Early diagnosis and treatment of Nocardia keratitis are difficult because of its infrequent occurrence and variable clinical manifestations. We describe a case of Nocardia keratitis that was initially misdiagnosed and treated with multiple antibacterial, antiviral, and anti-inflammatory agents. Due to its superior location, SLK was considered and prompted a superior conjunctival resection that disproved the diagnosis. Of note, the initial cultures were negative and it was only after a second corneal scraping that Nocardia was correctly identified by cytology and confirmed by cultures. Once diagnosed, this case of Nocardia keratitis responded effectively to treatment with trimethoprim-sulfamethoxazole (SEPTRA) in the setting of amikacin resistance.
Patient consent
The patient consented to publication of the case in writing and orally.
CRediT authorship contribution statement
Eileen L. Chang: Project administration, Writing - original draft, Writing - review & editing. Rachel L. Chu: Writing - original draft. John R. Wittpenn: Investigation, Writing - review & editing. Henry D. Perry: Supervision, Conceptualization, Investigation, Writing - review & editing.
Acknowledgments and Disclosures
No funding or grant support. There are no conflicts of interest or financial disclosures for any of the authors listed. All authors attest that they meet the current ICMJE criteria for Authorship. | Recovering | ReactionOutcome | CC BY-NC-ND | 33665477 | 19,356,229 | 2021-06 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Decreased appetite'. | Palliative Radiation Therapy for Metastatic, Persistent, or Recurrent Epithelial Ovarian Cancer: Efficacy in the Era of Modern Technology and Targeted Agents.
Metastatic, persistent, or recurrent epithelial ovarian cancer (MPR-EOC) remains a significant threat to patient mortality despite advances in novel targeted agents. Radiation therapy (RT) is often used as a palliative option. We report outcomes of a large series of MPR-EOC patients treated with modern palliative RT (PRT) in an era of novel systemic therapies.
A retrospective review was conducted of women treated with PRT for MPR-EOC between 2007 and 2019 at an academic institution. Clinical response rates were recorded at <1 month, 1 to 3 months, and >3 months. Radiographic responses were categorized by RECIST 1.1 criteria. Overall response rate (ORR) was the sum of complete and partial response. Linear regression analyses of baseline characteristics were conducted for statistical testing.
Eighty-six patients with PMR-OC received 120 courses of palliative RT. Median follow-up was 8.6 months. Median age was 61 (range, 22-82). Thirty-six percent of women received central nervous system (CNS)-directed RT. In addition, 43% received targeted therapies before RT. Clinical ORR within 1 month and at last follow-up for non-CNS lesions was 79% and 61% (69% and 88% for CNS lesions, respectively). High-grade serous lesions were more likely to have clinical response (P = .04). Biologically effective doses (BED) >39 Gy were associated with improved clinical response in CNS lesions (P = .049). Bony sites were associated with worse clinical (P = .004) response in non-CNS lesions compared with soft tissue or nodal sites. Acute or late grade 3+ toxicities with bevacizumab were low (8.7%/4.3%).
PRT offers excellent rates of response for symptomatic patients with MPR-EOC within 1 month of treatment, with durable responses beyond 3 months. High-grade serous lesions were associated with improved response in all patients. Higher BED and soft tissue or nodal sites were associated with improved response in CNS and non-CNS patients, respectively. Acute or late toxicities with bevacizumab and PRT were low. Prospective investigation is warranted to determine the optimal PRT regimen.
Introduction
Ovarian cancer (OC) is a highly aggressive gynecologic malignancy, with the majority of patients presenting with advanced disease at diagnosis. The general treatment paradigm for advanced OC is maximal cytoreductive surgery with platinum-based chemotherapy.1 Recent literature has also reported a progression-free survival benefit with maintenance inhibition of poly (adenosine diphosphate-ribose) polymerase (PARP) in women with partial or complete response to platinum-based regimens.2,3
Whole abdominal radiation therapy was historically indicated as adjuvant therapy to address microscopic residual disease.4 However, due to its considerable toxicity and the development of platinum-based chemotherapy, whole abdominal radiation therapy is no longer included in primary OC treatment paradigms.1
Despite advances in cytoreductive strategies and front-line systemic therapy, >70% of women relapse within 3 years of diagnosis.5 As such, many patients with OC benefit from palliative care referrals to assist with symptom management, goals of care discussions, and complex medical decision making at the end of life.
There is a growing body of evidence to support the incorporation of palliative services in cancer care. In 2010, a seminal randomized trial6 reported early palliative care among patients with metastatic non-small cell lung cancer significantly improved quality of life, led to less aggressive care at the end of life, and resulted in longer overall survival. Furthermore, both the American Society of Clinical Oncology and the Society of Gynecologic Oncology have published official practice guidelines recommending the routine and early integration of palliative services.7,8
Radiation therapy (RT) is often used as an effective therapeutic option in the palliation of patients with metastatic, persistent, or recurrent epithelial OC (MPR-EOC) as a means for symptomatic relief and local control. This includes oligometastatic disease or symptomatic disease causing pain, bowel or ureteral obstruction, or bleeding. Despite their rarity in OC (2% incidence9), brain metastases can also cause significant morbidity and can be treated with palliative RT to reduce the risk of progression and neurocognitive deficits.10,11
As patient survival improves with modern systemic agents, there is a growing need to understand the efficacy of palliative RT regimens for MPR-EOC in the same era. Although radiation therapy has traditionally been delivered for symptomatic control in MPR-EOC, the recognition of the biologically distinct (and potentially curable) oligometastatic state12,13 is expanding the scope of RT indications. Data from phase 2 trials in other malignancies evaluating the effect of locally directed therapy to oligometastatic lesions has demonstrated improvements in overall survival.14,15
We therefore conducted, a large contemporary retrospective analysis of palliative RT in MPR-EOC. This patient cohort is highly relevant to modern practice given the number of patients who received novel systemic agents, the prominent usage of advanced RT technology, and the representation of patients with BMs from OC (an area with limited data but increasing prevalence in practice). The analysis will report the outcomes and durability of palliative RT in MPR-EOC and delineate factors predictive of response in the modern era.
Methods and Materials
We conducted a retrospective chart review of women treated with palliative radiation therapy for metastatic ovarian cancer from 2007 through 2019 at [University of Pennsylvania] and affiliate sites. Institutional review board approval was obtained before conducting this review. Patients were included in this analysis if they were treated for palliative intent, including treatment of oligometastatic disease. All patients had MPR-EOC ovarian cancer and received anywhere from one to 5 courses of radiation treatment.
Given the poor prognosis of patients with metastatic ovarian cancer, clinical and radiographic response rates were categorized in intervals of <1 month, 1 to 3 months, and >3 months after the end of radiation treatment to indicate acute and durable responses. Clinical responses were categorized as complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD). Pain scores were classified using the Bone Metastases Consensus Working Party guidelines16 (indeterminate responses, which are neither PR nor PD per BMWCP guidelines, were classified as SD to maintain consistency with other clinical response categorizations). Radiographic responses were categorized as CR, PR, SD, or PD based on the RECIST 1.1 criteria.17 Overall response rate (ORR) was the sum of CR and PR in a given patient. Given the large subset of patients with brain metastases (BMs), courses were stratified by central nervous system (CNS) and non-CNS anatomic locations. Acute (during RT and within 3 months of completion) and late (>3 months after completion of RT) toxicities were recorded with concurrent and prior bevacizumab using Common Terminology Criteria for Adverse Events version 5.018 classification.
Rates of response (CR or PR at any point) were compared with demographic and treatment characteristics. χ2 (n ≥ 20) or Fisher exact (n < 20) tests were used for such comparison with variables for race, histology, platinum chemotherapy, or targeted therapy before RT, RT technology, RT location, and biologically effective dose (BED) >39. Binary logistic regression analyses were used for comparison with continuous variables (age and BED). Covariates with P < .1 were included in multiple logistic regression modeling to assess for independent effect. Additionally, χ2 analyses were used to compare rates of radiographic response between patients treated for clinical symptoms and asymptomatic progression. Statistical analysis was conducted using IBM SPSS Statistics, version 26 (IBM Corporation, Armonk, NY).
Results
We identified 86 patients with PMR-OC that received 120 combined courses of palliative radiation treatment. Median follow-up was 8.6 months (range, 0.5-119 months). Excluding 10 patients (15 courses) with no evaluable clinical or radiographic follow-up, 51 patients (58 courses) were treated to non-CNS locations and 18 patients (25 courses) were treated to CNS locations; 7 patients (22 courses) received palliative RT to both CNS (13 courses) and non-CNS (9 courses) locations.
Table 1 describes baseline patient characteristics and details related to patient treatments. The median age of patients in this cohort was 61, with a range of 22 to 82. Patients were most commonly white (83%) and black (8%). Tumor histologies were primarily high-grade serous (HGS, 59%), although adenocarcinoma (undifferentiated or unspecified), low-grade serous, clear cell, endometrioid, and carcinosarcoma were also observed.Table 1 Patient characteristics and treatment details
No. of courses 105
No. of patients 76
Median age 61
Ethnicity
White 82.9% (63/76)
Black 9.2% (7/76)
Asian 3.9% (3/76)
Hispanic 2.6% (2/76)
Unknown 1.3% (1/76)
Histology
High-grade serous 59.2% (45/76)
Adenocarcinoma, other 13.2% (10/76)
Low grade serous 9.2% (7/76)
Clear cell 5.3% (4/76)
Other 7.9% (6/76)
Endometrioid 3.9% (3/76)
Carcinosarcoma 1.3% (1/76)
Anatomic site
Soft tissue/organ 35.2% (37/105)
Lymph node 21.0% (22/105)
Bone 11.4% (12/105)
CNS 36.2% (38/105)
Indications
Clinical symptoms 59.0% (62/105)
Progressive/metastatic 33.3% (35/105)
Postoperative 7.6% (8/105)
Systemic therapy before RT
Platinum chemotherapy 27.6% (29/105)
Nonplatinum chemotherapy 61.9% (65/105)
Targeted therapy 42.9% (45/105)
None/other 1.0% (1/105)
Technique
2D/3D CRT 53.3% (56/105)
SRS 21.9% (23/105)
VMAT/IMRT 16.2% (17/105)
SBRT 4.8% (5/105)
Proton 3.8% (4/105)
Non-SRS dose 14-63 Gy in 4-35 fractions
SBRT dose 24-50 Gy in 3-5 fractions
SRS dose 15-25 Gy in 1-5 fractions
Abbreviations: 2D = 2-dimensional; 3D CRT = 3-dimensional conformal radiation therapy; CNS = central nervous system; IMRT = intensity modulated radiation therapy; RT = radiation therapy; SBRT = stereotactic body radiation therapy; SRS = stereotactic radiosurgery; VMAT = volumetric modulated arc therapy.
Non-CNS treatment locations included tumors in soft tissue or organs (35%), lymph nodes (21%), and bone (11%); 4 patients were treated simultaneously to adjacent soft tissue and lymph nodes. Treatment for CNS metastases comprised the remaining 36% of patients.
Most patients were treated for clinical symptoms (59%). Pain and bleeding were the most common clinical indications. Others included neurologic deficits, spinal cord compression, airway compression, and bowel obstruction. A large cohort of patients were treated for asymptomatic progressive or metastatic disease (33%) with a small cohort treated adjuvantly after surgery (eg, metastasectomy or palliative debulking; 7.6%).
Almost all patients (90%) received chemotherapy immediately before radiation therapy. The most common systemic therapy regimens were platinum-based (ie, carboplatin) followed by taxanes and doxorubicin. Many patients (43%) also received treatment with targeted therapy agents before radiation treatment. Bevacizumab was the most commonly used targeted therapy agent (20%), although patients also received PARP inhibitors (9%) and immune checkpoint inhibitors (5%).
A wide range of palliative radiation regimens were delivered across several modalities. Nonstereotactic treatment regimens to both CNS and non-CNS locations ranged from 14 Gy in 4 fractions to 63 Gy in 35 fractions. Common palliative doses were 30 Gy in 10 fractions (14%), 20 Gy in 5 fractions (8.6%), and 35 Gy in 14 fractions (7.6%). Nonstereotactic modalities included 2-dimensional or 3-dimensional (53%), intensity modulated radiation therapy (IMRT) or volumetric-modulated arc therapy (16%), and proton therapy (3.8%). Stereotactic body radiation therapy (SBRT) was less commonly used (4.8%) with treatment regimen ranging from 24 Gy in 3 fractions to 50 Gy in 5 fractions. Lastly, patients with BMs commonly received stereotactic radiosurgery (SRS, 22% of all courses) with doses ranging from 15 Gy in 1 fraction to 25 Gy in 5 fractions. Nearly half of the patients who underwent SRS received 21 Gy in 1 fraction.
Across the entire cohort, the clinical ORR was 76% within the first month after treatment and 67% at least 3 months after treatment (Table 2). Radiographic ORR between patients treated for clinical symptoms (symptomatic) and asymptomatic progression (asymptomatic) were 48% and 59%, respectively. Although patients treated for asymptomatic progression had higher rates of response, no significant differences were observed between the 2 cohorts (P = .23).Table 2 Response rates (all lesions)
<1 mo 1-3 mo >3 mo
Clinical response
CR 32.8% (19/58) 45.0% (18/40) 48.4% (15/31)
PR 43.1% (25/58) 35.0% (14/40) 19.4% (6/31)
SD 12.1% (7/58) 2.5% (1/40) 0.0% (0/31)
PD 12.1% (7/58) 17.5% (7/40) 32.3% (10/31)
ORR 75.9% (44/58) 80.0% (32/40) 67.7% (21/31)
Radiographic response: symptomatic patients
CR 15.2% (5/33) 16.7% (5/30) 25.9% (7/27)
PR 24.2% (8/33) 30.0% (9/30) 22.2% (6/27)
SD 51.5% (17/33) 43.3% (13/30) 40.7% (11/27)
PD 9.1% (3/33) 10.% (3/30) 11.1% (3/27)
ORR 39.4% (13/33) 46.7% (14/30) 48.1% (13/27)
Radiographic response: asymptomatic patients
CR 39.4% (13/33) 47.1% (16/34) 53.1% (17/32)
PR 9.1% (3/33) 8.8% (3/34) 6.3% (2/32)
SD 45.5% (15/33) 41.2% (14/34) 34.4% (11/32)
PD 6.1% (2/33) 2.9% (1/34) 6.3% (2/32)
ORR 48.5% (16/33) 55.9% (19/34) 59.4% (19/32)
Abbreviations: CR = complete response; ORR = overall response rate; PD = progressive disease; PR = partial response; SD = stable disease.
Excludes patients treated with postoperative palliative radiation.
Denominator reflects evaluable patients.
Of patients treated to non-CNS locations, the clinical and radiographic ORR within the first month after treatment were 79% and 33%, respectively (Table 3). Clinical ORR at last follow-up (at least 3 months after treatment) was 61%. Notably, of the patients with a CR (38.1%) within the first month, only 2 went on to have PD at last follow-up (4 were lost to follow-up), indicating durable response to treatment. All but one patient treated for malignancy-related vaginal bleeding (13/14) had a clinical response within 1 month, of which only one patient had recurrence of bleeding at last follow-up. Seventy percent of patients treated for pain (n = 27) had a clinical response within 1 month, of which only 3 patients demonstrated worsening pain at last follow-up. Radiographically, ORR improved to 38% for symptomatic patients and 47% for asymptomatic patients at last follow-up, with no significant differences in response rates between the 2 groups (P = .44). All lesions that responded within 1 month of radiation treatment maintained response through last follow-up. Furthermore, only 3 of 22 lesions that were initially SD, progressed over time (1 treated for clinical symptoms, 2 treated for asymptomatic progression).Table 3 Response rates (non-CNS lesions)
<1 mo 1-3 mo >3 mo
Clinical response
CR 38.1% (16/42) 44.8% (13/29) 43.5% (10/23)
PR 40.5% (17/42) 31.0% (9/29) 17.4% (4/23)
SD 14.3% (6/42) 3.4% (1/29) 0.0% (0/23)
PD 7.1% (3/42) 20.7% (6/29) 39.1% (9/23)
ORR 78.6% (33/42) 75.9% (22/29) 60.9% (14/23)
Radiographic response: symptomatic patients
CR 9.5% (2/21) 10.5% (2/19) 18.8% (3/16)
PR 23.8% (5/21) 26.3% (5/19) 18.8% (3/16)
SD 52.4% (11/21) 52.6% (10/19) 50.0% (8/16)
PD 14.3% (3/21) 10.5% (2/19) 12.5% (2/16)
ORR 33.3% (7/21) 36.8% (7/19) 37.5% (6/16)
Radiographic response: asymptomatic patients
CR 21.1% (4/19) 31.6% (6/19) 41.2% (7/17)
PR 10.5% (2/19) 10.5% (2/19) 5.9% (1/17)
SD 57.9% (11/19) 52.6% (10/19) 41.2% (7/17)
PD 10.5% (2/19) 5.3% (1/19) 11.8% (2/17)
ORR 31.6% (6/19) 42.1% (8/19) 47.1% (8/17)
Abbreviations: CNS = central nervous system; CR = complete response; ORR = overall response rate; PD = progressive disease; PR = partial response; SD = stable disease.
Excludes patients treated with postoperative palliative radiation.
Denominator reflects evaluable patients.
Of patients treated to CNS locations, the clinical and radiographic ORR within the first month after treatment were 72% and 62%, respectively (Table 4). No patients with a demonstrated clinical or radiographic response within the first month went on to have documented progressive symptoms or imaging at last follow-up (although 2 patients died and 4 were lost to follow-up). Although clinical responses stayed constant over time, radiographic responses tended to improve, especially in patients treated for clinical symptoms. There was no difference in rates of radiographic responses between CNS patients treated for clinical symptoms and those treated for asymptomatic progression (P = .41). All patients receiving SRS responded or had SD at 1 month; only one patient had locally progressive symptoms and disease at last follow-up. Three of the 4 patients with progressive symptoms within the first month were those who received whole brain radiation therapy with more extensive CNS disease before treatment.Table 4 Response rates (CNS lesions)
<1 mo 1-3 mo >3 mo
Clinical response
CR 18.8% (3/16) 45.5% (5/11) 62.5% (5/8)
PR 50.0% (8/16) 45.5% (5/11) 25.0% (2/8)
SD 6.3% (1/16) 0.0% (0/11) 0.0% (0/8)
PD 25.0% (4/16) 9.1% (1/11) 12.5% (1/8)
ORR 68.8% (11/16) 90.9% (10/11) 87.5% (7/8)
Radiographic response: symptomatic patients
CR 25.0% (3/12) 27.3% (3/11) 36.4% (4/11)
PR 25.0% (3/12) 36.4% (4/11) 27.3% (3/11)
SD 50.% (6/12) 27.3% (3/11) 27.3% (3/11)
PD 0.0% (0/12) 9.1% (1/11) 9.1% (1/11)
ORR 50.0% (6/12) 63.6% (7/11) 63.6% (7/11)
Radiographic response: asymptomatic patients
CR 64.3% (9/14) 66.7% (10/15) 66.7% (10/15)
PR 7.1% (1/14) 6.7% (1/15) 6.7% (1/15)
SD 28.6% (4/14) 26.7% (4/15) 26.7% (4/15)
PD 0.0% (0/14) 0.0% (0/15) 0.0% (0/15)
ORR 71.4% (10/14) 73.3% (11/15) 73.3% (11/15)
Abbreviations: CNS = central nervous system; CR = complete response; PD = progressive disease; PR = partial response; ORR = overall response rate; SD = stable disease.
Excludes patients treated with postoperative palliative radiation.
Denominator reflects evaluable patients.
Patients in both CNS and non-CNS cohorts tended to have clinical responses early on, with sustained response at last follow-up. Furthermore, if a patient were to have a clinical CR, it most often occurred within the first month. Only 4 patients demonstrated a CR after the first month, and all of these patients had a PR initially; no patients with initially stable disease went on to have a CR. Most patients with radiographic SD at initial follow-up maintained SD over time. The initial responses of patients developing progressive symptoms after 3-month follow-up varied considerably: CR (2), PR (3), SD (2), and PD (3). No patients who progressed within the first month of follow-up went on to have any response.
Eight patients were treated with postoperative RT after surgical resection in the brain (6), mediastinal lymph node (1), and inguinal lymph node (1). Three patients with evaluable clinical symptoms before and after surgery-RT all demonstrated diminished (PR) or complete (CR) resolution of symptoms within 1 month after RT. Of the 6 patients with radiographic follow-up, one recurred 9 months after treatment; the rest maintained stable disease (ie, no recurrence) through last follow-up.
Acute and late grade 3 or higher (G3 +) toxicities with bevacizumab were low (8.7% and 4.3%, respectively). CNS and mediastinal locations were the only treatment sites in which G3 + toxicity occurred. CNS toxicity (acute G3 fatigue, late G3 radiation necrosis, and late G4 optic neuritis) was identified in a single patient who received craniospinal irradiation with prior Gamma Knife irradiation. A second patient treated to the mediastinum had acute but not chronic grade 3 esophagitis. Notably, no acute or late G3 + toxicity was seen in patients treated to the abdomen or pelvis (the most common treatment location; Table 5).Table 5 Observed toxicities in patients treated with bevacizumab before or concurrent with radiation therapy, by treatment course
None Grade 1-2 Grade 3 Grade 4
Acute
Non-CNS (17) 6 Anorexia (1),
depression (1),
dermatitis (1),
fatigue (5),
GI (6), GU (1),
odynophagia (1),
pneumonitis (1),
vaginal hemorrhage (1) Dermatitis (1),
esophagitis (1) -
CNS (6) 4 GI (1) Fatigue (1) -
Late
Non-CNS (9) 8 GI (1) - -
CNS (5) 3 Intracranial hemorrhage (1) Radionecrosis (1) Optic neuropathy (1)
Abbreviations: CNS = central nervous system; GI = gastrointestinal; GU = genitourinary.
Toxicities defined according to the Common Terminology Criteria for Adverse Events, version 5.0.
Numbers indicate number of treatment courses; more than one toxicity may be attributed to a single treatment course. Late toxicity data unavailable for 9 treatment courses (all due to patient death).
Late grade 3 and 4 toxicities occurred in the same patient.
An exploratory analysis examining patient demographics and treatment characteristics was performed to identify predictors of clinical or radiographic response. In all patients (CNS and non-CNS sites), HGS histology was associated with clinical responses (88% vs 64%, P = .04). In patients with CNS lesions, BED >39 Gy was associated with clinical response (P = .049). In non-CNS locations, bony site was associated with worse clinical (44% vs 89%, P = .004) response compared with soft tissue/nodal (STN) sites. Lastly, we compared BED regimens ≤39 Gy versus >39 Gy (assuming an alpha/beta ratio of 10,19,20 the BED of 30 Gy in 10 fractions is 39 Gy) in non-CNS locations and found no differences in clinical (P = .10) or radiographic response rates (P = .47). We otherwise compared the most common regimens of 20 Gy in 5 fractions and 30 Gy in 10 fractions and found no significant differences in clinical (P = .60) or radiographic responses (P = .29; Table E1).2
Discussion
We report the outcomes of a large modern cohort of women with PMR-OC who received palliative radiation therapy in an era of novel systemic agents. In a population with poor prognosis, palliative radiation therapy resulted in excellent clinical and radiographic response rates (Table 2) within 1 month of treatment, with many responses durable beyond 3 months. Brain metastases, a rare site of anatomic spread, were also well represented in this cohort (36%, 38 courses) and responded favorably to palliative intracranial radiation therapy (Table 3). Exploratory analyses demonstrated an association between HGS histology and improved clinical response in all patients, BED >39 Gy and improved clinical response in BMs, and STN sites with improved clinical response in non-CNS sites. Our analysis is unique in its (1) large sample size compared with prior reports with significant number of BMs, (2) high proportion of patients treated with modern RT techniques, (3) inclusion of patients treated with novel systemic agents (ie, PARP inhibitors, bevacizumab, and immunotherapy), and (4) dedicated toxicity analysis of RT with concurrent or prior bevacizumab, an area of increasing clinical significance in MPR-EOC with a dearth of robust data.
Our high clinical response rates (79% ORR within 1 month) are similar to other reports, including literature from prior decades demonstrating durable pain relief and bleeding control from locally directed palliative RT in 80% of OC patients.20, 21, 22 More recently, Bansal and colleagues also found pain control rates of 88.2% and vaginal bleeding control rates of 100% in 23 heavily pretreated women who received palliative pelvic RT.23 Investigators from Brigham and Women’s Hospital also recently published rates and predictors of response to palliative RT for recurrent OC from 2003 to 201424 and demonstrated high rates of response for pain and bleeding (87% and 93%, respectively).
Identified predictors of response, including HGS histology and STN sites of disease are also compatible with prior investigations. In the above Brigham and Women’s Hospital study, patients treated at nonbony sites had higher response rates than those with bony sites of disease (96% vs 75%, respectively). Furthermore, patients with clear cell histology had the lowest response rates (60%), compared with others like serous histology (82%).
The sizable nature of our cohort allowed for a temporal analysis of index lesion response rates. Patients in both CNS and non-CNS cohorts tended to have clinical responses early on, with some benefitting from sustained response at last follow-up. Lesions with clinical CR often occurred within the first month. Furthermore, no patients who progressed in the index lesion within the first month of follow-up went on to have any response, suggesting that initial response is of paramount importance. Patients who had progressive symptoms after 3 months had variable initial responses, suggesting progressive disease is still expected no matter what the initial response may be.
Regarding dose response, higher BED was associated with clinical response in brain metastases. This is a result of ablative SRS technology that radiobiologically induces high rates of cell kill compared with those of conventional palliative techniques or doses. Advanced stereotactic techniques permit the delivery of otherwise unsafe high dose-per-fraction regimens due to their sharp dose gradients that allow for normal tissue sparing. In non-CNS locations, however, regimens with BED >39 Gy (ie, greater than 30 Gy in 10 fractions) were no different than lower BED regimens, suggesting dose escalation may not increase the efficacy of palliative RT. Use of higher BED regimens in such (predominantly abdominopelvic) locations is typically limited by larger fields due to tumor size and organ motion. Dose-limiting toxicities from nearby organs at risk such as the stomach, bowel, kidneys, and bladder also constrain prescriptions.
Notably, 47% of all courses were delivered with advanced radiation therapy techniques (SRS, SBRT, IMRT/volumetric-modulated arc therapy, proton therapy). This is in keeping with the increasing number of patients referred for ablative or definitive therapy to oligometastatic or oligoprogressive disease or previously irradiated lesions requiring retreatment. In such scenarios, advanced techniques allow practitioners to deliver higher dose per fraction while sparing normal organs and tissue of radiation, or even reirradiation, toxicity. In fact, recently published reports have evaluated the roles of advanced RT in OC. For example, definitive involved-field RT using IMRT has demonstrated promising rates of local control (LC) and disease-free survival with low toxicity.25,26 Two recent retrospective studies also explored SBRT in oligometastatic OC. Lazzari et al reported the treatment of 82 patients with a median dose of 24 Gy in 3 fractions and demonstrated the safety of SBRT along with an increase in systemic therapy-free survival with reasonable LC27 (more than one-third of patients were disease-free at 1 year). Similarly, Macchia et al reported SBRT in MPR-EOC was well tolerated and afforded higher LC in patients receiving a total dose >25 Gy.28
Forty-three percent of patients received targeted therapy immediately before RT in this cohort. This is in keeping with the litany of recent publications studying the use of novel systemic agents (PARP inhibitors,29, 30, 31 bevacizumab,32 nivolumab33) in the setting of MPR-EOC. The response rates described thus reflect the potential outcomes of palliative RT in conjunction with advanced systemic therapies, a scenario that will be increasingly encountered by practitioners. Furthermore, given the sizeable population that received prior or concurrent bevacizumab, a dedicated subgroup analysis was conducted and demonstrated low acute and late grade 3 or higher (G3 +) toxicities (8.7% and 4.3%, respectively) with RT. Although G3 + toxicities occurred in patients treated to CNS and mediastinal locations, it is unclear if this was in relation to prior bevacizumab or reflected the increased risk toxicity with prior RT (Gamma Knife in the CNS patient treated with craniospinal irradiation) or unfavorable tumor location (in the mediastinal patient experiencing esophagitis after receiving 59.4 Gy). No acute or late G3 + toxicity was seen in patients treated to the abdomen or pelvis (the most common treatment location), suggesting that this may be a reasonable treatment option in symptomatic patients.
Limitations
The study is limited primarily by its retrospective nature which lends itself to both selection and sample bias. For example, patient performance status and prior lines of therapy (including prior radiation) may effect physician choice of RT technique, dose, and fractionation. Furthermore, lesions necessitating reirradiation demonstrate inherent radioresistance and may negatively affect response rates. Moreover, although the study population is sizeable, it is heterogenous with respect to treatment sites and prior lines of therapy. As such appropriate interpretation required subdivision of data (ie, CNS vs non-CNS, symptomatic vs asymptomatic indication), which led to more descriptive findings. Finally, the variety of systemic therapies used negatively affect our ability to make conclusions regarding the efficacy of RT with respect to individual agents.
Future directions
As the role for palliative radiation therapy expands in the context of the oligometastatic paradigm, nuanced decision-making must be taken to deliver the most efficacious treatment although promoting cost-effective care. As such, prospective evaluation is warranted to determine the optimal dose, timing, and fractionation of RT as it relates to systemic agents and surgery. The high response rates demonstrated in this cohort may warrant prospective investigation of RT as a standard component therapy in MPR-EOC, either before systemic agents as a cytoreductive strategy or after as consolidation therapy.
Conclusions
We performed a large retrospective cohort analysis of women with MPR-EOC receiving palliative RT in the era of modern technology and systemic agents. Our large population of patients with BMs adds relevant data to the limited body of existing literature and can be used as a practical reference when counseling women. Patients demonstrated favorable clinical and radiographic response rates within 1 month, with >60% experiencing durable clinical responses beyond 3 months. HGS histology was associated with improved clinical response in all patients. BED >39 Gy was associated with improved response in brain metastases. Bony sites were associated with worse response compared with STN sites in non-CNS locations. Acute and late grade 3 or higher toxicities were low with prior bevacizumab, and none of these occurred in patients treated to abdominopelvic locations.
Although MPR-EOC is associated with limited prognosis, our data demonstrate that responses to palliative RT can be durable and meaningful. As such, without a conclusive effect on survival, it would be reasonable to consider treatment of such disease after taking into consideration patient symptom severity, goals of care, prognosis, performance status, and extracranial disease burden for BM.
Supplementary Materials
Tables E1 and E2
Sources of support: The authors received no specific funding for this work.
Disclosures: The authors of this manuscript have no conflicts of interest to report.
Research data are stored in an institutional repository and will be shared upon request.
Supplementary material for this article can be found at https://doi.org/10.1016/j.adro.2020.11.009. | BEVACIZUMAB | DrugsGivenReaction | CC BY-NC-ND | 33665491 | 18,951,285 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Depression'. | Palliative Radiation Therapy for Metastatic, Persistent, or Recurrent Epithelial Ovarian Cancer: Efficacy in the Era of Modern Technology and Targeted Agents.
Metastatic, persistent, or recurrent epithelial ovarian cancer (MPR-EOC) remains a significant threat to patient mortality despite advances in novel targeted agents. Radiation therapy (RT) is often used as a palliative option. We report outcomes of a large series of MPR-EOC patients treated with modern palliative RT (PRT) in an era of novel systemic therapies.
A retrospective review was conducted of women treated with PRT for MPR-EOC between 2007 and 2019 at an academic institution. Clinical response rates were recorded at <1 month, 1 to 3 months, and >3 months. Radiographic responses were categorized by RECIST 1.1 criteria. Overall response rate (ORR) was the sum of complete and partial response. Linear regression analyses of baseline characteristics were conducted for statistical testing.
Eighty-six patients with PMR-OC received 120 courses of palliative RT. Median follow-up was 8.6 months. Median age was 61 (range, 22-82). Thirty-six percent of women received central nervous system (CNS)-directed RT. In addition, 43% received targeted therapies before RT. Clinical ORR within 1 month and at last follow-up for non-CNS lesions was 79% and 61% (69% and 88% for CNS lesions, respectively). High-grade serous lesions were more likely to have clinical response (P = .04). Biologically effective doses (BED) >39 Gy were associated with improved clinical response in CNS lesions (P = .049). Bony sites were associated with worse clinical (P = .004) response in non-CNS lesions compared with soft tissue or nodal sites. Acute or late grade 3+ toxicities with bevacizumab were low (8.7%/4.3%).
PRT offers excellent rates of response for symptomatic patients with MPR-EOC within 1 month of treatment, with durable responses beyond 3 months. High-grade serous lesions were associated with improved response in all patients. Higher BED and soft tissue or nodal sites were associated with improved response in CNS and non-CNS patients, respectively. Acute or late toxicities with bevacizumab and PRT were low. Prospective investigation is warranted to determine the optimal PRT regimen.
Introduction
Ovarian cancer (OC) is a highly aggressive gynecologic malignancy, with the majority of patients presenting with advanced disease at diagnosis. The general treatment paradigm for advanced OC is maximal cytoreductive surgery with platinum-based chemotherapy.1 Recent literature has also reported a progression-free survival benefit with maintenance inhibition of poly (adenosine diphosphate-ribose) polymerase (PARP) in women with partial or complete response to platinum-based regimens.2,3
Whole abdominal radiation therapy was historically indicated as adjuvant therapy to address microscopic residual disease.4 However, due to its considerable toxicity and the development of platinum-based chemotherapy, whole abdominal radiation therapy is no longer included in primary OC treatment paradigms.1
Despite advances in cytoreductive strategies and front-line systemic therapy, >70% of women relapse within 3 years of diagnosis.5 As such, many patients with OC benefit from palliative care referrals to assist with symptom management, goals of care discussions, and complex medical decision making at the end of life.
There is a growing body of evidence to support the incorporation of palliative services in cancer care. In 2010, a seminal randomized trial6 reported early palliative care among patients with metastatic non-small cell lung cancer significantly improved quality of life, led to less aggressive care at the end of life, and resulted in longer overall survival. Furthermore, both the American Society of Clinical Oncology and the Society of Gynecologic Oncology have published official practice guidelines recommending the routine and early integration of palliative services.7,8
Radiation therapy (RT) is often used as an effective therapeutic option in the palliation of patients with metastatic, persistent, or recurrent epithelial OC (MPR-EOC) as a means for symptomatic relief and local control. This includes oligometastatic disease or symptomatic disease causing pain, bowel or ureteral obstruction, or bleeding. Despite their rarity in OC (2% incidence9), brain metastases can also cause significant morbidity and can be treated with palliative RT to reduce the risk of progression and neurocognitive deficits.10,11
As patient survival improves with modern systemic agents, there is a growing need to understand the efficacy of palliative RT regimens for MPR-EOC in the same era. Although radiation therapy has traditionally been delivered for symptomatic control in MPR-EOC, the recognition of the biologically distinct (and potentially curable) oligometastatic state12,13 is expanding the scope of RT indications. Data from phase 2 trials in other malignancies evaluating the effect of locally directed therapy to oligometastatic lesions has demonstrated improvements in overall survival.14,15
We therefore conducted, a large contemporary retrospective analysis of palliative RT in MPR-EOC. This patient cohort is highly relevant to modern practice given the number of patients who received novel systemic agents, the prominent usage of advanced RT technology, and the representation of patients with BMs from OC (an area with limited data but increasing prevalence in practice). The analysis will report the outcomes and durability of palliative RT in MPR-EOC and delineate factors predictive of response in the modern era.
Methods and Materials
We conducted a retrospective chart review of women treated with palliative radiation therapy for metastatic ovarian cancer from 2007 through 2019 at [University of Pennsylvania] and affiliate sites. Institutional review board approval was obtained before conducting this review. Patients were included in this analysis if they were treated for palliative intent, including treatment of oligometastatic disease. All patients had MPR-EOC ovarian cancer and received anywhere from one to 5 courses of radiation treatment.
Given the poor prognosis of patients with metastatic ovarian cancer, clinical and radiographic response rates were categorized in intervals of <1 month, 1 to 3 months, and >3 months after the end of radiation treatment to indicate acute and durable responses. Clinical responses were categorized as complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD). Pain scores were classified using the Bone Metastases Consensus Working Party guidelines16 (indeterminate responses, which are neither PR nor PD per BMWCP guidelines, were classified as SD to maintain consistency with other clinical response categorizations). Radiographic responses were categorized as CR, PR, SD, or PD based on the RECIST 1.1 criteria.17 Overall response rate (ORR) was the sum of CR and PR in a given patient. Given the large subset of patients with brain metastases (BMs), courses were stratified by central nervous system (CNS) and non-CNS anatomic locations. Acute (during RT and within 3 months of completion) and late (>3 months after completion of RT) toxicities were recorded with concurrent and prior bevacizumab using Common Terminology Criteria for Adverse Events version 5.018 classification.
Rates of response (CR or PR at any point) were compared with demographic and treatment characteristics. χ2 (n ≥ 20) or Fisher exact (n < 20) tests were used for such comparison with variables for race, histology, platinum chemotherapy, or targeted therapy before RT, RT technology, RT location, and biologically effective dose (BED) >39. Binary logistic regression analyses were used for comparison with continuous variables (age and BED). Covariates with P < .1 were included in multiple logistic regression modeling to assess for independent effect. Additionally, χ2 analyses were used to compare rates of radiographic response between patients treated for clinical symptoms and asymptomatic progression. Statistical analysis was conducted using IBM SPSS Statistics, version 26 (IBM Corporation, Armonk, NY).
Results
We identified 86 patients with PMR-OC that received 120 combined courses of palliative radiation treatment. Median follow-up was 8.6 months (range, 0.5-119 months). Excluding 10 patients (15 courses) with no evaluable clinical or radiographic follow-up, 51 patients (58 courses) were treated to non-CNS locations and 18 patients (25 courses) were treated to CNS locations; 7 patients (22 courses) received palliative RT to both CNS (13 courses) and non-CNS (9 courses) locations.
Table 1 describes baseline patient characteristics and details related to patient treatments. The median age of patients in this cohort was 61, with a range of 22 to 82. Patients were most commonly white (83%) and black (8%). Tumor histologies were primarily high-grade serous (HGS, 59%), although adenocarcinoma (undifferentiated or unspecified), low-grade serous, clear cell, endometrioid, and carcinosarcoma were also observed.Table 1 Patient characteristics and treatment details
No. of courses 105
No. of patients 76
Median age 61
Ethnicity
White 82.9% (63/76)
Black 9.2% (7/76)
Asian 3.9% (3/76)
Hispanic 2.6% (2/76)
Unknown 1.3% (1/76)
Histology
High-grade serous 59.2% (45/76)
Adenocarcinoma, other 13.2% (10/76)
Low grade serous 9.2% (7/76)
Clear cell 5.3% (4/76)
Other 7.9% (6/76)
Endometrioid 3.9% (3/76)
Carcinosarcoma 1.3% (1/76)
Anatomic site
Soft tissue/organ 35.2% (37/105)
Lymph node 21.0% (22/105)
Bone 11.4% (12/105)
CNS 36.2% (38/105)
Indications
Clinical symptoms 59.0% (62/105)
Progressive/metastatic 33.3% (35/105)
Postoperative 7.6% (8/105)
Systemic therapy before RT
Platinum chemotherapy 27.6% (29/105)
Nonplatinum chemotherapy 61.9% (65/105)
Targeted therapy 42.9% (45/105)
None/other 1.0% (1/105)
Technique
2D/3D CRT 53.3% (56/105)
SRS 21.9% (23/105)
VMAT/IMRT 16.2% (17/105)
SBRT 4.8% (5/105)
Proton 3.8% (4/105)
Non-SRS dose 14-63 Gy in 4-35 fractions
SBRT dose 24-50 Gy in 3-5 fractions
SRS dose 15-25 Gy in 1-5 fractions
Abbreviations: 2D = 2-dimensional; 3D CRT = 3-dimensional conformal radiation therapy; CNS = central nervous system; IMRT = intensity modulated radiation therapy; RT = radiation therapy; SBRT = stereotactic body radiation therapy; SRS = stereotactic radiosurgery; VMAT = volumetric modulated arc therapy.
Non-CNS treatment locations included tumors in soft tissue or organs (35%), lymph nodes (21%), and bone (11%); 4 patients were treated simultaneously to adjacent soft tissue and lymph nodes. Treatment for CNS metastases comprised the remaining 36% of patients.
Most patients were treated for clinical symptoms (59%). Pain and bleeding were the most common clinical indications. Others included neurologic deficits, spinal cord compression, airway compression, and bowel obstruction. A large cohort of patients were treated for asymptomatic progressive or metastatic disease (33%) with a small cohort treated adjuvantly after surgery (eg, metastasectomy or palliative debulking; 7.6%).
Almost all patients (90%) received chemotherapy immediately before radiation therapy. The most common systemic therapy regimens were platinum-based (ie, carboplatin) followed by taxanes and doxorubicin. Many patients (43%) also received treatment with targeted therapy agents before radiation treatment. Bevacizumab was the most commonly used targeted therapy agent (20%), although patients also received PARP inhibitors (9%) and immune checkpoint inhibitors (5%).
A wide range of palliative radiation regimens were delivered across several modalities. Nonstereotactic treatment regimens to both CNS and non-CNS locations ranged from 14 Gy in 4 fractions to 63 Gy in 35 fractions. Common palliative doses were 30 Gy in 10 fractions (14%), 20 Gy in 5 fractions (8.6%), and 35 Gy in 14 fractions (7.6%). Nonstereotactic modalities included 2-dimensional or 3-dimensional (53%), intensity modulated radiation therapy (IMRT) or volumetric-modulated arc therapy (16%), and proton therapy (3.8%). Stereotactic body radiation therapy (SBRT) was less commonly used (4.8%) with treatment regimen ranging from 24 Gy in 3 fractions to 50 Gy in 5 fractions. Lastly, patients with BMs commonly received stereotactic radiosurgery (SRS, 22% of all courses) with doses ranging from 15 Gy in 1 fraction to 25 Gy in 5 fractions. Nearly half of the patients who underwent SRS received 21 Gy in 1 fraction.
Across the entire cohort, the clinical ORR was 76% within the first month after treatment and 67% at least 3 months after treatment (Table 2). Radiographic ORR between patients treated for clinical symptoms (symptomatic) and asymptomatic progression (asymptomatic) were 48% and 59%, respectively. Although patients treated for asymptomatic progression had higher rates of response, no significant differences were observed between the 2 cohorts (P = .23).Table 2 Response rates (all lesions)
<1 mo 1-3 mo >3 mo
Clinical response
CR 32.8% (19/58) 45.0% (18/40) 48.4% (15/31)
PR 43.1% (25/58) 35.0% (14/40) 19.4% (6/31)
SD 12.1% (7/58) 2.5% (1/40) 0.0% (0/31)
PD 12.1% (7/58) 17.5% (7/40) 32.3% (10/31)
ORR 75.9% (44/58) 80.0% (32/40) 67.7% (21/31)
Radiographic response: symptomatic patients
CR 15.2% (5/33) 16.7% (5/30) 25.9% (7/27)
PR 24.2% (8/33) 30.0% (9/30) 22.2% (6/27)
SD 51.5% (17/33) 43.3% (13/30) 40.7% (11/27)
PD 9.1% (3/33) 10.% (3/30) 11.1% (3/27)
ORR 39.4% (13/33) 46.7% (14/30) 48.1% (13/27)
Radiographic response: asymptomatic patients
CR 39.4% (13/33) 47.1% (16/34) 53.1% (17/32)
PR 9.1% (3/33) 8.8% (3/34) 6.3% (2/32)
SD 45.5% (15/33) 41.2% (14/34) 34.4% (11/32)
PD 6.1% (2/33) 2.9% (1/34) 6.3% (2/32)
ORR 48.5% (16/33) 55.9% (19/34) 59.4% (19/32)
Abbreviations: CR = complete response; ORR = overall response rate; PD = progressive disease; PR = partial response; SD = stable disease.
Excludes patients treated with postoperative palliative radiation.
Denominator reflects evaluable patients.
Of patients treated to non-CNS locations, the clinical and radiographic ORR within the first month after treatment were 79% and 33%, respectively (Table 3). Clinical ORR at last follow-up (at least 3 months after treatment) was 61%. Notably, of the patients with a CR (38.1%) within the first month, only 2 went on to have PD at last follow-up (4 were lost to follow-up), indicating durable response to treatment. All but one patient treated for malignancy-related vaginal bleeding (13/14) had a clinical response within 1 month, of which only one patient had recurrence of bleeding at last follow-up. Seventy percent of patients treated for pain (n = 27) had a clinical response within 1 month, of which only 3 patients demonstrated worsening pain at last follow-up. Radiographically, ORR improved to 38% for symptomatic patients and 47% for asymptomatic patients at last follow-up, with no significant differences in response rates between the 2 groups (P = .44). All lesions that responded within 1 month of radiation treatment maintained response through last follow-up. Furthermore, only 3 of 22 lesions that were initially SD, progressed over time (1 treated for clinical symptoms, 2 treated for asymptomatic progression).Table 3 Response rates (non-CNS lesions)
<1 mo 1-3 mo >3 mo
Clinical response
CR 38.1% (16/42) 44.8% (13/29) 43.5% (10/23)
PR 40.5% (17/42) 31.0% (9/29) 17.4% (4/23)
SD 14.3% (6/42) 3.4% (1/29) 0.0% (0/23)
PD 7.1% (3/42) 20.7% (6/29) 39.1% (9/23)
ORR 78.6% (33/42) 75.9% (22/29) 60.9% (14/23)
Radiographic response: symptomatic patients
CR 9.5% (2/21) 10.5% (2/19) 18.8% (3/16)
PR 23.8% (5/21) 26.3% (5/19) 18.8% (3/16)
SD 52.4% (11/21) 52.6% (10/19) 50.0% (8/16)
PD 14.3% (3/21) 10.5% (2/19) 12.5% (2/16)
ORR 33.3% (7/21) 36.8% (7/19) 37.5% (6/16)
Radiographic response: asymptomatic patients
CR 21.1% (4/19) 31.6% (6/19) 41.2% (7/17)
PR 10.5% (2/19) 10.5% (2/19) 5.9% (1/17)
SD 57.9% (11/19) 52.6% (10/19) 41.2% (7/17)
PD 10.5% (2/19) 5.3% (1/19) 11.8% (2/17)
ORR 31.6% (6/19) 42.1% (8/19) 47.1% (8/17)
Abbreviations: CNS = central nervous system; CR = complete response; ORR = overall response rate; PD = progressive disease; PR = partial response; SD = stable disease.
Excludes patients treated with postoperative palliative radiation.
Denominator reflects evaluable patients.
Of patients treated to CNS locations, the clinical and radiographic ORR within the first month after treatment were 72% and 62%, respectively (Table 4). No patients with a demonstrated clinical or radiographic response within the first month went on to have documented progressive symptoms or imaging at last follow-up (although 2 patients died and 4 were lost to follow-up). Although clinical responses stayed constant over time, radiographic responses tended to improve, especially in patients treated for clinical symptoms. There was no difference in rates of radiographic responses between CNS patients treated for clinical symptoms and those treated for asymptomatic progression (P = .41). All patients receiving SRS responded or had SD at 1 month; only one patient had locally progressive symptoms and disease at last follow-up. Three of the 4 patients with progressive symptoms within the first month were those who received whole brain radiation therapy with more extensive CNS disease before treatment.Table 4 Response rates (CNS lesions)
<1 mo 1-3 mo >3 mo
Clinical response
CR 18.8% (3/16) 45.5% (5/11) 62.5% (5/8)
PR 50.0% (8/16) 45.5% (5/11) 25.0% (2/8)
SD 6.3% (1/16) 0.0% (0/11) 0.0% (0/8)
PD 25.0% (4/16) 9.1% (1/11) 12.5% (1/8)
ORR 68.8% (11/16) 90.9% (10/11) 87.5% (7/8)
Radiographic response: symptomatic patients
CR 25.0% (3/12) 27.3% (3/11) 36.4% (4/11)
PR 25.0% (3/12) 36.4% (4/11) 27.3% (3/11)
SD 50.% (6/12) 27.3% (3/11) 27.3% (3/11)
PD 0.0% (0/12) 9.1% (1/11) 9.1% (1/11)
ORR 50.0% (6/12) 63.6% (7/11) 63.6% (7/11)
Radiographic response: asymptomatic patients
CR 64.3% (9/14) 66.7% (10/15) 66.7% (10/15)
PR 7.1% (1/14) 6.7% (1/15) 6.7% (1/15)
SD 28.6% (4/14) 26.7% (4/15) 26.7% (4/15)
PD 0.0% (0/14) 0.0% (0/15) 0.0% (0/15)
ORR 71.4% (10/14) 73.3% (11/15) 73.3% (11/15)
Abbreviations: CNS = central nervous system; CR = complete response; PD = progressive disease; PR = partial response; ORR = overall response rate; SD = stable disease.
Excludes patients treated with postoperative palliative radiation.
Denominator reflects evaluable patients.
Patients in both CNS and non-CNS cohorts tended to have clinical responses early on, with sustained response at last follow-up. Furthermore, if a patient were to have a clinical CR, it most often occurred within the first month. Only 4 patients demonstrated a CR after the first month, and all of these patients had a PR initially; no patients with initially stable disease went on to have a CR. Most patients with radiographic SD at initial follow-up maintained SD over time. The initial responses of patients developing progressive symptoms after 3-month follow-up varied considerably: CR (2), PR (3), SD (2), and PD (3). No patients who progressed within the first month of follow-up went on to have any response.
Eight patients were treated with postoperative RT after surgical resection in the brain (6), mediastinal lymph node (1), and inguinal lymph node (1). Three patients with evaluable clinical symptoms before and after surgery-RT all demonstrated diminished (PR) or complete (CR) resolution of symptoms within 1 month after RT. Of the 6 patients with radiographic follow-up, one recurred 9 months after treatment; the rest maintained stable disease (ie, no recurrence) through last follow-up.
Acute and late grade 3 or higher (G3 +) toxicities with bevacizumab were low (8.7% and 4.3%, respectively). CNS and mediastinal locations were the only treatment sites in which G3 + toxicity occurred. CNS toxicity (acute G3 fatigue, late G3 radiation necrosis, and late G4 optic neuritis) was identified in a single patient who received craniospinal irradiation with prior Gamma Knife irradiation. A second patient treated to the mediastinum had acute but not chronic grade 3 esophagitis. Notably, no acute or late G3 + toxicity was seen in patients treated to the abdomen or pelvis (the most common treatment location; Table 5).Table 5 Observed toxicities in patients treated with bevacizumab before or concurrent with radiation therapy, by treatment course
None Grade 1-2 Grade 3 Grade 4
Acute
Non-CNS (17) 6 Anorexia (1),
depression (1),
dermatitis (1),
fatigue (5),
GI (6), GU (1),
odynophagia (1),
pneumonitis (1),
vaginal hemorrhage (1) Dermatitis (1),
esophagitis (1) -
CNS (6) 4 GI (1) Fatigue (1) -
Late
Non-CNS (9) 8 GI (1) - -
CNS (5) 3 Intracranial hemorrhage (1) Radionecrosis (1) Optic neuropathy (1)
Abbreviations: CNS = central nervous system; GI = gastrointestinal; GU = genitourinary.
Toxicities defined according to the Common Terminology Criteria for Adverse Events, version 5.0.
Numbers indicate number of treatment courses; more than one toxicity may be attributed to a single treatment course. Late toxicity data unavailable for 9 treatment courses (all due to patient death).
Late grade 3 and 4 toxicities occurred in the same patient.
An exploratory analysis examining patient demographics and treatment characteristics was performed to identify predictors of clinical or radiographic response. In all patients (CNS and non-CNS sites), HGS histology was associated with clinical responses (88% vs 64%, P = .04). In patients with CNS lesions, BED >39 Gy was associated with clinical response (P = .049). In non-CNS locations, bony site was associated with worse clinical (44% vs 89%, P = .004) response compared with soft tissue/nodal (STN) sites. Lastly, we compared BED regimens ≤39 Gy versus >39 Gy (assuming an alpha/beta ratio of 10,19,20 the BED of 30 Gy in 10 fractions is 39 Gy) in non-CNS locations and found no differences in clinical (P = .10) or radiographic response rates (P = .47). We otherwise compared the most common regimens of 20 Gy in 5 fractions and 30 Gy in 10 fractions and found no significant differences in clinical (P = .60) or radiographic responses (P = .29; Table E1).2
Discussion
We report the outcomes of a large modern cohort of women with PMR-OC who received palliative radiation therapy in an era of novel systemic agents. In a population with poor prognosis, palliative radiation therapy resulted in excellent clinical and radiographic response rates (Table 2) within 1 month of treatment, with many responses durable beyond 3 months. Brain metastases, a rare site of anatomic spread, were also well represented in this cohort (36%, 38 courses) and responded favorably to palliative intracranial radiation therapy (Table 3). Exploratory analyses demonstrated an association between HGS histology and improved clinical response in all patients, BED >39 Gy and improved clinical response in BMs, and STN sites with improved clinical response in non-CNS sites. Our analysis is unique in its (1) large sample size compared with prior reports with significant number of BMs, (2) high proportion of patients treated with modern RT techniques, (3) inclusion of patients treated with novel systemic agents (ie, PARP inhibitors, bevacizumab, and immunotherapy), and (4) dedicated toxicity analysis of RT with concurrent or prior bevacizumab, an area of increasing clinical significance in MPR-EOC with a dearth of robust data.
Our high clinical response rates (79% ORR within 1 month) are similar to other reports, including literature from prior decades demonstrating durable pain relief and bleeding control from locally directed palliative RT in 80% of OC patients.20, 21, 22 More recently, Bansal and colleagues also found pain control rates of 88.2% and vaginal bleeding control rates of 100% in 23 heavily pretreated women who received palliative pelvic RT.23 Investigators from Brigham and Women’s Hospital also recently published rates and predictors of response to palliative RT for recurrent OC from 2003 to 201424 and demonstrated high rates of response for pain and bleeding (87% and 93%, respectively).
Identified predictors of response, including HGS histology and STN sites of disease are also compatible with prior investigations. In the above Brigham and Women’s Hospital study, patients treated at nonbony sites had higher response rates than those with bony sites of disease (96% vs 75%, respectively). Furthermore, patients with clear cell histology had the lowest response rates (60%), compared with others like serous histology (82%).
The sizable nature of our cohort allowed for a temporal analysis of index lesion response rates. Patients in both CNS and non-CNS cohorts tended to have clinical responses early on, with some benefitting from sustained response at last follow-up. Lesions with clinical CR often occurred within the first month. Furthermore, no patients who progressed in the index lesion within the first month of follow-up went on to have any response, suggesting that initial response is of paramount importance. Patients who had progressive symptoms after 3 months had variable initial responses, suggesting progressive disease is still expected no matter what the initial response may be.
Regarding dose response, higher BED was associated with clinical response in brain metastases. This is a result of ablative SRS technology that radiobiologically induces high rates of cell kill compared with those of conventional palliative techniques or doses. Advanced stereotactic techniques permit the delivery of otherwise unsafe high dose-per-fraction regimens due to their sharp dose gradients that allow for normal tissue sparing. In non-CNS locations, however, regimens with BED >39 Gy (ie, greater than 30 Gy in 10 fractions) were no different than lower BED regimens, suggesting dose escalation may not increase the efficacy of palliative RT. Use of higher BED regimens in such (predominantly abdominopelvic) locations is typically limited by larger fields due to tumor size and organ motion. Dose-limiting toxicities from nearby organs at risk such as the stomach, bowel, kidneys, and bladder also constrain prescriptions.
Notably, 47% of all courses were delivered with advanced radiation therapy techniques (SRS, SBRT, IMRT/volumetric-modulated arc therapy, proton therapy). This is in keeping with the increasing number of patients referred for ablative or definitive therapy to oligometastatic or oligoprogressive disease or previously irradiated lesions requiring retreatment. In such scenarios, advanced techniques allow practitioners to deliver higher dose per fraction while sparing normal organs and tissue of radiation, or even reirradiation, toxicity. In fact, recently published reports have evaluated the roles of advanced RT in OC. For example, definitive involved-field RT using IMRT has demonstrated promising rates of local control (LC) and disease-free survival with low toxicity.25,26 Two recent retrospective studies also explored SBRT in oligometastatic OC. Lazzari et al reported the treatment of 82 patients with a median dose of 24 Gy in 3 fractions and demonstrated the safety of SBRT along with an increase in systemic therapy-free survival with reasonable LC27 (more than one-third of patients were disease-free at 1 year). Similarly, Macchia et al reported SBRT in MPR-EOC was well tolerated and afforded higher LC in patients receiving a total dose >25 Gy.28
Forty-three percent of patients received targeted therapy immediately before RT in this cohort. This is in keeping with the litany of recent publications studying the use of novel systemic agents (PARP inhibitors,29, 30, 31 bevacizumab,32 nivolumab33) in the setting of MPR-EOC. The response rates described thus reflect the potential outcomes of palliative RT in conjunction with advanced systemic therapies, a scenario that will be increasingly encountered by practitioners. Furthermore, given the sizeable population that received prior or concurrent bevacizumab, a dedicated subgroup analysis was conducted and demonstrated low acute and late grade 3 or higher (G3 +) toxicities (8.7% and 4.3%, respectively) with RT. Although G3 + toxicities occurred in patients treated to CNS and mediastinal locations, it is unclear if this was in relation to prior bevacizumab or reflected the increased risk toxicity with prior RT (Gamma Knife in the CNS patient treated with craniospinal irradiation) or unfavorable tumor location (in the mediastinal patient experiencing esophagitis after receiving 59.4 Gy). No acute or late G3 + toxicity was seen in patients treated to the abdomen or pelvis (the most common treatment location), suggesting that this may be a reasonable treatment option in symptomatic patients.
Limitations
The study is limited primarily by its retrospective nature which lends itself to both selection and sample bias. For example, patient performance status and prior lines of therapy (including prior radiation) may effect physician choice of RT technique, dose, and fractionation. Furthermore, lesions necessitating reirradiation demonstrate inherent radioresistance and may negatively affect response rates. Moreover, although the study population is sizeable, it is heterogenous with respect to treatment sites and prior lines of therapy. As such appropriate interpretation required subdivision of data (ie, CNS vs non-CNS, symptomatic vs asymptomatic indication), which led to more descriptive findings. Finally, the variety of systemic therapies used negatively affect our ability to make conclusions regarding the efficacy of RT with respect to individual agents.
Future directions
As the role for palliative radiation therapy expands in the context of the oligometastatic paradigm, nuanced decision-making must be taken to deliver the most efficacious treatment although promoting cost-effective care. As such, prospective evaluation is warranted to determine the optimal dose, timing, and fractionation of RT as it relates to systemic agents and surgery. The high response rates demonstrated in this cohort may warrant prospective investigation of RT as a standard component therapy in MPR-EOC, either before systemic agents as a cytoreductive strategy or after as consolidation therapy.
Conclusions
We performed a large retrospective cohort analysis of women with MPR-EOC receiving palliative RT in the era of modern technology and systemic agents. Our large population of patients with BMs adds relevant data to the limited body of existing literature and can be used as a practical reference when counseling women. Patients demonstrated favorable clinical and radiographic response rates within 1 month, with >60% experiencing durable clinical responses beyond 3 months. HGS histology was associated with improved clinical response in all patients. BED >39 Gy was associated with improved response in brain metastases. Bony sites were associated with worse response compared with STN sites in non-CNS locations. Acute and late grade 3 or higher toxicities were low with prior bevacizumab, and none of these occurred in patients treated to abdominopelvic locations.
Although MPR-EOC is associated with limited prognosis, our data demonstrate that responses to palliative RT can be durable and meaningful. As such, without a conclusive effect on survival, it would be reasonable to consider treatment of such disease after taking into consideration patient symptom severity, goals of care, prognosis, performance status, and extracranial disease burden for BM.
Supplementary Materials
Tables E1 and E2
Sources of support: The authors received no specific funding for this work.
Disclosures: The authors of this manuscript have no conflicts of interest to report.
Research data are stored in an institutional repository and will be shared upon request.
Supplementary material for this article can be found at https://doi.org/10.1016/j.adro.2020.11.009. | BEVACIZUMAB | DrugsGivenReaction | CC BY-NC-ND | 33665491 | 18,951,285 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Dermatitis'. | Palliative Radiation Therapy for Metastatic, Persistent, or Recurrent Epithelial Ovarian Cancer: Efficacy in the Era of Modern Technology and Targeted Agents.
Metastatic, persistent, or recurrent epithelial ovarian cancer (MPR-EOC) remains a significant threat to patient mortality despite advances in novel targeted agents. Radiation therapy (RT) is often used as a palliative option. We report outcomes of a large series of MPR-EOC patients treated with modern palliative RT (PRT) in an era of novel systemic therapies.
A retrospective review was conducted of women treated with PRT for MPR-EOC between 2007 and 2019 at an academic institution. Clinical response rates were recorded at <1 month, 1 to 3 months, and >3 months. Radiographic responses were categorized by RECIST 1.1 criteria. Overall response rate (ORR) was the sum of complete and partial response. Linear regression analyses of baseline characteristics were conducted for statistical testing.
Eighty-six patients with PMR-OC received 120 courses of palliative RT. Median follow-up was 8.6 months. Median age was 61 (range, 22-82). Thirty-six percent of women received central nervous system (CNS)-directed RT. In addition, 43% received targeted therapies before RT. Clinical ORR within 1 month and at last follow-up for non-CNS lesions was 79% and 61% (69% and 88% for CNS lesions, respectively). High-grade serous lesions were more likely to have clinical response (P = .04). Biologically effective doses (BED) >39 Gy were associated with improved clinical response in CNS lesions (P = .049). Bony sites were associated with worse clinical (P = .004) response in non-CNS lesions compared with soft tissue or nodal sites. Acute or late grade 3+ toxicities with bevacizumab were low (8.7%/4.3%).
PRT offers excellent rates of response for symptomatic patients with MPR-EOC within 1 month of treatment, with durable responses beyond 3 months. High-grade serous lesions were associated with improved response in all patients. Higher BED and soft tissue or nodal sites were associated with improved response in CNS and non-CNS patients, respectively. Acute or late toxicities with bevacizumab and PRT were low. Prospective investigation is warranted to determine the optimal PRT regimen.
Introduction
Ovarian cancer (OC) is a highly aggressive gynecologic malignancy, with the majority of patients presenting with advanced disease at diagnosis. The general treatment paradigm for advanced OC is maximal cytoreductive surgery with platinum-based chemotherapy.1 Recent literature has also reported a progression-free survival benefit with maintenance inhibition of poly (adenosine diphosphate-ribose) polymerase (PARP) in women with partial or complete response to platinum-based regimens.2,3
Whole abdominal radiation therapy was historically indicated as adjuvant therapy to address microscopic residual disease.4 However, due to its considerable toxicity and the development of platinum-based chemotherapy, whole abdominal radiation therapy is no longer included in primary OC treatment paradigms.1
Despite advances in cytoreductive strategies and front-line systemic therapy, >70% of women relapse within 3 years of diagnosis.5 As such, many patients with OC benefit from palliative care referrals to assist with symptom management, goals of care discussions, and complex medical decision making at the end of life.
There is a growing body of evidence to support the incorporation of palliative services in cancer care. In 2010, a seminal randomized trial6 reported early palliative care among patients with metastatic non-small cell lung cancer significantly improved quality of life, led to less aggressive care at the end of life, and resulted in longer overall survival. Furthermore, both the American Society of Clinical Oncology and the Society of Gynecologic Oncology have published official practice guidelines recommending the routine and early integration of palliative services.7,8
Radiation therapy (RT) is often used as an effective therapeutic option in the palliation of patients with metastatic, persistent, or recurrent epithelial OC (MPR-EOC) as a means for symptomatic relief and local control. This includes oligometastatic disease or symptomatic disease causing pain, bowel or ureteral obstruction, or bleeding. Despite their rarity in OC (2% incidence9), brain metastases can also cause significant morbidity and can be treated with palliative RT to reduce the risk of progression and neurocognitive deficits.10,11
As patient survival improves with modern systemic agents, there is a growing need to understand the efficacy of palliative RT regimens for MPR-EOC in the same era. Although radiation therapy has traditionally been delivered for symptomatic control in MPR-EOC, the recognition of the biologically distinct (and potentially curable) oligometastatic state12,13 is expanding the scope of RT indications. Data from phase 2 trials in other malignancies evaluating the effect of locally directed therapy to oligometastatic lesions has demonstrated improvements in overall survival.14,15
We therefore conducted, a large contemporary retrospective analysis of palliative RT in MPR-EOC. This patient cohort is highly relevant to modern practice given the number of patients who received novel systemic agents, the prominent usage of advanced RT technology, and the representation of patients with BMs from OC (an area with limited data but increasing prevalence in practice). The analysis will report the outcomes and durability of palliative RT in MPR-EOC and delineate factors predictive of response in the modern era.
Methods and Materials
We conducted a retrospective chart review of women treated with palliative radiation therapy for metastatic ovarian cancer from 2007 through 2019 at [University of Pennsylvania] and affiliate sites. Institutional review board approval was obtained before conducting this review. Patients were included in this analysis if they were treated for palliative intent, including treatment of oligometastatic disease. All patients had MPR-EOC ovarian cancer and received anywhere from one to 5 courses of radiation treatment.
Given the poor prognosis of patients with metastatic ovarian cancer, clinical and radiographic response rates were categorized in intervals of <1 month, 1 to 3 months, and >3 months after the end of radiation treatment to indicate acute and durable responses. Clinical responses were categorized as complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD). Pain scores were classified using the Bone Metastases Consensus Working Party guidelines16 (indeterminate responses, which are neither PR nor PD per BMWCP guidelines, were classified as SD to maintain consistency with other clinical response categorizations). Radiographic responses were categorized as CR, PR, SD, or PD based on the RECIST 1.1 criteria.17 Overall response rate (ORR) was the sum of CR and PR in a given patient. Given the large subset of patients with brain metastases (BMs), courses were stratified by central nervous system (CNS) and non-CNS anatomic locations. Acute (during RT and within 3 months of completion) and late (>3 months after completion of RT) toxicities were recorded with concurrent and prior bevacizumab using Common Terminology Criteria for Adverse Events version 5.018 classification.
Rates of response (CR or PR at any point) were compared with demographic and treatment characteristics. χ2 (n ≥ 20) or Fisher exact (n < 20) tests were used for such comparison with variables for race, histology, platinum chemotherapy, or targeted therapy before RT, RT technology, RT location, and biologically effective dose (BED) >39. Binary logistic regression analyses were used for comparison with continuous variables (age and BED). Covariates with P < .1 were included in multiple logistic regression modeling to assess for independent effect. Additionally, χ2 analyses were used to compare rates of radiographic response between patients treated for clinical symptoms and asymptomatic progression. Statistical analysis was conducted using IBM SPSS Statistics, version 26 (IBM Corporation, Armonk, NY).
Results
We identified 86 patients with PMR-OC that received 120 combined courses of palliative radiation treatment. Median follow-up was 8.6 months (range, 0.5-119 months). Excluding 10 patients (15 courses) with no evaluable clinical or radiographic follow-up, 51 patients (58 courses) were treated to non-CNS locations and 18 patients (25 courses) were treated to CNS locations; 7 patients (22 courses) received palliative RT to both CNS (13 courses) and non-CNS (9 courses) locations.
Table 1 describes baseline patient characteristics and details related to patient treatments. The median age of patients in this cohort was 61, with a range of 22 to 82. Patients were most commonly white (83%) and black (8%). Tumor histologies were primarily high-grade serous (HGS, 59%), although adenocarcinoma (undifferentiated or unspecified), low-grade serous, clear cell, endometrioid, and carcinosarcoma were also observed.Table 1 Patient characteristics and treatment details
No. of courses 105
No. of patients 76
Median age 61
Ethnicity
White 82.9% (63/76)
Black 9.2% (7/76)
Asian 3.9% (3/76)
Hispanic 2.6% (2/76)
Unknown 1.3% (1/76)
Histology
High-grade serous 59.2% (45/76)
Adenocarcinoma, other 13.2% (10/76)
Low grade serous 9.2% (7/76)
Clear cell 5.3% (4/76)
Other 7.9% (6/76)
Endometrioid 3.9% (3/76)
Carcinosarcoma 1.3% (1/76)
Anatomic site
Soft tissue/organ 35.2% (37/105)
Lymph node 21.0% (22/105)
Bone 11.4% (12/105)
CNS 36.2% (38/105)
Indications
Clinical symptoms 59.0% (62/105)
Progressive/metastatic 33.3% (35/105)
Postoperative 7.6% (8/105)
Systemic therapy before RT
Platinum chemotherapy 27.6% (29/105)
Nonplatinum chemotherapy 61.9% (65/105)
Targeted therapy 42.9% (45/105)
None/other 1.0% (1/105)
Technique
2D/3D CRT 53.3% (56/105)
SRS 21.9% (23/105)
VMAT/IMRT 16.2% (17/105)
SBRT 4.8% (5/105)
Proton 3.8% (4/105)
Non-SRS dose 14-63 Gy in 4-35 fractions
SBRT dose 24-50 Gy in 3-5 fractions
SRS dose 15-25 Gy in 1-5 fractions
Abbreviations: 2D = 2-dimensional; 3D CRT = 3-dimensional conformal radiation therapy; CNS = central nervous system; IMRT = intensity modulated radiation therapy; RT = radiation therapy; SBRT = stereotactic body radiation therapy; SRS = stereotactic radiosurgery; VMAT = volumetric modulated arc therapy.
Non-CNS treatment locations included tumors in soft tissue or organs (35%), lymph nodes (21%), and bone (11%); 4 patients were treated simultaneously to adjacent soft tissue and lymph nodes. Treatment for CNS metastases comprised the remaining 36% of patients.
Most patients were treated for clinical symptoms (59%). Pain and bleeding were the most common clinical indications. Others included neurologic deficits, spinal cord compression, airway compression, and bowel obstruction. A large cohort of patients were treated for asymptomatic progressive or metastatic disease (33%) with a small cohort treated adjuvantly after surgery (eg, metastasectomy or palliative debulking; 7.6%).
Almost all patients (90%) received chemotherapy immediately before radiation therapy. The most common systemic therapy regimens were platinum-based (ie, carboplatin) followed by taxanes and doxorubicin. Many patients (43%) also received treatment with targeted therapy agents before radiation treatment. Bevacizumab was the most commonly used targeted therapy agent (20%), although patients also received PARP inhibitors (9%) and immune checkpoint inhibitors (5%).
A wide range of palliative radiation regimens were delivered across several modalities. Nonstereotactic treatment regimens to both CNS and non-CNS locations ranged from 14 Gy in 4 fractions to 63 Gy in 35 fractions. Common palliative doses were 30 Gy in 10 fractions (14%), 20 Gy in 5 fractions (8.6%), and 35 Gy in 14 fractions (7.6%). Nonstereotactic modalities included 2-dimensional or 3-dimensional (53%), intensity modulated radiation therapy (IMRT) or volumetric-modulated arc therapy (16%), and proton therapy (3.8%). Stereotactic body radiation therapy (SBRT) was less commonly used (4.8%) with treatment regimen ranging from 24 Gy in 3 fractions to 50 Gy in 5 fractions. Lastly, patients with BMs commonly received stereotactic radiosurgery (SRS, 22% of all courses) with doses ranging from 15 Gy in 1 fraction to 25 Gy in 5 fractions. Nearly half of the patients who underwent SRS received 21 Gy in 1 fraction.
Across the entire cohort, the clinical ORR was 76% within the first month after treatment and 67% at least 3 months after treatment (Table 2). Radiographic ORR between patients treated for clinical symptoms (symptomatic) and asymptomatic progression (asymptomatic) were 48% and 59%, respectively. Although patients treated for asymptomatic progression had higher rates of response, no significant differences were observed between the 2 cohorts (P = .23).Table 2 Response rates (all lesions)
<1 mo 1-3 mo >3 mo
Clinical response
CR 32.8% (19/58) 45.0% (18/40) 48.4% (15/31)
PR 43.1% (25/58) 35.0% (14/40) 19.4% (6/31)
SD 12.1% (7/58) 2.5% (1/40) 0.0% (0/31)
PD 12.1% (7/58) 17.5% (7/40) 32.3% (10/31)
ORR 75.9% (44/58) 80.0% (32/40) 67.7% (21/31)
Radiographic response: symptomatic patients
CR 15.2% (5/33) 16.7% (5/30) 25.9% (7/27)
PR 24.2% (8/33) 30.0% (9/30) 22.2% (6/27)
SD 51.5% (17/33) 43.3% (13/30) 40.7% (11/27)
PD 9.1% (3/33) 10.% (3/30) 11.1% (3/27)
ORR 39.4% (13/33) 46.7% (14/30) 48.1% (13/27)
Radiographic response: asymptomatic patients
CR 39.4% (13/33) 47.1% (16/34) 53.1% (17/32)
PR 9.1% (3/33) 8.8% (3/34) 6.3% (2/32)
SD 45.5% (15/33) 41.2% (14/34) 34.4% (11/32)
PD 6.1% (2/33) 2.9% (1/34) 6.3% (2/32)
ORR 48.5% (16/33) 55.9% (19/34) 59.4% (19/32)
Abbreviations: CR = complete response; ORR = overall response rate; PD = progressive disease; PR = partial response; SD = stable disease.
Excludes patients treated with postoperative palliative radiation.
Denominator reflects evaluable patients.
Of patients treated to non-CNS locations, the clinical and radiographic ORR within the first month after treatment were 79% and 33%, respectively (Table 3). Clinical ORR at last follow-up (at least 3 months after treatment) was 61%. Notably, of the patients with a CR (38.1%) within the first month, only 2 went on to have PD at last follow-up (4 were lost to follow-up), indicating durable response to treatment. All but one patient treated for malignancy-related vaginal bleeding (13/14) had a clinical response within 1 month, of which only one patient had recurrence of bleeding at last follow-up. Seventy percent of patients treated for pain (n = 27) had a clinical response within 1 month, of which only 3 patients demonstrated worsening pain at last follow-up. Radiographically, ORR improved to 38% for symptomatic patients and 47% for asymptomatic patients at last follow-up, with no significant differences in response rates between the 2 groups (P = .44). All lesions that responded within 1 month of radiation treatment maintained response through last follow-up. Furthermore, only 3 of 22 lesions that were initially SD, progressed over time (1 treated for clinical symptoms, 2 treated for asymptomatic progression).Table 3 Response rates (non-CNS lesions)
<1 mo 1-3 mo >3 mo
Clinical response
CR 38.1% (16/42) 44.8% (13/29) 43.5% (10/23)
PR 40.5% (17/42) 31.0% (9/29) 17.4% (4/23)
SD 14.3% (6/42) 3.4% (1/29) 0.0% (0/23)
PD 7.1% (3/42) 20.7% (6/29) 39.1% (9/23)
ORR 78.6% (33/42) 75.9% (22/29) 60.9% (14/23)
Radiographic response: symptomatic patients
CR 9.5% (2/21) 10.5% (2/19) 18.8% (3/16)
PR 23.8% (5/21) 26.3% (5/19) 18.8% (3/16)
SD 52.4% (11/21) 52.6% (10/19) 50.0% (8/16)
PD 14.3% (3/21) 10.5% (2/19) 12.5% (2/16)
ORR 33.3% (7/21) 36.8% (7/19) 37.5% (6/16)
Radiographic response: asymptomatic patients
CR 21.1% (4/19) 31.6% (6/19) 41.2% (7/17)
PR 10.5% (2/19) 10.5% (2/19) 5.9% (1/17)
SD 57.9% (11/19) 52.6% (10/19) 41.2% (7/17)
PD 10.5% (2/19) 5.3% (1/19) 11.8% (2/17)
ORR 31.6% (6/19) 42.1% (8/19) 47.1% (8/17)
Abbreviations: CNS = central nervous system; CR = complete response; ORR = overall response rate; PD = progressive disease; PR = partial response; SD = stable disease.
Excludes patients treated with postoperative palliative radiation.
Denominator reflects evaluable patients.
Of patients treated to CNS locations, the clinical and radiographic ORR within the first month after treatment were 72% and 62%, respectively (Table 4). No patients with a demonstrated clinical or radiographic response within the first month went on to have documented progressive symptoms or imaging at last follow-up (although 2 patients died and 4 were lost to follow-up). Although clinical responses stayed constant over time, radiographic responses tended to improve, especially in patients treated for clinical symptoms. There was no difference in rates of radiographic responses between CNS patients treated for clinical symptoms and those treated for asymptomatic progression (P = .41). All patients receiving SRS responded or had SD at 1 month; only one patient had locally progressive symptoms and disease at last follow-up. Three of the 4 patients with progressive symptoms within the first month were those who received whole brain radiation therapy with more extensive CNS disease before treatment.Table 4 Response rates (CNS lesions)
<1 mo 1-3 mo >3 mo
Clinical response
CR 18.8% (3/16) 45.5% (5/11) 62.5% (5/8)
PR 50.0% (8/16) 45.5% (5/11) 25.0% (2/8)
SD 6.3% (1/16) 0.0% (0/11) 0.0% (0/8)
PD 25.0% (4/16) 9.1% (1/11) 12.5% (1/8)
ORR 68.8% (11/16) 90.9% (10/11) 87.5% (7/8)
Radiographic response: symptomatic patients
CR 25.0% (3/12) 27.3% (3/11) 36.4% (4/11)
PR 25.0% (3/12) 36.4% (4/11) 27.3% (3/11)
SD 50.% (6/12) 27.3% (3/11) 27.3% (3/11)
PD 0.0% (0/12) 9.1% (1/11) 9.1% (1/11)
ORR 50.0% (6/12) 63.6% (7/11) 63.6% (7/11)
Radiographic response: asymptomatic patients
CR 64.3% (9/14) 66.7% (10/15) 66.7% (10/15)
PR 7.1% (1/14) 6.7% (1/15) 6.7% (1/15)
SD 28.6% (4/14) 26.7% (4/15) 26.7% (4/15)
PD 0.0% (0/14) 0.0% (0/15) 0.0% (0/15)
ORR 71.4% (10/14) 73.3% (11/15) 73.3% (11/15)
Abbreviations: CNS = central nervous system; CR = complete response; PD = progressive disease; PR = partial response; ORR = overall response rate; SD = stable disease.
Excludes patients treated with postoperative palliative radiation.
Denominator reflects evaluable patients.
Patients in both CNS and non-CNS cohorts tended to have clinical responses early on, with sustained response at last follow-up. Furthermore, if a patient were to have a clinical CR, it most often occurred within the first month. Only 4 patients demonstrated a CR after the first month, and all of these patients had a PR initially; no patients with initially stable disease went on to have a CR. Most patients with radiographic SD at initial follow-up maintained SD over time. The initial responses of patients developing progressive symptoms after 3-month follow-up varied considerably: CR (2), PR (3), SD (2), and PD (3). No patients who progressed within the first month of follow-up went on to have any response.
Eight patients were treated with postoperative RT after surgical resection in the brain (6), mediastinal lymph node (1), and inguinal lymph node (1). Three patients with evaluable clinical symptoms before and after surgery-RT all demonstrated diminished (PR) or complete (CR) resolution of symptoms within 1 month after RT. Of the 6 patients with radiographic follow-up, one recurred 9 months after treatment; the rest maintained stable disease (ie, no recurrence) through last follow-up.
Acute and late grade 3 or higher (G3 +) toxicities with bevacizumab were low (8.7% and 4.3%, respectively). CNS and mediastinal locations were the only treatment sites in which G3 + toxicity occurred. CNS toxicity (acute G3 fatigue, late G3 radiation necrosis, and late G4 optic neuritis) was identified in a single patient who received craniospinal irradiation with prior Gamma Knife irradiation. A second patient treated to the mediastinum had acute but not chronic grade 3 esophagitis. Notably, no acute or late G3 + toxicity was seen in patients treated to the abdomen or pelvis (the most common treatment location; Table 5).Table 5 Observed toxicities in patients treated with bevacizumab before or concurrent with radiation therapy, by treatment course
None Grade 1-2 Grade 3 Grade 4
Acute
Non-CNS (17) 6 Anorexia (1),
depression (1),
dermatitis (1),
fatigue (5),
GI (6), GU (1),
odynophagia (1),
pneumonitis (1),
vaginal hemorrhage (1) Dermatitis (1),
esophagitis (1) -
CNS (6) 4 GI (1) Fatigue (1) -
Late
Non-CNS (9) 8 GI (1) - -
CNS (5) 3 Intracranial hemorrhage (1) Radionecrosis (1) Optic neuropathy (1)
Abbreviations: CNS = central nervous system; GI = gastrointestinal; GU = genitourinary.
Toxicities defined according to the Common Terminology Criteria for Adverse Events, version 5.0.
Numbers indicate number of treatment courses; more than one toxicity may be attributed to a single treatment course. Late toxicity data unavailable for 9 treatment courses (all due to patient death).
Late grade 3 and 4 toxicities occurred in the same patient.
An exploratory analysis examining patient demographics and treatment characteristics was performed to identify predictors of clinical or radiographic response. In all patients (CNS and non-CNS sites), HGS histology was associated with clinical responses (88% vs 64%, P = .04). In patients with CNS lesions, BED >39 Gy was associated with clinical response (P = .049). In non-CNS locations, bony site was associated with worse clinical (44% vs 89%, P = .004) response compared with soft tissue/nodal (STN) sites. Lastly, we compared BED regimens ≤39 Gy versus >39 Gy (assuming an alpha/beta ratio of 10,19,20 the BED of 30 Gy in 10 fractions is 39 Gy) in non-CNS locations and found no differences in clinical (P = .10) or radiographic response rates (P = .47). We otherwise compared the most common regimens of 20 Gy in 5 fractions and 30 Gy in 10 fractions and found no significant differences in clinical (P = .60) or radiographic responses (P = .29; Table E1).2
Discussion
We report the outcomes of a large modern cohort of women with PMR-OC who received palliative radiation therapy in an era of novel systemic agents. In a population with poor prognosis, palliative radiation therapy resulted in excellent clinical and radiographic response rates (Table 2) within 1 month of treatment, with many responses durable beyond 3 months. Brain metastases, a rare site of anatomic spread, were also well represented in this cohort (36%, 38 courses) and responded favorably to palliative intracranial radiation therapy (Table 3). Exploratory analyses demonstrated an association between HGS histology and improved clinical response in all patients, BED >39 Gy and improved clinical response in BMs, and STN sites with improved clinical response in non-CNS sites. Our analysis is unique in its (1) large sample size compared with prior reports with significant number of BMs, (2) high proportion of patients treated with modern RT techniques, (3) inclusion of patients treated with novel systemic agents (ie, PARP inhibitors, bevacizumab, and immunotherapy), and (4) dedicated toxicity analysis of RT with concurrent or prior bevacizumab, an area of increasing clinical significance in MPR-EOC with a dearth of robust data.
Our high clinical response rates (79% ORR within 1 month) are similar to other reports, including literature from prior decades demonstrating durable pain relief and bleeding control from locally directed palliative RT in 80% of OC patients.20, 21, 22 More recently, Bansal and colleagues also found pain control rates of 88.2% and vaginal bleeding control rates of 100% in 23 heavily pretreated women who received palliative pelvic RT.23 Investigators from Brigham and Women’s Hospital also recently published rates and predictors of response to palliative RT for recurrent OC from 2003 to 201424 and demonstrated high rates of response for pain and bleeding (87% and 93%, respectively).
Identified predictors of response, including HGS histology and STN sites of disease are also compatible with prior investigations. In the above Brigham and Women’s Hospital study, patients treated at nonbony sites had higher response rates than those with bony sites of disease (96% vs 75%, respectively). Furthermore, patients with clear cell histology had the lowest response rates (60%), compared with others like serous histology (82%).
The sizable nature of our cohort allowed for a temporal analysis of index lesion response rates. Patients in both CNS and non-CNS cohorts tended to have clinical responses early on, with some benefitting from sustained response at last follow-up. Lesions with clinical CR often occurred within the first month. Furthermore, no patients who progressed in the index lesion within the first month of follow-up went on to have any response, suggesting that initial response is of paramount importance. Patients who had progressive symptoms after 3 months had variable initial responses, suggesting progressive disease is still expected no matter what the initial response may be.
Regarding dose response, higher BED was associated with clinical response in brain metastases. This is a result of ablative SRS technology that radiobiologically induces high rates of cell kill compared with those of conventional palliative techniques or doses. Advanced stereotactic techniques permit the delivery of otherwise unsafe high dose-per-fraction regimens due to their sharp dose gradients that allow for normal tissue sparing. In non-CNS locations, however, regimens with BED >39 Gy (ie, greater than 30 Gy in 10 fractions) were no different than lower BED regimens, suggesting dose escalation may not increase the efficacy of palliative RT. Use of higher BED regimens in such (predominantly abdominopelvic) locations is typically limited by larger fields due to tumor size and organ motion. Dose-limiting toxicities from nearby organs at risk such as the stomach, bowel, kidneys, and bladder also constrain prescriptions.
Notably, 47% of all courses were delivered with advanced radiation therapy techniques (SRS, SBRT, IMRT/volumetric-modulated arc therapy, proton therapy). This is in keeping with the increasing number of patients referred for ablative or definitive therapy to oligometastatic or oligoprogressive disease or previously irradiated lesions requiring retreatment. In such scenarios, advanced techniques allow practitioners to deliver higher dose per fraction while sparing normal organs and tissue of radiation, or even reirradiation, toxicity. In fact, recently published reports have evaluated the roles of advanced RT in OC. For example, definitive involved-field RT using IMRT has demonstrated promising rates of local control (LC) and disease-free survival with low toxicity.25,26 Two recent retrospective studies also explored SBRT in oligometastatic OC. Lazzari et al reported the treatment of 82 patients with a median dose of 24 Gy in 3 fractions and demonstrated the safety of SBRT along with an increase in systemic therapy-free survival with reasonable LC27 (more than one-third of patients were disease-free at 1 year). Similarly, Macchia et al reported SBRT in MPR-EOC was well tolerated and afforded higher LC in patients receiving a total dose >25 Gy.28
Forty-three percent of patients received targeted therapy immediately before RT in this cohort. This is in keeping with the litany of recent publications studying the use of novel systemic agents (PARP inhibitors,29, 30, 31 bevacizumab,32 nivolumab33) in the setting of MPR-EOC. The response rates described thus reflect the potential outcomes of palliative RT in conjunction with advanced systemic therapies, a scenario that will be increasingly encountered by practitioners. Furthermore, given the sizeable population that received prior or concurrent bevacizumab, a dedicated subgroup analysis was conducted and demonstrated low acute and late grade 3 or higher (G3 +) toxicities (8.7% and 4.3%, respectively) with RT. Although G3 + toxicities occurred in patients treated to CNS and mediastinal locations, it is unclear if this was in relation to prior bevacizumab or reflected the increased risk toxicity with prior RT (Gamma Knife in the CNS patient treated with craniospinal irradiation) or unfavorable tumor location (in the mediastinal patient experiencing esophagitis after receiving 59.4 Gy). No acute or late G3 + toxicity was seen in patients treated to the abdomen or pelvis (the most common treatment location), suggesting that this may be a reasonable treatment option in symptomatic patients.
Limitations
The study is limited primarily by its retrospective nature which lends itself to both selection and sample bias. For example, patient performance status and prior lines of therapy (including prior radiation) may effect physician choice of RT technique, dose, and fractionation. Furthermore, lesions necessitating reirradiation demonstrate inherent radioresistance and may negatively affect response rates. Moreover, although the study population is sizeable, it is heterogenous with respect to treatment sites and prior lines of therapy. As such appropriate interpretation required subdivision of data (ie, CNS vs non-CNS, symptomatic vs asymptomatic indication), which led to more descriptive findings. Finally, the variety of systemic therapies used negatively affect our ability to make conclusions regarding the efficacy of RT with respect to individual agents.
Future directions
As the role for palliative radiation therapy expands in the context of the oligometastatic paradigm, nuanced decision-making must be taken to deliver the most efficacious treatment although promoting cost-effective care. As such, prospective evaluation is warranted to determine the optimal dose, timing, and fractionation of RT as it relates to systemic agents and surgery. The high response rates demonstrated in this cohort may warrant prospective investigation of RT as a standard component therapy in MPR-EOC, either before systemic agents as a cytoreductive strategy or after as consolidation therapy.
Conclusions
We performed a large retrospective cohort analysis of women with MPR-EOC receiving palliative RT in the era of modern technology and systemic agents. Our large population of patients with BMs adds relevant data to the limited body of existing literature and can be used as a practical reference when counseling women. Patients demonstrated favorable clinical and radiographic response rates within 1 month, with >60% experiencing durable clinical responses beyond 3 months. HGS histology was associated with improved clinical response in all patients. BED >39 Gy was associated with improved response in brain metastases. Bony sites were associated with worse response compared with STN sites in non-CNS locations. Acute and late grade 3 or higher toxicities were low with prior bevacizumab, and none of these occurred in patients treated to abdominopelvic locations.
Although MPR-EOC is associated with limited prognosis, our data demonstrate that responses to palliative RT can be durable and meaningful. As such, without a conclusive effect on survival, it would be reasonable to consider treatment of such disease after taking into consideration patient symptom severity, goals of care, prognosis, performance status, and extracranial disease burden for BM.
Supplementary Materials
Tables E1 and E2
Sources of support: The authors received no specific funding for this work.
Disclosures: The authors of this manuscript have no conflicts of interest to report.
Research data are stored in an institutional repository and will be shared upon request.
Supplementary material for this article can be found at https://doi.org/10.1016/j.adro.2020.11.009. | BEVACIZUMAB | DrugsGivenReaction | CC BY-NC-ND | 33665491 | 18,951,285 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Fatigue'. | Palliative Radiation Therapy for Metastatic, Persistent, or Recurrent Epithelial Ovarian Cancer: Efficacy in the Era of Modern Technology and Targeted Agents.
Metastatic, persistent, or recurrent epithelial ovarian cancer (MPR-EOC) remains a significant threat to patient mortality despite advances in novel targeted agents. Radiation therapy (RT) is often used as a palliative option. We report outcomes of a large series of MPR-EOC patients treated with modern palliative RT (PRT) in an era of novel systemic therapies.
A retrospective review was conducted of women treated with PRT for MPR-EOC between 2007 and 2019 at an academic institution. Clinical response rates were recorded at <1 month, 1 to 3 months, and >3 months. Radiographic responses were categorized by RECIST 1.1 criteria. Overall response rate (ORR) was the sum of complete and partial response. Linear regression analyses of baseline characteristics were conducted for statistical testing.
Eighty-six patients with PMR-OC received 120 courses of palliative RT. Median follow-up was 8.6 months. Median age was 61 (range, 22-82). Thirty-six percent of women received central nervous system (CNS)-directed RT. In addition, 43% received targeted therapies before RT. Clinical ORR within 1 month and at last follow-up for non-CNS lesions was 79% and 61% (69% and 88% for CNS lesions, respectively). High-grade serous lesions were more likely to have clinical response (P = .04). Biologically effective doses (BED) >39 Gy were associated with improved clinical response in CNS lesions (P = .049). Bony sites were associated with worse clinical (P = .004) response in non-CNS lesions compared with soft tissue or nodal sites. Acute or late grade 3+ toxicities with bevacizumab were low (8.7%/4.3%).
PRT offers excellent rates of response for symptomatic patients with MPR-EOC within 1 month of treatment, with durable responses beyond 3 months. High-grade serous lesions were associated with improved response in all patients. Higher BED and soft tissue or nodal sites were associated with improved response in CNS and non-CNS patients, respectively. Acute or late toxicities with bevacizumab and PRT were low. Prospective investigation is warranted to determine the optimal PRT regimen.
Introduction
Ovarian cancer (OC) is a highly aggressive gynecologic malignancy, with the majority of patients presenting with advanced disease at diagnosis. The general treatment paradigm for advanced OC is maximal cytoreductive surgery with platinum-based chemotherapy.1 Recent literature has also reported a progression-free survival benefit with maintenance inhibition of poly (adenosine diphosphate-ribose) polymerase (PARP) in women with partial or complete response to platinum-based regimens.2,3
Whole abdominal radiation therapy was historically indicated as adjuvant therapy to address microscopic residual disease.4 However, due to its considerable toxicity and the development of platinum-based chemotherapy, whole abdominal radiation therapy is no longer included in primary OC treatment paradigms.1
Despite advances in cytoreductive strategies and front-line systemic therapy, >70% of women relapse within 3 years of diagnosis.5 As such, many patients with OC benefit from palliative care referrals to assist with symptom management, goals of care discussions, and complex medical decision making at the end of life.
There is a growing body of evidence to support the incorporation of palliative services in cancer care. In 2010, a seminal randomized trial6 reported early palliative care among patients with metastatic non-small cell lung cancer significantly improved quality of life, led to less aggressive care at the end of life, and resulted in longer overall survival. Furthermore, both the American Society of Clinical Oncology and the Society of Gynecologic Oncology have published official practice guidelines recommending the routine and early integration of palliative services.7,8
Radiation therapy (RT) is often used as an effective therapeutic option in the palliation of patients with metastatic, persistent, or recurrent epithelial OC (MPR-EOC) as a means for symptomatic relief and local control. This includes oligometastatic disease or symptomatic disease causing pain, bowel or ureteral obstruction, or bleeding. Despite their rarity in OC (2% incidence9), brain metastases can also cause significant morbidity and can be treated with palliative RT to reduce the risk of progression and neurocognitive deficits.10,11
As patient survival improves with modern systemic agents, there is a growing need to understand the efficacy of palliative RT regimens for MPR-EOC in the same era. Although radiation therapy has traditionally been delivered for symptomatic control in MPR-EOC, the recognition of the biologically distinct (and potentially curable) oligometastatic state12,13 is expanding the scope of RT indications. Data from phase 2 trials in other malignancies evaluating the effect of locally directed therapy to oligometastatic lesions has demonstrated improvements in overall survival.14,15
We therefore conducted, a large contemporary retrospective analysis of palliative RT in MPR-EOC. This patient cohort is highly relevant to modern practice given the number of patients who received novel systemic agents, the prominent usage of advanced RT technology, and the representation of patients with BMs from OC (an area with limited data but increasing prevalence in practice). The analysis will report the outcomes and durability of palliative RT in MPR-EOC and delineate factors predictive of response in the modern era.
Methods and Materials
We conducted a retrospective chart review of women treated with palliative radiation therapy for metastatic ovarian cancer from 2007 through 2019 at [University of Pennsylvania] and affiliate sites. Institutional review board approval was obtained before conducting this review. Patients were included in this analysis if they were treated for palliative intent, including treatment of oligometastatic disease. All patients had MPR-EOC ovarian cancer and received anywhere from one to 5 courses of radiation treatment.
Given the poor prognosis of patients with metastatic ovarian cancer, clinical and radiographic response rates were categorized in intervals of <1 month, 1 to 3 months, and >3 months after the end of radiation treatment to indicate acute and durable responses. Clinical responses were categorized as complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD). Pain scores were classified using the Bone Metastases Consensus Working Party guidelines16 (indeterminate responses, which are neither PR nor PD per BMWCP guidelines, were classified as SD to maintain consistency with other clinical response categorizations). Radiographic responses were categorized as CR, PR, SD, or PD based on the RECIST 1.1 criteria.17 Overall response rate (ORR) was the sum of CR and PR in a given patient. Given the large subset of patients with brain metastases (BMs), courses were stratified by central nervous system (CNS) and non-CNS anatomic locations. Acute (during RT and within 3 months of completion) and late (>3 months after completion of RT) toxicities were recorded with concurrent and prior bevacizumab using Common Terminology Criteria for Adverse Events version 5.018 classification.
Rates of response (CR or PR at any point) were compared with demographic and treatment characteristics. χ2 (n ≥ 20) or Fisher exact (n < 20) tests were used for such comparison with variables for race, histology, platinum chemotherapy, or targeted therapy before RT, RT technology, RT location, and biologically effective dose (BED) >39. Binary logistic regression analyses were used for comparison with continuous variables (age and BED). Covariates with P < .1 were included in multiple logistic regression modeling to assess for independent effect. Additionally, χ2 analyses were used to compare rates of radiographic response between patients treated for clinical symptoms and asymptomatic progression. Statistical analysis was conducted using IBM SPSS Statistics, version 26 (IBM Corporation, Armonk, NY).
Results
We identified 86 patients with PMR-OC that received 120 combined courses of palliative radiation treatment. Median follow-up was 8.6 months (range, 0.5-119 months). Excluding 10 patients (15 courses) with no evaluable clinical or radiographic follow-up, 51 patients (58 courses) were treated to non-CNS locations and 18 patients (25 courses) were treated to CNS locations; 7 patients (22 courses) received palliative RT to both CNS (13 courses) and non-CNS (9 courses) locations.
Table 1 describes baseline patient characteristics and details related to patient treatments. The median age of patients in this cohort was 61, with a range of 22 to 82. Patients were most commonly white (83%) and black (8%). Tumor histologies were primarily high-grade serous (HGS, 59%), although adenocarcinoma (undifferentiated or unspecified), low-grade serous, clear cell, endometrioid, and carcinosarcoma were also observed.Table 1 Patient characteristics and treatment details
No. of courses 105
No. of patients 76
Median age 61
Ethnicity
White 82.9% (63/76)
Black 9.2% (7/76)
Asian 3.9% (3/76)
Hispanic 2.6% (2/76)
Unknown 1.3% (1/76)
Histology
High-grade serous 59.2% (45/76)
Adenocarcinoma, other 13.2% (10/76)
Low grade serous 9.2% (7/76)
Clear cell 5.3% (4/76)
Other 7.9% (6/76)
Endometrioid 3.9% (3/76)
Carcinosarcoma 1.3% (1/76)
Anatomic site
Soft tissue/organ 35.2% (37/105)
Lymph node 21.0% (22/105)
Bone 11.4% (12/105)
CNS 36.2% (38/105)
Indications
Clinical symptoms 59.0% (62/105)
Progressive/metastatic 33.3% (35/105)
Postoperative 7.6% (8/105)
Systemic therapy before RT
Platinum chemotherapy 27.6% (29/105)
Nonplatinum chemotherapy 61.9% (65/105)
Targeted therapy 42.9% (45/105)
None/other 1.0% (1/105)
Technique
2D/3D CRT 53.3% (56/105)
SRS 21.9% (23/105)
VMAT/IMRT 16.2% (17/105)
SBRT 4.8% (5/105)
Proton 3.8% (4/105)
Non-SRS dose 14-63 Gy in 4-35 fractions
SBRT dose 24-50 Gy in 3-5 fractions
SRS dose 15-25 Gy in 1-5 fractions
Abbreviations: 2D = 2-dimensional; 3D CRT = 3-dimensional conformal radiation therapy; CNS = central nervous system; IMRT = intensity modulated radiation therapy; RT = radiation therapy; SBRT = stereotactic body radiation therapy; SRS = stereotactic radiosurgery; VMAT = volumetric modulated arc therapy.
Non-CNS treatment locations included tumors in soft tissue or organs (35%), lymph nodes (21%), and bone (11%); 4 patients were treated simultaneously to adjacent soft tissue and lymph nodes. Treatment for CNS metastases comprised the remaining 36% of patients.
Most patients were treated for clinical symptoms (59%). Pain and bleeding were the most common clinical indications. Others included neurologic deficits, spinal cord compression, airway compression, and bowel obstruction. A large cohort of patients were treated for asymptomatic progressive or metastatic disease (33%) with a small cohort treated adjuvantly after surgery (eg, metastasectomy or palliative debulking; 7.6%).
Almost all patients (90%) received chemotherapy immediately before radiation therapy. The most common systemic therapy regimens were platinum-based (ie, carboplatin) followed by taxanes and doxorubicin. Many patients (43%) also received treatment with targeted therapy agents before radiation treatment. Bevacizumab was the most commonly used targeted therapy agent (20%), although patients also received PARP inhibitors (9%) and immune checkpoint inhibitors (5%).
A wide range of palliative radiation regimens were delivered across several modalities. Nonstereotactic treatment regimens to both CNS and non-CNS locations ranged from 14 Gy in 4 fractions to 63 Gy in 35 fractions. Common palliative doses were 30 Gy in 10 fractions (14%), 20 Gy in 5 fractions (8.6%), and 35 Gy in 14 fractions (7.6%). Nonstereotactic modalities included 2-dimensional or 3-dimensional (53%), intensity modulated radiation therapy (IMRT) or volumetric-modulated arc therapy (16%), and proton therapy (3.8%). Stereotactic body radiation therapy (SBRT) was less commonly used (4.8%) with treatment regimen ranging from 24 Gy in 3 fractions to 50 Gy in 5 fractions. Lastly, patients with BMs commonly received stereotactic radiosurgery (SRS, 22% of all courses) with doses ranging from 15 Gy in 1 fraction to 25 Gy in 5 fractions. Nearly half of the patients who underwent SRS received 21 Gy in 1 fraction.
Across the entire cohort, the clinical ORR was 76% within the first month after treatment and 67% at least 3 months after treatment (Table 2). Radiographic ORR between patients treated for clinical symptoms (symptomatic) and asymptomatic progression (asymptomatic) were 48% and 59%, respectively. Although patients treated for asymptomatic progression had higher rates of response, no significant differences were observed between the 2 cohorts (P = .23).Table 2 Response rates (all lesions)
<1 mo 1-3 mo >3 mo
Clinical response
CR 32.8% (19/58) 45.0% (18/40) 48.4% (15/31)
PR 43.1% (25/58) 35.0% (14/40) 19.4% (6/31)
SD 12.1% (7/58) 2.5% (1/40) 0.0% (0/31)
PD 12.1% (7/58) 17.5% (7/40) 32.3% (10/31)
ORR 75.9% (44/58) 80.0% (32/40) 67.7% (21/31)
Radiographic response: symptomatic patients
CR 15.2% (5/33) 16.7% (5/30) 25.9% (7/27)
PR 24.2% (8/33) 30.0% (9/30) 22.2% (6/27)
SD 51.5% (17/33) 43.3% (13/30) 40.7% (11/27)
PD 9.1% (3/33) 10.% (3/30) 11.1% (3/27)
ORR 39.4% (13/33) 46.7% (14/30) 48.1% (13/27)
Radiographic response: asymptomatic patients
CR 39.4% (13/33) 47.1% (16/34) 53.1% (17/32)
PR 9.1% (3/33) 8.8% (3/34) 6.3% (2/32)
SD 45.5% (15/33) 41.2% (14/34) 34.4% (11/32)
PD 6.1% (2/33) 2.9% (1/34) 6.3% (2/32)
ORR 48.5% (16/33) 55.9% (19/34) 59.4% (19/32)
Abbreviations: CR = complete response; ORR = overall response rate; PD = progressive disease; PR = partial response; SD = stable disease.
Excludes patients treated with postoperative palliative radiation.
Denominator reflects evaluable patients.
Of patients treated to non-CNS locations, the clinical and radiographic ORR within the first month after treatment were 79% and 33%, respectively (Table 3). Clinical ORR at last follow-up (at least 3 months after treatment) was 61%. Notably, of the patients with a CR (38.1%) within the first month, only 2 went on to have PD at last follow-up (4 were lost to follow-up), indicating durable response to treatment. All but one patient treated for malignancy-related vaginal bleeding (13/14) had a clinical response within 1 month, of which only one patient had recurrence of bleeding at last follow-up. Seventy percent of patients treated for pain (n = 27) had a clinical response within 1 month, of which only 3 patients demonstrated worsening pain at last follow-up. Radiographically, ORR improved to 38% for symptomatic patients and 47% for asymptomatic patients at last follow-up, with no significant differences in response rates between the 2 groups (P = .44). All lesions that responded within 1 month of radiation treatment maintained response through last follow-up. Furthermore, only 3 of 22 lesions that were initially SD, progressed over time (1 treated for clinical symptoms, 2 treated for asymptomatic progression).Table 3 Response rates (non-CNS lesions)
<1 mo 1-3 mo >3 mo
Clinical response
CR 38.1% (16/42) 44.8% (13/29) 43.5% (10/23)
PR 40.5% (17/42) 31.0% (9/29) 17.4% (4/23)
SD 14.3% (6/42) 3.4% (1/29) 0.0% (0/23)
PD 7.1% (3/42) 20.7% (6/29) 39.1% (9/23)
ORR 78.6% (33/42) 75.9% (22/29) 60.9% (14/23)
Radiographic response: symptomatic patients
CR 9.5% (2/21) 10.5% (2/19) 18.8% (3/16)
PR 23.8% (5/21) 26.3% (5/19) 18.8% (3/16)
SD 52.4% (11/21) 52.6% (10/19) 50.0% (8/16)
PD 14.3% (3/21) 10.5% (2/19) 12.5% (2/16)
ORR 33.3% (7/21) 36.8% (7/19) 37.5% (6/16)
Radiographic response: asymptomatic patients
CR 21.1% (4/19) 31.6% (6/19) 41.2% (7/17)
PR 10.5% (2/19) 10.5% (2/19) 5.9% (1/17)
SD 57.9% (11/19) 52.6% (10/19) 41.2% (7/17)
PD 10.5% (2/19) 5.3% (1/19) 11.8% (2/17)
ORR 31.6% (6/19) 42.1% (8/19) 47.1% (8/17)
Abbreviations: CNS = central nervous system; CR = complete response; ORR = overall response rate; PD = progressive disease; PR = partial response; SD = stable disease.
Excludes patients treated with postoperative palliative radiation.
Denominator reflects evaluable patients.
Of patients treated to CNS locations, the clinical and radiographic ORR within the first month after treatment were 72% and 62%, respectively (Table 4). No patients with a demonstrated clinical or radiographic response within the first month went on to have documented progressive symptoms or imaging at last follow-up (although 2 patients died and 4 were lost to follow-up). Although clinical responses stayed constant over time, radiographic responses tended to improve, especially in patients treated for clinical symptoms. There was no difference in rates of radiographic responses between CNS patients treated for clinical symptoms and those treated for asymptomatic progression (P = .41). All patients receiving SRS responded or had SD at 1 month; only one patient had locally progressive symptoms and disease at last follow-up. Three of the 4 patients with progressive symptoms within the first month were those who received whole brain radiation therapy with more extensive CNS disease before treatment.Table 4 Response rates (CNS lesions)
<1 mo 1-3 mo >3 mo
Clinical response
CR 18.8% (3/16) 45.5% (5/11) 62.5% (5/8)
PR 50.0% (8/16) 45.5% (5/11) 25.0% (2/8)
SD 6.3% (1/16) 0.0% (0/11) 0.0% (0/8)
PD 25.0% (4/16) 9.1% (1/11) 12.5% (1/8)
ORR 68.8% (11/16) 90.9% (10/11) 87.5% (7/8)
Radiographic response: symptomatic patients
CR 25.0% (3/12) 27.3% (3/11) 36.4% (4/11)
PR 25.0% (3/12) 36.4% (4/11) 27.3% (3/11)
SD 50.% (6/12) 27.3% (3/11) 27.3% (3/11)
PD 0.0% (0/12) 9.1% (1/11) 9.1% (1/11)
ORR 50.0% (6/12) 63.6% (7/11) 63.6% (7/11)
Radiographic response: asymptomatic patients
CR 64.3% (9/14) 66.7% (10/15) 66.7% (10/15)
PR 7.1% (1/14) 6.7% (1/15) 6.7% (1/15)
SD 28.6% (4/14) 26.7% (4/15) 26.7% (4/15)
PD 0.0% (0/14) 0.0% (0/15) 0.0% (0/15)
ORR 71.4% (10/14) 73.3% (11/15) 73.3% (11/15)
Abbreviations: CNS = central nervous system; CR = complete response; PD = progressive disease; PR = partial response; ORR = overall response rate; SD = stable disease.
Excludes patients treated with postoperative palliative radiation.
Denominator reflects evaluable patients.
Patients in both CNS and non-CNS cohorts tended to have clinical responses early on, with sustained response at last follow-up. Furthermore, if a patient were to have a clinical CR, it most often occurred within the first month. Only 4 patients demonstrated a CR after the first month, and all of these patients had a PR initially; no patients with initially stable disease went on to have a CR. Most patients with radiographic SD at initial follow-up maintained SD over time. The initial responses of patients developing progressive symptoms after 3-month follow-up varied considerably: CR (2), PR (3), SD (2), and PD (3). No patients who progressed within the first month of follow-up went on to have any response.
Eight patients were treated with postoperative RT after surgical resection in the brain (6), mediastinal lymph node (1), and inguinal lymph node (1). Three patients with evaluable clinical symptoms before and after surgery-RT all demonstrated diminished (PR) or complete (CR) resolution of symptoms within 1 month after RT. Of the 6 patients with radiographic follow-up, one recurred 9 months after treatment; the rest maintained stable disease (ie, no recurrence) through last follow-up.
Acute and late grade 3 or higher (G3 +) toxicities with bevacizumab were low (8.7% and 4.3%, respectively). CNS and mediastinal locations were the only treatment sites in which G3 + toxicity occurred. CNS toxicity (acute G3 fatigue, late G3 radiation necrosis, and late G4 optic neuritis) was identified in a single patient who received craniospinal irradiation with prior Gamma Knife irradiation. A second patient treated to the mediastinum had acute but not chronic grade 3 esophagitis. Notably, no acute or late G3 + toxicity was seen in patients treated to the abdomen or pelvis (the most common treatment location; Table 5).Table 5 Observed toxicities in patients treated with bevacizumab before or concurrent with radiation therapy, by treatment course
None Grade 1-2 Grade 3 Grade 4
Acute
Non-CNS (17) 6 Anorexia (1),
depression (1),
dermatitis (1),
fatigue (5),
GI (6), GU (1),
odynophagia (1),
pneumonitis (1),
vaginal hemorrhage (1) Dermatitis (1),
esophagitis (1) -
CNS (6) 4 GI (1) Fatigue (1) -
Late
Non-CNS (9) 8 GI (1) - -
CNS (5) 3 Intracranial hemorrhage (1) Radionecrosis (1) Optic neuropathy (1)
Abbreviations: CNS = central nervous system; GI = gastrointestinal; GU = genitourinary.
Toxicities defined according to the Common Terminology Criteria for Adverse Events, version 5.0.
Numbers indicate number of treatment courses; more than one toxicity may be attributed to a single treatment course. Late toxicity data unavailable for 9 treatment courses (all due to patient death).
Late grade 3 and 4 toxicities occurred in the same patient.
An exploratory analysis examining patient demographics and treatment characteristics was performed to identify predictors of clinical or radiographic response. In all patients (CNS and non-CNS sites), HGS histology was associated with clinical responses (88% vs 64%, P = .04). In patients with CNS lesions, BED >39 Gy was associated with clinical response (P = .049). In non-CNS locations, bony site was associated with worse clinical (44% vs 89%, P = .004) response compared with soft tissue/nodal (STN) sites. Lastly, we compared BED regimens ≤39 Gy versus >39 Gy (assuming an alpha/beta ratio of 10,19,20 the BED of 30 Gy in 10 fractions is 39 Gy) in non-CNS locations and found no differences in clinical (P = .10) or radiographic response rates (P = .47). We otherwise compared the most common regimens of 20 Gy in 5 fractions and 30 Gy in 10 fractions and found no significant differences in clinical (P = .60) or radiographic responses (P = .29; Table E1).2
Discussion
We report the outcomes of a large modern cohort of women with PMR-OC who received palliative radiation therapy in an era of novel systemic agents. In a population with poor prognosis, palliative radiation therapy resulted in excellent clinical and radiographic response rates (Table 2) within 1 month of treatment, with many responses durable beyond 3 months. Brain metastases, a rare site of anatomic spread, were also well represented in this cohort (36%, 38 courses) and responded favorably to palliative intracranial radiation therapy (Table 3). Exploratory analyses demonstrated an association between HGS histology and improved clinical response in all patients, BED >39 Gy and improved clinical response in BMs, and STN sites with improved clinical response in non-CNS sites. Our analysis is unique in its (1) large sample size compared with prior reports with significant number of BMs, (2) high proportion of patients treated with modern RT techniques, (3) inclusion of patients treated with novel systemic agents (ie, PARP inhibitors, bevacizumab, and immunotherapy), and (4) dedicated toxicity analysis of RT with concurrent or prior bevacizumab, an area of increasing clinical significance in MPR-EOC with a dearth of robust data.
Our high clinical response rates (79% ORR within 1 month) are similar to other reports, including literature from prior decades demonstrating durable pain relief and bleeding control from locally directed palliative RT in 80% of OC patients.20, 21, 22 More recently, Bansal and colleagues also found pain control rates of 88.2% and vaginal bleeding control rates of 100% in 23 heavily pretreated women who received palliative pelvic RT.23 Investigators from Brigham and Women’s Hospital also recently published rates and predictors of response to palliative RT for recurrent OC from 2003 to 201424 and demonstrated high rates of response for pain and bleeding (87% and 93%, respectively).
Identified predictors of response, including HGS histology and STN sites of disease are also compatible with prior investigations. In the above Brigham and Women’s Hospital study, patients treated at nonbony sites had higher response rates than those with bony sites of disease (96% vs 75%, respectively). Furthermore, patients with clear cell histology had the lowest response rates (60%), compared with others like serous histology (82%).
The sizable nature of our cohort allowed for a temporal analysis of index lesion response rates. Patients in both CNS and non-CNS cohorts tended to have clinical responses early on, with some benefitting from sustained response at last follow-up. Lesions with clinical CR often occurred within the first month. Furthermore, no patients who progressed in the index lesion within the first month of follow-up went on to have any response, suggesting that initial response is of paramount importance. Patients who had progressive symptoms after 3 months had variable initial responses, suggesting progressive disease is still expected no matter what the initial response may be.
Regarding dose response, higher BED was associated with clinical response in brain metastases. This is a result of ablative SRS technology that radiobiologically induces high rates of cell kill compared with those of conventional palliative techniques or doses. Advanced stereotactic techniques permit the delivery of otherwise unsafe high dose-per-fraction regimens due to their sharp dose gradients that allow for normal tissue sparing. In non-CNS locations, however, regimens with BED >39 Gy (ie, greater than 30 Gy in 10 fractions) were no different than lower BED regimens, suggesting dose escalation may not increase the efficacy of palliative RT. Use of higher BED regimens in such (predominantly abdominopelvic) locations is typically limited by larger fields due to tumor size and organ motion. Dose-limiting toxicities from nearby organs at risk such as the stomach, bowel, kidneys, and bladder also constrain prescriptions.
Notably, 47% of all courses were delivered with advanced radiation therapy techniques (SRS, SBRT, IMRT/volumetric-modulated arc therapy, proton therapy). This is in keeping with the increasing number of patients referred for ablative or definitive therapy to oligometastatic or oligoprogressive disease or previously irradiated lesions requiring retreatment. In such scenarios, advanced techniques allow practitioners to deliver higher dose per fraction while sparing normal organs and tissue of radiation, or even reirradiation, toxicity. In fact, recently published reports have evaluated the roles of advanced RT in OC. For example, definitive involved-field RT using IMRT has demonstrated promising rates of local control (LC) and disease-free survival with low toxicity.25,26 Two recent retrospective studies also explored SBRT in oligometastatic OC. Lazzari et al reported the treatment of 82 patients with a median dose of 24 Gy in 3 fractions and demonstrated the safety of SBRT along with an increase in systemic therapy-free survival with reasonable LC27 (more than one-third of patients were disease-free at 1 year). Similarly, Macchia et al reported SBRT in MPR-EOC was well tolerated and afforded higher LC in patients receiving a total dose >25 Gy.28
Forty-three percent of patients received targeted therapy immediately before RT in this cohort. This is in keeping with the litany of recent publications studying the use of novel systemic agents (PARP inhibitors,29, 30, 31 bevacizumab,32 nivolumab33) in the setting of MPR-EOC. The response rates described thus reflect the potential outcomes of palliative RT in conjunction with advanced systemic therapies, a scenario that will be increasingly encountered by practitioners. Furthermore, given the sizeable population that received prior or concurrent bevacizumab, a dedicated subgroup analysis was conducted and demonstrated low acute and late grade 3 or higher (G3 +) toxicities (8.7% and 4.3%, respectively) with RT. Although G3 + toxicities occurred in patients treated to CNS and mediastinal locations, it is unclear if this was in relation to prior bevacizumab or reflected the increased risk toxicity with prior RT (Gamma Knife in the CNS patient treated with craniospinal irradiation) or unfavorable tumor location (in the mediastinal patient experiencing esophagitis after receiving 59.4 Gy). No acute or late G3 + toxicity was seen in patients treated to the abdomen or pelvis (the most common treatment location), suggesting that this may be a reasonable treatment option in symptomatic patients.
Limitations
The study is limited primarily by its retrospective nature which lends itself to both selection and sample bias. For example, patient performance status and prior lines of therapy (including prior radiation) may effect physician choice of RT technique, dose, and fractionation. Furthermore, lesions necessitating reirradiation demonstrate inherent radioresistance and may negatively affect response rates. Moreover, although the study population is sizeable, it is heterogenous with respect to treatment sites and prior lines of therapy. As such appropriate interpretation required subdivision of data (ie, CNS vs non-CNS, symptomatic vs asymptomatic indication), which led to more descriptive findings. Finally, the variety of systemic therapies used negatively affect our ability to make conclusions regarding the efficacy of RT with respect to individual agents.
Future directions
As the role for palliative radiation therapy expands in the context of the oligometastatic paradigm, nuanced decision-making must be taken to deliver the most efficacious treatment although promoting cost-effective care. As such, prospective evaluation is warranted to determine the optimal dose, timing, and fractionation of RT as it relates to systemic agents and surgery. The high response rates demonstrated in this cohort may warrant prospective investigation of RT as a standard component therapy in MPR-EOC, either before systemic agents as a cytoreductive strategy or after as consolidation therapy.
Conclusions
We performed a large retrospective cohort analysis of women with MPR-EOC receiving palliative RT in the era of modern technology and systemic agents. Our large population of patients with BMs adds relevant data to the limited body of existing literature and can be used as a practical reference when counseling women. Patients demonstrated favorable clinical and radiographic response rates within 1 month, with >60% experiencing durable clinical responses beyond 3 months. HGS histology was associated with improved clinical response in all patients. BED >39 Gy was associated with improved response in brain metastases. Bony sites were associated with worse response compared with STN sites in non-CNS locations. Acute and late grade 3 or higher toxicities were low with prior bevacizumab, and none of these occurred in patients treated to abdominopelvic locations.
Although MPR-EOC is associated with limited prognosis, our data demonstrate that responses to palliative RT can be durable and meaningful. As such, without a conclusive effect on survival, it would be reasonable to consider treatment of such disease after taking into consideration patient symptom severity, goals of care, prognosis, performance status, and extracranial disease burden for BM.
Supplementary Materials
Tables E1 and E2
Sources of support: The authors received no specific funding for this work.
Disclosures: The authors of this manuscript have no conflicts of interest to report.
Research data are stored in an institutional repository and will be shared upon request.
Supplementary material for this article can be found at https://doi.org/10.1016/j.adro.2020.11.009. | BEVACIZUMAB | DrugsGivenReaction | CC BY-NC-ND | 33665491 | 18,951,285 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Gastrointestinal toxicity'. | Palliative Radiation Therapy for Metastatic, Persistent, or Recurrent Epithelial Ovarian Cancer: Efficacy in the Era of Modern Technology and Targeted Agents.
Metastatic, persistent, or recurrent epithelial ovarian cancer (MPR-EOC) remains a significant threat to patient mortality despite advances in novel targeted agents. Radiation therapy (RT) is often used as a palliative option. We report outcomes of a large series of MPR-EOC patients treated with modern palliative RT (PRT) in an era of novel systemic therapies.
A retrospective review was conducted of women treated with PRT for MPR-EOC between 2007 and 2019 at an academic institution. Clinical response rates were recorded at <1 month, 1 to 3 months, and >3 months. Radiographic responses were categorized by RECIST 1.1 criteria. Overall response rate (ORR) was the sum of complete and partial response. Linear regression analyses of baseline characteristics were conducted for statistical testing.
Eighty-six patients with PMR-OC received 120 courses of palliative RT. Median follow-up was 8.6 months. Median age was 61 (range, 22-82). Thirty-six percent of women received central nervous system (CNS)-directed RT. In addition, 43% received targeted therapies before RT. Clinical ORR within 1 month and at last follow-up for non-CNS lesions was 79% and 61% (69% and 88% for CNS lesions, respectively). High-grade serous lesions were more likely to have clinical response (P = .04). Biologically effective doses (BED) >39 Gy were associated with improved clinical response in CNS lesions (P = .049). Bony sites were associated with worse clinical (P = .004) response in non-CNS lesions compared with soft tissue or nodal sites. Acute or late grade 3+ toxicities with bevacizumab were low (8.7%/4.3%).
PRT offers excellent rates of response for symptomatic patients with MPR-EOC within 1 month of treatment, with durable responses beyond 3 months. High-grade serous lesions were associated with improved response in all patients. Higher BED and soft tissue or nodal sites were associated with improved response in CNS and non-CNS patients, respectively. Acute or late toxicities with bevacizumab and PRT were low. Prospective investigation is warranted to determine the optimal PRT regimen.
Introduction
Ovarian cancer (OC) is a highly aggressive gynecologic malignancy, with the majority of patients presenting with advanced disease at diagnosis. The general treatment paradigm for advanced OC is maximal cytoreductive surgery with platinum-based chemotherapy.1 Recent literature has also reported a progression-free survival benefit with maintenance inhibition of poly (adenosine diphosphate-ribose) polymerase (PARP) in women with partial or complete response to platinum-based regimens.2,3
Whole abdominal radiation therapy was historically indicated as adjuvant therapy to address microscopic residual disease.4 However, due to its considerable toxicity and the development of platinum-based chemotherapy, whole abdominal radiation therapy is no longer included in primary OC treatment paradigms.1
Despite advances in cytoreductive strategies and front-line systemic therapy, >70% of women relapse within 3 years of diagnosis.5 As such, many patients with OC benefit from palliative care referrals to assist with symptom management, goals of care discussions, and complex medical decision making at the end of life.
There is a growing body of evidence to support the incorporation of palliative services in cancer care. In 2010, a seminal randomized trial6 reported early palliative care among patients with metastatic non-small cell lung cancer significantly improved quality of life, led to less aggressive care at the end of life, and resulted in longer overall survival. Furthermore, both the American Society of Clinical Oncology and the Society of Gynecologic Oncology have published official practice guidelines recommending the routine and early integration of palliative services.7,8
Radiation therapy (RT) is often used as an effective therapeutic option in the palliation of patients with metastatic, persistent, or recurrent epithelial OC (MPR-EOC) as a means for symptomatic relief and local control. This includes oligometastatic disease or symptomatic disease causing pain, bowel or ureteral obstruction, or bleeding. Despite their rarity in OC (2% incidence9), brain metastases can also cause significant morbidity and can be treated with palliative RT to reduce the risk of progression and neurocognitive deficits.10,11
As patient survival improves with modern systemic agents, there is a growing need to understand the efficacy of palliative RT regimens for MPR-EOC in the same era. Although radiation therapy has traditionally been delivered for symptomatic control in MPR-EOC, the recognition of the biologically distinct (and potentially curable) oligometastatic state12,13 is expanding the scope of RT indications. Data from phase 2 trials in other malignancies evaluating the effect of locally directed therapy to oligometastatic lesions has demonstrated improvements in overall survival.14,15
We therefore conducted, a large contemporary retrospective analysis of palliative RT in MPR-EOC. This patient cohort is highly relevant to modern practice given the number of patients who received novel systemic agents, the prominent usage of advanced RT technology, and the representation of patients with BMs from OC (an area with limited data but increasing prevalence in practice). The analysis will report the outcomes and durability of palliative RT in MPR-EOC and delineate factors predictive of response in the modern era.
Methods and Materials
We conducted a retrospective chart review of women treated with palliative radiation therapy for metastatic ovarian cancer from 2007 through 2019 at [University of Pennsylvania] and affiliate sites. Institutional review board approval was obtained before conducting this review. Patients were included in this analysis if they were treated for palliative intent, including treatment of oligometastatic disease. All patients had MPR-EOC ovarian cancer and received anywhere from one to 5 courses of radiation treatment.
Given the poor prognosis of patients with metastatic ovarian cancer, clinical and radiographic response rates were categorized in intervals of <1 month, 1 to 3 months, and >3 months after the end of radiation treatment to indicate acute and durable responses. Clinical responses were categorized as complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD). Pain scores were classified using the Bone Metastases Consensus Working Party guidelines16 (indeterminate responses, which are neither PR nor PD per BMWCP guidelines, were classified as SD to maintain consistency with other clinical response categorizations). Radiographic responses were categorized as CR, PR, SD, or PD based on the RECIST 1.1 criteria.17 Overall response rate (ORR) was the sum of CR and PR in a given patient. Given the large subset of patients with brain metastases (BMs), courses were stratified by central nervous system (CNS) and non-CNS anatomic locations. Acute (during RT and within 3 months of completion) and late (>3 months after completion of RT) toxicities were recorded with concurrent and prior bevacizumab using Common Terminology Criteria for Adverse Events version 5.018 classification.
Rates of response (CR or PR at any point) were compared with demographic and treatment characteristics. χ2 (n ≥ 20) or Fisher exact (n < 20) tests were used for such comparison with variables for race, histology, platinum chemotherapy, or targeted therapy before RT, RT technology, RT location, and biologically effective dose (BED) >39. Binary logistic regression analyses were used for comparison with continuous variables (age and BED). Covariates with P < .1 were included in multiple logistic regression modeling to assess for independent effect. Additionally, χ2 analyses were used to compare rates of radiographic response between patients treated for clinical symptoms and asymptomatic progression. Statistical analysis was conducted using IBM SPSS Statistics, version 26 (IBM Corporation, Armonk, NY).
Results
We identified 86 patients with PMR-OC that received 120 combined courses of palliative radiation treatment. Median follow-up was 8.6 months (range, 0.5-119 months). Excluding 10 patients (15 courses) with no evaluable clinical or radiographic follow-up, 51 patients (58 courses) were treated to non-CNS locations and 18 patients (25 courses) were treated to CNS locations; 7 patients (22 courses) received palliative RT to both CNS (13 courses) and non-CNS (9 courses) locations.
Table 1 describes baseline patient characteristics and details related to patient treatments. The median age of patients in this cohort was 61, with a range of 22 to 82. Patients were most commonly white (83%) and black (8%). Tumor histologies were primarily high-grade serous (HGS, 59%), although adenocarcinoma (undifferentiated or unspecified), low-grade serous, clear cell, endometrioid, and carcinosarcoma were also observed.Table 1 Patient characteristics and treatment details
No. of courses 105
No. of patients 76
Median age 61
Ethnicity
White 82.9% (63/76)
Black 9.2% (7/76)
Asian 3.9% (3/76)
Hispanic 2.6% (2/76)
Unknown 1.3% (1/76)
Histology
High-grade serous 59.2% (45/76)
Adenocarcinoma, other 13.2% (10/76)
Low grade serous 9.2% (7/76)
Clear cell 5.3% (4/76)
Other 7.9% (6/76)
Endometrioid 3.9% (3/76)
Carcinosarcoma 1.3% (1/76)
Anatomic site
Soft tissue/organ 35.2% (37/105)
Lymph node 21.0% (22/105)
Bone 11.4% (12/105)
CNS 36.2% (38/105)
Indications
Clinical symptoms 59.0% (62/105)
Progressive/metastatic 33.3% (35/105)
Postoperative 7.6% (8/105)
Systemic therapy before RT
Platinum chemotherapy 27.6% (29/105)
Nonplatinum chemotherapy 61.9% (65/105)
Targeted therapy 42.9% (45/105)
None/other 1.0% (1/105)
Technique
2D/3D CRT 53.3% (56/105)
SRS 21.9% (23/105)
VMAT/IMRT 16.2% (17/105)
SBRT 4.8% (5/105)
Proton 3.8% (4/105)
Non-SRS dose 14-63 Gy in 4-35 fractions
SBRT dose 24-50 Gy in 3-5 fractions
SRS dose 15-25 Gy in 1-5 fractions
Abbreviations: 2D = 2-dimensional; 3D CRT = 3-dimensional conformal radiation therapy; CNS = central nervous system; IMRT = intensity modulated radiation therapy; RT = radiation therapy; SBRT = stereotactic body radiation therapy; SRS = stereotactic radiosurgery; VMAT = volumetric modulated arc therapy.
Non-CNS treatment locations included tumors in soft tissue or organs (35%), lymph nodes (21%), and bone (11%); 4 patients were treated simultaneously to adjacent soft tissue and lymph nodes. Treatment for CNS metastases comprised the remaining 36% of patients.
Most patients were treated for clinical symptoms (59%). Pain and bleeding were the most common clinical indications. Others included neurologic deficits, spinal cord compression, airway compression, and bowel obstruction. A large cohort of patients were treated for asymptomatic progressive or metastatic disease (33%) with a small cohort treated adjuvantly after surgery (eg, metastasectomy or palliative debulking; 7.6%).
Almost all patients (90%) received chemotherapy immediately before radiation therapy. The most common systemic therapy regimens were platinum-based (ie, carboplatin) followed by taxanes and doxorubicin. Many patients (43%) also received treatment with targeted therapy agents before radiation treatment. Bevacizumab was the most commonly used targeted therapy agent (20%), although patients also received PARP inhibitors (9%) and immune checkpoint inhibitors (5%).
A wide range of palliative radiation regimens were delivered across several modalities. Nonstereotactic treatment regimens to both CNS and non-CNS locations ranged from 14 Gy in 4 fractions to 63 Gy in 35 fractions. Common palliative doses were 30 Gy in 10 fractions (14%), 20 Gy in 5 fractions (8.6%), and 35 Gy in 14 fractions (7.6%). Nonstereotactic modalities included 2-dimensional or 3-dimensional (53%), intensity modulated radiation therapy (IMRT) or volumetric-modulated arc therapy (16%), and proton therapy (3.8%). Stereotactic body radiation therapy (SBRT) was less commonly used (4.8%) with treatment regimen ranging from 24 Gy in 3 fractions to 50 Gy in 5 fractions. Lastly, patients with BMs commonly received stereotactic radiosurgery (SRS, 22% of all courses) with doses ranging from 15 Gy in 1 fraction to 25 Gy in 5 fractions. Nearly half of the patients who underwent SRS received 21 Gy in 1 fraction.
Across the entire cohort, the clinical ORR was 76% within the first month after treatment and 67% at least 3 months after treatment (Table 2). Radiographic ORR between patients treated for clinical symptoms (symptomatic) and asymptomatic progression (asymptomatic) were 48% and 59%, respectively. Although patients treated for asymptomatic progression had higher rates of response, no significant differences were observed between the 2 cohorts (P = .23).Table 2 Response rates (all lesions)
<1 mo 1-3 mo >3 mo
Clinical response
CR 32.8% (19/58) 45.0% (18/40) 48.4% (15/31)
PR 43.1% (25/58) 35.0% (14/40) 19.4% (6/31)
SD 12.1% (7/58) 2.5% (1/40) 0.0% (0/31)
PD 12.1% (7/58) 17.5% (7/40) 32.3% (10/31)
ORR 75.9% (44/58) 80.0% (32/40) 67.7% (21/31)
Radiographic response: symptomatic patients
CR 15.2% (5/33) 16.7% (5/30) 25.9% (7/27)
PR 24.2% (8/33) 30.0% (9/30) 22.2% (6/27)
SD 51.5% (17/33) 43.3% (13/30) 40.7% (11/27)
PD 9.1% (3/33) 10.% (3/30) 11.1% (3/27)
ORR 39.4% (13/33) 46.7% (14/30) 48.1% (13/27)
Radiographic response: asymptomatic patients
CR 39.4% (13/33) 47.1% (16/34) 53.1% (17/32)
PR 9.1% (3/33) 8.8% (3/34) 6.3% (2/32)
SD 45.5% (15/33) 41.2% (14/34) 34.4% (11/32)
PD 6.1% (2/33) 2.9% (1/34) 6.3% (2/32)
ORR 48.5% (16/33) 55.9% (19/34) 59.4% (19/32)
Abbreviations: CR = complete response; ORR = overall response rate; PD = progressive disease; PR = partial response; SD = stable disease.
Excludes patients treated with postoperative palliative radiation.
Denominator reflects evaluable patients.
Of patients treated to non-CNS locations, the clinical and radiographic ORR within the first month after treatment were 79% and 33%, respectively (Table 3). Clinical ORR at last follow-up (at least 3 months after treatment) was 61%. Notably, of the patients with a CR (38.1%) within the first month, only 2 went on to have PD at last follow-up (4 were lost to follow-up), indicating durable response to treatment. All but one patient treated for malignancy-related vaginal bleeding (13/14) had a clinical response within 1 month, of which only one patient had recurrence of bleeding at last follow-up. Seventy percent of patients treated for pain (n = 27) had a clinical response within 1 month, of which only 3 patients demonstrated worsening pain at last follow-up. Radiographically, ORR improved to 38% for symptomatic patients and 47% for asymptomatic patients at last follow-up, with no significant differences in response rates between the 2 groups (P = .44). All lesions that responded within 1 month of radiation treatment maintained response through last follow-up. Furthermore, only 3 of 22 lesions that were initially SD, progressed over time (1 treated for clinical symptoms, 2 treated for asymptomatic progression).Table 3 Response rates (non-CNS lesions)
<1 mo 1-3 mo >3 mo
Clinical response
CR 38.1% (16/42) 44.8% (13/29) 43.5% (10/23)
PR 40.5% (17/42) 31.0% (9/29) 17.4% (4/23)
SD 14.3% (6/42) 3.4% (1/29) 0.0% (0/23)
PD 7.1% (3/42) 20.7% (6/29) 39.1% (9/23)
ORR 78.6% (33/42) 75.9% (22/29) 60.9% (14/23)
Radiographic response: symptomatic patients
CR 9.5% (2/21) 10.5% (2/19) 18.8% (3/16)
PR 23.8% (5/21) 26.3% (5/19) 18.8% (3/16)
SD 52.4% (11/21) 52.6% (10/19) 50.0% (8/16)
PD 14.3% (3/21) 10.5% (2/19) 12.5% (2/16)
ORR 33.3% (7/21) 36.8% (7/19) 37.5% (6/16)
Radiographic response: asymptomatic patients
CR 21.1% (4/19) 31.6% (6/19) 41.2% (7/17)
PR 10.5% (2/19) 10.5% (2/19) 5.9% (1/17)
SD 57.9% (11/19) 52.6% (10/19) 41.2% (7/17)
PD 10.5% (2/19) 5.3% (1/19) 11.8% (2/17)
ORR 31.6% (6/19) 42.1% (8/19) 47.1% (8/17)
Abbreviations: CNS = central nervous system; CR = complete response; ORR = overall response rate; PD = progressive disease; PR = partial response; SD = stable disease.
Excludes patients treated with postoperative palliative radiation.
Denominator reflects evaluable patients.
Of patients treated to CNS locations, the clinical and radiographic ORR within the first month after treatment were 72% and 62%, respectively (Table 4). No patients with a demonstrated clinical or radiographic response within the first month went on to have documented progressive symptoms or imaging at last follow-up (although 2 patients died and 4 were lost to follow-up). Although clinical responses stayed constant over time, radiographic responses tended to improve, especially in patients treated for clinical symptoms. There was no difference in rates of radiographic responses between CNS patients treated for clinical symptoms and those treated for asymptomatic progression (P = .41). All patients receiving SRS responded or had SD at 1 month; only one patient had locally progressive symptoms and disease at last follow-up. Three of the 4 patients with progressive symptoms within the first month were those who received whole brain radiation therapy with more extensive CNS disease before treatment.Table 4 Response rates (CNS lesions)
<1 mo 1-3 mo >3 mo
Clinical response
CR 18.8% (3/16) 45.5% (5/11) 62.5% (5/8)
PR 50.0% (8/16) 45.5% (5/11) 25.0% (2/8)
SD 6.3% (1/16) 0.0% (0/11) 0.0% (0/8)
PD 25.0% (4/16) 9.1% (1/11) 12.5% (1/8)
ORR 68.8% (11/16) 90.9% (10/11) 87.5% (7/8)
Radiographic response: symptomatic patients
CR 25.0% (3/12) 27.3% (3/11) 36.4% (4/11)
PR 25.0% (3/12) 36.4% (4/11) 27.3% (3/11)
SD 50.% (6/12) 27.3% (3/11) 27.3% (3/11)
PD 0.0% (0/12) 9.1% (1/11) 9.1% (1/11)
ORR 50.0% (6/12) 63.6% (7/11) 63.6% (7/11)
Radiographic response: asymptomatic patients
CR 64.3% (9/14) 66.7% (10/15) 66.7% (10/15)
PR 7.1% (1/14) 6.7% (1/15) 6.7% (1/15)
SD 28.6% (4/14) 26.7% (4/15) 26.7% (4/15)
PD 0.0% (0/14) 0.0% (0/15) 0.0% (0/15)
ORR 71.4% (10/14) 73.3% (11/15) 73.3% (11/15)
Abbreviations: CNS = central nervous system; CR = complete response; PD = progressive disease; PR = partial response; ORR = overall response rate; SD = stable disease.
Excludes patients treated with postoperative palliative radiation.
Denominator reflects evaluable patients.
Patients in both CNS and non-CNS cohorts tended to have clinical responses early on, with sustained response at last follow-up. Furthermore, if a patient were to have a clinical CR, it most often occurred within the first month. Only 4 patients demonstrated a CR after the first month, and all of these patients had a PR initially; no patients with initially stable disease went on to have a CR. Most patients with radiographic SD at initial follow-up maintained SD over time. The initial responses of patients developing progressive symptoms after 3-month follow-up varied considerably: CR (2), PR (3), SD (2), and PD (3). No patients who progressed within the first month of follow-up went on to have any response.
Eight patients were treated with postoperative RT after surgical resection in the brain (6), mediastinal lymph node (1), and inguinal lymph node (1). Three patients with evaluable clinical symptoms before and after surgery-RT all demonstrated diminished (PR) or complete (CR) resolution of symptoms within 1 month after RT. Of the 6 patients with radiographic follow-up, one recurred 9 months after treatment; the rest maintained stable disease (ie, no recurrence) through last follow-up.
Acute and late grade 3 or higher (G3 +) toxicities with bevacizumab were low (8.7% and 4.3%, respectively). CNS and mediastinal locations were the only treatment sites in which G3 + toxicity occurred. CNS toxicity (acute G3 fatigue, late G3 radiation necrosis, and late G4 optic neuritis) was identified in a single patient who received craniospinal irradiation with prior Gamma Knife irradiation. A second patient treated to the mediastinum had acute but not chronic grade 3 esophagitis. Notably, no acute or late G3 + toxicity was seen in patients treated to the abdomen or pelvis (the most common treatment location; Table 5).Table 5 Observed toxicities in patients treated with bevacizumab before or concurrent with radiation therapy, by treatment course
None Grade 1-2 Grade 3 Grade 4
Acute
Non-CNS (17) 6 Anorexia (1),
depression (1),
dermatitis (1),
fatigue (5),
GI (6), GU (1),
odynophagia (1),
pneumonitis (1),
vaginal hemorrhage (1) Dermatitis (1),
esophagitis (1) -
CNS (6) 4 GI (1) Fatigue (1) -
Late
Non-CNS (9) 8 GI (1) - -
CNS (5) 3 Intracranial hemorrhage (1) Radionecrosis (1) Optic neuropathy (1)
Abbreviations: CNS = central nervous system; GI = gastrointestinal; GU = genitourinary.
Toxicities defined according to the Common Terminology Criteria for Adverse Events, version 5.0.
Numbers indicate number of treatment courses; more than one toxicity may be attributed to a single treatment course. Late toxicity data unavailable for 9 treatment courses (all due to patient death).
Late grade 3 and 4 toxicities occurred in the same patient.
An exploratory analysis examining patient demographics and treatment characteristics was performed to identify predictors of clinical or radiographic response. In all patients (CNS and non-CNS sites), HGS histology was associated with clinical responses (88% vs 64%, P = .04). In patients with CNS lesions, BED >39 Gy was associated with clinical response (P = .049). In non-CNS locations, bony site was associated with worse clinical (44% vs 89%, P = .004) response compared with soft tissue/nodal (STN) sites. Lastly, we compared BED regimens ≤39 Gy versus >39 Gy (assuming an alpha/beta ratio of 10,19,20 the BED of 30 Gy in 10 fractions is 39 Gy) in non-CNS locations and found no differences in clinical (P = .10) or radiographic response rates (P = .47). We otherwise compared the most common regimens of 20 Gy in 5 fractions and 30 Gy in 10 fractions and found no significant differences in clinical (P = .60) or radiographic responses (P = .29; Table E1).2
Discussion
We report the outcomes of a large modern cohort of women with PMR-OC who received palliative radiation therapy in an era of novel systemic agents. In a population with poor prognosis, palliative radiation therapy resulted in excellent clinical and radiographic response rates (Table 2) within 1 month of treatment, with many responses durable beyond 3 months. Brain metastases, a rare site of anatomic spread, were also well represented in this cohort (36%, 38 courses) and responded favorably to palliative intracranial radiation therapy (Table 3). Exploratory analyses demonstrated an association between HGS histology and improved clinical response in all patients, BED >39 Gy and improved clinical response in BMs, and STN sites with improved clinical response in non-CNS sites. Our analysis is unique in its (1) large sample size compared with prior reports with significant number of BMs, (2) high proportion of patients treated with modern RT techniques, (3) inclusion of patients treated with novel systemic agents (ie, PARP inhibitors, bevacizumab, and immunotherapy), and (4) dedicated toxicity analysis of RT with concurrent or prior bevacizumab, an area of increasing clinical significance in MPR-EOC with a dearth of robust data.
Our high clinical response rates (79% ORR within 1 month) are similar to other reports, including literature from prior decades demonstrating durable pain relief and bleeding control from locally directed palliative RT in 80% of OC patients.20, 21, 22 More recently, Bansal and colleagues also found pain control rates of 88.2% and vaginal bleeding control rates of 100% in 23 heavily pretreated women who received palliative pelvic RT.23 Investigators from Brigham and Women’s Hospital also recently published rates and predictors of response to palliative RT for recurrent OC from 2003 to 201424 and demonstrated high rates of response for pain and bleeding (87% and 93%, respectively).
Identified predictors of response, including HGS histology and STN sites of disease are also compatible with prior investigations. In the above Brigham and Women’s Hospital study, patients treated at nonbony sites had higher response rates than those with bony sites of disease (96% vs 75%, respectively). Furthermore, patients with clear cell histology had the lowest response rates (60%), compared with others like serous histology (82%).
The sizable nature of our cohort allowed for a temporal analysis of index lesion response rates. Patients in both CNS and non-CNS cohorts tended to have clinical responses early on, with some benefitting from sustained response at last follow-up. Lesions with clinical CR often occurred within the first month. Furthermore, no patients who progressed in the index lesion within the first month of follow-up went on to have any response, suggesting that initial response is of paramount importance. Patients who had progressive symptoms after 3 months had variable initial responses, suggesting progressive disease is still expected no matter what the initial response may be.
Regarding dose response, higher BED was associated with clinical response in brain metastases. This is a result of ablative SRS technology that radiobiologically induces high rates of cell kill compared with those of conventional palliative techniques or doses. Advanced stereotactic techniques permit the delivery of otherwise unsafe high dose-per-fraction regimens due to their sharp dose gradients that allow for normal tissue sparing. In non-CNS locations, however, regimens with BED >39 Gy (ie, greater than 30 Gy in 10 fractions) were no different than lower BED regimens, suggesting dose escalation may not increase the efficacy of palliative RT. Use of higher BED regimens in such (predominantly abdominopelvic) locations is typically limited by larger fields due to tumor size and organ motion. Dose-limiting toxicities from nearby organs at risk such as the stomach, bowel, kidneys, and bladder also constrain prescriptions.
Notably, 47% of all courses were delivered with advanced radiation therapy techniques (SRS, SBRT, IMRT/volumetric-modulated arc therapy, proton therapy). This is in keeping with the increasing number of patients referred for ablative or definitive therapy to oligometastatic or oligoprogressive disease or previously irradiated lesions requiring retreatment. In such scenarios, advanced techniques allow practitioners to deliver higher dose per fraction while sparing normal organs and tissue of radiation, or even reirradiation, toxicity. In fact, recently published reports have evaluated the roles of advanced RT in OC. For example, definitive involved-field RT using IMRT has demonstrated promising rates of local control (LC) and disease-free survival with low toxicity.25,26 Two recent retrospective studies also explored SBRT in oligometastatic OC. Lazzari et al reported the treatment of 82 patients with a median dose of 24 Gy in 3 fractions and demonstrated the safety of SBRT along with an increase in systemic therapy-free survival with reasonable LC27 (more than one-third of patients were disease-free at 1 year). Similarly, Macchia et al reported SBRT in MPR-EOC was well tolerated and afforded higher LC in patients receiving a total dose >25 Gy.28
Forty-three percent of patients received targeted therapy immediately before RT in this cohort. This is in keeping with the litany of recent publications studying the use of novel systemic agents (PARP inhibitors,29, 30, 31 bevacizumab,32 nivolumab33) in the setting of MPR-EOC. The response rates described thus reflect the potential outcomes of palliative RT in conjunction with advanced systemic therapies, a scenario that will be increasingly encountered by practitioners. Furthermore, given the sizeable population that received prior or concurrent bevacizumab, a dedicated subgroup analysis was conducted and demonstrated low acute and late grade 3 or higher (G3 +) toxicities (8.7% and 4.3%, respectively) with RT. Although G3 + toxicities occurred in patients treated to CNS and mediastinal locations, it is unclear if this was in relation to prior bevacizumab or reflected the increased risk toxicity with prior RT (Gamma Knife in the CNS patient treated with craniospinal irradiation) or unfavorable tumor location (in the mediastinal patient experiencing esophagitis after receiving 59.4 Gy). No acute or late G3 + toxicity was seen in patients treated to the abdomen or pelvis (the most common treatment location), suggesting that this may be a reasonable treatment option in symptomatic patients.
Limitations
The study is limited primarily by its retrospective nature which lends itself to both selection and sample bias. For example, patient performance status and prior lines of therapy (including prior radiation) may effect physician choice of RT technique, dose, and fractionation. Furthermore, lesions necessitating reirradiation demonstrate inherent radioresistance and may negatively affect response rates. Moreover, although the study population is sizeable, it is heterogenous with respect to treatment sites and prior lines of therapy. As such appropriate interpretation required subdivision of data (ie, CNS vs non-CNS, symptomatic vs asymptomatic indication), which led to more descriptive findings. Finally, the variety of systemic therapies used negatively affect our ability to make conclusions regarding the efficacy of RT with respect to individual agents.
Future directions
As the role for palliative radiation therapy expands in the context of the oligometastatic paradigm, nuanced decision-making must be taken to deliver the most efficacious treatment although promoting cost-effective care. As such, prospective evaluation is warranted to determine the optimal dose, timing, and fractionation of RT as it relates to systemic agents and surgery. The high response rates demonstrated in this cohort may warrant prospective investigation of RT as a standard component therapy in MPR-EOC, either before systemic agents as a cytoreductive strategy or after as consolidation therapy.
Conclusions
We performed a large retrospective cohort analysis of women with MPR-EOC receiving palliative RT in the era of modern technology and systemic agents. Our large population of patients with BMs adds relevant data to the limited body of existing literature and can be used as a practical reference when counseling women. Patients demonstrated favorable clinical and radiographic response rates within 1 month, with >60% experiencing durable clinical responses beyond 3 months. HGS histology was associated with improved clinical response in all patients. BED >39 Gy was associated with improved response in brain metastases. Bony sites were associated with worse response compared with STN sites in non-CNS locations. Acute and late grade 3 or higher toxicities were low with prior bevacizumab, and none of these occurred in patients treated to abdominopelvic locations.
Although MPR-EOC is associated with limited prognosis, our data demonstrate that responses to palliative RT can be durable and meaningful. As such, without a conclusive effect on survival, it would be reasonable to consider treatment of such disease after taking into consideration patient symptom severity, goals of care, prognosis, performance status, and extracranial disease burden for BM.
Supplementary Materials
Tables E1 and E2
Sources of support: The authors received no specific funding for this work.
Disclosures: The authors of this manuscript have no conflicts of interest to report.
Research data are stored in an institutional repository and will be shared upon request.
Supplementary material for this article can be found at https://doi.org/10.1016/j.adro.2020.11.009. | BEVACIZUMAB | DrugsGivenReaction | CC BY-NC-ND | 33665491 | 18,951,285 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Haemorrhage intracranial'. | Palliative Radiation Therapy for Metastatic, Persistent, or Recurrent Epithelial Ovarian Cancer: Efficacy in the Era of Modern Technology and Targeted Agents.
Metastatic, persistent, or recurrent epithelial ovarian cancer (MPR-EOC) remains a significant threat to patient mortality despite advances in novel targeted agents. Radiation therapy (RT) is often used as a palliative option. We report outcomes of a large series of MPR-EOC patients treated with modern palliative RT (PRT) in an era of novel systemic therapies.
A retrospective review was conducted of women treated with PRT for MPR-EOC between 2007 and 2019 at an academic institution. Clinical response rates were recorded at <1 month, 1 to 3 months, and >3 months. Radiographic responses were categorized by RECIST 1.1 criteria. Overall response rate (ORR) was the sum of complete and partial response. Linear regression analyses of baseline characteristics were conducted for statistical testing.
Eighty-six patients with PMR-OC received 120 courses of palliative RT. Median follow-up was 8.6 months. Median age was 61 (range, 22-82). Thirty-six percent of women received central nervous system (CNS)-directed RT. In addition, 43% received targeted therapies before RT. Clinical ORR within 1 month and at last follow-up for non-CNS lesions was 79% and 61% (69% and 88% for CNS lesions, respectively). High-grade serous lesions were more likely to have clinical response (P = .04). Biologically effective doses (BED) >39 Gy were associated with improved clinical response in CNS lesions (P = .049). Bony sites were associated with worse clinical (P = .004) response in non-CNS lesions compared with soft tissue or nodal sites. Acute or late grade 3+ toxicities with bevacizumab were low (8.7%/4.3%).
PRT offers excellent rates of response for symptomatic patients with MPR-EOC within 1 month of treatment, with durable responses beyond 3 months. High-grade serous lesions were associated with improved response in all patients. Higher BED and soft tissue or nodal sites were associated with improved response in CNS and non-CNS patients, respectively. Acute or late toxicities with bevacizumab and PRT were low. Prospective investigation is warranted to determine the optimal PRT regimen.
Introduction
Ovarian cancer (OC) is a highly aggressive gynecologic malignancy, with the majority of patients presenting with advanced disease at diagnosis. The general treatment paradigm for advanced OC is maximal cytoreductive surgery with platinum-based chemotherapy.1 Recent literature has also reported a progression-free survival benefit with maintenance inhibition of poly (adenosine diphosphate-ribose) polymerase (PARP) in women with partial or complete response to platinum-based regimens.2,3
Whole abdominal radiation therapy was historically indicated as adjuvant therapy to address microscopic residual disease.4 However, due to its considerable toxicity and the development of platinum-based chemotherapy, whole abdominal radiation therapy is no longer included in primary OC treatment paradigms.1
Despite advances in cytoreductive strategies and front-line systemic therapy, >70% of women relapse within 3 years of diagnosis.5 As such, many patients with OC benefit from palliative care referrals to assist with symptom management, goals of care discussions, and complex medical decision making at the end of life.
There is a growing body of evidence to support the incorporation of palliative services in cancer care. In 2010, a seminal randomized trial6 reported early palliative care among patients with metastatic non-small cell lung cancer significantly improved quality of life, led to less aggressive care at the end of life, and resulted in longer overall survival. Furthermore, both the American Society of Clinical Oncology and the Society of Gynecologic Oncology have published official practice guidelines recommending the routine and early integration of palliative services.7,8
Radiation therapy (RT) is often used as an effective therapeutic option in the palliation of patients with metastatic, persistent, or recurrent epithelial OC (MPR-EOC) as a means for symptomatic relief and local control. This includes oligometastatic disease or symptomatic disease causing pain, bowel or ureteral obstruction, or bleeding. Despite their rarity in OC (2% incidence9), brain metastases can also cause significant morbidity and can be treated with palliative RT to reduce the risk of progression and neurocognitive deficits.10,11
As patient survival improves with modern systemic agents, there is a growing need to understand the efficacy of palliative RT regimens for MPR-EOC in the same era. Although radiation therapy has traditionally been delivered for symptomatic control in MPR-EOC, the recognition of the biologically distinct (and potentially curable) oligometastatic state12,13 is expanding the scope of RT indications. Data from phase 2 trials in other malignancies evaluating the effect of locally directed therapy to oligometastatic lesions has demonstrated improvements in overall survival.14,15
We therefore conducted, a large contemporary retrospective analysis of palliative RT in MPR-EOC. This patient cohort is highly relevant to modern practice given the number of patients who received novel systemic agents, the prominent usage of advanced RT technology, and the representation of patients with BMs from OC (an area with limited data but increasing prevalence in practice). The analysis will report the outcomes and durability of palliative RT in MPR-EOC and delineate factors predictive of response in the modern era.
Methods and Materials
We conducted a retrospective chart review of women treated with palliative radiation therapy for metastatic ovarian cancer from 2007 through 2019 at [University of Pennsylvania] and affiliate sites. Institutional review board approval was obtained before conducting this review. Patients were included in this analysis if they were treated for palliative intent, including treatment of oligometastatic disease. All patients had MPR-EOC ovarian cancer and received anywhere from one to 5 courses of radiation treatment.
Given the poor prognosis of patients with metastatic ovarian cancer, clinical and radiographic response rates were categorized in intervals of <1 month, 1 to 3 months, and >3 months after the end of radiation treatment to indicate acute and durable responses. Clinical responses were categorized as complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD). Pain scores were classified using the Bone Metastases Consensus Working Party guidelines16 (indeterminate responses, which are neither PR nor PD per BMWCP guidelines, were classified as SD to maintain consistency with other clinical response categorizations). Radiographic responses were categorized as CR, PR, SD, or PD based on the RECIST 1.1 criteria.17 Overall response rate (ORR) was the sum of CR and PR in a given patient. Given the large subset of patients with brain metastases (BMs), courses were stratified by central nervous system (CNS) and non-CNS anatomic locations. Acute (during RT and within 3 months of completion) and late (>3 months after completion of RT) toxicities were recorded with concurrent and prior bevacizumab using Common Terminology Criteria for Adverse Events version 5.018 classification.
Rates of response (CR or PR at any point) were compared with demographic and treatment characteristics. χ2 (n ≥ 20) or Fisher exact (n < 20) tests were used for such comparison with variables for race, histology, platinum chemotherapy, or targeted therapy before RT, RT technology, RT location, and biologically effective dose (BED) >39. Binary logistic regression analyses were used for comparison with continuous variables (age and BED). Covariates with P < .1 were included in multiple logistic regression modeling to assess for independent effect. Additionally, χ2 analyses were used to compare rates of radiographic response between patients treated for clinical symptoms and asymptomatic progression. Statistical analysis was conducted using IBM SPSS Statistics, version 26 (IBM Corporation, Armonk, NY).
Results
We identified 86 patients with PMR-OC that received 120 combined courses of palliative radiation treatment. Median follow-up was 8.6 months (range, 0.5-119 months). Excluding 10 patients (15 courses) with no evaluable clinical or radiographic follow-up, 51 patients (58 courses) were treated to non-CNS locations and 18 patients (25 courses) were treated to CNS locations; 7 patients (22 courses) received palliative RT to both CNS (13 courses) and non-CNS (9 courses) locations.
Table 1 describes baseline patient characteristics and details related to patient treatments. The median age of patients in this cohort was 61, with a range of 22 to 82. Patients were most commonly white (83%) and black (8%). Tumor histologies were primarily high-grade serous (HGS, 59%), although adenocarcinoma (undifferentiated or unspecified), low-grade serous, clear cell, endometrioid, and carcinosarcoma were also observed.Table 1 Patient characteristics and treatment details
No. of courses 105
No. of patients 76
Median age 61
Ethnicity
White 82.9% (63/76)
Black 9.2% (7/76)
Asian 3.9% (3/76)
Hispanic 2.6% (2/76)
Unknown 1.3% (1/76)
Histology
High-grade serous 59.2% (45/76)
Adenocarcinoma, other 13.2% (10/76)
Low grade serous 9.2% (7/76)
Clear cell 5.3% (4/76)
Other 7.9% (6/76)
Endometrioid 3.9% (3/76)
Carcinosarcoma 1.3% (1/76)
Anatomic site
Soft tissue/organ 35.2% (37/105)
Lymph node 21.0% (22/105)
Bone 11.4% (12/105)
CNS 36.2% (38/105)
Indications
Clinical symptoms 59.0% (62/105)
Progressive/metastatic 33.3% (35/105)
Postoperative 7.6% (8/105)
Systemic therapy before RT
Platinum chemotherapy 27.6% (29/105)
Nonplatinum chemotherapy 61.9% (65/105)
Targeted therapy 42.9% (45/105)
None/other 1.0% (1/105)
Technique
2D/3D CRT 53.3% (56/105)
SRS 21.9% (23/105)
VMAT/IMRT 16.2% (17/105)
SBRT 4.8% (5/105)
Proton 3.8% (4/105)
Non-SRS dose 14-63 Gy in 4-35 fractions
SBRT dose 24-50 Gy in 3-5 fractions
SRS dose 15-25 Gy in 1-5 fractions
Abbreviations: 2D = 2-dimensional; 3D CRT = 3-dimensional conformal radiation therapy; CNS = central nervous system; IMRT = intensity modulated radiation therapy; RT = radiation therapy; SBRT = stereotactic body radiation therapy; SRS = stereotactic radiosurgery; VMAT = volumetric modulated arc therapy.
Non-CNS treatment locations included tumors in soft tissue or organs (35%), lymph nodes (21%), and bone (11%); 4 patients were treated simultaneously to adjacent soft tissue and lymph nodes. Treatment for CNS metastases comprised the remaining 36% of patients.
Most patients were treated for clinical symptoms (59%). Pain and bleeding were the most common clinical indications. Others included neurologic deficits, spinal cord compression, airway compression, and bowel obstruction. A large cohort of patients were treated for asymptomatic progressive or metastatic disease (33%) with a small cohort treated adjuvantly after surgery (eg, metastasectomy or palliative debulking; 7.6%).
Almost all patients (90%) received chemotherapy immediately before radiation therapy. The most common systemic therapy regimens were platinum-based (ie, carboplatin) followed by taxanes and doxorubicin. Many patients (43%) also received treatment with targeted therapy agents before radiation treatment. Bevacizumab was the most commonly used targeted therapy agent (20%), although patients also received PARP inhibitors (9%) and immune checkpoint inhibitors (5%).
A wide range of palliative radiation regimens were delivered across several modalities. Nonstereotactic treatment regimens to both CNS and non-CNS locations ranged from 14 Gy in 4 fractions to 63 Gy in 35 fractions. Common palliative doses were 30 Gy in 10 fractions (14%), 20 Gy in 5 fractions (8.6%), and 35 Gy in 14 fractions (7.6%). Nonstereotactic modalities included 2-dimensional or 3-dimensional (53%), intensity modulated radiation therapy (IMRT) or volumetric-modulated arc therapy (16%), and proton therapy (3.8%). Stereotactic body radiation therapy (SBRT) was less commonly used (4.8%) with treatment regimen ranging from 24 Gy in 3 fractions to 50 Gy in 5 fractions. Lastly, patients with BMs commonly received stereotactic radiosurgery (SRS, 22% of all courses) with doses ranging from 15 Gy in 1 fraction to 25 Gy in 5 fractions. Nearly half of the patients who underwent SRS received 21 Gy in 1 fraction.
Across the entire cohort, the clinical ORR was 76% within the first month after treatment and 67% at least 3 months after treatment (Table 2). Radiographic ORR between patients treated for clinical symptoms (symptomatic) and asymptomatic progression (asymptomatic) were 48% and 59%, respectively. Although patients treated for asymptomatic progression had higher rates of response, no significant differences were observed between the 2 cohorts (P = .23).Table 2 Response rates (all lesions)
<1 mo 1-3 mo >3 mo
Clinical response
CR 32.8% (19/58) 45.0% (18/40) 48.4% (15/31)
PR 43.1% (25/58) 35.0% (14/40) 19.4% (6/31)
SD 12.1% (7/58) 2.5% (1/40) 0.0% (0/31)
PD 12.1% (7/58) 17.5% (7/40) 32.3% (10/31)
ORR 75.9% (44/58) 80.0% (32/40) 67.7% (21/31)
Radiographic response: symptomatic patients
CR 15.2% (5/33) 16.7% (5/30) 25.9% (7/27)
PR 24.2% (8/33) 30.0% (9/30) 22.2% (6/27)
SD 51.5% (17/33) 43.3% (13/30) 40.7% (11/27)
PD 9.1% (3/33) 10.% (3/30) 11.1% (3/27)
ORR 39.4% (13/33) 46.7% (14/30) 48.1% (13/27)
Radiographic response: asymptomatic patients
CR 39.4% (13/33) 47.1% (16/34) 53.1% (17/32)
PR 9.1% (3/33) 8.8% (3/34) 6.3% (2/32)
SD 45.5% (15/33) 41.2% (14/34) 34.4% (11/32)
PD 6.1% (2/33) 2.9% (1/34) 6.3% (2/32)
ORR 48.5% (16/33) 55.9% (19/34) 59.4% (19/32)
Abbreviations: CR = complete response; ORR = overall response rate; PD = progressive disease; PR = partial response; SD = stable disease.
Excludes patients treated with postoperative palliative radiation.
Denominator reflects evaluable patients.
Of patients treated to non-CNS locations, the clinical and radiographic ORR within the first month after treatment were 79% and 33%, respectively (Table 3). Clinical ORR at last follow-up (at least 3 months after treatment) was 61%. Notably, of the patients with a CR (38.1%) within the first month, only 2 went on to have PD at last follow-up (4 were lost to follow-up), indicating durable response to treatment. All but one patient treated for malignancy-related vaginal bleeding (13/14) had a clinical response within 1 month, of which only one patient had recurrence of bleeding at last follow-up. Seventy percent of patients treated for pain (n = 27) had a clinical response within 1 month, of which only 3 patients demonstrated worsening pain at last follow-up. Radiographically, ORR improved to 38% for symptomatic patients and 47% for asymptomatic patients at last follow-up, with no significant differences in response rates between the 2 groups (P = .44). All lesions that responded within 1 month of radiation treatment maintained response through last follow-up. Furthermore, only 3 of 22 lesions that were initially SD, progressed over time (1 treated for clinical symptoms, 2 treated for asymptomatic progression).Table 3 Response rates (non-CNS lesions)
<1 mo 1-3 mo >3 mo
Clinical response
CR 38.1% (16/42) 44.8% (13/29) 43.5% (10/23)
PR 40.5% (17/42) 31.0% (9/29) 17.4% (4/23)
SD 14.3% (6/42) 3.4% (1/29) 0.0% (0/23)
PD 7.1% (3/42) 20.7% (6/29) 39.1% (9/23)
ORR 78.6% (33/42) 75.9% (22/29) 60.9% (14/23)
Radiographic response: symptomatic patients
CR 9.5% (2/21) 10.5% (2/19) 18.8% (3/16)
PR 23.8% (5/21) 26.3% (5/19) 18.8% (3/16)
SD 52.4% (11/21) 52.6% (10/19) 50.0% (8/16)
PD 14.3% (3/21) 10.5% (2/19) 12.5% (2/16)
ORR 33.3% (7/21) 36.8% (7/19) 37.5% (6/16)
Radiographic response: asymptomatic patients
CR 21.1% (4/19) 31.6% (6/19) 41.2% (7/17)
PR 10.5% (2/19) 10.5% (2/19) 5.9% (1/17)
SD 57.9% (11/19) 52.6% (10/19) 41.2% (7/17)
PD 10.5% (2/19) 5.3% (1/19) 11.8% (2/17)
ORR 31.6% (6/19) 42.1% (8/19) 47.1% (8/17)
Abbreviations: CNS = central nervous system; CR = complete response; ORR = overall response rate; PD = progressive disease; PR = partial response; SD = stable disease.
Excludes patients treated with postoperative palliative radiation.
Denominator reflects evaluable patients.
Of patients treated to CNS locations, the clinical and radiographic ORR within the first month after treatment were 72% and 62%, respectively (Table 4). No patients with a demonstrated clinical or radiographic response within the first month went on to have documented progressive symptoms or imaging at last follow-up (although 2 patients died and 4 were lost to follow-up). Although clinical responses stayed constant over time, radiographic responses tended to improve, especially in patients treated for clinical symptoms. There was no difference in rates of radiographic responses between CNS patients treated for clinical symptoms and those treated for asymptomatic progression (P = .41). All patients receiving SRS responded or had SD at 1 month; only one patient had locally progressive symptoms and disease at last follow-up. Three of the 4 patients with progressive symptoms within the first month were those who received whole brain radiation therapy with more extensive CNS disease before treatment.Table 4 Response rates (CNS lesions)
<1 mo 1-3 mo >3 mo
Clinical response
CR 18.8% (3/16) 45.5% (5/11) 62.5% (5/8)
PR 50.0% (8/16) 45.5% (5/11) 25.0% (2/8)
SD 6.3% (1/16) 0.0% (0/11) 0.0% (0/8)
PD 25.0% (4/16) 9.1% (1/11) 12.5% (1/8)
ORR 68.8% (11/16) 90.9% (10/11) 87.5% (7/8)
Radiographic response: symptomatic patients
CR 25.0% (3/12) 27.3% (3/11) 36.4% (4/11)
PR 25.0% (3/12) 36.4% (4/11) 27.3% (3/11)
SD 50.% (6/12) 27.3% (3/11) 27.3% (3/11)
PD 0.0% (0/12) 9.1% (1/11) 9.1% (1/11)
ORR 50.0% (6/12) 63.6% (7/11) 63.6% (7/11)
Radiographic response: asymptomatic patients
CR 64.3% (9/14) 66.7% (10/15) 66.7% (10/15)
PR 7.1% (1/14) 6.7% (1/15) 6.7% (1/15)
SD 28.6% (4/14) 26.7% (4/15) 26.7% (4/15)
PD 0.0% (0/14) 0.0% (0/15) 0.0% (0/15)
ORR 71.4% (10/14) 73.3% (11/15) 73.3% (11/15)
Abbreviations: CNS = central nervous system; CR = complete response; PD = progressive disease; PR = partial response; ORR = overall response rate; SD = stable disease.
Excludes patients treated with postoperative palliative radiation.
Denominator reflects evaluable patients.
Patients in both CNS and non-CNS cohorts tended to have clinical responses early on, with sustained response at last follow-up. Furthermore, if a patient were to have a clinical CR, it most often occurred within the first month. Only 4 patients demonstrated a CR after the first month, and all of these patients had a PR initially; no patients with initially stable disease went on to have a CR. Most patients with radiographic SD at initial follow-up maintained SD over time. The initial responses of patients developing progressive symptoms after 3-month follow-up varied considerably: CR (2), PR (3), SD (2), and PD (3). No patients who progressed within the first month of follow-up went on to have any response.
Eight patients were treated with postoperative RT after surgical resection in the brain (6), mediastinal lymph node (1), and inguinal lymph node (1). Three patients with evaluable clinical symptoms before and after surgery-RT all demonstrated diminished (PR) or complete (CR) resolution of symptoms within 1 month after RT. Of the 6 patients with radiographic follow-up, one recurred 9 months after treatment; the rest maintained stable disease (ie, no recurrence) through last follow-up.
Acute and late grade 3 or higher (G3 +) toxicities with bevacizumab were low (8.7% and 4.3%, respectively). CNS and mediastinal locations were the only treatment sites in which G3 + toxicity occurred. CNS toxicity (acute G3 fatigue, late G3 radiation necrosis, and late G4 optic neuritis) was identified in a single patient who received craniospinal irradiation with prior Gamma Knife irradiation. A second patient treated to the mediastinum had acute but not chronic grade 3 esophagitis. Notably, no acute or late G3 + toxicity was seen in patients treated to the abdomen or pelvis (the most common treatment location; Table 5).Table 5 Observed toxicities in patients treated with bevacizumab before or concurrent with radiation therapy, by treatment course
None Grade 1-2 Grade 3 Grade 4
Acute
Non-CNS (17) 6 Anorexia (1),
depression (1),
dermatitis (1),
fatigue (5),
GI (6), GU (1),
odynophagia (1),
pneumonitis (1),
vaginal hemorrhage (1) Dermatitis (1),
esophagitis (1) -
CNS (6) 4 GI (1) Fatigue (1) -
Late
Non-CNS (9) 8 GI (1) - -
CNS (5) 3 Intracranial hemorrhage (1) Radionecrosis (1) Optic neuropathy (1)
Abbreviations: CNS = central nervous system; GI = gastrointestinal; GU = genitourinary.
Toxicities defined according to the Common Terminology Criteria for Adverse Events, version 5.0.
Numbers indicate number of treatment courses; more than one toxicity may be attributed to a single treatment course. Late toxicity data unavailable for 9 treatment courses (all due to patient death).
Late grade 3 and 4 toxicities occurred in the same patient.
An exploratory analysis examining patient demographics and treatment characteristics was performed to identify predictors of clinical or radiographic response. In all patients (CNS and non-CNS sites), HGS histology was associated with clinical responses (88% vs 64%, P = .04). In patients with CNS lesions, BED >39 Gy was associated with clinical response (P = .049). In non-CNS locations, bony site was associated with worse clinical (44% vs 89%, P = .004) response compared with soft tissue/nodal (STN) sites. Lastly, we compared BED regimens ≤39 Gy versus >39 Gy (assuming an alpha/beta ratio of 10,19,20 the BED of 30 Gy in 10 fractions is 39 Gy) in non-CNS locations and found no differences in clinical (P = .10) or radiographic response rates (P = .47). We otherwise compared the most common regimens of 20 Gy in 5 fractions and 30 Gy in 10 fractions and found no significant differences in clinical (P = .60) or radiographic responses (P = .29; Table E1).2
Discussion
We report the outcomes of a large modern cohort of women with PMR-OC who received palliative radiation therapy in an era of novel systemic agents. In a population with poor prognosis, palliative radiation therapy resulted in excellent clinical and radiographic response rates (Table 2) within 1 month of treatment, with many responses durable beyond 3 months. Brain metastases, a rare site of anatomic spread, were also well represented in this cohort (36%, 38 courses) and responded favorably to palliative intracranial radiation therapy (Table 3). Exploratory analyses demonstrated an association between HGS histology and improved clinical response in all patients, BED >39 Gy and improved clinical response in BMs, and STN sites with improved clinical response in non-CNS sites. Our analysis is unique in its (1) large sample size compared with prior reports with significant number of BMs, (2) high proportion of patients treated with modern RT techniques, (3) inclusion of patients treated with novel systemic agents (ie, PARP inhibitors, bevacizumab, and immunotherapy), and (4) dedicated toxicity analysis of RT with concurrent or prior bevacizumab, an area of increasing clinical significance in MPR-EOC with a dearth of robust data.
Our high clinical response rates (79% ORR within 1 month) are similar to other reports, including literature from prior decades demonstrating durable pain relief and bleeding control from locally directed palliative RT in 80% of OC patients.20, 21, 22 More recently, Bansal and colleagues also found pain control rates of 88.2% and vaginal bleeding control rates of 100% in 23 heavily pretreated women who received palliative pelvic RT.23 Investigators from Brigham and Women’s Hospital also recently published rates and predictors of response to palliative RT for recurrent OC from 2003 to 201424 and demonstrated high rates of response for pain and bleeding (87% and 93%, respectively).
Identified predictors of response, including HGS histology and STN sites of disease are also compatible with prior investigations. In the above Brigham and Women’s Hospital study, patients treated at nonbony sites had higher response rates than those with bony sites of disease (96% vs 75%, respectively). Furthermore, patients with clear cell histology had the lowest response rates (60%), compared with others like serous histology (82%).
The sizable nature of our cohort allowed for a temporal analysis of index lesion response rates. Patients in both CNS and non-CNS cohorts tended to have clinical responses early on, with some benefitting from sustained response at last follow-up. Lesions with clinical CR often occurred within the first month. Furthermore, no patients who progressed in the index lesion within the first month of follow-up went on to have any response, suggesting that initial response is of paramount importance. Patients who had progressive symptoms after 3 months had variable initial responses, suggesting progressive disease is still expected no matter what the initial response may be.
Regarding dose response, higher BED was associated with clinical response in brain metastases. This is a result of ablative SRS technology that radiobiologically induces high rates of cell kill compared with those of conventional palliative techniques or doses. Advanced stereotactic techniques permit the delivery of otherwise unsafe high dose-per-fraction regimens due to their sharp dose gradients that allow for normal tissue sparing. In non-CNS locations, however, regimens with BED >39 Gy (ie, greater than 30 Gy in 10 fractions) were no different than lower BED regimens, suggesting dose escalation may not increase the efficacy of palliative RT. Use of higher BED regimens in such (predominantly abdominopelvic) locations is typically limited by larger fields due to tumor size and organ motion. Dose-limiting toxicities from nearby organs at risk such as the stomach, bowel, kidneys, and bladder also constrain prescriptions.
Notably, 47% of all courses were delivered with advanced radiation therapy techniques (SRS, SBRT, IMRT/volumetric-modulated arc therapy, proton therapy). This is in keeping with the increasing number of patients referred for ablative or definitive therapy to oligometastatic or oligoprogressive disease or previously irradiated lesions requiring retreatment. In such scenarios, advanced techniques allow practitioners to deliver higher dose per fraction while sparing normal organs and tissue of radiation, or even reirradiation, toxicity. In fact, recently published reports have evaluated the roles of advanced RT in OC. For example, definitive involved-field RT using IMRT has demonstrated promising rates of local control (LC) and disease-free survival with low toxicity.25,26 Two recent retrospective studies also explored SBRT in oligometastatic OC. Lazzari et al reported the treatment of 82 patients with a median dose of 24 Gy in 3 fractions and demonstrated the safety of SBRT along with an increase in systemic therapy-free survival with reasonable LC27 (more than one-third of patients were disease-free at 1 year). Similarly, Macchia et al reported SBRT in MPR-EOC was well tolerated and afforded higher LC in patients receiving a total dose >25 Gy.28
Forty-three percent of patients received targeted therapy immediately before RT in this cohort. This is in keeping with the litany of recent publications studying the use of novel systemic agents (PARP inhibitors,29, 30, 31 bevacizumab,32 nivolumab33) in the setting of MPR-EOC. The response rates described thus reflect the potential outcomes of palliative RT in conjunction with advanced systemic therapies, a scenario that will be increasingly encountered by practitioners. Furthermore, given the sizeable population that received prior or concurrent bevacizumab, a dedicated subgroup analysis was conducted and demonstrated low acute and late grade 3 or higher (G3 +) toxicities (8.7% and 4.3%, respectively) with RT. Although G3 + toxicities occurred in patients treated to CNS and mediastinal locations, it is unclear if this was in relation to prior bevacizumab or reflected the increased risk toxicity with prior RT (Gamma Knife in the CNS patient treated with craniospinal irradiation) or unfavorable tumor location (in the mediastinal patient experiencing esophagitis after receiving 59.4 Gy). No acute or late G3 + toxicity was seen in patients treated to the abdomen or pelvis (the most common treatment location), suggesting that this may be a reasonable treatment option in symptomatic patients.
Limitations
The study is limited primarily by its retrospective nature which lends itself to both selection and sample bias. For example, patient performance status and prior lines of therapy (including prior radiation) may effect physician choice of RT technique, dose, and fractionation. Furthermore, lesions necessitating reirradiation demonstrate inherent radioresistance and may negatively affect response rates. Moreover, although the study population is sizeable, it is heterogenous with respect to treatment sites and prior lines of therapy. As such appropriate interpretation required subdivision of data (ie, CNS vs non-CNS, symptomatic vs asymptomatic indication), which led to more descriptive findings. Finally, the variety of systemic therapies used negatively affect our ability to make conclusions regarding the efficacy of RT with respect to individual agents.
Future directions
As the role for palliative radiation therapy expands in the context of the oligometastatic paradigm, nuanced decision-making must be taken to deliver the most efficacious treatment although promoting cost-effective care. As such, prospective evaluation is warranted to determine the optimal dose, timing, and fractionation of RT as it relates to systemic agents and surgery. The high response rates demonstrated in this cohort may warrant prospective investigation of RT as a standard component therapy in MPR-EOC, either before systemic agents as a cytoreductive strategy or after as consolidation therapy.
Conclusions
We performed a large retrospective cohort analysis of women with MPR-EOC receiving palliative RT in the era of modern technology and systemic agents. Our large population of patients with BMs adds relevant data to the limited body of existing literature and can be used as a practical reference when counseling women. Patients demonstrated favorable clinical and radiographic response rates within 1 month, with >60% experiencing durable clinical responses beyond 3 months. HGS histology was associated with improved clinical response in all patients. BED >39 Gy was associated with improved response in brain metastases. Bony sites were associated with worse response compared with STN sites in non-CNS locations. Acute and late grade 3 or higher toxicities were low with prior bevacizumab, and none of these occurred in patients treated to abdominopelvic locations.
Although MPR-EOC is associated with limited prognosis, our data demonstrate that responses to palliative RT can be durable and meaningful. As such, without a conclusive effect on survival, it would be reasonable to consider treatment of such disease after taking into consideration patient symptom severity, goals of care, prognosis, performance status, and extracranial disease burden for BM.
Supplementary Materials
Tables E1 and E2
Sources of support: The authors received no specific funding for this work.
Disclosures: The authors of this manuscript have no conflicts of interest to report.
Research data are stored in an institutional repository and will be shared upon request.
Supplementary material for this article can be found at https://doi.org/10.1016/j.adro.2020.11.009. | BEVACIZUMAB | DrugsGivenReaction | CC BY-NC-ND | 33665491 | 18,951,285 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Odynophagia'. | Palliative Radiation Therapy for Metastatic, Persistent, or Recurrent Epithelial Ovarian Cancer: Efficacy in the Era of Modern Technology and Targeted Agents.
Metastatic, persistent, or recurrent epithelial ovarian cancer (MPR-EOC) remains a significant threat to patient mortality despite advances in novel targeted agents. Radiation therapy (RT) is often used as a palliative option. We report outcomes of a large series of MPR-EOC patients treated with modern palliative RT (PRT) in an era of novel systemic therapies.
A retrospective review was conducted of women treated with PRT for MPR-EOC between 2007 and 2019 at an academic institution. Clinical response rates were recorded at <1 month, 1 to 3 months, and >3 months. Radiographic responses were categorized by RECIST 1.1 criteria. Overall response rate (ORR) was the sum of complete and partial response. Linear regression analyses of baseline characteristics were conducted for statistical testing.
Eighty-six patients with PMR-OC received 120 courses of palliative RT. Median follow-up was 8.6 months. Median age was 61 (range, 22-82). Thirty-six percent of women received central nervous system (CNS)-directed RT. In addition, 43% received targeted therapies before RT. Clinical ORR within 1 month and at last follow-up for non-CNS lesions was 79% and 61% (69% and 88% for CNS lesions, respectively). High-grade serous lesions were more likely to have clinical response (P = .04). Biologically effective doses (BED) >39 Gy were associated with improved clinical response in CNS lesions (P = .049). Bony sites were associated with worse clinical (P = .004) response in non-CNS lesions compared with soft tissue or nodal sites. Acute or late grade 3+ toxicities with bevacizumab were low (8.7%/4.3%).
PRT offers excellent rates of response for symptomatic patients with MPR-EOC within 1 month of treatment, with durable responses beyond 3 months. High-grade serous lesions were associated with improved response in all patients. Higher BED and soft tissue or nodal sites were associated with improved response in CNS and non-CNS patients, respectively. Acute or late toxicities with bevacizumab and PRT were low. Prospective investigation is warranted to determine the optimal PRT regimen.
Introduction
Ovarian cancer (OC) is a highly aggressive gynecologic malignancy, with the majority of patients presenting with advanced disease at diagnosis. The general treatment paradigm for advanced OC is maximal cytoreductive surgery with platinum-based chemotherapy.1 Recent literature has also reported a progression-free survival benefit with maintenance inhibition of poly (adenosine diphosphate-ribose) polymerase (PARP) in women with partial or complete response to platinum-based regimens.2,3
Whole abdominal radiation therapy was historically indicated as adjuvant therapy to address microscopic residual disease.4 However, due to its considerable toxicity and the development of platinum-based chemotherapy, whole abdominal radiation therapy is no longer included in primary OC treatment paradigms.1
Despite advances in cytoreductive strategies and front-line systemic therapy, >70% of women relapse within 3 years of diagnosis.5 As such, many patients with OC benefit from palliative care referrals to assist with symptom management, goals of care discussions, and complex medical decision making at the end of life.
There is a growing body of evidence to support the incorporation of palliative services in cancer care. In 2010, a seminal randomized trial6 reported early palliative care among patients with metastatic non-small cell lung cancer significantly improved quality of life, led to less aggressive care at the end of life, and resulted in longer overall survival. Furthermore, both the American Society of Clinical Oncology and the Society of Gynecologic Oncology have published official practice guidelines recommending the routine and early integration of palliative services.7,8
Radiation therapy (RT) is often used as an effective therapeutic option in the palliation of patients with metastatic, persistent, or recurrent epithelial OC (MPR-EOC) as a means for symptomatic relief and local control. This includes oligometastatic disease or symptomatic disease causing pain, bowel or ureteral obstruction, or bleeding. Despite their rarity in OC (2% incidence9), brain metastases can also cause significant morbidity and can be treated with palliative RT to reduce the risk of progression and neurocognitive deficits.10,11
As patient survival improves with modern systemic agents, there is a growing need to understand the efficacy of palliative RT regimens for MPR-EOC in the same era. Although radiation therapy has traditionally been delivered for symptomatic control in MPR-EOC, the recognition of the biologically distinct (and potentially curable) oligometastatic state12,13 is expanding the scope of RT indications. Data from phase 2 trials in other malignancies evaluating the effect of locally directed therapy to oligometastatic lesions has demonstrated improvements in overall survival.14,15
We therefore conducted, a large contemporary retrospective analysis of palliative RT in MPR-EOC. This patient cohort is highly relevant to modern practice given the number of patients who received novel systemic agents, the prominent usage of advanced RT technology, and the representation of patients with BMs from OC (an area with limited data but increasing prevalence in practice). The analysis will report the outcomes and durability of palliative RT in MPR-EOC and delineate factors predictive of response in the modern era.
Methods and Materials
We conducted a retrospective chart review of women treated with palliative radiation therapy for metastatic ovarian cancer from 2007 through 2019 at [University of Pennsylvania] and affiliate sites. Institutional review board approval was obtained before conducting this review. Patients were included in this analysis if they were treated for palliative intent, including treatment of oligometastatic disease. All patients had MPR-EOC ovarian cancer and received anywhere from one to 5 courses of radiation treatment.
Given the poor prognosis of patients with metastatic ovarian cancer, clinical and radiographic response rates were categorized in intervals of <1 month, 1 to 3 months, and >3 months after the end of radiation treatment to indicate acute and durable responses. Clinical responses were categorized as complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD). Pain scores were classified using the Bone Metastases Consensus Working Party guidelines16 (indeterminate responses, which are neither PR nor PD per BMWCP guidelines, were classified as SD to maintain consistency with other clinical response categorizations). Radiographic responses were categorized as CR, PR, SD, or PD based on the RECIST 1.1 criteria.17 Overall response rate (ORR) was the sum of CR and PR in a given patient. Given the large subset of patients with brain metastases (BMs), courses were stratified by central nervous system (CNS) and non-CNS anatomic locations. Acute (during RT and within 3 months of completion) and late (>3 months after completion of RT) toxicities were recorded with concurrent and prior bevacizumab using Common Terminology Criteria for Adverse Events version 5.018 classification.
Rates of response (CR or PR at any point) were compared with demographic and treatment characteristics. χ2 (n ≥ 20) or Fisher exact (n < 20) tests were used for such comparison with variables for race, histology, platinum chemotherapy, or targeted therapy before RT, RT technology, RT location, and biologically effective dose (BED) >39. Binary logistic regression analyses were used for comparison with continuous variables (age and BED). Covariates with P < .1 were included in multiple logistic regression modeling to assess for independent effect. Additionally, χ2 analyses were used to compare rates of radiographic response between patients treated for clinical symptoms and asymptomatic progression. Statistical analysis was conducted using IBM SPSS Statistics, version 26 (IBM Corporation, Armonk, NY).
Results
We identified 86 patients with PMR-OC that received 120 combined courses of palliative radiation treatment. Median follow-up was 8.6 months (range, 0.5-119 months). Excluding 10 patients (15 courses) with no evaluable clinical or radiographic follow-up, 51 patients (58 courses) were treated to non-CNS locations and 18 patients (25 courses) were treated to CNS locations; 7 patients (22 courses) received palliative RT to both CNS (13 courses) and non-CNS (9 courses) locations.
Table 1 describes baseline patient characteristics and details related to patient treatments. The median age of patients in this cohort was 61, with a range of 22 to 82. Patients were most commonly white (83%) and black (8%). Tumor histologies were primarily high-grade serous (HGS, 59%), although adenocarcinoma (undifferentiated or unspecified), low-grade serous, clear cell, endometrioid, and carcinosarcoma were also observed.Table 1 Patient characteristics and treatment details
No. of courses 105
No. of patients 76
Median age 61
Ethnicity
White 82.9% (63/76)
Black 9.2% (7/76)
Asian 3.9% (3/76)
Hispanic 2.6% (2/76)
Unknown 1.3% (1/76)
Histology
High-grade serous 59.2% (45/76)
Adenocarcinoma, other 13.2% (10/76)
Low grade serous 9.2% (7/76)
Clear cell 5.3% (4/76)
Other 7.9% (6/76)
Endometrioid 3.9% (3/76)
Carcinosarcoma 1.3% (1/76)
Anatomic site
Soft tissue/organ 35.2% (37/105)
Lymph node 21.0% (22/105)
Bone 11.4% (12/105)
CNS 36.2% (38/105)
Indications
Clinical symptoms 59.0% (62/105)
Progressive/metastatic 33.3% (35/105)
Postoperative 7.6% (8/105)
Systemic therapy before RT
Platinum chemotherapy 27.6% (29/105)
Nonplatinum chemotherapy 61.9% (65/105)
Targeted therapy 42.9% (45/105)
None/other 1.0% (1/105)
Technique
2D/3D CRT 53.3% (56/105)
SRS 21.9% (23/105)
VMAT/IMRT 16.2% (17/105)
SBRT 4.8% (5/105)
Proton 3.8% (4/105)
Non-SRS dose 14-63 Gy in 4-35 fractions
SBRT dose 24-50 Gy in 3-5 fractions
SRS dose 15-25 Gy in 1-5 fractions
Abbreviations: 2D = 2-dimensional; 3D CRT = 3-dimensional conformal radiation therapy; CNS = central nervous system; IMRT = intensity modulated radiation therapy; RT = radiation therapy; SBRT = stereotactic body radiation therapy; SRS = stereotactic radiosurgery; VMAT = volumetric modulated arc therapy.
Non-CNS treatment locations included tumors in soft tissue or organs (35%), lymph nodes (21%), and bone (11%); 4 patients were treated simultaneously to adjacent soft tissue and lymph nodes. Treatment for CNS metastases comprised the remaining 36% of patients.
Most patients were treated for clinical symptoms (59%). Pain and bleeding were the most common clinical indications. Others included neurologic deficits, spinal cord compression, airway compression, and bowel obstruction. A large cohort of patients were treated for asymptomatic progressive or metastatic disease (33%) with a small cohort treated adjuvantly after surgery (eg, metastasectomy or palliative debulking; 7.6%).
Almost all patients (90%) received chemotherapy immediately before radiation therapy. The most common systemic therapy regimens were platinum-based (ie, carboplatin) followed by taxanes and doxorubicin. Many patients (43%) also received treatment with targeted therapy agents before radiation treatment. Bevacizumab was the most commonly used targeted therapy agent (20%), although patients also received PARP inhibitors (9%) and immune checkpoint inhibitors (5%).
A wide range of palliative radiation regimens were delivered across several modalities. Nonstereotactic treatment regimens to both CNS and non-CNS locations ranged from 14 Gy in 4 fractions to 63 Gy in 35 fractions. Common palliative doses were 30 Gy in 10 fractions (14%), 20 Gy in 5 fractions (8.6%), and 35 Gy in 14 fractions (7.6%). Nonstereotactic modalities included 2-dimensional or 3-dimensional (53%), intensity modulated radiation therapy (IMRT) or volumetric-modulated arc therapy (16%), and proton therapy (3.8%). Stereotactic body radiation therapy (SBRT) was less commonly used (4.8%) with treatment regimen ranging from 24 Gy in 3 fractions to 50 Gy in 5 fractions. Lastly, patients with BMs commonly received stereotactic radiosurgery (SRS, 22% of all courses) with doses ranging from 15 Gy in 1 fraction to 25 Gy in 5 fractions. Nearly half of the patients who underwent SRS received 21 Gy in 1 fraction.
Across the entire cohort, the clinical ORR was 76% within the first month after treatment and 67% at least 3 months after treatment (Table 2). Radiographic ORR between patients treated for clinical symptoms (symptomatic) and asymptomatic progression (asymptomatic) were 48% and 59%, respectively. Although patients treated for asymptomatic progression had higher rates of response, no significant differences were observed between the 2 cohorts (P = .23).Table 2 Response rates (all lesions)
<1 mo 1-3 mo >3 mo
Clinical response
CR 32.8% (19/58) 45.0% (18/40) 48.4% (15/31)
PR 43.1% (25/58) 35.0% (14/40) 19.4% (6/31)
SD 12.1% (7/58) 2.5% (1/40) 0.0% (0/31)
PD 12.1% (7/58) 17.5% (7/40) 32.3% (10/31)
ORR 75.9% (44/58) 80.0% (32/40) 67.7% (21/31)
Radiographic response: symptomatic patients
CR 15.2% (5/33) 16.7% (5/30) 25.9% (7/27)
PR 24.2% (8/33) 30.0% (9/30) 22.2% (6/27)
SD 51.5% (17/33) 43.3% (13/30) 40.7% (11/27)
PD 9.1% (3/33) 10.% (3/30) 11.1% (3/27)
ORR 39.4% (13/33) 46.7% (14/30) 48.1% (13/27)
Radiographic response: asymptomatic patients
CR 39.4% (13/33) 47.1% (16/34) 53.1% (17/32)
PR 9.1% (3/33) 8.8% (3/34) 6.3% (2/32)
SD 45.5% (15/33) 41.2% (14/34) 34.4% (11/32)
PD 6.1% (2/33) 2.9% (1/34) 6.3% (2/32)
ORR 48.5% (16/33) 55.9% (19/34) 59.4% (19/32)
Abbreviations: CR = complete response; ORR = overall response rate; PD = progressive disease; PR = partial response; SD = stable disease.
Excludes patients treated with postoperative palliative radiation.
Denominator reflects evaluable patients.
Of patients treated to non-CNS locations, the clinical and radiographic ORR within the first month after treatment were 79% and 33%, respectively (Table 3). Clinical ORR at last follow-up (at least 3 months after treatment) was 61%. Notably, of the patients with a CR (38.1%) within the first month, only 2 went on to have PD at last follow-up (4 were lost to follow-up), indicating durable response to treatment. All but one patient treated for malignancy-related vaginal bleeding (13/14) had a clinical response within 1 month, of which only one patient had recurrence of bleeding at last follow-up. Seventy percent of patients treated for pain (n = 27) had a clinical response within 1 month, of which only 3 patients demonstrated worsening pain at last follow-up. Radiographically, ORR improved to 38% for symptomatic patients and 47% for asymptomatic patients at last follow-up, with no significant differences in response rates between the 2 groups (P = .44). All lesions that responded within 1 month of radiation treatment maintained response through last follow-up. Furthermore, only 3 of 22 lesions that were initially SD, progressed over time (1 treated for clinical symptoms, 2 treated for asymptomatic progression).Table 3 Response rates (non-CNS lesions)
<1 mo 1-3 mo >3 mo
Clinical response
CR 38.1% (16/42) 44.8% (13/29) 43.5% (10/23)
PR 40.5% (17/42) 31.0% (9/29) 17.4% (4/23)
SD 14.3% (6/42) 3.4% (1/29) 0.0% (0/23)
PD 7.1% (3/42) 20.7% (6/29) 39.1% (9/23)
ORR 78.6% (33/42) 75.9% (22/29) 60.9% (14/23)
Radiographic response: symptomatic patients
CR 9.5% (2/21) 10.5% (2/19) 18.8% (3/16)
PR 23.8% (5/21) 26.3% (5/19) 18.8% (3/16)
SD 52.4% (11/21) 52.6% (10/19) 50.0% (8/16)
PD 14.3% (3/21) 10.5% (2/19) 12.5% (2/16)
ORR 33.3% (7/21) 36.8% (7/19) 37.5% (6/16)
Radiographic response: asymptomatic patients
CR 21.1% (4/19) 31.6% (6/19) 41.2% (7/17)
PR 10.5% (2/19) 10.5% (2/19) 5.9% (1/17)
SD 57.9% (11/19) 52.6% (10/19) 41.2% (7/17)
PD 10.5% (2/19) 5.3% (1/19) 11.8% (2/17)
ORR 31.6% (6/19) 42.1% (8/19) 47.1% (8/17)
Abbreviations: CNS = central nervous system; CR = complete response; ORR = overall response rate; PD = progressive disease; PR = partial response; SD = stable disease.
Excludes patients treated with postoperative palliative radiation.
Denominator reflects evaluable patients.
Of patients treated to CNS locations, the clinical and radiographic ORR within the first month after treatment were 72% and 62%, respectively (Table 4). No patients with a demonstrated clinical or radiographic response within the first month went on to have documented progressive symptoms or imaging at last follow-up (although 2 patients died and 4 were lost to follow-up). Although clinical responses stayed constant over time, radiographic responses tended to improve, especially in patients treated for clinical symptoms. There was no difference in rates of radiographic responses between CNS patients treated for clinical symptoms and those treated for asymptomatic progression (P = .41). All patients receiving SRS responded or had SD at 1 month; only one patient had locally progressive symptoms and disease at last follow-up. Three of the 4 patients with progressive symptoms within the first month were those who received whole brain radiation therapy with more extensive CNS disease before treatment.Table 4 Response rates (CNS lesions)
<1 mo 1-3 mo >3 mo
Clinical response
CR 18.8% (3/16) 45.5% (5/11) 62.5% (5/8)
PR 50.0% (8/16) 45.5% (5/11) 25.0% (2/8)
SD 6.3% (1/16) 0.0% (0/11) 0.0% (0/8)
PD 25.0% (4/16) 9.1% (1/11) 12.5% (1/8)
ORR 68.8% (11/16) 90.9% (10/11) 87.5% (7/8)
Radiographic response: symptomatic patients
CR 25.0% (3/12) 27.3% (3/11) 36.4% (4/11)
PR 25.0% (3/12) 36.4% (4/11) 27.3% (3/11)
SD 50.% (6/12) 27.3% (3/11) 27.3% (3/11)
PD 0.0% (0/12) 9.1% (1/11) 9.1% (1/11)
ORR 50.0% (6/12) 63.6% (7/11) 63.6% (7/11)
Radiographic response: asymptomatic patients
CR 64.3% (9/14) 66.7% (10/15) 66.7% (10/15)
PR 7.1% (1/14) 6.7% (1/15) 6.7% (1/15)
SD 28.6% (4/14) 26.7% (4/15) 26.7% (4/15)
PD 0.0% (0/14) 0.0% (0/15) 0.0% (0/15)
ORR 71.4% (10/14) 73.3% (11/15) 73.3% (11/15)
Abbreviations: CNS = central nervous system; CR = complete response; PD = progressive disease; PR = partial response; ORR = overall response rate; SD = stable disease.
Excludes patients treated with postoperative palliative radiation.
Denominator reflects evaluable patients.
Patients in both CNS and non-CNS cohorts tended to have clinical responses early on, with sustained response at last follow-up. Furthermore, if a patient were to have a clinical CR, it most often occurred within the first month. Only 4 patients demonstrated a CR after the first month, and all of these patients had a PR initially; no patients with initially stable disease went on to have a CR. Most patients with radiographic SD at initial follow-up maintained SD over time. The initial responses of patients developing progressive symptoms after 3-month follow-up varied considerably: CR (2), PR (3), SD (2), and PD (3). No patients who progressed within the first month of follow-up went on to have any response.
Eight patients were treated with postoperative RT after surgical resection in the brain (6), mediastinal lymph node (1), and inguinal lymph node (1). Three patients with evaluable clinical symptoms before and after surgery-RT all demonstrated diminished (PR) or complete (CR) resolution of symptoms within 1 month after RT. Of the 6 patients with radiographic follow-up, one recurred 9 months after treatment; the rest maintained stable disease (ie, no recurrence) through last follow-up.
Acute and late grade 3 or higher (G3 +) toxicities with bevacizumab were low (8.7% and 4.3%, respectively). CNS and mediastinal locations were the only treatment sites in which G3 + toxicity occurred. CNS toxicity (acute G3 fatigue, late G3 radiation necrosis, and late G4 optic neuritis) was identified in a single patient who received craniospinal irradiation with prior Gamma Knife irradiation. A second patient treated to the mediastinum had acute but not chronic grade 3 esophagitis. Notably, no acute or late G3 + toxicity was seen in patients treated to the abdomen or pelvis (the most common treatment location; Table 5).Table 5 Observed toxicities in patients treated with bevacizumab before or concurrent with radiation therapy, by treatment course
None Grade 1-2 Grade 3 Grade 4
Acute
Non-CNS (17) 6 Anorexia (1),
depression (1),
dermatitis (1),
fatigue (5),
GI (6), GU (1),
odynophagia (1),
pneumonitis (1),
vaginal hemorrhage (1) Dermatitis (1),
esophagitis (1) -
CNS (6) 4 GI (1) Fatigue (1) -
Late
Non-CNS (9) 8 GI (1) - -
CNS (5) 3 Intracranial hemorrhage (1) Radionecrosis (1) Optic neuropathy (1)
Abbreviations: CNS = central nervous system; GI = gastrointestinal; GU = genitourinary.
Toxicities defined according to the Common Terminology Criteria for Adverse Events, version 5.0.
Numbers indicate number of treatment courses; more than one toxicity may be attributed to a single treatment course. Late toxicity data unavailable for 9 treatment courses (all due to patient death).
Late grade 3 and 4 toxicities occurred in the same patient.
An exploratory analysis examining patient demographics and treatment characteristics was performed to identify predictors of clinical or radiographic response. In all patients (CNS and non-CNS sites), HGS histology was associated with clinical responses (88% vs 64%, P = .04). In patients with CNS lesions, BED >39 Gy was associated with clinical response (P = .049). In non-CNS locations, bony site was associated with worse clinical (44% vs 89%, P = .004) response compared with soft tissue/nodal (STN) sites. Lastly, we compared BED regimens ≤39 Gy versus >39 Gy (assuming an alpha/beta ratio of 10,19,20 the BED of 30 Gy in 10 fractions is 39 Gy) in non-CNS locations and found no differences in clinical (P = .10) or radiographic response rates (P = .47). We otherwise compared the most common regimens of 20 Gy in 5 fractions and 30 Gy in 10 fractions and found no significant differences in clinical (P = .60) or radiographic responses (P = .29; Table E1).2
Discussion
We report the outcomes of a large modern cohort of women with PMR-OC who received palliative radiation therapy in an era of novel systemic agents. In a population with poor prognosis, palliative radiation therapy resulted in excellent clinical and radiographic response rates (Table 2) within 1 month of treatment, with many responses durable beyond 3 months. Brain metastases, a rare site of anatomic spread, were also well represented in this cohort (36%, 38 courses) and responded favorably to palliative intracranial radiation therapy (Table 3). Exploratory analyses demonstrated an association between HGS histology and improved clinical response in all patients, BED >39 Gy and improved clinical response in BMs, and STN sites with improved clinical response in non-CNS sites. Our analysis is unique in its (1) large sample size compared with prior reports with significant number of BMs, (2) high proportion of patients treated with modern RT techniques, (3) inclusion of patients treated with novel systemic agents (ie, PARP inhibitors, bevacizumab, and immunotherapy), and (4) dedicated toxicity analysis of RT with concurrent or prior bevacizumab, an area of increasing clinical significance in MPR-EOC with a dearth of robust data.
Our high clinical response rates (79% ORR within 1 month) are similar to other reports, including literature from prior decades demonstrating durable pain relief and bleeding control from locally directed palliative RT in 80% of OC patients.20, 21, 22 More recently, Bansal and colleagues also found pain control rates of 88.2% and vaginal bleeding control rates of 100% in 23 heavily pretreated women who received palliative pelvic RT.23 Investigators from Brigham and Women’s Hospital also recently published rates and predictors of response to palliative RT for recurrent OC from 2003 to 201424 and demonstrated high rates of response for pain and bleeding (87% and 93%, respectively).
Identified predictors of response, including HGS histology and STN sites of disease are also compatible with prior investigations. In the above Brigham and Women’s Hospital study, patients treated at nonbony sites had higher response rates than those with bony sites of disease (96% vs 75%, respectively). Furthermore, patients with clear cell histology had the lowest response rates (60%), compared with others like serous histology (82%).
The sizable nature of our cohort allowed for a temporal analysis of index lesion response rates. Patients in both CNS and non-CNS cohorts tended to have clinical responses early on, with some benefitting from sustained response at last follow-up. Lesions with clinical CR often occurred within the first month. Furthermore, no patients who progressed in the index lesion within the first month of follow-up went on to have any response, suggesting that initial response is of paramount importance. Patients who had progressive symptoms after 3 months had variable initial responses, suggesting progressive disease is still expected no matter what the initial response may be.
Regarding dose response, higher BED was associated with clinical response in brain metastases. This is a result of ablative SRS technology that radiobiologically induces high rates of cell kill compared with those of conventional palliative techniques or doses. Advanced stereotactic techniques permit the delivery of otherwise unsafe high dose-per-fraction regimens due to their sharp dose gradients that allow for normal tissue sparing. In non-CNS locations, however, regimens with BED >39 Gy (ie, greater than 30 Gy in 10 fractions) were no different than lower BED regimens, suggesting dose escalation may not increase the efficacy of palliative RT. Use of higher BED regimens in such (predominantly abdominopelvic) locations is typically limited by larger fields due to tumor size and organ motion. Dose-limiting toxicities from nearby organs at risk such as the stomach, bowel, kidneys, and bladder also constrain prescriptions.
Notably, 47% of all courses were delivered with advanced radiation therapy techniques (SRS, SBRT, IMRT/volumetric-modulated arc therapy, proton therapy). This is in keeping with the increasing number of patients referred for ablative or definitive therapy to oligometastatic or oligoprogressive disease or previously irradiated lesions requiring retreatment. In such scenarios, advanced techniques allow practitioners to deliver higher dose per fraction while sparing normal organs and tissue of radiation, or even reirradiation, toxicity. In fact, recently published reports have evaluated the roles of advanced RT in OC. For example, definitive involved-field RT using IMRT has demonstrated promising rates of local control (LC) and disease-free survival with low toxicity.25,26 Two recent retrospective studies also explored SBRT in oligometastatic OC. Lazzari et al reported the treatment of 82 patients with a median dose of 24 Gy in 3 fractions and demonstrated the safety of SBRT along with an increase in systemic therapy-free survival with reasonable LC27 (more than one-third of patients were disease-free at 1 year). Similarly, Macchia et al reported SBRT in MPR-EOC was well tolerated and afforded higher LC in patients receiving a total dose >25 Gy.28
Forty-three percent of patients received targeted therapy immediately before RT in this cohort. This is in keeping with the litany of recent publications studying the use of novel systemic agents (PARP inhibitors,29, 30, 31 bevacizumab,32 nivolumab33) in the setting of MPR-EOC. The response rates described thus reflect the potential outcomes of palliative RT in conjunction with advanced systemic therapies, a scenario that will be increasingly encountered by practitioners. Furthermore, given the sizeable population that received prior or concurrent bevacizumab, a dedicated subgroup analysis was conducted and demonstrated low acute and late grade 3 or higher (G3 +) toxicities (8.7% and 4.3%, respectively) with RT. Although G3 + toxicities occurred in patients treated to CNS and mediastinal locations, it is unclear if this was in relation to prior bevacizumab or reflected the increased risk toxicity with prior RT (Gamma Knife in the CNS patient treated with craniospinal irradiation) or unfavorable tumor location (in the mediastinal patient experiencing esophagitis after receiving 59.4 Gy). No acute or late G3 + toxicity was seen in patients treated to the abdomen or pelvis (the most common treatment location), suggesting that this may be a reasonable treatment option in symptomatic patients.
Limitations
The study is limited primarily by its retrospective nature which lends itself to both selection and sample bias. For example, patient performance status and prior lines of therapy (including prior radiation) may effect physician choice of RT technique, dose, and fractionation. Furthermore, lesions necessitating reirradiation demonstrate inherent radioresistance and may negatively affect response rates. Moreover, although the study population is sizeable, it is heterogenous with respect to treatment sites and prior lines of therapy. As such appropriate interpretation required subdivision of data (ie, CNS vs non-CNS, symptomatic vs asymptomatic indication), which led to more descriptive findings. Finally, the variety of systemic therapies used negatively affect our ability to make conclusions regarding the efficacy of RT with respect to individual agents.
Future directions
As the role for palliative radiation therapy expands in the context of the oligometastatic paradigm, nuanced decision-making must be taken to deliver the most efficacious treatment although promoting cost-effective care. As such, prospective evaluation is warranted to determine the optimal dose, timing, and fractionation of RT as it relates to systemic agents and surgery. The high response rates demonstrated in this cohort may warrant prospective investigation of RT as a standard component therapy in MPR-EOC, either before systemic agents as a cytoreductive strategy or after as consolidation therapy.
Conclusions
We performed a large retrospective cohort analysis of women with MPR-EOC receiving palliative RT in the era of modern technology and systemic agents. Our large population of patients with BMs adds relevant data to the limited body of existing literature and can be used as a practical reference when counseling women. Patients demonstrated favorable clinical and radiographic response rates within 1 month, with >60% experiencing durable clinical responses beyond 3 months. HGS histology was associated with improved clinical response in all patients. BED >39 Gy was associated with improved response in brain metastases. Bony sites were associated with worse response compared with STN sites in non-CNS locations. Acute and late grade 3 or higher toxicities were low with prior bevacizumab, and none of these occurred in patients treated to abdominopelvic locations.
Although MPR-EOC is associated with limited prognosis, our data demonstrate that responses to palliative RT can be durable and meaningful. As such, without a conclusive effect on survival, it would be reasonable to consider treatment of such disease after taking into consideration patient symptom severity, goals of care, prognosis, performance status, and extracranial disease burden for BM.
Supplementary Materials
Tables E1 and E2
Sources of support: The authors received no specific funding for this work.
Disclosures: The authors of this manuscript have no conflicts of interest to report.
Research data are stored in an institutional repository and will be shared upon request.
Supplementary material for this article can be found at https://doi.org/10.1016/j.adro.2020.11.009. | BEVACIZUMAB | DrugsGivenReaction | CC BY-NC-ND | 33665491 | 18,951,285 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Oesophagitis'. | Palliative Radiation Therapy for Metastatic, Persistent, or Recurrent Epithelial Ovarian Cancer: Efficacy in the Era of Modern Technology and Targeted Agents.
Metastatic, persistent, or recurrent epithelial ovarian cancer (MPR-EOC) remains a significant threat to patient mortality despite advances in novel targeted agents. Radiation therapy (RT) is often used as a palliative option. We report outcomes of a large series of MPR-EOC patients treated with modern palliative RT (PRT) in an era of novel systemic therapies.
A retrospective review was conducted of women treated with PRT for MPR-EOC between 2007 and 2019 at an academic institution. Clinical response rates were recorded at <1 month, 1 to 3 months, and >3 months. Radiographic responses were categorized by RECIST 1.1 criteria. Overall response rate (ORR) was the sum of complete and partial response. Linear regression analyses of baseline characteristics were conducted for statistical testing.
Eighty-six patients with PMR-OC received 120 courses of palliative RT. Median follow-up was 8.6 months. Median age was 61 (range, 22-82). Thirty-six percent of women received central nervous system (CNS)-directed RT. In addition, 43% received targeted therapies before RT. Clinical ORR within 1 month and at last follow-up for non-CNS lesions was 79% and 61% (69% and 88% for CNS lesions, respectively). High-grade serous lesions were more likely to have clinical response (P = .04). Biologically effective doses (BED) >39 Gy were associated with improved clinical response in CNS lesions (P = .049). Bony sites were associated with worse clinical (P = .004) response in non-CNS lesions compared with soft tissue or nodal sites. Acute or late grade 3+ toxicities with bevacizumab were low (8.7%/4.3%).
PRT offers excellent rates of response for symptomatic patients with MPR-EOC within 1 month of treatment, with durable responses beyond 3 months. High-grade serous lesions were associated with improved response in all patients. Higher BED and soft tissue or nodal sites were associated with improved response in CNS and non-CNS patients, respectively. Acute or late toxicities with bevacizumab and PRT were low. Prospective investigation is warranted to determine the optimal PRT regimen.
Introduction
Ovarian cancer (OC) is a highly aggressive gynecologic malignancy, with the majority of patients presenting with advanced disease at diagnosis. The general treatment paradigm for advanced OC is maximal cytoreductive surgery with platinum-based chemotherapy.1 Recent literature has also reported a progression-free survival benefit with maintenance inhibition of poly (adenosine diphosphate-ribose) polymerase (PARP) in women with partial or complete response to platinum-based regimens.2,3
Whole abdominal radiation therapy was historically indicated as adjuvant therapy to address microscopic residual disease.4 However, due to its considerable toxicity and the development of platinum-based chemotherapy, whole abdominal radiation therapy is no longer included in primary OC treatment paradigms.1
Despite advances in cytoreductive strategies and front-line systemic therapy, >70% of women relapse within 3 years of diagnosis.5 As such, many patients with OC benefit from palliative care referrals to assist with symptom management, goals of care discussions, and complex medical decision making at the end of life.
There is a growing body of evidence to support the incorporation of palliative services in cancer care. In 2010, a seminal randomized trial6 reported early palliative care among patients with metastatic non-small cell lung cancer significantly improved quality of life, led to less aggressive care at the end of life, and resulted in longer overall survival. Furthermore, both the American Society of Clinical Oncology and the Society of Gynecologic Oncology have published official practice guidelines recommending the routine and early integration of palliative services.7,8
Radiation therapy (RT) is often used as an effective therapeutic option in the palliation of patients with metastatic, persistent, or recurrent epithelial OC (MPR-EOC) as a means for symptomatic relief and local control. This includes oligometastatic disease or symptomatic disease causing pain, bowel or ureteral obstruction, or bleeding. Despite their rarity in OC (2% incidence9), brain metastases can also cause significant morbidity and can be treated with palliative RT to reduce the risk of progression and neurocognitive deficits.10,11
As patient survival improves with modern systemic agents, there is a growing need to understand the efficacy of palliative RT regimens for MPR-EOC in the same era. Although radiation therapy has traditionally been delivered for symptomatic control in MPR-EOC, the recognition of the biologically distinct (and potentially curable) oligometastatic state12,13 is expanding the scope of RT indications. Data from phase 2 trials in other malignancies evaluating the effect of locally directed therapy to oligometastatic lesions has demonstrated improvements in overall survival.14,15
We therefore conducted, a large contemporary retrospective analysis of palliative RT in MPR-EOC. This patient cohort is highly relevant to modern practice given the number of patients who received novel systemic agents, the prominent usage of advanced RT technology, and the representation of patients with BMs from OC (an area with limited data but increasing prevalence in practice). The analysis will report the outcomes and durability of palliative RT in MPR-EOC and delineate factors predictive of response in the modern era.
Methods and Materials
We conducted a retrospective chart review of women treated with palliative radiation therapy for metastatic ovarian cancer from 2007 through 2019 at [University of Pennsylvania] and affiliate sites. Institutional review board approval was obtained before conducting this review. Patients were included in this analysis if they were treated for palliative intent, including treatment of oligometastatic disease. All patients had MPR-EOC ovarian cancer and received anywhere from one to 5 courses of radiation treatment.
Given the poor prognosis of patients with metastatic ovarian cancer, clinical and radiographic response rates were categorized in intervals of <1 month, 1 to 3 months, and >3 months after the end of radiation treatment to indicate acute and durable responses. Clinical responses were categorized as complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD). Pain scores were classified using the Bone Metastases Consensus Working Party guidelines16 (indeterminate responses, which are neither PR nor PD per BMWCP guidelines, were classified as SD to maintain consistency with other clinical response categorizations). Radiographic responses were categorized as CR, PR, SD, or PD based on the RECIST 1.1 criteria.17 Overall response rate (ORR) was the sum of CR and PR in a given patient. Given the large subset of patients with brain metastases (BMs), courses were stratified by central nervous system (CNS) and non-CNS anatomic locations. Acute (during RT and within 3 months of completion) and late (>3 months after completion of RT) toxicities were recorded with concurrent and prior bevacizumab using Common Terminology Criteria for Adverse Events version 5.018 classification.
Rates of response (CR or PR at any point) were compared with demographic and treatment characteristics. χ2 (n ≥ 20) or Fisher exact (n < 20) tests were used for such comparison with variables for race, histology, platinum chemotherapy, or targeted therapy before RT, RT technology, RT location, and biologically effective dose (BED) >39. Binary logistic regression analyses were used for comparison with continuous variables (age and BED). Covariates with P < .1 were included in multiple logistic regression modeling to assess for independent effect. Additionally, χ2 analyses were used to compare rates of radiographic response between patients treated for clinical symptoms and asymptomatic progression. Statistical analysis was conducted using IBM SPSS Statistics, version 26 (IBM Corporation, Armonk, NY).
Results
We identified 86 patients with PMR-OC that received 120 combined courses of palliative radiation treatment. Median follow-up was 8.6 months (range, 0.5-119 months). Excluding 10 patients (15 courses) with no evaluable clinical or radiographic follow-up, 51 patients (58 courses) were treated to non-CNS locations and 18 patients (25 courses) were treated to CNS locations; 7 patients (22 courses) received palliative RT to both CNS (13 courses) and non-CNS (9 courses) locations.
Table 1 describes baseline patient characteristics and details related to patient treatments. The median age of patients in this cohort was 61, with a range of 22 to 82. Patients were most commonly white (83%) and black (8%). Tumor histologies were primarily high-grade serous (HGS, 59%), although adenocarcinoma (undifferentiated or unspecified), low-grade serous, clear cell, endometrioid, and carcinosarcoma were also observed.Table 1 Patient characteristics and treatment details
No. of courses 105
No. of patients 76
Median age 61
Ethnicity
White 82.9% (63/76)
Black 9.2% (7/76)
Asian 3.9% (3/76)
Hispanic 2.6% (2/76)
Unknown 1.3% (1/76)
Histology
High-grade serous 59.2% (45/76)
Adenocarcinoma, other 13.2% (10/76)
Low grade serous 9.2% (7/76)
Clear cell 5.3% (4/76)
Other 7.9% (6/76)
Endometrioid 3.9% (3/76)
Carcinosarcoma 1.3% (1/76)
Anatomic site
Soft tissue/organ 35.2% (37/105)
Lymph node 21.0% (22/105)
Bone 11.4% (12/105)
CNS 36.2% (38/105)
Indications
Clinical symptoms 59.0% (62/105)
Progressive/metastatic 33.3% (35/105)
Postoperative 7.6% (8/105)
Systemic therapy before RT
Platinum chemotherapy 27.6% (29/105)
Nonplatinum chemotherapy 61.9% (65/105)
Targeted therapy 42.9% (45/105)
None/other 1.0% (1/105)
Technique
2D/3D CRT 53.3% (56/105)
SRS 21.9% (23/105)
VMAT/IMRT 16.2% (17/105)
SBRT 4.8% (5/105)
Proton 3.8% (4/105)
Non-SRS dose 14-63 Gy in 4-35 fractions
SBRT dose 24-50 Gy in 3-5 fractions
SRS dose 15-25 Gy in 1-5 fractions
Abbreviations: 2D = 2-dimensional; 3D CRT = 3-dimensional conformal radiation therapy; CNS = central nervous system; IMRT = intensity modulated radiation therapy; RT = radiation therapy; SBRT = stereotactic body radiation therapy; SRS = stereotactic radiosurgery; VMAT = volumetric modulated arc therapy.
Non-CNS treatment locations included tumors in soft tissue or organs (35%), lymph nodes (21%), and bone (11%); 4 patients were treated simultaneously to adjacent soft tissue and lymph nodes. Treatment for CNS metastases comprised the remaining 36% of patients.
Most patients were treated for clinical symptoms (59%). Pain and bleeding were the most common clinical indications. Others included neurologic deficits, spinal cord compression, airway compression, and bowel obstruction. A large cohort of patients were treated for asymptomatic progressive or metastatic disease (33%) with a small cohort treated adjuvantly after surgery (eg, metastasectomy or palliative debulking; 7.6%).
Almost all patients (90%) received chemotherapy immediately before radiation therapy. The most common systemic therapy regimens were platinum-based (ie, carboplatin) followed by taxanes and doxorubicin. Many patients (43%) also received treatment with targeted therapy agents before radiation treatment. Bevacizumab was the most commonly used targeted therapy agent (20%), although patients also received PARP inhibitors (9%) and immune checkpoint inhibitors (5%).
A wide range of palliative radiation regimens were delivered across several modalities. Nonstereotactic treatment regimens to both CNS and non-CNS locations ranged from 14 Gy in 4 fractions to 63 Gy in 35 fractions. Common palliative doses were 30 Gy in 10 fractions (14%), 20 Gy in 5 fractions (8.6%), and 35 Gy in 14 fractions (7.6%). Nonstereotactic modalities included 2-dimensional or 3-dimensional (53%), intensity modulated radiation therapy (IMRT) or volumetric-modulated arc therapy (16%), and proton therapy (3.8%). Stereotactic body radiation therapy (SBRT) was less commonly used (4.8%) with treatment regimen ranging from 24 Gy in 3 fractions to 50 Gy in 5 fractions. Lastly, patients with BMs commonly received stereotactic radiosurgery (SRS, 22% of all courses) with doses ranging from 15 Gy in 1 fraction to 25 Gy in 5 fractions. Nearly half of the patients who underwent SRS received 21 Gy in 1 fraction.
Across the entire cohort, the clinical ORR was 76% within the first month after treatment and 67% at least 3 months after treatment (Table 2). Radiographic ORR between patients treated for clinical symptoms (symptomatic) and asymptomatic progression (asymptomatic) were 48% and 59%, respectively. Although patients treated for asymptomatic progression had higher rates of response, no significant differences were observed between the 2 cohorts (P = .23).Table 2 Response rates (all lesions)
<1 mo 1-3 mo >3 mo
Clinical response
CR 32.8% (19/58) 45.0% (18/40) 48.4% (15/31)
PR 43.1% (25/58) 35.0% (14/40) 19.4% (6/31)
SD 12.1% (7/58) 2.5% (1/40) 0.0% (0/31)
PD 12.1% (7/58) 17.5% (7/40) 32.3% (10/31)
ORR 75.9% (44/58) 80.0% (32/40) 67.7% (21/31)
Radiographic response: symptomatic patients
CR 15.2% (5/33) 16.7% (5/30) 25.9% (7/27)
PR 24.2% (8/33) 30.0% (9/30) 22.2% (6/27)
SD 51.5% (17/33) 43.3% (13/30) 40.7% (11/27)
PD 9.1% (3/33) 10.% (3/30) 11.1% (3/27)
ORR 39.4% (13/33) 46.7% (14/30) 48.1% (13/27)
Radiographic response: asymptomatic patients
CR 39.4% (13/33) 47.1% (16/34) 53.1% (17/32)
PR 9.1% (3/33) 8.8% (3/34) 6.3% (2/32)
SD 45.5% (15/33) 41.2% (14/34) 34.4% (11/32)
PD 6.1% (2/33) 2.9% (1/34) 6.3% (2/32)
ORR 48.5% (16/33) 55.9% (19/34) 59.4% (19/32)
Abbreviations: CR = complete response; ORR = overall response rate; PD = progressive disease; PR = partial response; SD = stable disease.
Excludes patients treated with postoperative palliative radiation.
Denominator reflects evaluable patients.
Of patients treated to non-CNS locations, the clinical and radiographic ORR within the first month after treatment were 79% and 33%, respectively (Table 3). Clinical ORR at last follow-up (at least 3 months after treatment) was 61%. Notably, of the patients with a CR (38.1%) within the first month, only 2 went on to have PD at last follow-up (4 were lost to follow-up), indicating durable response to treatment. All but one patient treated for malignancy-related vaginal bleeding (13/14) had a clinical response within 1 month, of which only one patient had recurrence of bleeding at last follow-up. Seventy percent of patients treated for pain (n = 27) had a clinical response within 1 month, of which only 3 patients demonstrated worsening pain at last follow-up. Radiographically, ORR improved to 38% for symptomatic patients and 47% for asymptomatic patients at last follow-up, with no significant differences in response rates between the 2 groups (P = .44). All lesions that responded within 1 month of radiation treatment maintained response through last follow-up. Furthermore, only 3 of 22 lesions that were initially SD, progressed over time (1 treated for clinical symptoms, 2 treated for asymptomatic progression).Table 3 Response rates (non-CNS lesions)
<1 mo 1-3 mo >3 mo
Clinical response
CR 38.1% (16/42) 44.8% (13/29) 43.5% (10/23)
PR 40.5% (17/42) 31.0% (9/29) 17.4% (4/23)
SD 14.3% (6/42) 3.4% (1/29) 0.0% (0/23)
PD 7.1% (3/42) 20.7% (6/29) 39.1% (9/23)
ORR 78.6% (33/42) 75.9% (22/29) 60.9% (14/23)
Radiographic response: symptomatic patients
CR 9.5% (2/21) 10.5% (2/19) 18.8% (3/16)
PR 23.8% (5/21) 26.3% (5/19) 18.8% (3/16)
SD 52.4% (11/21) 52.6% (10/19) 50.0% (8/16)
PD 14.3% (3/21) 10.5% (2/19) 12.5% (2/16)
ORR 33.3% (7/21) 36.8% (7/19) 37.5% (6/16)
Radiographic response: asymptomatic patients
CR 21.1% (4/19) 31.6% (6/19) 41.2% (7/17)
PR 10.5% (2/19) 10.5% (2/19) 5.9% (1/17)
SD 57.9% (11/19) 52.6% (10/19) 41.2% (7/17)
PD 10.5% (2/19) 5.3% (1/19) 11.8% (2/17)
ORR 31.6% (6/19) 42.1% (8/19) 47.1% (8/17)
Abbreviations: CNS = central nervous system; CR = complete response; ORR = overall response rate; PD = progressive disease; PR = partial response; SD = stable disease.
Excludes patients treated with postoperative palliative radiation.
Denominator reflects evaluable patients.
Of patients treated to CNS locations, the clinical and radiographic ORR within the first month after treatment were 72% and 62%, respectively (Table 4). No patients with a demonstrated clinical or radiographic response within the first month went on to have documented progressive symptoms or imaging at last follow-up (although 2 patients died and 4 were lost to follow-up). Although clinical responses stayed constant over time, radiographic responses tended to improve, especially in patients treated for clinical symptoms. There was no difference in rates of radiographic responses between CNS patients treated for clinical symptoms and those treated for asymptomatic progression (P = .41). All patients receiving SRS responded or had SD at 1 month; only one patient had locally progressive symptoms and disease at last follow-up. Three of the 4 patients with progressive symptoms within the first month were those who received whole brain radiation therapy with more extensive CNS disease before treatment.Table 4 Response rates (CNS lesions)
<1 mo 1-3 mo >3 mo
Clinical response
CR 18.8% (3/16) 45.5% (5/11) 62.5% (5/8)
PR 50.0% (8/16) 45.5% (5/11) 25.0% (2/8)
SD 6.3% (1/16) 0.0% (0/11) 0.0% (0/8)
PD 25.0% (4/16) 9.1% (1/11) 12.5% (1/8)
ORR 68.8% (11/16) 90.9% (10/11) 87.5% (7/8)
Radiographic response: symptomatic patients
CR 25.0% (3/12) 27.3% (3/11) 36.4% (4/11)
PR 25.0% (3/12) 36.4% (4/11) 27.3% (3/11)
SD 50.% (6/12) 27.3% (3/11) 27.3% (3/11)
PD 0.0% (0/12) 9.1% (1/11) 9.1% (1/11)
ORR 50.0% (6/12) 63.6% (7/11) 63.6% (7/11)
Radiographic response: asymptomatic patients
CR 64.3% (9/14) 66.7% (10/15) 66.7% (10/15)
PR 7.1% (1/14) 6.7% (1/15) 6.7% (1/15)
SD 28.6% (4/14) 26.7% (4/15) 26.7% (4/15)
PD 0.0% (0/14) 0.0% (0/15) 0.0% (0/15)
ORR 71.4% (10/14) 73.3% (11/15) 73.3% (11/15)
Abbreviations: CNS = central nervous system; CR = complete response; PD = progressive disease; PR = partial response; ORR = overall response rate; SD = stable disease.
Excludes patients treated with postoperative palliative radiation.
Denominator reflects evaluable patients.
Patients in both CNS and non-CNS cohorts tended to have clinical responses early on, with sustained response at last follow-up. Furthermore, if a patient were to have a clinical CR, it most often occurred within the first month. Only 4 patients demonstrated a CR after the first month, and all of these patients had a PR initially; no patients with initially stable disease went on to have a CR. Most patients with radiographic SD at initial follow-up maintained SD over time. The initial responses of patients developing progressive symptoms after 3-month follow-up varied considerably: CR (2), PR (3), SD (2), and PD (3). No patients who progressed within the first month of follow-up went on to have any response.
Eight patients were treated with postoperative RT after surgical resection in the brain (6), mediastinal lymph node (1), and inguinal lymph node (1). Three patients with evaluable clinical symptoms before and after surgery-RT all demonstrated diminished (PR) or complete (CR) resolution of symptoms within 1 month after RT. Of the 6 patients with radiographic follow-up, one recurred 9 months after treatment; the rest maintained stable disease (ie, no recurrence) through last follow-up.
Acute and late grade 3 or higher (G3 +) toxicities with bevacizumab were low (8.7% and 4.3%, respectively). CNS and mediastinal locations were the only treatment sites in which G3 + toxicity occurred. CNS toxicity (acute G3 fatigue, late G3 radiation necrosis, and late G4 optic neuritis) was identified in a single patient who received craniospinal irradiation with prior Gamma Knife irradiation. A second patient treated to the mediastinum had acute but not chronic grade 3 esophagitis. Notably, no acute or late G3 + toxicity was seen in patients treated to the abdomen or pelvis (the most common treatment location; Table 5).Table 5 Observed toxicities in patients treated with bevacizumab before or concurrent with radiation therapy, by treatment course
None Grade 1-2 Grade 3 Grade 4
Acute
Non-CNS (17) 6 Anorexia (1),
depression (1),
dermatitis (1),
fatigue (5),
GI (6), GU (1),
odynophagia (1),
pneumonitis (1),
vaginal hemorrhage (1) Dermatitis (1),
esophagitis (1) -
CNS (6) 4 GI (1) Fatigue (1) -
Late
Non-CNS (9) 8 GI (1) - -
CNS (5) 3 Intracranial hemorrhage (1) Radionecrosis (1) Optic neuropathy (1)
Abbreviations: CNS = central nervous system; GI = gastrointestinal; GU = genitourinary.
Toxicities defined according to the Common Terminology Criteria for Adverse Events, version 5.0.
Numbers indicate number of treatment courses; more than one toxicity may be attributed to a single treatment course. Late toxicity data unavailable for 9 treatment courses (all due to patient death).
Late grade 3 and 4 toxicities occurred in the same patient.
An exploratory analysis examining patient demographics and treatment characteristics was performed to identify predictors of clinical or radiographic response. In all patients (CNS and non-CNS sites), HGS histology was associated with clinical responses (88% vs 64%, P = .04). In patients with CNS lesions, BED >39 Gy was associated with clinical response (P = .049). In non-CNS locations, bony site was associated with worse clinical (44% vs 89%, P = .004) response compared with soft tissue/nodal (STN) sites. Lastly, we compared BED regimens ≤39 Gy versus >39 Gy (assuming an alpha/beta ratio of 10,19,20 the BED of 30 Gy in 10 fractions is 39 Gy) in non-CNS locations and found no differences in clinical (P = .10) or radiographic response rates (P = .47). We otherwise compared the most common regimens of 20 Gy in 5 fractions and 30 Gy in 10 fractions and found no significant differences in clinical (P = .60) or radiographic responses (P = .29; Table E1).2
Discussion
We report the outcomes of a large modern cohort of women with PMR-OC who received palliative radiation therapy in an era of novel systemic agents. In a population with poor prognosis, palliative radiation therapy resulted in excellent clinical and radiographic response rates (Table 2) within 1 month of treatment, with many responses durable beyond 3 months. Brain metastases, a rare site of anatomic spread, were also well represented in this cohort (36%, 38 courses) and responded favorably to palliative intracranial radiation therapy (Table 3). Exploratory analyses demonstrated an association between HGS histology and improved clinical response in all patients, BED >39 Gy and improved clinical response in BMs, and STN sites with improved clinical response in non-CNS sites. Our analysis is unique in its (1) large sample size compared with prior reports with significant number of BMs, (2) high proportion of patients treated with modern RT techniques, (3) inclusion of patients treated with novel systemic agents (ie, PARP inhibitors, bevacizumab, and immunotherapy), and (4) dedicated toxicity analysis of RT with concurrent or prior bevacizumab, an area of increasing clinical significance in MPR-EOC with a dearth of robust data.
Our high clinical response rates (79% ORR within 1 month) are similar to other reports, including literature from prior decades demonstrating durable pain relief and bleeding control from locally directed palliative RT in 80% of OC patients.20, 21, 22 More recently, Bansal and colleagues also found pain control rates of 88.2% and vaginal bleeding control rates of 100% in 23 heavily pretreated women who received palliative pelvic RT.23 Investigators from Brigham and Women’s Hospital also recently published rates and predictors of response to palliative RT for recurrent OC from 2003 to 201424 and demonstrated high rates of response for pain and bleeding (87% and 93%, respectively).
Identified predictors of response, including HGS histology and STN sites of disease are also compatible with prior investigations. In the above Brigham and Women’s Hospital study, patients treated at nonbony sites had higher response rates than those with bony sites of disease (96% vs 75%, respectively). Furthermore, patients with clear cell histology had the lowest response rates (60%), compared with others like serous histology (82%).
The sizable nature of our cohort allowed for a temporal analysis of index lesion response rates. Patients in both CNS and non-CNS cohorts tended to have clinical responses early on, with some benefitting from sustained response at last follow-up. Lesions with clinical CR often occurred within the first month. Furthermore, no patients who progressed in the index lesion within the first month of follow-up went on to have any response, suggesting that initial response is of paramount importance. Patients who had progressive symptoms after 3 months had variable initial responses, suggesting progressive disease is still expected no matter what the initial response may be.
Regarding dose response, higher BED was associated with clinical response in brain metastases. This is a result of ablative SRS technology that radiobiologically induces high rates of cell kill compared with those of conventional palliative techniques or doses. Advanced stereotactic techniques permit the delivery of otherwise unsafe high dose-per-fraction regimens due to their sharp dose gradients that allow for normal tissue sparing. In non-CNS locations, however, regimens with BED >39 Gy (ie, greater than 30 Gy in 10 fractions) were no different than lower BED regimens, suggesting dose escalation may not increase the efficacy of palliative RT. Use of higher BED regimens in such (predominantly abdominopelvic) locations is typically limited by larger fields due to tumor size and organ motion. Dose-limiting toxicities from nearby organs at risk such as the stomach, bowel, kidneys, and bladder also constrain prescriptions.
Notably, 47% of all courses were delivered with advanced radiation therapy techniques (SRS, SBRT, IMRT/volumetric-modulated arc therapy, proton therapy). This is in keeping with the increasing number of patients referred for ablative or definitive therapy to oligometastatic or oligoprogressive disease or previously irradiated lesions requiring retreatment. In such scenarios, advanced techniques allow practitioners to deliver higher dose per fraction while sparing normal organs and tissue of radiation, or even reirradiation, toxicity. In fact, recently published reports have evaluated the roles of advanced RT in OC. For example, definitive involved-field RT using IMRT has demonstrated promising rates of local control (LC) and disease-free survival with low toxicity.25,26 Two recent retrospective studies also explored SBRT in oligometastatic OC. Lazzari et al reported the treatment of 82 patients with a median dose of 24 Gy in 3 fractions and demonstrated the safety of SBRT along with an increase in systemic therapy-free survival with reasonable LC27 (more than one-third of patients were disease-free at 1 year). Similarly, Macchia et al reported SBRT in MPR-EOC was well tolerated and afforded higher LC in patients receiving a total dose >25 Gy.28
Forty-three percent of patients received targeted therapy immediately before RT in this cohort. This is in keeping with the litany of recent publications studying the use of novel systemic agents (PARP inhibitors,29, 30, 31 bevacizumab,32 nivolumab33) in the setting of MPR-EOC. The response rates described thus reflect the potential outcomes of palliative RT in conjunction with advanced systemic therapies, a scenario that will be increasingly encountered by practitioners. Furthermore, given the sizeable population that received prior or concurrent bevacizumab, a dedicated subgroup analysis was conducted and demonstrated low acute and late grade 3 or higher (G3 +) toxicities (8.7% and 4.3%, respectively) with RT. Although G3 + toxicities occurred in patients treated to CNS and mediastinal locations, it is unclear if this was in relation to prior bevacizumab or reflected the increased risk toxicity with prior RT (Gamma Knife in the CNS patient treated with craniospinal irradiation) or unfavorable tumor location (in the mediastinal patient experiencing esophagitis after receiving 59.4 Gy). No acute or late G3 + toxicity was seen in patients treated to the abdomen or pelvis (the most common treatment location), suggesting that this may be a reasonable treatment option in symptomatic patients.
Limitations
The study is limited primarily by its retrospective nature which lends itself to both selection and sample bias. For example, patient performance status and prior lines of therapy (including prior radiation) may effect physician choice of RT technique, dose, and fractionation. Furthermore, lesions necessitating reirradiation demonstrate inherent radioresistance and may negatively affect response rates. Moreover, although the study population is sizeable, it is heterogenous with respect to treatment sites and prior lines of therapy. As such appropriate interpretation required subdivision of data (ie, CNS vs non-CNS, symptomatic vs asymptomatic indication), which led to more descriptive findings. Finally, the variety of systemic therapies used negatively affect our ability to make conclusions regarding the efficacy of RT with respect to individual agents.
Future directions
As the role for palliative radiation therapy expands in the context of the oligometastatic paradigm, nuanced decision-making must be taken to deliver the most efficacious treatment although promoting cost-effective care. As such, prospective evaluation is warranted to determine the optimal dose, timing, and fractionation of RT as it relates to systemic agents and surgery. The high response rates demonstrated in this cohort may warrant prospective investigation of RT as a standard component therapy in MPR-EOC, either before systemic agents as a cytoreductive strategy or after as consolidation therapy.
Conclusions
We performed a large retrospective cohort analysis of women with MPR-EOC receiving palliative RT in the era of modern technology and systemic agents. Our large population of patients with BMs adds relevant data to the limited body of existing literature and can be used as a practical reference when counseling women. Patients demonstrated favorable clinical and radiographic response rates within 1 month, with >60% experiencing durable clinical responses beyond 3 months. HGS histology was associated with improved clinical response in all patients. BED >39 Gy was associated with improved response in brain metastases. Bony sites were associated with worse response compared with STN sites in non-CNS locations. Acute and late grade 3 or higher toxicities were low with prior bevacizumab, and none of these occurred in patients treated to abdominopelvic locations.
Although MPR-EOC is associated with limited prognosis, our data demonstrate that responses to palliative RT can be durable and meaningful. As such, without a conclusive effect on survival, it would be reasonable to consider treatment of such disease after taking into consideration patient symptom severity, goals of care, prognosis, performance status, and extracranial disease burden for BM.
Supplementary Materials
Tables E1 and E2
Sources of support: The authors received no specific funding for this work.
Disclosures: The authors of this manuscript have no conflicts of interest to report.
Research data are stored in an institutional repository and will be shared upon request.
Supplementary material for this article can be found at https://doi.org/10.1016/j.adro.2020.11.009. | BEVACIZUMAB | DrugsGivenReaction | CC BY-NC-ND | 33665491 | 18,951,285 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Optic neuropathy'. | Palliative Radiation Therapy for Metastatic, Persistent, or Recurrent Epithelial Ovarian Cancer: Efficacy in the Era of Modern Technology and Targeted Agents.
Metastatic, persistent, or recurrent epithelial ovarian cancer (MPR-EOC) remains a significant threat to patient mortality despite advances in novel targeted agents. Radiation therapy (RT) is often used as a palliative option. We report outcomes of a large series of MPR-EOC patients treated with modern palliative RT (PRT) in an era of novel systemic therapies.
A retrospective review was conducted of women treated with PRT for MPR-EOC between 2007 and 2019 at an academic institution. Clinical response rates were recorded at <1 month, 1 to 3 months, and >3 months. Radiographic responses were categorized by RECIST 1.1 criteria. Overall response rate (ORR) was the sum of complete and partial response. Linear regression analyses of baseline characteristics were conducted for statistical testing.
Eighty-six patients with PMR-OC received 120 courses of palliative RT. Median follow-up was 8.6 months. Median age was 61 (range, 22-82). Thirty-six percent of women received central nervous system (CNS)-directed RT. In addition, 43% received targeted therapies before RT. Clinical ORR within 1 month and at last follow-up for non-CNS lesions was 79% and 61% (69% and 88% for CNS lesions, respectively). High-grade serous lesions were more likely to have clinical response (P = .04). Biologically effective doses (BED) >39 Gy were associated with improved clinical response in CNS lesions (P = .049). Bony sites were associated with worse clinical (P = .004) response in non-CNS lesions compared with soft tissue or nodal sites. Acute or late grade 3+ toxicities with bevacizumab were low (8.7%/4.3%).
PRT offers excellent rates of response for symptomatic patients with MPR-EOC within 1 month of treatment, with durable responses beyond 3 months. High-grade serous lesions were associated with improved response in all patients. Higher BED and soft tissue or nodal sites were associated with improved response in CNS and non-CNS patients, respectively. Acute or late toxicities with bevacizumab and PRT were low. Prospective investigation is warranted to determine the optimal PRT regimen.
Introduction
Ovarian cancer (OC) is a highly aggressive gynecologic malignancy, with the majority of patients presenting with advanced disease at diagnosis. The general treatment paradigm for advanced OC is maximal cytoreductive surgery with platinum-based chemotherapy.1 Recent literature has also reported a progression-free survival benefit with maintenance inhibition of poly (adenosine diphosphate-ribose) polymerase (PARP) in women with partial or complete response to platinum-based regimens.2,3
Whole abdominal radiation therapy was historically indicated as adjuvant therapy to address microscopic residual disease.4 However, due to its considerable toxicity and the development of platinum-based chemotherapy, whole abdominal radiation therapy is no longer included in primary OC treatment paradigms.1
Despite advances in cytoreductive strategies and front-line systemic therapy, >70% of women relapse within 3 years of diagnosis.5 As such, many patients with OC benefit from palliative care referrals to assist with symptom management, goals of care discussions, and complex medical decision making at the end of life.
There is a growing body of evidence to support the incorporation of palliative services in cancer care. In 2010, a seminal randomized trial6 reported early palliative care among patients with metastatic non-small cell lung cancer significantly improved quality of life, led to less aggressive care at the end of life, and resulted in longer overall survival. Furthermore, both the American Society of Clinical Oncology and the Society of Gynecologic Oncology have published official practice guidelines recommending the routine and early integration of palliative services.7,8
Radiation therapy (RT) is often used as an effective therapeutic option in the palliation of patients with metastatic, persistent, or recurrent epithelial OC (MPR-EOC) as a means for symptomatic relief and local control. This includes oligometastatic disease or symptomatic disease causing pain, bowel or ureteral obstruction, or bleeding. Despite their rarity in OC (2% incidence9), brain metastases can also cause significant morbidity and can be treated with palliative RT to reduce the risk of progression and neurocognitive deficits.10,11
As patient survival improves with modern systemic agents, there is a growing need to understand the efficacy of palliative RT regimens for MPR-EOC in the same era. Although radiation therapy has traditionally been delivered for symptomatic control in MPR-EOC, the recognition of the biologically distinct (and potentially curable) oligometastatic state12,13 is expanding the scope of RT indications. Data from phase 2 trials in other malignancies evaluating the effect of locally directed therapy to oligometastatic lesions has demonstrated improvements in overall survival.14,15
We therefore conducted, a large contemporary retrospective analysis of palliative RT in MPR-EOC. This patient cohort is highly relevant to modern practice given the number of patients who received novel systemic agents, the prominent usage of advanced RT technology, and the representation of patients with BMs from OC (an area with limited data but increasing prevalence in practice). The analysis will report the outcomes and durability of palliative RT in MPR-EOC and delineate factors predictive of response in the modern era.
Methods and Materials
We conducted a retrospective chart review of women treated with palliative radiation therapy for metastatic ovarian cancer from 2007 through 2019 at [University of Pennsylvania] and affiliate sites. Institutional review board approval was obtained before conducting this review. Patients were included in this analysis if they were treated for palliative intent, including treatment of oligometastatic disease. All patients had MPR-EOC ovarian cancer and received anywhere from one to 5 courses of radiation treatment.
Given the poor prognosis of patients with metastatic ovarian cancer, clinical and radiographic response rates were categorized in intervals of <1 month, 1 to 3 months, and >3 months after the end of radiation treatment to indicate acute and durable responses. Clinical responses were categorized as complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD). Pain scores were classified using the Bone Metastases Consensus Working Party guidelines16 (indeterminate responses, which are neither PR nor PD per BMWCP guidelines, were classified as SD to maintain consistency with other clinical response categorizations). Radiographic responses were categorized as CR, PR, SD, or PD based on the RECIST 1.1 criteria.17 Overall response rate (ORR) was the sum of CR and PR in a given patient. Given the large subset of patients with brain metastases (BMs), courses were stratified by central nervous system (CNS) and non-CNS anatomic locations. Acute (during RT and within 3 months of completion) and late (>3 months after completion of RT) toxicities were recorded with concurrent and prior bevacizumab using Common Terminology Criteria for Adverse Events version 5.018 classification.
Rates of response (CR or PR at any point) were compared with demographic and treatment characteristics. χ2 (n ≥ 20) or Fisher exact (n < 20) tests were used for such comparison with variables for race, histology, platinum chemotherapy, or targeted therapy before RT, RT technology, RT location, and biologically effective dose (BED) >39. Binary logistic regression analyses were used for comparison with continuous variables (age and BED). Covariates with P < .1 were included in multiple logistic regression modeling to assess for independent effect. Additionally, χ2 analyses were used to compare rates of radiographic response between patients treated for clinical symptoms and asymptomatic progression. Statistical analysis was conducted using IBM SPSS Statistics, version 26 (IBM Corporation, Armonk, NY).
Results
We identified 86 patients with PMR-OC that received 120 combined courses of palliative radiation treatment. Median follow-up was 8.6 months (range, 0.5-119 months). Excluding 10 patients (15 courses) with no evaluable clinical or radiographic follow-up, 51 patients (58 courses) were treated to non-CNS locations and 18 patients (25 courses) were treated to CNS locations; 7 patients (22 courses) received palliative RT to both CNS (13 courses) and non-CNS (9 courses) locations.
Table 1 describes baseline patient characteristics and details related to patient treatments. The median age of patients in this cohort was 61, with a range of 22 to 82. Patients were most commonly white (83%) and black (8%). Tumor histologies were primarily high-grade serous (HGS, 59%), although adenocarcinoma (undifferentiated or unspecified), low-grade serous, clear cell, endometrioid, and carcinosarcoma were also observed.Table 1 Patient characteristics and treatment details
No. of courses 105
No. of patients 76
Median age 61
Ethnicity
White 82.9% (63/76)
Black 9.2% (7/76)
Asian 3.9% (3/76)
Hispanic 2.6% (2/76)
Unknown 1.3% (1/76)
Histology
High-grade serous 59.2% (45/76)
Adenocarcinoma, other 13.2% (10/76)
Low grade serous 9.2% (7/76)
Clear cell 5.3% (4/76)
Other 7.9% (6/76)
Endometrioid 3.9% (3/76)
Carcinosarcoma 1.3% (1/76)
Anatomic site
Soft tissue/organ 35.2% (37/105)
Lymph node 21.0% (22/105)
Bone 11.4% (12/105)
CNS 36.2% (38/105)
Indications
Clinical symptoms 59.0% (62/105)
Progressive/metastatic 33.3% (35/105)
Postoperative 7.6% (8/105)
Systemic therapy before RT
Platinum chemotherapy 27.6% (29/105)
Nonplatinum chemotherapy 61.9% (65/105)
Targeted therapy 42.9% (45/105)
None/other 1.0% (1/105)
Technique
2D/3D CRT 53.3% (56/105)
SRS 21.9% (23/105)
VMAT/IMRT 16.2% (17/105)
SBRT 4.8% (5/105)
Proton 3.8% (4/105)
Non-SRS dose 14-63 Gy in 4-35 fractions
SBRT dose 24-50 Gy in 3-5 fractions
SRS dose 15-25 Gy in 1-5 fractions
Abbreviations: 2D = 2-dimensional; 3D CRT = 3-dimensional conformal radiation therapy; CNS = central nervous system; IMRT = intensity modulated radiation therapy; RT = radiation therapy; SBRT = stereotactic body radiation therapy; SRS = stereotactic radiosurgery; VMAT = volumetric modulated arc therapy.
Non-CNS treatment locations included tumors in soft tissue or organs (35%), lymph nodes (21%), and bone (11%); 4 patients were treated simultaneously to adjacent soft tissue and lymph nodes. Treatment for CNS metastases comprised the remaining 36% of patients.
Most patients were treated for clinical symptoms (59%). Pain and bleeding were the most common clinical indications. Others included neurologic deficits, spinal cord compression, airway compression, and bowel obstruction. A large cohort of patients were treated for asymptomatic progressive or metastatic disease (33%) with a small cohort treated adjuvantly after surgery (eg, metastasectomy or palliative debulking; 7.6%).
Almost all patients (90%) received chemotherapy immediately before radiation therapy. The most common systemic therapy regimens were platinum-based (ie, carboplatin) followed by taxanes and doxorubicin. Many patients (43%) also received treatment with targeted therapy agents before radiation treatment. Bevacizumab was the most commonly used targeted therapy agent (20%), although patients also received PARP inhibitors (9%) and immune checkpoint inhibitors (5%).
A wide range of palliative radiation regimens were delivered across several modalities. Nonstereotactic treatment regimens to both CNS and non-CNS locations ranged from 14 Gy in 4 fractions to 63 Gy in 35 fractions. Common palliative doses were 30 Gy in 10 fractions (14%), 20 Gy in 5 fractions (8.6%), and 35 Gy in 14 fractions (7.6%). Nonstereotactic modalities included 2-dimensional or 3-dimensional (53%), intensity modulated radiation therapy (IMRT) or volumetric-modulated arc therapy (16%), and proton therapy (3.8%). Stereotactic body radiation therapy (SBRT) was less commonly used (4.8%) with treatment regimen ranging from 24 Gy in 3 fractions to 50 Gy in 5 fractions. Lastly, patients with BMs commonly received stereotactic radiosurgery (SRS, 22% of all courses) with doses ranging from 15 Gy in 1 fraction to 25 Gy in 5 fractions. Nearly half of the patients who underwent SRS received 21 Gy in 1 fraction.
Across the entire cohort, the clinical ORR was 76% within the first month after treatment and 67% at least 3 months after treatment (Table 2). Radiographic ORR between patients treated for clinical symptoms (symptomatic) and asymptomatic progression (asymptomatic) were 48% and 59%, respectively. Although patients treated for asymptomatic progression had higher rates of response, no significant differences were observed between the 2 cohorts (P = .23).Table 2 Response rates (all lesions)
<1 mo 1-3 mo >3 mo
Clinical response
CR 32.8% (19/58) 45.0% (18/40) 48.4% (15/31)
PR 43.1% (25/58) 35.0% (14/40) 19.4% (6/31)
SD 12.1% (7/58) 2.5% (1/40) 0.0% (0/31)
PD 12.1% (7/58) 17.5% (7/40) 32.3% (10/31)
ORR 75.9% (44/58) 80.0% (32/40) 67.7% (21/31)
Radiographic response: symptomatic patients
CR 15.2% (5/33) 16.7% (5/30) 25.9% (7/27)
PR 24.2% (8/33) 30.0% (9/30) 22.2% (6/27)
SD 51.5% (17/33) 43.3% (13/30) 40.7% (11/27)
PD 9.1% (3/33) 10.% (3/30) 11.1% (3/27)
ORR 39.4% (13/33) 46.7% (14/30) 48.1% (13/27)
Radiographic response: asymptomatic patients
CR 39.4% (13/33) 47.1% (16/34) 53.1% (17/32)
PR 9.1% (3/33) 8.8% (3/34) 6.3% (2/32)
SD 45.5% (15/33) 41.2% (14/34) 34.4% (11/32)
PD 6.1% (2/33) 2.9% (1/34) 6.3% (2/32)
ORR 48.5% (16/33) 55.9% (19/34) 59.4% (19/32)
Abbreviations: CR = complete response; ORR = overall response rate; PD = progressive disease; PR = partial response; SD = stable disease.
Excludes patients treated with postoperative palliative radiation.
Denominator reflects evaluable patients.
Of patients treated to non-CNS locations, the clinical and radiographic ORR within the first month after treatment were 79% and 33%, respectively (Table 3). Clinical ORR at last follow-up (at least 3 months after treatment) was 61%. Notably, of the patients with a CR (38.1%) within the first month, only 2 went on to have PD at last follow-up (4 were lost to follow-up), indicating durable response to treatment. All but one patient treated for malignancy-related vaginal bleeding (13/14) had a clinical response within 1 month, of which only one patient had recurrence of bleeding at last follow-up. Seventy percent of patients treated for pain (n = 27) had a clinical response within 1 month, of which only 3 patients demonstrated worsening pain at last follow-up. Radiographically, ORR improved to 38% for symptomatic patients and 47% for asymptomatic patients at last follow-up, with no significant differences in response rates between the 2 groups (P = .44). All lesions that responded within 1 month of radiation treatment maintained response through last follow-up. Furthermore, only 3 of 22 lesions that were initially SD, progressed over time (1 treated for clinical symptoms, 2 treated for asymptomatic progression).Table 3 Response rates (non-CNS lesions)
<1 mo 1-3 mo >3 mo
Clinical response
CR 38.1% (16/42) 44.8% (13/29) 43.5% (10/23)
PR 40.5% (17/42) 31.0% (9/29) 17.4% (4/23)
SD 14.3% (6/42) 3.4% (1/29) 0.0% (0/23)
PD 7.1% (3/42) 20.7% (6/29) 39.1% (9/23)
ORR 78.6% (33/42) 75.9% (22/29) 60.9% (14/23)
Radiographic response: symptomatic patients
CR 9.5% (2/21) 10.5% (2/19) 18.8% (3/16)
PR 23.8% (5/21) 26.3% (5/19) 18.8% (3/16)
SD 52.4% (11/21) 52.6% (10/19) 50.0% (8/16)
PD 14.3% (3/21) 10.5% (2/19) 12.5% (2/16)
ORR 33.3% (7/21) 36.8% (7/19) 37.5% (6/16)
Radiographic response: asymptomatic patients
CR 21.1% (4/19) 31.6% (6/19) 41.2% (7/17)
PR 10.5% (2/19) 10.5% (2/19) 5.9% (1/17)
SD 57.9% (11/19) 52.6% (10/19) 41.2% (7/17)
PD 10.5% (2/19) 5.3% (1/19) 11.8% (2/17)
ORR 31.6% (6/19) 42.1% (8/19) 47.1% (8/17)
Abbreviations: CNS = central nervous system; CR = complete response; ORR = overall response rate; PD = progressive disease; PR = partial response; SD = stable disease.
Excludes patients treated with postoperative palliative radiation.
Denominator reflects evaluable patients.
Of patients treated to CNS locations, the clinical and radiographic ORR within the first month after treatment were 72% and 62%, respectively (Table 4). No patients with a demonstrated clinical or radiographic response within the first month went on to have documented progressive symptoms or imaging at last follow-up (although 2 patients died and 4 were lost to follow-up). Although clinical responses stayed constant over time, radiographic responses tended to improve, especially in patients treated for clinical symptoms. There was no difference in rates of radiographic responses between CNS patients treated for clinical symptoms and those treated for asymptomatic progression (P = .41). All patients receiving SRS responded or had SD at 1 month; only one patient had locally progressive symptoms and disease at last follow-up. Three of the 4 patients with progressive symptoms within the first month were those who received whole brain radiation therapy with more extensive CNS disease before treatment.Table 4 Response rates (CNS lesions)
<1 mo 1-3 mo >3 mo
Clinical response
CR 18.8% (3/16) 45.5% (5/11) 62.5% (5/8)
PR 50.0% (8/16) 45.5% (5/11) 25.0% (2/8)
SD 6.3% (1/16) 0.0% (0/11) 0.0% (0/8)
PD 25.0% (4/16) 9.1% (1/11) 12.5% (1/8)
ORR 68.8% (11/16) 90.9% (10/11) 87.5% (7/8)
Radiographic response: symptomatic patients
CR 25.0% (3/12) 27.3% (3/11) 36.4% (4/11)
PR 25.0% (3/12) 36.4% (4/11) 27.3% (3/11)
SD 50.% (6/12) 27.3% (3/11) 27.3% (3/11)
PD 0.0% (0/12) 9.1% (1/11) 9.1% (1/11)
ORR 50.0% (6/12) 63.6% (7/11) 63.6% (7/11)
Radiographic response: asymptomatic patients
CR 64.3% (9/14) 66.7% (10/15) 66.7% (10/15)
PR 7.1% (1/14) 6.7% (1/15) 6.7% (1/15)
SD 28.6% (4/14) 26.7% (4/15) 26.7% (4/15)
PD 0.0% (0/14) 0.0% (0/15) 0.0% (0/15)
ORR 71.4% (10/14) 73.3% (11/15) 73.3% (11/15)
Abbreviations: CNS = central nervous system; CR = complete response; PD = progressive disease; PR = partial response; ORR = overall response rate; SD = stable disease.
Excludes patients treated with postoperative palliative radiation.
Denominator reflects evaluable patients.
Patients in both CNS and non-CNS cohorts tended to have clinical responses early on, with sustained response at last follow-up. Furthermore, if a patient were to have a clinical CR, it most often occurred within the first month. Only 4 patients demonstrated a CR after the first month, and all of these patients had a PR initially; no patients with initially stable disease went on to have a CR. Most patients with radiographic SD at initial follow-up maintained SD over time. The initial responses of patients developing progressive symptoms after 3-month follow-up varied considerably: CR (2), PR (3), SD (2), and PD (3). No patients who progressed within the first month of follow-up went on to have any response.
Eight patients were treated with postoperative RT after surgical resection in the brain (6), mediastinal lymph node (1), and inguinal lymph node (1). Three patients with evaluable clinical symptoms before and after surgery-RT all demonstrated diminished (PR) or complete (CR) resolution of symptoms within 1 month after RT. Of the 6 patients with radiographic follow-up, one recurred 9 months after treatment; the rest maintained stable disease (ie, no recurrence) through last follow-up.
Acute and late grade 3 or higher (G3 +) toxicities with bevacizumab were low (8.7% and 4.3%, respectively). CNS and mediastinal locations were the only treatment sites in which G3 + toxicity occurred. CNS toxicity (acute G3 fatigue, late G3 radiation necrosis, and late G4 optic neuritis) was identified in a single patient who received craniospinal irradiation with prior Gamma Knife irradiation. A second patient treated to the mediastinum had acute but not chronic grade 3 esophagitis. Notably, no acute or late G3 + toxicity was seen in patients treated to the abdomen or pelvis (the most common treatment location; Table 5).Table 5 Observed toxicities in patients treated with bevacizumab before or concurrent with radiation therapy, by treatment course
None Grade 1-2 Grade 3 Grade 4
Acute
Non-CNS (17) 6 Anorexia (1),
depression (1),
dermatitis (1),
fatigue (5),
GI (6), GU (1),
odynophagia (1),
pneumonitis (1),
vaginal hemorrhage (1) Dermatitis (1),
esophagitis (1) -
CNS (6) 4 GI (1) Fatigue (1) -
Late
Non-CNS (9) 8 GI (1) - -
CNS (5) 3 Intracranial hemorrhage (1) Radionecrosis (1) Optic neuropathy (1)
Abbreviations: CNS = central nervous system; GI = gastrointestinal; GU = genitourinary.
Toxicities defined according to the Common Terminology Criteria for Adverse Events, version 5.0.
Numbers indicate number of treatment courses; more than one toxicity may be attributed to a single treatment course. Late toxicity data unavailable for 9 treatment courses (all due to patient death).
Late grade 3 and 4 toxicities occurred in the same patient.
An exploratory analysis examining patient demographics and treatment characteristics was performed to identify predictors of clinical or radiographic response. In all patients (CNS and non-CNS sites), HGS histology was associated with clinical responses (88% vs 64%, P = .04). In patients with CNS lesions, BED >39 Gy was associated with clinical response (P = .049). In non-CNS locations, bony site was associated with worse clinical (44% vs 89%, P = .004) response compared with soft tissue/nodal (STN) sites. Lastly, we compared BED regimens ≤39 Gy versus >39 Gy (assuming an alpha/beta ratio of 10,19,20 the BED of 30 Gy in 10 fractions is 39 Gy) in non-CNS locations and found no differences in clinical (P = .10) or radiographic response rates (P = .47). We otherwise compared the most common regimens of 20 Gy in 5 fractions and 30 Gy in 10 fractions and found no significant differences in clinical (P = .60) or radiographic responses (P = .29; Table E1).2
Discussion
We report the outcomes of a large modern cohort of women with PMR-OC who received palliative radiation therapy in an era of novel systemic agents. In a population with poor prognosis, palliative radiation therapy resulted in excellent clinical and radiographic response rates (Table 2) within 1 month of treatment, with many responses durable beyond 3 months. Brain metastases, a rare site of anatomic spread, were also well represented in this cohort (36%, 38 courses) and responded favorably to palliative intracranial radiation therapy (Table 3). Exploratory analyses demonstrated an association between HGS histology and improved clinical response in all patients, BED >39 Gy and improved clinical response in BMs, and STN sites with improved clinical response in non-CNS sites. Our analysis is unique in its (1) large sample size compared with prior reports with significant number of BMs, (2) high proportion of patients treated with modern RT techniques, (3) inclusion of patients treated with novel systemic agents (ie, PARP inhibitors, bevacizumab, and immunotherapy), and (4) dedicated toxicity analysis of RT with concurrent or prior bevacizumab, an area of increasing clinical significance in MPR-EOC with a dearth of robust data.
Our high clinical response rates (79% ORR within 1 month) are similar to other reports, including literature from prior decades demonstrating durable pain relief and bleeding control from locally directed palliative RT in 80% of OC patients.20, 21, 22 More recently, Bansal and colleagues also found pain control rates of 88.2% and vaginal bleeding control rates of 100% in 23 heavily pretreated women who received palliative pelvic RT.23 Investigators from Brigham and Women’s Hospital also recently published rates and predictors of response to palliative RT for recurrent OC from 2003 to 201424 and demonstrated high rates of response for pain and bleeding (87% and 93%, respectively).
Identified predictors of response, including HGS histology and STN sites of disease are also compatible with prior investigations. In the above Brigham and Women’s Hospital study, patients treated at nonbony sites had higher response rates than those with bony sites of disease (96% vs 75%, respectively). Furthermore, patients with clear cell histology had the lowest response rates (60%), compared with others like serous histology (82%).
The sizable nature of our cohort allowed for a temporal analysis of index lesion response rates. Patients in both CNS and non-CNS cohorts tended to have clinical responses early on, with some benefitting from sustained response at last follow-up. Lesions with clinical CR often occurred within the first month. Furthermore, no patients who progressed in the index lesion within the first month of follow-up went on to have any response, suggesting that initial response is of paramount importance. Patients who had progressive symptoms after 3 months had variable initial responses, suggesting progressive disease is still expected no matter what the initial response may be.
Regarding dose response, higher BED was associated with clinical response in brain metastases. This is a result of ablative SRS technology that radiobiologically induces high rates of cell kill compared with those of conventional palliative techniques or doses. Advanced stereotactic techniques permit the delivery of otherwise unsafe high dose-per-fraction regimens due to their sharp dose gradients that allow for normal tissue sparing. In non-CNS locations, however, regimens with BED >39 Gy (ie, greater than 30 Gy in 10 fractions) were no different than lower BED regimens, suggesting dose escalation may not increase the efficacy of palliative RT. Use of higher BED regimens in such (predominantly abdominopelvic) locations is typically limited by larger fields due to tumor size and organ motion. Dose-limiting toxicities from nearby organs at risk such as the stomach, bowel, kidneys, and bladder also constrain prescriptions.
Notably, 47% of all courses were delivered with advanced radiation therapy techniques (SRS, SBRT, IMRT/volumetric-modulated arc therapy, proton therapy). This is in keeping with the increasing number of patients referred for ablative or definitive therapy to oligometastatic or oligoprogressive disease or previously irradiated lesions requiring retreatment. In such scenarios, advanced techniques allow practitioners to deliver higher dose per fraction while sparing normal organs and tissue of radiation, or even reirradiation, toxicity. In fact, recently published reports have evaluated the roles of advanced RT in OC. For example, definitive involved-field RT using IMRT has demonstrated promising rates of local control (LC) and disease-free survival with low toxicity.25,26 Two recent retrospective studies also explored SBRT in oligometastatic OC. Lazzari et al reported the treatment of 82 patients with a median dose of 24 Gy in 3 fractions and demonstrated the safety of SBRT along with an increase in systemic therapy-free survival with reasonable LC27 (more than one-third of patients were disease-free at 1 year). Similarly, Macchia et al reported SBRT in MPR-EOC was well tolerated and afforded higher LC in patients receiving a total dose >25 Gy.28
Forty-three percent of patients received targeted therapy immediately before RT in this cohort. This is in keeping with the litany of recent publications studying the use of novel systemic agents (PARP inhibitors,29, 30, 31 bevacizumab,32 nivolumab33) in the setting of MPR-EOC. The response rates described thus reflect the potential outcomes of palliative RT in conjunction with advanced systemic therapies, a scenario that will be increasingly encountered by practitioners. Furthermore, given the sizeable population that received prior or concurrent bevacizumab, a dedicated subgroup analysis was conducted and demonstrated low acute and late grade 3 or higher (G3 +) toxicities (8.7% and 4.3%, respectively) with RT. Although G3 + toxicities occurred in patients treated to CNS and mediastinal locations, it is unclear if this was in relation to prior bevacizumab or reflected the increased risk toxicity with prior RT (Gamma Knife in the CNS patient treated with craniospinal irradiation) or unfavorable tumor location (in the mediastinal patient experiencing esophagitis after receiving 59.4 Gy). No acute or late G3 + toxicity was seen in patients treated to the abdomen or pelvis (the most common treatment location), suggesting that this may be a reasonable treatment option in symptomatic patients.
Limitations
The study is limited primarily by its retrospective nature which lends itself to both selection and sample bias. For example, patient performance status and prior lines of therapy (including prior radiation) may effect physician choice of RT technique, dose, and fractionation. Furthermore, lesions necessitating reirradiation demonstrate inherent radioresistance and may negatively affect response rates. Moreover, although the study population is sizeable, it is heterogenous with respect to treatment sites and prior lines of therapy. As such appropriate interpretation required subdivision of data (ie, CNS vs non-CNS, symptomatic vs asymptomatic indication), which led to more descriptive findings. Finally, the variety of systemic therapies used negatively affect our ability to make conclusions regarding the efficacy of RT with respect to individual agents.
Future directions
As the role for palliative radiation therapy expands in the context of the oligometastatic paradigm, nuanced decision-making must be taken to deliver the most efficacious treatment although promoting cost-effective care. As such, prospective evaluation is warranted to determine the optimal dose, timing, and fractionation of RT as it relates to systemic agents and surgery. The high response rates demonstrated in this cohort may warrant prospective investigation of RT as a standard component therapy in MPR-EOC, either before systemic agents as a cytoreductive strategy or after as consolidation therapy.
Conclusions
We performed a large retrospective cohort analysis of women with MPR-EOC receiving palliative RT in the era of modern technology and systemic agents. Our large population of patients with BMs adds relevant data to the limited body of existing literature and can be used as a practical reference when counseling women. Patients demonstrated favorable clinical and radiographic response rates within 1 month, with >60% experiencing durable clinical responses beyond 3 months. HGS histology was associated with improved clinical response in all patients. BED >39 Gy was associated with improved response in brain metastases. Bony sites were associated with worse response compared with STN sites in non-CNS locations. Acute and late grade 3 or higher toxicities were low with prior bevacizumab, and none of these occurred in patients treated to abdominopelvic locations.
Although MPR-EOC is associated with limited prognosis, our data demonstrate that responses to palliative RT can be durable and meaningful. As such, without a conclusive effect on survival, it would be reasonable to consider treatment of such disease after taking into consideration patient symptom severity, goals of care, prognosis, performance status, and extracranial disease burden for BM.
Supplementary Materials
Tables E1 and E2
Sources of support: The authors received no specific funding for this work.
Disclosures: The authors of this manuscript have no conflicts of interest to report.
Research data are stored in an institutional repository and will be shared upon request.
Supplementary material for this article can be found at https://doi.org/10.1016/j.adro.2020.11.009. | BEVACIZUMAB | DrugsGivenReaction | CC BY-NC-ND | 33665491 | 18,951,285 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Pneumonitis'. | Palliative Radiation Therapy for Metastatic, Persistent, or Recurrent Epithelial Ovarian Cancer: Efficacy in the Era of Modern Technology and Targeted Agents.
Metastatic, persistent, or recurrent epithelial ovarian cancer (MPR-EOC) remains a significant threat to patient mortality despite advances in novel targeted agents. Radiation therapy (RT) is often used as a palliative option. We report outcomes of a large series of MPR-EOC patients treated with modern palliative RT (PRT) in an era of novel systemic therapies.
A retrospective review was conducted of women treated with PRT for MPR-EOC between 2007 and 2019 at an academic institution. Clinical response rates were recorded at <1 month, 1 to 3 months, and >3 months. Radiographic responses were categorized by RECIST 1.1 criteria. Overall response rate (ORR) was the sum of complete and partial response. Linear regression analyses of baseline characteristics were conducted for statistical testing.
Eighty-six patients with PMR-OC received 120 courses of palliative RT. Median follow-up was 8.6 months. Median age was 61 (range, 22-82). Thirty-six percent of women received central nervous system (CNS)-directed RT. In addition, 43% received targeted therapies before RT. Clinical ORR within 1 month and at last follow-up for non-CNS lesions was 79% and 61% (69% and 88% for CNS lesions, respectively). High-grade serous lesions were more likely to have clinical response (P = .04). Biologically effective doses (BED) >39 Gy were associated with improved clinical response in CNS lesions (P = .049). Bony sites were associated with worse clinical (P = .004) response in non-CNS lesions compared with soft tissue or nodal sites. Acute or late grade 3+ toxicities with bevacizumab were low (8.7%/4.3%).
PRT offers excellent rates of response for symptomatic patients with MPR-EOC within 1 month of treatment, with durable responses beyond 3 months. High-grade serous lesions were associated with improved response in all patients. Higher BED and soft tissue or nodal sites were associated with improved response in CNS and non-CNS patients, respectively. Acute or late toxicities with bevacizumab and PRT were low. Prospective investigation is warranted to determine the optimal PRT regimen.
Introduction
Ovarian cancer (OC) is a highly aggressive gynecologic malignancy, with the majority of patients presenting with advanced disease at diagnosis. The general treatment paradigm for advanced OC is maximal cytoreductive surgery with platinum-based chemotherapy.1 Recent literature has also reported a progression-free survival benefit with maintenance inhibition of poly (adenosine diphosphate-ribose) polymerase (PARP) in women with partial or complete response to platinum-based regimens.2,3
Whole abdominal radiation therapy was historically indicated as adjuvant therapy to address microscopic residual disease.4 However, due to its considerable toxicity and the development of platinum-based chemotherapy, whole abdominal radiation therapy is no longer included in primary OC treatment paradigms.1
Despite advances in cytoreductive strategies and front-line systemic therapy, >70% of women relapse within 3 years of diagnosis.5 As such, many patients with OC benefit from palliative care referrals to assist with symptom management, goals of care discussions, and complex medical decision making at the end of life.
There is a growing body of evidence to support the incorporation of palliative services in cancer care. In 2010, a seminal randomized trial6 reported early palliative care among patients with metastatic non-small cell lung cancer significantly improved quality of life, led to less aggressive care at the end of life, and resulted in longer overall survival. Furthermore, both the American Society of Clinical Oncology and the Society of Gynecologic Oncology have published official practice guidelines recommending the routine and early integration of palliative services.7,8
Radiation therapy (RT) is often used as an effective therapeutic option in the palliation of patients with metastatic, persistent, or recurrent epithelial OC (MPR-EOC) as a means for symptomatic relief and local control. This includes oligometastatic disease or symptomatic disease causing pain, bowel or ureteral obstruction, or bleeding. Despite their rarity in OC (2% incidence9), brain metastases can also cause significant morbidity and can be treated with palliative RT to reduce the risk of progression and neurocognitive deficits.10,11
As patient survival improves with modern systemic agents, there is a growing need to understand the efficacy of palliative RT regimens for MPR-EOC in the same era. Although radiation therapy has traditionally been delivered for symptomatic control in MPR-EOC, the recognition of the biologically distinct (and potentially curable) oligometastatic state12,13 is expanding the scope of RT indications. Data from phase 2 trials in other malignancies evaluating the effect of locally directed therapy to oligometastatic lesions has demonstrated improvements in overall survival.14,15
We therefore conducted, a large contemporary retrospective analysis of palliative RT in MPR-EOC. This patient cohort is highly relevant to modern practice given the number of patients who received novel systemic agents, the prominent usage of advanced RT technology, and the representation of patients with BMs from OC (an area with limited data but increasing prevalence in practice). The analysis will report the outcomes and durability of palliative RT in MPR-EOC and delineate factors predictive of response in the modern era.
Methods and Materials
We conducted a retrospective chart review of women treated with palliative radiation therapy for metastatic ovarian cancer from 2007 through 2019 at [University of Pennsylvania] and affiliate sites. Institutional review board approval was obtained before conducting this review. Patients were included in this analysis if they were treated for palliative intent, including treatment of oligometastatic disease. All patients had MPR-EOC ovarian cancer and received anywhere from one to 5 courses of radiation treatment.
Given the poor prognosis of patients with metastatic ovarian cancer, clinical and radiographic response rates were categorized in intervals of <1 month, 1 to 3 months, and >3 months after the end of radiation treatment to indicate acute and durable responses. Clinical responses were categorized as complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD). Pain scores were classified using the Bone Metastases Consensus Working Party guidelines16 (indeterminate responses, which are neither PR nor PD per BMWCP guidelines, were classified as SD to maintain consistency with other clinical response categorizations). Radiographic responses were categorized as CR, PR, SD, or PD based on the RECIST 1.1 criteria.17 Overall response rate (ORR) was the sum of CR and PR in a given patient. Given the large subset of patients with brain metastases (BMs), courses were stratified by central nervous system (CNS) and non-CNS anatomic locations. Acute (during RT and within 3 months of completion) and late (>3 months after completion of RT) toxicities were recorded with concurrent and prior bevacizumab using Common Terminology Criteria for Adverse Events version 5.018 classification.
Rates of response (CR or PR at any point) were compared with demographic and treatment characteristics. χ2 (n ≥ 20) or Fisher exact (n < 20) tests were used for such comparison with variables for race, histology, platinum chemotherapy, or targeted therapy before RT, RT technology, RT location, and biologically effective dose (BED) >39. Binary logistic regression analyses were used for comparison with continuous variables (age and BED). Covariates with P < .1 were included in multiple logistic regression modeling to assess for independent effect. Additionally, χ2 analyses were used to compare rates of radiographic response between patients treated for clinical symptoms and asymptomatic progression. Statistical analysis was conducted using IBM SPSS Statistics, version 26 (IBM Corporation, Armonk, NY).
Results
We identified 86 patients with PMR-OC that received 120 combined courses of palliative radiation treatment. Median follow-up was 8.6 months (range, 0.5-119 months). Excluding 10 patients (15 courses) with no evaluable clinical or radiographic follow-up, 51 patients (58 courses) were treated to non-CNS locations and 18 patients (25 courses) were treated to CNS locations; 7 patients (22 courses) received palliative RT to both CNS (13 courses) and non-CNS (9 courses) locations.
Table 1 describes baseline patient characteristics and details related to patient treatments. The median age of patients in this cohort was 61, with a range of 22 to 82. Patients were most commonly white (83%) and black (8%). Tumor histologies were primarily high-grade serous (HGS, 59%), although adenocarcinoma (undifferentiated or unspecified), low-grade serous, clear cell, endometrioid, and carcinosarcoma were also observed.Table 1 Patient characteristics and treatment details
No. of courses 105
No. of patients 76
Median age 61
Ethnicity
White 82.9% (63/76)
Black 9.2% (7/76)
Asian 3.9% (3/76)
Hispanic 2.6% (2/76)
Unknown 1.3% (1/76)
Histology
High-grade serous 59.2% (45/76)
Adenocarcinoma, other 13.2% (10/76)
Low grade serous 9.2% (7/76)
Clear cell 5.3% (4/76)
Other 7.9% (6/76)
Endometrioid 3.9% (3/76)
Carcinosarcoma 1.3% (1/76)
Anatomic site
Soft tissue/organ 35.2% (37/105)
Lymph node 21.0% (22/105)
Bone 11.4% (12/105)
CNS 36.2% (38/105)
Indications
Clinical symptoms 59.0% (62/105)
Progressive/metastatic 33.3% (35/105)
Postoperative 7.6% (8/105)
Systemic therapy before RT
Platinum chemotherapy 27.6% (29/105)
Nonplatinum chemotherapy 61.9% (65/105)
Targeted therapy 42.9% (45/105)
None/other 1.0% (1/105)
Technique
2D/3D CRT 53.3% (56/105)
SRS 21.9% (23/105)
VMAT/IMRT 16.2% (17/105)
SBRT 4.8% (5/105)
Proton 3.8% (4/105)
Non-SRS dose 14-63 Gy in 4-35 fractions
SBRT dose 24-50 Gy in 3-5 fractions
SRS dose 15-25 Gy in 1-5 fractions
Abbreviations: 2D = 2-dimensional; 3D CRT = 3-dimensional conformal radiation therapy; CNS = central nervous system; IMRT = intensity modulated radiation therapy; RT = radiation therapy; SBRT = stereotactic body radiation therapy; SRS = stereotactic radiosurgery; VMAT = volumetric modulated arc therapy.
Non-CNS treatment locations included tumors in soft tissue or organs (35%), lymph nodes (21%), and bone (11%); 4 patients were treated simultaneously to adjacent soft tissue and lymph nodes. Treatment for CNS metastases comprised the remaining 36% of patients.
Most patients were treated for clinical symptoms (59%). Pain and bleeding were the most common clinical indications. Others included neurologic deficits, spinal cord compression, airway compression, and bowel obstruction. A large cohort of patients were treated for asymptomatic progressive or metastatic disease (33%) with a small cohort treated adjuvantly after surgery (eg, metastasectomy or palliative debulking; 7.6%).
Almost all patients (90%) received chemotherapy immediately before radiation therapy. The most common systemic therapy regimens were platinum-based (ie, carboplatin) followed by taxanes and doxorubicin. Many patients (43%) also received treatment with targeted therapy agents before radiation treatment. Bevacizumab was the most commonly used targeted therapy agent (20%), although patients also received PARP inhibitors (9%) and immune checkpoint inhibitors (5%).
A wide range of palliative radiation regimens were delivered across several modalities. Nonstereotactic treatment regimens to both CNS and non-CNS locations ranged from 14 Gy in 4 fractions to 63 Gy in 35 fractions. Common palliative doses were 30 Gy in 10 fractions (14%), 20 Gy in 5 fractions (8.6%), and 35 Gy in 14 fractions (7.6%). Nonstereotactic modalities included 2-dimensional or 3-dimensional (53%), intensity modulated radiation therapy (IMRT) or volumetric-modulated arc therapy (16%), and proton therapy (3.8%). Stereotactic body radiation therapy (SBRT) was less commonly used (4.8%) with treatment regimen ranging from 24 Gy in 3 fractions to 50 Gy in 5 fractions. Lastly, patients with BMs commonly received stereotactic radiosurgery (SRS, 22% of all courses) with doses ranging from 15 Gy in 1 fraction to 25 Gy in 5 fractions. Nearly half of the patients who underwent SRS received 21 Gy in 1 fraction.
Across the entire cohort, the clinical ORR was 76% within the first month after treatment and 67% at least 3 months after treatment (Table 2). Radiographic ORR between patients treated for clinical symptoms (symptomatic) and asymptomatic progression (asymptomatic) were 48% and 59%, respectively. Although patients treated for asymptomatic progression had higher rates of response, no significant differences were observed between the 2 cohorts (P = .23).Table 2 Response rates (all lesions)
<1 mo 1-3 mo >3 mo
Clinical response
CR 32.8% (19/58) 45.0% (18/40) 48.4% (15/31)
PR 43.1% (25/58) 35.0% (14/40) 19.4% (6/31)
SD 12.1% (7/58) 2.5% (1/40) 0.0% (0/31)
PD 12.1% (7/58) 17.5% (7/40) 32.3% (10/31)
ORR 75.9% (44/58) 80.0% (32/40) 67.7% (21/31)
Radiographic response: symptomatic patients
CR 15.2% (5/33) 16.7% (5/30) 25.9% (7/27)
PR 24.2% (8/33) 30.0% (9/30) 22.2% (6/27)
SD 51.5% (17/33) 43.3% (13/30) 40.7% (11/27)
PD 9.1% (3/33) 10.% (3/30) 11.1% (3/27)
ORR 39.4% (13/33) 46.7% (14/30) 48.1% (13/27)
Radiographic response: asymptomatic patients
CR 39.4% (13/33) 47.1% (16/34) 53.1% (17/32)
PR 9.1% (3/33) 8.8% (3/34) 6.3% (2/32)
SD 45.5% (15/33) 41.2% (14/34) 34.4% (11/32)
PD 6.1% (2/33) 2.9% (1/34) 6.3% (2/32)
ORR 48.5% (16/33) 55.9% (19/34) 59.4% (19/32)
Abbreviations: CR = complete response; ORR = overall response rate; PD = progressive disease; PR = partial response; SD = stable disease.
Excludes patients treated with postoperative palliative radiation.
Denominator reflects evaluable patients.
Of patients treated to non-CNS locations, the clinical and radiographic ORR within the first month after treatment were 79% and 33%, respectively (Table 3). Clinical ORR at last follow-up (at least 3 months after treatment) was 61%. Notably, of the patients with a CR (38.1%) within the first month, only 2 went on to have PD at last follow-up (4 were lost to follow-up), indicating durable response to treatment. All but one patient treated for malignancy-related vaginal bleeding (13/14) had a clinical response within 1 month, of which only one patient had recurrence of bleeding at last follow-up. Seventy percent of patients treated for pain (n = 27) had a clinical response within 1 month, of which only 3 patients demonstrated worsening pain at last follow-up. Radiographically, ORR improved to 38% for symptomatic patients and 47% for asymptomatic patients at last follow-up, with no significant differences in response rates between the 2 groups (P = .44). All lesions that responded within 1 month of radiation treatment maintained response through last follow-up. Furthermore, only 3 of 22 lesions that were initially SD, progressed over time (1 treated for clinical symptoms, 2 treated for asymptomatic progression).Table 3 Response rates (non-CNS lesions)
<1 mo 1-3 mo >3 mo
Clinical response
CR 38.1% (16/42) 44.8% (13/29) 43.5% (10/23)
PR 40.5% (17/42) 31.0% (9/29) 17.4% (4/23)
SD 14.3% (6/42) 3.4% (1/29) 0.0% (0/23)
PD 7.1% (3/42) 20.7% (6/29) 39.1% (9/23)
ORR 78.6% (33/42) 75.9% (22/29) 60.9% (14/23)
Radiographic response: symptomatic patients
CR 9.5% (2/21) 10.5% (2/19) 18.8% (3/16)
PR 23.8% (5/21) 26.3% (5/19) 18.8% (3/16)
SD 52.4% (11/21) 52.6% (10/19) 50.0% (8/16)
PD 14.3% (3/21) 10.5% (2/19) 12.5% (2/16)
ORR 33.3% (7/21) 36.8% (7/19) 37.5% (6/16)
Radiographic response: asymptomatic patients
CR 21.1% (4/19) 31.6% (6/19) 41.2% (7/17)
PR 10.5% (2/19) 10.5% (2/19) 5.9% (1/17)
SD 57.9% (11/19) 52.6% (10/19) 41.2% (7/17)
PD 10.5% (2/19) 5.3% (1/19) 11.8% (2/17)
ORR 31.6% (6/19) 42.1% (8/19) 47.1% (8/17)
Abbreviations: CNS = central nervous system; CR = complete response; ORR = overall response rate; PD = progressive disease; PR = partial response; SD = stable disease.
Excludes patients treated with postoperative palliative radiation.
Denominator reflects evaluable patients.
Of patients treated to CNS locations, the clinical and radiographic ORR within the first month after treatment were 72% and 62%, respectively (Table 4). No patients with a demonstrated clinical or radiographic response within the first month went on to have documented progressive symptoms or imaging at last follow-up (although 2 patients died and 4 were lost to follow-up). Although clinical responses stayed constant over time, radiographic responses tended to improve, especially in patients treated for clinical symptoms. There was no difference in rates of radiographic responses between CNS patients treated for clinical symptoms and those treated for asymptomatic progression (P = .41). All patients receiving SRS responded or had SD at 1 month; only one patient had locally progressive symptoms and disease at last follow-up. Three of the 4 patients with progressive symptoms within the first month were those who received whole brain radiation therapy with more extensive CNS disease before treatment.Table 4 Response rates (CNS lesions)
<1 mo 1-3 mo >3 mo
Clinical response
CR 18.8% (3/16) 45.5% (5/11) 62.5% (5/8)
PR 50.0% (8/16) 45.5% (5/11) 25.0% (2/8)
SD 6.3% (1/16) 0.0% (0/11) 0.0% (0/8)
PD 25.0% (4/16) 9.1% (1/11) 12.5% (1/8)
ORR 68.8% (11/16) 90.9% (10/11) 87.5% (7/8)
Radiographic response: symptomatic patients
CR 25.0% (3/12) 27.3% (3/11) 36.4% (4/11)
PR 25.0% (3/12) 36.4% (4/11) 27.3% (3/11)
SD 50.% (6/12) 27.3% (3/11) 27.3% (3/11)
PD 0.0% (0/12) 9.1% (1/11) 9.1% (1/11)
ORR 50.0% (6/12) 63.6% (7/11) 63.6% (7/11)
Radiographic response: asymptomatic patients
CR 64.3% (9/14) 66.7% (10/15) 66.7% (10/15)
PR 7.1% (1/14) 6.7% (1/15) 6.7% (1/15)
SD 28.6% (4/14) 26.7% (4/15) 26.7% (4/15)
PD 0.0% (0/14) 0.0% (0/15) 0.0% (0/15)
ORR 71.4% (10/14) 73.3% (11/15) 73.3% (11/15)
Abbreviations: CNS = central nervous system; CR = complete response; PD = progressive disease; PR = partial response; ORR = overall response rate; SD = stable disease.
Excludes patients treated with postoperative palliative radiation.
Denominator reflects evaluable patients.
Patients in both CNS and non-CNS cohorts tended to have clinical responses early on, with sustained response at last follow-up. Furthermore, if a patient were to have a clinical CR, it most often occurred within the first month. Only 4 patients demonstrated a CR after the first month, and all of these patients had a PR initially; no patients with initially stable disease went on to have a CR. Most patients with radiographic SD at initial follow-up maintained SD over time. The initial responses of patients developing progressive symptoms after 3-month follow-up varied considerably: CR (2), PR (3), SD (2), and PD (3). No patients who progressed within the first month of follow-up went on to have any response.
Eight patients were treated with postoperative RT after surgical resection in the brain (6), mediastinal lymph node (1), and inguinal lymph node (1). Three patients with evaluable clinical symptoms before and after surgery-RT all demonstrated diminished (PR) or complete (CR) resolution of symptoms within 1 month after RT. Of the 6 patients with radiographic follow-up, one recurred 9 months after treatment; the rest maintained stable disease (ie, no recurrence) through last follow-up.
Acute and late grade 3 or higher (G3 +) toxicities with bevacizumab were low (8.7% and 4.3%, respectively). CNS and mediastinal locations were the only treatment sites in which G3 + toxicity occurred. CNS toxicity (acute G3 fatigue, late G3 radiation necrosis, and late G4 optic neuritis) was identified in a single patient who received craniospinal irradiation with prior Gamma Knife irradiation. A second patient treated to the mediastinum had acute but not chronic grade 3 esophagitis. Notably, no acute or late G3 + toxicity was seen in patients treated to the abdomen or pelvis (the most common treatment location; Table 5).Table 5 Observed toxicities in patients treated with bevacizumab before or concurrent with radiation therapy, by treatment course
None Grade 1-2 Grade 3 Grade 4
Acute
Non-CNS (17) 6 Anorexia (1),
depression (1),
dermatitis (1),
fatigue (5),
GI (6), GU (1),
odynophagia (1),
pneumonitis (1),
vaginal hemorrhage (1) Dermatitis (1),
esophagitis (1) -
CNS (6) 4 GI (1) Fatigue (1) -
Late
Non-CNS (9) 8 GI (1) - -
CNS (5) 3 Intracranial hemorrhage (1) Radionecrosis (1) Optic neuropathy (1)
Abbreviations: CNS = central nervous system; GI = gastrointestinal; GU = genitourinary.
Toxicities defined according to the Common Terminology Criteria for Adverse Events, version 5.0.
Numbers indicate number of treatment courses; more than one toxicity may be attributed to a single treatment course. Late toxicity data unavailable for 9 treatment courses (all due to patient death).
Late grade 3 and 4 toxicities occurred in the same patient.
An exploratory analysis examining patient demographics and treatment characteristics was performed to identify predictors of clinical or radiographic response. In all patients (CNS and non-CNS sites), HGS histology was associated with clinical responses (88% vs 64%, P = .04). In patients with CNS lesions, BED >39 Gy was associated with clinical response (P = .049). In non-CNS locations, bony site was associated with worse clinical (44% vs 89%, P = .004) response compared with soft tissue/nodal (STN) sites. Lastly, we compared BED regimens ≤39 Gy versus >39 Gy (assuming an alpha/beta ratio of 10,19,20 the BED of 30 Gy in 10 fractions is 39 Gy) in non-CNS locations and found no differences in clinical (P = .10) or radiographic response rates (P = .47). We otherwise compared the most common regimens of 20 Gy in 5 fractions and 30 Gy in 10 fractions and found no significant differences in clinical (P = .60) or radiographic responses (P = .29; Table E1).2
Discussion
We report the outcomes of a large modern cohort of women with PMR-OC who received palliative radiation therapy in an era of novel systemic agents. In a population with poor prognosis, palliative radiation therapy resulted in excellent clinical and radiographic response rates (Table 2) within 1 month of treatment, with many responses durable beyond 3 months. Brain metastases, a rare site of anatomic spread, were also well represented in this cohort (36%, 38 courses) and responded favorably to palliative intracranial radiation therapy (Table 3). Exploratory analyses demonstrated an association between HGS histology and improved clinical response in all patients, BED >39 Gy and improved clinical response in BMs, and STN sites with improved clinical response in non-CNS sites. Our analysis is unique in its (1) large sample size compared with prior reports with significant number of BMs, (2) high proportion of patients treated with modern RT techniques, (3) inclusion of patients treated with novel systemic agents (ie, PARP inhibitors, bevacizumab, and immunotherapy), and (4) dedicated toxicity analysis of RT with concurrent or prior bevacizumab, an area of increasing clinical significance in MPR-EOC with a dearth of robust data.
Our high clinical response rates (79% ORR within 1 month) are similar to other reports, including literature from prior decades demonstrating durable pain relief and bleeding control from locally directed palliative RT in 80% of OC patients.20, 21, 22 More recently, Bansal and colleagues also found pain control rates of 88.2% and vaginal bleeding control rates of 100% in 23 heavily pretreated women who received palliative pelvic RT.23 Investigators from Brigham and Women’s Hospital also recently published rates and predictors of response to palliative RT for recurrent OC from 2003 to 201424 and demonstrated high rates of response for pain and bleeding (87% and 93%, respectively).
Identified predictors of response, including HGS histology and STN sites of disease are also compatible with prior investigations. In the above Brigham and Women’s Hospital study, patients treated at nonbony sites had higher response rates than those with bony sites of disease (96% vs 75%, respectively). Furthermore, patients with clear cell histology had the lowest response rates (60%), compared with others like serous histology (82%).
The sizable nature of our cohort allowed for a temporal analysis of index lesion response rates. Patients in both CNS and non-CNS cohorts tended to have clinical responses early on, with some benefitting from sustained response at last follow-up. Lesions with clinical CR often occurred within the first month. Furthermore, no patients who progressed in the index lesion within the first month of follow-up went on to have any response, suggesting that initial response is of paramount importance. Patients who had progressive symptoms after 3 months had variable initial responses, suggesting progressive disease is still expected no matter what the initial response may be.
Regarding dose response, higher BED was associated with clinical response in brain metastases. This is a result of ablative SRS technology that radiobiologically induces high rates of cell kill compared with those of conventional palliative techniques or doses. Advanced stereotactic techniques permit the delivery of otherwise unsafe high dose-per-fraction regimens due to their sharp dose gradients that allow for normal tissue sparing. In non-CNS locations, however, regimens with BED >39 Gy (ie, greater than 30 Gy in 10 fractions) were no different than lower BED regimens, suggesting dose escalation may not increase the efficacy of palliative RT. Use of higher BED regimens in such (predominantly abdominopelvic) locations is typically limited by larger fields due to tumor size and organ motion. Dose-limiting toxicities from nearby organs at risk such as the stomach, bowel, kidneys, and bladder also constrain prescriptions.
Notably, 47% of all courses were delivered with advanced radiation therapy techniques (SRS, SBRT, IMRT/volumetric-modulated arc therapy, proton therapy). This is in keeping with the increasing number of patients referred for ablative or definitive therapy to oligometastatic or oligoprogressive disease or previously irradiated lesions requiring retreatment. In such scenarios, advanced techniques allow practitioners to deliver higher dose per fraction while sparing normal organs and tissue of radiation, or even reirradiation, toxicity. In fact, recently published reports have evaluated the roles of advanced RT in OC. For example, definitive involved-field RT using IMRT has demonstrated promising rates of local control (LC) and disease-free survival with low toxicity.25,26 Two recent retrospective studies also explored SBRT in oligometastatic OC. Lazzari et al reported the treatment of 82 patients with a median dose of 24 Gy in 3 fractions and demonstrated the safety of SBRT along with an increase in systemic therapy-free survival with reasonable LC27 (more than one-third of patients were disease-free at 1 year). Similarly, Macchia et al reported SBRT in MPR-EOC was well tolerated and afforded higher LC in patients receiving a total dose >25 Gy.28
Forty-three percent of patients received targeted therapy immediately before RT in this cohort. This is in keeping with the litany of recent publications studying the use of novel systemic agents (PARP inhibitors,29, 30, 31 bevacizumab,32 nivolumab33) in the setting of MPR-EOC. The response rates described thus reflect the potential outcomes of palliative RT in conjunction with advanced systemic therapies, a scenario that will be increasingly encountered by practitioners. Furthermore, given the sizeable population that received prior or concurrent bevacizumab, a dedicated subgroup analysis was conducted and demonstrated low acute and late grade 3 or higher (G3 +) toxicities (8.7% and 4.3%, respectively) with RT. Although G3 + toxicities occurred in patients treated to CNS and mediastinal locations, it is unclear if this was in relation to prior bevacizumab or reflected the increased risk toxicity with prior RT (Gamma Knife in the CNS patient treated with craniospinal irradiation) or unfavorable tumor location (in the mediastinal patient experiencing esophagitis after receiving 59.4 Gy). No acute or late G3 + toxicity was seen in patients treated to the abdomen or pelvis (the most common treatment location), suggesting that this may be a reasonable treatment option in symptomatic patients.
Limitations
The study is limited primarily by its retrospective nature which lends itself to both selection and sample bias. For example, patient performance status and prior lines of therapy (including prior radiation) may effect physician choice of RT technique, dose, and fractionation. Furthermore, lesions necessitating reirradiation demonstrate inherent radioresistance and may negatively affect response rates. Moreover, although the study population is sizeable, it is heterogenous with respect to treatment sites and prior lines of therapy. As such appropriate interpretation required subdivision of data (ie, CNS vs non-CNS, symptomatic vs asymptomatic indication), which led to more descriptive findings. Finally, the variety of systemic therapies used negatively affect our ability to make conclusions regarding the efficacy of RT with respect to individual agents.
Future directions
As the role for palliative radiation therapy expands in the context of the oligometastatic paradigm, nuanced decision-making must be taken to deliver the most efficacious treatment although promoting cost-effective care. As such, prospective evaluation is warranted to determine the optimal dose, timing, and fractionation of RT as it relates to systemic agents and surgery. The high response rates demonstrated in this cohort may warrant prospective investigation of RT as a standard component therapy in MPR-EOC, either before systemic agents as a cytoreductive strategy or after as consolidation therapy.
Conclusions
We performed a large retrospective cohort analysis of women with MPR-EOC receiving palliative RT in the era of modern technology and systemic agents. Our large population of patients with BMs adds relevant data to the limited body of existing literature and can be used as a practical reference when counseling women. Patients demonstrated favorable clinical and radiographic response rates within 1 month, with >60% experiencing durable clinical responses beyond 3 months. HGS histology was associated with improved clinical response in all patients. BED >39 Gy was associated with improved response in brain metastases. Bony sites were associated with worse response compared with STN sites in non-CNS locations. Acute and late grade 3 or higher toxicities were low with prior bevacizumab, and none of these occurred in patients treated to abdominopelvic locations.
Although MPR-EOC is associated with limited prognosis, our data demonstrate that responses to palliative RT can be durable and meaningful. As such, without a conclusive effect on survival, it would be reasonable to consider treatment of such disease after taking into consideration patient symptom severity, goals of care, prognosis, performance status, and extracranial disease burden for BM.
Supplementary Materials
Tables E1 and E2
Sources of support: The authors received no specific funding for this work.
Disclosures: The authors of this manuscript have no conflicts of interest to report.
Research data are stored in an institutional repository and will be shared upon request.
Supplementary material for this article can be found at https://doi.org/10.1016/j.adro.2020.11.009. | BEVACIZUMAB | DrugsGivenReaction | CC BY-NC-ND | 33665491 | 18,951,285 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Toxicity to various agents'. | Palliative Radiation Therapy for Metastatic, Persistent, or Recurrent Epithelial Ovarian Cancer: Efficacy in the Era of Modern Technology and Targeted Agents.
Metastatic, persistent, or recurrent epithelial ovarian cancer (MPR-EOC) remains a significant threat to patient mortality despite advances in novel targeted agents. Radiation therapy (RT) is often used as a palliative option. We report outcomes of a large series of MPR-EOC patients treated with modern palliative RT (PRT) in an era of novel systemic therapies.
A retrospective review was conducted of women treated with PRT for MPR-EOC between 2007 and 2019 at an academic institution. Clinical response rates were recorded at <1 month, 1 to 3 months, and >3 months. Radiographic responses were categorized by RECIST 1.1 criteria. Overall response rate (ORR) was the sum of complete and partial response. Linear regression analyses of baseline characteristics were conducted for statistical testing.
Eighty-six patients with PMR-OC received 120 courses of palliative RT. Median follow-up was 8.6 months. Median age was 61 (range, 22-82). Thirty-six percent of women received central nervous system (CNS)-directed RT. In addition, 43% received targeted therapies before RT. Clinical ORR within 1 month and at last follow-up for non-CNS lesions was 79% and 61% (69% and 88% for CNS lesions, respectively). High-grade serous lesions were more likely to have clinical response (P = .04). Biologically effective doses (BED) >39 Gy were associated with improved clinical response in CNS lesions (P = .049). Bony sites were associated with worse clinical (P = .004) response in non-CNS lesions compared with soft tissue or nodal sites. Acute or late grade 3+ toxicities with bevacizumab were low (8.7%/4.3%).
PRT offers excellent rates of response for symptomatic patients with MPR-EOC within 1 month of treatment, with durable responses beyond 3 months. High-grade serous lesions were associated with improved response in all patients. Higher BED and soft tissue or nodal sites were associated with improved response in CNS and non-CNS patients, respectively. Acute or late toxicities with bevacizumab and PRT were low. Prospective investigation is warranted to determine the optimal PRT regimen.
Introduction
Ovarian cancer (OC) is a highly aggressive gynecologic malignancy, with the majority of patients presenting with advanced disease at diagnosis. The general treatment paradigm for advanced OC is maximal cytoreductive surgery with platinum-based chemotherapy.1 Recent literature has also reported a progression-free survival benefit with maintenance inhibition of poly (adenosine diphosphate-ribose) polymerase (PARP) in women with partial or complete response to platinum-based regimens.2,3
Whole abdominal radiation therapy was historically indicated as adjuvant therapy to address microscopic residual disease.4 However, due to its considerable toxicity and the development of platinum-based chemotherapy, whole abdominal radiation therapy is no longer included in primary OC treatment paradigms.1
Despite advances in cytoreductive strategies and front-line systemic therapy, >70% of women relapse within 3 years of diagnosis.5 As such, many patients with OC benefit from palliative care referrals to assist with symptom management, goals of care discussions, and complex medical decision making at the end of life.
There is a growing body of evidence to support the incorporation of palliative services in cancer care. In 2010, a seminal randomized trial6 reported early palliative care among patients with metastatic non-small cell lung cancer significantly improved quality of life, led to less aggressive care at the end of life, and resulted in longer overall survival. Furthermore, both the American Society of Clinical Oncology and the Society of Gynecologic Oncology have published official practice guidelines recommending the routine and early integration of palliative services.7,8
Radiation therapy (RT) is often used as an effective therapeutic option in the palliation of patients with metastatic, persistent, or recurrent epithelial OC (MPR-EOC) as a means for symptomatic relief and local control. This includes oligometastatic disease or symptomatic disease causing pain, bowel or ureteral obstruction, or bleeding. Despite their rarity in OC (2% incidence9), brain metastases can also cause significant morbidity and can be treated with palliative RT to reduce the risk of progression and neurocognitive deficits.10,11
As patient survival improves with modern systemic agents, there is a growing need to understand the efficacy of palliative RT regimens for MPR-EOC in the same era. Although radiation therapy has traditionally been delivered for symptomatic control in MPR-EOC, the recognition of the biologically distinct (and potentially curable) oligometastatic state12,13 is expanding the scope of RT indications. Data from phase 2 trials in other malignancies evaluating the effect of locally directed therapy to oligometastatic lesions has demonstrated improvements in overall survival.14,15
We therefore conducted, a large contemporary retrospective analysis of palliative RT in MPR-EOC. This patient cohort is highly relevant to modern practice given the number of patients who received novel systemic agents, the prominent usage of advanced RT technology, and the representation of patients with BMs from OC (an area with limited data but increasing prevalence in practice). The analysis will report the outcomes and durability of palliative RT in MPR-EOC and delineate factors predictive of response in the modern era.
Methods and Materials
We conducted a retrospective chart review of women treated with palliative radiation therapy for metastatic ovarian cancer from 2007 through 2019 at [University of Pennsylvania] and affiliate sites. Institutional review board approval was obtained before conducting this review. Patients were included in this analysis if they were treated for palliative intent, including treatment of oligometastatic disease. All patients had MPR-EOC ovarian cancer and received anywhere from one to 5 courses of radiation treatment.
Given the poor prognosis of patients with metastatic ovarian cancer, clinical and radiographic response rates were categorized in intervals of <1 month, 1 to 3 months, and >3 months after the end of radiation treatment to indicate acute and durable responses. Clinical responses were categorized as complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD). Pain scores were classified using the Bone Metastases Consensus Working Party guidelines16 (indeterminate responses, which are neither PR nor PD per BMWCP guidelines, were classified as SD to maintain consistency with other clinical response categorizations). Radiographic responses were categorized as CR, PR, SD, or PD based on the RECIST 1.1 criteria.17 Overall response rate (ORR) was the sum of CR and PR in a given patient. Given the large subset of patients with brain metastases (BMs), courses were stratified by central nervous system (CNS) and non-CNS anatomic locations. Acute (during RT and within 3 months of completion) and late (>3 months after completion of RT) toxicities were recorded with concurrent and prior bevacizumab using Common Terminology Criteria for Adverse Events version 5.018 classification.
Rates of response (CR or PR at any point) were compared with demographic and treatment characteristics. χ2 (n ≥ 20) or Fisher exact (n < 20) tests were used for such comparison with variables for race, histology, platinum chemotherapy, or targeted therapy before RT, RT technology, RT location, and biologically effective dose (BED) >39. Binary logistic regression analyses were used for comparison with continuous variables (age and BED). Covariates with P < .1 were included in multiple logistic regression modeling to assess for independent effect. Additionally, χ2 analyses were used to compare rates of radiographic response between patients treated for clinical symptoms and asymptomatic progression. Statistical analysis was conducted using IBM SPSS Statistics, version 26 (IBM Corporation, Armonk, NY).
Results
We identified 86 patients with PMR-OC that received 120 combined courses of palliative radiation treatment. Median follow-up was 8.6 months (range, 0.5-119 months). Excluding 10 patients (15 courses) with no evaluable clinical or radiographic follow-up, 51 patients (58 courses) were treated to non-CNS locations and 18 patients (25 courses) were treated to CNS locations; 7 patients (22 courses) received palliative RT to both CNS (13 courses) and non-CNS (9 courses) locations.
Table 1 describes baseline patient characteristics and details related to patient treatments. The median age of patients in this cohort was 61, with a range of 22 to 82. Patients were most commonly white (83%) and black (8%). Tumor histologies were primarily high-grade serous (HGS, 59%), although adenocarcinoma (undifferentiated or unspecified), low-grade serous, clear cell, endometrioid, and carcinosarcoma were also observed.Table 1 Patient characteristics and treatment details
No. of courses 105
No. of patients 76
Median age 61
Ethnicity
White 82.9% (63/76)
Black 9.2% (7/76)
Asian 3.9% (3/76)
Hispanic 2.6% (2/76)
Unknown 1.3% (1/76)
Histology
High-grade serous 59.2% (45/76)
Adenocarcinoma, other 13.2% (10/76)
Low grade serous 9.2% (7/76)
Clear cell 5.3% (4/76)
Other 7.9% (6/76)
Endometrioid 3.9% (3/76)
Carcinosarcoma 1.3% (1/76)
Anatomic site
Soft tissue/organ 35.2% (37/105)
Lymph node 21.0% (22/105)
Bone 11.4% (12/105)
CNS 36.2% (38/105)
Indications
Clinical symptoms 59.0% (62/105)
Progressive/metastatic 33.3% (35/105)
Postoperative 7.6% (8/105)
Systemic therapy before RT
Platinum chemotherapy 27.6% (29/105)
Nonplatinum chemotherapy 61.9% (65/105)
Targeted therapy 42.9% (45/105)
None/other 1.0% (1/105)
Technique
2D/3D CRT 53.3% (56/105)
SRS 21.9% (23/105)
VMAT/IMRT 16.2% (17/105)
SBRT 4.8% (5/105)
Proton 3.8% (4/105)
Non-SRS dose 14-63 Gy in 4-35 fractions
SBRT dose 24-50 Gy in 3-5 fractions
SRS dose 15-25 Gy in 1-5 fractions
Abbreviations: 2D = 2-dimensional; 3D CRT = 3-dimensional conformal radiation therapy; CNS = central nervous system; IMRT = intensity modulated radiation therapy; RT = radiation therapy; SBRT = stereotactic body radiation therapy; SRS = stereotactic radiosurgery; VMAT = volumetric modulated arc therapy.
Non-CNS treatment locations included tumors in soft tissue or organs (35%), lymph nodes (21%), and bone (11%); 4 patients were treated simultaneously to adjacent soft tissue and lymph nodes. Treatment for CNS metastases comprised the remaining 36% of patients.
Most patients were treated for clinical symptoms (59%). Pain and bleeding were the most common clinical indications. Others included neurologic deficits, spinal cord compression, airway compression, and bowel obstruction. A large cohort of patients were treated for asymptomatic progressive or metastatic disease (33%) with a small cohort treated adjuvantly after surgery (eg, metastasectomy or palliative debulking; 7.6%).
Almost all patients (90%) received chemotherapy immediately before radiation therapy. The most common systemic therapy regimens were platinum-based (ie, carboplatin) followed by taxanes and doxorubicin. Many patients (43%) also received treatment with targeted therapy agents before radiation treatment. Bevacizumab was the most commonly used targeted therapy agent (20%), although patients also received PARP inhibitors (9%) and immune checkpoint inhibitors (5%).
A wide range of palliative radiation regimens were delivered across several modalities. Nonstereotactic treatment regimens to both CNS and non-CNS locations ranged from 14 Gy in 4 fractions to 63 Gy in 35 fractions. Common palliative doses were 30 Gy in 10 fractions (14%), 20 Gy in 5 fractions (8.6%), and 35 Gy in 14 fractions (7.6%). Nonstereotactic modalities included 2-dimensional or 3-dimensional (53%), intensity modulated radiation therapy (IMRT) or volumetric-modulated arc therapy (16%), and proton therapy (3.8%). Stereotactic body radiation therapy (SBRT) was less commonly used (4.8%) with treatment regimen ranging from 24 Gy in 3 fractions to 50 Gy in 5 fractions. Lastly, patients with BMs commonly received stereotactic radiosurgery (SRS, 22% of all courses) with doses ranging from 15 Gy in 1 fraction to 25 Gy in 5 fractions. Nearly half of the patients who underwent SRS received 21 Gy in 1 fraction.
Across the entire cohort, the clinical ORR was 76% within the first month after treatment and 67% at least 3 months after treatment (Table 2). Radiographic ORR between patients treated for clinical symptoms (symptomatic) and asymptomatic progression (asymptomatic) were 48% and 59%, respectively. Although patients treated for asymptomatic progression had higher rates of response, no significant differences were observed between the 2 cohorts (P = .23).Table 2 Response rates (all lesions)
<1 mo 1-3 mo >3 mo
Clinical response
CR 32.8% (19/58) 45.0% (18/40) 48.4% (15/31)
PR 43.1% (25/58) 35.0% (14/40) 19.4% (6/31)
SD 12.1% (7/58) 2.5% (1/40) 0.0% (0/31)
PD 12.1% (7/58) 17.5% (7/40) 32.3% (10/31)
ORR 75.9% (44/58) 80.0% (32/40) 67.7% (21/31)
Radiographic response: symptomatic patients
CR 15.2% (5/33) 16.7% (5/30) 25.9% (7/27)
PR 24.2% (8/33) 30.0% (9/30) 22.2% (6/27)
SD 51.5% (17/33) 43.3% (13/30) 40.7% (11/27)
PD 9.1% (3/33) 10.% (3/30) 11.1% (3/27)
ORR 39.4% (13/33) 46.7% (14/30) 48.1% (13/27)
Radiographic response: asymptomatic patients
CR 39.4% (13/33) 47.1% (16/34) 53.1% (17/32)
PR 9.1% (3/33) 8.8% (3/34) 6.3% (2/32)
SD 45.5% (15/33) 41.2% (14/34) 34.4% (11/32)
PD 6.1% (2/33) 2.9% (1/34) 6.3% (2/32)
ORR 48.5% (16/33) 55.9% (19/34) 59.4% (19/32)
Abbreviations: CR = complete response; ORR = overall response rate; PD = progressive disease; PR = partial response; SD = stable disease.
Excludes patients treated with postoperative palliative radiation.
Denominator reflects evaluable patients.
Of patients treated to non-CNS locations, the clinical and radiographic ORR within the first month after treatment were 79% and 33%, respectively (Table 3). Clinical ORR at last follow-up (at least 3 months after treatment) was 61%. Notably, of the patients with a CR (38.1%) within the first month, only 2 went on to have PD at last follow-up (4 were lost to follow-up), indicating durable response to treatment. All but one patient treated for malignancy-related vaginal bleeding (13/14) had a clinical response within 1 month, of which only one patient had recurrence of bleeding at last follow-up. Seventy percent of patients treated for pain (n = 27) had a clinical response within 1 month, of which only 3 patients demonstrated worsening pain at last follow-up. Radiographically, ORR improved to 38% for symptomatic patients and 47% for asymptomatic patients at last follow-up, with no significant differences in response rates between the 2 groups (P = .44). All lesions that responded within 1 month of radiation treatment maintained response through last follow-up. Furthermore, only 3 of 22 lesions that were initially SD, progressed over time (1 treated for clinical symptoms, 2 treated for asymptomatic progression).Table 3 Response rates (non-CNS lesions)
<1 mo 1-3 mo >3 mo
Clinical response
CR 38.1% (16/42) 44.8% (13/29) 43.5% (10/23)
PR 40.5% (17/42) 31.0% (9/29) 17.4% (4/23)
SD 14.3% (6/42) 3.4% (1/29) 0.0% (0/23)
PD 7.1% (3/42) 20.7% (6/29) 39.1% (9/23)
ORR 78.6% (33/42) 75.9% (22/29) 60.9% (14/23)
Radiographic response: symptomatic patients
CR 9.5% (2/21) 10.5% (2/19) 18.8% (3/16)
PR 23.8% (5/21) 26.3% (5/19) 18.8% (3/16)
SD 52.4% (11/21) 52.6% (10/19) 50.0% (8/16)
PD 14.3% (3/21) 10.5% (2/19) 12.5% (2/16)
ORR 33.3% (7/21) 36.8% (7/19) 37.5% (6/16)
Radiographic response: asymptomatic patients
CR 21.1% (4/19) 31.6% (6/19) 41.2% (7/17)
PR 10.5% (2/19) 10.5% (2/19) 5.9% (1/17)
SD 57.9% (11/19) 52.6% (10/19) 41.2% (7/17)
PD 10.5% (2/19) 5.3% (1/19) 11.8% (2/17)
ORR 31.6% (6/19) 42.1% (8/19) 47.1% (8/17)
Abbreviations: CNS = central nervous system; CR = complete response; ORR = overall response rate; PD = progressive disease; PR = partial response; SD = stable disease.
Excludes patients treated with postoperative palliative radiation.
Denominator reflects evaluable patients.
Of patients treated to CNS locations, the clinical and radiographic ORR within the first month after treatment were 72% and 62%, respectively (Table 4). No patients with a demonstrated clinical or radiographic response within the first month went on to have documented progressive symptoms or imaging at last follow-up (although 2 patients died and 4 were lost to follow-up). Although clinical responses stayed constant over time, radiographic responses tended to improve, especially in patients treated for clinical symptoms. There was no difference in rates of radiographic responses between CNS patients treated for clinical symptoms and those treated for asymptomatic progression (P = .41). All patients receiving SRS responded or had SD at 1 month; only one patient had locally progressive symptoms and disease at last follow-up. Three of the 4 patients with progressive symptoms within the first month were those who received whole brain radiation therapy with more extensive CNS disease before treatment.Table 4 Response rates (CNS lesions)
<1 mo 1-3 mo >3 mo
Clinical response
CR 18.8% (3/16) 45.5% (5/11) 62.5% (5/8)
PR 50.0% (8/16) 45.5% (5/11) 25.0% (2/8)
SD 6.3% (1/16) 0.0% (0/11) 0.0% (0/8)
PD 25.0% (4/16) 9.1% (1/11) 12.5% (1/8)
ORR 68.8% (11/16) 90.9% (10/11) 87.5% (7/8)
Radiographic response: symptomatic patients
CR 25.0% (3/12) 27.3% (3/11) 36.4% (4/11)
PR 25.0% (3/12) 36.4% (4/11) 27.3% (3/11)
SD 50.% (6/12) 27.3% (3/11) 27.3% (3/11)
PD 0.0% (0/12) 9.1% (1/11) 9.1% (1/11)
ORR 50.0% (6/12) 63.6% (7/11) 63.6% (7/11)
Radiographic response: asymptomatic patients
CR 64.3% (9/14) 66.7% (10/15) 66.7% (10/15)
PR 7.1% (1/14) 6.7% (1/15) 6.7% (1/15)
SD 28.6% (4/14) 26.7% (4/15) 26.7% (4/15)
PD 0.0% (0/14) 0.0% (0/15) 0.0% (0/15)
ORR 71.4% (10/14) 73.3% (11/15) 73.3% (11/15)
Abbreviations: CNS = central nervous system; CR = complete response; PD = progressive disease; PR = partial response; ORR = overall response rate; SD = stable disease.
Excludes patients treated with postoperative palliative radiation.
Denominator reflects evaluable patients.
Patients in both CNS and non-CNS cohorts tended to have clinical responses early on, with sustained response at last follow-up. Furthermore, if a patient were to have a clinical CR, it most often occurred within the first month. Only 4 patients demonstrated a CR after the first month, and all of these patients had a PR initially; no patients with initially stable disease went on to have a CR. Most patients with radiographic SD at initial follow-up maintained SD over time. The initial responses of patients developing progressive symptoms after 3-month follow-up varied considerably: CR (2), PR (3), SD (2), and PD (3). No patients who progressed within the first month of follow-up went on to have any response.
Eight patients were treated with postoperative RT after surgical resection in the brain (6), mediastinal lymph node (1), and inguinal lymph node (1). Three patients with evaluable clinical symptoms before and after surgery-RT all demonstrated diminished (PR) or complete (CR) resolution of symptoms within 1 month after RT. Of the 6 patients with radiographic follow-up, one recurred 9 months after treatment; the rest maintained stable disease (ie, no recurrence) through last follow-up.
Acute and late grade 3 or higher (G3 +) toxicities with bevacizumab were low (8.7% and 4.3%, respectively). CNS and mediastinal locations were the only treatment sites in which G3 + toxicity occurred. CNS toxicity (acute G3 fatigue, late G3 radiation necrosis, and late G4 optic neuritis) was identified in a single patient who received craniospinal irradiation with prior Gamma Knife irradiation. A second patient treated to the mediastinum had acute but not chronic grade 3 esophagitis. Notably, no acute or late G3 + toxicity was seen in patients treated to the abdomen or pelvis (the most common treatment location; Table 5).Table 5 Observed toxicities in patients treated with bevacizumab before or concurrent with radiation therapy, by treatment course
None Grade 1-2 Grade 3 Grade 4
Acute
Non-CNS (17) 6 Anorexia (1),
depression (1),
dermatitis (1),
fatigue (5),
GI (6), GU (1),
odynophagia (1),
pneumonitis (1),
vaginal hemorrhage (1) Dermatitis (1),
esophagitis (1) -
CNS (6) 4 GI (1) Fatigue (1) -
Late
Non-CNS (9) 8 GI (1) - -
CNS (5) 3 Intracranial hemorrhage (1) Radionecrosis (1) Optic neuropathy (1)
Abbreviations: CNS = central nervous system; GI = gastrointestinal; GU = genitourinary.
Toxicities defined according to the Common Terminology Criteria for Adverse Events, version 5.0.
Numbers indicate number of treatment courses; more than one toxicity may be attributed to a single treatment course. Late toxicity data unavailable for 9 treatment courses (all due to patient death).
Late grade 3 and 4 toxicities occurred in the same patient.
An exploratory analysis examining patient demographics and treatment characteristics was performed to identify predictors of clinical or radiographic response. In all patients (CNS and non-CNS sites), HGS histology was associated with clinical responses (88% vs 64%, P = .04). In patients with CNS lesions, BED >39 Gy was associated with clinical response (P = .049). In non-CNS locations, bony site was associated with worse clinical (44% vs 89%, P = .004) response compared with soft tissue/nodal (STN) sites. Lastly, we compared BED regimens ≤39 Gy versus >39 Gy (assuming an alpha/beta ratio of 10,19,20 the BED of 30 Gy in 10 fractions is 39 Gy) in non-CNS locations and found no differences in clinical (P = .10) or radiographic response rates (P = .47). We otherwise compared the most common regimens of 20 Gy in 5 fractions and 30 Gy in 10 fractions and found no significant differences in clinical (P = .60) or radiographic responses (P = .29; Table E1).2
Discussion
We report the outcomes of a large modern cohort of women with PMR-OC who received palliative radiation therapy in an era of novel systemic agents. In a population with poor prognosis, palliative radiation therapy resulted in excellent clinical and radiographic response rates (Table 2) within 1 month of treatment, with many responses durable beyond 3 months. Brain metastases, a rare site of anatomic spread, were also well represented in this cohort (36%, 38 courses) and responded favorably to palliative intracranial radiation therapy (Table 3). Exploratory analyses demonstrated an association between HGS histology and improved clinical response in all patients, BED >39 Gy and improved clinical response in BMs, and STN sites with improved clinical response in non-CNS sites. Our analysis is unique in its (1) large sample size compared with prior reports with significant number of BMs, (2) high proportion of patients treated with modern RT techniques, (3) inclusion of patients treated with novel systemic agents (ie, PARP inhibitors, bevacizumab, and immunotherapy), and (4) dedicated toxicity analysis of RT with concurrent or prior bevacizumab, an area of increasing clinical significance in MPR-EOC with a dearth of robust data.
Our high clinical response rates (79% ORR within 1 month) are similar to other reports, including literature from prior decades demonstrating durable pain relief and bleeding control from locally directed palliative RT in 80% of OC patients.20, 21, 22 More recently, Bansal and colleagues also found pain control rates of 88.2% and vaginal bleeding control rates of 100% in 23 heavily pretreated women who received palliative pelvic RT.23 Investigators from Brigham and Women’s Hospital also recently published rates and predictors of response to palliative RT for recurrent OC from 2003 to 201424 and demonstrated high rates of response for pain and bleeding (87% and 93%, respectively).
Identified predictors of response, including HGS histology and STN sites of disease are also compatible with prior investigations. In the above Brigham and Women’s Hospital study, patients treated at nonbony sites had higher response rates than those with bony sites of disease (96% vs 75%, respectively). Furthermore, patients with clear cell histology had the lowest response rates (60%), compared with others like serous histology (82%).
The sizable nature of our cohort allowed for a temporal analysis of index lesion response rates. Patients in both CNS and non-CNS cohorts tended to have clinical responses early on, with some benefitting from sustained response at last follow-up. Lesions with clinical CR often occurred within the first month. Furthermore, no patients who progressed in the index lesion within the first month of follow-up went on to have any response, suggesting that initial response is of paramount importance. Patients who had progressive symptoms after 3 months had variable initial responses, suggesting progressive disease is still expected no matter what the initial response may be.
Regarding dose response, higher BED was associated with clinical response in brain metastases. This is a result of ablative SRS technology that radiobiologically induces high rates of cell kill compared with those of conventional palliative techniques or doses. Advanced stereotactic techniques permit the delivery of otherwise unsafe high dose-per-fraction regimens due to their sharp dose gradients that allow for normal tissue sparing. In non-CNS locations, however, regimens with BED >39 Gy (ie, greater than 30 Gy in 10 fractions) were no different than lower BED regimens, suggesting dose escalation may not increase the efficacy of palliative RT. Use of higher BED regimens in such (predominantly abdominopelvic) locations is typically limited by larger fields due to tumor size and organ motion. Dose-limiting toxicities from nearby organs at risk such as the stomach, bowel, kidneys, and bladder also constrain prescriptions.
Notably, 47% of all courses were delivered with advanced radiation therapy techniques (SRS, SBRT, IMRT/volumetric-modulated arc therapy, proton therapy). This is in keeping with the increasing number of patients referred for ablative or definitive therapy to oligometastatic or oligoprogressive disease or previously irradiated lesions requiring retreatment. In such scenarios, advanced techniques allow practitioners to deliver higher dose per fraction while sparing normal organs and tissue of radiation, or even reirradiation, toxicity. In fact, recently published reports have evaluated the roles of advanced RT in OC. For example, definitive involved-field RT using IMRT has demonstrated promising rates of local control (LC) and disease-free survival with low toxicity.25,26 Two recent retrospective studies also explored SBRT in oligometastatic OC. Lazzari et al reported the treatment of 82 patients with a median dose of 24 Gy in 3 fractions and demonstrated the safety of SBRT along with an increase in systemic therapy-free survival with reasonable LC27 (more than one-third of patients were disease-free at 1 year). Similarly, Macchia et al reported SBRT in MPR-EOC was well tolerated and afforded higher LC in patients receiving a total dose >25 Gy.28
Forty-three percent of patients received targeted therapy immediately before RT in this cohort. This is in keeping with the litany of recent publications studying the use of novel systemic agents (PARP inhibitors,29, 30, 31 bevacizumab,32 nivolumab33) in the setting of MPR-EOC. The response rates described thus reflect the potential outcomes of palliative RT in conjunction with advanced systemic therapies, a scenario that will be increasingly encountered by practitioners. Furthermore, given the sizeable population that received prior or concurrent bevacizumab, a dedicated subgroup analysis was conducted and demonstrated low acute and late grade 3 or higher (G3 +) toxicities (8.7% and 4.3%, respectively) with RT. Although G3 + toxicities occurred in patients treated to CNS and mediastinal locations, it is unclear if this was in relation to prior bevacizumab or reflected the increased risk toxicity with prior RT (Gamma Knife in the CNS patient treated with craniospinal irradiation) or unfavorable tumor location (in the mediastinal patient experiencing esophagitis after receiving 59.4 Gy). No acute or late G3 + toxicity was seen in patients treated to the abdomen or pelvis (the most common treatment location), suggesting that this may be a reasonable treatment option in symptomatic patients.
Limitations
The study is limited primarily by its retrospective nature which lends itself to both selection and sample bias. For example, patient performance status and prior lines of therapy (including prior radiation) may effect physician choice of RT technique, dose, and fractionation. Furthermore, lesions necessitating reirradiation demonstrate inherent radioresistance and may negatively affect response rates. Moreover, although the study population is sizeable, it is heterogenous with respect to treatment sites and prior lines of therapy. As such appropriate interpretation required subdivision of data (ie, CNS vs non-CNS, symptomatic vs asymptomatic indication), which led to more descriptive findings. Finally, the variety of systemic therapies used negatively affect our ability to make conclusions regarding the efficacy of RT with respect to individual agents.
Future directions
As the role for palliative radiation therapy expands in the context of the oligometastatic paradigm, nuanced decision-making must be taken to deliver the most efficacious treatment although promoting cost-effective care. As such, prospective evaluation is warranted to determine the optimal dose, timing, and fractionation of RT as it relates to systemic agents and surgery. The high response rates demonstrated in this cohort may warrant prospective investigation of RT as a standard component therapy in MPR-EOC, either before systemic agents as a cytoreductive strategy or after as consolidation therapy.
Conclusions
We performed a large retrospective cohort analysis of women with MPR-EOC receiving palliative RT in the era of modern technology and systemic agents. Our large population of patients with BMs adds relevant data to the limited body of existing literature and can be used as a practical reference when counseling women. Patients demonstrated favorable clinical and radiographic response rates within 1 month, with >60% experiencing durable clinical responses beyond 3 months. HGS histology was associated with improved clinical response in all patients. BED >39 Gy was associated with improved response in brain metastases. Bony sites were associated with worse response compared with STN sites in non-CNS locations. Acute and late grade 3 or higher toxicities were low with prior bevacizumab, and none of these occurred in patients treated to abdominopelvic locations.
Although MPR-EOC is associated with limited prognosis, our data demonstrate that responses to palliative RT can be durable and meaningful. As such, without a conclusive effect on survival, it would be reasonable to consider treatment of such disease after taking into consideration patient symptom severity, goals of care, prognosis, performance status, and extracranial disease burden for BM.
Supplementary Materials
Tables E1 and E2
Sources of support: The authors received no specific funding for this work.
Disclosures: The authors of this manuscript have no conflicts of interest to report.
Research data are stored in an institutional repository and will be shared upon request.
Supplementary material for this article can be found at https://doi.org/10.1016/j.adro.2020.11.009. | BEVACIZUMAB | DrugsGivenReaction | CC BY-NC-ND | 33665491 | 18,951,285 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Vaginal haemorrhage'. | Palliative Radiation Therapy for Metastatic, Persistent, or Recurrent Epithelial Ovarian Cancer: Efficacy in the Era of Modern Technology and Targeted Agents.
Metastatic, persistent, or recurrent epithelial ovarian cancer (MPR-EOC) remains a significant threat to patient mortality despite advances in novel targeted agents. Radiation therapy (RT) is often used as a palliative option. We report outcomes of a large series of MPR-EOC patients treated with modern palliative RT (PRT) in an era of novel systemic therapies.
A retrospective review was conducted of women treated with PRT for MPR-EOC between 2007 and 2019 at an academic institution. Clinical response rates were recorded at <1 month, 1 to 3 months, and >3 months. Radiographic responses were categorized by RECIST 1.1 criteria. Overall response rate (ORR) was the sum of complete and partial response. Linear regression analyses of baseline characteristics were conducted for statistical testing.
Eighty-six patients with PMR-OC received 120 courses of palliative RT. Median follow-up was 8.6 months. Median age was 61 (range, 22-82). Thirty-six percent of women received central nervous system (CNS)-directed RT. In addition, 43% received targeted therapies before RT. Clinical ORR within 1 month and at last follow-up for non-CNS lesions was 79% and 61% (69% and 88% for CNS lesions, respectively). High-grade serous lesions were more likely to have clinical response (P = .04). Biologically effective doses (BED) >39 Gy were associated with improved clinical response in CNS lesions (P = .049). Bony sites were associated with worse clinical (P = .004) response in non-CNS lesions compared with soft tissue or nodal sites. Acute or late grade 3+ toxicities with bevacizumab were low (8.7%/4.3%).
PRT offers excellent rates of response for symptomatic patients with MPR-EOC within 1 month of treatment, with durable responses beyond 3 months. High-grade serous lesions were associated with improved response in all patients. Higher BED and soft tissue or nodal sites were associated with improved response in CNS and non-CNS patients, respectively. Acute or late toxicities with bevacizumab and PRT were low. Prospective investigation is warranted to determine the optimal PRT regimen.
Introduction
Ovarian cancer (OC) is a highly aggressive gynecologic malignancy, with the majority of patients presenting with advanced disease at diagnosis. The general treatment paradigm for advanced OC is maximal cytoreductive surgery with platinum-based chemotherapy.1 Recent literature has also reported a progression-free survival benefit with maintenance inhibition of poly (adenosine diphosphate-ribose) polymerase (PARP) in women with partial or complete response to platinum-based regimens.2,3
Whole abdominal radiation therapy was historically indicated as adjuvant therapy to address microscopic residual disease.4 However, due to its considerable toxicity and the development of platinum-based chemotherapy, whole abdominal radiation therapy is no longer included in primary OC treatment paradigms.1
Despite advances in cytoreductive strategies and front-line systemic therapy, >70% of women relapse within 3 years of diagnosis.5 As such, many patients with OC benefit from palliative care referrals to assist with symptom management, goals of care discussions, and complex medical decision making at the end of life.
There is a growing body of evidence to support the incorporation of palliative services in cancer care. In 2010, a seminal randomized trial6 reported early palliative care among patients with metastatic non-small cell lung cancer significantly improved quality of life, led to less aggressive care at the end of life, and resulted in longer overall survival. Furthermore, both the American Society of Clinical Oncology and the Society of Gynecologic Oncology have published official practice guidelines recommending the routine and early integration of palliative services.7,8
Radiation therapy (RT) is often used as an effective therapeutic option in the palliation of patients with metastatic, persistent, or recurrent epithelial OC (MPR-EOC) as a means for symptomatic relief and local control. This includes oligometastatic disease or symptomatic disease causing pain, bowel or ureteral obstruction, or bleeding. Despite their rarity in OC (2% incidence9), brain metastases can also cause significant morbidity and can be treated with palliative RT to reduce the risk of progression and neurocognitive deficits.10,11
As patient survival improves with modern systemic agents, there is a growing need to understand the efficacy of palliative RT regimens for MPR-EOC in the same era. Although radiation therapy has traditionally been delivered for symptomatic control in MPR-EOC, the recognition of the biologically distinct (and potentially curable) oligometastatic state12,13 is expanding the scope of RT indications. Data from phase 2 trials in other malignancies evaluating the effect of locally directed therapy to oligometastatic lesions has demonstrated improvements in overall survival.14,15
We therefore conducted, a large contemporary retrospective analysis of palliative RT in MPR-EOC. This patient cohort is highly relevant to modern practice given the number of patients who received novel systemic agents, the prominent usage of advanced RT technology, and the representation of patients with BMs from OC (an area with limited data but increasing prevalence in practice). The analysis will report the outcomes and durability of palliative RT in MPR-EOC and delineate factors predictive of response in the modern era.
Methods and Materials
We conducted a retrospective chart review of women treated with palliative radiation therapy for metastatic ovarian cancer from 2007 through 2019 at [University of Pennsylvania] and affiliate sites. Institutional review board approval was obtained before conducting this review. Patients were included in this analysis if they were treated for palliative intent, including treatment of oligometastatic disease. All patients had MPR-EOC ovarian cancer and received anywhere from one to 5 courses of radiation treatment.
Given the poor prognosis of patients with metastatic ovarian cancer, clinical and radiographic response rates were categorized in intervals of <1 month, 1 to 3 months, and >3 months after the end of radiation treatment to indicate acute and durable responses. Clinical responses were categorized as complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD). Pain scores were classified using the Bone Metastases Consensus Working Party guidelines16 (indeterminate responses, which are neither PR nor PD per BMWCP guidelines, were classified as SD to maintain consistency with other clinical response categorizations). Radiographic responses were categorized as CR, PR, SD, or PD based on the RECIST 1.1 criteria.17 Overall response rate (ORR) was the sum of CR and PR in a given patient. Given the large subset of patients with brain metastases (BMs), courses were stratified by central nervous system (CNS) and non-CNS anatomic locations. Acute (during RT and within 3 months of completion) and late (>3 months after completion of RT) toxicities were recorded with concurrent and prior bevacizumab using Common Terminology Criteria for Adverse Events version 5.018 classification.
Rates of response (CR or PR at any point) were compared with demographic and treatment characteristics. χ2 (n ≥ 20) or Fisher exact (n < 20) tests were used for such comparison with variables for race, histology, platinum chemotherapy, or targeted therapy before RT, RT technology, RT location, and biologically effective dose (BED) >39. Binary logistic regression analyses were used for comparison with continuous variables (age and BED). Covariates with P < .1 were included in multiple logistic regression modeling to assess for independent effect. Additionally, χ2 analyses were used to compare rates of radiographic response between patients treated for clinical symptoms and asymptomatic progression. Statistical analysis was conducted using IBM SPSS Statistics, version 26 (IBM Corporation, Armonk, NY).
Results
We identified 86 patients with PMR-OC that received 120 combined courses of palliative radiation treatment. Median follow-up was 8.6 months (range, 0.5-119 months). Excluding 10 patients (15 courses) with no evaluable clinical or radiographic follow-up, 51 patients (58 courses) were treated to non-CNS locations and 18 patients (25 courses) were treated to CNS locations; 7 patients (22 courses) received palliative RT to both CNS (13 courses) and non-CNS (9 courses) locations.
Table 1 describes baseline patient characteristics and details related to patient treatments. The median age of patients in this cohort was 61, with a range of 22 to 82. Patients were most commonly white (83%) and black (8%). Tumor histologies were primarily high-grade serous (HGS, 59%), although adenocarcinoma (undifferentiated or unspecified), low-grade serous, clear cell, endometrioid, and carcinosarcoma were also observed.Table 1 Patient characteristics and treatment details
No. of courses 105
No. of patients 76
Median age 61
Ethnicity
White 82.9% (63/76)
Black 9.2% (7/76)
Asian 3.9% (3/76)
Hispanic 2.6% (2/76)
Unknown 1.3% (1/76)
Histology
High-grade serous 59.2% (45/76)
Adenocarcinoma, other 13.2% (10/76)
Low grade serous 9.2% (7/76)
Clear cell 5.3% (4/76)
Other 7.9% (6/76)
Endometrioid 3.9% (3/76)
Carcinosarcoma 1.3% (1/76)
Anatomic site
Soft tissue/organ 35.2% (37/105)
Lymph node 21.0% (22/105)
Bone 11.4% (12/105)
CNS 36.2% (38/105)
Indications
Clinical symptoms 59.0% (62/105)
Progressive/metastatic 33.3% (35/105)
Postoperative 7.6% (8/105)
Systemic therapy before RT
Platinum chemotherapy 27.6% (29/105)
Nonplatinum chemotherapy 61.9% (65/105)
Targeted therapy 42.9% (45/105)
None/other 1.0% (1/105)
Technique
2D/3D CRT 53.3% (56/105)
SRS 21.9% (23/105)
VMAT/IMRT 16.2% (17/105)
SBRT 4.8% (5/105)
Proton 3.8% (4/105)
Non-SRS dose 14-63 Gy in 4-35 fractions
SBRT dose 24-50 Gy in 3-5 fractions
SRS dose 15-25 Gy in 1-5 fractions
Abbreviations: 2D = 2-dimensional; 3D CRT = 3-dimensional conformal radiation therapy; CNS = central nervous system; IMRT = intensity modulated radiation therapy; RT = radiation therapy; SBRT = stereotactic body radiation therapy; SRS = stereotactic radiosurgery; VMAT = volumetric modulated arc therapy.
Non-CNS treatment locations included tumors in soft tissue or organs (35%), lymph nodes (21%), and bone (11%); 4 patients were treated simultaneously to adjacent soft tissue and lymph nodes. Treatment for CNS metastases comprised the remaining 36% of patients.
Most patients were treated for clinical symptoms (59%). Pain and bleeding were the most common clinical indications. Others included neurologic deficits, spinal cord compression, airway compression, and bowel obstruction. A large cohort of patients were treated for asymptomatic progressive or metastatic disease (33%) with a small cohort treated adjuvantly after surgery (eg, metastasectomy or palliative debulking; 7.6%).
Almost all patients (90%) received chemotherapy immediately before radiation therapy. The most common systemic therapy regimens were platinum-based (ie, carboplatin) followed by taxanes and doxorubicin. Many patients (43%) also received treatment with targeted therapy agents before radiation treatment. Bevacizumab was the most commonly used targeted therapy agent (20%), although patients also received PARP inhibitors (9%) and immune checkpoint inhibitors (5%).
A wide range of palliative radiation regimens were delivered across several modalities. Nonstereotactic treatment regimens to both CNS and non-CNS locations ranged from 14 Gy in 4 fractions to 63 Gy in 35 fractions. Common palliative doses were 30 Gy in 10 fractions (14%), 20 Gy in 5 fractions (8.6%), and 35 Gy in 14 fractions (7.6%). Nonstereotactic modalities included 2-dimensional or 3-dimensional (53%), intensity modulated radiation therapy (IMRT) or volumetric-modulated arc therapy (16%), and proton therapy (3.8%). Stereotactic body radiation therapy (SBRT) was less commonly used (4.8%) with treatment regimen ranging from 24 Gy in 3 fractions to 50 Gy in 5 fractions. Lastly, patients with BMs commonly received stereotactic radiosurgery (SRS, 22% of all courses) with doses ranging from 15 Gy in 1 fraction to 25 Gy in 5 fractions. Nearly half of the patients who underwent SRS received 21 Gy in 1 fraction.
Across the entire cohort, the clinical ORR was 76% within the first month after treatment and 67% at least 3 months after treatment (Table 2). Radiographic ORR between patients treated for clinical symptoms (symptomatic) and asymptomatic progression (asymptomatic) were 48% and 59%, respectively. Although patients treated for asymptomatic progression had higher rates of response, no significant differences were observed between the 2 cohorts (P = .23).Table 2 Response rates (all lesions)
<1 mo 1-3 mo >3 mo
Clinical response
CR 32.8% (19/58) 45.0% (18/40) 48.4% (15/31)
PR 43.1% (25/58) 35.0% (14/40) 19.4% (6/31)
SD 12.1% (7/58) 2.5% (1/40) 0.0% (0/31)
PD 12.1% (7/58) 17.5% (7/40) 32.3% (10/31)
ORR 75.9% (44/58) 80.0% (32/40) 67.7% (21/31)
Radiographic response: symptomatic patients
CR 15.2% (5/33) 16.7% (5/30) 25.9% (7/27)
PR 24.2% (8/33) 30.0% (9/30) 22.2% (6/27)
SD 51.5% (17/33) 43.3% (13/30) 40.7% (11/27)
PD 9.1% (3/33) 10.% (3/30) 11.1% (3/27)
ORR 39.4% (13/33) 46.7% (14/30) 48.1% (13/27)
Radiographic response: asymptomatic patients
CR 39.4% (13/33) 47.1% (16/34) 53.1% (17/32)
PR 9.1% (3/33) 8.8% (3/34) 6.3% (2/32)
SD 45.5% (15/33) 41.2% (14/34) 34.4% (11/32)
PD 6.1% (2/33) 2.9% (1/34) 6.3% (2/32)
ORR 48.5% (16/33) 55.9% (19/34) 59.4% (19/32)
Abbreviations: CR = complete response; ORR = overall response rate; PD = progressive disease; PR = partial response; SD = stable disease.
Excludes patients treated with postoperative palliative radiation.
Denominator reflects evaluable patients.
Of patients treated to non-CNS locations, the clinical and radiographic ORR within the first month after treatment were 79% and 33%, respectively (Table 3). Clinical ORR at last follow-up (at least 3 months after treatment) was 61%. Notably, of the patients with a CR (38.1%) within the first month, only 2 went on to have PD at last follow-up (4 were lost to follow-up), indicating durable response to treatment. All but one patient treated for malignancy-related vaginal bleeding (13/14) had a clinical response within 1 month, of which only one patient had recurrence of bleeding at last follow-up. Seventy percent of patients treated for pain (n = 27) had a clinical response within 1 month, of which only 3 patients demonstrated worsening pain at last follow-up. Radiographically, ORR improved to 38% for symptomatic patients and 47% for asymptomatic patients at last follow-up, with no significant differences in response rates between the 2 groups (P = .44). All lesions that responded within 1 month of radiation treatment maintained response through last follow-up. Furthermore, only 3 of 22 lesions that were initially SD, progressed over time (1 treated for clinical symptoms, 2 treated for asymptomatic progression).Table 3 Response rates (non-CNS lesions)
<1 mo 1-3 mo >3 mo
Clinical response
CR 38.1% (16/42) 44.8% (13/29) 43.5% (10/23)
PR 40.5% (17/42) 31.0% (9/29) 17.4% (4/23)
SD 14.3% (6/42) 3.4% (1/29) 0.0% (0/23)
PD 7.1% (3/42) 20.7% (6/29) 39.1% (9/23)
ORR 78.6% (33/42) 75.9% (22/29) 60.9% (14/23)
Radiographic response: symptomatic patients
CR 9.5% (2/21) 10.5% (2/19) 18.8% (3/16)
PR 23.8% (5/21) 26.3% (5/19) 18.8% (3/16)
SD 52.4% (11/21) 52.6% (10/19) 50.0% (8/16)
PD 14.3% (3/21) 10.5% (2/19) 12.5% (2/16)
ORR 33.3% (7/21) 36.8% (7/19) 37.5% (6/16)
Radiographic response: asymptomatic patients
CR 21.1% (4/19) 31.6% (6/19) 41.2% (7/17)
PR 10.5% (2/19) 10.5% (2/19) 5.9% (1/17)
SD 57.9% (11/19) 52.6% (10/19) 41.2% (7/17)
PD 10.5% (2/19) 5.3% (1/19) 11.8% (2/17)
ORR 31.6% (6/19) 42.1% (8/19) 47.1% (8/17)
Abbreviations: CNS = central nervous system; CR = complete response; ORR = overall response rate; PD = progressive disease; PR = partial response; SD = stable disease.
Excludes patients treated with postoperative palliative radiation.
Denominator reflects evaluable patients.
Of patients treated to CNS locations, the clinical and radiographic ORR within the first month after treatment were 72% and 62%, respectively (Table 4). No patients with a demonstrated clinical or radiographic response within the first month went on to have documented progressive symptoms or imaging at last follow-up (although 2 patients died and 4 were lost to follow-up). Although clinical responses stayed constant over time, radiographic responses tended to improve, especially in patients treated for clinical symptoms. There was no difference in rates of radiographic responses between CNS patients treated for clinical symptoms and those treated for asymptomatic progression (P = .41). All patients receiving SRS responded or had SD at 1 month; only one patient had locally progressive symptoms and disease at last follow-up. Three of the 4 patients with progressive symptoms within the first month were those who received whole brain radiation therapy with more extensive CNS disease before treatment.Table 4 Response rates (CNS lesions)
<1 mo 1-3 mo >3 mo
Clinical response
CR 18.8% (3/16) 45.5% (5/11) 62.5% (5/8)
PR 50.0% (8/16) 45.5% (5/11) 25.0% (2/8)
SD 6.3% (1/16) 0.0% (0/11) 0.0% (0/8)
PD 25.0% (4/16) 9.1% (1/11) 12.5% (1/8)
ORR 68.8% (11/16) 90.9% (10/11) 87.5% (7/8)
Radiographic response: symptomatic patients
CR 25.0% (3/12) 27.3% (3/11) 36.4% (4/11)
PR 25.0% (3/12) 36.4% (4/11) 27.3% (3/11)
SD 50.% (6/12) 27.3% (3/11) 27.3% (3/11)
PD 0.0% (0/12) 9.1% (1/11) 9.1% (1/11)
ORR 50.0% (6/12) 63.6% (7/11) 63.6% (7/11)
Radiographic response: asymptomatic patients
CR 64.3% (9/14) 66.7% (10/15) 66.7% (10/15)
PR 7.1% (1/14) 6.7% (1/15) 6.7% (1/15)
SD 28.6% (4/14) 26.7% (4/15) 26.7% (4/15)
PD 0.0% (0/14) 0.0% (0/15) 0.0% (0/15)
ORR 71.4% (10/14) 73.3% (11/15) 73.3% (11/15)
Abbreviations: CNS = central nervous system; CR = complete response; PD = progressive disease; PR = partial response; ORR = overall response rate; SD = stable disease.
Excludes patients treated with postoperative palliative radiation.
Denominator reflects evaluable patients.
Patients in both CNS and non-CNS cohorts tended to have clinical responses early on, with sustained response at last follow-up. Furthermore, if a patient were to have a clinical CR, it most often occurred within the first month. Only 4 patients demonstrated a CR after the first month, and all of these patients had a PR initially; no patients with initially stable disease went on to have a CR. Most patients with radiographic SD at initial follow-up maintained SD over time. The initial responses of patients developing progressive symptoms after 3-month follow-up varied considerably: CR (2), PR (3), SD (2), and PD (3). No patients who progressed within the first month of follow-up went on to have any response.
Eight patients were treated with postoperative RT after surgical resection in the brain (6), mediastinal lymph node (1), and inguinal lymph node (1). Three patients with evaluable clinical symptoms before and after surgery-RT all demonstrated diminished (PR) or complete (CR) resolution of symptoms within 1 month after RT. Of the 6 patients with radiographic follow-up, one recurred 9 months after treatment; the rest maintained stable disease (ie, no recurrence) through last follow-up.
Acute and late grade 3 or higher (G3 +) toxicities with bevacizumab were low (8.7% and 4.3%, respectively). CNS and mediastinal locations were the only treatment sites in which G3 + toxicity occurred. CNS toxicity (acute G3 fatigue, late G3 radiation necrosis, and late G4 optic neuritis) was identified in a single patient who received craniospinal irradiation with prior Gamma Knife irradiation. A second patient treated to the mediastinum had acute but not chronic grade 3 esophagitis. Notably, no acute or late G3 + toxicity was seen in patients treated to the abdomen or pelvis (the most common treatment location; Table 5).Table 5 Observed toxicities in patients treated with bevacizumab before or concurrent with radiation therapy, by treatment course
None Grade 1-2 Grade 3 Grade 4
Acute
Non-CNS (17) 6 Anorexia (1),
depression (1),
dermatitis (1),
fatigue (5),
GI (6), GU (1),
odynophagia (1),
pneumonitis (1),
vaginal hemorrhage (1) Dermatitis (1),
esophagitis (1) -
CNS (6) 4 GI (1) Fatigue (1) -
Late
Non-CNS (9) 8 GI (1) - -
CNS (5) 3 Intracranial hemorrhage (1) Radionecrosis (1) Optic neuropathy (1)
Abbreviations: CNS = central nervous system; GI = gastrointestinal; GU = genitourinary.
Toxicities defined according to the Common Terminology Criteria for Adverse Events, version 5.0.
Numbers indicate number of treatment courses; more than one toxicity may be attributed to a single treatment course. Late toxicity data unavailable for 9 treatment courses (all due to patient death).
Late grade 3 and 4 toxicities occurred in the same patient.
An exploratory analysis examining patient demographics and treatment characteristics was performed to identify predictors of clinical or radiographic response. In all patients (CNS and non-CNS sites), HGS histology was associated with clinical responses (88% vs 64%, P = .04). In patients with CNS lesions, BED >39 Gy was associated with clinical response (P = .049). In non-CNS locations, bony site was associated with worse clinical (44% vs 89%, P = .004) response compared with soft tissue/nodal (STN) sites. Lastly, we compared BED regimens ≤39 Gy versus >39 Gy (assuming an alpha/beta ratio of 10,19,20 the BED of 30 Gy in 10 fractions is 39 Gy) in non-CNS locations and found no differences in clinical (P = .10) or radiographic response rates (P = .47). We otherwise compared the most common regimens of 20 Gy in 5 fractions and 30 Gy in 10 fractions and found no significant differences in clinical (P = .60) or radiographic responses (P = .29; Table E1).2
Discussion
We report the outcomes of a large modern cohort of women with PMR-OC who received palliative radiation therapy in an era of novel systemic agents. In a population with poor prognosis, palliative radiation therapy resulted in excellent clinical and radiographic response rates (Table 2) within 1 month of treatment, with many responses durable beyond 3 months. Brain metastases, a rare site of anatomic spread, were also well represented in this cohort (36%, 38 courses) and responded favorably to palliative intracranial radiation therapy (Table 3). Exploratory analyses demonstrated an association between HGS histology and improved clinical response in all patients, BED >39 Gy and improved clinical response in BMs, and STN sites with improved clinical response in non-CNS sites. Our analysis is unique in its (1) large sample size compared with prior reports with significant number of BMs, (2) high proportion of patients treated with modern RT techniques, (3) inclusion of patients treated with novel systemic agents (ie, PARP inhibitors, bevacizumab, and immunotherapy), and (4) dedicated toxicity analysis of RT with concurrent or prior bevacizumab, an area of increasing clinical significance in MPR-EOC with a dearth of robust data.
Our high clinical response rates (79% ORR within 1 month) are similar to other reports, including literature from prior decades demonstrating durable pain relief and bleeding control from locally directed palliative RT in 80% of OC patients.20, 21, 22 More recently, Bansal and colleagues also found pain control rates of 88.2% and vaginal bleeding control rates of 100% in 23 heavily pretreated women who received palliative pelvic RT.23 Investigators from Brigham and Women’s Hospital also recently published rates and predictors of response to palliative RT for recurrent OC from 2003 to 201424 and demonstrated high rates of response for pain and bleeding (87% and 93%, respectively).
Identified predictors of response, including HGS histology and STN sites of disease are also compatible with prior investigations. In the above Brigham and Women’s Hospital study, patients treated at nonbony sites had higher response rates than those with bony sites of disease (96% vs 75%, respectively). Furthermore, patients with clear cell histology had the lowest response rates (60%), compared with others like serous histology (82%).
The sizable nature of our cohort allowed for a temporal analysis of index lesion response rates. Patients in both CNS and non-CNS cohorts tended to have clinical responses early on, with some benefitting from sustained response at last follow-up. Lesions with clinical CR often occurred within the first month. Furthermore, no patients who progressed in the index lesion within the first month of follow-up went on to have any response, suggesting that initial response is of paramount importance. Patients who had progressive symptoms after 3 months had variable initial responses, suggesting progressive disease is still expected no matter what the initial response may be.
Regarding dose response, higher BED was associated with clinical response in brain metastases. This is a result of ablative SRS technology that radiobiologically induces high rates of cell kill compared with those of conventional palliative techniques or doses. Advanced stereotactic techniques permit the delivery of otherwise unsafe high dose-per-fraction regimens due to their sharp dose gradients that allow for normal tissue sparing. In non-CNS locations, however, regimens with BED >39 Gy (ie, greater than 30 Gy in 10 fractions) were no different than lower BED regimens, suggesting dose escalation may not increase the efficacy of palliative RT. Use of higher BED regimens in such (predominantly abdominopelvic) locations is typically limited by larger fields due to tumor size and organ motion. Dose-limiting toxicities from nearby organs at risk such as the stomach, bowel, kidneys, and bladder also constrain prescriptions.
Notably, 47% of all courses were delivered with advanced radiation therapy techniques (SRS, SBRT, IMRT/volumetric-modulated arc therapy, proton therapy). This is in keeping with the increasing number of patients referred for ablative or definitive therapy to oligometastatic or oligoprogressive disease or previously irradiated lesions requiring retreatment. In such scenarios, advanced techniques allow practitioners to deliver higher dose per fraction while sparing normal organs and tissue of radiation, or even reirradiation, toxicity. In fact, recently published reports have evaluated the roles of advanced RT in OC. For example, definitive involved-field RT using IMRT has demonstrated promising rates of local control (LC) and disease-free survival with low toxicity.25,26 Two recent retrospective studies also explored SBRT in oligometastatic OC. Lazzari et al reported the treatment of 82 patients with a median dose of 24 Gy in 3 fractions and demonstrated the safety of SBRT along with an increase in systemic therapy-free survival with reasonable LC27 (more than one-third of patients were disease-free at 1 year). Similarly, Macchia et al reported SBRT in MPR-EOC was well tolerated and afforded higher LC in patients receiving a total dose >25 Gy.28
Forty-three percent of patients received targeted therapy immediately before RT in this cohort. This is in keeping with the litany of recent publications studying the use of novel systemic agents (PARP inhibitors,29, 30, 31 bevacizumab,32 nivolumab33) in the setting of MPR-EOC. The response rates described thus reflect the potential outcomes of palliative RT in conjunction with advanced systemic therapies, a scenario that will be increasingly encountered by practitioners. Furthermore, given the sizeable population that received prior or concurrent bevacizumab, a dedicated subgroup analysis was conducted and demonstrated low acute and late grade 3 or higher (G3 +) toxicities (8.7% and 4.3%, respectively) with RT. Although G3 + toxicities occurred in patients treated to CNS and mediastinal locations, it is unclear if this was in relation to prior bevacizumab or reflected the increased risk toxicity with prior RT (Gamma Knife in the CNS patient treated with craniospinal irradiation) or unfavorable tumor location (in the mediastinal patient experiencing esophagitis after receiving 59.4 Gy). No acute or late G3 + toxicity was seen in patients treated to the abdomen or pelvis (the most common treatment location), suggesting that this may be a reasonable treatment option in symptomatic patients.
Limitations
The study is limited primarily by its retrospective nature which lends itself to both selection and sample bias. For example, patient performance status and prior lines of therapy (including prior radiation) may effect physician choice of RT technique, dose, and fractionation. Furthermore, lesions necessitating reirradiation demonstrate inherent radioresistance and may negatively affect response rates. Moreover, although the study population is sizeable, it is heterogenous with respect to treatment sites and prior lines of therapy. As such appropriate interpretation required subdivision of data (ie, CNS vs non-CNS, symptomatic vs asymptomatic indication), which led to more descriptive findings. Finally, the variety of systemic therapies used negatively affect our ability to make conclusions regarding the efficacy of RT with respect to individual agents.
Future directions
As the role for palliative radiation therapy expands in the context of the oligometastatic paradigm, nuanced decision-making must be taken to deliver the most efficacious treatment although promoting cost-effective care. As such, prospective evaluation is warranted to determine the optimal dose, timing, and fractionation of RT as it relates to systemic agents and surgery. The high response rates demonstrated in this cohort may warrant prospective investigation of RT as a standard component therapy in MPR-EOC, either before systemic agents as a cytoreductive strategy or after as consolidation therapy.
Conclusions
We performed a large retrospective cohort analysis of women with MPR-EOC receiving palliative RT in the era of modern technology and systemic agents. Our large population of patients with BMs adds relevant data to the limited body of existing literature and can be used as a practical reference when counseling women. Patients demonstrated favorable clinical and radiographic response rates within 1 month, with >60% experiencing durable clinical responses beyond 3 months. HGS histology was associated with improved clinical response in all patients. BED >39 Gy was associated with improved response in brain metastases. Bony sites were associated with worse response compared with STN sites in non-CNS locations. Acute and late grade 3 or higher toxicities were low with prior bevacizumab, and none of these occurred in patients treated to abdominopelvic locations.
Although MPR-EOC is associated with limited prognosis, our data demonstrate that responses to palliative RT can be durable and meaningful. As such, without a conclusive effect on survival, it would be reasonable to consider treatment of such disease after taking into consideration patient symptom severity, goals of care, prognosis, performance status, and extracranial disease burden for BM.
Supplementary Materials
Tables E1 and E2
Sources of support: The authors received no specific funding for this work.
Disclosures: The authors of this manuscript have no conflicts of interest to report.
Research data are stored in an institutional repository and will be shared upon request.
Supplementary material for this article can be found at https://doi.org/10.1016/j.adro.2020.11.009. | BEVACIZUMAB | DrugsGivenReaction | CC BY-NC-ND | 33665491 | 18,951,285 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Drug ineffective for unapproved indication'. | Periodic electroclinical seizures following an ischemic stroke revealed by continuous-EEG.
Periodic EEG patterns are mostly associated with critical illnesses and acute disruptions of the central nervous system. Periodic or cyclic seizures are extremely rare phenomena, most of which are nonconvulsive, only reported in critically ill patients. Here we report a patient with periodic focal impaired awareness seizures following a minor stroke and address possible pathophysiological mechanisms.
A 49 years old male patient presented with periodic seizures, associated with an acute stroke in the left occipital and parietal regions. These focal seizures, recorded during long-term video-EEG monitoring in the scalp EEG, appeared every 9-11 min, and responded to iv valproic acid treatment but not to iv treatments of diazepam, phenytoin, and levetiracetam.
We believe that the blood-brain barrier disruption due to stroke, in conjunction with hyperglycemia and antiphospholipid antibodies have led to an imbalance of the surrounding tissue and sustained hyperexcitability to a point of pacemaker potentials. It is tempting to speculate that repetitive cycles of cortical spreading depression due to tissue injury have aided the periodicity of the seizures.
Continuous EEG monitoring is crucial, not only to diagnose and appropriately treat accompanying subtle seizures but also to further understand the underlying intriguing pathophysiological processes like periodicity.
Periodicity in the EEG terminology is defined as “repetition of a discharge or pattern with relatively uniform morphology and duration with a quantifiable interdischarge interval between consecutive waveforms and recurrence of the waveform at nearly regular intervals” by Hirsch et al. [1] Periodic EEG patterns are almost never “benign” in nature, mostly observed in critically ill patients with acute disruptions of the integrity of the central nervous system. Periodic or cyclic focal seizures, on the other hand, are extremely uncommon encounters. They are first reported by Blume in 1997 as “periodic seizures” and later called “cyclic” by Friedman in 2008. They are only reported in critically ill patients and almost all of them are nonconvulsive, lacking clinical correlates [2], [3], [4].
Here we report a 49 years old male patient with sudden onset of strictly periodic, frequent focal impaired awareness seizures following a minor stroke and address the possible pathophysiological mechanisms.
1 Case report
Forty-nine years old male patient with a history of poorly controlled diabetes mellitus has presented to our emergency room with right-sided mild paresis, right homonymous hemianopia and confusion. Brain MR imaging revealed scattered small diffusion restriction area and low signal on the ADC map in the left occipital and parietal regions compatible with an acute ischemic stroke (Fig. 1). His cranial MRI also showed a former silent ischemic infarction in the right occipital region. Vascular and cardiac investigations did not reveal any pathological findings. There were no other biochemical abnormalities except elevated glucose levels of 237 mg/dl (concomitant bicarbonate levels were 25.1 mmol/L) on admission with an HbA1C level of 12.7%. He had a history of peripheral artery disease treated surgically two years ago and family history disclosed that one of his sons was diagnosed with systemic lupus erythematosus.Fig. 1 Axial diffusion-weighted MR imaging showing scattered small diffusion restriction areas in the left occipital and parietal regions (a), confirmed on ADC map (b) in accordance with an acute ischemic stroke.
Episodes of fluctuating confusion suggestive of seizures were noted and his emergency EEG showed 2 focal seizures starting from the left occipitoparietal region, spreading rapidly throughout the hemisphere with a limited extension to the posterior regions of the right hemisphere. These seizures lasted approximately 90–120 s before ending abruptly on both hemispheres. During these seizures, the patient became non-responsive, kept uttering his last sentence immediately before the seizure onset (ictal speech), and left upper manual automatisms starting after 60 s were observed. In the continuous video-EEG monitoring lasting 48 h, we observed that these uniform seizures repeated every 9–11 min (range 505–665 seconds, mean 607.4 ± 37.1) in a strictly periodic manner (Fig. 2). Early postictal EEG following the seizure was insignificant other than mild background slowing on the left hemisphere, lateralized periodic discharges emerged later on. Neuropsychological evaluation demonstrated fluctuating frontal dysfunction.Fig. 2 Low pass filter: 70 Hz, High pass filter: 0.5 Hz, Notch filter: 50 Hz. (a). Ictal EEG findings: seizure activity starting from the left occipitoparietal region, spreading rapidly throughout the hemisphere with a limited extension to the posterior regions of the right hemisphere. Seizures lasted approximately 90–120 s before ending abruptly on both hemispheres. (b). Periodicity of the seizures can be observed in the bar and table. (c). Interictal findings: Within seconds after the seizure, periodic lateralized discharges emerged in the left hemisphere. They became more prominent and showed generalization and multiplication immediately before the impending seizure. This interictal pattern also emerged periodically.
The periodicity and seizure frequency did not change despite iv diazepam (10 mg), iv phenytoin (18 mg/kg), and iv levetiracetam (20 mg/kg) treatments as monitored closely by continuous-EEG. Only after an iv valproic acid (20 mg/kg) treatment, the intervals between seizures became longer (90 min) and the duration of the seizures lengthened (30 min), and diminished altogether under 2000 mg valproic acid, 200 mg lacosamide and 400 mg carbamazepine treatments, after 3 days following admission. (Please see Supp Table 1 for the treatment trials) Lumbar puncture did not reveal any remarkable abnormalities. Viral panels, serologic studies and paraneoplastic antibody screening were all negative. However, he had ANA positivity (homogenous, 1/2560) and antiphospholipid antibodies (beta2 glycoprotein IgM: 36.9 U/ml, beta2 glycoprotein IgG: 19.4 U/ml and anticardiolipin IgG: 19.8 U/ml) but did not fulfill the criteria for systemic lupus erythematosus or primary antiphospholipid syndrome yet. The patient was discharged without any disability and he was seizure-free, his control EEG exam after one month was unremarkable other than scant generalized slow wave paroxysms.
2 Discussion
Our patient showed acute symptomatic, focal impaired awareness seizures emerging in a remarkable periodic manner. We believe calling these seizures “periodic” is more appropriate than cyclic, based on the definition of periodicity in the ACNS guideline [1]. These seizures are most likely to occur in older patients with acute or progressive brain injury and more likely to be associated with poor outcomes [4]. This report presents a rather pleasing contrast; our case is a younger gentleman with a comparatively minor stroke and his prognosis has been excellent.
There has been a long-standing controversy on whether periodic lateralized epileptiform discharges (PLED) represent an ictal finding or an interictal phenomenon [5]. We believe this patient might represent an example of the extreme end of a spectrum in interictal to ictal lateralized periodic discharges continuum. Seizures are common consequences of stroke and stroke-related seizures are divided into two groups according to seizure onset; seizures occurring in the first seven days are classified as early seizures [6]. In early seizures, disruption of the blood brain barrier and ischemic insult of the neurons may result in ion channel dysfunctions and disturbed homeostasis of the neurotransmitters, in addition to biochemical dysfunctions leading to irritability of the offended tissue [7].
The association of auto-antibodies with seizures is also a well-known but complicated issue; the present autoantibodies might have contributed to the seizure generation in our case. Moreover, PLEDs were reported in patients with SLE and seizures [8]. Although multiple recurrent seizures are well described in autoimmune epilepsies, (e.g. frequent facio-brachial dystonic seizures in LGI1 antibody encephalitis) they are not periodic in nature [9]. Furthermore, hyperglycemia, as observed in our patient is also a known contributor to the blood–brain barrier disruption and generation of periodic patterns like PLEDs and also involved in seizure generation [10]. Glucose is also an important mediator in the regulation of potassium metabolism, higher glucose and insulin levels increase the cellular uptake of potassium. Malfunctions in the ion channels due to neuronal damage and such mediators might give rise to leaky Na or Ca and K channels leading to spontaneous rhythmic depolarizations similar to a pacemaker potential.
The lobar origin of these periodic seizures also needs further attention. The damage to the cortex in stroke may lead to cortical spreading depression (CSD), which relates to a loss of ion homeostasis leading to a widespread depolarization of the neurons and astrocytes with altered metabolism and blood flow [11]. Accumulating evidence indicated that CSD is the pathophysiological hallmark of the migraine aura, starting in the occipital cortex, specifically. Infarct of the posterior cerebral artery caused by atherothrombosis may be the key factor in our case, as previous ICU series also report a tendency of posterior onset for cyclic seizures [3], [4]. It has been shown that focal seizures involving primarily the consciousness may originate from any lobe including parietooccipital regions, however rare it may be [12]. Thus the parieto-occipital origin of the periodic seizures may support the involvement of CSD by this minor stroke.
CSD and CSD-like events can be triggered by injury of the tissue due to trauma, hemorrhage, ischemia etc. [13]. CSD has been reported to co-occur or even cause seizure by means of synchronizing the affected tissue [14]. The opposite has also been demonstrated, epileptiform activity initiated waves of CSD. In a rat model, spike triggered spreading depression was seen to repeat in cycles lasting a mean of 6 min and up to 20 cycles [15]. Repetitive cycles of CSD have also been reported in a patient with increased intracranial pressure due to traumatic contusion [16]. The common point of these important but anecdotal observations is the use of intracranial electrodes. It is tempting to speculate that this periodic pattern might be a common phenomenon after tissue injury (in conjunction with biochemical abnormalities as a double hit) that is greatly missed via routine scalp EEG. We think that the same cyclic interplay between focal seizure activity and CSD might be the underlying explanation for the intriguing periodicity of our patient’s seizures. The lack of any effect of the standard iv antiepileptic drug treatments other than valproic acid, which is also effective against CSD in migraine patients, further strengthens this hypothesis [17]. There is a synergistic pharmacodynamic interaction between PHT and VPA in vivo. We think that this might have been helpful in the limitation of the cycling seizures [18].
A very recent study has also suggested that cyclic seizures may point out to a more favorable outcome in younger patients compared to noncyclic ones. [19] The peculiar build-up phenomenon has also been reported in the literature and may constitute a clue for the ongoing cyclic seizures, which may be missed in short routine EEG recordings. [3]
3 Conclusion
In conclusion; an important point raised from this case is the indispensability of continuous EEG monitoring for such patients since peculiar patterns like periodicity would be missed on routine EEGs. Although previous studies reported that cyclic seizures are a negative prognostic factor, this particular case had an excellent prognosis. Further clinical and experimental studies are needed to explore this seemingly vicious cycle of periodic seizures and develop neuroprotective treatment strategies.
Conflict of interest
On behalf of all authors, the corresponding author states that there is no conflict of interest.
Disclosure
ADE, EE, IC, NY, OC, BB: no relevant financial or nonfinancial relationships to disclose.
6 Compliance with ethical standards
There was no funding for this study.
All of the authors declare that they have no conflict of interest.
All procedures performed were in accordance with the ethical standards of the institutional and national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Informed consent was obtained from the person hereby reported.
CRediT authorship contribution statement
Ayse Deniz Elmali: Conceptualization, Data curation, Formal analysis, Investigation, Resources, Software, Visualization, Writing - original draft, Writing - review & editing. Esme Ekizoglu: Data curation, Supervision, Validation, Writing - review & editing. Irem Ciftci: Data curation, Writing - original draft. Nilufer Yesilot: Data curation, Supervision, Validation, Writing - review & editing. Oguzhan Coban: Conceptualization, Supervision, Validation, Writing - review & editing. Betul Baykan: Conceptualization, Data curation, Formal analysis, Investigation, Resources, Software, Supervision, Validation, Visualization, Writing - original draft, Writing - review & editing. | DIAZEPAM, LEVETIRACETAM, PHENYTOIN SODIUM | DrugsGivenReaction | CC BY-NC-ND | 33665600 | 20,563,834 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Off label use'. | Periodic electroclinical seizures following an ischemic stroke revealed by continuous-EEG.
Periodic EEG patterns are mostly associated with critical illnesses and acute disruptions of the central nervous system. Periodic or cyclic seizures are extremely rare phenomena, most of which are nonconvulsive, only reported in critically ill patients. Here we report a patient with periodic focal impaired awareness seizures following a minor stroke and address possible pathophysiological mechanisms.
A 49 years old male patient presented with periodic seizures, associated with an acute stroke in the left occipital and parietal regions. These focal seizures, recorded during long-term video-EEG monitoring in the scalp EEG, appeared every 9-11 min, and responded to iv valproic acid treatment but not to iv treatments of diazepam, phenytoin, and levetiracetam.
We believe that the blood-brain barrier disruption due to stroke, in conjunction with hyperglycemia and antiphospholipid antibodies have led to an imbalance of the surrounding tissue and sustained hyperexcitability to a point of pacemaker potentials. It is tempting to speculate that repetitive cycles of cortical spreading depression due to tissue injury have aided the periodicity of the seizures.
Continuous EEG monitoring is crucial, not only to diagnose and appropriately treat accompanying subtle seizures but also to further understand the underlying intriguing pathophysiological processes like periodicity.
Periodicity in the EEG terminology is defined as “repetition of a discharge or pattern with relatively uniform morphology and duration with a quantifiable interdischarge interval between consecutive waveforms and recurrence of the waveform at nearly regular intervals” by Hirsch et al. [1] Periodic EEG patterns are almost never “benign” in nature, mostly observed in critically ill patients with acute disruptions of the integrity of the central nervous system. Periodic or cyclic focal seizures, on the other hand, are extremely uncommon encounters. They are first reported by Blume in 1997 as “periodic seizures” and later called “cyclic” by Friedman in 2008. They are only reported in critically ill patients and almost all of them are nonconvulsive, lacking clinical correlates [2], [3], [4].
Here we report a 49 years old male patient with sudden onset of strictly periodic, frequent focal impaired awareness seizures following a minor stroke and address the possible pathophysiological mechanisms.
1 Case report
Forty-nine years old male patient with a history of poorly controlled diabetes mellitus has presented to our emergency room with right-sided mild paresis, right homonymous hemianopia and confusion. Brain MR imaging revealed scattered small diffusion restriction area and low signal on the ADC map in the left occipital and parietal regions compatible with an acute ischemic stroke (Fig. 1). His cranial MRI also showed a former silent ischemic infarction in the right occipital region. Vascular and cardiac investigations did not reveal any pathological findings. There were no other biochemical abnormalities except elevated glucose levels of 237 mg/dl (concomitant bicarbonate levels were 25.1 mmol/L) on admission with an HbA1C level of 12.7%. He had a history of peripheral artery disease treated surgically two years ago and family history disclosed that one of his sons was diagnosed with systemic lupus erythematosus.Fig. 1 Axial diffusion-weighted MR imaging showing scattered small diffusion restriction areas in the left occipital and parietal regions (a), confirmed on ADC map (b) in accordance with an acute ischemic stroke.
Episodes of fluctuating confusion suggestive of seizures were noted and his emergency EEG showed 2 focal seizures starting from the left occipitoparietal region, spreading rapidly throughout the hemisphere with a limited extension to the posterior regions of the right hemisphere. These seizures lasted approximately 90–120 s before ending abruptly on both hemispheres. During these seizures, the patient became non-responsive, kept uttering his last sentence immediately before the seizure onset (ictal speech), and left upper manual automatisms starting after 60 s were observed. In the continuous video-EEG monitoring lasting 48 h, we observed that these uniform seizures repeated every 9–11 min (range 505–665 seconds, mean 607.4 ± 37.1) in a strictly periodic manner (Fig. 2). Early postictal EEG following the seizure was insignificant other than mild background slowing on the left hemisphere, lateralized periodic discharges emerged later on. Neuropsychological evaluation demonstrated fluctuating frontal dysfunction.Fig. 2 Low pass filter: 70 Hz, High pass filter: 0.5 Hz, Notch filter: 50 Hz. (a). Ictal EEG findings: seizure activity starting from the left occipitoparietal region, spreading rapidly throughout the hemisphere with a limited extension to the posterior regions of the right hemisphere. Seizures lasted approximately 90–120 s before ending abruptly on both hemispheres. (b). Periodicity of the seizures can be observed in the bar and table. (c). Interictal findings: Within seconds after the seizure, periodic lateralized discharges emerged in the left hemisphere. They became more prominent and showed generalization and multiplication immediately before the impending seizure. This interictal pattern also emerged periodically.
The periodicity and seizure frequency did not change despite iv diazepam (10 mg), iv phenytoin (18 mg/kg), and iv levetiracetam (20 mg/kg) treatments as monitored closely by continuous-EEG. Only after an iv valproic acid (20 mg/kg) treatment, the intervals between seizures became longer (90 min) and the duration of the seizures lengthened (30 min), and diminished altogether under 2000 mg valproic acid, 200 mg lacosamide and 400 mg carbamazepine treatments, after 3 days following admission. (Please see Supp Table 1 for the treatment trials) Lumbar puncture did not reveal any remarkable abnormalities. Viral panels, serologic studies and paraneoplastic antibody screening were all negative. However, he had ANA positivity (homogenous, 1/2560) and antiphospholipid antibodies (beta2 glycoprotein IgM: 36.9 U/ml, beta2 glycoprotein IgG: 19.4 U/ml and anticardiolipin IgG: 19.8 U/ml) but did not fulfill the criteria for systemic lupus erythematosus or primary antiphospholipid syndrome yet. The patient was discharged without any disability and he was seizure-free, his control EEG exam after one month was unremarkable other than scant generalized slow wave paroxysms.
2 Discussion
Our patient showed acute symptomatic, focal impaired awareness seizures emerging in a remarkable periodic manner. We believe calling these seizures “periodic” is more appropriate than cyclic, based on the definition of periodicity in the ACNS guideline [1]. These seizures are most likely to occur in older patients with acute or progressive brain injury and more likely to be associated with poor outcomes [4]. This report presents a rather pleasing contrast; our case is a younger gentleman with a comparatively minor stroke and his prognosis has been excellent.
There has been a long-standing controversy on whether periodic lateralized epileptiform discharges (PLED) represent an ictal finding or an interictal phenomenon [5]. We believe this patient might represent an example of the extreme end of a spectrum in interictal to ictal lateralized periodic discharges continuum. Seizures are common consequences of stroke and stroke-related seizures are divided into two groups according to seizure onset; seizures occurring in the first seven days are classified as early seizures [6]. In early seizures, disruption of the blood brain barrier and ischemic insult of the neurons may result in ion channel dysfunctions and disturbed homeostasis of the neurotransmitters, in addition to biochemical dysfunctions leading to irritability of the offended tissue [7].
The association of auto-antibodies with seizures is also a well-known but complicated issue; the present autoantibodies might have contributed to the seizure generation in our case. Moreover, PLEDs were reported in patients with SLE and seizures [8]. Although multiple recurrent seizures are well described in autoimmune epilepsies, (e.g. frequent facio-brachial dystonic seizures in LGI1 antibody encephalitis) they are not periodic in nature [9]. Furthermore, hyperglycemia, as observed in our patient is also a known contributor to the blood–brain barrier disruption and generation of periodic patterns like PLEDs and also involved in seizure generation [10]. Glucose is also an important mediator in the regulation of potassium metabolism, higher glucose and insulin levels increase the cellular uptake of potassium. Malfunctions in the ion channels due to neuronal damage and such mediators might give rise to leaky Na or Ca and K channels leading to spontaneous rhythmic depolarizations similar to a pacemaker potential.
The lobar origin of these periodic seizures also needs further attention. The damage to the cortex in stroke may lead to cortical spreading depression (CSD), which relates to a loss of ion homeostasis leading to a widespread depolarization of the neurons and astrocytes with altered metabolism and blood flow [11]. Accumulating evidence indicated that CSD is the pathophysiological hallmark of the migraine aura, starting in the occipital cortex, specifically. Infarct of the posterior cerebral artery caused by atherothrombosis may be the key factor in our case, as previous ICU series also report a tendency of posterior onset for cyclic seizures [3], [4]. It has been shown that focal seizures involving primarily the consciousness may originate from any lobe including parietooccipital regions, however rare it may be [12]. Thus the parieto-occipital origin of the periodic seizures may support the involvement of CSD by this minor stroke.
CSD and CSD-like events can be triggered by injury of the tissue due to trauma, hemorrhage, ischemia etc. [13]. CSD has been reported to co-occur or even cause seizure by means of synchronizing the affected tissue [14]. The opposite has also been demonstrated, epileptiform activity initiated waves of CSD. In a rat model, spike triggered spreading depression was seen to repeat in cycles lasting a mean of 6 min and up to 20 cycles [15]. Repetitive cycles of CSD have also been reported in a patient with increased intracranial pressure due to traumatic contusion [16]. The common point of these important but anecdotal observations is the use of intracranial electrodes. It is tempting to speculate that this periodic pattern might be a common phenomenon after tissue injury (in conjunction with biochemical abnormalities as a double hit) that is greatly missed via routine scalp EEG. We think that the same cyclic interplay between focal seizure activity and CSD might be the underlying explanation for the intriguing periodicity of our patient’s seizures. The lack of any effect of the standard iv antiepileptic drug treatments other than valproic acid, which is also effective against CSD in migraine patients, further strengthens this hypothesis [17]. There is a synergistic pharmacodynamic interaction between PHT and VPA in vivo. We think that this might have been helpful in the limitation of the cycling seizures [18].
A very recent study has also suggested that cyclic seizures may point out to a more favorable outcome in younger patients compared to noncyclic ones. [19] The peculiar build-up phenomenon has also been reported in the literature and may constitute a clue for the ongoing cyclic seizures, which may be missed in short routine EEG recordings. [3]
3 Conclusion
In conclusion; an important point raised from this case is the indispensability of continuous EEG monitoring for such patients since peculiar patterns like periodicity would be missed on routine EEGs. Although previous studies reported that cyclic seizures are a negative prognostic factor, this particular case had an excellent prognosis. Further clinical and experimental studies are needed to explore this seemingly vicious cycle of periodic seizures and develop neuroprotective treatment strategies.
Conflict of interest
On behalf of all authors, the corresponding author states that there is no conflict of interest.
Disclosure
ADE, EE, IC, NY, OC, BB: no relevant financial or nonfinancial relationships to disclose.
6 Compliance with ethical standards
There was no funding for this study.
All of the authors declare that they have no conflict of interest.
All procedures performed were in accordance with the ethical standards of the institutional and national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Informed consent was obtained from the person hereby reported.
CRediT authorship contribution statement
Ayse Deniz Elmali: Conceptualization, Data curation, Formal analysis, Investigation, Resources, Software, Visualization, Writing - original draft, Writing - review & editing. Esme Ekizoglu: Data curation, Supervision, Validation, Writing - review & editing. Irem Ciftci: Data curation, Writing - original draft. Nilufer Yesilot: Data curation, Supervision, Validation, Writing - review & editing. Oguzhan Coban: Conceptualization, Supervision, Validation, Writing - review & editing. Betul Baykan: Conceptualization, Data curation, Formal analysis, Investigation, Resources, Software, Supervision, Validation, Visualization, Writing - original draft, Writing - review & editing. | DIAZEPAM, LEVETIRACETAM, PHENYTOIN SODIUM | DrugsGivenReaction | CC BY-NC-ND | 33665600 | 20,563,834 | 2021 |
What was the administration route of drug 'DIAZEPAM'? | Periodic electroclinical seizures following an ischemic stroke revealed by continuous-EEG.
Periodic EEG patterns are mostly associated with critical illnesses and acute disruptions of the central nervous system. Periodic or cyclic seizures are extremely rare phenomena, most of which are nonconvulsive, only reported in critically ill patients. Here we report a patient with periodic focal impaired awareness seizures following a minor stroke and address possible pathophysiological mechanisms.
A 49 years old male patient presented with periodic seizures, associated with an acute stroke in the left occipital and parietal regions. These focal seizures, recorded during long-term video-EEG monitoring in the scalp EEG, appeared every 9-11 min, and responded to iv valproic acid treatment but not to iv treatments of diazepam, phenytoin, and levetiracetam.
We believe that the blood-brain barrier disruption due to stroke, in conjunction with hyperglycemia and antiphospholipid antibodies have led to an imbalance of the surrounding tissue and sustained hyperexcitability to a point of pacemaker potentials. It is tempting to speculate that repetitive cycles of cortical spreading depression due to tissue injury have aided the periodicity of the seizures.
Continuous EEG monitoring is crucial, not only to diagnose and appropriately treat accompanying subtle seizures but also to further understand the underlying intriguing pathophysiological processes like periodicity.
Periodicity in the EEG terminology is defined as “repetition of a discharge or pattern with relatively uniform morphology and duration with a quantifiable interdischarge interval between consecutive waveforms and recurrence of the waveform at nearly regular intervals” by Hirsch et al. [1] Periodic EEG patterns are almost never “benign” in nature, mostly observed in critically ill patients with acute disruptions of the integrity of the central nervous system. Periodic or cyclic focal seizures, on the other hand, are extremely uncommon encounters. They are first reported by Blume in 1997 as “periodic seizures” and later called “cyclic” by Friedman in 2008. They are only reported in critically ill patients and almost all of them are nonconvulsive, lacking clinical correlates [2], [3], [4].
Here we report a 49 years old male patient with sudden onset of strictly periodic, frequent focal impaired awareness seizures following a minor stroke and address the possible pathophysiological mechanisms.
1 Case report
Forty-nine years old male patient with a history of poorly controlled diabetes mellitus has presented to our emergency room with right-sided mild paresis, right homonymous hemianopia and confusion. Brain MR imaging revealed scattered small diffusion restriction area and low signal on the ADC map in the left occipital and parietal regions compatible with an acute ischemic stroke (Fig. 1). His cranial MRI also showed a former silent ischemic infarction in the right occipital region. Vascular and cardiac investigations did not reveal any pathological findings. There were no other biochemical abnormalities except elevated glucose levels of 237 mg/dl (concomitant bicarbonate levels were 25.1 mmol/L) on admission with an HbA1C level of 12.7%. He had a history of peripheral artery disease treated surgically two years ago and family history disclosed that one of his sons was diagnosed with systemic lupus erythematosus.Fig. 1 Axial diffusion-weighted MR imaging showing scattered small diffusion restriction areas in the left occipital and parietal regions (a), confirmed on ADC map (b) in accordance with an acute ischemic stroke.
Episodes of fluctuating confusion suggestive of seizures were noted and his emergency EEG showed 2 focal seizures starting from the left occipitoparietal region, spreading rapidly throughout the hemisphere with a limited extension to the posterior regions of the right hemisphere. These seizures lasted approximately 90–120 s before ending abruptly on both hemispheres. During these seizures, the patient became non-responsive, kept uttering his last sentence immediately before the seizure onset (ictal speech), and left upper manual automatisms starting after 60 s were observed. In the continuous video-EEG monitoring lasting 48 h, we observed that these uniform seizures repeated every 9–11 min (range 505–665 seconds, mean 607.4 ± 37.1) in a strictly periodic manner (Fig. 2). Early postictal EEG following the seizure was insignificant other than mild background slowing on the left hemisphere, lateralized periodic discharges emerged later on. Neuropsychological evaluation demonstrated fluctuating frontal dysfunction.Fig. 2 Low pass filter: 70 Hz, High pass filter: 0.5 Hz, Notch filter: 50 Hz. (a). Ictal EEG findings: seizure activity starting from the left occipitoparietal region, spreading rapidly throughout the hemisphere with a limited extension to the posterior regions of the right hemisphere. Seizures lasted approximately 90–120 s before ending abruptly on both hemispheres. (b). Periodicity of the seizures can be observed in the bar and table. (c). Interictal findings: Within seconds after the seizure, periodic lateralized discharges emerged in the left hemisphere. They became more prominent and showed generalization and multiplication immediately before the impending seizure. This interictal pattern also emerged periodically.
The periodicity and seizure frequency did not change despite iv diazepam (10 mg), iv phenytoin (18 mg/kg), and iv levetiracetam (20 mg/kg) treatments as monitored closely by continuous-EEG. Only after an iv valproic acid (20 mg/kg) treatment, the intervals between seizures became longer (90 min) and the duration of the seizures lengthened (30 min), and diminished altogether under 2000 mg valproic acid, 200 mg lacosamide and 400 mg carbamazepine treatments, after 3 days following admission. (Please see Supp Table 1 for the treatment trials) Lumbar puncture did not reveal any remarkable abnormalities. Viral panels, serologic studies and paraneoplastic antibody screening were all negative. However, he had ANA positivity (homogenous, 1/2560) and antiphospholipid antibodies (beta2 glycoprotein IgM: 36.9 U/ml, beta2 glycoprotein IgG: 19.4 U/ml and anticardiolipin IgG: 19.8 U/ml) but did not fulfill the criteria for systemic lupus erythematosus or primary antiphospholipid syndrome yet. The patient was discharged without any disability and he was seizure-free, his control EEG exam after one month was unremarkable other than scant generalized slow wave paroxysms.
2 Discussion
Our patient showed acute symptomatic, focal impaired awareness seizures emerging in a remarkable periodic manner. We believe calling these seizures “periodic” is more appropriate than cyclic, based on the definition of periodicity in the ACNS guideline [1]. These seizures are most likely to occur in older patients with acute or progressive brain injury and more likely to be associated with poor outcomes [4]. This report presents a rather pleasing contrast; our case is a younger gentleman with a comparatively minor stroke and his prognosis has been excellent.
There has been a long-standing controversy on whether periodic lateralized epileptiform discharges (PLED) represent an ictal finding or an interictal phenomenon [5]. We believe this patient might represent an example of the extreme end of a spectrum in interictal to ictal lateralized periodic discharges continuum. Seizures are common consequences of stroke and stroke-related seizures are divided into two groups according to seizure onset; seizures occurring in the first seven days are classified as early seizures [6]. In early seizures, disruption of the blood brain barrier and ischemic insult of the neurons may result in ion channel dysfunctions and disturbed homeostasis of the neurotransmitters, in addition to biochemical dysfunctions leading to irritability of the offended tissue [7].
The association of auto-antibodies with seizures is also a well-known but complicated issue; the present autoantibodies might have contributed to the seizure generation in our case. Moreover, PLEDs were reported in patients with SLE and seizures [8]. Although multiple recurrent seizures are well described in autoimmune epilepsies, (e.g. frequent facio-brachial dystonic seizures in LGI1 antibody encephalitis) they are not periodic in nature [9]. Furthermore, hyperglycemia, as observed in our patient is also a known contributor to the blood–brain barrier disruption and generation of periodic patterns like PLEDs and also involved in seizure generation [10]. Glucose is also an important mediator in the regulation of potassium metabolism, higher glucose and insulin levels increase the cellular uptake of potassium. Malfunctions in the ion channels due to neuronal damage and such mediators might give rise to leaky Na or Ca and K channels leading to spontaneous rhythmic depolarizations similar to a pacemaker potential.
The lobar origin of these periodic seizures also needs further attention. The damage to the cortex in stroke may lead to cortical spreading depression (CSD), which relates to a loss of ion homeostasis leading to a widespread depolarization of the neurons and astrocytes with altered metabolism and blood flow [11]. Accumulating evidence indicated that CSD is the pathophysiological hallmark of the migraine aura, starting in the occipital cortex, specifically. Infarct of the posterior cerebral artery caused by atherothrombosis may be the key factor in our case, as previous ICU series also report a tendency of posterior onset for cyclic seizures [3], [4]. It has been shown that focal seizures involving primarily the consciousness may originate from any lobe including parietooccipital regions, however rare it may be [12]. Thus the parieto-occipital origin of the periodic seizures may support the involvement of CSD by this minor stroke.
CSD and CSD-like events can be triggered by injury of the tissue due to trauma, hemorrhage, ischemia etc. [13]. CSD has been reported to co-occur or even cause seizure by means of synchronizing the affected tissue [14]. The opposite has also been demonstrated, epileptiform activity initiated waves of CSD. In a rat model, spike triggered spreading depression was seen to repeat in cycles lasting a mean of 6 min and up to 20 cycles [15]. Repetitive cycles of CSD have also been reported in a patient with increased intracranial pressure due to traumatic contusion [16]. The common point of these important but anecdotal observations is the use of intracranial electrodes. It is tempting to speculate that this periodic pattern might be a common phenomenon after tissue injury (in conjunction with biochemical abnormalities as a double hit) that is greatly missed via routine scalp EEG. We think that the same cyclic interplay between focal seizure activity and CSD might be the underlying explanation for the intriguing periodicity of our patient’s seizures. The lack of any effect of the standard iv antiepileptic drug treatments other than valproic acid, which is also effective against CSD in migraine patients, further strengthens this hypothesis [17]. There is a synergistic pharmacodynamic interaction between PHT and VPA in vivo. We think that this might have been helpful in the limitation of the cycling seizures [18].
A very recent study has also suggested that cyclic seizures may point out to a more favorable outcome in younger patients compared to noncyclic ones. [19] The peculiar build-up phenomenon has also been reported in the literature and may constitute a clue for the ongoing cyclic seizures, which may be missed in short routine EEG recordings. [3]
3 Conclusion
In conclusion; an important point raised from this case is the indispensability of continuous EEG monitoring for such patients since peculiar patterns like periodicity would be missed on routine EEGs. Although previous studies reported that cyclic seizures are a negative prognostic factor, this particular case had an excellent prognosis. Further clinical and experimental studies are needed to explore this seemingly vicious cycle of periodic seizures and develop neuroprotective treatment strategies.
Conflict of interest
On behalf of all authors, the corresponding author states that there is no conflict of interest.
Disclosure
ADE, EE, IC, NY, OC, BB: no relevant financial or nonfinancial relationships to disclose.
6 Compliance with ethical standards
There was no funding for this study.
All of the authors declare that they have no conflict of interest.
All procedures performed were in accordance with the ethical standards of the institutional and national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Informed consent was obtained from the person hereby reported.
CRediT authorship contribution statement
Ayse Deniz Elmali: Conceptualization, Data curation, Formal analysis, Investigation, Resources, Software, Visualization, Writing - original draft, Writing - review & editing. Esme Ekizoglu: Data curation, Supervision, Validation, Writing - review & editing. Irem Ciftci: Data curation, Writing - original draft. Nilufer Yesilot: Data curation, Supervision, Validation, Writing - review & editing. Oguzhan Coban: Conceptualization, Supervision, Validation, Writing - review & editing. Betul Baykan: Conceptualization, Data curation, Formal analysis, Investigation, Resources, Software, Supervision, Validation, Visualization, Writing - original draft, Writing - review & editing. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY-NC-ND | 33665600 | 20,563,834 | 2021 |
What was the administration route of drug 'LEVETIRACETAM'? | Periodic electroclinical seizures following an ischemic stroke revealed by continuous-EEG.
Periodic EEG patterns are mostly associated with critical illnesses and acute disruptions of the central nervous system. Periodic or cyclic seizures are extremely rare phenomena, most of which are nonconvulsive, only reported in critically ill patients. Here we report a patient with periodic focal impaired awareness seizures following a minor stroke and address possible pathophysiological mechanisms.
A 49 years old male patient presented with periodic seizures, associated with an acute stroke in the left occipital and parietal regions. These focal seizures, recorded during long-term video-EEG monitoring in the scalp EEG, appeared every 9-11 min, and responded to iv valproic acid treatment but not to iv treatments of diazepam, phenytoin, and levetiracetam.
We believe that the blood-brain barrier disruption due to stroke, in conjunction with hyperglycemia and antiphospholipid antibodies have led to an imbalance of the surrounding tissue and sustained hyperexcitability to a point of pacemaker potentials. It is tempting to speculate that repetitive cycles of cortical spreading depression due to tissue injury have aided the periodicity of the seizures.
Continuous EEG monitoring is crucial, not only to diagnose and appropriately treat accompanying subtle seizures but also to further understand the underlying intriguing pathophysiological processes like periodicity.
Periodicity in the EEG terminology is defined as “repetition of a discharge or pattern with relatively uniform morphology and duration with a quantifiable interdischarge interval between consecutive waveforms and recurrence of the waveform at nearly regular intervals” by Hirsch et al. [1] Periodic EEG patterns are almost never “benign” in nature, mostly observed in critically ill patients with acute disruptions of the integrity of the central nervous system. Periodic or cyclic focal seizures, on the other hand, are extremely uncommon encounters. They are first reported by Blume in 1997 as “periodic seizures” and later called “cyclic” by Friedman in 2008. They are only reported in critically ill patients and almost all of them are nonconvulsive, lacking clinical correlates [2], [3], [4].
Here we report a 49 years old male patient with sudden onset of strictly periodic, frequent focal impaired awareness seizures following a minor stroke and address the possible pathophysiological mechanisms.
1 Case report
Forty-nine years old male patient with a history of poorly controlled diabetes mellitus has presented to our emergency room with right-sided mild paresis, right homonymous hemianopia and confusion. Brain MR imaging revealed scattered small diffusion restriction area and low signal on the ADC map in the left occipital and parietal regions compatible with an acute ischemic stroke (Fig. 1). His cranial MRI also showed a former silent ischemic infarction in the right occipital region. Vascular and cardiac investigations did not reveal any pathological findings. There were no other biochemical abnormalities except elevated glucose levels of 237 mg/dl (concomitant bicarbonate levels were 25.1 mmol/L) on admission with an HbA1C level of 12.7%. He had a history of peripheral artery disease treated surgically two years ago and family history disclosed that one of his sons was diagnosed with systemic lupus erythematosus.Fig. 1 Axial diffusion-weighted MR imaging showing scattered small diffusion restriction areas in the left occipital and parietal regions (a), confirmed on ADC map (b) in accordance with an acute ischemic stroke.
Episodes of fluctuating confusion suggestive of seizures were noted and his emergency EEG showed 2 focal seizures starting from the left occipitoparietal region, spreading rapidly throughout the hemisphere with a limited extension to the posterior regions of the right hemisphere. These seizures lasted approximately 90–120 s before ending abruptly on both hemispheres. During these seizures, the patient became non-responsive, kept uttering his last sentence immediately before the seizure onset (ictal speech), and left upper manual automatisms starting after 60 s were observed. In the continuous video-EEG monitoring lasting 48 h, we observed that these uniform seizures repeated every 9–11 min (range 505–665 seconds, mean 607.4 ± 37.1) in a strictly periodic manner (Fig. 2). Early postictal EEG following the seizure was insignificant other than mild background slowing on the left hemisphere, lateralized periodic discharges emerged later on. Neuropsychological evaluation demonstrated fluctuating frontal dysfunction.Fig. 2 Low pass filter: 70 Hz, High pass filter: 0.5 Hz, Notch filter: 50 Hz. (a). Ictal EEG findings: seizure activity starting from the left occipitoparietal region, spreading rapidly throughout the hemisphere with a limited extension to the posterior regions of the right hemisphere. Seizures lasted approximately 90–120 s before ending abruptly on both hemispheres. (b). Periodicity of the seizures can be observed in the bar and table. (c). Interictal findings: Within seconds after the seizure, periodic lateralized discharges emerged in the left hemisphere. They became more prominent and showed generalization and multiplication immediately before the impending seizure. This interictal pattern also emerged periodically.
The periodicity and seizure frequency did not change despite iv diazepam (10 mg), iv phenytoin (18 mg/kg), and iv levetiracetam (20 mg/kg) treatments as monitored closely by continuous-EEG. Only after an iv valproic acid (20 mg/kg) treatment, the intervals between seizures became longer (90 min) and the duration of the seizures lengthened (30 min), and diminished altogether under 2000 mg valproic acid, 200 mg lacosamide and 400 mg carbamazepine treatments, after 3 days following admission. (Please see Supp Table 1 for the treatment trials) Lumbar puncture did not reveal any remarkable abnormalities. Viral panels, serologic studies and paraneoplastic antibody screening were all negative. However, he had ANA positivity (homogenous, 1/2560) and antiphospholipid antibodies (beta2 glycoprotein IgM: 36.9 U/ml, beta2 glycoprotein IgG: 19.4 U/ml and anticardiolipin IgG: 19.8 U/ml) but did not fulfill the criteria for systemic lupus erythematosus or primary antiphospholipid syndrome yet. The patient was discharged without any disability and he was seizure-free, his control EEG exam after one month was unremarkable other than scant generalized slow wave paroxysms.
2 Discussion
Our patient showed acute symptomatic, focal impaired awareness seizures emerging in a remarkable periodic manner. We believe calling these seizures “periodic” is more appropriate than cyclic, based on the definition of periodicity in the ACNS guideline [1]. These seizures are most likely to occur in older patients with acute or progressive brain injury and more likely to be associated with poor outcomes [4]. This report presents a rather pleasing contrast; our case is a younger gentleman with a comparatively minor stroke and his prognosis has been excellent.
There has been a long-standing controversy on whether periodic lateralized epileptiform discharges (PLED) represent an ictal finding or an interictal phenomenon [5]. We believe this patient might represent an example of the extreme end of a spectrum in interictal to ictal lateralized periodic discharges continuum. Seizures are common consequences of stroke and stroke-related seizures are divided into two groups according to seizure onset; seizures occurring in the first seven days are classified as early seizures [6]. In early seizures, disruption of the blood brain barrier and ischemic insult of the neurons may result in ion channel dysfunctions and disturbed homeostasis of the neurotransmitters, in addition to biochemical dysfunctions leading to irritability of the offended tissue [7].
The association of auto-antibodies with seizures is also a well-known but complicated issue; the present autoantibodies might have contributed to the seizure generation in our case. Moreover, PLEDs were reported in patients with SLE and seizures [8]. Although multiple recurrent seizures are well described in autoimmune epilepsies, (e.g. frequent facio-brachial dystonic seizures in LGI1 antibody encephalitis) they are not periodic in nature [9]. Furthermore, hyperglycemia, as observed in our patient is also a known contributor to the blood–brain barrier disruption and generation of periodic patterns like PLEDs and also involved in seizure generation [10]. Glucose is also an important mediator in the regulation of potassium metabolism, higher glucose and insulin levels increase the cellular uptake of potassium. Malfunctions in the ion channels due to neuronal damage and such mediators might give rise to leaky Na or Ca and K channels leading to spontaneous rhythmic depolarizations similar to a pacemaker potential.
The lobar origin of these periodic seizures also needs further attention. The damage to the cortex in stroke may lead to cortical spreading depression (CSD), which relates to a loss of ion homeostasis leading to a widespread depolarization of the neurons and astrocytes with altered metabolism and blood flow [11]. Accumulating evidence indicated that CSD is the pathophysiological hallmark of the migraine aura, starting in the occipital cortex, specifically. Infarct of the posterior cerebral artery caused by atherothrombosis may be the key factor in our case, as previous ICU series also report a tendency of posterior onset for cyclic seizures [3], [4]. It has been shown that focal seizures involving primarily the consciousness may originate from any lobe including parietooccipital regions, however rare it may be [12]. Thus the parieto-occipital origin of the periodic seizures may support the involvement of CSD by this minor stroke.
CSD and CSD-like events can be triggered by injury of the tissue due to trauma, hemorrhage, ischemia etc. [13]. CSD has been reported to co-occur or even cause seizure by means of synchronizing the affected tissue [14]. The opposite has also been demonstrated, epileptiform activity initiated waves of CSD. In a rat model, spike triggered spreading depression was seen to repeat in cycles lasting a mean of 6 min and up to 20 cycles [15]. Repetitive cycles of CSD have also been reported in a patient with increased intracranial pressure due to traumatic contusion [16]. The common point of these important but anecdotal observations is the use of intracranial electrodes. It is tempting to speculate that this periodic pattern might be a common phenomenon after tissue injury (in conjunction with biochemical abnormalities as a double hit) that is greatly missed via routine scalp EEG. We think that the same cyclic interplay between focal seizure activity and CSD might be the underlying explanation for the intriguing periodicity of our patient’s seizures. The lack of any effect of the standard iv antiepileptic drug treatments other than valproic acid, which is also effective against CSD in migraine patients, further strengthens this hypothesis [17]. There is a synergistic pharmacodynamic interaction between PHT and VPA in vivo. We think that this might have been helpful in the limitation of the cycling seizures [18].
A very recent study has also suggested that cyclic seizures may point out to a more favorable outcome in younger patients compared to noncyclic ones. [19] The peculiar build-up phenomenon has also been reported in the literature and may constitute a clue for the ongoing cyclic seizures, which may be missed in short routine EEG recordings. [3]
3 Conclusion
In conclusion; an important point raised from this case is the indispensability of continuous EEG monitoring for such patients since peculiar patterns like periodicity would be missed on routine EEGs. Although previous studies reported that cyclic seizures are a negative prognostic factor, this particular case had an excellent prognosis. Further clinical and experimental studies are needed to explore this seemingly vicious cycle of periodic seizures and develop neuroprotective treatment strategies.
Conflict of interest
On behalf of all authors, the corresponding author states that there is no conflict of interest.
Disclosure
ADE, EE, IC, NY, OC, BB: no relevant financial or nonfinancial relationships to disclose.
6 Compliance with ethical standards
There was no funding for this study.
All of the authors declare that they have no conflict of interest.
All procedures performed were in accordance with the ethical standards of the institutional and national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Informed consent was obtained from the person hereby reported.
CRediT authorship contribution statement
Ayse Deniz Elmali: Conceptualization, Data curation, Formal analysis, Investigation, Resources, Software, Visualization, Writing - original draft, Writing - review & editing. Esme Ekizoglu: Data curation, Supervision, Validation, Writing - review & editing. Irem Ciftci: Data curation, Writing - original draft. Nilufer Yesilot: Data curation, Supervision, Validation, Writing - review & editing. Oguzhan Coban: Conceptualization, Supervision, Validation, Writing - review & editing. Betul Baykan: Conceptualization, Data curation, Formal analysis, Investigation, Resources, Software, Supervision, Validation, Visualization, Writing - original draft, Writing - review & editing. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY-NC-ND | 33665600 | 20,563,834 | 2021 |
What was the administration route of drug 'PHENYTOIN SODIUM'? | Periodic electroclinical seizures following an ischemic stroke revealed by continuous-EEG.
Periodic EEG patterns are mostly associated with critical illnesses and acute disruptions of the central nervous system. Periodic or cyclic seizures are extremely rare phenomena, most of which are nonconvulsive, only reported in critically ill patients. Here we report a patient with periodic focal impaired awareness seizures following a minor stroke and address possible pathophysiological mechanisms.
A 49 years old male patient presented with periodic seizures, associated with an acute stroke in the left occipital and parietal regions. These focal seizures, recorded during long-term video-EEG monitoring in the scalp EEG, appeared every 9-11 min, and responded to iv valproic acid treatment but not to iv treatments of diazepam, phenytoin, and levetiracetam.
We believe that the blood-brain barrier disruption due to stroke, in conjunction with hyperglycemia and antiphospholipid antibodies have led to an imbalance of the surrounding tissue and sustained hyperexcitability to a point of pacemaker potentials. It is tempting to speculate that repetitive cycles of cortical spreading depression due to tissue injury have aided the periodicity of the seizures.
Continuous EEG monitoring is crucial, not only to diagnose and appropriately treat accompanying subtle seizures but also to further understand the underlying intriguing pathophysiological processes like periodicity.
Periodicity in the EEG terminology is defined as “repetition of a discharge or pattern with relatively uniform morphology and duration with a quantifiable interdischarge interval between consecutive waveforms and recurrence of the waveform at nearly regular intervals” by Hirsch et al. [1] Periodic EEG patterns are almost never “benign” in nature, mostly observed in critically ill patients with acute disruptions of the integrity of the central nervous system. Periodic or cyclic focal seizures, on the other hand, are extremely uncommon encounters. They are first reported by Blume in 1997 as “periodic seizures” and later called “cyclic” by Friedman in 2008. They are only reported in critically ill patients and almost all of them are nonconvulsive, lacking clinical correlates [2], [3], [4].
Here we report a 49 years old male patient with sudden onset of strictly periodic, frequent focal impaired awareness seizures following a minor stroke and address the possible pathophysiological mechanisms.
1 Case report
Forty-nine years old male patient with a history of poorly controlled diabetes mellitus has presented to our emergency room with right-sided mild paresis, right homonymous hemianopia and confusion. Brain MR imaging revealed scattered small diffusion restriction area and low signal on the ADC map in the left occipital and parietal regions compatible with an acute ischemic stroke (Fig. 1). His cranial MRI also showed a former silent ischemic infarction in the right occipital region. Vascular and cardiac investigations did not reveal any pathological findings. There were no other biochemical abnormalities except elevated glucose levels of 237 mg/dl (concomitant bicarbonate levels were 25.1 mmol/L) on admission with an HbA1C level of 12.7%. He had a history of peripheral artery disease treated surgically two years ago and family history disclosed that one of his sons was diagnosed with systemic lupus erythematosus.Fig. 1 Axial diffusion-weighted MR imaging showing scattered small diffusion restriction areas in the left occipital and parietal regions (a), confirmed on ADC map (b) in accordance with an acute ischemic stroke.
Episodes of fluctuating confusion suggestive of seizures were noted and his emergency EEG showed 2 focal seizures starting from the left occipitoparietal region, spreading rapidly throughout the hemisphere with a limited extension to the posterior regions of the right hemisphere. These seizures lasted approximately 90–120 s before ending abruptly on both hemispheres. During these seizures, the patient became non-responsive, kept uttering his last sentence immediately before the seizure onset (ictal speech), and left upper manual automatisms starting after 60 s were observed. In the continuous video-EEG monitoring lasting 48 h, we observed that these uniform seizures repeated every 9–11 min (range 505–665 seconds, mean 607.4 ± 37.1) in a strictly periodic manner (Fig. 2). Early postictal EEG following the seizure was insignificant other than mild background slowing on the left hemisphere, lateralized periodic discharges emerged later on. Neuropsychological evaluation demonstrated fluctuating frontal dysfunction.Fig. 2 Low pass filter: 70 Hz, High pass filter: 0.5 Hz, Notch filter: 50 Hz. (a). Ictal EEG findings: seizure activity starting from the left occipitoparietal region, spreading rapidly throughout the hemisphere with a limited extension to the posterior regions of the right hemisphere. Seizures lasted approximately 90–120 s before ending abruptly on both hemispheres. (b). Periodicity of the seizures can be observed in the bar and table. (c). Interictal findings: Within seconds after the seizure, periodic lateralized discharges emerged in the left hemisphere. They became more prominent and showed generalization and multiplication immediately before the impending seizure. This interictal pattern also emerged periodically.
The periodicity and seizure frequency did not change despite iv diazepam (10 mg), iv phenytoin (18 mg/kg), and iv levetiracetam (20 mg/kg) treatments as monitored closely by continuous-EEG. Only after an iv valproic acid (20 mg/kg) treatment, the intervals between seizures became longer (90 min) and the duration of the seizures lengthened (30 min), and diminished altogether under 2000 mg valproic acid, 200 mg lacosamide and 400 mg carbamazepine treatments, after 3 days following admission. (Please see Supp Table 1 for the treatment trials) Lumbar puncture did not reveal any remarkable abnormalities. Viral panels, serologic studies and paraneoplastic antibody screening were all negative. However, he had ANA positivity (homogenous, 1/2560) and antiphospholipid antibodies (beta2 glycoprotein IgM: 36.9 U/ml, beta2 glycoprotein IgG: 19.4 U/ml and anticardiolipin IgG: 19.8 U/ml) but did not fulfill the criteria for systemic lupus erythematosus or primary antiphospholipid syndrome yet. The patient was discharged without any disability and he was seizure-free, his control EEG exam after one month was unremarkable other than scant generalized slow wave paroxysms.
2 Discussion
Our patient showed acute symptomatic, focal impaired awareness seizures emerging in a remarkable periodic manner. We believe calling these seizures “periodic” is more appropriate than cyclic, based on the definition of periodicity in the ACNS guideline [1]. These seizures are most likely to occur in older patients with acute or progressive brain injury and more likely to be associated with poor outcomes [4]. This report presents a rather pleasing contrast; our case is a younger gentleman with a comparatively minor stroke and his prognosis has been excellent.
There has been a long-standing controversy on whether periodic lateralized epileptiform discharges (PLED) represent an ictal finding or an interictal phenomenon [5]. We believe this patient might represent an example of the extreme end of a spectrum in interictal to ictal lateralized periodic discharges continuum. Seizures are common consequences of stroke and stroke-related seizures are divided into two groups according to seizure onset; seizures occurring in the first seven days are classified as early seizures [6]. In early seizures, disruption of the blood brain barrier and ischemic insult of the neurons may result in ion channel dysfunctions and disturbed homeostasis of the neurotransmitters, in addition to biochemical dysfunctions leading to irritability of the offended tissue [7].
The association of auto-antibodies with seizures is also a well-known but complicated issue; the present autoantibodies might have contributed to the seizure generation in our case. Moreover, PLEDs were reported in patients with SLE and seizures [8]. Although multiple recurrent seizures are well described in autoimmune epilepsies, (e.g. frequent facio-brachial dystonic seizures in LGI1 antibody encephalitis) they are not periodic in nature [9]. Furthermore, hyperglycemia, as observed in our patient is also a known contributor to the blood–brain barrier disruption and generation of periodic patterns like PLEDs and also involved in seizure generation [10]. Glucose is also an important mediator in the regulation of potassium metabolism, higher glucose and insulin levels increase the cellular uptake of potassium. Malfunctions in the ion channels due to neuronal damage and such mediators might give rise to leaky Na or Ca and K channels leading to spontaneous rhythmic depolarizations similar to a pacemaker potential.
The lobar origin of these periodic seizures also needs further attention. The damage to the cortex in stroke may lead to cortical spreading depression (CSD), which relates to a loss of ion homeostasis leading to a widespread depolarization of the neurons and astrocytes with altered metabolism and blood flow [11]. Accumulating evidence indicated that CSD is the pathophysiological hallmark of the migraine aura, starting in the occipital cortex, specifically. Infarct of the posterior cerebral artery caused by atherothrombosis may be the key factor in our case, as previous ICU series also report a tendency of posterior onset for cyclic seizures [3], [4]. It has been shown that focal seizures involving primarily the consciousness may originate from any lobe including parietooccipital regions, however rare it may be [12]. Thus the parieto-occipital origin of the periodic seizures may support the involvement of CSD by this minor stroke.
CSD and CSD-like events can be triggered by injury of the tissue due to trauma, hemorrhage, ischemia etc. [13]. CSD has been reported to co-occur or even cause seizure by means of synchronizing the affected tissue [14]. The opposite has also been demonstrated, epileptiform activity initiated waves of CSD. In a rat model, spike triggered spreading depression was seen to repeat in cycles lasting a mean of 6 min and up to 20 cycles [15]. Repetitive cycles of CSD have also been reported in a patient with increased intracranial pressure due to traumatic contusion [16]. The common point of these important but anecdotal observations is the use of intracranial electrodes. It is tempting to speculate that this periodic pattern might be a common phenomenon after tissue injury (in conjunction with biochemical abnormalities as a double hit) that is greatly missed via routine scalp EEG. We think that the same cyclic interplay between focal seizure activity and CSD might be the underlying explanation for the intriguing periodicity of our patient’s seizures. The lack of any effect of the standard iv antiepileptic drug treatments other than valproic acid, which is also effective against CSD in migraine patients, further strengthens this hypothesis [17]. There is a synergistic pharmacodynamic interaction between PHT and VPA in vivo. We think that this might have been helpful in the limitation of the cycling seizures [18].
A very recent study has also suggested that cyclic seizures may point out to a more favorable outcome in younger patients compared to noncyclic ones. [19] The peculiar build-up phenomenon has also been reported in the literature and may constitute a clue for the ongoing cyclic seizures, which may be missed in short routine EEG recordings. [3]
3 Conclusion
In conclusion; an important point raised from this case is the indispensability of continuous EEG monitoring for such patients since peculiar patterns like periodicity would be missed on routine EEGs. Although previous studies reported that cyclic seizures are a negative prognostic factor, this particular case had an excellent prognosis. Further clinical and experimental studies are needed to explore this seemingly vicious cycle of periodic seizures and develop neuroprotective treatment strategies.
Conflict of interest
On behalf of all authors, the corresponding author states that there is no conflict of interest.
Disclosure
ADE, EE, IC, NY, OC, BB: no relevant financial or nonfinancial relationships to disclose.
6 Compliance with ethical standards
There was no funding for this study.
All of the authors declare that they have no conflict of interest.
All procedures performed were in accordance with the ethical standards of the institutional and national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Informed consent was obtained from the person hereby reported.
CRediT authorship contribution statement
Ayse Deniz Elmali: Conceptualization, Data curation, Formal analysis, Investigation, Resources, Software, Visualization, Writing - original draft, Writing - review & editing. Esme Ekizoglu: Data curation, Supervision, Validation, Writing - review & editing. Irem Ciftci: Data curation, Writing - original draft. Nilufer Yesilot: Data curation, Supervision, Validation, Writing - review & editing. Oguzhan Coban: Conceptualization, Supervision, Validation, Writing - review & editing. Betul Baykan: Conceptualization, Data curation, Formal analysis, Investigation, Resources, Software, Supervision, Validation, Visualization, Writing - original draft, Writing - review & editing. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY-NC-ND | 33665600 | 20,563,834 | 2021 |
What was the dosage of drug 'DIAZEPAM'? | Periodic electroclinical seizures following an ischemic stroke revealed by continuous-EEG.
Periodic EEG patterns are mostly associated with critical illnesses and acute disruptions of the central nervous system. Periodic or cyclic seizures are extremely rare phenomena, most of which are nonconvulsive, only reported in critically ill patients. Here we report a patient with periodic focal impaired awareness seizures following a minor stroke and address possible pathophysiological mechanisms.
A 49 years old male patient presented with periodic seizures, associated with an acute stroke in the left occipital and parietal regions. These focal seizures, recorded during long-term video-EEG monitoring in the scalp EEG, appeared every 9-11 min, and responded to iv valproic acid treatment but not to iv treatments of diazepam, phenytoin, and levetiracetam.
We believe that the blood-brain barrier disruption due to stroke, in conjunction with hyperglycemia and antiphospholipid antibodies have led to an imbalance of the surrounding tissue and sustained hyperexcitability to a point of pacemaker potentials. It is tempting to speculate that repetitive cycles of cortical spreading depression due to tissue injury have aided the periodicity of the seizures.
Continuous EEG monitoring is crucial, not only to diagnose and appropriately treat accompanying subtle seizures but also to further understand the underlying intriguing pathophysiological processes like periodicity.
Periodicity in the EEG terminology is defined as “repetition of a discharge or pattern with relatively uniform morphology and duration with a quantifiable interdischarge interval between consecutive waveforms and recurrence of the waveform at nearly regular intervals” by Hirsch et al. [1] Periodic EEG patterns are almost never “benign” in nature, mostly observed in critically ill patients with acute disruptions of the integrity of the central nervous system. Periodic or cyclic focal seizures, on the other hand, are extremely uncommon encounters. They are first reported by Blume in 1997 as “periodic seizures” and later called “cyclic” by Friedman in 2008. They are only reported in critically ill patients and almost all of them are nonconvulsive, lacking clinical correlates [2], [3], [4].
Here we report a 49 years old male patient with sudden onset of strictly periodic, frequent focal impaired awareness seizures following a minor stroke and address the possible pathophysiological mechanisms.
1 Case report
Forty-nine years old male patient with a history of poorly controlled diabetes mellitus has presented to our emergency room with right-sided mild paresis, right homonymous hemianopia and confusion. Brain MR imaging revealed scattered small diffusion restriction area and low signal on the ADC map in the left occipital and parietal regions compatible with an acute ischemic stroke (Fig. 1). His cranial MRI also showed a former silent ischemic infarction in the right occipital region. Vascular and cardiac investigations did not reveal any pathological findings. There were no other biochemical abnormalities except elevated glucose levels of 237 mg/dl (concomitant bicarbonate levels were 25.1 mmol/L) on admission with an HbA1C level of 12.7%. He had a history of peripheral artery disease treated surgically two years ago and family history disclosed that one of his sons was diagnosed with systemic lupus erythematosus.Fig. 1 Axial diffusion-weighted MR imaging showing scattered small diffusion restriction areas in the left occipital and parietal regions (a), confirmed on ADC map (b) in accordance with an acute ischemic stroke.
Episodes of fluctuating confusion suggestive of seizures were noted and his emergency EEG showed 2 focal seizures starting from the left occipitoparietal region, spreading rapidly throughout the hemisphere with a limited extension to the posterior regions of the right hemisphere. These seizures lasted approximately 90–120 s before ending abruptly on both hemispheres. During these seizures, the patient became non-responsive, kept uttering his last sentence immediately before the seizure onset (ictal speech), and left upper manual automatisms starting after 60 s were observed. In the continuous video-EEG monitoring lasting 48 h, we observed that these uniform seizures repeated every 9–11 min (range 505–665 seconds, mean 607.4 ± 37.1) in a strictly periodic manner (Fig. 2). Early postictal EEG following the seizure was insignificant other than mild background slowing on the left hemisphere, lateralized periodic discharges emerged later on. Neuropsychological evaluation demonstrated fluctuating frontal dysfunction.Fig. 2 Low pass filter: 70 Hz, High pass filter: 0.5 Hz, Notch filter: 50 Hz. (a). Ictal EEG findings: seizure activity starting from the left occipitoparietal region, spreading rapidly throughout the hemisphere with a limited extension to the posterior regions of the right hemisphere. Seizures lasted approximately 90–120 s before ending abruptly on both hemispheres. (b). Periodicity of the seizures can be observed in the bar and table. (c). Interictal findings: Within seconds after the seizure, periodic lateralized discharges emerged in the left hemisphere. They became more prominent and showed generalization and multiplication immediately before the impending seizure. This interictal pattern also emerged periodically.
The periodicity and seizure frequency did not change despite iv diazepam (10 mg), iv phenytoin (18 mg/kg), and iv levetiracetam (20 mg/kg) treatments as monitored closely by continuous-EEG. Only after an iv valproic acid (20 mg/kg) treatment, the intervals between seizures became longer (90 min) and the duration of the seizures lengthened (30 min), and diminished altogether under 2000 mg valproic acid, 200 mg lacosamide and 400 mg carbamazepine treatments, after 3 days following admission. (Please see Supp Table 1 for the treatment trials) Lumbar puncture did not reveal any remarkable abnormalities. Viral panels, serologic studies and paraneoplastic antibody screening were all negative. However, he had ANA positivity (homogenous, 1/2560) and antiphospholipid antibodies (beta2 glycoprotein IgM: 36.9 U/ml, beta2 glycoprotein IgG: 19.4 U/ml and anticardiolipin IgG: 19.8 U/ml) but did not fulfill the criteria for systemic lupus erythematosus or primary antiphospholipid syndrome yet. The patient was discharged without any disability and he was seizure-free, his control EEG exam after one month was unremarkable other than scant generalized slow wave paroxysms.
2 Discussion
Our patient showed acute symptomatic, focal impaired awareness seizures emerging in a remarkable periodic manner. We believe calling these seizures “periodic” is more appropriate than cyclic, based on the definition of periodicity in the ACNS guideline [1]. These seizures are most likely to occur in older patients with acute or progressive brain injury and more likely to be associated with poor outcomes [4]. This report presents a rather pleasing contrast; our case is a younger gentleman with a comparatively minor stroke and his prognosis has been excellent.
There has been a long-standing controversy on whether periodic lateralized epileptiform discharges (PLED) represent an ictal finding or an interictal phenomenon [5]. We believe this patient might represent an example of the extreme end of a spectrum in interictal to ictal lateralized periodic discharges continuum. Seizures are common consequences of stroke and stroke-related seizures are divided into two groups according to seizure onset; seizures occurring in the first seven days are classified as early seizures [6]. In early seizures, disruption of the blood brain barrier and ischemic insult of the neurons may result in ion channel dysfunctions and disturbed homeostasis of the neurotransmitters, in addition to biochemical dysfunctions leading to irritability of the offended tissue [7].
The association of auto-antibodies with seizures is also a well-known but complicated issue; the present autoantibodies might have contributed to the seizure generation in our case. Moreover, PLEDs were reported in patients with SLE and seizures [8]. Although multiple recurrent seizures are well described in autoimmune epilepsies, (e.g. frequent facio-brachial dystonic seizures in LGI1 antibody encephalitis) they are not periodic in nature [9]. Furthermore, hyperglycemia, as observed in our patient is also a known contributor to the blood–brain barrier disruption and generation of periodic patterns like PLEDs and also involved in seizure generation [10]. Glucose is also an important mediator in the regulation of potassium metabolism, higher glucose and insulin levels increase the cellular uptake of potassium. Malfunctions in the ion channels due to neuronal damage and such mediators might give rise to leaky Na or Ca and K channels leading to spontaneous rhythmic depolarizations similar to a pacemaker potential.
The lobar origin of these periodic seizures also needs further attention. The damage to the cortex in stroke may lead to cortical spreading depression (CSD), which relates to a loss of ion homeostasis leading to a widespread depolarization of the neurons and astrocytes with altered metabolism and blood flow [11]. Accumulating evidence indicated that CSD is the pathophysiological hallmark of the migraine aura, starting in the occipital cortex, specifically. Infarct of the posterior cerebral artery caused by atherothrombosis may be the key factor in our case, as previous ICU series also report a tendency of posterior onset for cyclic seizures [3], [4]. It has been shown that focal seizures involving primarily the consciousness may originate from any lobe including parietooccipital regions, however rare it may be [12]. Thus the parieto-occipital origin of the periodic seizures may support the involvement of CSD by this minor stroke.
CSD and CSD-like events can be triggered by injury of the tissue due to trauma, hemorrhage, ischemia etc. [13]. CSD has been reported to co-occur or even cause seizure by means of synchronizing the affected tissue [14]. The opposite has also been demonstrated, epileptiform activity initiated waves of CSD. In a rat model, spike triggered spreading depression was seen to repeat in cycles lasting a mean of 6 min and up to 20 cycles [15]. Repetitive cycles of CSD have also been reported in a patient with increased intracranial pressure due to traumatic contusion [16]. The common point of these important but anecdotal observations is the use of intracranial electrodes. It is tempting to speculate that this periodic pattern might be a common phenomenon after tissue injury (in conjunction with biochemical abnormalities as a double hit) that is greatly missed via routine scalp EEG. We think that the same cyclic interplay between focal seizure activity and CSD might be the underlying explanation for the intriguing periodicity of our patient’s seizures. The lack of any effect of the standard iv antiepileptic drug treatments other than valproic acid, which is also effective against CSD in migraine patients, further strengthens this hypothesis [17]. There is a synergistic pharmacodynamic interaction between PHT and VPA in vivo. We think that this might have been helpful in the limitation of the cycling seizures [18].
A very recent study has also suggested that cyclic seizures may point out to a more favorable outcome in younger patients compared to noncyclic ones. [19] The peculiar build-up phenomenon has also been reported in the literature and may constitute a clue for the ongoing cyclic seizures, which may be missed in short routine EEG recordings. [3]
3 Conclusion
In conclusion; an important point raised from this case is the indispensability of continuous EEG monitoring for such patients since peculiar patterns like periodicity would be missed on routine EEGs. Although previous studies reported that cyclic seizures are a negative prognostic factor, this particular case had an excellent prognosis. Further clinical and experimental studies are needed to explore this seemingly vicious cycle of periodic seizures and develop neuroprotective treatment strategies.
Conflict of interest
On behalf of all authors, the corresponding author states that there is no conflict of interest.
Disclosure
ADE, EE, IC, NY, OC, BB: no relevant financial or nonfinancial relationships to disclose.
6 Compliance with ethical standards
There was no funding for this study.
All of the authors declare that they have no conflict of interest.
All procedures performed were in accordance with the ethical standards of the institutional and national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Informed consent was obtained from the person hereby reported.
CRediT authorship contribution statement
Ayse Deniz Elmali: Conceptualization, Data curation, Formal analysis, Investigation, Resources, Software, Visualization, Writing - original draft, Writing - review & editing. Esme Ekizoglu: Data curation, Supervision, Validation, Writing - review & editing. Irem Ciftci: Data curation, Writing - original draft. Nilufer Yesilot: Data curation, Supervision, Validation, Writing - review & editing. Oguzhan Coban: Conceptualization, Supervision, Validation, Writing - review & editing. Betul Baykan: Conceptualization, Data curation, Formal analysis, Investigation, Resources, Software, Supervision, Validation, Visualization, Writing - original draft, Writing - review & editing. | 10 MG | DrugDosageText | CC BY-NC-ND | 33665600 | 20,563,834 | 2021 |
What was the dosage of drug 'LEVETIRACETAM'? | Periodic electroclinical seizures following an ischemic stroke revealed by continuous-EEG.
Periodic EEG patterns are mostly associated with critical illnesses and acute disruptions of the central nervous system. Periodic or cyclic seizures are extremely rare phenomena, most of which are nonconvulsive, only reported in critically ill patients. Here we report a patient with periodic focal impaired awareness seizures following a minor stroke and address possible pathophysiological mechanisms.
A 49 years old male patient presented with periodic seizures, associated with an acute stroke in the left occipital and parietal regions. These focal seizures, recorded during long-term video-EEG monitoring in the scalp EEG, appeared every 9-11 min, and responded to iv valproic acid treatment but not to iv treatments of diazepam, phenytoin, and levetiracetam.
We believe that the blood-brain barrier disruption due to stroke, in conjunction with hyperglycemia and antiphospholipid antibodies have led to an imbalance of the surrounding tissue and sustained hyperexcitability to a point of pacemaker potentials. It is tempting to speculate that repetitive cycles of cortical spreading depression due to tissue injury have aided the periodicity of the seizures.
Continuous EEG monitoring is crucial, not only to diagnose and appropriately treat accompanying subtle seizures but also to further understand the underlying intriguing pathophysiological processes like periodicity.
Periodicity in the EEG terminology is defined as “repetition of a discharge or pattern with relatively uniform morphology and duration with a quantifiable interdischarge interval between consecutive waveforms and recurrence of the waveform at nearly regular intervals” by Hirsch et al. [1] Periodic EEG patterns are almost never “benign” in nature, mostly observed in critically ill patients with acute disruptions of the integrity of the central nervous system. Periodic or cyclic focal seizures, on the other hand, are extremely uncommon encounters. They are first reported by Blume in 1997 as “periodic seizures” and later called “cyclic” by Friedman in 2008. They are only reported in critically ill patients and almost all of them are nonconvulsive, lacking clinical correlates [2], [3], [4].
Here we report a 49 years old male patient with sudden onset of strictly periodic, frequent focal impaired awareness seizures following a minor stroke and address the possible pathophysiological mechanisms.
1 Case report
Forty-nine years old male patient with a history of poorly controlled diabetes mellitus has presented to our emergency room with right-sided mild paresis, right homonymous hemianopia and confusion. Brain MR imaging revealed scattered small diffusion restriction area and low signal on the ADC map in the left occipital and parietal regions compatible with an acute ischemic stroke (Fig. 1). His cranial MRI also showed a former silent ischemic infarction in the right occipital region. Vascular and cardiac investigations did not reveal any pathological findings. There were no other biochemical abnormalities except elevated glucose levels of 237 mg/dl (concomitant bicarbonate levels were 25.1 mmol/L) on admission with an HbA1C level of 12.7%. He had a history of peripheral artery disease treated surgically two years ago and family history disclosed that one of his sons was diagnosed with systemic lupus erythematosus.Fig. 1 Axial diffusion-weighted MR imaging showing scattered small diffusion restriction areas in the left occipital and parietal regions (a), confirmed on ADC map (b) in accordance with an acute ischemic stroke.
Episodes of fluctuating confusion suggestive of seizures were noted and his emergency EEG showed 2 focal seizures starting from the left occipitoparietal region, spreading rapidly throughout the hemisphere with a limited extension to the posterior regions of the right hemisphere. These seizures lasted approximately 90–120 s before ending abruptly on both hemispheres. During these seizures, the patient became non-responsive, kept uttering his last sentence immediately before the seizure onset (ictal speech), and left upper manual automatisms starting after 60 s were observed. In the continuous video-EEG monitoring lasting 48 h, we observed that these uniform seizures repeated every 9–11 min (range 505–665 seconds, mean 607.4 ± 37.1) in a strictly periodic manner (Fig. 2). Early postictal EEG following the seizure was insignificant other than mild background slowing on the left hemisphere, lateralized periodic discharges emerged later on. Neuropsychological evaluation demonstrated fluctuating frontal dysfunction.Fig. 2 Low pass filter: 70 Hz, High pass filter: 0.5 Hz, Notch filter: 50 Hz. (a). Ictal EEG findings: seizure activity starting from the left occipitoparietal region, spreading rapidly throughout the hemisphere with a limited extension to the posterior regions of the right hemisphere. Seizures lasted approximately 90–120 s before ending abruptly on both hemispheres. (b). Periodicity of the seizures can be observed in the bar and table. (c). Interictal findings: Within seconds after the seizure, periodic lateralized discharges emerged in the left hemisphere. They became more prominent and showed generalization and multiplication immediately before the impending seizure. This interictal pattern also emerged periodically.
The periodicity and seizure frequency did not change despite iv diazepam (10 mg), iv phenytoin (18 mg/kg), and iv levetiracetam (20 mg/kg) treatments as monitored closely by continuous-EEG. Only after an iv valproic acid (20 mg/kg) treatment, the intervals between seizures became longer (90 min) and the duration of the seizures lengthened (30 min), and diminished altogether under 2000 mg valproic acid, 200 mg lacosamide and 400 mg carbamazepine treatments, after 3 days following admission. (Please see Supp Table 1 for the treatment trials) Lumbar puncture did not reveal any remarkable abnormalities. Viral panels, serologic studies and paraneoplastic antibody screening were all negative. However, he had ANA positivity (homogenous, 1/2560) and antiphospholipid antibodies (beta2 glycoprotein IgM: 36.9 U/ml, beta2 glycoprotein IgG: 19.4 U/ml and anticardiolipin IgG: 19.8 U/ml) but did not fulfill the criteria for systemic lupus erythematosus or primary antiphospholipid syndrome yet. The patient was discharged without any disability and he was seizure-free, his control EEG exam after one month was unremarkable other than scant generalized slow wave paroxysms.
2 Discussion
Our patient showed acute symptomatic, focal impaired awareness seizures emerging in a remarkable periodic manner. We believe calling these seizures “periodic” is more appropriate than cyclic, based on the definition of periodicity in the ACNS guideline [1]. These seizures are most likely to occur in older patients with acute or progressive brain injury and more likely to be associated with poor outcomes [4]. This report presents a rather pleasing contrast; our case is a younger gentleman with a comparatively minor stroke and his prognosis has been excellent.
There has been a long-standing controversy on whether periodic lateralized epileptiform discharges (PLED) represent an ictal finding or an interictal phenomenon [5]. We believe this patient might represent an example of the extreme end of a spectrum in interictal to ictal lateralized periodic discharges continuum. Seizures are common consequences of stroke and stroke-related seizures are divided into two groups according to seizure onset; seizures occurring in the first seven days are classified as early seizures [6]. In early seizures, disruption of the blood brain barrier and ischemic insult of the neurons may result in ion channel dysfunctions and disturbed homeostasis of the neurotransmitters, in addition to biochemical dysfunctions leading to irritability of the offended tissue [7].
The association of auto-antibodies with seizures is also a well-known but complicated issue; the present autoantibodies might have contributed to the seizure generation in our case. Moreover, PLEDs were reported in patients with SLE and seizures [8]. Although multiple recurrent seizures are well described in autoimmune epilepsies, (e.g. frequent facio-brachial dystonic seizures in LGI1 antibody encephalitis) they are not periodic in nature [9]. Furthermore, hyperglycemia, as observed in our patient is also a known contributor to the blood–brain barrier disruption and generation of periodic patterns like PLEDs and also involved in seizure generation [10]. Glucose is also an important mediator in the regulation of potassium metabolism, higher glucose and insulin levels increase the cellular uptake of potassium. Malfunctions in the ion channels due to neuronal damage and such mediators might give rise to leaky Na or Ca and K channels leading to spontaneous rhythmic depolarizations similar to a pacemaker potential.
The lobar origin of these periodic seizures also needs further attention. The damage to the cortex in stroke may lead to cortical spreading depression (CSD), which relates to a loss of ion homeostasis leading to a widespread depolarization of the neurons and astrocytes with altered metabolism and blood flow [11]. Accumulating evidence indicated that CSD is the pathophysiological hallmark of the migraine aura, starting in the occipital cortex, specifically. Infarct of the posterior cerebral artery caused by atherothrombosis may be the key factor in our case, as previous ICU series also report a tendency of posterior onset for cyclic seizures [3], [4]. It has been shown that focal seizures involving primarily the consciousness may originate from any lobe including parietooccipital regions, however rare it may be [12]. Thus the parieto-occipital origin of the periodic seizures may support the involvement of CSD by this minor stroke.
CSD and CSD-like events can be triggered by injury of the tissue due to trauma, hemorrhage, ischemia etc. [13]. CSD has been reported to co-occur or even cause seizure by means of synchronizing the affected tissue [14]. The opposite has also been demonstrated, epileptiform activity initiated waves of CSD. In a rat model, spike triggered spreading depression was seen to repeat in cycles lasting a mean of 6 min and up to 20 cycles [15]. Repetitive cycles of CSD have also been reported in a patient with increased intracranial pressure due to traumatic contusion [16]. The common point of these important but anecdotal observations is the use of intracranial electrodes. It is tempting to speculate that this periodic pattern might be a common phenomenon after tissue injury (in conjunction with biochemical abnormalities as a double hit) that is greatly missed via routine scalp EEG. We think that the same cyclic interplay between focal seizure activity and CSD might be the underlying explanation for the intriguing periodicity of our patient’s seizures. The lack of any effect of the standard iv antiepileptic drug treatments other than valproic acid, which is also effective against CSD in migraine patients, further strengthens this hypothesis [17]. There is a synergistic pharmacodynamic interaction between PHT and VPA in vivo. We think that this might have been helpful in the limitation of the cycling seizures [18].
A very recent study has also suggested that cyclic seizures may point out to a more favorable outcome in younger patients compared to noncyclic ones. [19] The peculiar build-up phenomenon has also been reported in the literature and may constitute a clue for the ongoing cyclic seizures, which may be missed in short routine EEG recordings. [3]
3 Conclusion
In conclusion; an important point raised from this case is the indispensability of continuous EEG monitoring for such patients since peculiar patterns like periodicity would be missed on routine EEGs. Although previous studies reported that cyclic seizures are a negative prognostic factor, this particular case had an excellent prognosis. Further clinical and experimental studies are needed to explore this seemingly vicious cycle of periodic seizures and develop neuroprotective treatment strategies.
Conflict of interest
On behalf of all authors, the corresponding author states that there is no conflict of interest.
Disclosure
ADE, EE, IC, NY, OC, BB: no relevant financial or nonfinancial relationships to disclose.
6 Compliance with ethical standards
There was no funding for this study.
All of the authors declare that they have no conflict of interest.
All procedures performed were in accordance with the ethical standards of the institutional and national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Informed consent was obtained from the person hereby reported.
CRediT authorship contribution statement
Ayse Deniz Elmali: Conceptualization, Data curation, Formal analysis, Investigation, Resources, Software, Visualization, Writing - original draft, Writing - review & editing. Esme Ekizoglu: Data curation, Supervision, Validation, Writing - review & editing. Irem Ciftci: Data curation, Writing - original draft. Nilufer Yesilot: Data curation, Supervision, Validation, Writing - review & editing. Oguzhan Coban: Conceptualization, Supervision, Validation, Writing - review & editing. Betul Baykan: Conceptualization, Data curation, Formal analysis, Investigation, Resources, Software, Supervision, Validation, Visualization, Writing - original draft, Writing - review & editing. | 20 MILLIGRAM/KILOGRAM | DrugDosageText | CC BY-NC-ND | 33665600 | 20,563,834 | 2021 |
What was the dosage of drug 'PHENYTOIN SODIUM'? | Periodic electroclinical seizures following an ischemic stroke revealed by continuous-EEG.
Periodic EEG patterns are mostly associated with critical illnesses and acute disruptions of the central nervous system. Periodic or cyclic seizures are extremely rare phenomena, most of which are nonconvulsive, only reported in critically ill patients. Here we report a patient with periodic focal impaired awareness seizures following a minor stroke and address possible pathophysiological mechanisms.
A 49 years old male patient presented with periodic seizures, associated with an acute stroke in the left occipital and parietal regions. These focal seizures, recorded during long-term video-EEG monitoring in the scalp EEG, appeared every 9-11 min, and responded to iv valproic acid treatment but not to iv treatments of diazepam, phenytoin, and levetiracetam.
We believe that the blood-brain barrier disruption due to stroke, in conjunction with hyperglycemia and antiphospholipid antibodies have led to an imbalance of the surrounding tissue and sustained hyperexcitability to a point of pacemaker potentials. It is tempting to speculate that repetitive cycles of cortical spreading depression due to tissue injury have aided the periodicity of the seizures.
Continuous EEG monitoring is crucial, not only to diagnose and appropriately treat accompanying subtle seizures but also to further understand the underlying intriguing pathophysiological processes like periodicity.
Periodicity in the EEG terminology is defined as “repetition of a discharge or pattern with relatively uniform morphology and duration with a quantifiable interdischarge interval between consecutive waveforms and recurrence of the waveform at nearly regular intervals” by Hirsch et al. [1] Periodic EEG patterns are almost never “benign” in nature, mostly observed in critically ill patients with acute disruptions of the integrity of the central nervous system. Periodic or cyclic focal seizures, on the other hand, are extremely uncommon encounters. They are first reported by Blume in 1997 as “periodic seizures” and later called “cyclic” by Friedman in 2008. They are only reported in critically ill patients and almost all of them are nonconvulsive, lacking clinical correlates [2], [3], [4].
Here we report a 49 years old male patient with sudden onset of strictly periodic, frequent focal impaired awareness seizures following a minor stroke and address the possible pathophysiological mechanisms.
1 Case report
Forty-nine years old male patient with a history of poorly controlled diabetes mellitus has presented to our emergency room with right-sided mild paresis, right homonymous hemianopia and confusion. Brain MR imaging revealed scattered small diffusion restriction area and low signal on the ADC map in the left occipital and parietal regions compatible with an acute ischemic stroke (Fig. 1). His cranial MRI also showed a former silent ischemic infarction in the right occipital region. Vascular and cardiac investigations did not reveal any pathological findings. There were no other biochemical abnormalities except elevated glucose levels of 237 mg/dl (concomitant bicarbonate levels were 25.1 mmol/L) on admission with an HbA1C level of 12.7%. He had a history of peripheral artery disease treated surgically two years ago and family history disclosed that one of his sons was diagnosed with systemic lupus erythematosus.Fig. 1 Axial diffusion-weighted MR imaging showing scattered small diffusion restriction areas in the left occipital and parietal regions (a), confirmed on ADC map (b) in accordance with an acute ischemic stroke.
Episodes of fluctuating confusion suggestive of seizures were noted and his emergency EEG showed 2 focal seizures starting from the left occipitoparietal region, spreading rapidly throughout the hemisphere with a limited extension to the posterior regions of the right hemisphere. These seizures lasted approximately 90–120 s before ending abruptly on both hemispheres. During these seizures, the patient became non-responsive, kept uttering his last sentence immediately before the seizure onset (ictal speech), and left upper manual automatisms starting after 60 s were observed. In the continuous video-EEG monitoring lasting 48 h, we observed that these uniform seizures repeated every 9–11 min (range 505–665 seconds, mean 607.4 ± 37.1) in a strictly periodic manner (Fig. 2). Early postictal EEG following the seizure was insignificant other than mild background slowing on the left hemisphere, lateralized periodic discharges emerged later on. Neuropsychological evaluation demonstrated fluctuating frontal dysfunction.Fig. 2 Low pass filter: 70 Hz, High pass filter: 0.5 Hz, Notch filter: 50 Hz. (a). Ictal EEG findings: seizure activity starting from the left occipitoparietal region, spreading rapidly throughout the hemisphere with a limited extension to the posterior regions of the right hemisphere. Seizures lasted approximately 90–120 s before ending abruptly on both hemispheres. (b). Periodicity of the seizures can be observed in the bar and table. (c). Interictal findings: Within seconds after the seizure, periodic lateralized discharges emerged in the left hemisphere. They became more prominent and showed generalization and multiplication immediately before the impending seizure. This interictal pattern also emerged periodically.
The periodicity and seizure frequency did not change despite iv diazepam (10 mg), iv phenytoin (18 mg/kg), and iv levetiracetam (20 mg/kg) treatments as monitored closely by continuous-EEG. Only after an iv valproic acid (20 mg/kg) treatment, the intervals between seizures became longer (90 min) and the duration of the seizures lengthened (30 min), and diminished altogether under 2000 mg valproic acid, 200 mg lacosamide and 400 mg carbamazepine treatments, after 3 days following admission. (Please see Supp Table 1 for the treatment trials) Lumbar puncture did not reveal any remarkable abnormalities. Viral panels, serologic studies and paraneoplastic antibody screening were all negative. However, he had ANA positivity (homogenous, 1/2560) and antiphospholipid antibodies (beta2 glycoprotein IgM: 36.9 U/ml, beta2 glycoprotein IgG: 19.4 U/ml and anticardiolipin IgG: 19.8 U/ml) but did not fulfill the criteria for systemic lupus erythematosus or primary antiphospholipid syndrome yet. The patient was discharged without any disability and he was seizure-free, his control EEG exam after one month was unremarkable other than scant generalized slow wave paroxysms.
2 Discussion
Our patient showed acute symptomatic, focal impaired awareness seizures emerging in a remarkable periodic manner. We believe calling these seizures “periodic” is more appropriate than cyclic, based on the definition of periodicity in the ACNS guideline [1]. These seizures are most likely to occur in older patients with acute or progressive brain injury and more likely to be associated with poor outcomes [4]. This report presents a rather pleasing contrast; our case is a younger gentleman with a comparatively minor stroke and his prognosis has been excellent.
There has been a long-standing controversy on whether periodic lateralized epileptiform discharges (PLED) represent an ictal finding or an interictal phenomenon [5]. We believe this patient might represent an example of the extreme end of a spectrum in interictal to ictal lateralized periodic discharges continuum. Seizures are common consequences of stroke and stroke-related seizures are divided into two groups according to seizure onset; seizures occurring in the first seven days are classified as early seizures [6]. In early seizures, disruption of the blood brain barrier and ischemic insult of the neurons may result in ion channel dysfunctions and disturbed homeostasis of the neurotransmitters, in addition to biochemical dysfunctions leading to irritability of the offended tissue [7].
The association of auto-antibodies with seizures is also a well-known but complicated issue; the present autoantibodies might have contributed to the seizure generation in our case. Moreover, PLEDs were reported in patients with SLE and seizures [8]. Although multiple recurrent seizures are well described in autoimmune epilepsies, (e.g. frequent facio-brachial dystonic seizures in LGI1 antibody encephalitis) they are not periodic in nature [9]. Furthermore, hyperglycemia, as observed in our patient is also a known contributor to the blood–brain barrier disruption and generation of periodic patterns like PLEDs and also involved in seizure generation [10]. Glucose is also an important mediator in the regulation of potassium metabolism, higher glucose and insulin levels increase the cellular uptake of potassium. Malfunctions in the ion channels due to neuronal damage and such mediators might give rise to leaky Na or Ca and K channels leading to spontaneous rhythmic depolarizations similar to a pacemaker potential.
The lobar origin of these periodic seizures also needs further attention. The damage to the cortex in stroke may lead to cortical spreading depression (CSD), which relates to a loss of ion homeostasis leading to a widespread depolarization of the neurons and astrocytes with altered metabolism and blood flow [11]. Accumulating evidence indicated that CSD is the pathophysiological hallmark of the migraine aura, starting in the occipital cortex, specifically. Infarct of the posterior cerebral artery caused by atherothrombosis may be the key factor in our case, as previous ICU series also report a tendency of posterior onset for cyclic seizures [3], [4]. It has been shown that focal seizures involving primarily the consciousness may originate from any lobe including parietooccipital regions, however rare it may be [12]. Thus the parieto-occipital origin of the periodic seizures may support the involvement of CSD by this minor stroke.
CSD and CSD-like events can be triggered by injury of the tissue due to trauma, hemorrhage, ischemia etc. [13]. CSD has been reported to co-occur or even cause seizure by means of synchronizing the affected tissue [14]. The opposite has also been demonstrated, epileptiform activity initiated waves of CSD. In a rat model, spike triggered spreading depression was seen to repeat in cycles lasting a mean of 6 min and up to 20 cycles [15]. Repetitive cycles of CSD have also been reported in a patient with increased intracranial pressure due to traumatic contusion [16]. The common point of these important but anecdotal observations is the use of intracranial electrodes. It is tempting to speculate that this periodic pattern might be a common phenomenon after tissue injury (in conjunction with biochemical abnormalities as a double hit) that is greatly missed via routine scalp EEG. We think that the same cyclic interplay between focal seizure activity and CSD might be the underlying explanation for the intriguing periodicity of our patient’s seizures. The lack of any effect of the standard iv antiepileptic drug treatments other than valproic acid, which is also effective against CSD in migraine patients, further strengthens this hypothesis [17]. There is a synergistic pharmacodynamic interaction between PHT and VPA in vivo. We think that this might have been helpful in the limitation of the cycling seizures [18].
A very recent study has also suggested that cyclic seizures may point out to a more favorable outcome in younger patients compared to noncyclic ones. [19] The peculiar build-up phenomenon has also been reported in the literature and may constitute a clue for the ongoing cyclic seizures, which may be missed in short routine EEG recordings. [3]
3 Conclusion
In conclusion; an important point raised from this case is the indispensability of continuous EEG monitoring for such patients since peculiar patterns like periodicity would be missed on routine EEGs. Although previous studies reported that cyclic seizures are a negative prognostic factor, this particular case had an excellent prognosis. Further clinical and experimental studies are needed to explore this seemingly vicious cycle of periodic seizures and develop neuroprotective treatment strategies.
Conflict of interest
On behalf of all authors, the corresponding author states that there is no conflict of interest.
Disclosure
ADE, EE, IC, NY, OC, BB: no relevant financial or nonfinancial relationships to disclose.
6 Compliance with ethical standards
There was no funding for this study.
All of the authors declare that they have no conflict of interest.
All procedures performed were in accordance with the ethical standards of the institutional and national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Informed consent was obtained from the person hereby reported.
CRediT authorship contribution statement
Ayse Deniz Elmali: Conceptualization, Data curation, Formal analysis, Investigation, Resources, Software, Visualization, Writing - original draft, Writing - review & editing. Esme Ekizoglu: Data curation, Supervision, Validation, Writing - review & editing. Irem Ciftci: Data curation, Writing - original draft. Nilufer Yesilot: Data curation, Supervision, Validation, Writing - review & editing. Oguzhan Coban: Conceptualization, Supervision, Validation, Writing - review & editing. Betul Baykan: Conceptualization, Data curation, Formal analysis, Investigation, Resources, Software, Supervision, Validation, Visualization, Writing - original draft, Writing - review & editing. | 18 MILLIGRAM/KILOGRAM | DrugDosageText | CC BY-NC-ND | 33665600 | 20,563,834 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Drug ineffective'. | Vagus nerve stimulation as a potential modulator of periictal psychotic episodes: A report of four cases.
Drug resistant epilepsy (DRE) has been associated with a high incidence of psychotic disorders. Patients can develop psychosis after starting a new antiseizure medication, after undergoing resective surgery, or after implantation of a vagus nerve stimulation (VNS) system. The aim of this study was to investigate the modulation effect of VNS on psychotic episodes in DRE patients with a pre-existing history of periictal psychotic episodes (PPE). We retrospectively report the outcome of four patients from a single tertiary center with PPE prior to implantation. None of the implanted patients developed de novo PPE after VNS therapy. Regarding seizure outcome, all patients demonstrated a response to VNS with two who experienced who status epilepticus and three patients wtih a change in semiology with after VNS implantation. PPE disappeared in all the study patients, two of them at 6 months post-implantation and in the others after 2 and 3 years, respectively. 18F-FDG-PET results showed hypermetabolism in both anterior insular and medial frontal lobes which disappeared in the 18F -FDG-PET 4 years post-implantation. Based on the results of this series of cases we suggest that VNS therapy may be useful to modulatet PPE in patients with DRE, though effectiveness may be time-dependent.
1 Introduction
Psychiatric disorders affect patients with epilepsy more frequently than they do the general population. The reported prevalence of psychotic disturbances varies between 2% and 7%, with a pooled prevalence of 5.6% [1]. The variation becomes higher when compared to the general population (1%), especially in those with temporal lobe epilepsy (TLE), affecting nearly 20% of patients [2]. Psychosis may be seen based upon its temporal relationship with seizures and include preictal, ictal, and postictal psychosis. We separated them into periictal psychotic episodes (PPE) and interictal psychosis (IIP) when a relationship between psychosis and seizures did not exist.
For PPE we used the same definitions as those identified by Logsdail and Toone. PIP was a defined as appearing within one week after a seizure or cluster of seizures, lasting from at least 15 hours up to 2 months, and preceded by a lucid period (24–72 h). Ictal psychosis was defined as psychosis appearing simultaneously with a prolonged seizure or status epilepticus as the clinical expression confirmed by an EEG without prominent motor symptoms [3].
Most of the old and new antiseizure drugs (ASD) as well as surgical treatment have been implicated in the emergence of PPE [4], [5]. Psychotic symptoms in epileptic patients with PPE are thought to be influenced by a disruption in a chronic inhibitory mechanism. Immediately after a cluster of seizures, PIP patients may experience an unusually profound depression of limbic function producing a disconnection of the temporal-limbic structures and the prefrontal structures and a loss of control over the prefrontal structures [6]. This concept was first introduced in 1953 by Landolt with the concept of ‘forced normalization theory’ to describe the appearance of psychotic episodes associated with total or partial normalization of the electroencephalogram (EEG) in patients with epilepsy [7]. In regard to this, vagus nerve stimulation (VNS) therapy has also played a role [8], [9], [10], [11]. Paradoxically, a positive effect in the modulation of psychiatric symptoms has been observed in VNS treated patients, and it has been approved as a non-pharmacological adunctive treatment for depression [12]. Moreover, a recent study conducted in an animal model for schizophrenia found VNS provided a positive effect in controlling psychotic symptoms [13].
We aimed to study the neuro-modulatory effect of VNS on psychotic episodes in drug-resistant epilepsy (DRE) patients with a pre-existing history of PPE in a single-center retrospective analysis. A total of 48 patients diagnosed with DRE and treated with VNS therapy from 2006 to 2016 were identified. None of the implanted patients developed psychosis. In the present study we included 4 patients from the series with a prior history of PPE.
Patient evaluation included a formal intermittent psychiatric examination, prolonged video-EEG (vEEG), structural magnetic resonance imaging (MRI) study with a standard epilepsy protocol, and 18F-labelled fluoro-2-deoxyglucose-positron emission tomography (18F-FDG-PET) co-registered with MRI.
1.1 Case 1
A 40-year-old male patient was diagnosed at the age of 23 with non-lesional bitemporal DRE. The patient experienced 8 episodes per month of focal impaired awareness seizure (FIAS), and occasionally focal to bilateral tonic-clonic seizure (FBTCS). Several ASDs were tested without achieving seizure control, with oxcarbazepine (OXC), clobazam (CBM) and brivaracetam (BRV) the last combination tried. Anterior temporal lobe resection of the most affected temporal lobe was done at the age of 34 without changes in seizure frequency. After nine months, the patient started suffering PIP episodes at a frequency of 3 episodes per year. PIP episodes began in the 12–24 hours after the seizure and lasted for 3–5 days. These episodes were characterised by a state of confusion and auditory hallucinations, requiring hospitalization in one case. No prior history of psychotic disorder was reported. During PIP episodes normal EEG background with fronto–temporal interictal epileptiform discharges was recorded (see Fig. 1). VNS device was implanted one year later to achieve better seizure control. After a 5-year follow-up seizures were reduced by 62.5% in additio to a change in semiology (focal aware seizure with distorted body perception) and reduced seizure severity. In terms of PIP, 3 episodes in the 2nd year was noted and no new episodes appeared after the third year of stimulation.Fig. 1 EEG recording during a postictal psychosis Patient with visual hallucinations and feelings of being harmed by others. EEG records show a left temporal breach rhythm due to previous craniotomy. There were occasional interictal epileptiform discharges in the recording (box).
1.2 Case 2
A 54-year-old male patient was diagnosed at the age of 14 with DRE secondary to a malformation of cortical development. Bitemporal seizures at a frequency of 6–8 episodes per month were reported. FIAS not preceded by aura and occasionally Focal to bilateral tonic-clonic seizures (FBTCS) were the typical seizure types. Several ASDs (OXC, phenytoin (PHT) and lacosamide (LCM)) were tested without achieving seizure control. At the age of 43 the patient started suffering recurrent episodes of postictal psychosis which started between 8 and 12 hours after a seizure, characterised by a state of confusion with hallucinations and paranoia. No prior history of psychotic disorder was reported. Antipsychotic treatment was initiated with quetiapine (QTP) and haloperidol (HLP); however, episodes were still present occurring with a frequency of 2–3 times per year, requiring hospitalization on two occasions. VNS therapy was implanted at the age of 48. After a 6-year follow-up seizures were reduced by 42.8% with a change in semiology (appearing only nocturnally). No further episodes of postictal psychosis were documented one year after VNS implantation.
1.3 Case 3
A 47-year-old female patient was diagnosed at the age of 12 with DRE secondary to a parietal tumour. Initial surgery was done in another center when the patient was 16 and the histopathology was reported as oligodendroglioma, with complete resection. The patient was seizure free for 3 years but then the seizures reappeared and became more and more frequent. No evidence of tumor relapse was observed. She was reoperated twice, at the ages of 25 and 31 including a left parietal topectomy and a right amygdalohippocampectomy. At the age of 36 she started suffering ictal psychosis during episodes characterised by delusions, anxiety, agitation, and heteroaggressivity. These psychotic episodes appeared simultaneously with an exacerbation of seizure clustering. No prior history of psychotic disorder was reported. She was monitored in our center from 2012, and at that time she suffered 1–2 seizures per day and 1 episode of psychosis per month. EEG findings during these episodes showed seizures arising in one parietal or temporal lobe evolving to contralateral areas without recovery between them (see Fig. 2). Antipsychotic treatment was initiated with QTP and clozapine (CPZ), but unfortunately the episodes remained, with a frequency of 6–8 per year. In relation to post-surgical changes, MRI showed areas of encephalomalacia-gliosis on the right temporal-insular cortex and left parietal splenium of the corpus callosum. At the age of 43, a VNS was implanted achieving a reduction of seizures by 82.5% and elimination of the episodes of SE over a 4 year follow-up period. Post-VNS the semiology of seizures also changed to focal aware seizures and falls. Only 1 episode of ictal psychosis was documented in the 1st year and was completely eliminated by the 2nd year after VNS implantation.Fig. 2 EEG recording during an ictal psychosis Patient with visual hallucinations and heteroaggressive behaviour. EEG record during the episode shows (A) interictal epileptiform activity over T7, P7, P3 (box) and (B) subclinical seizures (42 subclinical seizures in 6 hours) starting with alpha rhythm in T8 and spreading to the right frontotemporal area (box).
1.4 Case 4
A 61-year-old female patient was diagnosed at the age of 18 with non-lesional DRE, temporal and biparietal lobes. The patient experienced FIAS not preceded by aura with a frequency of 10–15 episodes per month, and 1–2 SE per month (starting with clusters of 5–7 seizures for 3–4 hours and continuing with an altered mental state of confusion and disorientation for 3 days). Several ASDs were trialed without achieving seizure control. The last trial included combination therapy with levetiracetam and lamotrigine. At the age of 50 during periods when the frequency of seizures was higher, the patient started suffering ictal psychosis characterised by episodes of agitation, auditory hallucinations, and perspicuous feelings. No prior history of psychotic disorders was reported. Antipsychotic treatment was initiated with risperidone without achieving control of psychotic episodes which continued with a frequency of 2–4 per year requiring hospitalization on 7 occasions, 3 of them due to suicide attempts.
At the age of 58 VNS was implanted achieving a reduction of seizure frequency by 60% and elimination of SE over a 4 year follow-up period. Seizure severity also changed due to changes in semiology to focal aware seizures with somatosensory aura in the right foot not followed by impaired awareness most of the time when she acutely activated magnet-induced VNS stimulation. No further psychotic episodes were documented after the first year of VNS implantation.
Additionally, 18F-FDG-PET before VNS implantation was performed showing hypometabolism in both superior parietal lobes, more evident in the right, and relative hypermetabolism in the mesial frontal areas and anterior insulas. 18F-FDG-PET after 4 years following VNS implantation showed less intense hypometabolism in both superior parietal lobes with a normalisation of the hypermetabolism in the frontal lobes, insular lobes, and left caudate nucleus (shown in Fig. 3).Fig. 3 18F-FDG-PET pre- and post-VNS implantation a)18F-FDG-PET pre-VNS shows hypometabolism in both superior parietal lobes (^), more intense in the right (epileptogenic area) and relative hypermetabolism in the mesial frontal areas (*) and the anterior insulas ( ). b)18F-FDG-PET post-VNS shows less intense hypometabolism in both superior parietal lobes (^) with a normalization of the hypermetabolism in the frontal lobes (*) and insular lobes ( ). c) Z map of the18F-FDG-PET subtraction co-recorded with the MRI, showing the cortical areas that underwent a change of more than 2SD in metabolism; frontal areas with a decrease of metabolism (blue blob) and right parietal areas with increase of metabolism (orange blob). (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
A summary of demographics and clinical characteristics of the reported cases and VNS therapy effects are shown in Table 1 and Table 2, respectively.Table 1 Demographics and clinical characteristics of patients with prior history of periictal psychosis (PPE) and VNS. therapy.
P 1 P 2 P 3 P 4
Gender Male Male Female Female
Age (Yrs) 40 54 47 61
Age at epilepsy onset (Yrs) 23 14 12 18
Aetiology Unknown Malformation of cortical development Left oligodendroglioma Unknown
Seizures localization Bitemporal Bitemporal Left parietal, bitemporal Left temporal, biparietal
Age at psychosis onset (Yrs) 34 43 36 50
Psychiatric symptoms Confusion, auditory hallucinations Confusion, Hallucinations, paranoia Anxiety, agitation, heteroaggressivity Agitation, auditory hallucinations, perspicuous feelings
Psychiatric disorder in relation to seizures* Postictal Postictal Ictal Ictal
Age at VNS implantation (Yrs) 35 48 43 58
VNS** follow-up time (Yrs) 5 6 4 3
Intensity/frequency VNS* 1 mA/ on 30″ off 5′ 2 mA/ on 30″ off 5′ 2.25 mA/ on 30″ off 1.8′ 2 mA/ on 30″ off 3′
* Psychotic disorder due to epilepsy, according to DSM-IV criteria (code 293.0: Diagnostic and Statistical Manual of Mental Disorders); **VNS: Vagal nerve stimulation.
Table 2 VNS therapy effects.
Pre-VNS Post-VNS
Seizure type Seizure frequency (per month) Seizure treatment (dose mg/day) Psychotic episode frequency (per year) Psychiatric treatment (dose mg/day) Seizure type Reduction Seizure frequency (%) Seizure treatment (dose mg/day) Magnet-controlled seizures Psychotic episode Frequency (per year) Psychiatric treatment (dose mg/day) Psychotic episode-free* (Yrs) Psychotic episode-free period (Yrs)
PT1 FIAS, occasionally FBTCS 8 Surgery OXC (1500)
CBM (10) BRV (100) 3 – Focal awareness 62.5% OXC (1200)
CBM (10)
LCM (20) Yes 3 episodes in the 1-2nd year – 3rd 2
PT2 FIAS, occasionally FBTCS 8–6 OXC (1200)
PHT (350)
LCM (200) 2–3 QTP (200) HLP (6) Nocturnal seizures 42.8% PHT (350)
LCM (200)
ESL (1600) No No episodes QTP (100)
HLP (4) 1st 6
PT3 FIAS 30–50
SE 1 Surgery (3)
ZNS (300) CBZ (1200)
CBM (20) 6–8 QTP (100) CZP (100) Focal awareness and falls 82.5%
SE 100% CBZ (1200)
ZNS (300)
CBM (20) No 1 episode in the 1st year QTP (100) 2nd 3
PT4 FIAS 10–15
SE 1–2 LVT (2000) LMT (400) 2–4 RPD (10) Focal awareness 60%
SE 100% LVT (1000)
LMT (400) Yes No episodes QTP (100) 1st 3
Abbreviations: FIAS: Focal impaired awareness seizure; FBTCS: focal to bilateral tonic-clonic seizure, SE: status epilepticus; BRV: brivaracetam, CBZ: carbamazepine, CBM: clobazam, LCM: lacosamide, LMT: lamotrigine, LVT: levetiracetam, OXC: oxcarbazepine, PHT: phenytoin, ZNS: zonisamide; CPZ: clozapine, HLP: haloperidol, QTP: quetiapine, RPD: risperidone. * Determined to be the first psychotic episode-free year after VNS implantation.
2 Discussion/Conclusion
New onset psychotic episodes after VNS implantation have been reported in the literature [10]. These are may be seen in patients with DRE when they suddenly become seizure-free, presumably due to forced normalization. In contrast, one study has shown an antipsychotic effect after VNS implantation [12]. Recently, Lee et al. [14] reported the first case of forced normalization after turning off VNS in a patient suffering from Lennox-Gastaut syndrome.
Regarding the VNS mechanisms of action, it is thought that afferent vagal fibers modulate the release of different neurotransmitters in the brainstem involving the locus coeruleus, the nucleus of the solitary tract, thalamus, and limbic system structures. The dysregulation of neurotransmitters has also been identified relative to altered seizure threshold and in psychiatric disorders [15].
In our study, the results showed that patients suffering from PPE had their ictal or postictal psychotic episodes controlled after VNS implantation. However, the positive psychotropic effect was not immediate. Combined time-frame analysis showed a latency effect of VNS to control psychosis of 8.3 months (range: 6–36 months). This occurred despite the absemce of seizure control, however, in three of the cases semiology changed after VNS implantation.
18F-FDG-PET images showed a normalization of metabolism in both medial prefrontal cortical areas and anterior insulas in one of our patients, after VNS implantation. Interestingly, perfusion changes in the same areas have been described apart from the epileptogenic foci in psychotic and epileptic patients [16], [17], [18]. Normalization of medial frontal metabolism, one of the cortical areas of the cortico-striatal-thalamic-cortical loop circuits has been suggested as important in schizophrenia patients and has also been observed in DRE patients suffering psychosis [19].
Although it is speculative, this positive psychotropic effect in DRE patients suffering ictal and postictal psychosis could be related to a long-term neuromodulator effect of the VNS, independent of its antiseizure effect [20], [21], [22]. Despite these encouraging preliminary results, future research is needed to confirm our findings and to determine whether VNS-induced brain changes are associated with a favorable outcome in patients with VNS and ictal or postictal psychosis. Larger prospective studies are recommendable to validate our initial observation.
3 Statements
3.1 Ethics statement
The study was approved by the Ethics Committee of the University Hospital of Bellvitge (Hospitalet de Llobregat, Barcelona, Spain) and conducted in accordance with the Declaration of Helsinki, PR 349/18. The patients’ confidential information was protected according to the current European and Spanish regulations. All patients signed an informed consent.
Acknowledgments
We gratefully thank all the patients who selflessly participated in the study.
Declaration of Competing Interest
T. Vancamp is also an employee of LivaNova. All other authors report no conflicts of interest.
Study funding
No financial or any other support has been provided to the authors to perform this study, nor to compose this manuscript.
Authors’ contributions:
I. Conception and design: M. Falip, T. Vancamp, and M. Alemany.
II. Administrative support: M. Santurino.
III. Provision of study materials for patients: G. Plans, E. Real, N.Custal, and J. Mora.
IV. Collection and assembly of data: M. Falip, L. Rodríguez-Bel, and M. Alemany.
V. Data analysis and interpretation: M. Falip, J. Sala-Padró, and M. Alemany.
VI. Manuscript writing: All authors.
VII. Final approval of manuscript: All authors | LAMOTRIGINE, LEVETIRACETAM | DrugsGivenReaction | CC BY-NC-ND | 33665601 | 19,111,971 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Off label use'. | Vagus nerve stimulation as a potential modulator of periictal psychotic episodes: A report of four cases.
Drug resistant epilepsy (DRE) has been associated with a high incidence of psychotic disorders. Patients can develop psychosis after starting a new antiseizure medication, after undergoing resective surgery, or after implantation of a vagus nerve stimulation (VNS) system. The aim of this study was to investigate the modulation effect of VNS on psychotic episodes in DRE patients with a pre-existing history of periictal psychotic episodes (PPE). We retrospectively report the outcome of four patients from a single tertiary center with PPE prior to implantation. None of the implanted patients developed de novo PPE after VNS therapy. Regarding seizure outcome, all patients demonstrated a response to VNS with two who experienced who status epilepticus and three patients wtih a change in semiology with after VNS implantation. PPE disappeared in all the study patients, two of them at 6 months post-implantation and in the others after 2 and 3 years, respectively. 18F-FDG-PET results showed hypermetabolism in both anterior insular and medial frontal lobes which disappeared in the 18F -FDG-PET 4 years post-implantation. Based on the results of this series of cases we suggest that VNS therapy may be useful to modulatet PPE in patients with DRE, though effectiveness may be time-dependent.
1 Introduction
Psychiatric disorders affect patients with epilepsy more frequently than they do the general population. The reported prevalence of psychotic disturbances varies between 2% and 7%, with a pooled prevalence of 5.6% [1]. The variation becomes higher when compared to the general population (1%), especially in those with temporal lobe epilepsy (TLE), affecting nearly 20% of patients [2]. Psychosis may be seen based upon its temporal relationship with seizures and include preictal, ictal, and postictal psychosis. We separated them into periictal psychotic episodes (PPE) and interictal psychosis (IIP) when a relationship between psychosis and seizures did not exist.
For PPE we used the same definitions as those identified by Logsdail and Toone. PIP was a defined as appearing within one week after a seizure or cluster of seizures, lasting from at least 15 hours up to 2 months, and preceded by a lucid period (24–72 h). Ictal psychosis was defined as psychosis appearing simultaneously with a prolonged seizure or status epilepticus as the clinical expression confirmed by an EEG without prominent motor symptoms [3].
Most of the old and new antiseizure drugs (ASD) as well as surgical treatment have been implicated in the emergence of PPE [4], [5]. Psychotic symptoms in epileptic patients with PPE are thought to be influenced by a disruption in a chronic inhibitory mechanism. Immediately after a cluster of seizures, PIP patients may experience an unusually profound depression of limbic function producing a disconnection of the temporal-limbic structures and the prefrontal structures and a loss of control over the prefrontal structures [6]. This concept was first introduced in 1953 by Landolt with the concept of ‘forced normalization theory’ to describe the appearance of psychotic episodes associated with total or partial normalization of the electroencephalogram (EEG) in patients with epilepsy [7]. In regard to this, vagus nerve stimulation (VNS) therapy has also played a role [8], [9], [10], [11]. Paradoxically, a positive effect in the modulation of psychiatric symptoms has been observed in VNS treated patients, and it has been approved as a non-pharmacological adunctive treatment for depression [12]. Moreover, a recent study conducted in an animal model for schizophrenia found VNS provided a positive effect in controlling psychotic symptoms [13].
We aimed to study the neuro-modulatory effect of VNS on psychotic episodes in drug-resistant epilepsy (DRE) patients with a pre-existing history of PPE in a single-center retrospective analysis. A total of 48 patients diagnosed with DRE and treated with VNS therapy from 2006 to 2016 were identified. None of the implanted patients developed psychosis. In the present study we included 4 patients from the series with a prior history of PPE.
Patient evaluation included a formal intermittent psychiatric examination, prolonged video-EEG (vEEG), structural magnetic resonance imaging (MRI) study with a standard epilepsy protocol, and 18F-labelled fluoro-2-deoxyglucose-positron emission tomography (18F-FDG-PET) co-registered with MRI.
1.1 Case 1
A 40-year-old male patient was diagnosed at the age of 23 with non-lesional bitemporal DRE. The patient experienced 8 episodes per month of focal impaired awareness seizure (FIAS), and occasionally focal to bilateral tonic-clonic seizure (FBTCS). Several ASDs were tested without achieving seizure control, with oxcarbazepine (OXC), clobazam (CBM) and brivaracetam (BRV) the last combination tried. Anterior temporal lobe resection of the most affected temporal lobe was done at the age of 34 without changes in seizure frequency. After nine months, the patient started suffering PIP episodes at a frequency of 3 episodes per year. PIP episodes began in the 12–24 hours after the seizure and lasted for 3–5 days. These episodes were characterised by a state of confusion and auditory hallucinations, requiring hospitalization in one case. No prior history of psychotic disorder was reported. During PIP episodes normal EEG background with fronto–temporal interictal epileptiform discharges was recorded (see Fig. 1). VNS device was implanted one year later to achieve better seizure control. After a 5-year follow-up seizures were reduced by 62.5% in additio to a change in semiology (focal aware seizure with distorted body perception) and reduced seizure severity. In terms of PIP, 3 episodes in the 2nd year was noted and no new episodes appeared after the third year of stimulation.Fig. 1 EEG recording during a postictal psychosis Patient with visual hallucinations and feelings of being harmed by others. EEG records show a left temporal breach rhythm due to previous craniotomy. There were occasional interictal epileptiform discharges in the recording (box).
1.2 Case 2
A 54-year-old male patient was diagnosed at the age of 14 with DRE secondary to a malformation of cortical development. Bitemporal seizures at a frequency of 6–8 episodes per month were reported. FIAS not preceded by aura and occasionally Focal to bilateral tonic-clonic seizures (FBTCS) were the typical seizure types. Several ASDs (OXC, phenytoin (PHT) and lacosamide (LCM)) were tested without achieving seizure control. At the age of 43 the patient started suffering recurrent episodes of postictal psychosis which started between 8 and 12 hours after a seizure, characterised by a state of confusion with hallucinations and paranoia. No prior history of psychotic disorder was reported. Antipsychotic treatment was initiated with quetiapine (QTP) and haloperidol (HLP); however, episodes were still present occurring with a frequency of 2–3 times per year, requiring hospitalization on two occasions. VNS therapy was implanted at the age of 48. After a 6-year follow-up seizures were reduced by 42.8% with a change in semiology (appearing only nocturnally). No further episodes of postictal psychosis were documented one year after VNS implantation.
1.3 Case 3
A 47-year-old female patient was diagnosed at the age of 12 with DRE secondary to a parietal tumour. Initial surgery was done in another center when the patient was 16 and the histopathology was reported as oligodendroglioma, with complete resection. The patient was seizure free for 3 years but then the seizures reappeared and became more and more frequent. No evidence of tumor relapse was observed. She was reoperated twice, at the ages of 25 and 31 including a left parietal topectomy and a right amygdalohippocampectomy. At the age of 36 she started suffering ictal psychosis during episodes characterised by delusions, anxiety, agitation, and heteroaggressivity. These psychotic episodes appeared simultaneously with an exacerbation of seizure clustering. No prior history of psychotic disorder was reported. She was monitored in our center from 2012, and at that time she suffered 1–2 seizures per day and 1 episode of psychosis per month. EEG findings during these episodes showed seizures arising in one parietal or temporal lobe evolving to contralateral areas without recovery between them (see Fig. 2). Antipsychotic treatment was initiated with QTP and clozapine (CPZ), but unfortunately the episodes remained, with a frequency of 6–8 per year. In relation to post-surgical changes, MRI showed areas of encephalomalacia-gliosis on the right temporal-insular cortex and left parietal splenium of the corpus callosum. At the age of 43, a VNS was implanted achieving a reduction of seizures by 82.5% and elimination of the episodes of SE over a 4 year follow-up period. Post-VNS the semiology of seizures also changed to focal aware seizures and falls. Only 1 episode of ictal psychosis was documented in the 1st year and was completely eliminated by the 2nd year after VNS implantation.Fig. 2 EEG recording during an ictal psychosis Patient with visual hallucinations and heteroaggressive behaviour. EEG record during the episode shows (A) interictal epileptiform activity over T7, P7, P3 (box) and (B) subclinical seizures (42 subclinical seizures in 6 hours) starting with alpha rhythm in T8 and spreading to the right frontotemporal area (box).
1.4 Case 4
A 61-year-old female patient was diagnosed at the age of 18 with non-lesional DRE, temporal and biparietal lobes. The patient experienced FIAS not preceded by aura with a frequency of 10–15 episodes per month, and 1–2 SE per month (starting with clusters of 5–7 seizures for 3–4 hours and continuing with an altered mental state of confusion and disorientation for 3 days). Several ASDs were trialed without achieving seizure control. The last trial included combination therapy with levetiracetam and lamotrigine. At the age of 50 during periods when the frequency of seizures was higher, the patient started suffering ictal psychosis characterised by episodes of agitation, auditory hallucinations, and perspicuous feelings. No prior history of psychotic disorders was reported. Antipsychotic treatment was initiated with risperidone without achieving control of psychotic episodes which continued with a frequency of 2–4 per year requiring hospitalization on 7 occasions, 3 of them due to suicide attempts.
At the age of 58 VNS was implanted achieving a reduction of seizure frequency by 60% and elimination of SE over a 4 year follow-up period. Seizure severity also changed due to changes in semiology to focal aware seizures with somatosensory aura in the right foot not followed by impaired awareness most of the time when she acutely activated magnet-induced VNS stimulation. No further psychotic episodes were documented after the first year of VNS implantation.
Additionally, 18F-FDG-PET before VNS implantation was performed showing hypometabolism in both superior parietal lobes, more evident in the right, and relative hypermetabolism in the mesial frontal areas and anterior insulas. 18F-FDG-PET after 4 years following VNS implantation showed less intense hypometabolism in both superior parietal lobes with a normalisation of the hypermetabolism in the frontal lobes, insular lobes, and left caudate nucleus (shown in Fig. 3).Fig. 3 18F-FDG-PET pre- and post-VNS implantation a)18F-FDG-PET pre-VNS shows hypometabolism in both superior parietal lobes (^), more intense in the right (epileptogenic area) and relative hypermetabolism in the mesial frontal areas (*) and the anterior insulas ( ). b)18F-FDG-PET post-VNS shows less intense hypometabolism in both superior parietal lobes (^) with a normalization of the hypermetabolism in the frontal lobes (*) and insular lobes ( ). c) Z map of the18F-FDG-PET subtraction co-recorded with the MRI, showing the cortical areas that underwent a change of more than 2SD in metabolism; frontal areas with a decrease of metabolism (blue blob) and right parietal areas with increase of metabolism (orange blob). (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
A summary of demographics and clinical characteristics of the reported cases and VNS therapy effects are shown in Table 1 and Table 2, respectively.Table 1 Demographics and clinical characteristics of patients with prior history of periictal psychosis (PPE) and VNS. therapy.
P 1 P 2 P 3 P 4
Gender Male Male Female Female
Age (Yrs) 40 54 47 61
Age at epilepsy onset (Yrs) 23 14 12 18
Aetiology Unknown Malformation of cortical development Left oligodendroglioma Unknown
Seizures localization Bitemporal Bitemporal Left parietal, bitemporal Left temporal, biparietal
Age at psychosis onset (Yrs) 34 43 36 50
Psychiatric symptoms Confusion, auditory hallucinations Confusion, Hallucinations, paranoia Anxiety, agitation, heteroaggressivity Agitation, auditory hallucinations, perspicuous feelings
Psychiatric disorder in relation to seizures* Postictal Postictal Ictal Ictal
Age at VNS implantation (Yrs) 35 48 43 58
VNS** follow-up time (Yrs) 5 6 4 3
Intensity/frequency VNS* 1 mA/ on 30″ off 5′ 2 mA/ on 30″ off 5′ 2.25 mA/ on 30″ off 1.8′ 2 mA/ on 30″ off 3′
* Psychotic disorder due to epilepsy, according to DSM-IV criteria (code 293.0: Diagnostic and Statistical Manual of Mental Disorders); **VNS: Vagal nerve stimulation.
Table 2 VNS therapy effects.
Pre-VNS Post-VNS
Seizure type Seizure frequency (per month) Seizure treatment (dose mg/day) Psychotic episode frequency (per year) Psychiatric treatment (dose mg/day) Seizure type Reduction Seizure frequency (%) Seizure treatment (dose mg/day) Magnet-controlled seizures Psychotic episode Frequency (per year) Psychiatric treatment (dose mg/day) Psychotic episode-free* (Yrs) Psychotic episode-free period (Yrs)
PT1 FIAS, occasionally FBTCS 8 Surgery OXC (1500)
CBM (10) BRV (100) 3 – Focal awareness 62.5% OXC (1200)
CBM (10)
LCM (20) Yes 3 episodes in the 1-2nd year – 3rd 2
PT2 FIAS, occasionally FBTCS 8–6 OXC (1200)
PHT (350)
LCM (200) 2–3 QTP (200) HLP (6) Nocturnal seizures 42.8% PHT (350)
LCM (200)
ESL (1600) No No episodes QTP (100)
HLP (4) 1st 6
PT3 FIAS 30–50
SE 1 Surgery (3)
ZNS (300) CBZ (1200)
CBM (20) 6–8 QTP (100) CZP (100) Focal awareness and falls 82.5%
SE 100% CBZ (1200)
ZNS (300)
CBM (20) No 1 episode in the 1st year QTP (100) 2nd 3
PT4 FIAS 10–15
SE 1–2 LVT (2000) LMT (400) 2–4 RPD (10) Focal awareness 60%
SE 100% LVT (1000)
LMT (400) Yes No episodes QTP (100) 1st 3
Abbreviations: FIAS: Focal impaired awareness seizure; FBTCS: focal to bilateral tonic-clonic seizure, SE: status epilepticus; BRV: brivaracetam, CBZ: carbamazepine, CBM: clobazam, LCM: lacosamide, LMT: lamotrigine, LVT: levetiracetam, OXC: oxcarbazepine, PHT: phenytoin, ZNS: zonisamide; CPZ: clozapine, HLP: haloperidol, QTP: quetiapine, RPD: risperidone. * Determined to be the first psychotic episode-free year after VNS implantation.
2 Discussion/Conclusion
New onset psychotic episodes after VNS implantation have been reported in the literature [10]. These are may be seen in patients with DRE when they suddenly become seizure-free, presumably due to forced normalization. In contrast, one study has shown an antipsychotic effect after VNS implantation [12]. Recently, Lee et al. [14] reported the first case of forced normalization after turning off VNS in a patient suffering from Lennox-Gastaut syndrome.
Regarding the VNS mechanisms of action, it is thought that afferent vagal fibers modulate the release of different neurotransmitters in the brainstem involving the locus coeruleus, the nucleus of the solitary tract, thalamus, and limbic system structures. The dysregulation of neurotransmitters has also been identified relative to altered seizure threshold and in psychiatric disorders [15].
In our study, the results showed that patients suffering from PPE had their ictal or postictal psychotic episodes controlled after VNS implantation. However, the positive psychotropic effect was not immediate. Combined time-frame analysis showed a latency effect of VNS to control psychosis of 8.3 months (range: 6–36 months). This occurred despite the absemce of seizure control, however, in three of the cases semiology changed after VNS implantation.
18F-FDG-PET images showed a normalization of metabolism in both medial prefrontal cortical areas and anterior insulas in one of our patients, after VNS implantation. Interestingly, perfusion changes in the same areas have been described apart from the epileptogenic foci in psychotic and epileptic patients [16], [17], [18]. Normalization of medial frontal metabolism, one of the cortical areas of the cortico-striatal-thalamic-cortical loop circuits has been suggested as important in schizophrenia patients and has also been observed in DRE patients suffering psychosis [19].
Although it is speculative, this positive psychotropic effect in DRE patients suffering ictal and postictal psychosis could be related to a long-term neuromodulator effect of the VNS, independent of its antiseizure effect [20], [21], [22]. Despite these encouraging preliminary results, future research is needed to confirm our findings and to determine whether VNS-induced brain changes are associated with a favorable outcome in patients with VNS and ictal or postictal psychosis. Larger prospective studies are recommendable to validate our initial observation.
3 Statements
3.1 Ethics statement
The study was approved by the Ethics Committee of the University Hospital of Bellvitge (Hospitalet de Llobregat, Barcelona, Spain) and conducted in accordance with the Declaration of Helsinki, PR 349/18. The patients’ confidential information was protected according to the current European and Spanish regulations. All patients signed an informed consent.
Acknowledgments
We gratefully thank all the patients who selflessly participated in the study.
Declaration of Competing Interest
T. Vancamp is also an employee of LivaNova. All other authors report no conflicts of interest.
Study funding
No financial or any other support has been provided to the authors to perform this study, nor to compose this manuscript.
Authors’ contributions:
I. Conception and design: M. Falip, T. Vancamp, and M. Alemany.
II. Administrative support: M. Santurino.
III. Provision of study materials for patients: G. Plans, E. Real, N.Custal, and J. Mora.
IV. Collection and assembly of data: M. Falip, L. Rodríguez-Bel, and M. Alemany.
V. Data analysis and interpretation: M. Falip, J. Sala-Padró, and M. Alemany.
VI. Manuscript writing: All authors.
VII. Final approval of manuscript: All authors | LAMOTRIGINE, LEVETIRACETAM | DrugsGivenReaction | CC BY-NC-ND | 33665601 | 19,065,855 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Suicide attempt'. | Vagus nerve stimulation as a potential modulator of periictal psychotic episodes: A report of four cases.
Drug resistant epilepsy (DRE) has been associated with a high incidence of psychotic disorders. Patients can develop psychosis after starting a new antiseizure medication, after undergoing resective surgery, or after implantation of a vagus nerve stimulation (VNS) system. The aim of this study was to investigate the modulation effect of VNS on psychotic episodes in DRE patients with a pre-existing history of periictal psychotic episodes (PPE). We retrospectively report the outcome of four patients from a single tertiary center with PPE prior to implantation. None of the implanted patients developed de novo PPE after VNS therapy. Regarding seizure outcome, all patients demonstrated a response to VNS with two who experienced who status epilepticus and three patients wtih a change in semiology with after VNS implantation. PPE disappeared in all the study patients, two of them at 6 months post-implantation and in the others after 2 and 3 years, respectively. 18F-FDG-PET results showed hypermetabolism in both anterior insular and medial frontal lobes which disappeared in the 18F -FDG-PET 4 years post-implantation. Based on the results of this series of cases we suggest that VNS therapy may be useful to modulatet PPE in patients with DRE, though effectiveness may be time-dependent.
1 Introduction
Psychiatric disorders affect patients with epilepsy more frequently than they do the general population. The reported prevalence of psychotic disturbances varies between 2% and 7%, with a pooled prevalence of 5.6% [1]. The variation becomes higher when compared to the general population (1%), especially in those with temporal lobe epilepsy (TLE), affecting nearly 20% of patients [2]. Psychosis may be seen based upon its temporal relationship with seizures and include preictal, ictal, and postictal psychosis. We separated them into periictal psychotic episodes (PPE) and interictal psychosis (IIP) when a relationship between psychosis and seizures did not exist.
For PPE we used the same definitions as those identified by Logsdail and Toone. PIP was a defined as appearing within one week after a seizure or cluster of seizures, lasting from at least 15 hours up to 2 months, and preceded by a lucid period (24–72 h). Ictal psychosis was defined as psychosis appearing simultaneously with a prolonged seizure or status epilepticus as the clinical expression confirmed by an EEG without prominent motor symptoms [3].
Most of the old and new antiseizure drugs (ASD) as well as surgical treatment have been implicated in the emergence of PPE [4], [5]. Psychotic symptoms in epileptic patients with PPE are thought to be influenced by a disruption in a chronic inhibitory mechanism. Immediately after a cluster of seizures, PIP patients may experience an unusually profound depression of limbic function producing a disconnection of the temporal-limbic structures and the prefrontal structures and a loss of control over the prefrontal structures [6]. This concept was first introduced in 1953 by Landolt with the concept of ‘forced normalization theory’ to describe the appearance of psychotic episodes associated with total or partial normalization of the electroencephalogram (EEG) in patients with epilepsy [7]. In regard to this, vagus nerve stimulation (VNS) therapy has also played a role [8], [9], [10], [11]. Paradoxically, a positive effect in the modulation of psychiatric symptoms has been observed in VNS treated patients, and it has been approved as a non-pharmacological adunctive treatment for depression [12]. Moreover, a recent study conducted in an animal model for schizophrenia found VNS provided a positive effect in controlling psychotic symptoms [13].
We aimed to study the neuro-modulatory effect of VNS on psychotic episodes in drug-resistant epilepsy (DRE) patients with a pre-existing history of PPE in a single-center retrospective analysis. A total of 48 patients diagnosed with DRE and treated with VNS therapy from 2006 to 2016 were identified. None of the implanted patients developed psychosis. In the present study we included 4 patients from the series with a prior history of PPE.
Patient evaluation included a formal intermittent psychiatric examination, prolonged video-EEG (vEEG), structural magnetic resonance imaging (MRI) study with a standard epilepsy protocol, and 18F-labelled fluoro-2-deoxyglucose-positron emission tomography (18F-FDG-PET) co-registered with MRI.
1.1 Case 1
A 40-year-old male patient was diagnosed at the age of 23 with non-lesional bitemporal DRE. The patient experienced 8 episodes per month of focal impaired awareness seizure (FIAS), and occasionally focal to bilateral tonic-clonic seizure (FBTCS). Several ASDs were tested without achieving seizure control, with oxcarbazepine (OXC), clobazam (CBM) and brivaracetam (BRV) the last combination tried. Anterior temporal lobe resection of the most affected temporal lobe was done at the age of 34 without changes in seizure frequency. After nine months, the patient started suffering PIP episodes at a frequency of 3 episodes per year. PIP episodes began in the 12–24 hours after the seizure and lasted for 3–5 days. These episodes were characterised by a state of confusion and auditory hallucinations, requiring hospitalization in one case. No prior history of psychotic disorder was reported. During PIP episodes normal EEG background with fronto–temporal interictal epileptiform discharges was recorded (see Fig. 1). VNS device was implanted one year later to achieve better seizure control. After a 5-year follow-up seizures were reduced by 62.5% in additio to a change in semiology (focal aware seizure with distorted body perception) and reduced seizure severity. In terms of PIP, 3 episodes in the 2nd year was noted and no new episodes appeared after the third year of stimulation.Fig. 1 EEG recording during a postictal psychosis Patient with visual hallucinations and feelings of being harmed by others. EEG records show a left temporal breach rhythm due to previous craniotomy. There were occasional interictal epileptiform discharges in the recording (box).
1.2 Case 2
A 54-year-old male patient was diagnosed at the age of 14 with DRE secondary to a malformation of cortical development. Bitemporal seizures at a frequency of 6–8 episodes per month were reported. FIAS not preceded by aura and occasionally Focal to bilateral tonic-clonic seizures (FBTCS) were the typical seizure types. Several ASDs (OXC, phenytoin (PHT) and lacosamide (LCM)) were tested without achieving seizure control. At the age of 43 the patient started suffering recurrent episodes of postictal psychosis which started between 8 and 12 hours after a seizure, characterised by a state of confusion with hallucinations and paranoia. No prior history of psychotic disorder was reported. Antipsychotic treatment was initiated with quetiapine (QTP) and haloperidol (HLP); however, episodes were still present occurring with a frequency of 2–3 times per year, requiring hospitalization on two occasions. VNS therapy was implanted at the age of 48. After a 6-year follow-up seizures were reduced by 42.8% with a change in semiology (appearing only nocturnally). No further episodes of postictal psychosis were documented one year after VNS implantation.
1.3 Case 3
A 47-year-old female patient was diagnosed at the age of 12 with DRE secondary to a parietal tumour. Initial surgery was done in another center when the patient was 16 and the histopathology was reported as oligodendroglioma, with complete resection. The patient was seizure free for 3 years but then the seizures reappeared and became more and more frequent. No evidence of tumor relapse was observed. She was reoperated twice, at the ages of 25 and 31 including a left parietal topectomy and a right amygdalohippocampectomy. At the age of 36 she started suffering ictal psychosis during episodes characterised by delusions, anxiety, agitation, and heteroaggressivity. These psychotic episodes appeared simultaneously with an exacerbation of seizure clustering. No prior history of psychotic disorder was reported. She was monitored in our center from 2012, and at that time she suffered 1–2 seizures per day and 1 episode of psychosis per month. EEG findings during these episodes showed seizures arising in one parietal or temporal lobe evolving to contralateral areas without recovery between them (see Fig. 2). Antipsychotic treatment was initiated with QTP and clozapine (CPZ), but unfortunately the episodes remained, with a frequency of 6–8 per year. In relation to post-surgical changes, MRI showed areas of encephalomalacia-gliosis on the right temporal-insular cortex and left parietal splenium of the corpus callosum. At the age of 43, a VNS was implanted achieving a reduction of seizures by 82.5% and elimination of the episodes of SE over a 4 year follow-up period. Post-VNS the semiology of seizures also changed to focal aware seizures and falls. Only 1 episode of ictal psychosis was documented in the 1st year and was completely eliminated by the 2nd year after VNS implantation.Fig. 2 EEG recording during an ictal psychosis Patient with visual hallucinations and heteroaggressive behaviour. EEG record during the episode shows (A) interictal epileptiform activity over T7, P7, P3 (box) and (B) subclinical seizures (42 subclinical seizures in 6 hours) starting with alpha rhythm in T8 and spreading to the right frontotemporal area (box).
1.4 Case 4
A 61-year-old female patient was diagnosed at the age of 18 with non-lesional DRE, temporal and biparietal lobes. The patient experienced FIAS not preceded by aura with a frequency of 10–15 episodes per month, and 1–2 SE per month (starting with clusters of 5–7 seizures for 3–4 hours and continuing with an altered mental state of confusion and disorientation for 3 days). Several ASDs were trialed without achieving seizure control. The last trial included combination therapy with levetiracetam and lamotrigine. At the age of 50 during periods when the frequency of seizures was higher, the patient started suffering ictal psychosis characterised by episodes of agitation, auditory hallucinations, and perspicuous feelings. No prior history of psychotic disorders was reported. Antipsychotic treatment was initiated with risperidone without achieving control of psychotic episodes which continued with a frequency of 2–4 per year requiring hospitalization on 7 occasions, 3 of them due to suicide attempts.
At the age of 58 VNS was implanted achieving a reduction of seizure frequency by 60% and elimination of SE over a 4 year follow-up period. Seizure severity also changed due to changes in semiology to focal aware seizures with somatosensory aura in the right foot not followed by impaired awareness most of the time when she acutely activated magnet-induced VNS stimulation. No further psychotic episodes were documented after the first year of VNS implantation.
Additionally, 18F-FDG-PET before VNS implantation was performed showing hypometabolism in both superior parietal lobes, more evident in the right, and relative hypermetabolism in the mesial frontal areas and anterior insulas. 18F-FDG-PET after 4 years following VNS implantation showed less intense hypometabolism in both superior parietal lobes with a normalisation of the hypermetabolism in the frontal lobes, insular lobes, and left caudate nucleus (shown in Fig. 3).Fig. 3 18F-FDG-PET pre- and post-VNS implantation a)18F-FDG-PET pre-VNS shows hypometabolism in both superior parietal lobes (^), more intense in the right (epileptogenic area) and relative hypermetabolism in the mesial frontal areas (*) and the anterior insulas ( ). b)18F-FDG-PET post-VNS shows less intense hypometabolism in both superior parietal lobes (^) with a normalization of the hypermetabolism in the frontal lobes (*) and insular lobes ( ). c) Z map of the18F-FDG-PET subtraction co-recorded with the MRI, showing the cortical areas that underwent a change of more than 2SD in metabolism; frontal areas with a decrease of metabolism (blue blob) and right parietal areas with increase of metabolism (orange blob). (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
A summary of demographics and clinical characteristics of the reported cases and VNS therapy effects are shown in Table 1 and Table 2, respectively.Table 1 Demographics and clinical characteristics of patients with prior history of periictal psychosis (PPE) and VNS. therapy.
P 1 P 2 P 3 P 4
Gender Male Male Female Female
Age (Yrs) 40 54 47 61
Age at epilepsy onset (Yrs) 23 14 12 18
Aetiology Unknown Malformation of cortical development Left oligodendroglioma Unknown
Seizures localization Bitemporal Bitemporal Left parietal, bitemporal Left temporal, biparietal
Age at psychosis onset (Yrs) 34 43 36 50
Psychiatric symptoms Confusion, auditory hallucinations Confusion, Hallucinations, paranoia Anxiety, agitation, heteroaggressivity Agitation, auditory hallucinations, perspicuous feelings
Psychiatric disorder in relation to seizures* Postictal Postictal Ictal Ictal
Age at VNS implantation (Yrs) 35 48 43 58
VNS** follow-up time (Yrs) 5 6 4 3
Intensity/frequency VNS* 1 mA/ on 30″ off 5′ 2 mA/ on 30″ off 5′ 2.25 mA/ on 30″ off 1.8′ 2 mA/ on 30″ off 3′
* Psychotic disorder due to epilepsy, according to DSM-IV criteria (code 293.0: Diagnostic and Statistical Manual of Mental Disorders); **VNS: Vagal nerve stimulation.
Table 2 VNS therapy effects.
Pre-VNS Post-VNS
Seizure type Seizure frequency (per month) Seizure treatment (dose mg/day) Psychotic episode frequency (per year) Psychiatric treatment (dose mg/day) Seizure type Reduction Seizure frequency (%) Seizure treatment (dose mg/day) Magnet-controlled seizures Psychotic episode Frequency (per year) Psychiatric treatment (dose mg/day) Psychotic episode-free* (Yrs) Psychotic episode-free period (Yrs)
PT1 FIAS, occasionally FBTCS 8 Surgery OXC (1500)
CBM (10) BRV (100) 3 – Focal awareness 62.5% OXC (1200)
CBM (10)
LCM (20) Yes 3 episodes in the 1-2nd year – 3rd 2
PT2 FIAS, occasionally FBTCS 8–6 OXC (1200)
PHT (350)
LCM (200) 2–3 QTP (200) HLP (6) Nocturnal seizures 42.8% PHT (350)
LCM (200)
ESL (1600) No No episodes QTP (100)
HLP (4) 1st 6
PT3 FIAS 30–50
SE 1 Surgery (3)
ZNS (300) CBZ (1200)
CBM (20) 6–8 QTP (100) CZP (100) Focal awareness and falls 82.5%
SE 100% CBZ (1200)
ZNS (300)
CBM (20) No 1 episode in the 1st year QTP (100) 2nd 3
PT4 FIAS 10–15
SE 1–2 LVT (2000) LMT (400) 2–4 RPD (10) Focal awareness 60%
SE 100% LVT (1000)
LMT (400) Yes No episodes QTP (100) 1st 3
Abbreviations: FIAS: Focal impaired awareness seizure; FBTCS: focal to bilateral tonic-clonic seizure, SE: status epilepticus; BRV: brivaracetam, CBZ: carbamazepine, CBM: clobazam, LCM: lacosamide, LMT: lamotrigine, LVT: levetiracetam, OXC: oxcarbazepine, PHT: phenytoin, ZNS: zonisamide; CPZ: clozapine, HLP: haloperidol, QTP: quetiapine, RPD: risperidone. * Determined to be the first psychotic episode-free year after VNS implantation.
2 Discussion/Conclusion
New onset psychotic episodes after VNS implantation have been reported in the literature [10]. These are may be seen in patients with DRE when they suddenly become seizure-free, presumably due to forced normalization. In contrast, one study has shown an antipsychotic effect after VNS implantation [12]. Recently, Lee et al. [14] reported the first case of forced normalization after turning off VNS in a patient suffering from Lennox-Gastaut syndrome.
Regarding the VNS mechanisms of action, it is thought that afferent vagal fibers modulate the release of different neurotransmitters in the brainstem involving the locus coeruleus, the nucleus of the solitary tract, thalamus, and limbic system structures. The dysregulation of neurotransmitters has also been identified relative to altered seizure threshold and in psychiatric disorders [15].
In our study, the results showed that patients suffering from PPE had their ictal or postictal psychotic episodes controlled after VNS implantation. However, the positive psychotropic effect was not immediate. Combined time-frame analysis showed a latency effect of VNS to control psychosis of 8.3 months (range: 6–36 months). This occurred despite the absemce of seizure control, however, in three of the cases semiology changed after VNS implantation.
18F-FDG-PET images showed a normalization of metabolism in both medial prefrontal cortical areas and anterior insulas in one of our patients, after VNS implantation. Interestingly, perfusion changes in the same areas have been described apart from the epileptogenic foci in psychotic and epileptic patients [16], [17], [18]. Normalization of medial frontal metabolism, one of the cortical areas of the cortico-striatal-thalamic-cortical loop circuits has been suggested as important in schizophrenia patients and has also been observed in DRE patients suffering psychosis [19].
Although it is speculative, this positive psychotropic effect in DRE patients suffering ictal and postictal psychosis could be related to a long-term neuromodulator effect of the VNS, independent of its antiseizure effect [20], [21], [22]. Despite these encouraging preliminary results, future research is needed to confirm our findings and to determine whether VNS-induced brain changes are associated with a favorable outcome in patients with VNS and ictal or postictal psychosis. Larger prospective studies are recommendable to validate our initial observation.
3 Statements
3.1 Ethics statement
The study was approved by the Ethics Committee of the University Hospital of Bellvitge (Hospitalet de Llobregat, Barcelona, Spain) and conducted in accordance with the Declaration of Helsinki, PR 349/18. The patients’ confidential information was protected according to the current European and Spanish regulations. All patients signed an informed consent.
Acknowledgments
We gratefully thank all the patients who selflessly participated in the study.
Declaration of Competing Interest
T. Vancamp is also an employee of LivaNova. All other authors report no conflicts of interest.
Study funding
No financial or any other support has been provided to the authors to perform this study, nor to compose this manuscript.
Authors’ contributions:
I. Conception and design: M. Falip, T. Vancamp, and M. Alemany.
II. Administrative support: M. Santurino.
III. Provision of study materials for patients: G. Plans, E. Real, N.Custal, and J. Mora.
IV. Collection and assembly of data: M. Falip, L. Rodríguez-Bel, and M. Alemany.
V. Data analysis and interpretation: M. Falip, J. Sala-Padró, and M. Alemany.
VI. Manuscript writing: All authors.
VII. Final approval of manuscript: All authors | LAMOTRIGINE, LEVETIRACETAM | DrugsGivenReaction | CC BY-NC-ND | 33665601 | 19,065,855 | 2021 |
What was the dosage of drug 'BRIVARACETAM'? | Vagus nerve stimulation as a potential modulator of periictal psychotic episodes: A report of four cases.
Drug resistant epilepsy (DRE) has been associated with a high incidence of psychotic disorders. Patients can develop psychosis after starting a new antiseizure medication, after undergoing resective surgery, or after implantation of a vagus nerve stimulation (VNS) system. The aim of this study was to investigate the modulation effect of VNS on psychotic episodes in DRE patients with a pre-existing history of periictal psychotic episodes (PPE). We retrospectively report the outcome of four patients from a single tertiary center with PPE prior to implantation. None of the implanted patients developed de novo PPE after VNS therapy. Regarding seizure outcome, all patients demonstrated a response to VNS with two who experienced who status epilepticus and three patients wtih a change in semiology with after VNS implantation. PPE disappeared in all the study patients, two of them at 6 months post-implantation and in the others after 2 and 3 years, respectively. 18F-FDG-PET results showed hypermetabolism in both anterior insular and medial frontal lobes which disappeared in the 18F -FDG-PET 4 years post-implantation. Based on the results of this series of cases we suggest that VNS therapy may be useful to modulatet PPE in patients with DRE, though effectiveness may be time-dependent.
1 Introduction
Psychiatric disorders affect patients with epilepsy more frequently than they do the general population. The reported prevalence of psychotic disturbances varies between 2% and 7%, with a pooled prevalence of 5.6% [1]. The variation becomes higher when compared to the general population (1%), especially in those with temporal lobe epilepsy (TLE), affecting nearly 20% of patients [2]. Psychosis may be seen based upon its temporal relationship with seizures and include preictal, ictal, and postictal psychosis. We separated them into periictal psychotic episodes (PPE) and interictal psychosis (IIP) when a relationship between psychosis and seizures did not exist.
For PPE we used the same definitions as those identified by Logsdail and Toone. PIP was a defined as appearing within one week after a seizure or cluster of seizures, lasting from at least 15 hours up to 2 months, and preceded by a lucid period (24–72 h). Ictal psychosis was defined as psychosis appearing simultaneously with a prolonged seizure or status epilepticus as the clinical expression confirmed by an EEG without prominent motor symptoms [3].
Most of the old and new antiseizure drugs (ASD) as well as surgical treatment have been implicated in the emergence of PPE [4], [5]. Psychotic symptoms in epileptic patients with PPE are thought to be influenced by a disruption in a chronic inhibitory mechanism. Immediately after a cluster of seizures, PIP patients may experience an unusually profound depression of limbic function producing a disconnection of the temporal-limbic structures and the prefrontal structures and a loss of control over the prefrontal structures [6]. This concept was first introduced in 1953 by Landolt with the concept of ‘forced normalization theory’ to describe the appearance of psychotic episodes associated with total or partial normalization of the electroencephalogram (EEG) in patients with epilepsy [7]. In regard to this, vagus nerve stimulation (VNS) therapy has also played a role [8], [9], [10], [11]. Paradoxically, a positive effect in the modulation of psychiatric symptoms has been observed in VNS treated patients, and it has been approved as a non-pharmacological adunctive treatment for depression [12]. Moreover, a recent study conducted in an animal model for schizophrenia found VNS provided a positive effect in controlling psychotic symptoms [13].
We aimed to study the neuro-modulatory effect of VNS on psychotic episodes in drug-resistant epilepsy (DRE) patients with a pre-existing history of PPE in a single-center retrospective analysis. A total of 48 patients diagnosed with DRE and treated with VNS therapy from 2006 to 2016 were identified. None of the implanted patients developed psychosis. In the present study we included 4 patients from the series with a prior history of PPE.
Patient evaluation included a formal intermittent psychiatric examination, prolonged video-EEG (vEEG), structural magnetic resonance imaging (MRI) study with a standard epilepsy protocol, and 18F-labelled fluoro-2-deoxyglucose-positron emission tomography (18F-FDG-PET) co-registered with MRI.
1.1 Case 1
A 40-year-old male patient was diagnosed at the age of 23 with non-lesional bitemporal DRE. The patient experienced 8 episodes per month of focal impaired awareness seizure (FIAS), and occasionally focal to bilateral tonic-clonic seizure (FBTCS). Several ASDs were tested without achieving seizure control, with oxcarbazepine (OXC), clobazam (CBM) and brivaracetam (BRV) the last combination tried. Anterior temporal lobe resection of the most affected temporal lobe was done at the age of 34 without changes in seizure frequency. After nine months, the patient started suffering PIP episodes at a frequency of 3 episodes per year. PIP episodes began in the 12–24 hours after the seizure and lasted for 3–5 days. These episodes were characterised by a state of confusion and auditory hallucinations, requiring hospitalization in one case. No prior history of psychotic disorder was reported. During PIP episodes normal EEG background with fronto–temporal interictal epileptiform discharges was recorded (see Fig. 1). VNS device was implanted one year later to achieve better seizure control. After a 5-year follow-up seizures were reduced by 62.5% in additio to a change in semiology (focal aware seizure with distorted body perception) and reduced seizure severity. In terms of PIP, 3 episodes in the 2nd year was noted and no new episodes appeared after the third year of stimulation.Fig. 1 EEG recording during a postictal psychosis Patient with visual hallucinations and feelings of being harmed by others. EEG records show a left temporal breach rhythm due to previous craniotomy. There were occasional interictal epileptiform discharges in the recording (box).
1.2 Case 2
A 54-year-old male patient was diagnosed at the age of 14 with DRE secondary to a malformation of cortical development. Bitemporal seizures at a frequency of 6–8 episodes per month were reported. FIAS not preceded by aura and occasionally Focal to bilateral tonic-clonic seizures (FBTCS) were the typical seizure types. Several ASDs (OXC, phenytoin (PHT) and lacosamide (LCM)) were tested without achieving seizure control. At the age of 43 the patient started suffering recurrent episodes of postictal psychosis which started between 8 and 12 hours after a seizure, characterised by a state of confusion with hallucinations and paranoia. No prior history of psychotic disorder was reported. Antipsychotic treatment was initiated with quetiapine (QTP) and haloperidol (HLP); however, episodes were still present occurring with a frequency of 2–3 times per year, requiring hospitalization on two occasions. VNS therapy was implanted at the age of 48. After a 6-year follow-up seizures were reduced by 42.8% with a change in semiology (appearing only nocturnally). No further episodes of postictal psychosis were documented one year after VNS implantation.
1.3 Case 3
A 47-year-old female patient was diagnosed at the age of 12 with DRE secondary to a parietal tumour. Initial surgery was done in another center when the patient was 16 and the histopathology was reported as oligodendroglioma, with complete resection. The patient was seizure free for 3 years but then the seizures reappeared and became more and more frequent. No evidence of tumor relapse was observed. She was reoperated twice, at the ages of 25 and 31 including a left parietal topectomy and a right amygdalohippocampectomy. At the age of 36 she started suffering ictal psychosis during episodes characterised by delusions, anxiety, agitation, and heteroaggressivity. These psychotic episodes appeared simultaneously with an exacerbation of seizure clustering. No prior history of psychotic disorder was reported. She was monitored in our center from 2012, and at that time she suffered 1–2 seizures per day and 1 episode of psychosis per month. EEG findings during these episodes showed seizures arising in one parietal or temporal lobe evolving to contralateral areas without recovery between them (see Fig. 2). Antipsychotic treatment was initiated with QTP and clozapine (CPZ), but unfortunately the episodes remained, with a frequency of 6–8 per year. In relation to post-surgical changes, MRI showed areas of encephalomalacia-gliosis on the right temporal-insular cortex and left parietal splenium of the corpus callosum. At the age of 43, a VNS was implanted achieving a reduction of seizures by 82.5% and elimination of the episodes of SE over a 4 year follow-up period. Post-VNS the semiology of seizures also changed to focal aware seizures and falls. Only 1 episode of ictal psychosis was documented in the 1st year and was completely eliminated by the 2nd year after VNS implantation.Fig. 2 EEG recording during an ictal psychosis Patient with visual hallucinations and heteroaggressive behaviour. EEG record during the episode shows (A) interictal epileptiform activity over T7, P7, P3 (box) and (B) subclinical seizures (42 subclinical seizures in 6 hours) starting with alpha rhythm in T8 and spreading to the right frontotemporal area (box).
1.4 Case 4
A 61-year-old female patient was diagnosed at the age of 18 with non-lesional DRE, temporal and biparietal lobes. The patient experienced FIAS not preceded by aura with a frequency of 10–15 episodes per month, and 1–2 SE per month (starting with clusters of 5–7 seizures for 3–4 hours and continuing with an altered mental state of confusion and disorientation for 3 days). Several ASDs were trialed without achieving seizure control. The last trial included combination therapy with levetiracetam and lamotrigine. At the age of 50 during periods when the frequency of seizures was higher, the patient started suffering ictal psychosis characterised by episodes of agitation, auditory hallucinations, and perspicuous feelings. No prior history of psychotic disorders was reported. Antipsychotic treatment was initiated with risperidone without achieving control of psychotic episodes which continued with a frequency of 2–4 per year requiring hospitalization on 7 occasions, 3 of them due to suicide attempts.
At the age of 58 VNS was implanted achieving a reduction of seizure frequency by 60% and elimination of SE over a 4 year follow-up period. Seizure severity also changed due to changes in semiology to focal aware seizures with somatosensory aura in the right foot not followed by impaired awareness most of the time when she acutely activated magnet-induced VNS stimulation. No further psychotic episodes were documented after the first year of VNS implantation.
Additionally, 18F-FDG-PET before VNS implantation was performed showing hypometabolism in both superior parietal lobes, more evident in the right, and relative hypermetabolism in the mesial frontal areas and anterior insulas. 18F-FDG-PET after 4 years following VNS implantation showed less intense hypometabolism in both superior parietal lobes with a normalisation of the hypermetabolism in the frontal lobes, insular lobes, and left caudate nucleus (shown in Fig. 3).Fig. 3 18F-FDG-PET pre- and post-VNS implantation a)18F-FDG-PET pre-VNS shows hypometabolism in both superior parietal lobes (^), more intense in the right (epileptogenic area) and relative hypermetabolism in the mesial frontal areas (*) and the anterior insulas ( ). b)18F-FDG-PET post-VNS shows less intense hypometabolism in both superior parietal lobes (^) with a normalization of the hypermetabolism in the frontal lobes (*) and insular lobes ( ). c) Z map of the18F-FDG-PET subtraction co-recorded with the MRI, showing the cortical areas that underwent a change of more than 2SD in metabolism; frontal areas with a decrease of metabolism (blue blob) and right parietal areas with increase of metabolism (orange blob). (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
A summary of demographics and clinical characteristics of the reported cases and VNS therapy effects are shown in Table 1 and Table 2, respectively.Table 1 Demographics and clinical characteristics of patients with prior history of periictal psychosis (PPE) and VNS. therapy.
P 1 P 2 P 3 P 4
Gender Male Male Female Female
Age (Yrs) 40 54 47 61
Age at epilepsy onset (Yrs) 23 14 12 18
Aetiology Unknown Malformation of cortical development Left oligodendroglioma Unknown
Seizures localization Bitemporal Bitemporal Left parietal, bitemporal Left temporal, biparietal
Age at psychosis onset (Yrs) 34 43 36 50
Psychiatric symptoms Confusion, auditory hallucinations Confusion, Hallucinations, paranoia Anxiety, agitation, heteroaggressivity Agitation, auditory hallucinations, perspicuous feelings
Psychiatric disorder in relation to seizures* Postictal Postictal Ictal Ictal
Age at VNS implantation (Yrs) 35 48 43 58
VNS** follow-up time (Yrs) 5 6 4 3
Intensity/frequency VNS* 1 mA/ on 30″ off 5′ 2 mA/ on 30″ off 5′ 2.25 mA/ on 30″ off 1.8′ 2 mA/ on 30″ off 3′
* Psychotic disorder due to epilepsy, according to DSM-IV criteria (code 293.0: Diagnostic and Statistical Manual of Mental Disorders); **VNS: Vagal nerve stimulation.
Table 2 VNS therapy effects.
Pre-VNS Post-VNS
Seizure type Seizure frequency (per month) Seizure treatment (dose mg/day) Psychotic episode frequency (per year) Psychiatric treatment (dose mg/day) Seizure type Reduction Seizure frequency (%) Seizure treatment (dose mg/day) Magnet-controlled seizures Psychotic episode Frequency (per year) Psychiatric treatment (dose mg/day) Psychotic episode-free* (Yrs) Psychotic episode-free period (Yrs)
PT1 FIAS, occasionally FBTCS 8 Surgery OXC (1500)
CBM (10) BRV (100) 3 – Focal awareness 62.5% OXC (1200)
CBM (10)
LCM (20) Yes 3 episodes in the 1-2nd year – 3rd 2
PT2 FIAS, occasionally FBTCS 8–6 OXC (1200)
PHT (350)
LCM (200) 2–3 QTP (200) HLP (6) Nocturnal seizures 42.8% PHT (350)
LCM (200)
ESL (1600) No No episodes QTP (100)
HLP (4) 1st 6
PT3 FIAS 30–50
SE 1 Surgery (3)
ZNS (300) CBZ (1200)
CBM (20) 6–8 QTP (100) CZP (100) Focal awareness and falls 82.5%
SE 100% CBZ (1200)
ZNS (300)
CBM (20) No 1 episode in the 1st year QTP (100) 2nd 3
PT4 FIAS 10–15
SE 1–2 LVT (2000) LMT (400) 2–4 RPD (10) Focal awareness 60%
SE 100% LVT (1000)
LMT (400) Yes No episodes QTP (100) 1st 3
Abbreviations: FIAS: Focal impaired awareness seizure; FBTCS: focal to bilateral tonic-clonic seizure, SE: status epilepticus; BRV: brivaracetam, CBZ: carbamazepine, CBM: clobazam, LCM: lacosamide, LMT: lamotrigine, LVT: levetiracetam, OXC: oxcarbazepine, PHT: phenytoin, ZNS: zonisamide; CPZ: clozapine, HLP: haloperidol, QTP: quetiapine, RPD: risperidone. * Determined to be the first psychotic episode-free year after VNS implantation.
2 Discussion/Conclusion
New onset psychotic episodes after VNS implantation have been reported in the literature [10]. These are may be seen in patients with DRE when they suddenly become seizure-free, presumably due to forced normalization. In contrast, one study has shown an antipsychotic effect after VNS implantation [12]. Recently, Lee et al. [14] reported the first case of forced normalization after turning off VNS in a patient suffering from Lennox-Gastaut syndrome.
Regarding the VNS mechanisms of action, it is thought that afferent vagal fibers modulate the release of different neurotransmitters in the brainstem involving the locus coeruleus, the nucleus of the solitary tract, thalamus, and limbic system structures. The dysregulation of neurotransmitters has also been identified relative to altered seizure threshold and in psychiatric disorders [15].
In our study, the results showed that patients suffering from PPE had their ictal or postictal psychotic episodes controlled after VNS implantation. However, the positive psychotropic effect was not immediate. Combined time-frame analysis showed a latency effect of VNS to control psychosis of 8.3 months (range: 6–36 months). This occurred despite the absemce of seizure control, however, in three of the cases semiology changed after VNS implantation.
18F-FDG-PET images showed a normalization of metabolism in both medial prefrontal cortical areas and anterior insulas in one of our patients, after VNS implantation. Interestingly, perfusion changes in the same areas have been described apart from the epileptogenic foci in psychotic and epileptic patients [16], [17], [18]. Normalization of medial frontal metabolism, one of the cortical areas of the cortico-striatal-thalamic-cortical loop circuits has been suggested as important in schizophrenia patients and has also been observed in DRE patients suffering psychosis [19].
Although it is speculative, this positive psychotropic effect in DRE patients suffering ictal and postictal psychosis could be related to a long-term neuromodulator effect of the VNS, independent of its antiseizure effect [20], [21], [22]. Despite these encouraging preliminary results, future research is needed to confirm our findings and to determine whether VNS-induced brain changes are associated with a favorable outcome in patients with VNS and ictal or postictal psychosis. Larger prospective studies are recommendable to validate our initial observation.
3 Statements
3.1 Ethics statement
The study was approved by the Ethics Committee of the University Hospital of Bellvitge (Hospitalet de Llobregat, Barcelona, Spain) and conducted in accordance with the Declaration of Helsinki, PR 349/18. The patients’ confidential information was protected according to the current European and Spanish regulations. All patients signed an informed consent.
Acknowledgments
We gratefully thank all the patients who selflessly participated in the study.
Declaration of Competing Interest
T. Vancamp is also an employee of LivaNova. All other authors report no conflicts of interest.
Study funding
No financial or any other support has been provided to the authors to perform this study, nor to compose this manuscript.
Authors’ contributions:
I. Conception and design: M. Falip, T. Vancamp, and M. Alemany.
II. Administrative support: M. Santurino.
III. Provision of study materials for patients: G. Plans, E. Real, N.Custal, and J. Mora.
IV. Collection and assembly of data: M. Falip, L. Rodríguez-Bel, and M. Alemany.
V. Data analysis and interpretation: M. Falip, J. Sala-Padró, and M. Alemany.
VI. Manuscript writing: All authors.
VII. Final approval of manuscript: All authors | UNKNOWN DOSE | DrugDosageText | CC BY-NC-ND | 33665601 | 19,065,895 | 2021 |
What was the dosage of drug 'CLOBAZAM'? | Vagus nerve stimulation as a potential modulator of periictal psychotic episodes: A report of four cases.
Drug resistant epilepsy (DRE) has been associated with a high incidence of psychotic disorders. Patients can develop psychosis after starting a new antiseizure medication, after undergoing resective surgery, or after implantation of a vagus nerve stimulation (VNS) system. The aim of this study was to investigate the modulation effect of VNS on psychotic episodes in DRE patients with a pre-existing history of periictal psychotic episodes (PPE). We retrospectively report the outcome of four patients from a single tertiary center with PPE prior to implantation. None of the implanted patients developed de novo PPE after VNS therapy. Regarding seizure outcome, all patients demonstrated a response to VNS with two who experienced who status epilepticus and three patients wtih a change in semiology with after VNS implantation. PPE disappeared in all the study patients, two of them at 6 months post-implantation and in the others after 2 and 3 years, respectively. 18F-FDG-PET results showed hypermetabolism in both anterior insular and medial frontal lobes which disappeared in the 18F -FDG-PET 4 years post-implantation. Based on the results of this series of cases we suggest that VNS therapy may be useful to modulatet PPE in patients with DRE, though effectiveness may be time-dependent.
1 Introduction
Psychiatric disorders affect patients with epilepsy more frequently than they do the general population. The reported prevalence of psychotic disturbances varies between 2% and 7%, with a pooled prevalence of 5.6% [1]. The variation becomes higher when compared to the general population (1%), especially in those with temporal lobe epilepsy (TLE), affecting nearly 20% of patients [2]. Psychosis may be seen based upon its temporal relationship with seizures and include preictal, ictal, and postictal psychosis. We separated them into periictal psychotic episodes (PPE) and interictal psychosis (IIP) when a relationship between psychosis and seizures did not exist.
For PPE we used the same definitions as those identified by Logsdail and Toone. PIP was a defined as appearing within one week after a seizure or cluster of seizures, lasting from at least 15 hours up to 2 months, and preceded by a lucid period (24–72 h). Ictal psychosis was defined as psychosis appearing simultaneously with a prolonged seizure or status epilepticus as the clinical expression confirmed by an EEG without prominent motor symptoms [3].
Most of the old and new antiseizure drugs (ASD) as well as surgical treatment have been implicated in the emergence of PPE [4], [5]. Psychotic symptoms in epileptic patients with PPE are thought to be influenced by a disruption in a chronic inhibitory mechanism. Immediately after a cluster of seizures, PIP patients may experience an unusually profound depression of limbic function producing a disconnection of the temporal-limbic structures and the prefrontal structures and a loss of control over the prefrontal structures [6]. This concept was first introduced in 1953 by Landolt with the concept of ‘forced normalization theory’ to describe the appearance of psychotic episodes associated with total or partial normalization of the electroencephalogram (EEG) in patients with epilepsy [7]. In regard to this, vagus nerve stimulation (VNS) therapy has also played a role [8], [9], [10], [11]. Paradoxically, a positive effect in the modulation of psychiatric symptoms has been observed in VNS treated patients, and it has been approved as a non-pharmacological adunctive treatment for depression [12]. Moreover, a recent study conducted in an animal model for schizophrenia found VNS provided a positive effect in controlling psychotic symptoms [13].
We aimed to study the neuro-modulatory effect of VNS on psychotic episodes in drug-resistant epilepsy (DRE) patients with a pre-existing history of PPE in a single-center retrospective analysis. A total of 48 patients diagnosed with DRE and treated with VNS therapy from 2006 to 2016 were identified. None of the implanted patients developed psychosis. In the present study we included 4 patients from the series with a prior history of PPE.
Patient evaluation included a formal intermittent psychiatric examination, prolonged video-EEG (vEEG), structural magnetic resonance imaging (MRI) study with a standard epilepsy protocol, and 18F-labelled fluoro-2-deoxyglucose-positron emission tomography (18F-FDG-PET) co-registered with MRI.
1.1 Case 1
A 40-year-old male patient was diagnosed at the age of 23 with non-lesional bitemporal DRE. The patient experienced 8 episodes per month of focal impaired awareness seizure (FIAS), and occasionally focal to bilateral tonic-clonic seizure (FBTCS). Several ASDs were tested without achieving seizure control, with oxcarbazepine (OXC), clobazam (CBM) and brivaracetam (BRV) the last combination tried. Anterior temporal lobe resection of the most affected temporal lobe was done at the age of 34 without changes in seizure frequency. After nine months, the patient started suffering PIP episodes at a frequency of 3 episodes per year. PIP episodes began in the 12–24 hours after the seizure and lasted for 3–5 days. These episodes were characterised by a state of confusion and auditory hallucinations, requiring hospitalization in one case. No prior history of psychotic disorder was reported. During PIP episodes normal EEG background with fronto–temporal interictal epileptiform discharges was recorded (see Fig. 1). VNS device was implanted one year later to achieve better seizure control. After a 5-year follow-up seizures were reduced by 62.5% in additio to a change in semiology (focal aware seizure with distorted body perception) and reduced seizure severity. In terms of PIP, 3 episodes in the 2nd year was noted and no new episodes appeared after the third year of stimulation.Fig. 1 EEG recording during a postictal psychosis Patient with visual hallucinations and feelings of being harmed by others. EEG records show a left temporal breach rhythm due to previous craniotomy. There were occasional interictal epileptiform discharges in the recording (box).
1.2 Case 2
A 54-year-old male patient was diagnosed at the age of 14 with DRE secondary to a malformation of cortical development. Bitemporal seizures at a frequency of 6–8 episodes per month were reported. FIAS not preceded by aura and occasionally Focal to bilateral tonic-clonic seizures (FBTCS) were the typical seizure types. Several ASDs (OXC, phenytoin (PHT) and lacosamide (LCM)) were tested without achieving seizure control. At the age of 43 the patient started suffering recurrent episodes of postictal psychosis which started between 8 and 12 hours after a seizure, characterised by a state of confusion with hallucinations and paranoia. No prior history of psychotic disorder was reported. Antipsychotic treatment was initiated with quetiapine (QTP) and haloperidol (HLP); however, episodes were still present occurring with a frequency of 2–3 times per year, requiring hospitalization on two occasions. VNS therapy was implanted at the age of 48. After a 6-year follow-up seizures were reduced by 42.8% with a change in semiology (appearing only nocturnally). No further episodes of postictal psychosis were documented one year after VNS implantation.
1.3 Case 3
A 47-year-old female patient was diagnosed at the age of 12 with DRE secondary to a parietal tumour. Initial surgery was done in another center when the patient was 16 and the histopathology was reported as oligodendroglioma, with complete resection. The patient was seizure free for 3 years but then the seizures reappeared and became more and more frequent. No evidence of tumor relapse was observed. She was reoperated twice, at the ages of 25 and 31 including a left parietal topectomy and a right amygdalohippocampectomy. At the age of 36 she started suffering ictal psychosis during episodes characterised by delusions, anxiety, agitation, and heteroaggressivity. These psychotic episodes appeared simultaneously with an exacerbation of seizure clustering. No prior history of psychotic disorder was reported. She was monitored in our center from 2012, and at that time she suffered 1–2 seizures per day and 1 episode of psychosis per month. EEG findings during these episodes showed seizures arising in one parietal or temporal lobe evolving to contralateral areas without recovery between them (see Fig. 2). Antipsychotic treatment was initiated with QTP and clozapine (CPZ), but unfortunately the episodes remained, with a frequency of 6–8 per year. In relation to post-surgical changes, MRI showed areas of encephalomalacia-gliosis on the right temporal-insular cortex and left parietal splenium of the corpus callosum. At the age of 43, a VNS was implanted achieving a reduction of seizures by 82.5% and elimination of the episodes of SE over a 4 year follow-up period. Post-VNS the semiology of seizures also changed to focal aware seizures and falls. Only 1 episode of ictal psychosis was documented in the 1st year and was completely eliminated by the 2nd year after VNS implantation.Fig. 2 EEG recording during an ictal psychosis Patient with visual hallucinations and heteroaggressive behaviour. EEG record during the episode shows (A) interictal epileptiform activity over T7, P7, P3 (box) and (B) subclinical seizures (42 subclinical seizures in 6 hours) starting with alpha rhythm in T8 and spreading to the right frontotemporal area (box).
1.4 Case 4
A 61-year-old female patient was diagnosed at the age of 18 with non-lesional DRE, temporal and biparietal lobes. The patient experienced FIAS not preceded by aura with a frequency of 10–15 episodes per month, and 1–2 SE per month (starting with clusters of 5–7 seizures for 3–4 hours and continuing with an altered mental state of confusion and disorientation for 3 days). Several ASDs were trialed without achieving seizure control. The last trial included combination therapy with levetiracetam and lamotrigine. At the age of 50 during periods when the frequency of seizures was higher, the patient started suffering ictal psychosis characterised by episodes of agitation, auditory hallucinations, and perspicuous feelings. No prior history of psychotic disorders was reported. Antipsychotic treatment was initiated with risperidone without achieving control of psychotic episodes which continued with a frequency of 2–4 per year requiring hospitalization on 7 occasions, 3 of them due to suicide attempts.
At the age of 58 VNS was implanted achieving a reduction of seizure frequency by 60% and elimination of SE over a 4 year follow-up period. Seizure severity also changed due to changes in semiology to focal aware seizures with somatosensory aura in the right foot not followed by impaired awareness most of the time when she acutely activated magnet-induced VNS stimulation. No further psychotic episodes were documented after the first year of VNS implantation.
Additionally, 18F-FDG-PET before VNS implantation was performed showing hypometabolism in both superior parietal lobes, more evident in the right, and relative hypermetabolism in the mesial frontal areas and anterior insulas. 18F-FDG-PET after 4 years following VNS implantation showed less intense hypometabolism in both superior parietal lobes with a normalisation of the hypermetabolism in the frontal lobes, insular lobes, and left caudate nucleus (shown in Fig. 3).Fig. 3 18F-FDG-PET pre- and post-VNS implantation a)18F-FDG-PET pre-VNS shows hypometabolism in both superior parietal lobes (^), more intense in the right (epileptogenic area) and relative hypermetabolism in the mesial frontal areas (*) and the anterior insulas ( ). b)18F-FDG-PET post-VNS shows less intense hypometabolism in both superior parietal lobes (^) with a normalization of the hypermetabolism in the frontal lobes (*) and insular lobes ( ). c) Z map of the18F-FDG-PET subtraction co-recorded with the MRI, showing the cortical areas that underwent a change of more than 2SD in metabolism; frontal areas with a decrease of metabolism (blue blob) and right parietal areas with increase of metabolism (orange blob). (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
A summary of demographics and clinical characteristics of the reported cases and VNS therapy effects are shown in Table 1 and Table 2, respectively.Table 1 Demographics and clinical characteristics of patients with prior history of periictal psychosis (PPE) and VNS. therapy.
P 1 P 2 P 3 P 4
Gender Male Male Female Female
Age (Yrs) 40 54 47 61
Age at epilepsy onset (Yrs) 23 14 12 18
Aetiology Unknown Malformation of cortical development Left oligodendroglioma Unknown
Seizures localization Bitemporal Bitemporal Left parietal, bitemporal Left temporal, biparietal
Age at psychosis onset (Yrs) 34 43 36 50
Psychiatric symptoms Confusion, auditory hallucinations Confusion, Hallucinations, paranoia Anxiety, agitation, heteroaggressivity Agitation, auditory hallucinations, perspicuous feelings
Psychiatric disorder in relation to seizures* Postictal Postictal Ictal Ictal
Age at VNS implantation (Yrs) 35 48 43 58
VNS** follow-up time (Yrs) 5 6 4 3
Intensity/frequency VNS* 1 mA/ on 30″ off 5′ 2 mA/ on 30″ off 5′ 2.25 mA/ on 30″ off 1.8′ 2 mA/ on 30″ off 3′
* Psychotic disorder due to epilepsy, according to DSM-IV criteria (code 293.0: Diagnostic and Statistical Manual of Mental Disorders); **VNS: Vagal nerve stimulation.
Table 2 VNS therapy effects.
Pre-VNS Post-VNS
Seizure type Seizure frequency (per month) Seizure treatment (dose mg/day) Psychotic episode frequency (per year) Psychiatric treatment (dose mg/day) Seizure type Reduction Seizure frequency (%) Seizure treatment (dose mg/day) Magnet-controlled seizures Psychotic episode Frequency (per year) Psychiatric treatment (dose mg/day) Psychotic episode-free* (Yrs) Psychotic episode-free period (Yrs)
PT1 FIAS, occasionally FBTCS 8 Surgery OXC (1500)
CBM (10) BRV (100) 3 – Focal awareness 62.5% OXC (1200)
CBM (10)
LCM (20) Yes 3 episodes in the 1-2nd year – 3rd 2
PT2 FIAS, occasionally FBTCS 8–6 OXC (1200)
PHT (350)
LCM (200) 2–3 QTP (200) HLP (6) Nocturnal seizures 42.8% PHT (350)
LCM (200)
ESL (1600) No No episodes QTP (100)
HLP (4) 1st 6
PT3 FIAS 30–50
SE 1 Surgery (3)
ZNS (300) CBZ (1200)
CBM (20) 6–8 QTP (100) CZP (100) Focal awareness and falls 82.5%
SE 100% CBZ (1200)
ZNS (300)
CBM (20) No 1 episode in the 1st year QTP (100) 2nd 3
PT4 FIAS 10–15
SE 1–2 LVT (2000) LMT (400) 2–4 RPD (10) Focal awareness 60%
SE 100% LVT (1000)
LMT (400) Yes No episodes QTP (100) 1st 3
Abbreviations: FIAS: Focal impaired awareness seizure; FBTCS: focal to bilateral tonic-clonic seizure, SE: status epilepticus; BRV: brivaracetam, CBZ: carbamazepine, CBM: clobazam, LCM: lacosamide, LMT: lamotrigine, LVT: levetiracetam, OXC: oxcarbazepine, PHT: phenytoin, ZNS: zonisamide; CPZ: clozapine, HLP: haloperidol, QTP: quetiapine, RPD: risperidone. * Determined to be the first psychotic episode-free year after VNS implantation.
2 Discussion/Conclusion
New onset psychotic episodes after VNS implantation have been reported in the literature [10]. These are may be seen in patients with DRE when they suddenly become seizure-free, presumably due to forced normalization. In contrast, one study has shown an antipsychotic effect after VNS implantation [12]. Recently, Lee et al. [14] reported the first case of forced normalization after turning off VNS in a patient suffering from Lennox-Gastaut syndrome.
Regarding the VNS mechanisms of action, it is thought that afferent vagal fibers modulate the release of different neurotransmitters in the brainstem involving the locus coeruleus, the nucleus of the solitary tract, thalamus, and limbic system structures. The dysregulation of neurotransmitters has also been identified relative to altered seizure threshold and in psychiatric disorders [15].
In our study, the results showed that patients suffering from PPE had their ictal or postictal psychotic episodes controlled after VNS implantation. However, the positive psychotropic effect was not immediate. Combined time-frame analysis showed a latency effect of VNS to control psychosis of 8.3 months (range: 6–36 months). This occurred despite the absemce of seizure control, however, in three of the cases semiology changed after VNS implantation.
18F-FDG-PET images showed a normalization of metabolism in both medial prefrontal cortical areas and anterior insulas in one of our patients, after VNS implantation. Interestingly, perfusion changes in the same areas have been described apart from the epileptogenic foci in psychotic and epileptic patients [16], [17], [18]. Normalization of medial frontal metabolism, one of the cortical areas of the cortico-striatal-thalamic-cortical loop circuits has been suggested as important in schizophrenia patients and has also been observed in DRE patients suffering psychosis [19].
Although it is speculative, this positive psychotropic effect in DRE patients suffering ictal and postictal psychosis could be related to a long-term neuromodulator effect of the VNS, independent of its antiseizure effect [20], [21], [22]. Despite these encouraging preliminary results, future research is needed to confirm our findings and to determine whether VNS-induced brain changes are associated with a favorable outcome in patients with VNS and ictal or postictal psychosis. Larger prospective studies are recommendable to validate our initial observation.
3 Statements
3.1 Ethics statement
The study was approved by the Ethics Committee of the University Hospital of Bellvitge (Hospitalet de Llobregat, Barcelona, Spain) and conducted in accordance with the Declaration of Helsinki, PR 349/18. The patients’ confidential information was protected according to the current European and Spanish regulations. All patients signed an informed consent.
Acknowledgments
We gratefully thank all the patients who selflessly participated in the study.
Declaration of Competing Interest
T. Vancamp is also an employee of LivaNova. All other authors report no conflicts of interest.
Study funding
No financial or any other support has been provided to the authors to perform this study, nor to compose this manuscript.
Authors’ contributions:
I. Conception and design: M. Falip, T. Vancamp, and M. Alemany.
II. Administrative support: M. Santurino.
III. Provision of study materials for patients: G. Plans, E. Real, N.Custal, and J. Mora.
IV. Collection and assembly of data: M. Falip, L. Rodríguez-Bel, and M. Alemany.
V. Data analysis and interpretation: M. Falip, J. Sala-Padró, and M. Alemany.
VI. Manuscript writing: All authors.
VII. Final approval of manuscript: All authors | UNKNOWN DOSE | DrugDosageText | CC BY-NC-ND | 33665601 | 19,065,895 | 2021 |
What was the dosage of drug 'LACOSAMIDE'? | Vagus nerve stimulation as a potential modulator of periictal psychotic episodes: A report of four cases.
Drug resistant epilepsy (DRE) has been associated with a high incidence of psychotic disorders. Patients can develop psychosis after starting a new antiseizure medication, after undergoing resective surgery, or after implantation of a vagus nerve stimulation (VNS) system. The aim of this study was to investigate the modulation effect of VNS on psychotic episodes in DRE patients with a pre-existing history of periictal psychotic episodes (PPE). We retrospectively report the outcome of four patients from a single tertiary center with PPE prior to implantation. None of the implanted patients developed de novo PPE after VNS therapy. Regarding seizure outcome, all patients demonstrated a response to VNS with two who experienced who status epilepticus and three patients wtih a change in semiology with after VNS implantation. PPE disappeared in all the study patients, two of them at 6 months post-implantation and in the others after 2 and 3 years, respectively. 18F-FDG-PET results showed hypermetabolism in both anterior insular and medial frontal lobes which disappeared in the 18F -FDG-PET 4 years post-implantation. Based on the results of this series of cases we suggest that VNS therapy may be useful to modulatet PPE in patients with DRE, though effectiveness may be time-dependent.
1 Introduction
Psychiatric disorders affect patients with epilepsy more frequently than they do the general population. The reported prevalence of psychotic disturbances varies between 2% and 7%, with a pooled prevalence of 5.6% [1]. The variation becomes higher when compared to the general population (1%), especially in those with temporal lobe epilepsy (TLE), affecting nearly 20% of patients [2]. Psychosis may be seen based upon its temporal relationship with seizures and include preictal, ictal, and postictal psychosis. We separated them into periictal psychotic episodes (PPE) and interictal psychosis (IIP) when a relationship between psychosis and seizures did not exist.
For PPE we used the same definitions as those identified by Logsdail and Toone. PIP was a defined as appearing within one week after a seizure or cluster of seizures, lasting from at least 15 hours up to 2 months, and preceded by a lucid period (24–72 h). Ictal psychosis was defined as psychosis appearing simultaneously with a prolonged seizure or status epilepticus as the clinical expression confirmed by an EEG without prominent motor symptoms [3].
Most of the old and new antiseizure drugs (ASD) as well as surgical treatment have been implicated in the emergence of PPE [4], [5]. Psychotic symptoms in epileptic patients with PPE are thought to be influenced by a disruption in a chronic inhibitory mechanism. Immediately after a cluster of seizures, PIP patients may experience an unusually profound depression of limbic function producing a disconnection of the temporal-limbic structures and the prefrontal structures and a loss of control over the prefrontal structures [6]. This concept was first introduced in 1953 by Landolt with the concept of ‘forced normalization theory’ to describe the appearance of psychotic episodes associated with total or partial normalization of the electroencephalogram (EEG) in patients with epilepsy [7]. In regard to this, vagus nerve stimulation (VNS) therapy has also played a role [8], [9], [10], [11]. Paradoxically, a positive effect in the modulation of psychiatric symptoms has been observed in VNS treated patients, and it has been approved as a non-pharmacological adunctive treatment for depression [12]. Moreover, a recent study conducted in an animal model for schizophrenia found VNS provided a positive effect in controlling psychotic symptoms [13].
We aimed to study the neuro-modulatory effect of VNS on psychotic episodes in drug-resistant epilepsy (DRE) patients with a pre-existing history of PPE in a single-center retrospective analysis. A total of 48 patients diagnosed with DRE and treated with VNS therapy from 2006 to 2016 were identified. None of the implanted patients developed psychosis. In the present study we included 4 patients from the series with a prior history of PPE.
Patient evaluation included a formal intermittent psychiatric examination, prolonged video-EEG (vEEG), structural magnetic resonance imaging (MRI) study with a standard epilepsy protocol, and 18F-labelled fluoro-2-deoxyglucose-positron emission tomography (18F-FDG-PET) co-registered with MRI.
1.1 Case 1
A 40-year-old male patient was diagnosed at the age of 23 with non-lesional bitemporal DRE. The patient experienced 8 episodes per month of focal impaired awareness seizure (FIAS), and occasionally focal to bilateral tonic-clonic seizure (FBTCS). Several ASDs were tested without achieving seizure control, with oxcarbazepine (OXC), clobazam (CBM) and brivaracetam (BRV) the last combination tried. Anterior temporal lobe resection of the most affected temporal lobe was done at the age of 34 without changes in seizure frequency. After nine months, the patient started suffering PIP episodes at a frequency of 3 episodes per year. PIP episodes began in the 12–24 hours after the seizure and lasted for 3–5 days. These episodes were characterised by a state of confusion and auditory hallucinations, requiring hospitalization in one case. No prior history of psychotic disorder was reported. During PIP episodes normal EEG background with fronto–temporal interictal epileptiform discharges was recorded (see Fig. 1). VNS device was implanted one year later to achieve better seizure control. After a 5-year follow-up seizures were reduced by 62.5% in additio to a change in semiology (focal aware seizure with distorted body perception) and reduced seizure severity. In terms of PIP, 3 episodes in the 2nd year was noted and no new episodes appeared after the third year of stimulation.Fig. 1 EEG recording during a postictal psychosis Patient with visual hallucinations and feelings of being harmed by others. EEG records show a left temporal breach rhythm due to previous craniotomy. There were occasional interictal epileptiform discharges in the recording (box).
1.2 Case 2
A 54-year-old male patient was diagnosed at the age of 14 with DRE secondary to a malformation of cortical development. Bitemporal seizures at a frequency of 6–8 episodes per month were reported. FIAS not preceded by aura and occasionally Focal to bilateral tonic-clonic seizures (FBTCS) were the typical seizure types. Several ASDs (OXC, phenytoin (PHT) and lacosamide (LCM)) were tested without achieving seizure control. At the age of 43 the patient started suffering recurrent episodes of postictal psychosis which started between 8 and 12 hours after a seizure, characterised by a state of confusion with hallucinations and paranoia. No prior history of psychotic disorder was reported. Antipsychotic treatment was initiated with quetiapine (QTP) and haloperidol (HLP); however, episodes were still present occurring with a frequency of 2–3 times per year, requiring hospitalization on two occasions. VNS therapy was implanted at the age of 48. After a 6-year follow-up seizures were reduced by 42.8% with a change in semiology (appearing only nocturnally). No further episodes of postictal psychosis were documented one year after VNS implantation.
1.3 Case 3
A 47-year-old female patient was diagnosed at the age of 12 with DRE secondary to a parietal tumour. Initial surgery was done in another center when the patient was 16 and the histopathology was reported as oligodendroglioma, with complete resection. The patient was seizure free for 3 years but then the seizures reappeared and became more and more frequent. No evidence of tumor relapse was observed. She was reoperated twice, at the ages of 25 and 31 including a left parietal topectomy and a right amygdalohippocampectomy. At the age of 36 she started suffering ictal psychosis during episodes characterised by delusions, anxiety, agitation, and heteroaggressivity. These psychotic episodes appeared simultaneously with an exacerbation of seizure clustering. No prior history of psychotic disorder was reported. She was monitored in our center from 2012, and at that time she suffered 1–2 seizures per day and 1 episode of psychosis per month. EEG findings during these episodes showed seizures arising in one parietal or temporal lobe evolving to contralateral areas without recovery between them (see Fig. 2). Antipsychotic treatment was initiated with QTP and clozapine (CPZ), but unfortunately the episodes remained, with a frequency of 6–8 per year. In relation to post-surgical changes, MRI showed areas of encephalomalacia-gliosis on the right temporal-insular cortex and left parietal splenium of the corpus callosum. At the age of 43, a VNS was implanted achieving a reduction of seizures by 82.5% and elimination of the episodes of SE over a 4 year follow-up period. Post-VNS the semiology of seizures also changed to focal aware seizures and falls. Only 1 episode of ictal psychosis was documented in the 1st year and was completely eliminated by the 2nd year after VNS implantation.Fig. 2 EEG recording during an ictal psychosis Patient with visual hallucinations and heteroaggressive behaviour. EEG record during the episode shows (A) interictal epileptiform activity over T7, P7, P3 (box) and (B) subclinical seizures (42 subclinical seizures in 6 hours) starting with alpha rhythm in T8 and spreading to the right frontotemporal area (box).
1.4 Case 4
A 61-year-old female patient was diagnosed at the age of 18 with non-lesional DRE, temporal and biparietal lobes. The patient experienced FIAS not preceded by aura with a frequency of 10–15 episodes per month, and 1–2 SE per month (starting with clusters of 5–7 seizures for 3–4 hours and continuing with an altered mental state of confusion and disorientation for 3 days). Several ASDs were trialed without achieving seizure control. The last trial included combination therapy with levetiracetam and lamotrigine. At the age of 50 during periods when the frequency of seizures was higher, the patient started suffering ictal psychosis characterised by episodes of agitation, auditory hallucinations, and perspicuous feelings. No prior history of psychotic disorders was reported. Antipsychotic treatment was initiated with risperidone without achieving control of psychotic episodes which continued with a frequency of 2–4 per year requiring hospitalization on 7 occasions, 3 of them due to suicide attempts.
At the age of 58 VNS was implanted achieving a reduction of seizure frequency by 60% and elimination of SE over a 4 year follow-up period. Seizure severity also changed due to changes in semiology to focal aware seizures with somatosensory aura in the right foot not followed by impaired awareness most of the time when she acutely activated magnet-induced VNS stimulation. No further psychotic episodes were documented after the first year of VNS implantation.
Additionally, 18F-FDG-PET before VNS implantation was performed showing hypometabolism in both superior parietal lobes, more evident in the right, and relative hypermetabolism in the mesial frontal areas and anterior insulas. 18F-FDG-PET after 4 years following VNS implantation showed less intense hypometabolism in both superior parietal lobes with a normalisation of the hypermetabolism in the frontal lobes, insular lobes, and left caudate nucleus (shown in Fig. 3).Fig. 3 18F-FDG-PET pre- and post-VNS implantation a)18F-FDG-PET pre-VNS shows hypometabolism in both superior parietal lobes (^), more intense in the right (epileptogenic area) and relative hypermetabolism in the mesial frontal areas (*) and the anterior insulas ( ). b)18F-FDG-PET post-VNS shows less intense hypometabolism in both superior parietal lobes (^) with a normalization of the hypermetabolism in the frontal lobes (*) and insular lobes ( ). c) Z map of the18F-FDG-PET subtraction co-recorded with the MRI, showing the cortical areas that underwent a change of more than 2SD in metabolism; frontal areas with a decrease of metabolism (blue blob) and right parietal areas with increase of metabolism (orange blob). (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
A summary of demographics and clinical characteristics of the reported cases and VNS therapy effects are shown in Table 1 and Table 2, respectively.Table 1 Demographics and clinical characteristics of patients with prior history of periictal psychosis (PPE) and VNS. therapy.
P 1 P 2 P 3 P 4
Gender Male Male Female Female
Age (Yrs) 40 54 47 61
Age at epilepsy onset (Yrs) 23 14 12 18
Aetiology Unknown Malformation of cortical development Left oligodendroglioma Unknown
Seizures localization Bitemporal Bitemporal Left parietal, bitemporal Left temporal, biparietal
Age at psychosis onset (Yrs) 34 43 36 50
Psychiatric symptoms Confusion, auditory hallucinations Confusion, Hallucinations, paranoia Anxiety, agitation, heteroaggressivity Agitation, auditory hallucinations, perspicuous feelings
Psychiatric disorder in relation to seizures* Postictal Postictal Ictal Ictal
Age at VNS implantation (Yrs) 35 48 43 58
VNS** follow-up time (Yrs) 5 6 4 3
Intensity/frequency VNS* 1 mA/ on 30″ off 5′ 2 mA/ on 30″ off 5′ 2.25 mA/ on 30″ off 1.8′ 2 mA/ on 30″ off 3′
* Psychotic disorder due to epilepsy, according to DSM-IV criteria (code 293.0: Diagnostic and Statistical Manual of Mental Disorders); **VNS: Vagal nerve stimulation.
Table 2 VNS therapy effects.
Pre-VNS Post-VNS
Seizure type Seizure frequency (per month) Seizure treatment (dose mg/day) Psychotic episode frequency (per year) Psychiatric treatment (dose mg/day) Seizure type Reduction Seizure frequency (%) Seizure treatment (dose mg/day) Magnet-controlled seizures Psychotic episode Frequency (per year) Psychiatric treatment (dose mg/day) Psychotic episode-free* (Yrs) Psychotic episode-free period (Yrs)
PT1 FIAS, occasionally FBTCS 8 Surgery OXC (1500)
CBM (10) BRV (100) 3 – Focal awareness 62.5% OXC (1200)
CBM (10)
LCM (20) Yes 3 episodes in the 1-2nd year – 3rd 2
PT2 FIAS, occasionally FBTCS 8–6 OXC (1200)
PHT (350)
LCM (200) 2–3 QTP (200) HLP (6) Nocturnal seizures 42.8% PHT (350)
LCM (200)
ESL (1600) No No episodes QTP (100)
HLP (4) 1st 6
PT3 FIAS 30–50
SE 1 Surgery (3)
ZNS (300) CBZ (1200)
CBM (20) 6–8 QTP (100) CZP (100) Focal awareness and falls 82.5%
SE 100% CBZ (1200)
ZNS (300)
CBM (20) No 1 episode in the 1st year QTP (100) 2nd 3
PT4 FIAS 10–15
SE 1–2 LVT (2000) LMT (400) 2–4 RPD (10) Focal awareness 60%
SE 100% LVT (1000)
LMT (400) Yes No episodes QTP (100) 1st 3
Abbreviations: FIAS: Focal impaired awareness seizure; FBTCS: focal to bilateral tonic-clonic seizure, SE: status epilepticus; BRV: brivaracetam, CBZ: carbamazepine, CBM: clobazam, LCM: lacosamide, LMT: lamotrigine, LVT: levetiracetam, OXC: oxcarbazepine, PHT: phenytoin, ZNS: zonisamide; CPZ: clozapine, HLP: haloperidol, QTP: quetiapine, RPD: risperidone. * Determined to be the first psychotic episode-free year after VNS implantation.
2 Discussion/Conclusion
New onset psychotic episodes after VNS implantation have been reported in the literature [10]. These are may be seen in patients with DRE when they suddenly become seizure-free, presumably due to forced normalization. In contrast, one study has shown an antipsychotic effect after VNS implantation [12]. Recently, Lee et al. [14] reported the first case of forced normalization after turning off VNS in a patient suffering from Lennox-Gastaut syndrome.
Regarding the VNS mechanisms of action, it is thought that afferent vagal fibers modulate the release of different neurotransmitters in the brainstem involving the locus coeruleus, the nucleus of the solitary tract, thalamus, and limbic system structures. The dysregulation of neurotransmitters has also been identified relative to altered seizure threshold and in psychiatric disorders [15].
In our study, the results showed that patients suffering from PPE had their ictal or postictal psychotic episodes controlled after VNS implantation. However, the positive psychotropic effect was not immediate. Combined time-frame analysis showed a latency effect of VNS to control psychosis of 8.3 months (range: 6–36 months). This occurred despite the absemce of seizure control, however, in three of the cases semiology changed after VNS implantation.
18F-FDG-PET images showed a normalization of metabolism in both medial prefrontal cortical areas and anterior insulas in one of our patients, after VNS implantation. Interestingly, perfusion changes in the same areas have been described apart from the epileptogenic foci in psychotic and epileptic patients [16], [17], [18]. Normalization of medial frontal metabolism, one of the cortical areas of the cortico-striatal-thalamic-cortical loop circuits has been suggested as important in schizophrenia patients and has also been observed in DRE patients suffering psychosis [19].
Although it is speculative, this positive psychotropic effect in DRE patients suffering ictal and postictal psychosis could be related to a long-term neuromodulator effect of the VNS, independent of its antiseizure effect [20], [21], [22]. Despite these encouraging preliminary results, future research is needed to confirm our findings and to determine whether VNS-induced brain changes are associated with a favorable outcome in patients with VNS and ictal or postictal psychosis. Larger prospective studies are recommendable to validate our initial observation.
3 Statements
3.1 Ethics statement
The study was approved by the Ethics Committee of the University Hospital of Bellvitge (Hospitalet de Llobregat, Barcelona, Spain) and conducted in accordance with the Declaration of Helsinki, PR 349/18. The patients’ confidential information was protected according to the current European and Spanish regulations. All patients signed an informed consent.
Acknowledgments
We gratefully thank all the patients who selflessly participated in the study.
Declaration of Competing Interest
T. Vancamp is also an employee of LivaNova. All other authors report no conflicts of interest.
Study funding
No financial or any other support has been provided to the authors to perform this study, nor to compose this manuscript.
Authors’ contributions:
I. Conception and design: M. Falip, T. Vancamp, and M. Alemany.
II. Administrative support: M. Santurino.
III. Provision of study materials for patients: G. Plans, E. Real, N.Custal, and J. Mora.
IV. Collection and assembly of data: M. Falip, L. Rodríguez-Bel, and M. Alemany.
V. Data analysis and interpretation: M. Falip, J. Sala-Padró, and M. Alemany.
VI. Manuscript writing: All authors.
VII. Final approval of manuscript: All authors | UNKNOWN DOSE | DrugDosageText | CC BY-NC-ND | 33665601 | 19,065,854 | 2021 |
What was the dosage of drug 'LAMOTRIGINE'? | Vagus nerve stimulation as a potential modulator of periictal psychotic episodes: A report of four cases.
Drug resistant epilepsy (DRE) has been associated with a high incidence of psychotic disorders. Patients can develop psychosis after starting a new antiseizure medication, after undergoing resective surgery, or after implantation of a vagus nerve stimulation (VNS) system. The aim of this study was to investigate the modulation effect of VNS on psychotic episodes in DRE patients with a pre-existing history of periictal psychotic episodes (PPE). We retrospectively report the outcome of four patients from a single tertiary center with PPE prior to implantation. None of the implanted patients developed de novo PPE after VNS therapy. Regarding seizure outcome, all patients demonstrated a response to VNS with two who experienced who status epilepticus and three patients wtih a change in semiology with after VNS implantation. PPE disappeared in all the study patients, two of them at 6 months post-implantation and in the others after 2 and 3 years, respectively. 18F-FDG-PET results showed hypermetabolism in both anterior insular and medial frontal lobes which disappeared in the 18F -FDG-PET 4 years post-implantation. Based on the results of this series of cases we suggest that VNS therapy may be useful to modulatet PPE in patients with DRE, though effectiveness may be time-dependent.
1 Introduction
Psychiatric disorders affect patients with epilepsy more frequently than they do the general population. The reported prevalence of psychotic disturbances varies between 2% and 7%, with a pooled prevalence of 5.6% [1]. The variation becomes higher when compared to the general population (1%), especially in those with temporal lobe epilepsy (TLE), affecting nearly 20% of patients [2]. Psychosis may be seen based upon its temporal relationship with seizures and include preictal, ictal, and postictal psychosis. We separated them into periictal psychotic episodes (PPE) and interictal psychosis (IIP) when a relationship between psychosis and seizures did not exist.
For PPE we used the same definitions as those identified by Logsdail and Toone. PIP was a defined as appearing within one week after a seizure or cluster of seizures, lasting from at least 15 hours up to 2 months, and preceded by a lucid period (24–72 h). Ictal psychosis was defined as psychosis appearing simultaneously with a prolonged seizure or status epilepticus as the clinical expression confirmed by an EEG without prominent motor symptoms [3].
Most of the old and new antiseizure drugs (ASD) as well as surgical treatment have been implicated in the emergence of PPE [4], [5]. Psychotic symptoms in epileptic patients with PPE are thought to be influenced by a disruption in a chronic inhibitory mechanism. Immediately after a cluster of seizures, PIP patients may experience an unusually profound depression of limbic function producing a disconnection of the temporal-limbic structures and the prefrontal structures and a loss of control over the prefrontal structures [6]. This concept was first introduced in 1953 by Landolt with the concept of ‘forced normalization theory’ to describe the appearance of psychotic episodes associated with total or partial normalization of the electroencephalogram (EEG) in patients with epilepsy [7]. In regard to this, vagus nerve stimulation (VNS) therapy has also played a role [8], [9], [10], [11]. Paradoxically, a positive effect in the modulation of psychiatric symptoms has been observed in VNS treated patients, and it has been approved as a non-pharmacological adunctive treatment for depression [12]. Moreover, a recent study conducted in an animal model for schizophrenia found VNS provided a positive effect in controlling psychotic symptoms [13].
We aimed to study the neuro-modulatory effect of VNS on psychotic episodes in drug-resistant epilepsy (DRE) patients with a pre-existing history of PPE in a single-center retrospective analysis. A total of 48 patients diagnosed with DRE and treated with VNS therapy from 2006 to 2016 were identified. None of the implanted patients developed psychosis. In the present study we included 4 patients from the series with a prior history of PPE.
Patient evaluation included a formal intermittent psychiatric examination, prolonged video-EEG (vEEG), structural magnetic resonance imaging (MRI) study with a standard epilepsy protocol, and 18F-labelled fluoro-2-deoxyglucose-positron emission tomography (18F-FDG-PET) co-registered with MRI.
1.1 Case 1
A 40-year-old male patient was diagnosed at the age of 23 with non-lesional bitemporal DRE. The patient experienced 8 episodes per month of focal impaired awareness seizure (FIAS), and occasionally focal to bilateral tonic-clonic seizure (FBTCS). Several ASDs were tested without achieving seizure control, with oxcarbazepine (OXC), clobazam (CBM) and brivaracetam (BRV) the last combination tried. Anterior temporal lobe resection of the most affected temporal lobe was done at the age of 34 without changes in seizure frequency. After nine months, the patient started suffering PIP episodes at a frequency of 3 episodes per year. PIP episodes began in the 12–24 hours after the seizure and lasted for 3–5 days. These episodes were characterised by a state of confusion and auditory hallucinations, requiring hospitalization in one case. No prior history of psychotic disorder was reported. During PIP episodes normal EEG background with fronto–temporal interictal epileptiform discharges was recorded (see Fig. 1). VNS device was implanted one year later to achieve better seizure control. After a 5-year follow-up seizures were reduced by 62.5% in additio to a change in semiology (focal aware seizure with distorted body perception) and reduced seizure severity. In terms of PIP, 3 episodes in the 2nd year was noted and no new episodes appeared after the third year of stimulation.Fig. 1 EEG recording during a postictal psychosis Patient with visual hallucinations and feelings of being harmed by others. EEG records show a left temporal breach rhythm due to previous craniotomy. There were occasional interictal epileptiform discharges in the recording (box).
1.2 Case 2
A 54-year-old male patient was diagnosed at the age of 14 with DRE secondary to a malformation of cortical development. Bitemporal seizures at a frequency of 6–8 episodes per month were reported. FIAS not preceded by aura and occasionally Focal to bilateral tonic-clonic seizures (FBTCS) were the typical seizure types. Several ASDs (OXC, phenytoin (PHT) and lacosamide (LCM)) were tested without achieving seizure control. At the age of 43 the patient started suffering recurrent episodes of postictal psychosis which started between 8 and 12 hours after a seizure, characterised by a state of confusion with hallucinations and paranoia. No prior history of psychotic disorder was reported. Antipsychotic treatment was initiated with quetiapine (QTP) and haloperidol (HLP); however, episodes were still present occurring with a frequency of 2–3 times per year, requiring hospitalization on two occasions. VNS therapy was implanted at the age of 48. After a 6-year follow-up seizures were reduced by 42.8% with a change in semiology (appearing only nocturnally). No further episodes of postictal psychosis were documented one year after VNS implantation.
1.3 Case 3
A 47-year-old female patient was diagnosed at the age of 12 with DRE secondary to a parietal tumour. Initial surgery was done in another center when the patient was 16 and the histopathology was reported as oligodendroglioma, with complete resection. The patient was seizure free for 3 years but then the seizures reappeared and became more and more frequent. No evidence of tumor relapse was observed. She was reoperated twice, at the ages of 25 and 31 including a left parietal topectomy and a right amygdalohippocampectomy. At the age of 36 she started suffering ictal psychosis during episodes characterised by delusions, anxiety, agitation, and heteroaggressivity. These psychotic episodes appeared simultaneously with an exacerbation of seizure clustering. No prior history of psychotic disorder was reported. She was monitored in our center from 2012, and at that time she suffered 1–2 seizures per day and 1 episode of psychosis per month. EEG findings during these episodes showed seizures arising in one parietal or temporal lobe evolving to contralateral areas without recovery between them (see Fig. 2). Antipsychotic treatment was initiated with QTP and clozapine (CPZ), but unfortunately the episodes remained, with a frequency of 6–8 per year. In relation to post-surgical changes, MRI showed areas of encephalomalacia-gliosis on the right temporal-insular cortex and left parietal splenium of the corpus callosum. At the age of 43, a VNS was implanted achieving a reduction of seizures by 82.5% and elimination of the episodes of SE over a 4 year follow-up period. Post-VNS the semiology of seizures also changed to focal aware seizures and falls. Only 1 episode of ictal psychosis was documented in the 1st year and was completely eliminated by the 2nd year after VNS implantation.Fig. 2 EEG recording during an ictal psychosis Patient with visual hallucinations and heteroaggressive behaviour. EEG record during the episode shows (A) interictal epileptiform activity over T7, P7, P3 (box) and (B) subclinical seizures (42 subclinical seizures in 6 hours) starting with alpha rhythm in T8 and spreading to the right frontotemporal area (box).
1.4 Case 4
A 61-year-old female patient was diagnosed at the age of 18 with non-lesional DRE, temporal and biparietal lobes. The patient experienced FIAS not preceded by aura with a frequency of 10–15 episodes per month, and 1–2 SE per month (starting with clusters of 5–7 seizures for 3–4 hours and continuing with an altered mental state of confusion and disorientation for 3 days). Several ASDs were trialed without achieving seizure control. The last trial included combination therapy with levetiracetam and lamotrigine. At the age of 50 during periods when the frequency of seizures was higher, the patient started suffering ictal psychosis characterised by episodes of agitation, auditory hallucinations, and perspicuous feelings. No prior history of psychotic disorders was reported. Antipsychotic treatment was initiated with risperidone without achieving control of psychotic episodes which continued with a frequency of 2–4 per year requiring hospitalization on 7 occasions, 3 of them due to suicide attempts.
At the age of 58 VNS was implanted achieving a reduction of seizure frequency by 60% and elimination of SE over a 4 year follow-up period. Seizure severity also changed due to changes in semiology to focal aware seizures with somatosensory aura in the right foot not followed by impaired awareness most of the time when she acutely activated magnet-induced VNS stimulation. No further psychotic episodes were documented after the first year of VNS implantation.
Additionally, 18F-FDG-PET before VNS implantation was performed showing hypometabolism in both superior parietal lobes, more evident in the right, and relative hypermetabolism in the mesial frontal areas and anterior insulas. 18F-FDG-PET after 4 years following VNS implantation showed less intense hypometabolism in both superior parietal lobes with a normalisation of the hypermetabolism in the frontal lobes, insular lobes, and left caudate nucleus (shown in Fig. 3).Fig. 3 18F-FDG-PET pre- and post-VNS implantation a)18F-FDG-PET pre-VNS shows hypometabolism in both superior parietal lobes (^), more intense in the right (epileptogenic area) and relative hypermetabolism in the mesial frontal areas (*) and the anterior insulas ( ). b)18F-FDG-PET post-VNS shows less intense hypometabolism in both superior parietal lobes (^) with a normalization of the hypermetabolism in the frontal lobes (*) and insular lobes ( ). c) Z map of the18F-FDG-PET subtraction co-recorded with the MRI, showing the cortical areas that underwent a change of more than 2SD in metabolism; frontal areas with a decrease of metabolism (blue blob) and right parietal areas with increase of metabolism (orange blob). (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
A summary of demographics and clinical characteristics of the reported cases and VNS therapy effects are shown in Table 1 and Table 2, respectively.Table 1 Demographics and clinical characteristics of patients with prior history of periictal psychosis (PPE) and VNS. therapy.
P 1 P 2 P 3 P 4
Gender Male Male Female Female
Age (Yrs) 40 54 47 61
Age at epilepsy onset (Yrs) 23 14 12 18
Aetiology Unknown Malformation of cortical development Left oligodendroglioma Unknown
Seizures localization Bitemporal Bitemporal Left parietal, bitemporal Left temporal, biparietal
Age at psychosis onset (Yrs) 34 43 36 50
Psychiatric symptoms Confusion, auditory hallucinations Confusion, Hallucinations, paranoia Anxiety, agitation, heteroaggressivity Agitation, auditory hallucinations, perspicuous feelings
Psychiatric disorder in relation to seizures* Postictal Postictal Ictal Ictal
Age at VNS implantation (Yrs) 35 48 43 58
VNS** follow-up time (Yrs) 5 6 4 3
Intensity/frequency VNS* 1 mA/ on 30″ off 5′ 2 mA/ on 30″ off 5′ 2.25 mA/ on 30″ off 1.8′ 2 mA/ on 30″ off 3′
* Psychotic disorder due to epilepsy, according to DSM-IV criteria (code 293.0: Diagnostic and Statistical Manual of Mental Disorders); **VNS: Vagal nerve stimulation.
Table 2 VNS therapy effects.
Pre-VNS Post-VNS
Seizure type Seizure frequency (per month) Seizure treatment (dose mg/day) Psychotic episode frequency (per year) Psychiatric treatment (dose mg/day) Seizure type Reduction Seizure frequency (%) Seizure treatment (dose mg/day) Magnet-controlled seizures Psychotic episode Frequency (per year) Psychiatric treatment (dose mg/day) Psychotic episode-free* (Yrs) Psychotic episode-free period (Yrs)
PT1 FIAS, occasionally FBTCS 8 Surgery OXC (1500)
CBM (10) BRV (100) 3 – Focal awareness 62.5% OXC (1200)
CBM (10)
LCM (20) Yes 3 episodes in the 1-2nd year – 3rd 2
PT2 FIAS, occasionally FBTCS 8–6 OXC (1200)
PHT (350)
LCM (200) 2–3 QTP (200) HLP (6) Nocturnal seizures 42.8% PHT (350)
LCM (200)
ESL (1600) No No episodes QTP (100)
HLP (4) 1st 6
PT3 FIAS 30–50
SE 1 Surgery (3)
ZNS (300) CBZ (1200)
CBM (20) 6–8 QTP (100) CZP (100) Focal awareness and falls 82.5%
SE 100% CBZ (1200)
ZNS (300)
CBM (20) No 1 episode in the 1st year QTP (100) 2nd 3
PT4 FIAS 10–15
SE 1–2 LVT (2000) LMT (400) 2–4 RPD (10) Focal awareness 60%
SE 100% LVT (1000)
LMT (400) Yes No episodes QTP (100) 1st 3
Abbreviations: FIAS: Focal impaired awareness seizure; FBTCS: focal to bilateral tonic-clonic seizure, SE: status epilepticus; BRV: brivaracetam, CBZ: carbamazepine, CBM: clobazam, LCM: lacosamide, LMT: lamotrigine, LVT: levetiracetam, OXC: oxcarbazepine, PHT: phenytoin, ZNS: zonisamide; CPZ: clozapine, HLP: haloperidol, QTP: quetiapine, RPD: risperidone. * Determined to be the first psychotic episode-free year after VNS implantation.
2 Discussion/Conclusion
New onset psychotic episodes after VNS implantation have been reported in the literature [10]. These are may be seen in patients with DRE when they suddenly become seizure-free, presumably due to forced normalization. In contrast, one study has shown an antipsychotic effect after VNS implantation [12]. Recently, Lee et al. [14] reported the first case of forced normalization after turning off VNS in a patient suffering from Lennox-Gastaut syndrome.
Regarding the VNS mechanisms of action, it is thought that afferent vagal fibers modulate the release of different neurotransmitters in the brainstem involving the locus coeruleus, the nucleus of the solitary tract, thalamus, and limbic system structures. The dysregulation of neurotransmitters has also been identified relative to altered seizure threshold and in psychiatric disorders [15].
In our study, the results showed that patients suffering from PPE had their ictal or postictal psychotic episodes controlled after VNS implantation. However, the positive psychotropic effect was not immediate. Combined time-frame analysis showed a latency effect of VNS to control psychosis of 8.3 months (range: 6–36 months). This occurred despite the absemce of seizure control, however, in three of the cases semiology changed after VNS implantation.
18F-FDG-PET images showed a normalization of metabolism in both medial prefrontal cortical areas and anterior insulas in one of our patients, after VNS implantation. Interestingly, perfusion changes in the same areas have been described apart from the epileptogenic foci in psychotic and epileptic patients [16], [17], [18]. Normalization of medial frontal metabolism, one of the cortical areas of the cortico-striatal-thalamic-cortical loop circuits has been suggested as important in schizophrenia patients and has also been observed in DRE patients suffering psychosis [19].
Although it is speculative, this positive psychotropic effect in DRE patients suffering ictal and postictal psychosis could be related to a long-term neuromodulator effect of the VNS, independent of its antiseizure effect [20], [21], [22]. Despite these encouraging preliminary results, future research is needed to confirm our findings and to determine whether VNS-induced brain changes are associated with a favorable outcome in patients with VNS and ictal or postictal psychosis. Larger prospective studies are recommendable to validate our initial observation.
3 Statements
3.1 Ethics statement
The study was approved by the Ethics Committee of the University Hospital of Bellvitge (Hospitalet de Llobregat, Barcelona, Spain) and conducted in accordance with the Declaration of Helsinki, PR 349/18. The patients’ confidential information was protected according to the current European and Spanish regulations. All patients signed an informed consent.
Acknowledgments
We gratefully thank all the patients who selflessly participated in the study.
Declaration of Competing Interest
T. Vancamp is also an employee of LivaNova. All other authors report no conflicts of interest.
Study funding
No financial or any other support has been provided to the authors to perform this study, nor to compose this manuscript.
Authors’ contributions:
I. Conception and design: M. Falip, T. Vancamp, and M. Alemany.
II. Administrative support: M. Santurino.
III. Provision of study materials for patients: G. Plans, E. Real, N.Custal, and J. Mora.
IV. Collection and assembly of data: M. Falip, L. Rodríguez-Bel, and M. Alemany.
V. Data analysis and interpretation: M. Falip, J. Sala-Padró, and M. Alemany.
VI. Manuscript writing: All authors.
VII. Final approval of manuscript: All authors | UNKNOWN DOSE | DrugDosageText | CC BY-NC-ND | 33665601 | 19,065,855 | 2021 |
What was the dosage of drug 'LEVETIRACETAM'? | Vagus nerve stimulation as a potential modulator of periictal psychotic episodes: A report of four cases.
Drug resistant epilepsy (DRE) has been associated with a high incidence of psychotic disorders. Patients can develop psychosis after starting a new antiseizure medication, after undergoing resective surgery, or after implantation of a vagus nerve stimulation (VNS) system. The aim of this study was to investigate the modulation effect of VNS on psychotic episodes in DRE patients with a pre-existing history of periictal psychotic episodes (PPE). We retrospectively report the outcome of four patients from a single tertiary center with PPE prior to implantation. None of the implanted patients developed de novo PPE after VNS therapy. Regarding seizure outcome, all patients demonstrated a response to VNS with two who experienced who status epilepticus and three patients wtih a change in semiology with after VNS implantation. PPE disappeared in all the study patients, two of them at 6 months post-implantation and in the others after 2 and 3 years, respectively. 18F-FDG-PET results showed hypermetabolism in both anterior insular and medial frontal lobes which disappeared in the 18F -FDG-PET 4 years post-implantation. Based on the results of this series of cases we suggest that VNS therapy may be useful to modulatet PPE in patients with DRE, though effectiveness may be time-dependent.
1 Introduction
Psychiatric disorders affect patients with epilepsy more frequently than they do the general population. The reported prevalence of psychotic disturbances varies between 2% and 7%, with a pooled prevalence of 5.6% [1]. The variation becomes higher when compared to the general population (1%), especially in those with temporal lobe epilepsy (TLE), affecting nearly 20% of patients [2]. Psychosis may be seen based upon its temporal relationship with seizures and include preictal, ictal, and postictal psychosis. We separated them into periictal psychotic episodes (PPE) and interictal psychosis (IIP) when a relationship between psychosis and seizures did not exist.
For PPE we used the same definitions as those identified by Logsdail and Toone. PIP was a defined as appearing within one week after a seizure or cluster of seizures, lasting from at least 15 hours up to 2 months, and preceded by a lucid period (24–72 h). Ictal psychosis was defined as psychosis appearing simultaneously with a prolonged seizure or status epilepticus as the clinical expression confirmed by an EEG without prominent motor symptoms [3].
Most of the old and new antiseizure drugs (ASD) as well as surgical treatment have been implicated in the emergence of PPE [4], [5]. Psychotic symptoms in epileptic patients with PPE are thought to be influenced by a disruption in a chronic inhibitory mechanism. Immediately after a cluster of seizures, PIP patients may experience an unusually profound depression of limbic function producing a disconnection of the temporal-limbic structures and the prefrontal structures and a loss of control over the prefrontal structures [6]. This concept was first introduced in 1953 by Landolt with the concept of ‘forced normalization theory’ to describe the appearance of psychotic episodes associated with total or partial normalization of the electroencephalogram (EEG) in patients with epilepsy [7]. In regard to this, vagus nerve stimulation (VNS) therapy has also played a role [8], [9], [10], [11]. Paradoxically, a positive effect in the modulation of psychiatric symptoms has been observed in VNS treated patients, and it has been approved as a non-pharmacological adunctive treatment for depression [12]. Moreover, a recent study conducted in an animal model for schizophrenia found VNS provided a positive effect in controlling psychotic symptoms [13].
We aimed to study the neuro-modulatory effect of VNS on psychotic episodes in drug-resistant epilepsy (DRE) patients with a pre-existing history of PPE in a single-center retrospective analysis. A total of 48 patients diagnosed with DRE and treated with VNS therapy from 2006 to 2016 were identified. None of the implanted patients developed psychosis. In the present study we included 4 patients from the series with a prior history of PPE.
Patient evaluation included a formal intermittent psychiatric examination, prolonged video-EEG (vEEG), structural magnetic resonance imaging (MRI) study with a standard epilepsy protocol, and 18F-labelled fluoro-2-deoxyglucose-positron emission tomography (18F-FDG-PET) co-registered with MRI.
1.1 Case 1
A 40-year-old male patient was diagnosed at the age of 23 with non-lesional bitemporal DRE. The patient experienced 8 episodes per month of focal impaired awareness seizure (FIAS), and occasionally focal to bilateral tonic-clonic seizure (FBTCS). Several ASDs were tested without achieving seizure control, with oxcarbazepine (OXC), clobazam (CBM) and brivaracetam (BRV) the last combination tried. Anterior temporal lobe resection of the most affected temporal lobe was done at the age of 34 without changes in seizure frequency. After nine months, the patient started suffering PIP episodes at a frequency of 3 episodes per year. PIP episodes began in the 12–24 hours after the seizure and lasted for 3–5 days. These episodes were characterised by a state of confusion and auditory hallucinations, requiring hospitalization in one case. No prior history of psychotic disorder was reported. During PIP episodes normal EEG background with fronto–temporal interictal epileptiform discharges was recorded (see Fig. 1). VNS device was implanted one year later to achieve better seizure control. After a 5-year follow-up seizures were reduced by 62.5% in additio to a change in semiology (focal aware seizure with distorted body perception) and reduced seizure severity. In terms of PIP, 3 episodes in the 2nd year was noted and no new episodes appeared after the third year of stimulation.Fig. 1 EEG recording during a postictal psychosis Patient with visual hallucinations and feelings of being harmed by others. EEG records show a left temporal breach rhythm due to previous craniotomy. There were occasional interictal epileptiform discharges in the recording (box).
1.2 Case 2
A 54-year-old male patient was diagnosed at the age of 14 with DRE secondary to a malformation of cortical development. Bitemporal seizures at a frequency of 6–8 episodes per month were reported. FIAS not preceded by aura and occasionally Focal to bilateral tonic-clonic seizures (FBTCS) were the typical seizure types. Several ASDs (OXC, phenytoin (PHT) and lacosamide (LCM)) were tested without achieving seizure control. At the age of 43 the patient started suffering recurrent episodes of postictal psychosis which started between 8 and 12 hours after a seizure, characterised by a state of confusion with hallucinations and paranoia. No prior history of psychotic disorder was reported. Antipsychotic treatment was initiated with quetiapine (QTP) and haloperidol (HLP); however, episodes were still present occurring with a frequency of 2–3 times per year, requiring hospitalization on two occasions. VNS therapy was implanted at the age of 48. After a 6-year follow-up seizures were reduced by 42.8% with a change in semiology (appearing only nocturnally). No further episodes of postictal psychosis were documented one year after VNS implantation.
1.3 Case 3
A 47-year-old female patient was diagnosed at the age of 12 with DRE secondary to a parietal tumour. Initial surgery was done in another center when the patient was 16 and the histopathology was reported as oligodendroglioma, with complete resection. The patient was seizure free for 3 years but then the seizures reappeared and became more and more frequent. No evidence of tumor relapse was observed. She was reoperated twice, at the ages of 25 and 31 including a left parietal topectomy and a right amygdalohippocampectomy. At the age of 36 she started suffering ictal psychosis during episodes characterised by delusions, anxiety, agitation, and heteroaggressivity. These psychotic episodes appeared simultaneously with an exacerbation of seizure clustering. No prior history of psychotic disorder was reported. She was monitored in our center from 2012, and at that time she suffered 1–2 seizures per day and 1 episode of psychosis per month. EEG findings during these episodes showed seizures arising in one parietal or temporal lobe evolving to contralateral areas without recovery between them (see Fig. 2). Antipsychotic treatment was initiated with QTP and clozapine (CPZ), but unfortunately the episodes remained, with a frequency of 6–8 per year. In relation to post-surgical changes, MRI showed areas of encephalomalacia-gliosis on the right temporal-insular cortex and left parietal splenium of the corpus callosum. At the age of 43, a VNS was implanted achieving a reduction of seizures by 82.5% and elimination of the episodes of SE over a 4 year follow-up period. Post-VNS the semiology of seizures also changed to focal aware seizures and falls. Only 1 episode of ictal psychosis was documented in the 1st year and was completely eliminated by the 2nd year after VNS implantation.Fig. 2 EEG recording during an ictal psychosis Patient with visual hallucinations and heteroaggressive behaviour. EEG record during the episode shows (A) interictal epileptiform activity over T7, P7, P3 (box) and (B) subclinical seizures (42 subclinical seizures in 6 hours) starting with alpha rhythm in T8 and spreading to the right frontotemporal area (box).
1.4 Case 4
A 61-year-old female patient was diagnosed at the age of 18 with non-lesional DRE, temporal and biparietal lobes. The patient experienced FIAS not preceded by aura with a frequency of 10–15 episodes per month, and 1–2 SE per month (starting with clusters of 5–7 seizures for 3–4 hours and continuing with an altered mental state of confusion and disorientation for 3 days). Several ASDs were trialed without achieving seizure control. The last trial included combination therapy with levetiracetam and lamotrigine. At the age of 50 during periods when the frequency of seizures was higher, the patient started suffering ictal psychosis characterised by episodes of agitation, auditory hallucinations, and perspicuous feelings. No prior history of psychotic disorders was reported. Antipsychotic treatment was initiated with risperidone without achieving control of psychotic episodes which continued with a frequency of 2–4 per year requiring hospitalization on 7 occasions, 3 of them due to suicide attempts.
At the age of 58 VNS was implanted achieving a reduction of seizure frequency by 60% and elimination of SE over a 4 year follow-up period. Seizure severity also changed due to changes in semiology to focal aware seizures with somatosensory aura in the right foot not followed by impaired awareness most of the time when she acutely activated magnet-induced VNS stimulation. No further psychotic episodes were documented after the first year of VNS implantation.
Additionally, 18F-FDG-PET before VNS implantation was performed showing hypometabolism in both superior parietal lobes, more evident in the right, and relative hypermetabolism in the mesial frontal areas and anterior insulas. 18F-FDG-PET after 4 years following VNS implantation showed less intense hypometabolism in both superior parietal lobes with a normalisation of the hypermetabolism in the frontal lobes, insular lobes, and left caudate nucleus (shown in Fig. 3).Fig. 3 18F-FDG-PET pre- and post-VNS implantation a)18F-FDG-PET pre-VNS shows hypometabolism in both superior parietal lobes (^), more intense in the right (epileptogenic area) and relative hypermetabolism in the mesial frontal areas (*) and the anterior insulas ( ). b)18F-FDG-PET post-VNS shows less intense hypometabolism in both superior parietal lobes (^) with a normalization of the hypermetabolism in the frontal lobes (*) and insular lobes ( ). c) Z map of the18F-FDG-PET subtraction co-recorded with the MRI, showing the cortical areas that underwent a change of more than 2SD in metabolism; frontal areas with a decrease of metabolism (blue blob) and right parietal areas with increase of metabolism (orange blob). (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
A summary of demographics and clinical characteristics of the reported cases and VNS therapy effects are shown in Table 1 and Table 2, respectively.Table 1 Demographics and clinical characteristics of patients with prior history of periictal psychosis (PPE) and VNS. therapy.
P 1 P 2 P 3 P 4
Gender Male Male Female Female
Age (Yrs) 40 54 47 61
Age at epilepsy onset (Yrs) 23 14 12 18
Aetiology Unknown Malformation of cortical development Left oligodendroglioma Unknown
Seizures localization Bitemporal Bitemporal Left parietal, bitemporal Left temporal, biparietal
Age at psychosis onset (Yrs) 34 43 36 50
Psychiatric symptoms Confusion, auditory hallucinations Confusion, Hallucinations, paranoia Anxiety, agitation, heteroaggressivity Agitation, auditory hallucinations, perspicuous feelings
Psychiatric disorder in relation to seizures* Postictal Postictal Ictal Ictal
Age at VNS implantation (Yrs) 35 48 43 58
VNS** follow-up time (Yrs) 5 6 4 3
Intensity/frequency VNS* 1 mA/ on 30″ off 5′ 2 mA/ on 30″ off 5′ 2.25 mA/ on 30″ off 1.8′ 2 mA/ on 30″ off 3′
* Psychotic disorder due to epilepsy, according to DSM-IV criteria (code 293.0: Diagnostic and Statistical Manual of Mental Disorders); **VNS: Vagal nerve stimulation.
Table 2 VNS therapy effects.
Pre-VNS Post-VNS
Seizure type Seizure frequency (per month) Seizure treatment (dose mg/day) Psychotic episode frequency (per year) Psychiatric treatment (dose mg/day) Seizure type Reduction Seizure frequency (%) Seizure treatment (dose mg/day) Magnet-controlled seizures Psychotic episode Frequency (per year) Psychiatric treatment (dose mg/day) Psychotic episode-free* (Yrs) Psychotic episode-free period (Yrs)
PT1 FIAS, occasionally FBTCS 8 Surgery OXC (1500)
CBM (10) BRV (100) 3 – Focal awareness 62.5% OXC (1200)
CBM (10)
LCM (20) Yes 3 episodes in the 1-2nd year – 3rd 2
PT2 FIAS, occasionally FBTCS 8–6 OXC (1200)
PHT (350)
LCM (200) 2–3 QTP (200) HLP (6) Nocturnal seizures 42.8% PHT (350)
LCM (200)
ESL (1600) No No episodes QTP (100)
HLP (4) 1st 6
PT3 FIAS 30–50
SE 1 Surgery (3)
ZNS (300) CBZ (1200)
CBM (20) 6–8 QTP (100) CZP (100) Focal awareness and falls 82.5%
SE 100% CBZ (1200)
ZNS (300)
CBM (20) No 1 episode in the 1st year QTP (100) 2nd 3
PT4 FIAS 10–15
SE 1–2 LVT (2000) LMT (400) 2–4 RPD (10) Focal awareness 60%
SE 100% LVT (1000)
LMT (400) Yes No episodes QTP (100) 1st 3
Abbreviations: FIAS: Focal impaired awareness seizure; FBTCS: focal to bilateral tonic-clonic seizure, SE: status epilepticus; BRV: brivaracetam, CBZ: carbamazepine, CBM: clobazam, LCM: lacosamide, LMT: lamotrigine, LVT: levetiracetam, OXC: oxcarbazepine, PHT: phenytoin, ZNS: zonisamide; CPZ: clozapine, HLP: haloperidol, QTP: quetiapine, RPD: risperidone. * Determined to be the first psychotic episode-free year after VNS implantation.
2 Discussion/Conclusion
New onset psychotic episodes after VNS implantation have been reported in the literature [10]. These are may be seen in patients with DRE when they suddenly become seizure-free, presumably due to forced normalization. In contrast, one study has shown an antipsychotic effect after VNS implantation [12]. Recently, Lee et al. [14] reported the first case of forced normalization after turning off VNS in a patient suffering from Lennox-Gastaut syndrome.
Regarding the VNS mechanisms of action, it is thought that afferent vagal fibers modulate the release of different neurotransmitters in the brainstem involving the locus coeruleus, the nucleus of the solitary tract, thalamus, and limbic system structures. The dysregulation of neurotransmitters has also been identified relative to altered seizure threshold and in psychiatric disorders [15].
In our study, the results showed that patients suffering from PPE had their ictal or postictal psychotic episodes controlled after VNS implantation. However, the positive psychotropic effect was not immediate. Combined time-frame analysis showed a latency effect of VNS to control psychosis of 8.3 months (range: 6–36 months). This occurred despite the absemce of seizure control, however, in three of the cases semiology changed after VNS implantation.
18F-FDG-PET images showed a normalization of metabolism in both medial prefrontal cortical areas and anterior insulas in one of our patients, after VNS implantation. Interestingly, perfusion changes in the same areas have been described apart from the epileptogenic foci in psychotic and epileptic patients [16], [17], [18]. Normalization of medial frontal metabolism, one of the cortical areas of the cortico-striatal-thalamic-cortical loop circuits has been suggested as important in schizophrenia patients and has also been observed in DRE patients suffering psychosis [19].
Although it is speculative, this positive psychotropic effect in DRE patients suffering ictal and postictal psychosis could be related to a long-term neuromodulator effect of the VNS, independent of its antiseizure effect [20], [21], [22]. Despite these encouraging preliminary results, future research is needed to confirm our findings and to determine whether VNS-induced brain changes are associated with a favorable outcome in patients with VNS and ictal or postictal psychosis. Larger prospective studies are recommendable to validate our initial observation.
3 Statements
3.1 Ethics statement
The study was approved by the Ethics Committee of the University Hospital of Bellvitge (Hospitalet de Llobregat, Barcelona, Spain) and conducted in accordance with the Declaration of Helsinki, PR 349/18. The patients’ confidential information was protected according to the current European and Spanish regulations. All patients signed an informed consent.
Acknowledgments
We gratefully thank all the patients who selflessly participated in the study.
Declaration of Competing Interest
T. Vancamp is also an employee of LivaNova. All other authors report no conflicts of interest.
Study funding
No financial or any other support has been provided to the authors to perform this study, nor to compose this manuscript.
Authors’ contributions:
I. Conception and design: M. Falip, T. Vancamp, and M. Alemany.
II. Administrative support: M. Santurino.
III. Provision of study materials for patients: G. Plans, E. Real, N.Custal, and J. Mora.
IV. Collection and assembly of data: M. Falip, L. Rodríguez-Bel, and M. Alemany.
V. Data analysis and interpretation: M. Falip, J. Sala-Padró, and M. Alemany.
VI. Manuscript writing: All authors.
VII. Final approval of manuscript: All authors | UNKNOWN DOSE | DrugDosageText | CC BY-NC-ND | 33665601 | 19,065,855 | 2021 |
What was the dosage of drug 'OXCARBAZEPINE'? | Vagus nerve stimulation as a potential modulator of periictal psychotic episodes: A report of four cases.
Drug resistant epilepsy (DRE) has been associated with a high incidence of psychotic disorders. Patients can develop psychosis after starting a new antiseizure medication, after undergoing resective surgery, or after implantation of a vagus nerve stimulation (VNS) system. The aim of this study was to investigate the modulation effect of VNS on psychotic episodes in DRE patients with a pre-existing history of periictal psychotic episodes (PPE). We retrospectively report the outcome of four patients from a single tertiary center with PPE prior to implantation. None of the implanted patients developed de novo PPE after VNS therapy. Regarding seizure outcome, all patients demonstrated a response to VNS with two who experienced who status epilepticus and three patients wtih a change in semiology with after VNS implantation. PPE disappeared in all the study patients, two of them at 6 months post-implantation and in the others after 2 and 3 years, respectively. 18F-FDG-PET results showed hypermetabolism in both anterior insular and medial frontal lobes which disappeared in the 18F -FDG-PET 4 years post-implantation. Based on the results of this series of cases we suggest that VNS therapy may be useful to modulatet PPE in patients with DRE, though effectiveness may be time-dependent.
1 Introduction
Psychiatric disorders affect patients with epilepsy more frequently than they do the general population. The reported prevalence of psychotic disturbances varies between 2% and 7%, with a pooled prevalence of 5.6% [1]. The variation becomes higher when compared to the general population (1%), especially in those with temporal lobe epilepsy (TLE), affecting nearly 20% of patients [2]. Psychosis may be seen based upon its temporal relationship with seizures and include preictal, ictal, and postictal psychosis. We separated them into periictal psychotic episodes (PPE) and interictal psychosis (IIP) when a relationship between psychosis and seizures did not exist.
For PPE we used the same definitions as those identified by Logsdail and Toone. PIP was a defined as appearing within one week after a seizure or cluster of seizures, lasting from at least 15 hours up to 2 months, and preceded by a lucid period (24–72 h). Ictal psychosis was defined as psychosis appearing simultaneously with a prolonged seizure or status epilepticus as the clinical expression confirmed by an EEG without prominent motor symptoms [3].
Most of the old and new antiseizure drugs (ASD) as well as surgical treatment have been implicated in the emergence of PPE [4], [5]. Psychotic symptoms in epileptic patients with PPE are thought to be influenced by a disruption in a chronic inhibitory mechanism. Immediately after a cluster of seizures, PIP patients may experience an unusually profound depression of limbic function producing a disconnection of the temporal-limbic structures and the prefrontal structures and a loss of control over the prefrontal structures [6]. This concept was first introduced in 1953 by Landolt with the concept of ‘forced normalization theory’ to describe the appearance of psychotic episodes associated with total or partial normalization of the electroencephalogram (EEG) in patients with epilepsy [7]. In regard to this, vagus nerve stimulation (VNS) therapy has also played a role [8], [9], [10], [11]. Paradoxically, a positive effect in the modulation of psychiatric symptoms has been observed in VNS treated patients, and it has been approved as a non-pharmacological adunctive treatment for depression [12]. Moreover, a recent study conducted in an animal model for schizophrenia found VNS provided a positive effect in controlling psychotic symptoms [13].
We aimed to study the neuro-modulatory effect of VNS on psychotic episodes in drug-resistant epilepsy (DRE) patients with a pre-existing history of PPE in a single-center retrospective analysis. A total of 48 patients diagnosed with DRE and treated with VNS therapy from 2006 to 2016 were identified. None of the implanted patients developed psychosis. In the present study we included 4 patients from the series with a prior history of PPE.
Patient evaluation included a formal intermittent psychiatric examination, prolonged video-EEG (vEEG), structural magnetic resonance imaging (MRI) study with a standard epilepsy protocol, and 18F-labelled fluoro-2-deoxyglucose-positron emission tomography (18F-FDG-PET) co-registered with MRI.
1.1 Case 1
A 40-year-old male patient was diagnosed at the age of 23 with non-lesional bitemporal DRE. The patient experienced 8 episodes per month of focal impaired awareness seizure (FIAS), and occasionally focal to bilateral tonic-clonic seizure (FBTCS). Several ASDs were tested without achieving seizure control, with oxcarbazepine (OXC), clobazam (CBM) and brivaracetam (BRV) the last combination tried. Anterior temporal lobe resection of the most affected temporal lobe was done at the age of 34 without changes in seizure frequency. After nine months, the patient started suffering PIP episodes at a frequency of 3 episodes per year. PIP episodes began in the 12–24 hours after the seizure and lasted for 3–5 days. These episodes were characterised by a state of confusion and auditory hallucinations, requiring hospitalization in one case. No prior history of psychotic disorder was reported. During PIP episodes normal EEG background with fronto–temporal interictal epileptiform discharges was recorded (see Fig. 1). VNS device was implanted one year later to achieve better seizure control. After a 5-year follow-up seizures were reduced by 62.5% in additio to a change in semiology (focal aware seizure with distorted body perception) and reduced seizure severity. In terms of PIP, 3 episodes in the 2nd year was noted and no new episodes appeared after the third year of stimulation.Fig. 1 EEG recording during a postictal psychosis Patient with visual hallucinations and feelings of being harmed by others. EEG records show a left temporal breach rhythm due to previous craniotomy. There were occasional interictal epileptiform discharges in the recording (box).
1.2 Case 2
A 54-year-old male patient was diagnosed at the age of 14 with DRE secondary to a malformation of cortical development. Bitemporal seizures at a frequency of 6–8 episodes per month were reported. FIAS not preceded by aura and occasionally Focal to bilateral tonic-clonic seizures (FBTCS) were the typical seizure types. Several ASDs (OXC, phenytoin (PHT) and lacosamide (LCM)) were tested without achieving seizure control. At the age of 43 the patient started suffering recurrent episodes of postictal psychosis which started between 8 and 12 hours after a seizure, characterised by a state of confusion with hallucinations and paranoia. No prior history of psychotic disorder was reported. Antipsychotic treatment was initiated with quetiapine (QTP) and haloperidol (HLP); however, episodes were still present occurring with a frequency of 2–3 times per year, requiring hospitalization on two occasions. VNS therapy was implanted at the age of 48. After a 6-year follow-up seizures were reduced by 42.8% with a change in semiology (appearing only nocturnally). No further episodes of postictal psychosis were documented one year after VNS implantation.
1.3 Case 3
A 47-year-old female patient was diagnosed at the age of 12 with DRE secondary to a parietal tumour. Initial surgery was done in another center when the patient was 16 and the histopathology was reported as oligodendroglioma, with complete resection. The patient was seizure free for 3 years but then the seizures reappeared and became more and more frequent. No evidence of tumor relapse was observed. She was reoperated twice, at the ages of 25 and 31 including a left parietal topectomy and a right amygdalohippocampectomy. At the age of 36 she started suffering ictal psychosis during episodes characterised by delusions, anxiety, agitation, and heteroaggressivity. These psychotic episodes appeared simultaneously with an exacerbation of seizure clustering. No prior history of psychotic disorder was reported. She was monitored in our center from 2012, and at that time she suffered 1–2 seizures per day and 1 episode of psychosis per month. EEG findings during these episodes showed seizures arising in one parietal or temporal lobe evolving to contralateral areas without recovery between them (see Fig. 2). Antipsychotic treatment was initiated with QTP and clozapine (CPZ), but unfortunately the episodes remained, with a frequency of 6–8 per year. In relation to post-surgical changes, MRI showed areas of encephalomalacia-gliosis on the right temporal-insular cortex and left parietal splenium of the corpus callosum. At the age of 43, a VNS was implanted achieving a reduction of seizures by 82.5% and elimination of the episodes of SE over a 4 year follow-up period. Post-VNS the semiology of seizures also changed to focal aware seizures and falls. Only 1 episode of ictal psychosis was documented in the 1st year and was completely eliminated by the 2nd year after VNS implantation.Fig. 2 EEG recording during an ictal psychosis Patient with visual hallucinations and heteroaggressive behaviour. EEG record during the episode shows (A) interictal epileptiform activity over T7, P7, P3 (box) and (B) subclinical seizures (42 subclinical seizures in 6 hours) starting with alpha rhythm in T8 and spreading to the right frontotemporal area (box).
1.4 Case 4
A 61-year-old female patient was diagnosed at the age of 18 with non-lesional DRE, temporal and biparietal lobes. The patient experienced FIAS not preceded by aura with a frequency of 10–15 episodes per month, and 1–2 SE per month (starting with clusters of 5–7 seizures for 3–4 hours and continuing with an altered mental state of confusion and disorientation for 3 days). Several ASDs were trialed without achieving seizure control. The last trial included combination therapy with levetiracetam and lamotrigine. At the age of 50 during periods when the frequency of seizures was higher, the patient started suffering ictal psychosis characterised by episodes of agitation, auditory hallucinations, and perspicuous feelings. No prior history of psychotic disorders was reported. Antipsychotic treatment was initiated with risperidone without achieving control of psychotic episodes which continued with a frequency of 2–4 per year requiring hospitalization on 7 occasions, 3 of them due to suicide attempts.
At the age of 58 VNS was implanted achieving a reduction of seizure frequency by 60% and elimination of SE over a 4 year follow-up period. Seizure severity also changed due to changes in semiology to focal aware seizures with somatosensory aura in the right foot not followed by impaired awareness most of the time when she acutely activated magnet-induced VNS stimulation. No further psychotic episodes were documented after the first year of VNS implantation.
Additionally, 18F-FDG-PET before VNS implantation was performed showing hypometabolism in both superior parietal lobes, more evident in the right, and relative hypermetabolism in the mesial frontal areas and anterior insulas. 18F-FDG-PET after 4 years following VNS implantation showed less intense hypometabolism in both superior parietal lobes with a normalisation of the hypermetabolism in the frontal lobes, insular lobes, and left caudate nucleus (shown in Fig. 3).Fig. 3 18F-FDG-PET pre- and post-VNS implantation a)18F-FDG-PET pre-VNS shows hypometabolism in both superior parietal lobes (^), more intense in the right (epileptogenic area) and relative hypermetabolism in the mesial frontal areas (*) and the anterior insulas ( ). b)18F-FDG-PET post-VNS shows less intense hypometabolism in both superior parietal lobes (^) with a normalization of the hypermetabolism in the frontal lobes (*) and insular lobes ( ). c) Z map of the18F-FDG-PET subtraction co-recorded with the MRI, showing the cortical areas that underwent a change of more than 2SD in metabolism; frontal areas with a decrease of metabolism (blue blob) and right parietal areas with increase of metabolism (orange blob). (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
A summary of demographics and clinical characteristics of the reported cases and VNS therapy effects are shown in Table 1 and Table 2, respectively.Table 1 Demographics and clinical characteristics of patients with prior history of periictal psychosis (PPE) and VNS. therapy.
P 1 P 2 P 3 P 4
Gender Male Male Female Female
Age (Yrs) 40 54 47 61
Age at epilepsy onset (Yrs) 23 14 12 18
Aetiology Unknown Malformation of cortical development Left oligodendroglioma Unknown
Seizures localization Bitemporal Bitemporal Left parietal, bitemporal Left temporal, biparietal
Age at psychosis onset (Yrs) 34 43 36 50
Psychiatric symptoms Confusion, auditory hallucinations Confusion, Hallucinations, paranoia Anxiety, agitation, heteroaggressivity Agitation, auditory hallucinations, perspicuous feelings
Psychiatric disorder in relation to seizures* Postictal Postictal Ictal Ictal
Age at VNS implantation (Yrs) 35 48 43 58
VNS** follow-up time (Yrs) 5 6 4 3
Intensity/frequency VNS* 1 mA/ on 30″ off 5′ 2 mA/ on 30″ off 5′ 2.25 mA/ on 30″ off 1.8′ 2 mA/ on 30″ off 3′
* Psychotic disorder due to epilepsy, according to DSM-IV criteria (code 293.0: Diagnostic and Statistical Manual of Mental Disorders); **VNS: Vagal nerve stimulation.
Table 2 VNS therapy effects.
Pre-VNS Post-VNS
Seizure type Seizure frequency (per month) Seizure treatment (dose mg/day) Psychotic episode frequency (per year) Psychiatric treatment (dose mg/day) Seizure type Reduction Seizure frequency (%) Seizure treatment (dose mg/day) Magnet-controlled seizures Psychotic episode Frequency (per year) Psychiatric treatment (dose mg/day) Psychotic episode-free* (Yrs) Psychotic episode-free period (Yrs)
PT1 FIAS, occasionally FBTCS 8 Surgery OXC (1500)
CBM (10) BRV (100) 3 – Focal awareness 62.5% OXC (1200)
CBM (10)
LCM (20) Yes 3 episodes in the 1-2nd year – 3rd 2
PT2 FIAS, occasionally FBTCS 8–6 OXC (1200)
PHT (350)
LCM (200) 2–3 QTP (200) HLP (6) Nocturnal seizures 42.8% PHT (350)
LCM (200)
ESL (1600) No No episodes QTP (100)
HLP (4) 1st 6
PT3 FIAS 30–50
SE 1 Surgery (3)
ZNS (300) CBZ (1200)
CBM (20) 6–8 QTP (100) CZP (100) Focal awareness and falls 82.5%
SE 100% CBZ (1200)
ZNS (300)
CBM (20) No 1 episode in the 1st year QTP (100) 2nd 3
PT4 FIAS 10–15
SE 1–2 LVT (2000) LMT (400) 2–4 RPD (10) Focal awareness 60%
SE 100% LVT (1000)
LMT (400) Yes No episodes QTP (100) 1st 3
Abbreviations: FIAS: Focal impaired awareness seizure; FBTCS: focal to bilateral tonic-clonic seizure, SE: status epilepticus; BRV: brivaracetam, CBZ: carbamazepine, CBM: clobazam, LCM: lacosamide, LMT: lamotrigine, LVT: levetiracetam, OXC: oxcarbazepine, PHT: phenytoin, ZNS: zonisamide; CPZ: clozapine, HLP: haloperidol, QTP: quetiapine, RPD: risperidone. * Determined to be the first psychotic episode-free year after VNS implantation.
2 Discussion/Conclusion
New onset psychotic episodes after VNS implantation have been reported in the literature [10]. These are may be seen in patients with DRE when they suddenly become seizure-free, presumably due to forced normalization. In contrast, one study has shown an antipsychotic effect after VNS implantation [12]. Recently, Lee et al. [14] reported the first case of forced normalization after turning off VNS in a patient suffering from Lennox-Gastaut syndrome.
Regarding the VNS mechanisms of action, it is thought that afferent vagal fibers modulate the release of different neurotransmitters in the brainstem involving the locus coeruleus, the nucleus of the solitary tract, thalamus, and limbic system structures. The dysregulation of neurotransmitters has also been identified relative to altered seizure threshold and in psychiatric disorders [15].
In our study, the results showed that patients suffering from PPE had their ictal or postictal psychotic episodes controlled after VNS implantation. However, the positive psychotropic effect was not immediate. Combined time-frame analysis showed a latency effect of VNS to control psychosis of 8.3 months (range: 6–36 months). This occurred despite the absemce of seizure control, however, in three of the cases semiology changed after VNS implantation.
18F-FDG-PET images showed a normalization of metabolism in both medial prefrontal cortical areas and anterior insulas in one of our patients, after VNS implantation. Interestingly, perfusion changes in the same areas have been described apart from the epileptogenic foci in psychotic and epileptic patients [16], [17], [18]. Normalization of medial frontal metabolism, one of the cortical areas of the cortico-striatal-thalamic-cortical loop circuits has been suggested as important in schizophrenia patients and has also been observed in DRE patients suffering psychosis [19].
Although it is speculative, this positive psychotropic effect in DRE patients suffering ictal and postictal psychosis could be related to a long-term neuromodulator effect of the VNS, independent of its antiseizure effect [20], [21], [22]. Despite these encouraging preliminary results, future research is needed to confirm our findings and to determine whether VNS-induced brain changes are associated with a favorable outcome in patients with VNS and ictal or postictal psychosis. Larger prospective studies are recommendable to validate our initial observation.
3 Statements
3.1 Ethics statement
The study was approved by the Ethics Committee of the University Hospital of Bellvitge (Hospitalet de Llobregat, Barcelona, Spain) and conducted in accordance with the Declaration of Helsinki, PR 349/18. The patients’ confidential information was protected according to the current European and Spanish regulations. All patients signed an informed consent.
Acknowledgments
We gratefully thank all the patients who selflessly participated in the study.
Declaration of Competing Interest
T. Vancamp is also an employee of LivaNova. All other authors report no conflicts of interest.
Study funding
No financial or any other support has been provided to the authors to perform this study, nor to compose this manuscript.
Authors’ contributions:
I. Conception and design: M. Falip, T. Vancamp, and M. Alemany.
II. Administrative support: M. Santurino.
III. Provision of study materials for patients: G. Plans, E. Real, N.Custal, and J. Mora.
IV. Collection and assembly of data: M. Falip, L. Rodríguez-Bel, and M. Alemany.
V. Data analysis and interpretation: M. Falip, J. Sala-Padró, and M. Alemany.
VI. Manuscript writing: All authors.
VII. Final approval of manuscript: All authors | UNKNOWN DOSE | DrugDosageText | CC BY-NC-ND | 33665601 | 19,065,854 | 2021 |
What was the dosage of drug 'PHENYTOIN'? | Vagus nerve stimulation as a potential modulator of periictal psychotic episodes: A report of four cases.
Drug resistant epilepsy (DRE) has been associated with a high incidence of psychotic disorders. Patients can develop psychosis after starting a new antiseizure medication, after undergoing resective surgery, or after implantation of a vagus nerve stimulation (VNS) system. The aim of this study was to investigate the modulation effect of VNS on psychotic episodes in DRE patients with a pre-existing history of periictal psychotic episodes (PPE). We retrospectively report the outcome of four patients from a single tertiary center with PPE prior to implantation. None of the implanted patients developed de novo PPE after VNS therapy. Regarding seizure outcome, all patients demonstrated a response to VNS with two who experienced who status epilepticus and three patients wtih a change in semiology with after VNS implantation. PPE disappeared in all the study patients, two of them at 6 months post-implantation and in the others after 2 and 3 years, respectively. 18F-FDG-PET results showed hypermetabolism in both anterior insular and medial frontal lobes which disappeared in the 18F -FDG-PET 4 years post-implantation. Based on the results of this series of cases we suggest that VNS therapy may be useful to modulatet PPE in patients with DRE, though effectiveness may be time-dependent.
1 Introduction
Psychiatric disorders affect patients with epilepsy more frequently than they do the general population. The reported prevalence of psychotic disturbances varies between 2% and 7%, with a pooled prevalence of 5.6% [1]. The variation becomes higher when compared to the general population (1%), especially in those with temporal lobe epilepsy (TLE), affecting nearly 20% of patients [2]. Psychosis may be seen based upon its temporal relationship with seizures and include preictal, ictal, and postictal psychosis. We separated them into periictal psychotic episodes (PPE) and interictal psychosis (IIP) when a relationship between psychosis and seizures did not exist.
For PPE we used the same definitions as those identified by Logsdail and Toone. PIP was a defined as appearing within one week after a seizure or cluster of seizures, lasting from at least 15 hours up to 2 months, and preceded by a lucid period (24–72 h). Ictal psychosis was defined as psychosis appearing simultaneously with a prolonged seizure or status epilepticus as the clinical expression confirmed by an EEG without prominent motor symptoms [3].
Most of the old and new antiseizure drugs (ASD) as well as surgical treatment have been implicated in the emergence of PPE [4], [5]. Psychotic symptoms in epileptic patients with PPE are thought to be influenced by a disruption in a chronic inhibitory mechanism. Immediately after a cluster of seizures, PIP patients may experience an unusually profound depression of limbic function producing a disconnection of the temporal-limbic structures and the prefrontal structures and a loss of control over the prefrontal structures [6]. This concept was first introduced in 1953 by Landolt with the concept of ‘forced normalization theory’ to describe the appearance of psychotic episodes associated with total or partial normalization of the electroencephalogram (EEG) in patients with epilepsy [7]. In regard to this, vagus nerve stimulation (VNS) therapy has also played a role [8], [9], [10], [11]. Paradoxically, a positive effect in the modulation of psychiatric symptoms has been observed in VNS treated patients, and it has been approved as a non-pharmacological adunctive treatment for depression [12]. Moreover, a recent study conducted in an animal model for schizophrenia found VNS provided a positive effect in controlling psychotic symptoms [13].
We aimed to study the neuro-modulatory effect of VNS on psychotic episodes in drug-resistant epilepsy (DRE) patients with a pre-existing history of PPE in a single-center retrospective analysis. A total of 48 patients diagnosed with DRE and treated with VNS therapy from 2006 to 2016 were identified. None of the implanted patients developed psychosis. In the present study we included 4 patients from the series with a prior history of PPE.
Patient evaluation included a formal intermittent psychiatric examination, prolonged video-EEG (vEEG), structural magnetic resonance imaging (MRI) study with a standard epilepsy protocol, and 18F-labelled fluoro-2-deoxyglucose-positron emission tomography (18F-FDG-PET) co-registered with MRI.
1.1 Case 1
A 40-year-old male patient was diagnosed at the age of 23 with non-lesional bitemporal DRE. The patient experienced 8 episodes per month of focal impaired awareness seizure (FIAS), and occasionally focal to bilateral tonic-clonic seizure (FBTCS). Several ASDs were tested without achieving seizure control, with oxcarbazepine (OXC), clobazam (CBM) and brivaracetam (BRV) the last combination tried. Anterior temporal lobe resection of the most affected temporal lobe was done at the age of 34 without changes in seizure frequency. After nine months, the patient started suffering PIP episodes at a frequency of 3 episodes per year. PIP episodes began in the 12–24 hours after the seizure and lasted for 3–5 days. These episodes were characterised by a state of confusion and auditory hallucinations, requiring hospitalization in one case. No prior history of psychotic disorder was reported. During PIP episodes normal EEG background with fronto–temporal interictal epileptiform discharges was recorded (see Fig. 1). VNS device was implanted one year later to achieve better seizure control. After a 5-year follow-up seizures were reduced by 62.5% in additio to a change in semiology (focal aware seizure with distorted body perception) and reduced seizure severity. In terms of PIP, 3 episodes in the 2nd year was noted and no new episodes appeared after the third year of stimulation.Fig. 1 EEG recording during a postictal psychosis Patient with visual hallucinations and feelings of being harmed by others. EEG records show a left temporal breach rhythm due to previous craniotomy. There were occasional interictal epileptiform discharges in the recording (box).
1.2 Case 2
A 54-year-old male patient was diagnosed at the age of 14 with DRE secondary to a malformation of cortical development. Bitemporal seizures at a frequency of 6–8 episodes per month were reported. FIAS not preceded by aura and occasionally Focal to bilateral tonic-clonic seizures (FBTCS) were the typical seizure types. Several ASDs (OXC, phenytoin (PHT) and lacosamide (LCM)) were tested without achieving seizure control. At the age of 43 the patient started suffering recurrent episodes of postictal psychosis which started between 8 and 12 hours after a seizure, characterised by a state of confusion with hallucinations and paranoia. No prior history of psychotic disorder was reported. Antipsychotic treatment was initiated with quetiapine (QTP) and haloperidol (HLP); however, episodes were still present occurring with a frequency of 2–3 times per year, requiring hospitalization on two occasions. VNS therapy was implanted at the age of 48. After a 6-year follow-up seizures were reduced by 42.8% with a change in semiology (appearing only nocturnally). No further episodes of postictal psychosis were documented one year after VNS implantation.
1.3 Case 3
A 47-year-old female patient was diagnosed at the age of 12 with DRE secondary to a parietal tumour. Initial surgery was done in another center when the patient was 16 and the histopathology was reported as oligodendroglioma, with complete resection. The patient was seizure free for 3 years but then the seizures reappeared and became more and more frequent. No evidence of tumor relapse was observed. She was reoperated twice, at the ages of 25 and 31 including a left parietal topectomy and a right amygdalohippocampectomy. At the age of 36 she started suffering ictal psychosis during episodes characterised by delusions, anxiety, agitation, and heteroaggressivity. These psychotic episodes appeared simultaneously with an exacerbation of seizure clustering. No prior history of psychotic disorder was reported. She was monitored in our center from 2012, and at that time she suffered 1–2 seizures per day and 1 episode of psychosis per month. EEG findings during these episodes showed seizures arising in one parietal or temporal lobe evolving to contralateral areas without recovery between them (see Fig. 2). Antipsychotic treatment was initiated with QTP and clozapine (CPZ), but unfortunately the episodes remained, with a frequency of 6–8 per year. In relation to post-surgical changes, MRI showed areas of encephalomalacia-gliosis on the right temporal-insular cortex and left parietal splenium of the corpus callosum. At the age of 43, a VNS was implanted achieving a reduction of seizures by 82.5% and elimination of the episodes of SE over a 4 year follow-up period. Post-VNS the semiology of seizures also changed to focal aware seizures and falls. Only 1 episode of ictal psychosis was documented in the 1st year and was completely eliminated by the 2nd year after VNS implantation.Fig. 2 EEG recording during an ictal psychosis Patient with visual hallucinations and heteroaggressive behaviour. EEG record during the episode shows (A) interictal epileptiform activity over T7, P7, P3 (box) and (B) subclinical seizures (42 subclinical seizures in 6 hours) starting with alpha rhythm in T8 and spreading to the right frontotemporal area (box).
1.4 Case 4
A 61-year-old female patient was diagnosed at the age of 18 with non-lesional DRE, temporal and biparietal lobes. The patient experienced FIAS not preceded by aura with a frequency of 10–15 episodes per month, and 1–2 SE per month (starting with clusters of 5–7 seizures for 3–4 hours and continuing with an altered mental state of confusion and disorientation for 3 days). Several ASDs were trialed without achieving seizure control. The last trial included combination therapy with levetiracetam and lamotrigine. At the age of 50 during periods when the frequency of seizures was higher, the patient started suffering ictal psychosis characterised by episodes of agitation, auditory hallucinations, and perspicuous feelings. No prior history of psychotic disorders was reported. Antipsychotic treatment was initiated with risperidone without achieving control of psychotic episodes which continued with a frequency of 2–4 per year requiring hospitalization on 7 occasions, 3 of them due to suicide attempts.
At the age of 58 VNS was implanted achieving a reduction of seizure frequency by 60% and elimination of SE over a 4 year follow-up period. Seizure severity also changed due to changes in semiology to focal aware seizures with somatosensory aura in the right foot not followed by impaired awareness most of the time when she acutely activated magnet-induced VNS stimulation. No further psychotic episodes were documented after the first year of VNS implantation.
Additionally, 18F-FDG-PET before VNS implantation was performed showing hypometabolism in both superior parietal lobes, more evident in the right, and relative hypermetabolism in the mesial frontal areas and anterior insulas. 18F-FDG-PET after 4 years following VNS implantation showed less intense hypometabolism in both superior parietal lobes with a normalisation of the hypermetabolism in the frontal lobes, insular lobes, and left caudate nucleus (shown in Fig. 3).Fig. 3 18F-FDG-PET pre- and post-VNS implantation a)18F-FDG-PET pre-VNS shows hypometabolism in both superior parietal lobes (^), more intense in the right (epileptogenic area) and relative hypermetabolism in the mesial frontal areas (*) and the anterior insulas ( ). b)18F-FDG-PET post-VNS shows less intense hypometabolism in both superior parietal lobes (^) with a normalization of the hypermetabolism in the frontal lobes (*) and insular lobes ( ). c) Z map of the18F-FDG-PET subtraction co-recorded with the MRI, showing the cortical areas that underwent a change of more than 2SD in metabolism; frontal areas with a decrease of metabolism (blue blob) and right parietal areas with increase of metabolism (orange blob). (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
A summary of demographics and clinical characteristics of the reported cases and VNS therapy effects are shown in Table 1 and Table 2, respectively.Table 1 Demographics and clinical characteristics of patients with prior history of periictal psychosis (PPE) and VNS. therapy.
P 1 P 2 P 3 P 4
Gender Male Male Female Female
Age (Yrs) 40 54 47 61
Age at epilepsy onset (Yrs) 23 14 12 18
Aetiology Unknown Malformation of cortical development Left oligodendroglioma Unknown
Seizures localization Bitemporal Bitemporal Left parietal, bitemporal Left temporal, biparietal
Age at psychosis onset (Yrs) 34 43 36 50
Psychiatric symptoms Confusion, auditory hallucinations Confusion, Hallucinations, paranoia Anxiety, agitation, heteroaggressivity Agitation, auditory hallucinations, perspicuous feelings
Psychiatric disorder in relation to seizures* Postictal Postictal Ictal Ictal
Age at VNS implantation (Yrs) 35 48 43 58
VNS** follow-up time (Yrs) 5 6 4 3
Intensity/frequency VNS* 1 mA/ on 30″ off 5′ 2 mA/ on 30″ off 5′ 2.25 mA/ on 30″ off 1.8′ 2 mA/ on 30″ off 3′
* Psychotic disorder due to epilepsy, according to DSM-IV criteria (code 293.0: Diagnostic and Statistical Manual of Mental Disorders); **VNS: Vagal nerve stimulation.
Table 2 VNS therapy effects.
Pre-VNS Post-VNS
Seizure type Seizure frequency (per month) Seizure treatment (dose mg/day) Psychotic episode frequency (per year) Psychiatric treatment (dose mg/day) Seizure type Reduction Seizure frequency (%) Seizure treatment (dose mg/day) Magnet-controlled seizures Psychotic episode Frequency (per year) Psychiatric treatment (dose mg/day) Psychotic episode-free* (Yrs) Psychotic episode-free period (Yrs)
PT1 FIAS, occasionally FBTCS 8 Surgery OXC (1500)
CBM (10) BRV (100) 3 – Focal awareness 62.5% OXC (1200)
CBM (10)
LCM (20) Yes 3 episodes in the 1-2nd year – 3rd 2
PT2 FIAS, occasionally FBTCS 8–6 OXC (1200)
PHT (350)
LCM (200) 2–3 QTP (200) HLP (6) Nocturnal seizures 42.8% PHT (350)
LCM (200)
ESL (1600) No No episodes QTP (100)
HLP (4) 1st 6
PT3 FIAS 30–50
SE 1 Surgery (3)
ZNS (300) CBZ (1200)
CBM (20) 6–8 QTP (100) CZP (100) Focal awareness and falls 82.5%
SE 100% CBZ (1200)
ZNS (300)
CBM (20) No 1 episode in the 1st year QTP (100) 2nd 3
PT4 FIAS 10–15
SE 1–2 LVT (2000) LMT (400) 2–4 RPD (10) Focal awareness 60%
SE 100% LVT (1000)
LMT (400) Yes No episodes QTP (100) 1st 3
Abbreviations: FIAS: Focal impaired awareness seizure; FBTCS: focal to bilateral tonic-clonic seizure, SE: status epilepticus; BRV: brivaracetam, CBZ: carbamazepine, CBM: clobazam, LCM: lacosamide, LMT: lamotrigine, LVT: levetiracetam, OXC: oxcarbazepine, PHT: phenytoin, ZNS: zonisamide; CPZ: clozapine, HLP: haloperidol, QTP: quetiapine, RPD: risperidone. * Determined to be the first psychotic episode-free year after VNS implantation.
2 Discussion/Conclusion
New onset psychotic episodes after VNS implantation have been reported in the literature [10]. These are may be seen in patients with DRE when they suddenly become seizure-free, presumably due to forced normalization. In contrast, one study has shown an antipsychotic effect after VNS implantation [12]. Recently, Lee et al. [14] reported the first case of forced normalization after turning off VNS in a patient suffering from Lennox-Gastaut syndrome.
Regarding the VNS mechanisms of action, it is thought that afferent vagal fibers modulate the release of different neurotransmitters in the brainstem involving the locus coeruleus, the nucleus of the solitary tract, thalamus, and limbic system structures. The dysregulation of neurotransmitters has also been identified relative to altered seizure threshold and in psychiatric disorders [15].
In our study, the results showed that patients suffering from PPE had their ictal or postictal psychotic episodes controlled after VNS implantation. However, the positive psychotropic effect was not immediate. Combined time-frame analysis showed a latency effect of VNS to control psychosis of 8.3 months (range: 6–36 months). This occurred despite the absemce of seizure control, however, in three of the cases semiology changed after VNS implantation.
18F-FDG-PET images showed a normalization of metabolism in both medial prefrontal cortical areas and anterior insulas in one of our patients, after VNS implantation. Interestingly, perfusion changes in the same areas have been described apart from the epileptogenic foci in psychotic and epileptic patients [16], [17], [18]. Normalization of medial frontal metabolism, one of the cortical areas of the cortico-striatal-thalamic-cortical loop circuits has been suggested as important in schizophrenia patients and has also been observed in DRE patients suffering psychosis [19].
Although it is speculative, this positive psychotropic effect in DRE patients suffering ictal and postictal psychosis could be related to a long-term neuromodulator effect of the VNS, independent of its antiseizure effect [20], [21], [22]. Despite these encouraging preliminary results, future research is needed to confirm our findings and to determine whether VNS-induced brain changes are associated with a favorable outcome in patients with VNS and ictal or postictal psychosis. Larger prospective studies are recommendable to validate our initial observation.
3 Statements
3.1 Ethics statement
The study was approved by the Ethics Committee of the University Hospital of Bellvitge (Hospitalet de Llobregat, Barcelona, Spain) and conducted in accordance with the Declaration of Helsinki, PR 349/18. The patients’ confidential information was protected according to the current European and Spanish regulations. All patients signed an informed consent.
Acknowledgments
We gratefully thank all the patients who selflessly participated in the study.
Declaration of Competing Interest
T. Vancamp is also an employee of LivaNova. All other authors report no conflicts of interest.
Study funding
No financial or any other support has been provided to the authors to perform this study, nor to compose this manuscript.
Authors’ contributions:
I. Conception and design: M. Falip, T. Vancamp, and M. Alemany.
II. Administrative support: M. Santurino.
III. Provision of study materials for patients: G. Plans, E. Real, N.Custal, and J. Mora.
IV. Collection and assembly of data: M. Falip, L. Rodríguez-Bel, and M. Alemany.
V. Data analysis and interpretation: M. Falip, J. Sala-Padró, and M. Alemany.
VI. Manuscript writing: All authors.
VII. Final approval of manuscript: All authors | UNKNOWN DOSE | DrugDosageText | CC BY-NC-ND | 33665601 | 19,065,854 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Interstitial lung disease'. | A case with hepatic immune-related adverse events caused by nivolumab exhibiting impaired accumulation of regulatory T cells.
Systemic administration of anti-programmed cell death 1 (PD-1) antibody (Ab) has achieved remarkable success in metastatic cancers. The blockade of PD-1-mediated signaling pathways sometimes cause immune-related adverse events (irAEs) due to restored anti-cancer as well as anti-self immunity. Although the liver is a preferential organ for irAEs, the immuno-pathogenesis underlying hepatic irAEs has been poorly understood. We describe a 57-year-old man with Stage IV lung cancer who underwent the first-line regimen composed of carboplatin and paclitaxel. Nivolumab treatment (3.2 mg/kg, every 3 weeks) was initiated when the disease progressed after the first chemotherapy. Sequential occurrence of irAEs involving the multiorgan systems was observed. He developed hepatic irAEs (Grade 3) after endocrine, lung, and cutaneous irAEs. Lobular hepatitis characterized by predominant infiltration of CD8+ T cells was seen in the liver biopsy specimens. Interestingly, defective accumulation of regulatory T cells (Tregs) expressing forkhead box protein P3 (FOXP3) was evident in this case with hepatic irAEs as compared with typical cases with autoimmune hepatitis. This case suggests that hepatic irAEs are characterized not only by lobular infiltration of CD8+ T cells but also by defective accumulation of FOXP3+ Tregs.
Introduction
A recent remarkable success of treating advanced cancer with immune check-point inhibitors (ICIs) highlight important roles that programmed cell death protein-1 (PD-1) and cytotoxic T lymphocyte-associated protein-4 (CTLA-4) play in the suppression of anti-cancer immune responses [1, 2]. Nivolumab and ipilimumab targeting PD-1 and CTLA-4, respectively, are the representative ICIs. These ICIs restore anti-cancer immune responses through neutralization of negative regulation mediated by PD-1 or CTLA-4-mediated signaling pathways [1, 2]. In fact, introduction of nivolumab and ipilimumab into clinical practice has improved the prognosis of advanced malignancies, especially malignant melanoma [1, 2].
Despite effective restorement of anti-cancer immunity by nivolumab and ipilimumab, the blockade of PD-1 and CTLA-4, both of which are negative regulators of adaptive and innate immunity, sometimes causes excessive immune reactions in a broad range of organs, called immune-related adverse events (irAEs) [3, 4]. Liver toxicity associated with ICIs occurs in around 5–10% of patients, [5] and thus, the liver is a preferential organ targeted by ICIs in parallel to the skin, colon, endocrine system, kidney, and lung [3, 4]. Although activation and expansion of T cells through lack of negative regulation by PD-1 and CTLA-4 is considered to underlie the immuno-pathogenesis of irAEs [3–5], molecular mechanisms accounting for the development of hepatic irAEs have been poorly understood. Regulatory T cells (Tregs) expressing forkhead box protein P3 (FOXP3) are a critical component of immune systems with pivotal roles not only in the maintenance of self-tolerance but also in the suppression of anti-cancer immunity [6]. Here, we report a case with hepatic irAEs exhibiting little accumulation of FOXP3-expressing Tregs into the liver. This case suggests possible involvement of Treg deficiency in the development of hepatic irAEs.
Case reports
A 51-year-old man without any history of autoimmune diseases was diagnosed as lung adenocarcinoma (p-T3N0M0, Stage IIb) and received thoracoscopic right pneumonectomy in July 2012. Follow-up computed tomography (CT), which was performed in March 2017, revealed recurrence of his lung cancer in the left lobe accompanied by mediastinal lymph node metastasis. At this time point, he was diagnosed as Stage IV lung adenocarcinoma (p-T3N1M1). His surgical specimen was negative for epidermal growth factor receptor (EGFR) mutation or anaplastic lymphoma kinase 1 (ALK1) fusion oncogene. According to the guideline for Stage IV lung adenocarcinoma with intact EGFR and ALK1 [7], he was initially treated with the first-line regimen composed of carboplatin and paclitaxel from April 2017 for 4 courses followed by paclitaxel maintenance therapy from July 2017 to October 2017. These initial courses of chemotherapy were not successful and his lung cancer was judged as progressive disease (PD) based on computed tomography findings. Nivolumab was introduced from August 2018 at a dose of 3.2 mg/kg every 3 weeks.
Various kinds of irAEs occurred after the treatment with nivolumab and the severity was graded based on the clinical practice guideline following the Common Terminology Criteria for Adverse Events [version 5.0] [8].His initial irAEs involved the endocrine system as shown by the appearance of general fatigue caused by destructive thyroiditis. A significant elevation of serum free T3 (fT3, 6.2 pg/mL, normal range, 2.3–4) and fT4 (fT4, 2.1 ng/dL, normal range, 0.9–1.7) levels accompanied by a markedly reduced level of thyroid stimulating hormone (TSH, 0.02 μIU/mL, normal range, 0.5–5) was seen in September 2018. Three months later, thyroid hormone tests clearly showed hypothyroidism characterized by reduced fT3 and fT4 levels with elevated TSH levels. Further examination of his endocrine system revealed reduced serum levels of cortisol (3.3 μg/dL, normal range 6.2–19.4) and adrenocorticotropic hormone (ACTH 1.3 pg/mL, normal range 7.3–63.3), which suggested the presence of primary adrenal insufficiency despite normal levels of blood sugar, sodium and potassium. Oral supplementation of hydrocortisone (15 mg/day) and thyroid hormone (25 μg/day) were started for G1 primary hypothyroidism and G2 primary adrenal insufficiency, respectively. In addition to these endocrine toxicities, interstitial pneumonia (G1) was detected in February 2019 and then administration of nivolumab was discontinued. Moreover, skin rash judged as G3 irAE developed in March 2019. Prednisolone (PSL, 40 mg/day) with tapering schedule 5 mg/2 weeks was started after the appearance of irAEs involving the endocrine system, lung, and skin.
Although improvement of skin rash was achieved after the initiation of PSL treatment, he developed liver injury as shown by a marked elevation of serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), and γ-glutamyltransferase (γGTP) (Table 1 and Fig. 1). Viral hepatitis was unlikely since viral markers for hepatitis A virus, hepatitis B virus, hepatitis C virus, cytomegalovirus, and Epstein–Barr virus were negative. Moreover, liver injury due to autoimmune hepatitis (AIH) or primary biliary cholangitis (PBC) was also unlikely as assessed by serum IgG levels and titers for anti-nuclear antibody (ANA) or anti-mitochondrial Ab. These blood examination data led us to consider the possibility of hepatic irAEs. No metastatic lesions were detected in the liver by abdominal contrast-enhanced CT. Moreover, magnetic resonance cholangiopancreatography did not reveal any abnormalities in the intrahepatic or extrahepatic bile ducts, suggesting that an immune-related cholangitis caused by ICIs was less likely [9]. To verify the diagnosis of hepatis irAEs, liver biopsy samples were subjected to hematoxylin and eosin (H&E) staining and immuno-histochemical analyses.Table 1 Laboratory data on admission
Hematology Blood chemistry Serological tests
WBC 6.270/μL TP 6.2 g/dL ANA (–)
RBC 346 × 104/μL Alb 3.4 g/dL AMA2 (–)
Hb 13.5 g/dL BUN 13 mg/dL IgG 697 mg/dL
Hct 39.0% Cr 0.79 mg/dL IgM 25 mg/dL
Plt 12.1 × 104/μL T-Bil 1.5 mg/dL IgE 337 IU/mL
Neutro 85.7% D-Bil 0.7 mg/dL Viral marker
Lympho 9.9% ALP 1039 U/L HBsAg (–)
Eosino 0.5% AMY 31 U/L HBsAb (–)
Endocrine LDH 679 U/L HBcAb (–)
ACTH 1.0 pg/mL AST 651 U/L HCVAb (–)
CS 6.2 μg/dL ALT 547 U/L HA-IgM (–)
TSH 1.22 μIU/mL γGTP 2718 U/L CMV-IgM (–)
FT4 1.1 ng/dL CRP 10.22 mg/dL EBVVCA-IgM (–)
Coagulation
PT 119.6%
INR 0.93
ACTH adrenocorticotropic hormone, CS cortisol, PT prothrombin time, INR international normalized ratio, AMA2 anti-mitochondrial antibody 2, ANA anti-nuclear antibody, CMV cytomegalovirus, EBV Epstein–Barr virus
Fig. 1 Clinical course of the patients. See the clinical presentation section of the text. ALT alanine aminotransferase, ALP alkaline phosphatase, AST aspartate aminotransferase, γGTP γ-glutamyltransferase, MMF mycophenolate mofetil, mPSL methylprednisolone, PSL prednisolone, UDCA ursodeoxycholic acid
Liver biopsy samples were subjected to H&E staining and immuno-histochemical analysis using mouse or rabbit anti-human CD3 antibody (Ab, Roche Diagnostics; Tokyo, Japan), CD4 Ab (Roche Diagnostics; Tokyo, Japan), CD8 Ab (Nichirei Bioscience; Tokyo, Japan), CD20 Ab (Roche Diagnostics; Tokyo, Japan), and FOXP3 Ab (Abcam; Cambridge, United Kingdom). Visualization of CD3+ T cells, CD4+ T cells, CD8+ T cells, CD20+ B cells, and FOXP3+ Tregs were performed using DakO-EnVision+ systems (Dako Japan, Tokyo, Japan) as previously described [10, 11]. The liver biopsy sample obtained from a typical patient with AIH (74-year-old female) was used as a disease control. Clinical parameters of this AIH patient were shown in Supplementary Table 1. As shown in Supplementary Table 1, serum levels of IgG and ANA titers were markedly elevated. Moreover, interface hepatitis accompanied by infiltration of plasma cells was evident. The AIH score proposed by international AIH group was 23 in this patient, and thus, this patient was diagnosed with definite AIH [12].
Although lobular as well as portal inflammation was seen in the liver specimens of this patients, immune cell infiltration was predominantly seen in the liver lobes (Fig. 2, 1st and 2nd line panels). Moreover, hyperplasia of the bile duct as well as lymphocyte infiltration into the interlobular bile duct was seen in the pathological examinations, suggesting cholestasis as well as hepatocellular injury is involved in the development of hepatic irAEs in this case [13]. These pathological findings together with elevations of serum transaminases and biliary enzymes indicated that hepatic irAEs of this case was considered to be a mixed type [13].Fig. 2 Immuno-histochemical analyses of liver biopsy specimens. Liver biopsy specimens obtained from this case with hepatic immune-related adverse effects (irAEs, 1st and 2nd line panels) and from patients with autoimmune hepatitis (AIH, 3rd and 4th line panels) were subjected to immuno-histochemical analyses using anti-CD3 Ab, anti-CD4 Ab, anti-CD8 Ab, anti-CD20 Ab, and anti-forkhead box p3 (FOXP3) Ab. Hematoxylin and eosin (H&E) staining of the portal and lobular areas (1st row). Infiltration of CD3+ T cells (2nd row), CD4+ T cells (3rd row), CD8+ T cells (4th row), CD20+ B cells (5th row), and FOXP3+ Treg cells (6th row) was visualized. Scale bar is 20 µm
Interface hepatitis accompanied by plasma cell infiltration was seen in the liver specimen with the AIH patient (Fig. 2, 3rd line panel). Thus, H&E staining in this case was compatible to hepatic irAEs rather than AIH since the former and latter disorders preferentially affect the liver lobes and portal tracts, respectively [5, 14].
We then performed characterization of immune cell infiltration in this case. As shown in Fig. 2, accumulation of CD3+ T cells was seen in the liver lobes of the patient with hepatic irAEs whereas that was seen in the portal areas of the patient with AIH. Subpopulation analysis of T cells showed predominant infiltration of CD8+ T cells rather than CD4+ T cells into the liver lobes in this case (Fig. 2, 1st line panel). AIH lesions were characterized by portal accumulation of both CD4+ and CD8+ T cells (Fig. 2, 4th line panel). Moreover, infiltration of CD20+ B cells was seen in the portal areas of AIH patients, but not those in this case. These immuno-histochemical analyses strongly suggest that liver injury arose from a manifestation of irAEs in that lesions are characterized by predominant accumulation of CD8+ T cells into the liver lobes [5]. Although Tregs expressing FOXP3 play major roles in the suppression of pro-inflammatory responses [15], their involvement in the development of hepatic irAEs has been poorly defined. Interestingly, accumulation of Tregs expressing FOXP3 was barely seen in the liver lobes of this case with hepatic irAEs whereas abundant infiltration of FOXP3+ Tregs was observed in the portal areas of the AIH patient (Fig. 2). Abundant infiltration of T cells expressing CD4, CD8, or FOXP3 was also seen in the other three cases with AIH in this study (data not shown). Taken together, these data suggest hepatic irAEs due to nivolumab might be characterized not only by predominant lobular infiltration of CD8+ T cells but also by little accumulation of FOXP3+ Tregs.
This patient was diagnosed as irAEs involving the endocrine system (G2), lung (G1), skin (G3), and the liver (G3). According to the guideline for hepatic irAEs [3], this patient was initially treated with intravenous administration of methyl PSL (mPSL, 500 mg/day) in combination with oral administration of mycophenolate mofetil (MMF, 200 mg/day, Fig. 1). mPSL was switched to oral administration of PSL (60 mg/day) with a tapering schedule as depicted in Fig. 1. His serum levels of transaminases became normalized 2 months after the treatment and then he was treated with oral administration of Tegafur/Gimeracil/Oteracil (120 mg/day) for advanced lung cancer.
Discussion
Restorement of anti-cancer immunity by ICIs has dramatically improved the prognosis of patients with metastatic cancers [1, 2]. However, the blockade of PD-1 or CTLA-4-mediated signaling pathways sometimes causes irAEs, which can affect almost every organ in the body [3, 4]. In this case, administration of nivolumab led to the development of destructive thyroiditis, primary adrenal insufficiency, interstitial pneumonia, skin eruption and liver injury. Given the fact that the endocrine systems, lung, skin, and liver are preferential organs for irAEs [3–5], this case may be considered as typical irAEs due to nivolumab.
The incidence of hepatic irAEs by nivolumab alone was reported to be 6.4% [16] and liver injury by nivolumab usually develops 8–12 weeks after the initial injection [17]. Lobular infiltration of CD8+ T cells is one of the most characteristic findings in hepatic irAEs [5, 18, 19]. Consistent with this, lobular rather than portal hepatitis accompanied by predominant accumulation of CD8+ T cells was seen in this case. In contrast, AIH lesions were characterized by interface hepatitis associated with infiltration of plasma cells, CD4+ T cells, and CD8+ T cells. Thus, AIH and hepatic irAEs are distinctive disease entities in terms of the location of inflammation and effector T cell subpopulations. It should be noted, however, that molecular mechanisms accounting for such pathological differences between these two disorders have been poorly understood. In this study, we tried to elucidate the immuno-pathogenesis underlying the development of hepatic irAEs. We found that hepatic irAE lesions, but not AIH lesions were characterized by defective accumulation of FOXP3-expressing Tregs. Therefore, we assume possible involvement of defective Treg function in the development of hepatic irAEs. However, we need to be cautious regarding the interpretation of impaired Treg accumulation into the liver of hepatic irAEs. Liver biopsy samples were obtained in the middle of PSL tapering schedule in this patient. Thus, we could not completely exclude a possibility that prior PSL treatment might have affected the function of Tregs.
As mentioned above, defective accumulation of Tregs is associated with the development of hepatic irAEs in the present case. One major question arising from the present case is the molecular link between the PD-1 blockade and Treg differentiation. In this regards, neonatal thymectomy (NTx) leads to the development of much severe hepatitis in PD-1-deficient mice than in PD-1-intact mice through concurrent loss of FOXP3-expressing Tregs [20, 21]. Moreover, transient FOXP3-expressing Treg depletion in combination with systemic administration of anti-PD-1 Ab successfully induced severe hepatic irAEs in orthotopic cancer mice [22]. Thus, these previous studies together with the present case suggest the idea that PD-1 blockade may promote the development of liver injury, i.e., hepatic irAEs, in the presence of defective Treg function. Since Tregs stably express cell-surface PD-1 [15], one might assume that neutralization of PD-1-mediated signaling pathways impair Treg function. In this regards, Asano et al. provide evidence that Tregs isolated from PD-1 deficient mice display enhanced apoptosis than those from PD-1-intact mice in the presence of low doses of IL-2, a crucial cytokine for Treg proliferation [23]. Therefore, it is likely that systemic administration of anti-PD-1 Ab reduces the number of Tregs due to enhanced apoptosis. Such defective proliferation and activation of Tregs caused by nivolumab might be involved in the development of multiorgan system irAEs involving the endocrine system, lung, skin, and the liver, as seen in this case. This idea is supported by the fact that loss of function mutations in FOXP3 causes autoimmune diseases affecting multiple organs, called IPEX syndrome [15]. Confirmation of this idea requires future studies addressing the function of FOXP3+ Tregs in patients with multiorgan system irAEs and solitary hepatic irAEs.
Another important question arising from this case is why lung, skin, and hepatic irAEs developed even after the withdrawal of nivolumab. In this regards, recent studies by Osa et al. provide evidence that the binding of nivolumab to cell-surface PD-1 can be detected by flow-cytometry around 6 months after the withdrawal of nivolumab [24]. Thus, such long-lasting neutralization of PD-1 may contribute to the development of irAEs even after the withdrawal of nivolumab.
The number of Tregs was greater in the liver of AIH than that of irAEs in this study. Based on this observation, we hypothesized that defective Treg function mediates hepatic irAEs. However, defective Treg function can also be involved in the development of AIH since impaired Treg function as assessed by the inhibition of effector T cell proliferation was demonstrated in AIH patients [25].
In conclusion, hepatic irAEs might be characterized not only by lobular infiltration of CD8+ T cells but also by defective accumulation of FOXP3+ Tregs. Lack of Treg-mediated immune suppression might underlie the immuno-pathogenesis of hepatic irAEs. Verification of this idea awaits further studies addressing a large number of hepatic irAEs and hepatic Treg function isolated from patients with this disorder.
Supplementary Information
Below is the link to the electronic supplementary material.Supplementary file1 (DOCX 17 KB)
Compliance with ethical standards
Conflict of interest
Ikue Sekai, Satoru Hagiwara, Tomohiro Watanabe and Masatoshi Kudo declare that they have no conflict of interest.
Human Rights
All procedures followed have been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments.
Informed Consent
Informed consent was obtained from all patients for being included in the study.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | CARBOPLATIN, HYDROCORTISONE, NIVOLUMAB, PACLITAXEL | DrugsGivenReaction | CC BY | 33665689 | 19,779,825 | 2021-08 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Liver injury'. | A case with hepatic immune-related adverse events caused by nivolumab exhibiting impaired accumulation of regulatory T cells.
Systemic administration of anti-programmed cell death 1 (PD-1) antibody (Ab) has achieved remarkable success in metastatic cancers. The blockade of PD-1-mediated signaling pathways sometimes cause immune-related adverse events (irAEs) due to restored anti-cancer as well as anti-self immunity. Although the liver is a preferential organ for irAEs, the immuno-pathogenesis underlying hepatic irAEs has been poorly understood. We describe a 57-year-old man with Stage IV lung cancer who underwent the first-line regimen composed of carboplatin and paclitaxel. Nivolumab treatment (3.2 mg/kg, every 3 weeks) was initiated when the disease progressed after the first chemotherapy. Sequential occurrence of irAEs involving the multiorgan systems was observed. He developed hepatic irAEs (Grade 3) after endocrine, lung, and cutaneous irAEs. Lobular hepatitis characterized by predominant infiltration of CD8+ T cells was seen in the liver biopsy specimens. Interestingly, defective accumulation of regulatory T cells (Tregs) expressing forkhead box protein P3 (FOXP3) was evident in this case with hepatic irAEs as compared with typical cases with autoimmune hepatitis. This case suggests that hepatic irAEs are characterized not only by lobular infiltration of CD8+ T cells but also by defective accumulation of FOXP3+ Tregs.
Introduction
A recent remarkable success of treating advanced cancer with immune check-point inhibitors (ICIs) highlight important roles that programmed cell death protein-1 (PD-1) and cytotoxic T lymphocyte-associated protein-4 (CTLA-4) play in the suppression of anti-cancer immune responses [1, 2]. Nivolumab and ipilimumab targeting PD-1 and CTLA-4, respectively, are the representative ICIs. These ICIs restore anti-cancer immune responses through neutralization of negative regulation mediated by PD-1 or CTLA-4-mediated signaling pathways [1, 2]. In fact, introduction of nivolumab and ipilimumab into clinical practice has improved the prognosis of advanced malignancies, especially malignant melanoma [1, 2].
Despite effective restorement of anti-cancer immunity by nivolumab and ipilimumab, the blockade of PD-1 and CTLA-4, both of which are negative regulators of adaptive and innate immunity, sometimes causes excessive immune reactions in a broad range of organs, called immune-related adverse events (irAEs) [3, 4]. Liver toxicity associated with ICIs occurs in around 5–10% of patients, [5] and thus, the liver is a preferential organ targeted by ICIs in parallel to the skin, colon, endocrine system, kidney, and lung [3, 4]. Although activation and expansion of T cells through lack of negative regulation by PD-1 and CTLA-4 is considered to underlie the immuno-pathogenesis of irAEs [3–5], molecular mechanisms accounting for the development of hepatic irAEs have been poorly understood. Regulatory T cells (Tregs) expressing forkhead box protein P3 (FOXP3) are a critical component of immune systems with pivotal roles not only in the maintenance of self-tolerance but also in the suppression of anti-cancer immunity [6]. Here, we report a case with hepatic irAEs exhibiting little accumulation of FOXP3-expressing Tregs into the liver. This case suggests possible involvement of Treg deficiency in the development of hepatic irAEs.
Case reports
A 51-year-old man without any history of autoimmune diseases was diagnosed as lung adenocarcinoma (p-T3N0M0, Stage IIb) and received thoracoscopic right pneumonectomy in July 2012. Follow-up computed tomography (CT), which was performed in March 2017, revealed recurrence of his lung cancer in the left lobe accompanied by mediastinal lymph node metastasis. At this time point, he was diagnosed as Stage IV lung adenocarcinoma (p-T3N1M1). His surgical specimen was negative for epidermal growth factor receptor (EGFR) mutation or anaplastic lymphoma kinase 1 (ALK1) fusion oncogene. According to the guideline for Stage IV lung adenocarcinoma with intact EGFR and ALK1 [7], he was initially treated with the first-line regimen composed of carboplatin and paclitaxel from April 2017 for 4 courses followed by paclitaxel maintenance therapy from July 2017 to October 2017. These initial courses of chemotherapy were not successful and his lung cancer was judged as progressive disease (PD) based on computed tomography findings. Nivolumab was introduced from August 2018 at a dose of 3.2 mg/kg every 3 weeks.
Various kinds of irAEs occurred after the treatment with nivolumab and the severity was graded based on the clinical practice guideline following the Common Terminology Criteria for Adverse Events [version 5.0] [8].His initial irAEs involved the endocrine system as shown by the appearance of general fatigue caused by destructive thyroiditis. A significant elevation of serum free T3 (fT3, 6.2 pg/mL, normal range, 2.3–4) and fT4 (fT4, 2.1 ng/dL, normal range, 0.9–1.7) levels accompanied by a markedly reduced level of thyroid stimulating hormone (TSH, 0.02 μIU/mL, normal range, 0.5–5) was seen in September 2018. Three months later, thyroid hormone tests clearly showed hypothyroidism characterized by reduced fT3 and fT4 levels with elevated TSH levels. Further examination of his endocrine system revealed reduced serum levels of cortisol (3.3 μg/dL, normal range 6.2–19.4) and adrenocorticotropic hormone (ACTH 1.3 pg/mL, normal range 7.3–63.3), which suggested the presence of primary adrenal insufficiency despite normal levels of blood sugar, sodium and potassium. Oral supplementation of hydrocortisone (15 mg/day) and thyroid hormone (25 μg/day) were started for G1 primary hypothyroidism and G2 primary adrenal insufficiency, respectively. In addition to these endocrine toxicities, interstitial pneumonia (G1) was detected in February 2019 and then administration of nivolumab was discontinued. Moreover, skin rash judged as G3 irAE developed in March 2019. Prednisolone (PSL, 40 mg/day) with tapering schedule 5 mg/2 weeks was started after the appearance of irAEs involving the endocrine system, lung, and skin.
Although improvement of skin rash was achieved after the initiation of PSL treatment, he developed liver injury as shown by a marked elevation of serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), and γ-glutamyltransferase (γGTP) (Table 1 and Fig. 1). Viral hepatitis was unlikely since viral markers for hepatitis A virus, hepatitis B virus, hepatitis C virus, cytomegalovirus, and Epstein–Barr virus were negative. Moreover, liver injury due to autoimmune hepatitis (AIH) or primary biliary cholangitis (PBC) was also unlikely as assessed by serum IgG levels and titers for anti-nuclear antibody (ANA) or anti-mitochondrial Ab. These blood examination data led us to consider the possibility of hepatic irAEs. No metastatic lesions were detected in the liver by abdominal contrast-enhanced CT. Moreover, magnetic resonance cholangiopancreatography did not reveal any abnormalities in the intrahepatic or extrahepatic bile ducts, suggesting that an immune-related cholangitis caused by ICIs was less likely [9]. To verify the diagnosis of hepatis irAEs, liver biopsy samples were subjected to hematoxylin and eosin (H&E) staining and immuno-histochemical analyses.Table 1 Laboratory data on admission
Hematology Blood chemistry Serological tests
WBC 6.270/μL TP 6.2 g/dL ANA (–)
RBC 346 × 104/μL Alb 3.4 g/dL AMA2 (–)
Hb 13.5 g/dL BUN 13 mg/dL IgG 697 mg/dL
Hct 39.0% Cr 0.79 mg/dL IgM 25 mg/dL
Plt 12.1 × 104/μL T-Bil 1.5 mg/dL IgE 337 IU/mL
Neutro 85.7% D-Bil 0.7 mg/dL Viral marker
Lympho 9.9% ALP 1039 U/L HBsAg (–)
Eosino 0.5% AMY 31 U/L HBsAb (–)
Endocrine LDH 679 U/L HBcAb (–)
ACTH 1.0 pg/mL AST 651 U/L HCVAb (–)
CS 6.2 μg/dL ALT 547 U/L HA-IgM (–)
TSH 1.22 μIU/mL γGTP 2718 U/L CMV-IgM (–)
FT4 1.1 ng/dL CRP 10.22 mg/dL EBVVCA-IgM (–)
Coagulation
PT 119.6%
INR 0.93
ACTH adrenocorticotropic hormone, CS cortisol, PT prothrombin time, INR international normalized ratio, AMA2 anti-mitochondrial antibody 2, ANA anti-nuclear antibody, CMV cytomegalovirus, EBV Epstein–Barr virus
Fig. 1 Clinical course of the patients. See the clinical presentation section of the text. ALT alanine aminotransferase, ALP alkaline phosphatase, AST aspartate aminotransferase, γGTP γ-glutamyltransferase, MMF mycophenolate mofetil, mPSL methylprednisolone, PSL prednisolone, UDCA ursodeoxycholic acid
Liver biopsy samples were subjected to H&E staining and immuno-histochemical analysis using mouse or rabbit anti-human CD3 antibody (Ab, Roche Diagnostics; Tokyo, Japan), CD4 Ab (Roche Diagnostics; Tokyo, Japan), CD8 Ab (Nichirei Bioscience; Tokyo, Japan), CD20 Ab (Roche Diagnostics; Tokyo, Japan), and FOXP3 Ab (Abcam; Cambridge, United Kingdom). Visualization of CD3+ T cells, CD4+ T cells, CD8+ T cells, CD20+ B cells, and FOXP3+ Tregs were performed using DakO-EnVision+ systems (Dako Japan, Tokyo, Japan) as previously described [10, 11]. The liver biopsy sample obtained from a typical patient with AIH (74-year-old female) was used as a disease control. Clinical parameters of this AIH patient were shown in Supplementary Table 1. As shown in Supplementary Table 1, serum levels of IgG and ANA titers were markedly elevated. Moreover, interface hepatitis accompanied by infiltration of plasma cells was evident. The AIH score proposed by international AIH group was 23 in this patient, and thus, this patient was diagnosed with definite AIH [12].
Although lobular as well as portal inflammation was seen in the liver specimens of this patients, immune cell infiltration was predominantly seen in the liver lobes (Fig. 2, 1st and 2nd line panels). Moreover, hyperplasia of the bile duct as well as lymphocyte infiltration into the interlobular bile duct was seen in the pathological examinations, suggesting cholestasis as well as hepatocellular injury is involved in the development of hepatic irAEs in this case [13]. These pathological findings together with elevations of serum transaminases and biliary enzymes indicated that hepatic irAEs of this case was considered to be a mixed type [13].Fig. 2 Immuno-histochemical analyses of liver biopsy specimens. Liver biopsy specimens obtained from this case with hepatic immune-related adverse effects (irAEs, 1st and 2nd line panels) and from patients with autoimmune hepatitis (AIH, 3rd and 4th line panels) were subjected to immuno-histochemical analyses using anti-CD3 Ab, anti-CD4 Ab, anti-CD8 Ab, anti-CD20 Ab, and anti-forkhead box p3 (FOXP3) Ab. Hematoxylin and eosin (H&E) staining of the portal and lobular areas (1st row). Infiltration of CD3+ T cells (2nd row), CD4+ T cells (3rd row), CD8+ T cells (4th row), CD20+ B cells (5th row), and FOXP3+ Treg cells (6th row) was visualized. Scale bar is 20 µm
Interface hepatitis accompanied by plasma cell infiltration was seen in the liver specimen with the AIH patient (Fig. 2, 3rd line panel). Thus, H&E staining in this case was compatible to hepatic irAEs rather than AIH since the former and latter disorders preferentially affect the liver lobes and portal tracts, respectively [5, 14].
We then performed characterization of immune cell infiltration in this case. As shown in Fig. 2, accumulation of CD3+ T cells was seen in the liver lobes of the patient with hepatic irAEs whereas that was seen in the portal areas of the patient with AIH. Subpopulation analysis of T cells showed predominant infiltration of CD8+ T cells rather than CD4+ T cells into the liver lobes in this case (Fig. 2, 1st line panel). AIH lesions were characterized by portal accumulation of both CD4+ and CD8+ T cells (Fig. 2, 4th line panel). Moreover, infiltration of CD20+ B cells was seen in the portal areas of AIH patients, but not those in this case. These immuno-histochemical analyses strongly suggest that liver injury arose from a manifestation of irAEs in that lesions are characterized by predominant accumulation of CD8+ T cells into the liver lobes [5]. Although Tregs expressing FOXP3 play major roles in the suppression of pro-inflammatory responses [15], their involvement in the development of hepatic irAEs has been poorly defined. Interestingly, accumulation of Tregs expressing FOXP3 was barely seen in the liver lobes of this case with hepatic irAEs whereas abundant infiltration of FOXP3+ Tregs was observed in the portal areas of the AIH patient (Fig. 2). Abundant infiltration of T cells expressing CD4, CD8, or FOXP3 was also seen in the other three cases with AIH in this study (data not shown). Taken together, these data suggest hepatic irAEs due to nivolumab might be characterized not only by predominant lobular infiltration of CD8+ T cells but also by little accumulation of FOXP3+ Tregs.
This patient was diagnosed as irAEs involving the endocrine system (G2), lung (G1), skin (G3), and the liver (G3). According to the guideline for hepatic irAEs [3], this patient was initially treated with intravenous administration of methyl PSL (mPSL, 500 mg/day) in combination with oral administration of mycophenolate mofetil (MMF, 200 mg/day, Fig. 1). mPSL was switched to oral administration of PSL (60 mg/day) with a tapering schedule as depicted in Fig. 1. His serum levels of transaminases became normalized 2 months after the treatment and then he was treated with oral administration of Tegafur/Gimeracil/Oteracil (120 mg/day) for advanced lung cancer.
Discussion
Restorement of anti-cancer immunity by ICIs has dramatically improved the prognosis of patients with metastatic cancers [1, 2]. However, the blockade of PD-1 or CTLA-4-mediated signaling pathways sometimes causes irAEs, which can affect almost every organ in the body [3, 4]. In this case, administration of nivolumab led to the development of destructive thyroiditis, primary adrenal insufficiency, interstitial pneumonia, skin eruption and liver injury. Given the fact that the endocrine systems, lung, skin, and liver are preferential organs for irAEs [3–5], this case may be considered as typical irAEs due to nivolumab.
The incidence of hepatic irAEs by nivolumab alone was reported to be 6.4% [16] and liver injury by nivolumab usually develops 8–12 weeks after the initial injection [17]. Lobular infiltration of CD8+ T cells is one of the most characteristic findings in hepatic irAEs [5, 18, 19]. Consistent with this, lobular rather than portal hepatitis accompanied by predominant accumulation of CD8+ T cells was seen in this case. In contrast, AIH lesions were characterized by interface hepatitis associated with infiltration of plasma cells, CD4+ T cells, and CD8+ T cells. Thus, AIH and hepatic irAEs are distinctive disease entities in terms of the location of inflammation and effector T cell subpopulations. It should be noted, however, that molecular mechanisms accounting for such pathological differences between these two disorders have been poorly understood. In this study, we tried to elucidate the immuno-pathogenesis underlying the development of hepatic irAEs. We found that hepatic irAE lesions, but not AIH lesions were characterized by defective accumulation of FOXP3-expressing Tregs. Therefore, we assume possible involvement of defective Treg function in the development of hepatic irAEs. However, we need to be cautious regarding the interpretation of impaired Treg accumulation into the liver of hepatic irAEs. Liver biopsy samples were obtained in the middle of PSL tapering schedule in this patient. Thus, we could not completely exclude a possibility that prior PSL treatment might have affected the function of Tregs.
As mentioned above, defective accumulation of Tregs is associated with the development of hepatic irAEs in the present case. One major question arising from the present case is the molecular link between the PD-1 blockade and Treg differentiation. In this regards, neonatal thymectomy (NTx) leads to the development of much severe hepatitis in PD-1-deficient mice than in PD-1-intact mice through concurrent loss of FOXP3-expressing Tregs [20, 21]. Moreover, transient FOXP3-expressing Treg depletion in combination with systemic administration of anti-PD-1 Ab successfully induced severe hepatic irAEs in orthotopic cancer mice [22]. Thus, these previous studies together with the present case suggest the idea that PD-1 blockade may promote the development of liver injury, i.e., hepatic irAEs, in the presence of defective Treg function. Since Tregs stably express cell-surface PD-1 [15], one might assume that neutralization of PD-1-mediated signaling pathways impair Treg function. In this regards, Asano et al. provide evidence that Tregs isolated from PD-1 deficient mice display enhanced apoptosis than those from PD-1-intact mice in the presence of low doses of IL-2, a crucial cytokine for Treg proliferation [23]. Therefore, it is likely that systemic administration of anti-PD-1 Ab reduces the number of Tregs due to enhanced apoptosis. Such defective proliferation and activation of Tregs caused by nivolumab might be involved in the development of multiorgan system irAEs involving the endocrine system, lung, skin, and the liver, as seen in this case. This idea is supported by the fact that loss of function mutations in FOXP3 causes autoimmune diseases affecting multiple organs, called IPEX syndrome [15]. Confirmation of this idea requires future studies addressing the function of FOXP3+ Tregs in patients with multiorgan system irAEs and solitary hepatic irAEs.
Another important question arising from this case is why lung, skin, and hepatic irAEs developed even after the withdrawal of nivolumab. In this regards, recent studies by Osa et al. provide evidence that the binding of nivolumab to cell-surface PD-1 can be detected by flow-cytometry around 6 months after the withdrawal of nivolumab [24]. Thus, such long-lasting neutralization of PD-1 may contribute to the development of irAEs even after the withdrawal of nivolumab.
The number of Tregs was greater in the liver of AIH than that of irAEs in this study. Based on this observation, we hypothesized that defective Treg function mediates hepatic irAEs. However, defective Treg function can also be involved in the development of AIH since impaired Treg function as assessed by the inhibition of effector T cell proliferation was demonstrated in AIH patients [25].
In conclusion, hepatic irAEs might be characterized not only by lobular infiltration of CD8+ T cells but also by defective accumulation of FOXP3+ Tregs. Lack of Treg-mediated immune suppression might underlie the immuno-pathogenesis of hepatic irAEs. Verification of this idea awaits further studies addressing a large number of hepatic irAEs and hepatic Treg function isolated from patients with this disorder.
Supplementary Information
Below is the link to the electronic supplementary material.Supplementary file1 (DOCX 17 KB)
Compliance with ethical standards
Conflict of interest
Ikue Sekai, Satoru Hagiwara, Tomohiro Watanabe and Masatoshi Kudo declare that they have no conflict of interest.
Human Rights
All procedures followed have been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments.
Informed Consent
Informed consent was obtained from all patients for being included in the study.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | CARBOPLATIN, HYDROCORTISONE, NIVOLUMAB, PACLITAXEL | DrugsGivenReaction | CC BY | 33665689 | 19,779,825 | 2021-08 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Primary adrenal insufficiency'. | A case with hepatic immune-related adverse events caused by nivolumab exhibiting impaired accumulation of regulatory T cells.
Systemic administration of anti-programmed cell death 1 (PD-1) antibody (Ab) has achieved remarkable success in metastatic cancers. The blockade of PD-1-mediated signaling pathways sometimes cause immune-related adverse events (irAEs) due to restored anti-cancer as well as anti-self immunity. Although the liver is a preferential organ for irAEs, the immuno-pathogenesis underlying hepatic irAEs has been poorly understood. We describe a 57-year-old man with Stage IV lung cancer who underwent the first-line regimen composed of carboplatin and paclitaxel. Nivolumab treatment (3.2 mg/kg, every 3 weeks) was initiated when the disease progressed after the first chemotherapy. Sequential occurrence of irAEs involving the multiorgan systems was observed. He developed hepatic irAEs (Grade 3) after endocrine, lung, and cutaneous irAEs. Lobular hepatitis characterized by predominant infiltration of CD8+ T cells was seen in the liver biopsy specimens. Interestingly, defective accumulation of regulatory T cells (Tregs) expressing forkhead box protein P3 (FOXP3) was evident in this case with hepatic irAEs as compared with typical cases with autoimmune hepatitis. This case suggests that hepatic irAEs are characterized not only by lobular infiltration of CD8+ T cells but also by defective accumulation of FOXP3+ Tregs.
Introduction
A recent remarkable success of treating advanced cancer with immune check-point inhibitors (ICIs) highlight important roles that programmed cell death protein-1 (PD-1) and cytotoxic T lymphocyte-associated protein-4 (CTLA-4) play in the suppression of anti-cancer immune responses [1, 2]. Nivolumab and ipilimumab targeting PD-1 and CTLA-4, respectively, are the representative ICIs. These ICIs restore anti-cancer immune responses through neutralization of negative regulation mediated by PD-1 or CTLA-4-mediated signaling pathways [1, 2]. In fact, introduction of nivolumab and ipilimumab into clinical practice has improved the prognosis of advanced malignancies, especially malignant melanoma [1, 2].
Despite effective restorement of anti-cancer immunity by nivolumab and ipilimumab, the blockade of PD-1 and CTLA-4, both of which are negative regulators of adaptive and innate immunity, sometimes causes excessive immune reactions in a broad range of organs, called immune-related adverse events (irAEs) [3, 4]. Liver toxicity associated with ICIs occurs in around 5–10% of patients, [5] and thus, the liver is a preferential organ targeted by ICIs in parallel to the skin, colon, endocrine system, kidney, and lung [3, 4]. Although activation and expansion of T cells through lack of negative regulation by PD-1 and CTLA-4 is considered to underlie the immuno-pathogenesis of irAEs [3–5], molecular mechanisms accounting for the development of hepatic irAEs have been poorly understood. Regulatory T cells (Tregs) expressing forkhead box protein P3 (FOXP3) are a critical component of immune systems with pivotal roles not only in the maintenance of self-tolerance but also in the suppression of anti-cancer immunity [6]. Here, we report a case with hepatic irAEs exhibiting little accumulation of FOXP3-expressing Tregs into the liver. This case suggests possible involvement of Treg deficiency in the development of hepatic irAEs.
Case reports
A 51-year-old man without any history of autoimmune diseases was diagnosed as lung adenocarcinoma (p-T3N0M0, Stage IIb) and received thoracoscopic right pneumonectomy in July 2012. Follow-up computed tomography (CT), which was performed in March 2017, revealed recurrence of his lung cancer in the left lobe accompanied by mediastinal lymph node metastasis. At this time point, he was diagnosed as Stage IV lung adenocarcinoma (p-T3N1M1). His surgical specimen was negative for epidermal growth factor receptor (EGFR) mutation or anaplastic lymphoma kinase 1 (ALK1) fusion oncogene. According to the guideline for Stage IV lung adenocarcinoma with intact EGFR and ALK1 [7], he was initially treated with the first-line regimen composed of carboplatin and paclitaxel from April 2017 for 4 courses followed by paclitaxel maintenance therapy from July 2017 to October 2017. These initial courses of chemotherapy were not successful and his lung cancer was judged as progressive disease (PD) based on computed tomography findings. Nivolumab was introduced from August 2018 at a dose of 3.2 mg/kg every 3 weeks.
Various kinds of irAEs occurred after the treatment with nivolumab and the severity was graded based on the clinical practice guideline following the Common Terminology Criteria for Adverse Events [version 5.0] [8].His initial irAEs involved the endocrine system as shown by the appearance of general fatigue caused by destructive thyroiditis. A significant elevation of serum free T3 (fT3, 6.2 pg/mL, normal range, 2.3–4) and fT4 (fT4, 2.1 ng/dL, normal range, 0.9–1.7) levels accompanied by a markedly reduced level of thyroid stimulating hormone (TSH, 0.02 μIU/mL, normal range, 0.5–5) was seen in September 2018. Three months later, thyroid hormone tests clearly showed hypothyroidism characterized by reduced fT3 and fT4 levels with elevated TSH levels. Further examination of his endocrine system revealed reduced serum levels of cortisol (3.3 μg/dL, normal range 6.2–19.4) and adrenocorticotropic hormone (ACTH 1.3 pg/mL, normal range 7.3–63.3), which suggested the presence of primary adrenal insufficiency despite normal levels of blood sugar, sodium and potassium. Oral supplementation of hydrocortisone (15 mg/day) and thyroid hormone (25 μg/day) were started for G1 primary hypothyroidism and G2 primary adrenal insufficiency, respectively. In addition to these endocrine toxicities, interstitial pneumonia (G1) was detected in February 2019 and then administration of nivolumab was discontinued. Moreover, skin rash judged as G3 irAE developed in March 2019. Prednisolone (PSL, 40 mg/day) with tapering schedule 5 mg/2 weeks was started after the appearance of irAEs involving the endocrine system, lung, and skin.
Although improvement of skin rash was achieved after the initiation of PSL treatment, he developed liver injury as shown by a marked elevation of serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), and γ-glutamyltransferase (γGTP) (Table 1 and Fig. 1). Viral hepatitis was unlikely since viral markers for hepatitis A virus, hepatitis B virus, hepatitis C virus, cytomegalovirus, and Epstein–Barr virus were negative. Moreover, liver injury due to autoimmune hepatitis (AIH) or primary biliary cholangitis (PBC) was also unlikely as assessed by serum IgG levels and titers for anti-nuclear antibody (ANA) or anti-mitochondrial Ab. These blood examination data led us to consider the possibility of hepatic irAEs. No metastatic lesions were detected in the liver by abdominal contrast-enhanced CT. Moreover, magnetic resonance cholangiopancreatography did not reveal any abnormalities in the intrahepatic or extrahepatic bile ducts, suggesting that an immune-related cholangitis caused by ICIs was less likely [9]. To verify the diagnosis of hepatis irAEs, liver biopsy samples were subjected to hematoxylin and eosin (H&E) staining and immuno-histochemical analyses.Table 1 Laboratory data on admission
Hematology Blood chemistry Serological tests
WBC 6.270/μL TP 6.2 g/dL ANA (–)
RBC 346 × 104/μL Alb 3.4 g/dL AMA2 (–)
Hb 13.5 g/dL BUN 13 mg/dL IgG 697 mg/dL
Hct 39.0% Cr 0.79 mg/dL IgM 25 mg/dL
Plt 12.1 × 104/μL T-Bil 1.5 mg/dL IgE 337 IU/mL
Neutro 85.7% D-Bil 0.7 mg/dL Viral marker
Lympho 9.9% ALP 1039 U/L HBsAg (–)
Eosino 0.5% AMY 31 U/L HBsAb (–)
Endocrine LDH 679 U/L HBcAb (–)
ACTH 1.0 pg/mL AST 651 U/L HCVAb (–)
CS 6.2 μg/dL ALT 547 U/L HA-IgM (–)
TSH 1.22 μIU/mL γGTP 2718 U/L CMV-IgM (–)
FT4 1.1 ng/dL CRP 10.22 mg/dL EBVVCA-IgM (–)
Coagulation
PT 119.6%
INR 0.93
ACTH adrenocorticotropic hormone, CS cortisol, PT prothrombin time, INR international normalized ratio, AMA2 anti-mitochondrial antibody 2, ANA anti-nuclear antibody, CMV cytomegalovirus, EBV Epstein–Barr virus
Fig. 1 Clinical course of the patients. See the clinical presentation section of the text. ALT alanine aminotransferase, ALP alkaline phosphatase, AST aspartate aminotransferase, γGTP γ-glutamyltransferase, MMF mycophenolate mofetil, mPSL methylprednisolone, PSL prednisolone, UDCA ursodeoxycholic acid
Liver biopsy samples were subjected to H&E staining and immuno-histochemical analysis using mouse or rabbit anti-human CD3 antibody (Ab, Roche Diagnostics; Tokyo, Japan), CD4 Ab (Roche Diagnostics; Tokyo, Japan), CD8 Ab (Nichirei Bioscience; Tokyo, Japan), CD20 Ab (Roche Diagnostics; Tokyo, Japan), and FOXP3 Ab (Abcam; Cambridge, United Kingdom). Visualization of CD3+ T cells, CD4+ T cells, CD8+ T cells, CD20+ B cells, and FOXP3+ Tregs were performed using DakO-EnVision+ systems (Dako Japan, Tokyo, Japan) as previously described [10, 11]. The liver biopsy sample obtained from a typical patient with AIH (74-year-old female) was used as a disease control. Clinical parameters of this AIH patient were shown in Supplementary Table 1. As shown in Supplementary Table 1, serum levels of IgG and ANA titers were markedly elevated. Moreover, interface hepatitis accompanied by infiltration of plasma cells was evident. The AIH score proposed by international AIH group was 23 in this patient, and thus, this patient was diagnosed with definite AIH [12].
Although lobular as well as portal inflammation was seen in the liver specimens of this patients, immune cell infiltration was predominantly seen in the liver lobes (Fig. 2, 1st and 2nd line panels). Moreover, hyperplasia of the bile duct as well as lymphocyte infiltration into the interlobular bile duct was seen in the pathological examinations, suggesting cholestasis as well as hepatocellular injury is involved in the development of hepatic irAEs in this case [13]. These pathological findings together with elevations of serum transaminases and biliary enzymes indicated that hepatic irAEs of this case was considered to be a mixed type [13].Fig. 2 Immuno-histochemical analyses of liver biopsy specimens. Liver biopsy specimens obtained from this case with hepatic immune-related adverse effects (irAEs, 1st and 2nd line panels) and from patients with autoimmune hepatitis (AIH, 3rd and 4th line panels) were subjected to immuno-histochemical analyses using anti-CD3 Ab, anti-CD4 Ab, anti-CD8 Ab, anti-CD20 Ab, and anti-forkhead box p3 (FOXP3) Ab. Hematoxylin and eosin (H&E) staining of the portal and lobular areas (1st row). Infiltration of CD3+ T cells (2nd row), CD4+ T cells (3rd row), CD8+ T cells (4th row), CD20+ B cells (5th row), and FOXP3+ Treg cells (6th row) was visualized. Scale bar is 20 µm
Interface hepatitis accompanied by plasma cell infiltration was seen in the liver specimen with the AIH patient (Fig. 2, 3rd line panel). Thus, H&E staining in this case was compatible to hepatic irAEs rather than AIH since the former and latter disorders preferentially affect the liver lobes and portal tracts, respectively [5, 14].
We then performed characterization of immune cell infiltration in this case. As shown in Fig. 2, accumulation of CD3+ T cells was seen in the liver lobes of the patient with hepatic irAEs whereas that was seen in the portal areas of the patient with AIH. Subpopulation analysis of T cells showed predominant infiltration of CD8+ T cells rather than CD4+ T cells into the liver lobes in this case (Fig. 2, 1st line panel). AIH lesions were characterized by portal accumulation of both CD4+ and CD8+ T cells (Fig. 2, 4th line panel). Moreover, infiltration of CD20+ B cells was seen in the portal areas of AIH patients, but not those in this case. These immuno-histochemical analyses strongly suggest that liver injury arose from a manifestation of irAEs in that lesions are characterized by predominant accumulation of CD8+ T cells into the liver lobes [5]. Although Tregs expressing FOXP3 play major roles in the suppression of pro-inflammatory responses [15], their involvement in the development of hepatic irAEs has been poorly defined. Interestingly, accumulation of Tregs expressing FOXP3 was barely seen in the liver lobes of this case with hepatic irAEs whereas abundant infiltration of FOXP3+ Tregs was observed in the portal areas of the AIH patient (Fig. 2). Abundant infiltration of T cells expressing CD4, CD8, or FOXP3 was also seen in the other three cases with AIH in this study (data not shown). Taken together, these data suggest hepatic irAEs due to nivolumab might be characterized not only by predominant lobular infiltration of CD8+ T cells but also by little accumulation of FOXP3+ Tregs.
This patient was diagnosed as irAEs involving the endocrine system (G2), lung (G1), skin (G3), and the liver (G3). According to the guideline for hepatic irAEs [3], this patient was initially treated with intravenous administration of methyl PSL (mPSL, 500 mg/day) in combination with oral administration of mycophenolate mofetil (MMF, 200 mg/day, Fig. 1). mPSL was switched to oral administration of PSL (60 mg/day) with a tapering schedule as depicted in Fig. 1. His serum levels of transaminases became normalized 2 months after the treatment and then he was treated with oral administration of Tegafur/Gimeracil/Oteracil (120 mg/day) for advanced lung cancer.
Discussion
Restorement of anti-cancer immunity by ICIs has dramatically improved the prognosis of patients with metastatic cancers [1, 2]. However, the blockade of PD-1 or CTLA-4-mediated signaling pathways sometimes causes irAEs, which can affect almost every organ in the body [3, 4]. In this case, administration of nivolumab led to the development of destructive thyroiditis, primary adrenal insufficiency, interstitial pneumonia, skin eruption and liver injury. Given the fact that the endocrine systems, lung, skin, and liver are preferential organs for irAEs [3–5], this case may be considered as typical irAEs due to nivolumab.
The incidence of hepatic irAEs by nivolumab alone was reported to be 6.4% [16] and liver injury by nivolumab usually develops 8–12 weeks after the initial injection [17]. Lobular infiltration of CD8+ T cells is one of the most characteristic findings in hepatic irAEs [5, 18, 19]. Consistent with this, lobular rather than portal hepatitis accompanied by predominant accumulation of CD8+ T cells was seen in this case. In contrast, AIH lesions were characterized by interface hepatitis associated with infiltration of plasma cells, CD4+ T cells, and CD8+ T cells. Thus, AIH and hepatic irAEs are distinctive disease entities in terms of the location of inflammation and effector T cell subpopulations. It should be noted, however, that molecular mechanisms accounting for such pathological differences between these two disorders have been poorly understood. In this study, we tried to elucidate the immuno-pathogenesis underlying the development of hepatic irAEs. We found that hepatic irAE lesions, but not AIH lesions were characterized by defective accumulation of FOXP3-expressing Tregs. Therefore, we assume possible involvement of defective Treg function in the development of hepatic irAEs. However, we need to be cautious regarding the interpretation of impaired Treg accumulation into the liver of hepatic irAEs. Liver biopsy samples were obtained in the middle of PSL tapering schedule in this patient. Thus, we could not completely exclude a possibility that prior PSL treatment might have affected the function of Tregs.
As mentioned above, defective accumulation of Tregs is associated with the development of hepatic irAEs in the present case. One major question arising from the present case is the molecular link between the PD-1 blockade and Treg differentiation. In this regards, neonatal thymectomy (NTx) leads to the development of much severe hepatitis in PD-1-deficient mice than in PD-1-intact mice through concurrent loss of FOXP3-expressing Tregs [20, 21]. Moreover, transient FOXP3-expressing Treg depletion in combination with systemic administration of anti-PD-1 Ab successfully induced severe hepatic irAEs in orthotopic cancer mice [22]. Thus, these previous studies together with the present case suggest the idea that PD-1 blockade may promote the development of liver injury, i.e., hepatic irAEs, in the presence of defective Treg function. Since Tregs stably express cell-surface PD-1 [15], one might assume that neutralization of PD-1-mediated signaling pathways impair Treg function. In this regards, Asano et al. provide evidence that Tregs isolated from PD-1 deficient mice display enhanced apoptosis than those from PD-1-intact mice in the presence of low doses of IL-2, a crucial cytokine for Treg proliferation [23]. Therefore, it is likely that systemic administration of anti-PD-1 Ab reduces the number of Tregs due to enhanced apoptosis. Such defective proliferation and activation of Tregs caused by nivolumab might be involved in the development of multiorgan system irAEs involving the endocrine system, lung, skin, and the liver, as seen in this case. This idea is supported by the fact that loss of function mutations in FOXP3 causes autoimmune diseases affecting multiple organs, called IPEX syndrome [15]. Confirmation of this idea requires future studies addressing the function of FOXP3+ Tregs in patients with multiorgan system irAEs and solitary hepatic irAEs.
Another important question arising from this case is why lung, skin, and hepatic irAEs developed even after the withdrawal of nivolumab. In this regards, recent studies by Osa et al. provide evidence that the binding of nivolumab to cell-surface PD-1 can be detected by flow-cytometry around 6 months after the withdrawal of nivolumab [24]. Thus, such long-lasting neutralization of PD-1 may contribute to the development of irAEs even after the withdrawal of nivolumab.
The number of Tregs was greater in the liver of AIH than that of irAEs in this study. Based on this observation, we hypothesized that defective Treg function mediates hepatic irAEs. However, defective Treg function can also be involved in the development of AIH since impaired Treg function as assessed by the inhibition of effector T cell proliferation was demonstrated in AIH patients [25].
In conclusion, hepatic irAEs might be characterized not only by lobular infiltration of CD8+ T cells but also by defective accumulation of FOXP3+ Tregs. Lack of Treg-mediated immune suppression might underlie the immuno-pathogenesis of hepatic irAEs. Verification of this idea awaits further studies addressing a large number of hepatic irAEs and hepatic Treg function isolated from patients with this disorder.
Supplementary Information
Below is the link to the electronic supplementary material.Supplementary file1 (DOCX 17 KB)
Compliance with ethical standards
Conflict of interest
Ikue Sekai, Satoru Hagiwara, Tomohiro Watanabe and Masatoshi Kudo declare that they have no conflict of interest.
Human Rights
All procedures followed have been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments.
Informed Consent
Informed consent was obtained from all patients for being included in the study.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | CARBOPLATIN, HYDROCORTISONE, NIVOLUMAB, PACLITAXEL | DrugsGivenReaction | CC BY | 33665689 | 19,779,825 | 2021-08 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Primary hypothyroidism'. | A case with hepatic immune-related adverse events caused by nivolumab exhibiting impaired accumulation of regulatory T cells.
Systemic administration of anti-programmed cell death 1 (PD-1) antibody (Ab) has achieved remarkable success in metastatic cancers. The blockade of PD-1-mediated signaling pathways sometimes cause immune-related adverse events (irAEs) due to restored anti-cancer as well as anti-self immunity. Although the liver is a preferential organ for irAEs, the immuno-pathogenesis underlying hepatic irAEs has been poorly understood. We describe a 57-year-old man with Stage IV lung cancer who underwent the first-line regimen composed of carboplatin and paclitaxel. Nivolumab treatment (3.2 mg/kg, every 3 weeks) was initiated when the disease progressed after the first chemotherapy. Sequential occurrence of irAEs involving the multiorgan systems was observed. He developed hepatic irAEs (Grade 3) after endocrine, lung, and cutaneous irAEs. Lobular hepatitis characterized by predominant infiltration of CD8+ T cells was seen in the liver biopsy specimens. Interestingly, defective accumulation of regulatory T cells (Tregs) expressing forkhead box protein P3 (FOXP3) was evident in this case with hepatic irAEs as compared with typical cases with autoimmune hepatitis. This case suggests that hepatic irAEs are characterized not only by lobular infiltration of CD8+ T cells but also by defective accumulation of FOXP3+ Tregs.
Introduction
A recent remarkable success of treating advanced cancer with immune check-point inhibitors (ICIs) highlight important roles that programmed cell death protein-1 (PD-1) and cytotoxic T lymphocyte-associated protein-4 (CTLA-4) play in the suppression of anti-cancer immune responses [1, 2]. Nivolumab and ipilimumab targeting PD-1 and CTLA-4, respectively, are the representative ICIs. These ICIs restore anti-cancer immune responses through neutralization of negative regulation mediated by PD-1 or CTLA-4-mediated signaling pathways [1, 2]. In fact, introduction of nivolumab and ipilimumab into clinical practice has improved the prognosis of advanced malignancies, especially malignant melanoma [1, 2].
Despite effective restorement of anti-cancer immunity by nivolumab and ipilimumab, the blockade of PD-1 and CTLA-4, both of which are negative regulators of adaptive and innate immunity, sometimes causes excessive immune reactions in a broad range of organs, called immune-related adverse events (irAEs) [3, 4]. Liver toxicity associated with ICIs occurs in around 5–10% of patients, [5] and thus, the liver is a preferential organ targeted by ICIs in parallel to the skin, colon, endocrine system, kidney, and lung [3, 4]. Although activation and expansion of T cells through lack of negative regulation by PD-1 and CTLA-4 is considered to underlie the immuno-pathogenesis of irAEs [3–5], molecular mechanisms accounting for the development of hepatic irAEs have been poorly understood. Regulatory T cells (Tregs) expressing forkhead box protein P3 (FOXP3) are a critical component of immune systems with pivotal roles not only in the maintenance of self-tolerance but also in the suppression of anti-cancer immunity [6]. Here, we report a case with hepatic irAEs exhibiting little accumulation of FOXP3-expressing Tregs into the liver. This case suggests possible involvement of Treg deficiency in the development of hepatic irAEs.
Case reports
A 51-year-old man without any history of autoimmune diseases was diagnosed as lung adenocarcinoma (p-T3N0M0, Stage IIb) and received thoracoscopic right pneumonectomy in July 2012. Follow-up computed tomography (CT), which was performed in March 2017, revealed recurrence of his lung cancer in the left lobe accompanied by mediastinal lymph node metastasis. At this time point, he was diagnosed as Stage IV lung adenocarcinoma (p-T3N1M1). His surgical specimen was negative for epidermal growth factor receptor (EGFR) mutation or anaplastic lymphoma kinase 1 (ALK1) fusion oncogene. According to the guideline for Stage IV lung adenocarcinoma with intact EGFR and ALK1 [7], he was initially treated with the first-line regimen composed of carboplatin and paclitaxel from April 2017 for 4 courses followed by paclitaxel maintenance therapy from July 2017 to October 2017. These initial courses of chemotherapy were not successful and his lung cancer was judged as progressive disease (PD) based on computed tomography findings. Nivolumab was introduced from August 2018 at a dose of 3.2 mg/kg every 3 weeks.
Various kinds of irAEs occurred after the treatment with nivolumab and the severity was graded based on the clinical practice guideline following the Common Terminology Criteria for Adverse Events [version 5.0] [8].His initial irAEs involved the endocrine system as shown by the appearance of general fatigue caused by destructive thyroiditis. A significant elevation of serum free T3 (fT3, 6.2 pg/mL, normal range, 2.3–4) and fT4 (fT4, 2.1 ng/dL, normal range, 0.9–1.7) levels accompanied by a markedly reduced level of thyroid stimulating hormone (TSH, 0.02 μIU/mL, normal range, 0.5–5) was seen in September 2018. Three months later, thyroid hormone tests clearly showed hypothyroidism characterized by reduced fT3 and fT4 levels with elevated TSH levels. Further examination of his endocrine system revealed reduced serum levels of cortisol (3.3 μg/dL, normal range 6.2–19.4) and adrenocorticotropic hormone (ACTH 1.3 pg/mL, normal range 7.3–63.3), which suggested the presence of primary adrenal insufficiency despite normal levels of blood sugar, sodium and potassium. Oral supplementation of hydrocortisone (15 mg/day) and thyroid hormone (25 μg/day) were started for G1 primary hypothyroidism and G2 primary adrenal insufficiency, respectively. In addition to these endocrine toxicities, interstitial pneumonia (G1) was detected in February 2019 and then administration of nivolumab was discontinued. Moreover, skin rash judged as G3 irAE developed in March 2019. Prednisolone (PSL, 40 mg/day) with tapering schedule 5 mg/2 weeks was started after the appearance of irAEs involving the endocrine system, lung, and skin.
Although improvement of skin rash was achieved after the initiation of PSL treatment, he developed liver injury as shown by a marked elevation of serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), and γ-glutamyltransferase (γGTP) (Table 1 and Fig. 1). Viral hepatitis was unlikely since viral markers for hepatitis A virus, hepatitis B virus, hepatitis C virus, cytomegalovirus, and Epstein–Barr virus were negative. Moreover, liver injury due to autoimmune hepatitis (AIH) or primary biliary cholangitis (PBC) was also unlikely as assessed by serum IgG levels and titers for anti-nuclear antibody (ANA) or anti-mitochondrial Ab. These blood examination data led us to consider the possibility of hepatic irAEs. No metastatic lesions were detected in the liver by abdominal contrast-enhanced CT. Moreover, magnetic resonance cholangiopancreatography did not reveal any abnormalities in the intrahepatic or extrahepatic bile ducts, suggesting that an immune-related cholangitis caused by ICIs was less likely [9]. To verify the diagnosis of hepatis irAEs, liver biopsy samples were subjected to hematoxylin and eosin (H&E) staining and immuno-histochemical analyses.Table 1 Laboratory data on admission
Hematology Blood chemistry Serological tests
WBC 6.270/μL TP 6.2 g/dL ANA (–)
RBC 346 × 104/μL Alb 3.4 g/dL AMA2 (–)
Hb 13.5 g/dL BUN 13 mg/dL IgG 697 mg/dL
Hct 39.0% Cr 0.79 mg/dL IgM 25 mg/dL
Plt 12.1 × 104/μL T-Bil 1.5 mg/dL IgE 337 IU/mL
Neutro 85.7% D-Bil 0.7 mg/dL Viral marker
Lympho 9.9% ALP 1039 U/L HBsAg (–)
Eosino 0.5% AMY 31 U/L HBsAb (–)
Endocrine LDH 679 U/L HBcAb (–)
ACTH 1.0 pg/mL AST 651 U/L HCVAb (–)
CS 6.2 μg/dL ALT 547 U/L HA-IgM (–)
TSH 1.22 μIU/mL γGTP 2718 U/L CMV-IgM (–)
FT4 1.1 ng/dL CRP 10.22 mg/dL EBVVCA-IgM (–)
Coagulation
PT 119.6%
INR 0.93
ACTH adrenocorticotropic hormone, CS cortisol, PT prothrombin time, INR international normalized ratio, AMA2 anti-mitochondrial antibody 2, ANA anti-nuclear antibody, CMV cytomegalovirus, EBV Epstein–Barr virus
Fig. 1 Clinical course of the patients. See the clinical presentation section of the text. ALT alanine aminotransferase, ALP alkaline phosphatase, AST aspartate aminotransferase, γGTP γ-glutamyltransferase, MMF mycophenolate mofetil, mPSL methylprednisolone, PSL prednisolone, UDCA ursodeoxycholic acid
Liver biopsy samples were subjected to H&E staining and immuno-histochemical analysis using mouse or rabbit anti-human CD3 antibody (Ab, Roche Diagnostics; Tokyo, Japan), CD4 Ab (Roche Diagnostics; Tokyo, Japan), CD8 Ab (Nichirei Bioscience; Tokyo, Japan), CD20 Ab (Roche Diagnostics; Tokyo, Japan), and FOXP3 Ab (Abcam; Cambridge, United Kingdom). Visualization of CD3+ T cells, CD4+ T cells, CD8+ T cells, CD20+ B cells, and FOXP3+ Tregs were performed using DakO-EnVision+ systems (Dako Japan, Tokyo, Japan) as previously described [10, 11]. The liver biopsy sample obtained from a typical patient with AIH (74-year-old female) was used as a disease control. Clinical parameters of this AIH patient were shown in Supplementary Table 1. As shown in Supplementary Table 1, serum levels of IgG and ANA titers were markedly elevated. Moreover, interface hepatitis accompanied by infiltration of plasma cells was evident. The AIH score proposed by international AIH group was 23 in this patient, and thus, this patient was diagnosed with definite AIH [12].
Although lobular as well as portal inflammation was seen in the liver specimens of this patients, immune cell infiltration was predominantly seen in the liver lobes (Fig. 2, 1st and 2nd line panels). Moreover, hyperplasia of the bile duct as well as lymphocyte infiltration into the interlobular bile duct was seen in the pathological examinations, suggesting cholestasis as well as hepatocellular injury is involved in the development of hepatic irAEs in this case [13]. These pathological findings together with elevations of serum transaminases and biliary enzymes indicated that hepatic irAEs of this case was considered to be a mixed type [13].Fig. 2 Immuno-histochemical analyses of liver biopsy specimens. Liver biopsy specimens obtained from this case with hepatic immune-related adverse effects (irAEs, 1st and 2nd line panels) and from patients with autoimmune hepatitis (AIH, 3rd and 4th line panels) were subjected to immuno-histochemical analyses using anti-CD3 Ab, anti-CD4 Ab, anti-CD8 Ab, anti-CD20 Ab, and anti-forkhead box p3 (FOXP3) Ab. Hematoxylin and eosin (H&E) staining of the portal and lobular areas (1st row). Infiltration of CD3+ T cells (2nd row), CD4+ T cells (3rd row), CD8+ T cells (4th row), CD20+ B cells (5th row), and FOXP3+ Treg cells (6th row) was visualized. Scale bar is 20 µm
Interface hepatitis accompanied by plasma cell infiltration was seen in the liver specimen with the AIH patient (Fig. 2, 3rd line panel). Thus, H&E staining in this case was compatible to hepatic irAEs rather than AIH since the former and latter disorders preferentially affect the liver lobes and portal tracts, respectively [5, 14].
We then performed characterization of immune cell infiltration in this case. As shown in Fig. 2, accumulation of CD3+ T cells was seen in the liver lobes of the patient with hepatic irAEs whereas that was seen in the portal areas of the patient with AIH. Subpopulation analysis of T cells showed predominant infiltration of CD8+ T cells rather than CD4+ T cells into the liver lobes in this case (Fig. 2, 1st line panel). AIH lesions were characterized by portal accumulation of both CD4+ and CD8+ T cells (Fig. 2, 4th line panel). Moreover, infiltration of CD20+ B cells was seen in the portal areas of AIH patients, but not those in this case. These immuno-histochemical analyses strongly suggest that liver injury arose from a manifestation of irAEs in that lesions are characterized by predominant accumulation of CD8+ T cells into the liver lobes [5]. Although Tregs expressing FOXP3 play major roles in the suppression of pro-inflammatory responses [15], their involvement in the development of hepatic irAEs has been poorly defined. Interestingly, accumulation of Tregs expressing FOXP3 was barely seen in the liver lobes of this case with hepatic irAEs whereas abundant infiltration of FOXP3+ Tregs was observed in the portal areas of the AIH patient (Fig. 2). Abundant infiltration of T cells expressing CD4, CD8, or FOXP3 was also seen in the other three cases with AIH in this study (data not shown). Taken together, these data suggest hepatic irAEs due to nivolumab might be characterized not only by predominant lobular infiltration of CD8+ T cells but also by little accumulation of FOXP3+ Tregs.
This patient was diagnosed as irAEs involving the endocrine system (G2), lung (G1), skin (G3), and the liver (G3). According to the guideline for hepatic irAEs [3], this patient was initially treated with intravenous administration of methyl PSL (mPSL, 500 mg/day) in combination with oral administration of mycophenolate mofetil (MMF, 200 mg/day, Fig. 1). mPSL was switched to oral administration of PSL (60 mg/day) with a tapering schedule as depicted in Fig. 1. His serum levels of transaminases became normalized 2 months after the treatment and then he was treated with oral administration of Tegafur/Gimeracil/Oteracil (120 mg/day) for advanced lung cancer.
Discussion
Restorement of anti-cancer immunity by ICIs has dramatically improved the prognosis of patients with metastatic cancers [1, 2]. However, the blockade of PD-1 or CTLA-4-mediated signaling pathways sometimes causes irAEs, which can affect almost every organ in the body [3, 4]. In this case, administration of nivolumab led to the development of destructive thyroiditis, primary adrenal insufficiency, interstitial pneumonia, skin eruption and liver injury. Given the fact that the endocrine systems, lung, skin, and liver are preferential organs for irAEs [3–5], this case may be considered as typical irAEs due to nivolumab.
The incidence of hepatic irAEs by nivolumab alone was reported to be 6.4% [16] and liver injury by nivolumab usually develops 8–12 weeks after the initial injection [17]. Lobular infiltration of CD8+ T cells is one of the most characteristic findings in hepatic irAEs [5, 18, 19]. Consistent with this, lobular rather than portal hepatitis accompanied by predominant accumulation of CD8+ T cells was seen in this case. In contrast, AIH lesions were characterized by interface hepatitis associated with infiltration of plasma cells, CD4+ T cells, and CD8+ T cells. Thus, AIH and hepatic irAEs are distinctive disease entities in terms of the location of inflammation and effector T cell subpopulations. It should be noted, however, that molecular mechanisms accounting for such pathological differences between these two disorders have been poorly understood. In this study, we tried to elucidate the immuno-pathogenesis underlying the development of hepatic irAEs. We found that hepatic irAE lesions, but not AIH lesions were characterized by defective accumulation of FOXP3-expressing Tregs. Therefore, we assume possible involvement of defective Treg function in the development of hepatic irAEs. However, we need to be cautious regarding the interpretation of impaired Treg accumulation into the liver of hepatic irAEs. Liver biopsy samples were obtained in the middle of PSL tapering schedule in this patient. Thus, we could not completely exclude a possibility that prior PSL treatment might have affected the function of Tregs.
As mentioned above, defective accumulation of Tregs is associated with the development of hepatic irAEs in the present case. One major question arising from the present case is the molecular link between the PD-1 blockade and Treg differentiation. In this regards, neonatal thymectomy (NTx) leads to the development of much severe hepatitis in PD-1-deficient mice than in PD-1-intact mice through concurrent loss of FOXP3-expressing Tregs [20, 21]. Moreover, transient FOXP3-expressing Treg depletion in combination with systemic administration of anti-PD-1 Ab successfully induced severe hepatic irAEs in orthotopic cancer mice [22]. Thus, these previous studies together with the present case suggest the idea that PD-1 blockade may promote the development of liver injury, i.e., hepatic irAEs, in the presence of defective Treg function. Since Tregs stably express cell-surface PD-1 [15], one might assume that neutralization of PD-1-mediated signaling pathways impair Treg function. In this regards, Asano et al. provide evidence that Tregs isolated from PD-1 deficient mice display enhanced apoptosis than those from PD-1-intact mice in the presence of low doses of IL-2, a crucial cytokine for Treg proliferation [23]. Therefore, it is likely that systemic administration of anti-PD-1 Ab reduces the number of Tregs due to enhanced apoptosis. Such defective proliferation and activation of Tregs caused by nivolumab might be involved in the development of multiorgan system irAEs involving the endocrine system, lung, skin, and the liver, as seen in this case. This idea is supported by the fact that loss of function mutations in FOXP3 causes autoimmune diseases affecting multiple organs, called IPEX syndrome [15]. Confirmation of this idea requires future studies addressing the function of FOXP3+ Tregs in patients with multiorgan system irAEs and solitary hepatic irAEs.
Another important question arising from this case is why lung, skin, and hepatic irAEs developed even after the withdrawal of nivolumab. In this regards, recent studies by Osa et al. provide evidence that the binding of nivolumab to cell-surface PD-1 can be detected by flow-cytometry around 6 months after the withdrawal of nivolumab [24]. Thus, such long-lasting neutralization of PD-1 may contribute to the development of irAEs even after the withdrawal of nivolumab.
The number of Tregs was greater in the liver of AIH than that of irAEs in this study. Based on this observation, we hypothesized that defective Treg function mediates hepatic irAEs. However, defective Treg function can also be involved in the development of AIH since impaired Treg function as assessed by the inhibition of effector T cell proliferation was demonstrated in AIH patients [25].
In conclusion, hepatic irAEs might be characterized not only by lobular infiltration of CD8+ T cells but also by defective accumulation of FOXP3+ Tregs. Lack of Treg-mediated immune suppression might underlie the immuno-pathogenesis of hepatic irAEs. Verification of this idea awaits further studies addressing a large number of hepatic irAEs and hepatic Treg function isolated from patients with this disorder.
Supplementary Information
Below is the link to the electronic supplementary material.Supplementary file1 (DOCX 17 KB)
Compliance with ethical standards
Conflict of interest
Ikue Sekai, Satoru Hagiwara, Tomohiro Watanabe and Masatoshi Kudo declare that they have no conflict of interest.
Human Rights
All procedures followed have been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments.
Informed Consent
Informed consent was obtained from all patients for being included in the study.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | CARBOPLATIN, HYDROCORTISONE, NIVOLUMAB, PACLITAXEL | DrugsGivenReaction | CC BY | 33665689 | 19,779,825 | 2021-08 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Rash'. | A case with hepatic immune-related adverse events caused by nivolumab exhibiting impaired accumulation of regulatory T cells.
Systemic administration of anti-programmed cell death 1 (PD-1) antibody (Ab) has achieved remarkable success in metastatic cancers. The blockade of PD-1-mediated signaling pathways sometimes cause immune-related adverse events (irAEs) due to restored anti-cancer as well as anti-self immunity. Although the liver is a preferential organ for irAEs, the immuno-pathogenesis underlying hepatic irAEs has been poorly understood. We describe a 57-year-old man with Stage IV lung cancer who underwent the first-line regimen composed of carboplatin and paclitaxel. Nivolumab treatment (3.2 mg/kg, every 3 weeks) was initiated when the disease progressed after the first chemotherapy. Sequential occurrence of irAEs involving the multiorgan systems was observed. He developed hepatic irAEs (Grade 3) after endocrine, lung, and cutaneous irAEs. Lobular hepatitis characterized by predominant infiltration of CD8+ T cells was seen in the liver biopsy specimens. Interestingly, defective accumulation of regulatory T cells (Tregs) expressing forkhead box protein P3 (FOXP3) was evident in this case with hepatic irAEs as compared with typical cases with autoimmune hepatitis. This case suggests that hepatic irAEs are characterized not only by lobular infiltration of CD8+ T cells but also by defective accumulation of FOXP3+ Tregs.
Introduction
A recent remarkable success of treating advanced cancer with immune check-point inhibitors (ICIs) highlight important roles that programmed cell death protein-1 (PD-1) and cytotoxic T lymphocyte-associated protein-4 (CTLA-4) play in the suppression of anti-cancer immune responses [1, 2]. Nivolumab and ipilimumab targeting PD-1 and CTLA-4, respectively, are the representative ICIs. These ICIs restore anti-cancer immune responses through neutralization of negative regulation mediated by PD-1 or CTLA-4-mediated signaling pathways [1, 2]. In fact, introduction of nivolumab and ipilimumab into clinical practice has improved the prognosis of advanced malignancies, especially malignant melanoma [1, 2].
Despite effective restorement of anti-cancer immunity by nivolumab and ipilimumab, the blockade of PD-1 and CTLA-4, both of which are negative regulators of adaptive and innate immunity, sometimes causes excessive immune reactions in a broad range of organs, called immune-related adverse events (irAEs) [3, 4]. Liver toxicity associated with ICIs occurs in around 5–10% of patients, [5] and thus, the liver is a preferential organ targeted by ICIs in parallel to the skin, colon, endocrine system, kidney, and lung [3, 4]. Although activation and expansion of T cells through lack of negative regulation by PD-1 and CTLA-4 is considered to underlie the immuno-pathogenesis of irAEs [3–5], molecular mechanisms accounting for the development of hepatic irAEs have been poorly understood. Regulatory T cells (Tregs) expressing forkhead box protein P3 (FOXP3) are a critical component of immune systems with pivotal roles not only in the maintenance of self-tolerance but also in the suppression of anti-cancer immunity [6]. Here, we report a case with hepatic irAEs exhibiting little accumulation of FOXP3-expressing Tregs into the liver. This case suggests possible involvement of Treg deficiency in the development of hepatic irAEs.
Case reports
A 51-year-old man without any history of autoimmune diseases was diagnosed as lung adenocarcinoma (p-T3N0M0, Stage IIb) and received thoracoscopic right pneumonectomy in July 2012. Follow-up computed tomography (CT), which was performed in March 2017, revealed recurrence of his lung cancer in the left lobe accompanied by mediastinal lymph node metastasis. At this time point, he was diagnosed as Stage IV lung adenocarcinoma (p-T3N1M1). His surgical specimen was negative for epidermal growth factor receptor (EGFR) mutation or anaplastic lymphoma kinase 1 (ALK1) fusion oncogene. According to the guideline for Stage IV lung adenocarcinoma with intact EGFR and ALK1 [7], he was initially treated with the first-line regimen composed of carboplatin and paclitaxel from April 2017 for 4 courses followed by paclitaxel maintenance therapy from July 2017 to October 2017. These initial courses of chemotherapy were not successful and his lung cancer was judged as progressive disease (PD) based on computed tomography findings. Nivolumab was introduced from August 2018 at a dose of 3.2 mg/kg every 3 weeks.
Various kinds of irAEs occurred after the treatment with nivolumab and the severity was graded based on the clinical practice guideline following the Common Terminology Criteria for Adverse Events [version 5.0] [8].His initial irAEs involved the endocrine system as shown by the appearance of general fatigue caused by destructive thyroiditis. A significant elevation of serum free T3 (fT3, 6.2 pg/mL, normal range, 2.3–4) and fT4 (fT4, 2.1 ng/dL, normal range, 0.9–1.7) levels accompanied by a markedly reduced level of thyroid stimulating hormone (TSH, 0.02 μIU/mL, normal range, 0.5–5) was seen in September 2018. Three months later, thyroid hormone tests clearly showed hypothyroidism characterized by reduced fT3 and fT4 levels with elevated TSH levels. Further examination of his endocrine system revealed reduced serum levels of cortisol (3.3 μg/dL, normal range 6.2–19.4) and adrenocorticotropic hormone (ACTH 1.3 pg/mL, normal range 7.3–63.3), which suggested the presence of primary adrenal insufficiency despite normal levels of blood sugar, sodium and potassium. Oral supplementation of hydrocortisone (15 mg/day) and thyroid hormone (25 μg/day) were started for G1 primary hypothyroidism and G2 primary adrenal insufficiency, respectively. In addition to these endocrine toxicities, interstitial pneumonia (G1) was detected in February 2019 and then administration of nivolumab was discontinued. Moreover, skin rash judged as G3 irAE developed in March 2019. Prednisolone (PSL, 40 mg/day) with tapering schedule 5 mg/2 weeks was started after the appearance of irAEs involving the endocrine system, lung, and skin.
Although improvement of skin rash was achieved after the initiation of PSL treatment, he developed liver injury as shown by a marked elevation of serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), and γ-glutamyltransferase (γGTP) (Table 1 and Fig. 1). Viral hepatitis was unlikely since viral markers for hepatitis A virus, hepatitis B virus, hepatitis C virus, cytomegalovirus, and Epstein–Barr virus were negative. Moreover, liver injury due to autoimmune hepatitis (AIH) or primary biliary cholangitis (PBC) was also unlikely as assessed by serum IgG levels and titers for anti-nuclear antibody (ANA) or anti-mitochondrial Ab. These blood examination data led us to consider the possibility of hepatic irAEs. No metastatic lesions were detected in the liver by abdominal contrast-enhanced CT. Moreover, magnetic resonance cholangiopancreatography did not reveal any abnormalities in the intrahepatic or extrahepatic bile ducts, suggesting that an immune-related cholangitis caused by ICIs was less likely [9]. To verify the diagnosis of hepatis irAEs, liver biopsy samples were subjected to hematoxylin and eosin (H&E) staining and immuno-histochemical analyses.Table 1 Laboratory data on admission
Hematology Blood chemistry Serological tests
WBC 6.270/μL TP 6.2 g/dL ANA (–)
RBC 346 × 104/μL Alb 3.4 g/dL AMA2 (–)
Hb 13.5 g/dL BUN 13 mg/dL IgG 697 mg/dL
Hct 39.0% Cr 0.79 mg/dL IgM 25 mg/dL
Plt 12.1 × 104/μL T-Bil 1.5 mg/dL IgE 337 IU/mL
Neutro 85.7% D-Bil 0.7 mg/dL Viral marker
Lympho 9.9% ALP 1039 U/L HBsAg (–)
Eosino 0.5% AMY 31 U/L HBsAb (–)
Endocrine LDH 679 U/L HBcAb (–)
ACTH 1.0 pg/mL AST 651 U/L HCVAb (–)
CS 6.2 μg/dL ALT 547 U/L HA-IgM (–)
TSH 1.22 μIU/mL γGTP 2718 U/L CMV-IgM (–)
FT4 1.1 ng/dL CRP 10.22 mg/dL EBVVCA-IgM (–)
Coagulation
PT 119.6%
INR 0.93
ACTH adrenocorticotropic hormone, CS cortisol, PT prothrombin time, INR international normalized ratio, AMA2 anti-mitochondrial antibody 2, ANA anti-nuclear antibody, CMV cytomegalovirus, EBV Epstein–Barr virus
Fig. 1 Clinical course of the patients. See the clinical presentation section of the text. ALT alanine aminotransferase, ALP alkaline phosphatase, AST aspartate aminotransferase, γGTP γ-glutamyltransferase, MMF mycophenolate mofetil, mPSL methylprednisolone, PSL prednisolone, UDCA ursodeoxycholic acid
Liver biopsy samples were subjected to H&E staining and immuno-histochemical analysis using mouse or rabbit anti-human CD3 antibody (Ab, Roche Diagnostics; Tokyo, Japan), CD4 Ab (Roche Diagnostics; Tokyo, Japan), CD8 Ab (Nichirei Bioscience; Tokyo, Japan), CD20 Ab (Roche Diagnostics; Tokyo, Japan), and FOXP3 Ab (Abcam; Cambridge, United Kingdom). Visualization of CD3+ T cells, CD4+ T cells, CD8+ T cells, CD20+ B cells, and FOXP3+ Tregs were performed using DakO-EnVision+ systems (Dako Japan, Tokyo, Japan) as previously described [10, 11]. The liver biopsy sample obtained from a typical patient with AIH (74-year-old female) was used as a disease control. Clinical parameters of this AIH patient were shown in Supplementary Table 1. As shown in Supplementary Table 1, serum levels of IgG and ANA titers were markedly elevated. Moreover, interface hepatitis accompanied by infiltration of plasma cells was evident. The AIH score proposed by international AIH group was 23 in this patient, and thus, this patient was diagnosed with definite AIH [12].
Although lobular as well as portal inflammation was seen in the liver specimens of this patients, immune cell infiltration was predominantly seen in the liver lobes (Fig. 2, 1st and 2nd line panels). Moreover, hyperplasia of the bile duct as well as lymphocyte infiltration into the interlobular bile duct was seen in the pathological examinations, suggesting cholestasis as well as hepatocellular injury is involved in the development of hepatic irAEs in this case [13]. These pathological findings together with elevations of serum transaminases and biliary enzymes indicated that hepatic irAEs of this case was considered to be a mixed type [13].Fig. 2 Immuno-histochemical analyses of liver biopsy specimens. Liver biopsy specimens obtained from this case with hepatic immune-related adverse effects (irAEs, 1st and 2nd line panels) and from patients with autoimmune hepatitis (AIH, 3rd and 4th line panels) were subjected to immuno-histochemical analyses using anti-CD3 Ab, anti-CD4 Ab, anti-CD8 Ab, anti-CD20 Ab, and anti-forkhead box p3 (FOXP3) Ab. Hematoxylin and eosin (H&E) staining of the portal and lobular areas (1st row). Infiltration of CD3+ T cells (2nd row), CD4+ T cells (3rd row), CD8+ T cells (4th row), CD20+ B cells (5th row), and FOXP3+ Treg cells (6th row) was visualized. Scale bar is 20 µm
Interface hepatitis accompanied by plasma cell infiltration was seen in the liver specimen with the AIH patient (Fig. 2, 3rd line panel). Thus, H&E staining in this case was compatible to hepatic irAEs rather than AIH since the former and latter disorders preferentially affect the liver lobes and portal tracts, respectively [5, 14].
We then performed characterization of immune cell infiltration in this case. As shown in Fig. 2, accumulation of CD3+ T cells was seen in the liver lobes of the patient with hepatic irAEs whereas that was seen in the portal areas of the patient with AIH. Subpopulation analysis of T cells showed predominant infiltration of CD8+ T cells rather than CD4+ T cells into the liver lobes in this case (Fig. 2, 1st line panel). AIH lesions were characterized by portal accumulation of both CD4+ and CD8+ T cells (Fig. 2, 4th line panel). Moreover, infiltration of CD20+ B cells was seen in the portal areas of AIH patients, but not those in this case. These immuno-histochemical analyses strongly suggest that liver injury arose from a manifestation of irAEs in that lesions are characterized by predominant accumulation of CD8+ T cells into the liver lobes [5]. Although Tregs expressing FOXP3 play major roles in the suppression of pro-inflammatory responses [15], their involvement in the development of hepatic irAEs has been poorly defined. Interestingly, accumulation of Tregs expressing FOXP3 was barely seen in the liver lobes of this case with hepatic irAEs whereas abundant infiltration of FOXP3+ Tregs was observed in the portal areas of the AIH patient (Fig. 2). Abundant infiltration of T cells expressing CD4, CD8, or FOXP3 was also seen in the other three cases with AIH in this study (data not shown). Taken together, these data suggest hepatic irAEs due to nivolumab might be characterized not only by predominant lobular infiltration of CD8+ T cells but also by little accumulation of FOXP3+ Tregs.
This patient was diagnosed as irAEs involving the endocrine system (G2), lung (G1), skin (G3), and the liver (G3). According to the guideline for hepatic irAEs [3], this patient was initially treated with intravenous administration of methyl PSL (mPSL, 500 mg/day) in combination with oral administration of mycophenolate mofetil (MMF, 200 mg/day, Fig. 1). mPSL was switched to oral administration of PSL (60 mg/day) with a tapering schedule as depicted in Fig. 1. His serum levels of transaminases became normalized 2 months after the treatment and then he was treated with oral administration of Tegafur/Gimeracil/Oteracil (120 mg/day) for advanced lung cancer.
Discussion
Restorement of anti-cancer immunity by ICIs has dramatically improved the prognosis of patients with metastatic cancers [1, 2]. However, the blockade of PD-1 or CTLA-4-mediated signaling pathways sometimes causes irAEs, which can affect almost every organ in the body [3, 4]. In this case, administration of nivolumab led to the development of destructive thyroiditis, primary adrenal insufficiency, interstitial pneumonia, skin eruption and liver injury. Given the fact that the endocrine systems, lung, skin, and liver are preferential organs for irAEs [3–5], this case may be considered as typical irAEs due to nivolumab.
The incidence of hepatic irAEs by nivolumab alone was reported to be 6.4% [16] and liver injury by nivolumab usually develops 8–12 weeks after the initial injection [17]. Lobular infiltration of CD8+ T cells is one of the most characteristic findings in hepatic irAEs [5, 18, 19]. Consistent with this, lobular rather than portal hepatitis accompanied by predominant accumulation of CD8+ T cells was seen in this case. In contrast, AIH lesions were characterized by interface hepatitis associated with infiltration of plasma cells, CD4+ T cells, and CD8+ T cells. Thus, AIH and hepatic irAEs are distinctive disease entities in terms of the location of inflammation and effector T cell subpopulations. It should be noted, however, that molecular mechanisms accounting for such pathological differences between these two disorders have been poorly understood. In this study, we tried to elucidate the immuno-pathogenesis underlying the development of hepatic irAEs. We found that hepatic irAE lesions, but not AIH lesions were characterized by defective accumulation of FOXP3-expressing Tregs. Therefore, we assume possible involvement of defective Treg function in the development of hepatic irAEs. However, we need to be cautious regarding the interpretation of impaired Treg accumulation into the liver of hepatic irAEs. Liver biopsy samples were obtained in the middle of PSL tapering schedule in this patient. Thus, we could not completely exclude a possibility that prior PSL treatment might have affected the function of Tregs.
As mentioned above, defective accumulation of Tregs is associated with the development of hepatic irAEs in the present case. One major question arising from the present case is the molecular link between the PD-1 blockade and Treg differentiation. In this regards, neonatal thymectomy (NTx) leads to the development of much severe hepatitis in PD-1-deficient mice than in PD-1-intact mice through concurrent loss of FOXP3-expressing Tregs [20, 21]. Moreover, transient FOXP3-expressing Treg depletion in combination with systemic administration of anti-PD-1 Ab successfully induced severe hepatic irAEs in orthotopic cancer mice [22]. Thus, these previous studies together with the present case suggest the idea that PD-1 blockade may promote the development of liver injury, i.e., hepatic irAEs, in the presence of defective Treg function. Since Tregs stably express cell-surface PD-1 [15], one might assume that neutralization of PD-1-mediated signaling pathways impair Treg function. In this regards, Asano et al. provide evidence that Tregs isolated from PD-1 deficient mice display enhanced apoptosis than those from PD-1-intact mice in the presence of low doses of IL-2, a crucial cytokine for Treg proliferation [23]. Therefore, it is likely that systemic administration of anti-PD-1 Ab reduces the number of Tregs due to enhanced apoptosis. Such defective proliferation and activation of Tregs caused by nivolumab might be involved in the development of multiorgan system irAEs involving the endocrine system, lung, skin, and the liver, as seen in this case. This idea is supported by the fact that loss of function mutations in FOXP3 causes autoimmune diseases affecting multiple organs, called IPEX syndrome [15]. Confirmation of this idea requires future studies addressing the function of FOXP3+ Tregs in patients with multiorgan system irAEs and solitary hepatic irAEs.
Another important question arising from this case is why lung, skin, and hepatic irAEs developed even after the withdrawal of nivolumab. In this regards, recent studies by Osa et al. provide evidence that the binding of nivolumab to cell-surface PD-1 can be detected by flow-cytometry around 6 months after the withdrawal of nivolumab [24]. Thus, such long-lasting neutralization of PD-1 may contribute to the development of irAEs even after the withdrawal of nivolumab.
The number of Tregs was greater in the liver of AIH than that of irAEs in this study. Based on this observation, we hypothesized that defective Treg function mediates hepatic irAEs. However, defective Treg function can also be involved in the development of AIH since impaired Treg function as assessed by the inhibition of effector T cell proliferation was demonstrated in AIH patients [25].
In conclusion, hepatic irAEs might be characterized not only by lobular infiltration of CD8+ T cells but also by defective accumulation of FOXP3+ Tregs. Lack of Treg-mediated immune suppression might underlie the immuno-pathogenesis of hepatic irAEs. Verification of this idea awaits further studies addressing a large number of hepatic irAEs and hepatic Treg function isolated from patients with this disorder.
Supplementary Information
Below is the link to the electronic supplementary material.Supplementary file1 (DOCX 17 KB)
Compliance with ethical standards
Conflict of interest
Ikue Sekai, Satoru Hagiwara, Tomohiro Watanabe and Masatoshi Kudo declare that they have no conflict of interest.
Human Rights
All procedures followed have been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments.
Informed Consent
Informed consent was obtained from all patients for being included in the study.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | CARBOPLATIN, HYDROCORTISONE, NIVOLUMAB, PACLITAXEL | DrugsGivenReaction | CC BY | 33665689 | 19,779,825 | 2021-08 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Thyroiditis'. | A case with hepatic immune-related adverse events caused by nivolumab exhibiting impaired accumulation of regulatory T cells.
Systemic administration of anti-programmed cell death 1 (PD-1) antibody (Ab) has achieved remarkable success in metastatic cancers. The blockade of PD-1-mediated signaling pathways sometimes cause immune-related adverse events (irAEs) due to restored anti-cancer as well as anti-self immunity. Although the liver is a preferential organ for irAEs, the immuno-pathogenesis underlying hepatic irAEs has been poorly understood. We describe a 57-year-old man with Stage IV lung cancer who underwent the first-line regimen composed of carboplatin and paclitaxel. Nivolumab treatment (3.2 mg/kg, every 3 weeks) was initiated when the disease progressed after the first chemotherapy. Sequential occurrence of irAEs involving the multiorgan systems was observed. He developed hepatic irAEs (Grade 3) after endocrine, lung, and cutaneous irAEs. Lobular hepatitis characterized by predominant infiltration of CD8+ T cells was seen in the liver biopsy specimens. Interestingly, defective accumulation of regulatory T cells (Tregs) expressing forkhead box protein P3 (FOXP3) was evident in this case with hepatic irAEs as compared with typical cases with autoimmune hepatitis. This case suggests that hepatic irAEs are characterized not only by lobular infiltration of CD8+ T cells but also by defective accumulation of FOXP3+ Tregs.
Introduction
A recent remarkable success of treating advanced cancer with immune check-point inhibitors (ICIs) highlight important roles that programmed cell death protein-1 (PD-1) and cytotoxic T lymphocyte-associated protein-4 (CTLA-4) play in the suppression of anti-cancer immune responses [1, 2]. Nivolumab and ipilimumab targeting PD-1 and CTLA-4, respectively, are the representative ICIs. These ICIs restore anti-cancer immune responses through neutralization of negative regulation mediated by PD-1 or CTLA-4-mediated signaling pathways [1, 2]. In fact, introduction of nivolumab and ipilimumab into clinical practice has improved the prognosis of advanced malignancies, especially malignant melanoma [1, 2].
Despite effective restorement of anti-cancer immunity by nivolumab and ipilimumab, the blockade of PD-1 and CTLA-4, both of which are negative regulators of adaptive and innate immunity, sometimes causes excessive immune reactions in a broad range of organs, called immune-related adverse events (irAEs) [3, 4]. Liver toxicity associated with ICIs occurs in around 5–10% of patients, [5] and thus, the liver is a preferential organ targeted by ICIs in parallel to the skin, colon, endocrine system, kidney, and lung [3, 4]. Although activation and expansion of T cells through lack of negative regulation by PD-1 and CTLA-4 is considered to underlie the immuno-pathogenesis of irAEs [3–5], molecular mechanisms accounting for the development of hepatic irAEs have been poorly understood. Regulatory T cells (Tregs) expressing forkhead box protein P3 (FOXP3) are a critical component of immune systems with pivotal roles not only in the maintenance of self-tolerance but also in the suppression of anti-cancer immunity [6]. Here, we report a case with hepatic irAEs exhibiting little accumulation of FOXP3-expressing Tregs into the liver. This case suggests possible involvement of Treg deficiency in the development of hepatic irAEs.
Case reports
A 51-year-old man without any history of autoimmune diseases was diagnosed as lung adenocarcinoma (p-T3N0M0, Stage IIb) and received thoracoscopic right pneumonectomy in July 2012. Follow-up computed tomography (CT), which was performed in March 2017, revealed recurrence of his lung cancer in the left lobe accompanied by mediastinal lymph node metastasis. At this time point, he was diagnosed as Stage IV lung adenocarcinoma (p-T3N1M1). His surgical specimen was negative for epidermal growth factor receptor (EGFR) mutation or anaplastic lymphoma kinase 1 (ALK1) fusion oncogene. According to the guideline for Stage IV lung adenocarcinoma with intact EGFR and ALK1 [7], he was initially treated with the first-line regimen composed of carboplatin and paclitaxel from April 2017 for 4 courses followed by paclitaxel maintenance therapy from July 2017 to October 2017. These initial courses of chemotherapy were not successful and his lung cancer was judged as progressive disease (PD) based on computed tomography findings. Nivolumab was introduced from August 2018 at a dose of 3.2 mg/kg every 3 weeks.
Various kinds of irAEs occurred after the treatment with nivolumab and the severity was graded based on the clinical practice guideline following the Common Terminology Criteria for Adverse Events [version 5.0] [8].His initial irAEs involved the endocrine system as shown by the appearance of general fatigue caused by destructive thyroiditis. A significant elevation of serum free T3 (fT3, 6.2 pg/mL, normal range, 2.3–4) and fT4 (fT4, 2.1 ng/dL, normal range, 0.9–1.7) levels accompanied by a markedly reduced level of thyroid stimulating hormone (TSH, 0.02 μIU/mL, normal range, 0.5–5) was seen in September 2018. Three months later, thyroid hormone tests clearly showed hypothyroidism characterized by reduced fT3 and fT4 levels with elevated TSH levels. Further examination of his endocrine system revealed reduced serum levels of cortisol (3.3 μg/dL, normal range 6.2–19.4) and adrenocorticotropic hormone (ACTH 1.3 pg/mL, normal range 7.3–63.3), which suggested the presence of primary adrenal insufficiency despite normal levels of blood sugar, sodium and potassium. Oral supplementation of hydrocortisone (15 mg/day) and thyroid hormone (25 μg/day) were started for G1 primary hypothyroidism and G2 primary adrenal insufficiency, respectively. In addition to these endocrine toxicities, interstitial pneumonia (G1) was detected in February 2019 and then administration of nivolumab was discontinued. Moreover, skin rash judged as G3 irAE developed in March 2019. Prednisolone (PSL, 40 mg/day) with tapering schedule 5 mg/2 weeks was started after the appearance of irAEs involving the endocrine system, lung, and skin.
Although improvement of skin rash was achieved after the initiation of PSL treatment, he developed liver injury as shown by a marked elevation of serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), and γ-glutamyltransferase (γGTP) (Table 1 and Fig. 1). Viral hepatitis was unlikely since viral markers for hepatitis A virus, hepatitis B virus, hepatitis C virus, cytomegalovirus, and Epstein–Barr virus were negative. Moreover, liver injury due to autoimmune hepatitis (AIH) or primary biliary cholangitis (PBC) was also unlikely as assessed by serum IgG levels and titers for anti-nuclear antibody (ANA) or anti-mitochondrial Ab. These blood examination data led us to consider the possibility of hepatic irAEs. No metastatic lesions were detected in the liver by abdominal contrast-enhanced CT. Moreover, magnetic resonance cholangiopancreatography did not reveal any abnormalities in the intrahepatic or extrahepatic bile ducts, suggesting that an immune-related cholangitis caused by ICIs was less likely [9]. To verify the diagnosis of hepatis irAEs, liver biopsy samples were subjected to hematoxylin and eosin (H&E) staining and immuno-histochemical analyses.Table 1 Laboratory data on admission
Hematology Blood chemistry Serological tests
WBC 6.270/μL TP 6.2 g/dL ANA (–)
RBC 346 × 104/μL Alb 3.4 g/dL AMA2 (–)
Hb 13.5 g/dL BUN 13 mg/dL IgG 697 mg/dL
Hct 39.0% Cr 0.79 mg/dL IgM 25 mg/dL
Plt 12.1 × 104/μL T-Bil 1.5 mg/dL IgE 337 IU/mL
Neutro 85.7% D-Bil 0.7 mg/dL Viral marker
Lympho 9.9% ALP 1039 U/L HBsAg (–)
Eosino 0.5% AMY 31 U/L HBsAb (–)
Endocrine LDH 679 U/L HBcAb (–)
ACTH 1.0 pg/mL AST 651 U/L HCVAb (–)
CS 6.2 μg/dL ALT 547 U/L HA-IgM (–)
TSH 1.22 μIU/mL γGTP 2718 U/L CMV-IgM (–)
FT4 1.1 ng/dL CRP 10.22 mg/dL EBVVCA-IgM (–)
Coagulation
PT 119.6%
INR 0.93
ACTH adrenocorticotropic hormone, CS cortisol, PT prothrombin time, INR international normalized ratio, AMA2 anti-mitochondrial antibody 2, ANA anti-nuclear antibody, CMV cytomegalovirus, EBV Epstein–Barr virus
Fig. 1 Clinical course of the patients. See the clinical presentation section of the text. ALT alanine aminotransferase, ALP alkaline phosphatase, AST aspartate aminotransferase, γGTP γ-glutamyltransferase, MMF mycophenolate mofetil, mPSL methylprednisolone, PSL prednisolone, UDCA ursodeoxycholic acid
Liver biopsy samples were subjected to H&E staining and immuno-histochemical analysis using mouse or rabbit anti-human CD3 antibody (Ab, Roche Diagnostics; Tokyo, Japan), CD4 Ab (Roche Diagnostics; Tokyo, Japan), CD8 Ab (Nichirei Bioscience; Tokyo, Japan), CD20 Ab (Roche Diagnostics; Tokyo, Japan), and FOXP3 Ab (Abcam; Cambridge, United Kingdom). Visualization of CD3+ T cells, CD4+ T cells, CD8+ T cells, CD20+ B cells, and FOXP3+ Tregs were performed using DakO-EnVision+ systems (Dako Japan, Tokyo, Japan) as previously described [10, 11]. The liver biopsy sample obtained from a typical patient with AIH (74-year-old female) was used as a disease control. Clinical parameters of this AIH patient were shown in Supplementary Table 1. As shown in Supplementary Table 1, serum levels of IgG and ANA titers were markedly elevated. Moreover, interface hepatitis accompanied by infiltration of plasma cells was evident. The AIH score proposed by international AIH group was 23 in this patient, and thus, this patient was diagnosed with definite AIH [12].
Although lobular as well as portal inflammation was seen in the liver specimens of this patients, immune cell infiltration was predominantly seen in the liver lobes (Fig. 2, 1st and 2nd line panels). Moreover, hyperplasia of the bile duct as well as lymphocyte infiltration into the interlobular bile duct was seen in the pathological examinations, suggesting cholestasis as well as hepatocellular injury is involved in the development of hepatic irAEs in this case [13]. These pathological findings together with elevations of serum transaminases and biliary enzymes indicated that hepatic irAEs of this case was considered to be a mixed type [13].Fig. 2 Immuno-histochemical analyses of liver biopsy specimens. Liver biopsy specimens obtained from this case with hepatic immune-related adverse effects (irAEs, 1st and 2nd line panels) and from patients with autoimmune hepatitis (AIH, 3rd and 4th line panels) were subjected to immuno-histochemical analyses using anti-CD3 Ab, anti-CD4 Ab, anti-CD8 Ab, anti-CD20 Ab, and anti-forkhead box p3 (FOXP3) Ab. Hematoxylin and eosin (H&E) staining of the portal and lobular areas (1st row). Infiltration of CD3+ T cells (2nd row), CD4+ T cells (3rd row), CD8+ T cells (4th row), CD20+ B cells (5th row), and FOXP3+ Treg cells (6th row) was visualized. Scale bar is 20 µm
Interface hepatitis accompanied by plasma cell infiltration was seen in the liver specimen with the AIH patient (Fig. 2, 3rd line panel). Thus, H&E staining in this case was compatible to hepatic irAEs rather than AIH since the former and latter disorders preferentially affect the liver lobes and portal tracts, respectively [5, 14].
We then performed characterization of immune cell infiltration in this case. As shown in Fig. 2, accumulation of CD3+ T cells was seen in the liver lobes of the patient with hepatic irAEs whereas that was seen in the portal areas of the patient with AIH. Subpopulation analysis of T cells showed predominant infiltration of CD8+ T cells rather than CD4+ T cells into the liver lobes in this case (Fig. 2, 1st line panel). AIH lesions were characterized by portal accumulation of both CD4+ and CD8+ T cells (Fig. 2, 4th line panel). Moreover, infiltration of CD20+ B cells was seen in the portal areas of AIH patients, but not those in this case. These immuno-histochemical analyses strongly suggest that liver injury arose from a manifestation of irAEs in that lesions are characterized by predominant accumulation of CD8+ T cells into the liver lobes [5]. Although Tregs expressing FOXP3 play major roles in the suppression of pro-inflammatory responses [15], their involvement in the development of hepatic irAEs has been poorly defined. Interestingly, accumulation of Tregs expressing FOXP3 was barely seen in the liver lobes of this case with hepatic irAEs whereas abundant infiltration of FOXP3+ Tregs was observed in the portal areas of the AIH patient (Fig. 2). Abundant infiltration of T cells expressing CD4, CD8, or FOXP3 was also seen in the other three cases with AIH in this study (data not shown). Taken together, these data suggest hepatic irAEs due to nivolumab might be characterized not only by predominant lobular infiltration of CD8+ T cells but also by little accumulation of FOXP3+ Tregs.
This patient was diagnosed as irAEs involving the endocrine system (G2), lung (G1), skin (G3), and the liver (G3). According to the guideline for hepatic irAEs [3], this patient was initially treated with intravenous administration of methyl PSL (mPSL, 500 mg/day) in combination with oral administration of mycophenolate mofetil (MMF, 200 mg/day, Fig. 1). mPSL was switched to oral administration of PSL (60 mg/day) with a tapering schedule as depicted in Fig. 1. His serum levels of transaminases became normalized 2 months after the treatment and then he was treated with oral administration of Tegafur/Gimeracil/Oteracil (120 mg/day) for advanced lung cancer.
Discussion
Restorement of anti-cancer immunity by ICIs has dramatically improved the prognosis of patients with metastatic cancers [1, 2]. However, the blockade of PD-1 or CTLA-4-mediated signaling pathways sometimes causes irAEs, which can affect almost every organ in the body [3, 4]. In this case, administration of nivolumab led to the development of destructive thyroiditis, primary adrenal insufficiency, interstitial pneumonia, skin eruption and liver injury. Given the fact that the endocrine systems, lung, skin, and liver are preferential organs for irAEs [3–5], this case may be considered as typical irAEs due to nivolumab.
The incidence of hepatic irAEs by nivolumab alone was reported to be 6.4% [16] and liver injury by nivolumab usually develops 8–12 weeks after the initial injection [17]. Lobular infiltration of CD8+ T cells is one of the most characteristic findings in hepatic irAEs [5, 18, 19]. Consistent with this, lobular rather than portal hepatitis accompanied by predominant accumulation of CD8+ T cells was seen in this case. In contrast, AIH lesions were characterized by interface hepatitis associated with infiltration of plasma cells, CD4+ T cells, and CD8+ T cells. Thus, AIH and hepatic irAEs are distinctive disease entities in terms of the location of inflammation and effector T cell subpopulations. It should be noted, however, that molecular mechanisms accounting for such pathological differences between these two disorders have been poorly understood. In this study, we tried to elucidate the immuno-pathogenesis underlying the development of hepatic irAEs. We found that hepatic irAE lesions, but not AIH lesions were characterized by defective accumulation of FOXP3-expressing Tregs. Therefore, we assume possible involvement of defective Treg function in the development of hepatic irAEs. However, we need to be cautious regarding the interpretation of impaired Treg accumulation into the liver of hepatic irAEs. Liver biopsy samples were obtained in the middle of PSL tapering schedule in this patient. Thus, we could not completely exclude a possibility that prior PSL treatment might have affected the function of Tregs.
As mentioned above, defective accumulation of Tregs is associated with the development of hepatic irAEs in the present case. One major question arising from the present case is the molecular link between the PD-1 blockade and Treg differentiation. In this regards, neonatal thymectomy (NTx) leads to the development of much severe hepatitis in PD-1-deficient mice than in PD-1-intact mice through concurrent loss of FOXP3-expressing Tregs [20, 21]. Moreover, transient FOXP3-expressing Treg depletion in combination with systemic administration of anti-PD-1 Ab successfully induced severe hepatic irAEs in orthotopic cancer mice [22]. Thus, these previous studies together with the present case suggest the idea that PD-1 blockade may promote the development of liver injury, i.e., hepatic irAEs, in the presence of defective Treg function. Since Tregs stably express cell-surface PD-1 [15], one might assume that neutralization of PD-1-mediated signaling pathways impair Treg function. In this regards, Asano et al. provide evidence that Tregs isolated from PD-1 deficient mice display enhanced apoptosis than those from PD-1-intact mice in the presence of low doses of IL-2, a crucial cytokine for Treg proliferation [23]. Therefore, it is likely that systemic administration of anti-PD-1 Ab reduces the number of Tregs due to enhanced apoptosis. Such defective proliferation and activation of Tregs caused by nivolumab might be involved in the development of multiorgan system irAEs involving the endocrine system, lung, skin, and the liver, as seen in this case. This idea is supported by the fact that loss of function mutations in FOXP3 causes autoimmune diseases affecting multiple organs, called IPEX syndrome [15]. Confirmation of this idea requires future studies addressing the function of FOXP3+ Tregs in patients with multiorgan system irAEs and solitary hepatic irAEs.
Another important question arising from this case is why lung, skin, and hepatic irAEs developed even after the withdrawal of nivolumab. In this regards, recent studies by Osa et al. provide evidence that the binding of nivolumab to cell-surface PD-1 can be detected by flow-cytometry around 6 months after the withdrawal of nivolumab [24]. Thus, such long-lasting neutralization of PD-1 may contribute to the development of irAEs even after the withdrawal of nivolumab.
The number of Tregs was greater in the liver of AIH than that of irAEs in this study. Based on this observation, we hypothesized that defective Treg function mediates hepatic irAEs. However, defective Treg function can also be involved in the development of AIH since impaired Treg function as assessed by the inhibition of effector T cell proliferation was demonstrated in AIH patients [25].
In conclusion, hepatic irAEs might be characterized not only by lobular infiltration of CD8+ T cells but also by defective accumulation of FOXP3+ Tregs. Lack of Treg-mediated immune suppression might underlie the immuno-pathogenesis of hepatic irAEs. Verification of this idea awaits further studies addressing a large number of hepatic irAEs and hepatic Treg function isolated from patients with this disorder.
Supplementary Information
Below is the link to the electronic supplementary material.Supplementary file1 (DOCX 17 KB)
Compliance with ethical standards
Conflict of interest
Ikue Sekai, Satoru Hagiwara, Tomohiro Watanabe and Masatoshi Kudo declare that they have no conflict of interest.
Human Rights
All procedures followed have been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments.
Informed Consent
Informed consent was obtained from all patients for being included in the study.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | CARBOPLATIN, HYDROCORTISONE, NIVOLUMAB, PACLITAXEL | DrugsGivenReaction | CC BY | 33665689 | 19,779,825 | 2021-08 |
What was the administration route of drug 'HYDROCORTISONE'? | A case with hepatic immune-related adverse events caused by nivolumab exhibiting impaired accumulation of regulatory T cells.
Systemic administration of anti-programmed cell death 1 (PD-1) antibody (Ab) has achieved remarkable success in metastatic cancers. The blockade of PD-1-mediated signaling pathways sometimes cause immune-related adverse events (irAEs) due to restored anti-cancer as well as anti-self immunity. Although the liver is a preferential organ for irAEs, the immuno-pathogenesis underlying hepatic irAEs has been poorly understood. We describe a 57-year-old man with Stage IV lung cancer who underwent the first-line regimen composed of carboplatin and paclitaxel. Nivolumab treatment (3.2 mg/kg, every 3 weeks) was initiated when the disease progressed after the first chemotherapy. Sequential occurrence of irAEs involving the multiorgan systems was observed. He developed hepatic irAEs (Grade 3) after endocrine, lung, and cutaneous irAEs. Lobular hepatitis characterized by predominant infiltration of CD8+ T cells was seen in the liver biopsy specimens. Interestingly, defective accumulation of regulatory T cells (Tregs) expressing forkhead box protein P3 (FOXP3) was evident in this case with hepatic irAEs as compared with typical cases with autoimmune hepatitis. This case suggests that hepatic irAEs are characterized not only by lobular infiltration of CD8+ T cells but also by defective accumulation of FOXP3+ Tregs.
Introduction
A recent remarkable success of treating advanced cancer with immune check-point inhibitors (ICIs) highlight important roles that programmed cell death protein-1 (PD-1) and cytotoxic T lymphocyte-associated protein-4 (CTLA-4) play in the suppression of anti-cancer immune responses [1, 2]. Nivolumab and ipilimumab targeting PD-1 and CTLA-4, respectively, are the representative ICIs. These ICIs restore anti-cancer immune responses through neutralization of negative regulation mediated by PD-1 or CTLA-4-mediated signaling pathways [1, 2]. In fact, introduction of nivolumab and ipilimumab into clinical practice has improved the prognosis of advanced malignancies, especially malignant melanoma [1, 2].
Despite effective restorement of anti-cancer immunity by nivolumab and ipilimumab, the blockade of PD-1 and CTLA-4, both of which are negative regulators of adaptive and innate immunity, sometimes causes excessive immune reactions in a broad range of organs, called immune-related adverse events (irAEs) [3, 4]. Liver toxicity associated with ICIs occurs in around 5–10% of patients, [5] and thus, the liver is a preferential organ targeted by ICIs in parallel to the skin, colon, endocrine system, kidney, and lung [3, 4]. Although activation and expansion of T cells through lack of negative regulation by PD-1 and CTLA-4 is considered to underlie the immuno-pathogenesis of irAEs [3–5], molecular mechanisms accounting for the development of hepatic irAEs have been poorly understood. Regulatory T cells (Tregs) expressing forkhead box protein P3 (FOXP3) are a critical component of immune systems with pivotal roles not only in the maintenance of self-tolerance but also in the suppression of anti-cancer immunity [6]. Here, we report a case with hepatic irAEs exhibiting little accumulation of FOXP3-expressing Tregs into the liver. This case suggests possible involvement of Treg deficiency in the development of hepatic irAEs.
Case reports
A 51-year-old man without any history of autoimmune diseases was diagnosed as lung adenocarcinoma (p-T3N0M0, Stage IIb) and received thoracoscopic right pneumonectomy in July 2012. Follow-up computed tomography (CT), which was performed in March 2017, revealed recurrence of his lung cancer in the left lobe accompanied by mediastinal lymph node metastasis. At this time point, he was diagnosed as Stage IV lung adenocarcinoma (p-T3N1M1). His surgical specimen was negative for epidermal growth factor receptor (EGFR) mutation or anaplastic lymphoma kinase 1 (ALK1) fusion oncogene. According to the guideline for Stage IV lung adenocarcinoma with intact EGFR and ALK1 [7], he was initially treated with the first-line regimen composed of carboplatin and paclitaxel from April 2017 for 4 courses followed by paclitaxel maintenance therapy from July 2017 to October 2017. These initial courses of chemotherapy were not successful and his lung cancer was judged as progressive disease (PD) based on computed tomography findings. Nivolumab was introduced from August 2018 at a dose of 3.2 mg/kg every 3 weeks.
Various kinds of irAEs occurred after the treatment with nivolumab and the severity was graded based on the clinical practice guideline following the Common Terminology Criteria for Adverse Events [version 5.0] [8].His initial irAEs involved the endocrine system as shown by the appearance of general fatigue caused by destructive thyroiditis. A significant elevation of serum free T3 (fT3, 6.2 pg/mL, normal range, 2.3–4) and fT4 (fT4, 2.1 ng/dL, normal range, 0.9–1.7) levels accompanied by a markedly reduced level of thyroid stimulating hormone (TSH, 0.02 μIU/mL, normal range, 0.5–5) was seen in September 2018. Three months later, thyroid hormone tests clearly showed hypothyroidism characterized by reduced fT3 and fT4 levels with elevated TSH levels. Further examination of his endocrine system revealed reduced serum levels of cortisol (3.3 μg/dL, normal range 6.2–19.4) and adrenocorticotropic hormone (ACTH 1.3 pg/mL, normal range 7.3–63.3), which suggested the presence of primary adrenal insufficiency despite normal levels of blood sugar, sodium and potassium. Oral supplementation of hydrocortisone (15 mg/day) and thyroid hormone (25 μg/day) were started for G1 primary hypothyroidism and G2 primary adrenal insufficiency, respectively. In addition to these endocrine toxicities, interstitial pneumonia (G1) was detected in February 2019 and then administration of nivolumab was discontinued. Moreover, skin rash judged as G3 irAE developed in March 2019. Prednisolone (PSL, 40 mg/day) with tapering schedule 5 mg/2 weeks was started after the appearance of irAEs involving the endocrine system, lung, and skin.
Although improvement of skin rash was achieved after the initiation of PSL treatment, he developed liver injury as shown by a marked elevation of serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), and γ-glutamyltransferase (γGTP) (Table 1 and Fig. 1). Viral hepatitis was unlikely since viral markers for hepatitis A virus, hepatitis B virus, hepatitis C virus, cytomegalovirus, and Epstein–Barr virus were negative. Moreover, liver injury due to autoimmune hepatitis (AIH) or primary biliary cholangitis (PBC) was also unlikely as assessed by serum IgG levels and titers for anti-nuclear antibody (ANA) or anti-mitochondrial Ab. These blood examination data led us to consider the possibility of hepatic irAEs. No metastatic lesions were detected in the liver by abdominal contrast-enhanced CT. Moreover, magnetic resonance cholangiopancreatography did not reveal any abnormalities in the intrahepatic or extrahepatic bile ducts, suggesting that an immune-related cholangitis caused by ICIs was less likely [9]. To verify the diagnosis of hepatis irAEs, liver biopsy samples were subjected to hematoxylin and eosin (H&E) staining and immuno-histochemical analyses.Table 1 Laboratory data on admission
Hematology Blood chemistry Serological tests
WBC 6.270/μL TP 6.2 g/dL ANA (–)
RBC 346 × 104/μL Alb 3.4 g/dL AMA2 (–)
Hb 13.5 g/dL BUN 13 mg/dL IgG 697 mg/dL
Hct 39.0% Cr 0.79 mg/dL IgM 25 mg/dL
Plt 12.1 × 104/μL T-Bil 1.5 mg/dL IgE 337 IU/mL
Neutro 85.7% D-Bil 0.7 mg/dL Viral marker
Lympho 9.9% ALP 1039 U/L HBsAg (–)
Eosino 0.5% AMY 31 U/L HBsAb (–)
Endocrine LDH 679 U/L HBcAb (–)
ACTH 1.0 pg/mL AST 651 U/L HCVAb (–)
CS 6.2 μg/dL ALT 547 U/L HA-IgM (–)
TSH 1.22 μIU/mL γGTP 2718 U/L CMV-IgM (–)
FT4 1.1 ng/dL CRP 10.22 mg/dL EBVVCA-IgM (–)
Coagulation
PT 119.6%
INR 0.93
ACTH adrenocorticotropic hormone, CS cortisol, PT prothrombin time, INR international normalized ratio, AMA2 anti-mitochondrial antibody 2, ANA anti-nuclear antibody, CMV cytomegalovirus, EBV Epstein–Barr virus
Fig. 1 Clinical course of the patients. See the clinical presentation section of the text. ALT alanine aminotransferase, ALP alkaline phosphatase, AST aspartate aminotransferase, γGTP γ-glutamyltransferase, MMF mycophenolate mofetil, mPSL methylprednisolone, PSL prednisolone, UDCA ursodeoxycholic acid
Liver biopsy samples were subjected to H&E staining and immuno-histochemical analysis using mouse or rabbit anti-human CD3 antibody (Ab, Roche Diagnostics; Tokyo, Japan), CD4 Ab (Roche Diagnostics; Tokyo, Japan), CD8 Ab (Nichirei Bioscience; Tokyo, Japan), CD20 Ab (Roche Diagnostics; Tokyo, Japan), and FOXP3 Ab (Abcam; Cambridge, United Kingdom). Visualization of CD3+ T cells, CD4+ T cells, CD8+ T cells, CD20+ B cells, and FOXP3+ Tregs were performed using DakO-EnVision+ systems (Dako Japan, Tokyo, Japan) as previously described [10, 11]. The liver biopsy sample obtained from a typical patient with AIH (74-year-old female) was used as a disease control. Clinical parameters of this AIH patient were shown in Supplementary Table 1. As shown in Supplementary Table 1, serum levels of IgG and ANA titers were markedly elevated. Moreover, interface hepatitis accompanied by infiltration of plasma cells was evident. The AIH score proposed by international AIH group was 23 in this patient, and thus, this patient was diagnosed with definite AIH [12].
Although lobular as well as portal inflammation was seen in the liver specimens of this patients, immune cell infiltration was predominantly seen in the liver lobes (Fig. 2, 1st and 2nd line panels). Moreover, hyperplasia of the bile duct as well as lymphocyte infiltration into the interlobular bile duct was seen in the pathological examinations, suggesting cholestasis as well as hepatocellular injury is involved in the development of hepatic irAEs in this case [13]. These pathological findings together with elevations of serum transaminases and biliary enzymes indicated that hepatic irAEs of this case was considered to be a mixed type [13].Fig. 2 Immuno-histochemical analyses of liver biopsy specimens. Liver biopsy specimens obtained from this case with hepatic immune-related adverse effects (irAEs, 1st and 2nd line panels) and from patients with autoimmune hepatitis (AIH, 3rd and 4th line panels) were subjected to immuno-histochemical analyses using anti-CD3 Ab, anti-CD4 Ab, anti-CD8 Ab, anti-CD20 Ab, and anti-forkhead box p3 (FOXP3) Ab. Hematoxylin and eosin (H&E) staining of the portal and lobular areas (1st row). Infiltration of CD3+ T cells (2nd row), CD4+ T cells (3rd row), CD8+ T cells (4th row), CD20+ B cells (5th row), and FOXP3+ Treg cells (6th row) was visualized. Scale bar is 20 µm
Interface hepatitis accompanied by plasma cell infiltration was seen in the liver specimen with the AIH patient (Fig. 2, 3rd line panel). Thus, H&E staining in this case was compatible to hepatic irAEs rather than AIH since the former and latter disorders preferentially affect the liver lobes and portal tracts, respectively [5, 14].
We then performed characterization of immune cell infiltration in this case. As shown in Fig. 2, accumulation of CD3+ T cells was seen in the liver lobes of the patient with hepatic irAEs whereas that was seen in the portal areas of the patient with AIH. Subpopulation analysis of T cells showed predominant infiltration of CD8+ T cells rather than CD4+ T cells into the liver lobes in this case (Fig. 2, 1st line panel). AIH lesions were characterized by portal accumulation of both CD4+ and CD8+ T cells (Fig. 2, 4th line panel). Moreover, infiltration of CD20+ B cells was seen in the portal areas of AIH patients, but not those in this case. These immuno-histochemical analyses strongly suggest that liver injury arose from a manifestation of irAEs in that lesions are characterized by predominant accumulation of CD8+ T cells into the liver lobes [5]. Although Tregs expressing FOXP3 play major roles in the suppression of pro-inflammatory responses [15], their involvement in the development of hepatic irAEs has been poorly defined. Interestingly, accumulation of Tregs expressing FOXP3 was barely seen in the liver lobes of this case with hepatic irAEs whereas abundant infiltration of FOXP3+ Tregs was observed in the portal areas of the AIH patient (Fig. 2). Abundant infiltration of T cells expressing CD4, CD8, or FOXP3 was also seen in the other three cases with AIH in this study (data not shown). Taken together, these data suggest hepatic irAEs due to nivolumab might be characterized not only by predominant lobular infiltration of CD8+ T cells but also by little accumulation of FOXP3+ Tregs.
This patient was diagnosed as irAEs involving the endocrine system (G2), lung (G1), skin (G3), and the liver (G3). According to the guideline for hepatic irAEs [3], this patient was initially treated with intravenous administration of methyl PSL (mPSL, 500 mg/day) in combination with oral administration of mycophenolate mofetil (MMF, 200 mg/day, Fig. 1). mPSL was switched to oral administration of PSL (60 mg/day) with a tapering schedule as depicted in Fig. 1. His serum levels of transaminases became normalized 2 months after the treatment and then he was treated with oral administration of Tegafur/Gimeracil/Oteracil (120 mg/day) for advanced lung cancer.
Discussion
Restorement of anti-cancer immunity by ICIs has dramatically improved the prognosis of patients with metastatic cancers [1, 2]. However, the blockade of PD-1 or CTLA-4-mediated signaling pathways sometimes causes irAEs, which can affect almost every organ in the body [3, 4]. In this case, administration of nivolumab led to the development of destructive thyroiditis, primary adrenal insufficiency, interstitial pneumonia, skin eruption and liver injury. Given the fact that the endocrine systems, lung, skin, and liver are preferential organs for irAEs [3–5], this case may be considered as typical irAEs due to nivolumab.
The incidence of hepatic irAEs by nivolumab alone was reported to be 6.4% [16] and liver injury by nivolumab usually develops 8–12 weeks after the initial injection [17]. Lobular infiltration of CD8+ T cells is one of the most characteristic findings in hepatic irAEs [5, 18, 19]. Consistent with this, lobular rather than portal hepatitis accompanied by predominant accumulation of CD8+ T cells was seen in this case. In contrast, AIH lesions were characterized by interface hepatitis associated with infiltration of plasma cells, CD4+ T cells, and CD8+ T cells. Thus, AIH and hepatic irAEs are distinctive disease entities in terms of the location of inflammation and effector T cell subpopulations. It should be noted, however, that molecular mechanisms accounting for such pathological differences between these two disorders have been poorly understood. In this study, we tried to elucidate the immuno-pathogenesis underlying the development of hepatic irAEs. We found that hepatic irAE lesions, but not AIH lesions were characterized by defective accumulation of FOXP3-expressing Tregs. Therefore, we assume possible involvement of defective Treg function in the development of hepatic irAEs. However, we need to be cautious regarding the interpretation of impaired Treg accumulation into the liver of hepatic irAEs. Liver biopsy samples were obtained in the middle of PSL tapering schedule in this patient. Thus, we could not completely exclude a possibility that prior PSL treatment might have affected the function of Tregs.
As mentioned above, defective accumulation of Tregs is associated with the development of hepatic irAEs in the present case. One major question arising from the present case is the molecular link between the PD-1 blockade and Treg differentiation. In this regards, neonatal thymectomy (NTx) leads to the development of much severe hepatitis in PD-1-deficient mice than in PD-1-intact mice through concurrent loss of FOXP3-expressing Tregs [20, 21]. Moreover, transient FOXP3-expressing Treg depletion in combination with systemic administration of anti-PD-1 Ab successfully induced severe hepatic irAEs in orthotopic cancer mice [22]. Thus, these previous studies together with the present case suggest the idea that PD-1 blockade may promote the development of liver injury, i.e., hepatic irAEs, in the presence of defective Treg function. Since Tregs stably express cell-surface PD-1 [15], one might assume that neutralization of PD-1-mediated signaling pathways impair Treg function. In this regards, Asano et al. provide evidence that Tregs isolated from PD-1 deficient mice display enhanced apoptosis than those from PD-1-intact mice in the presence of low doses of IL-2, a crucial cytokine for Treg proliferation [23]. Therefore, it is likely that systemic administration of anti-PD-1 Ab reduces the number of Tregs due to enhanced apoptosis. Such defective proliferation and activation of Tregs caused by nivolumab might be involved in the development of multiorgan system irAEs involving the endocrine system, lung, skin, and the liver, as seen in this case. This idea is supported by the fact that loss of function mutations in FOXP3 causes autoimmune diseases affecting multiple organs, called IPEX syndrome [15]. Confirmation of this idea requires future studies addressing the function of FOXP3+ Tregs in patients with multiorgan system irAEs and solitary hepatic irAEs.
Another important question arising from this case is why lung, skin, and hepatic irAEs developed even after the withdrawal of nivolumab. In this regards, recent studies by Osa et al. provide evidence that the binding of nivolumab to cell-surface PD-1 can be detected by flow-cytometry around 6 months after the withdrawal of nivolumab [24]. Thus, such long-lasting neutralization of PD-1 may contribute to the development of irAEs even after the withdrawal of nivolumab.
The number of Tregs was greater in the liver of AIH than that of irAEs in this study. Based on this observation, we hypothesized that defective Treg function mediates hepatic irAEs. However, defective Treg function can also be involved in the development of AIH since impaired Treg function as assessed by the inhibition of effector T cell proliferation was demonstrated in AIH patients [25].
In conclusion, hepatic irAEs might be characterized not only by lobular infiltration of CD8+ T cells but also by defective accumulation of FOXP3+ Tregs. Lack of Treg-mediated immune suppression might underlie the immuno-pathogenesis of hepatic irAEs. Verification of this idea awaits further studies addressing a large number of hepatic irAEs and hepatic Treg function isolated from patients with this disorder.
Supplementary Information
Below is the link to the electronic supplementary material.Supplementary file1 (DOCX 17 KB)
Compliance with ethical standards
Conflict of interest
Ikue Sekai, Satoru Hagiwara, Tomohiro Watanabe and Masatoshi Kudo declare that they have no conflict of interest.
Human Rights
All procedures followed have been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments.
Informed Consent
Informed consent was obtained from all patients for being included in the study.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | Oral | DrugAdministrationRoute | CC BY | 33665689 | 19,779,825 | 2021-08 |
What was the dosage of drug 'CARBOPLATIN'? | A case with hepatic immune-related adverse events caused by nivolumab exhibiting impaired accumulation of regulatory T cells.
Systemic administration of anti-programmed cell death 1 (PD-1) antibody (Ab) has achieved remarkable success in metastatic cancers. The blockade of PD-1-mediated signaling pathways sometimes cause immune-related adverse events (irAEs) due to restored anti-cancer as well as anti-self immunity. Although the liver is a preferential organ for irAEs, the immuno-pathogenesis underlying hepatic irAEs has been poorly understood. We describe a 57-year-old man with Stage IV lung cancer who underwent the first-line regimen composed of carboplatin and paclitaxel. Nivolumab treatment (3.2 mg/kg, every 3 weeks) was initiated when the disease progressed after the first chemotherapy. Sequential occurrence of irAEs involving the multiorgan systems was observed. He developed hepatic irAEs (Grade 3) after endocrine, lung, and cutaneous irAEs. Lobular hepatitis characterized by predominant infiltration of CD8+ T cells was seen in the liver biopsy specimens. Interestingly, defective accumulation of regulatory T cells (Tregs) expressing forkhead box protein P3 (FOXP3) was evident in this case with hepatic irAEs as compared with typical cases with autoimmune hepatitis. This case suggests that hepatic irAEs are characterized not only by lobular infiltration of CD8+ T cells but also by defective accumulation of FOXP3+ Tregs.
Introduction
A recent remarkable success of treating advanced cancer with immune check-point inhibitors (ICIs) highlight important roles that programmed cell death protein-1 (PD-1) and cytotoxic T lymphocyte-associated protein-4 (CTLA-4) play in the suppression of anti-cancer immune responses [1, 2]. Nivolumab and ipilimumab targeting PD-1 and CTLA-4, respectively, are the representative ICIs. These ICIs restore anti-cancer immune responses through neutralization of negative regulation mediated by PD-1 or CTLA-4-mediated signaling pathways [1, 2]. In fact, introduction of nivolumab and ipilimumab into clinical practice has improved the prognosis of advanced malignancies, especially malignant melanoma [1, 2].
Despite effective restorement of anti-cancer immunity by nivolumab and ipilimumab, the blockade of PD-1 and CTLA-4, both of which are negative regulators of adaptive and innate immunity, sometimes causes excessive immune reactions in a broad range of organs, called immune-related adverse events (irAEs) [3, 4]. Liver toxicity associated with ICIs occurs in around 5–10% of patients, [5] and thus, the liver is a preferential organ targeted by ICIs in parallel to the skin, colon, endocrine system, kidney, and lung [3, 4]. Although activation and expansion of T cells through lack of negative regulation by PD-1 and CTLA-4 is considered to underlie the immuno-pathogenesis of irAEs [3–5], molecular mechanisms accounting for the development of hepatic irAEs have been poorly understood. Regulatory T cells (Tregs) expressing forkhead box protein P3 (FOXP3) are a critical component of immune systems with pivotal roles not only in the maintenance of self-tolerance but also in the suppression of anti-cancer immunity [6]. Here, we report a case with hepatic irAEs exhibiting little accumulation of FOXP3-expressing Tregs into the liver. This case suggests possible involvement of Treg deficiency in the development of hepatic irAEs.
Case reports
A 51-year-old man without any history of autoimmune diseases was diagnosed as lung adenocarcinoma (p-T3N0M0, Stage IIb) and received thoracoscopic right pneumonectomy in July 2012. Follow-up computed tomography (CT), which was performed in March 2017, revealed recurrence of his lung cancer in the left lobe accompanied by mediastinal lymph node metastasis. At this time point, he was diagnosed as Stage IV lung adenocarcinoma (p-T3N1M1). His surgical specimen was negative for epidermal growth factor receptor (EGFR) mutation or anaplastic lymphoma kinase 1 (ALK1) fusion oncogene. According to the guideline for Stage IV lung adenocarcinoma with intact EGFR and ALK1 [7], he was initially treated with the first-line regimen composed of carboplatin and paclitaxel from April 2017 for 4 courses followed by paclitaxel maintenance therapy from July 2017 to October 2017. These initial courses of chemotherapy were not successful and his lung cancer was judged as progressive disease (PD) based on computed tomography findings. Nivolumab was introduced from August 2018 at a dose of 3.2 mg/kg every 3 weeks.
Various kinds of irAEs occurred after the treatment with nivolumab and the severity was graded based on the clinical practice guideline following the Common Terminology Criteria for Adverse Events [version 5.0] [8].His initial irAEs involved the endocrine system as shown by the appearance of general fatigue caused by destructive thyroiditis. A significant elevation of serum free T3 (fT3, 6.2 pg/mL, normal range, 2.3–4) and fT4 (fT4, 2.1 ng/dL, normal range, 0.9–1.7) levels accompanied by a markedly reduced level of thyroid stimulating hormone (TSH, 0.02 μIU/mL, normal range, 0.5–5) was seen in September 2018. Three months later, thyroid hormone tests clearly showed hypothyroidism characterized by reduced fT3 and fT4 levels with elevated TSH levels. Further examination of his endocrine system revealed reduced serum levels of cortisol (3.3 μg/dL, normal range 6.2–19.4) and adrenocorticotropic hormone (ACTH 1.3 pg/mL, normal range 7.3–63.3), which suggested the presence of primary adrenal insufficiency despite normal levels of blood sugar, sodium and potassium. Oral supplementation of hydrocortisone (15 mg/day) and thyroid hormone (25 μg/day) were started for G1 primary hypothyroidism and G2 primary adrenal insufficiency, respectively. In addition to these endocrine toxicities, interstitial pneumonia (G1) was detected in February 2019 and then administration of nivolumab was discontinued. Moreover, skin rash judged as G3 irAE developed in March 2019. Prednisolone (PSL, 40 mg/day) with tapering schedule 5 mg/2 weeks was started after the appearance of irAEs involving the endocrine system, lung, and skin.
Although improvement of skin rash was achieved after the initiation of PSL treatment, he developed liver injury as shown by a marked elevation of serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), and γ-glutamyltransferase (γGTP) (Table 1 and Fig. 1). Viral hepatitis was unlikely since viral markers for hepatitis A virus, hepatitis B virus, hepatitis C virus, cytomegalovirus, and Epstein–Barr virus were negative. Moreover, liver injury due to autoimmune hepatitis (AIH) or primary biliary cholangitis (PBC) was also unlikely as assessed by serum IgG levels and titers for anti-nuclear antibody (ANA) or anti-mitochondrial Ab. These blood examination data led us to consider the possibility of hepatic irAEs. No metastatic lesions were detected in the liver by abdominal contrast-enhanced CT. Moreover, magnetic resonance cholangiopancreatography did not reveal any abnormalities in the intrahepatic or extrahepatic bile ducts, suggesting that an immune-related cholangitis caused by ICIs was less likely [9]. To verify the diagnosis of hepatis irAEs, liver biopsy samples were subjected to hematoxylin and eosin (H&E) staining and immuno-histochemical analyses.Table 1 Laboratory data on admission
Hematology Blood chemistry Serological tests
WBC 6.270/μL TP 6.2 g/dL ANA (–)
RBC 346 × 104/μL Alb 3.4 g/dL AMA2 (–)
Hb 13.5 g/dL BUN 13 mg/dL IgG 697 mg/dL
Hct 39.0% Cr 0.79 mg/dL IgM 25 mg/dL
Plt 12.1 × 104/μL T-Bil 1.5 mg/dL IgE 337 IU/mL
Neutro 85.7% D-Bil 0.7 mg/dL Viral marker
Lympho 9.9% ALP 1039 U/L HBsAg (–)
Eosino 0.5% AMY 31 U/L HBsAb (–)
Endocrine LDH 679 U/L HBcAb (–)
ACTH 1.0 pg/mL AST 651 U/L HCVAb (–)
CS 6.2 μg/dL ALT 547 U/L HA-IgM (–)
TSH 1.22 μIU/mL γGTP 2718 U/L CMV-IgM (–)
FT4 1.1 ng/dL CRP 10.22 mg/dL EBVVCA-IgM (–)
Coagulation
PT 119.6%
INR 0.93
ACTH adrenocorticotropic hormone, CS cortisol, PT prothrombin time, INR international normalized ratio, AMA2 anti-mitochondrial antibody 2, ANA anti-nuclear antibody, CMV cytomegalovirus, EBV Epstein–Barr virus
Fig. 1 Clinical course of the patients. See the clinical presentation section of the text. ALT alanine aminotransferase, ALP alkaline phosphatase, AST aspartate aminotransferase, γGTP γ-glutamyltransferase, MMF mycophenolate mofetil, mPSL methylprednisolone, PSL prednisolone, UDCA ursodeoxycholic acid
Liver biopsy samples were subjected to H&E staining and immuno-histochemical analysis using mouse or rabbit anti-human CD3 antibody (Ab, Roche Diagnostics; Tokyo, Japan), CD4 Ab (Roche Diagnostics; Tokyo, Japan), CD8 Ab (Nichirei Bioscience; Tokyo, Japan), CD20 Ab (Roche Diagnostics; Tokyo, Japan), and FOXP3 Ab (Abcam; Cambridge, United Kingdom). Visualization of CD3+ T cells, CD4+ T cells, CD8+ T cells, CD20+ B cells, and FOXP3+ Tregs were performed using DakO-EnVision+ systems (Dako Japan, Tokyo, Japan) as previously described [10, 11]. The liver biopsy sample obtained from a typical patient with AIH (74-year-old female) was used as a disease control. Clinical parameters of this AIH patient were shown in Supplementary Table 1. As shown in Supplementary Table 1, serum levels of IgG and ANA titers were markedly elevated. Moreover, interface hepatitis accompanied by infiltration of plasma cells was evident. The AIH score proposed by international AIH group was 23 in this patient, and thus, this patient was diagnosed with definite AIH [12].
Although lobular as well as portal inflammation was seen in the liver specimens of this patients, immune cell infiltration was predominantly seen in the liver lobes (Fig. 2, 1st and 2nd line panels). Moreover, hyperplasia of the bile duct as well as lymphocyte infiltration into the interlobular bile duct was seen in the pathological examinations, suggesting cholestasis as well as hepatocellular injury is involved in the development of hepatic irAEs in this case [13]. These pathological findings together with elevations of serum transaminases and biliary enzymes indicated that hepatic irAEs of this case was considered to be a mixed type [13].Fig. 2 Immuno-histochemical analyses of liver biopsy specimens. Liver biopsy specimens obtained from this case with hepatic immune-related adverse effects (irAEs, 1st and 2nd line panels) and from patients with autoimmune hepatitis (AIH, 3rd and 4th line panels) were subjected to immuno-histochemical analyses using anti-CD3 Ab, anti-CD4 Ab, anti-CD8 Ab, anti-CD20 Ab, and anti-forkhead box p3 (FOXP3) Ab. Hematoxylin and eosin (H&E) staining of the portal and lobular areas (1st row). Infiltration of CD3+ T cells (2nd row), CD4+ T cells (3rd row), CD8+ T cells (4th row), CD20+ B cells (5th row), and FOXP3+ Treg cells (6th row) was visualized. Scale bar is 20 µm
Interface hepatitis accompanied by plasma cell infiltration was seen in the liver specimen with the AIH patient (Fig. 2, 3rd line panel). Thus, H&E staining in this case was compatible to hepatic irAEs rather than AIH since the former and latter disorders preferentially affect the liver lobes and portal tracts, respectively [5, 14].
We then performed characterization of immune cell infiltration in this case. As shown in Fig. 2, accumulation of CD3+ T cells was seen in the liver lobes of the patient with hepatic irAEs whereas that was seen in the portal areas of the patient with AIH. Subpopulation analysis of T cells showed predominant infiltration of CD8+ T cells rather than CD4+ T cells into the liver lobes in this case (Fig. 2, 1st line panel). AIH lesions were characterized by portal accumulation of both CD4+ and CD8+ T cells (Fig. 2, 4th line panel). Moreover, infiltration of CD20+ B cells was seen in the portal areas of AIH patients, but not those in this case. These immuno-histochemical analyses strongly suggest that liver injury arose from a manifestation of irAEs in that lesions are characterized by predominant accumulation of CD8+ T cells into the liver lobes [5]. Although Tregs expressing FOXP3 play major roles in the suppression of pro-inflammatory responses [15], their involvement in the development of hepatic irAEs has been poorly defined. Interestingly, accumulation of Tregs expressing FOXP3 was barely seen in the liver lobes of this case with hepatic irAEs whereas abundant infiltration of FOXP3+ Tregs was observed in the portal areas of the AIH patient (Fig. 2). Abundant infiltration of T cells expressing CD4, CD8, or FOXP3 was also seen in the other three cases with AIH in this study (data not shown). Taken together, these data suggest hepatic irAEs due to nivolumab might be characterized not only by predominant lobular infiltration of CD8+ T cells but also by little accumulation of FOXP3+ Tregs.
This patient was diagnosed as irAEs involving the endocrine system (G2), lung (G1), skin (G3), and the liver (G3). According to the guideline for hepatic irAEs [3], this patient was initially treated with intravenous administration of methyl PSL (mPSL, 500 mg/day) in combination with oral administration of mycophenolate mofetil (MMF, 200 mg/day, Fig. 1). mPSL was switched to oral administration of PSL (60 mg/day) with a tapering schedule as depicted in Fig. 1. His serum levels of transaminases became normalized 2 months after the treatment and then he was treated with oral administration of Tegafur/Gimeracil/Oteracil (120 mg/day) for advanced lung cancer.
Discussion
Restorement of anti-cancer immunity by ICIs has dramatically improved the prognosis of patients with metastatic cancers [1, 2]. However, the blockade of PD-1 or CTLA-4-mediated signaling pathways sometimes causes irAEs, which can affect almost every organ in the body [3, 4]. In this case, administration of nivolumab led to the development of destructive thyroiditis, primary adrenal insufficiency, interstitial pneumonia, skin eruption and liver injury. Given the fact that the endocrine systems, lung, skin, and liver are preferential organs for irAEs [3–5], this case may be considered as typical irAEs due to nivolumab.
The incidence of hepatic irAEs by nivolumab alone was reported to be 6.4% [16] and liver injury by nivolumab usually develops 8–12 weeks after the initial injection [17]. Lobular infiltration of CD8+ T cells is one of the most characteristic findings in hepatic irAEs [5, 18, 19]. Consistent with this, lobular rather than portal hepatitis accompanied by predominant accumulation of CD8+ T cells was seen in this case. In contrast, AIH lesions were characterized by interface hepatitis associated with infiltration of plasma cells, CD4+ T cells, and CD8+ T cells. Thus, AIH and hepatic irAEs are distinctive disease entities in terms of the location of inflammation and effector T cell subpopulations. It should be noted, however, that molecular mechanisms accounting for such pathological differences between these two disorders have been poorly understood. In this study, we tried to elucidate the immuno-pathogenesis underlying the development of hepatic irAEs. We found that hepatic irAE lesions, but not AIH lesions were characterized by defective accumulation of FOXP3-expressing Tregs. Therefore, we assume possible involvement of defective Treg function in the development of hepatic irAEs. However, we need to be cautious regarding the interpretation of impaired Treg accumulation into the liver of hepatic irAEs. Liver biopsy samples were obtained in the middle of PSL tapering schedule in this patient. Thus, we could not completely exclude a possibility that prior PSL treatment might have affected the function of Tregs.
As mentioned above, defective accumulation of Tregs is associated with the development of hepatic irAEs in the present case. One major question arising from the present case is the molecular link between the PD-1 blockade and Treg differentiation. In this regards, neonatal thymectomy (NTx) leads to the development of much severe hepatitis in PD-1-deficient mice than in PD-1-intact mice through concurrent loss of FOXP3-expressing Tregs [20, 21]. Moreover, transient FOXP3-expressing Treg depletion in combination with systemic administration of anti-PD-1 Ab successfully induced severe hepatic irAEs in orthotopic cancer mice [22]. Thus, these previous studies together with the present case suggest the idea that PD-1 blockade may promote the development of liver injury, i.e., hepatic irAEs, in the presence of defective Treg function. Since Tregs stably express cell-surface PD-1 [15], one might assume that neutralization of PD-1-mediated signaling pathways impair Treg function. In this regards, Asano et al. provide evidence that Tregs isolated from PD-1 deficient mice display enhanced apoptosis than those from PD-1-intact mice in the presence of low doses of IL-2, a crucial cytokine for Treg proliferation [23]. Therefore, it is likely that systemic administration of anti-PD-1 Ab reduces the number of Tregs due to enhanced apoptosis. Such defective proliferation and activation of Tregs caused by nivolumab might be involved in the development of multiorgan system irAEs involving the endocrine system, lung, skin, and the liver, as seen in this case. This idea is supported by the fact that loss of function mutations in FOXP3 causes autoimmune diseases affecting multiple organs, called IPEX syndrome [15]. Confirmation of this idea requires future studies addressing the function of FOXP3+ Tregs in patients with multiorgan system irAEs and solitary hepatic irAEs.
Another important question arising from this case is why lung, skin, and hepatic irAEs developed even after the withdrawal of nivolumab. In this regards, recent studies by Osa et al. provide evidence that the binding of nivolumab to cell-surface PD-1 can be detected by flow-cytometry around 6 months after the withdrawal of nivolumab [24]. Thus, such long-lasting neutralization of PD-1 may contribute to the development of irAEs even after the withdrawal of nivolumab.
The number of Tregs was greater in the liver of AIH than that of irAEs in this study. Based on this observation, we hypothesized that defective Treg function mediates hepatic irAEs. However, defective Treg function can also be involved in the development of AIH since impaired Treg function as assessed by the inhibition of effector T cell proliferation was demonstrated in AIH patients [25].
In conclusion, hepatic irAEs might be characterized not only by lobular infiltration of CD8+ T cells but also by defective accumulation of FOXP3+ Tregs. Lack of Treg-mediated immune suppression might underlie the immuno-pathogenesis of hepatic irAEs. Verification of this idea awaits further studies addressing a large number of hepatic irAEs and hepatic Treg function isolated from patients with this disorder.
Supplementary Information
Below is the link to the electronic supplementary material.Supplementary file1 (DOCX 17 KB)
Compliance with ethical standards
Conflict of interest
Ikue Sekai, Satoru Hagiwara, Tomohiro Watanabe and Masatoshi Kudo declare that they have no conflict of interest.
Human Rights
All procedures followed have been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments.
Informed Consent
Informed consent was obtained from all patients for being included in the study.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | RECEIVED 4 COURSES | DrugDosageText | CC BY | 33665689 | 19,775,058 | 2021-08 |
What was the dosage of drug 'HYDROCORTISONE'? | A case with hepatic immune-related adverse events caused by nivolumab exhibiting impaired accumulation of regulatory T cells.
Systemic administration of anti-programmed cell death 1 (PD-1) antibody (Ab) has achieved remarkable success in metastatic cancers. The blockade of PD-1-mediated signaling pathways sometimes cause immune-related adverse events (irAEs) due to restored anti-cancer as well as anti-self immunity. Although the liver is a preferential organ for irAEs, the immuno-pathogenesis underlying hepatic irAEs has been poorly understood. We describe a 57-year-old man with Stage IV lung cancer who underwent the first-line regimen composed of carboplatin and paclitaxel. Nivolumab treatment (3.2 mg/kg, every 3 weeks) was initiated when the disease progressed after the first chemotherapy. Sequential occurrence of irAEs involving the multiorgan systems was observed. He developed hepatic irAEs (Grade 3) after endocrine, lung, and cutaneous irAEs. Lobular hepatitis characterized by predominant infiltration of CD8+ T cells was seen in the liver biopsy specimens. Interestingly, defective accumulation of regulatory T cells (Tregs) expressing forkhead box protein P3 (FOXP3) was evident in this case with hepatic irAEs as compared with typical cases with autoimmune hepatitis. This case suggests that hepatic irAEs are characterized not only by lobular infiltration of CD8+ T cells but also by defective accumulation of FOXP3+ Tregs.
Introduction
A recent remarkable success of treating advanced cancer with immune check-point inhibitors (ICIs) highlight important roles that programmed cell death protein-1 (PD-1) and cytotoxic T lymphocyte-associated protein-4 (CTLA-4) play in the suppression of anti-cancer immune responses [1, 2]. Nivolumab and ipilimumab targeting PD-1 and CTLA-4, respectively, are the representative ICIs. These ICIs restore anti-cancer immune responses through neutralization of negative regulation mediated by PD-1 or CTLA-4-mediated signaling pathways [1, 2]. In fact, introduction of nivolumab and ipilimumab into clinical practice has improved the prognosis of advanced malignancies, especially malignant melanoma [1, 2].
Despite effective restorement of anti-cancer immunity by nivolumab and ipilimumab, the blockade of PD-1 and CTLA-4, both of which are negative regulators of adaptive and innate immunity, sometimes causes excessive immune reactions in a broad range of organs, called immune-related adverse events (irAEs) [3, 4]. Liver toxicity associated with ICIs occurs in around 5–10% of patients, [5] and thus, the liver is a preferential organ targeted by ICIs in parallel to the skin, colon, endocrine system, kidney, and lung [3, 4]. Although activation and expansion of T cells through lack of negative regulation by PD-1 and CTLA-4 is considered to underlie the immuno-pathogenesis of irAEs [3–5], molecular mechanisms accounting for the development of hepatic irAEs have been poorly understood. Regulatory T cells (Tregs) expressing forkhead box protein P3 (FOXP3) are a critical component of immune systems with pivotal roles not only in the maintenance of self-tolerance but also in the suppression of anti-cancer immunity [6]. Here, we report a case with hepatic irAEs exhibiting little accumulation of FOXP3-expressing Tregs into the liver. This case suggests possible involvement of Treg deficiency in the development of hepatic irAEs.
Case reports
A 51-year-old man without any history of autoimmune diseases was diagnosed as lung adenocarcinoma (p-T3N0M0, Stage IIb) and received thoracoscopic right pneumonectomy in July 2012. Follow-up computed tomography (CT), which was performed in March 2017, revealed recurrence of his lung cancer in the left lobe accompanied by mediastinal lymph node metastasis. At this time point, he was diagnosed as Stage IV lung adenocarcinoma (p-T3N1M1). His surgical specimen was negative for epidermal growth factor receptor (EGFR) mutation or anaplastic lymphoma kinase 1 (ALK1) fusion oncogene. According to the guideline for Stage IV lung adenocarcinoma with intact EGFR and ALK1 [7], he was initially treated with the first-line regimen composed of carboplatin and paclitaxel from April 2017 for 4 courses followed by paclitaxel maintenance therapy from July 2017 to October 2017. These initial courses of chemotherapy were not successful and his lung cancer was judged as progressive disease (PD) based on computed tomography findings. Nivolumab was introduced from August 2018 at a dose of 3.2 mg/kg every 3 weeks.
Various kinds of irAEs occurred after the treatment with nivolumab and the severity was graded based on the clinical practice guideline following the Common Terminology Criteria for Adverse Events [version 5.0] [8].His initial irAEs involved the endocrine system as shown by the appearance of general fatigue caused by destructive thyroiditis. A significant elevation of serum free T3 (fT3, 6.2 pg/mL, normal range, 2.3–4) and fT4 (fT4, 2.1 ng/dL, normal range, 0.9–1.7) levels accompanied by a markedly reduced level of thyroid stimulating hormone (TSH, 0.02 μIU/mL, normal range, 0.5–5) was seen in September 2018. Three months later, thyroid hormone tests clearly showed hypothyroidism characterized by reduced fT3 and fT4 levels with elevated TSH levels. Further examination of his endocrine system revealed reduced serum levels of cortisol (3.3 μg/dL, normal range 6.2–19.4) and adrenocorticotropic hormone (ACTH 1.3 pg/mL, normal range 7.3–63.3), which suggested the presence of primary adrenal insufficiency despite normal levels of blood sugar, sodium and potassium. Oral supplementation of hydrocortisone (15 mg/day) and thyroid hormone (25 μg/day) were started for G1 primary hypothyroidism and G2 primary adrenal insufficiency, respectively. In addition to these endocrine toxicities, interstitial pneumonia (G1) was detected in February 2019 and then administration of nivolumab was discontinued. Moreover, skin rash judged as G3 irAE developed in March 2019. Prednisolone (PSL, 40 mg/day) with tapering schedule 5 mg/2 weeks was started after the appearance of irAEs involving the endocrine system, lung, and skin.
Although improvement of skin rash was achieved after the initiation of PSL treatment, he developed liver injury as shown by a marked elevation of serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), and γ-glutamyltransferase (γGTP) (Table 1 and Fig. 1). Viral hepatitis was unlikely since viral markers for hepatitis A virus, hepatitis B virus, hepatitis C virus, cytomegalovirus, and Epstein–Barr virus were negative. Moreover, liver injury due to autoimmune hepatitis (AIH) or primary biliary cholangitis (PBC) was also unlikely as assessed by serum IgG levels and titers for anti-nuclear antibody (ANA) or anti-mitochondrial Ab. These blood examination data led us to consider the possibility of hepatic irAEs. No metastatic lesions were detected in the liver by abdominal contrast-enhanced CT. Moreover, magnetic resonance cholangiopancreatography did not reveal any abnormalities in the intrahepatic or extrahepatic bile ducts, suggesting that an immune-related cholangitis caused by ICIs was less likely [9]. To verify the diagnosis of hepatis irAEs, liver biopsy samples were subjected to hematoxylin and eosin (H&E) staining and immuno-histochemical analyses.Table 1 Laboratory data on admission
Hematology Blood chemistry Serological tests
WBC 6.270/μL TP 6.2 g/dL ANA (–)
RBC 346 × 104/μL Alb 3.4 g/dL AMA2 (–)
Hb 13.5 g/dL BUN 13 mg/dL IgG 697 mg/dL
Hct 39.0% Cr 0.79 mg/dL IgM 25 mg/dL
Plt 12.1 × 104/μL T-Bil 1.5 mg/dL IgE 337 IU/mL
Neutro 85.7% D-Bil 0.7 mg/dL Viral marker
Lympho 9.9% ALP 1039 U/L HBsAg (–)
Eosino 0.5% AMY 31 U/L HBsAb (–)
Endocrine LDH 679 U/L HBcAb (–)
ACTH 1.0 pg/mL AST 651 U/L HCVAb (–)
CS 6.2 μg/dL ALT 547 U/L HA-IgM (–)
TSH 1.22 μIU/mL γGTP 2718 U/L CMV-IgM (–)
FT4 1.1 ng/dL CRP 10.22 mg/dL EBVVCA-IgM (–)
Coagulation
PT 119.6%
INR 0.93
ACTH adrenocorticotropic hormone, CS cortisol, PT prothrombin time, INR international normalized ratio, AMA2 anti-mitochondrial antibody 2, ANA anti-nuclear antibody, CMV cytomegalovirus, EBV Epstein–Barr virus
Fig. 1 Clinical course of the patients. See the clinical presentation section of the text. ALT alanine aminotransferase, ALP alkaline phosphatase, AST aspartate aminotransferase, γGTP γ-glutamyltransferase, MMF mycophenolate mofetil, mPSL methylprednisolone, PSL prednisolone, UDCA ursodeoxycholic acid
Liver biopsy samples were subjected to H&E staining and immuno-histochemical analysis using mouse or rabbit anti-human CD3 antibody (Ab, Roche Diagnostics; Tokyo, Japan), CD4 Ab (Roche Diagnostics; Tokyo, Japan), CD8 Ab (Nichirei Bioscience; Tokyo, Japan), CD20 Ab (Roche Diagnostics; Tokyo, Japan), and FOXP3 Ab (Abcam; Cambridge, United Kingdom). Visualization of CD3+ T cells, CD4+ T cells, CD8+ T cells, CD20+ B cells, and FOXP3+ Tregs were performed using DakO-EnVision+ systems (Dako Japan, Tokyo, Japan) as previously described [10, 11]. The liver biopsy sample obtained from a typical patient with AIH (74-year-old female) was used as a disease control. Clinical parameters of this AIH patient were shown in Supplementary Table 1. As shown in Supplementary Table 1, serum levels of IgG and ANA titers were markedly elevated. Moreover, interface hepatitis accompanied by infiltration of plasma cells was evident. The AIH score proposed by international AIH group was 23 in this patient, and thus, this patient was diagnosed with definite AIH [12].
Although lobular as well as portal inflammation was seen in the liver specimens of this patients, immune cell infiltration was predominantly seen in the liver lobes (Fig. 2, 1st and 2nd line panels). Moreover, hyperplasia of the bile duct as well as lymphocyte infiltration into the interlobular bile duct was seen in the pathological examinations, suggesting cholestasis as well as hepatocellular injury is involved in the development of hepatic irAEs in this case [13]. These pathological findings together with elevations of serum transaminases and biliary enzymes indicated that hepatic irAEs of this case was considered to be a mixed type [13].Fig. 2 Immuno-histochemical analyses of liver biopsy specimens. Liver biopsy specimens obtained from this case with hepatic immune-related adverse effects (irAEs, 1st and 2nd line panels) and from patients with autoimmune hepatitis (AIH, 3rd and 4th line panels) were subjected to immuno-histochemical analyses using anti-CD3 Ab, anti-CD4 Ab, anti-CD8 Ab, anti-CD20 Ab, and anti-forkhead box p3 (FOXP3) Ab. Hematoxylin and eosin (H&E) staining of the portal and lobular areas (1st row). Infiltration of CD3+ T cells (2nd row), CD4+ T cells (3rd row), CD8+ T cells (4th row), CD20+ B cells (5th row), and FOXP3+ Treg cells (6th row) was visualized. Scale bar is 20 µm
Interface hepatitis accompanied by plasma cell infiltration was seen in the liver specimen with the AIH patient (Fig. 2, 3rd line panel). Thus, H&E staining in this case was compatible to hepatic irAEs rather than AIH since the former and latter disorders preferentially affect the liver lobes and portal tracts, respectively [5, 14].
We then performed characterization of immune cell infiltration in this case. As shown in Fig. 2, accumulation of CD3+ T cells was seen in the liver lobes of the patient with hepatic irAEs whereas that was seen in the portal areas of the patient with AIH. Subpopulation analysis of T cells showed predominant infiltration of CD8+ T cells rather than CD4+ T cells into the liver lobes in this case (Fig. 2, 1st line panel). AIH lesions were characterized by portal accumulation of both CD4+ and CD8+ T cells (Fig. 2, 4th line panel). Moreover, infiltration of CD20+ B cells was seen in the portal areas of AIH patients, but not those in this case. These immuno-histochemical analyses strongly suggest that liver injury arose from a manifestation of irAEs in that lesions are characterized by predominant accumulation of CD8+ T cells into the liver lobes [5]. Although Tregs expressing FOXP3 play major roles in the suppression of pro-inflammatory responses [15], their involvement in the development of hepatic irAEs has been poorly defined. Interestingly, accumulation of Tregs expressing FOXP3 was barely seen in the liver lobes of this case with hepatic irAEs whereas abundant infiltration of FOXP3+ Tregs was observed in the portal areas of the AIH patient (Fig. 2). Abundant infiltration of T cells expressing CD4, CD8, or FOXP3 was also seen in the other three cases with AIH in this study (data not shown). Taken together, these data suggest hepatic irAEs due to nivolumab might be characterized not only by predominant lobular infiltration of CD8+ T cells but also by little accumulation of FOXP3+ Tregs.
This patient was diagnosed as irAEs involving the endocrine system (G2), lung (G1), skin (G3), and the liver (G3). According to the guideline for hepatic irAEs [3], this patient was initially treated with intravenous administration of methyl PSL (mPSL, 500 mg/day) in combination with oral administration of mycophenolate mofetil (MMF, 200 mg/day, Fig. 1). mPSL was switched to oral administration of PSL (60 mg/day) with a tapering schedule as depicted in Fig. 1. His serum levels of transaminases became normalized 2 months after the treatment and then he was treated with oral administration of Tegafur/Gimeracil/Oteracil (120 mg/day) for advanced lung cancer.
Discussion
Restorement of anti-cancer immunity by ICIs has dramatically improved the prognosis of patients with metastatic cancers [1, 2]. However, the blockade of PD-1 or CTLA-4-mediated signaling pathways sometimes causes irAEs, which can affect almost every organ in the body [3, 4]. In this case, administration of nivolumab led to the development of destructive thyroiditis, primary adrenal insufficiency, interstitial pneumonia, skin eruption and liver injury. Given the fact that the endocrine systems, lung, skin, and liver are preferential organs for irAEs [3–5], this case may be considered as typical irAEs due to nivolumab.
The incidence of hepatic irAEs by nivolumab alone was reported to be 6.4% [16] and liver injury by nivolumab usually develops 8–12 weeks after the initial injection [17]. Lobular infiltration of CD8+ T cells is one of the most characteristic findings in hepatic irAEs [5, 18, 19]. Consistent with this, lobular rather than portal hepatitis accompanied by predominant accumulation of CD8+ T cells was seen in this case. In contrast, AIH lesions were characterized by interface hepatitis associated with infiltration of plasma cells, CD4+ T cells, and CD8+ T cells. Thus, AIH and hepatic irAEs are distinctive disease entities in terms of the location of inflammation and effector T cell subpopulations. It should be noted, however, that molecular mechanisms accounting for such pathological differences between these two disorders have been poorly understood. In this study, we tried to elucidate the immuno-pathogenesis underlying the development of hepatic irAEs. We found that hepatic irAE lesions, but not AIH lesions were characterized by defective accumulation of FOXP3-expressing Tregs. Therefore, we assume possible involvement of defective Treg function in the development of hepatic irAEs. However, we need to be cautious regarding the interpretation of impaired Treg accumulation into the liver of hepatic irAEs. Liver biopsy samples were obtained in the middle of PSL tapering schedule in this patient. Thus, we could not completely exclude a possibility that prior PSL treatment might have affected the function of Tregs.
As mentioned above, defective accumulation of Tregs is associated with the development of hepatic irAEs in the present case. One major question arising from the present case is the molecular link between the PD-1 blockade and Treg differentiation. In this regards, neonatal thymectomy (NTx) leads to the development of much severe hepatitis in PD-1-deficient mice than in PD-1-intact mice through concurrent loss of FOXP3-expressing Tregs [20, 21]. Moreover, transient FOXP3-expressing Treg depletion in combination with systemic administration of anti-PD-1 Ab successfully induced severe hepatic irAEs in orthotopic cancer mice [22]. Thus, these previous studies together with the present case suggest the idea that PD-1 blockade may promote the development of liver injury, i.e., hepatic irAEs, in the presence of defective Treg function. Since Tregs stably express cell-surface PD-1 [15], one might assume that neutralization of PD-1-mediated signaling pathways impair Treg function. In this regards, Asano et al. provide evidence that Tregs isolated from PD-1 deficient mice display enhanced apoptosis than those from PD-1-intact mice in the presence of low doses of IL-2, a crucial cytokine for Treg proliferation [23]. Therefore, it is likely that systemic administration of anti-PD-1 Ab reduces the number of Tregs due to enhanced apoptosis. Such defective proliferation and activation of Tregs caused by nivolumab might be involved in the development of multiorgan system irAEs involving the endocrine system, lung, skin, and the liver, as seen in this case. This idea is supported by the fact that loss of function mutations in FOXP3 causes autoimmune diseases affecting multiple organs, called IPEX syndrome [15]. Confirmation of this idea requires future studies addressing the function of FOXP3+ Tregs in patients with multiorgan system irAEs and solitary hepatic irAEs.
Another important question arising from this case is why lung, skin, and hepatic irAEs developed even after the withdrawal of nivolumab. In this regards, recent studies by Osa et al. provide evidence that the binding of nivolumab to cell-surface PD-1 can be detected by flow-cytometry around 6 months after the withdrawal of nivolumab [24]. Thus, such long-lasting neutralization of PD-1 may contribute to the development of irAEs even after the withdrawal of nivolumab.
The number of Tregs was greater in the liver of AIH than that of irAEs in this study. Based on this observation, we hypothesized that defective Treg function mediates hepatic irAEs. However, defective Treg function can also be involved in the development of AIH since impaired Treg function as assessed by the inhibition of effector T cell proliferation was demonstrated in AIH patients [25].
In conclusion, hepatic irAEs might be characterized not only by lobular infiltration of CD8+ T cells but also by defective accumulation of FOXP3+ Tregs. Lack of Treg-mediated immune suppression might underlie the immuno-pathogenesis of hepatic irAEs. Verification of this idea awaits further studies addressing a large number of hepatic irAEs and hepatic Treg function isolated from patients with this disorder.
Supplementary Information
Below is the link to the electronic supplementary material.Supplementary file1 (DOCX 17 KB)
Compliance with ethical standards
Conflict of interest
Ikue Sekai, Satoru Hagiwara, Tomohiro Watanabe and Masatoshi Kudo declare that they have no conflict of interest.
Human Rights
All procedures followed have been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments.
Informed Consent
Informed consent was obtained from all patients for being included in the study.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | 15 MILLIGRAM DAILY; | DrugDosageText | CC BY | 33665689 | 19,779,825 | 2021-08 |
What was the dosage of drug 'PACLITAXEL'? | A case with hepatic immune-related adverse events caused by nivolumab exhibiting impaired accumulation of regulatory T cells.
Systemic administration of anti-programmed cell death 1 (PD-1) antibody (Ab) has achieved remarkable success in metastatic cancers. The blockade of PD-1-mediated signaling pathways sometimes cause immune-related adverse events (irAEs) due to restored anti-cancer as well as anti-self immunity. Although the liver is a preferential organ for irAEs, the immuno-pathogenesis underlying hepatic irAEs has been poorly understood. We describe a 57-year-old man with Stage IV lung cancer who underwent the first-line regimen composed of carboplatin and paclitaxel. Nivolumab treatment (3.2 mg/kg, every 3 weeks) was initiated when the disease progressed after the first chemotherapy. Sequential occurrence of irAEs involving the multiorgan systems was observed. He developed hepatic irAEs (Grade 3) after endocrine, lung, and cutaneous irAEs. Lobular hepatitis characterized by predominant infiltration of CD8+ T cells was seen in the liver biopsy specimens. Interestingly, defective accumulation of regulatory T cells (Tregs) expressing forkhead box protein P3 (FOXP3) was evident in this case with hepatic irAEs as compared with typical cases with autoimmune hepatitis. This case suggests that hepatic irAEs are characterized not only by lobular infiltration of CD8+ T cells but also by defective accumulation of FOXP3+ Tregs.
Introduction
A recent remarkable success of treating advanced cancer with immune check-point inhibitors (ICIs) highlight important roles that programmed cell death protein-1 (PD-1) and cytotoxic T lymphocyte-associated protein-4 (CTLA-4) play in the suppression of anti-cancer immune responses [1, 2]. Nivolumab and ipilimumab targeting PD-1 and CTLA-4, respectively, are the representative ICIs. These ICIs restore anti-cancer immune responses through neutralization of negative regulation mediated by PD-1 or CTLA-4-mediated signaling pathways [1, 2]. In fact, introduction of nivolumab and ipilimumab into clinical practice has improved the prognosis of advanced malignancies, especially malignant melanoma [1, 2].
Despite effective restorement of anti-cancer immunity by nivolumab and ipilimumab, the blockade of PD-1 and CTLA-4, both of which are negative regulators of adaptive and innate immunity, sometimes causes excessive immune reactions in a broad range of organs, called immune-related adverse events (irAEs) [3, 4]. Liver toxicity associated with ICIs occurs in around 5–10% of patients, [5] and thus, the liver is a preferential organ targeted by ICIs in parallel to the skin, colon, endocrine system, kidney, and lung [3, 4]. Although activation and expansion of T cells through lack of negative regulation by PD-1 and CTLA-4 is considered to underlie the immuno-pathogenesis of irAEs [3–5], molecular mechanisms accounting for the development of hepatic irAEs have been poorly understood. Regulatory T cells (Tregs) expressing forkhead box protein P3 (FOXP3) are a critical component of immune systems with pivotal roles not only in the maintenance of self-tolerance but also in the suppression of anti-cancer immunity [6]. Here, we report a case with hepatic irAEs exhibiting little accumulation of FOXP3-expressing Tregs into the liver. This case suggests possible involvement of Treg deficiency in the development of hepatic irAEs.
Case reports
A 51-year-old man without any history of autoimmune diseases was diagnosed as lung adenocarcinoma (p-T3N0M0, Stage IIb) and received thoracoscopic right pneumonectomy in July 2012. Follow-up computed tomography (CT), which was performed in March 2017, revealed recurrence of his lung cancer in the left lobe accompanied by mediastinal lymph node metastasis. At this time point, he was diagnosed as Stage IV lung adenocarcinoma (p-T3N1M1). His surgical specimen was negative for epidermal growth factor receptor (EGFR) mutation or anaplastic lymphoma kinase 1 (ALK1) fusion oncogene. According to the guideline for Stage IV lung adenocarcinoma with intact EGFR and ALK1 [7], he was initially treated with the first-line regimen composed of carboplatin and paclitaxel from April 2017 for 4 courses followed by paclitaxel maintenance therapy from July 2017 to October 2017. These initial courses of chemotherapy were not successful and his lung cancer was judged as progressive disease (PD) based on computed tomography findings. Nivolumab was introduced from August 2018 at a dose of 3.2 mg/kg every 3 weeks.
Various kinds of irAEs occurred after the treatment with nivolumab and the severity was graded based on the clinical practice guideline following the Common Terminology Criteria for Adverse Events [version 5.0] [8].His initial irAEs involved the endocrine system as shown by the appearance of general fatigue caused by destructive thyroiditis. A significant elevation of serum free T3 (fT3, 6.2 pg/mL, normal range, 2.3–4) and fT4 (fT4, 2.1 ng/dL, normal range, 0.9–1.7) levels accompanied by a markedly reduced level of thyroid stimulating hormone (TSH, 0.02 μIU/mL, normal range, 0.5–5) was seen in September 2018. Three months later, thyroid hormone tests clearly showed hypothyroidism characterized by reduced fT3 and fT4 levels with elevated TSH levels. Further examination of his endocrine system revealed reduced serum levels of cortisol (3.3 μg/dL, normal range 6.2–19.4) and adrenocorticotropic hormone (ACTH 1.3 pg/mL, normal range 7.3–63.3), which suggested the presence of primary adrenal insufficiency despite normal levels of blood sugar, sodium and potassium. Oral supplementation of hydrocortisone (15 mg/day) and thyroid hormone (25 μg/day) were started for G1 primary hypothyroidism and G2 primary adrenal insufficiency, respectively. In addition to these endocrine toxicities, interstitial pneumonia (G1) was detected in February 2019 and then administration of nivolumab was discontinued. Moreover, skin rash judged as G3 irAE developed in March 2019. Prednisolone (PSL, 40 mg/day) with tapering schedule 5 mg/2 weeks was started after the appearance of irAEs involving the endocrine system, lung, and skin.
Although improvement of skin rash was achieved after the initiation of PSL treatment, he developed liver injury as shown by a marked elevation of serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), and γ-glutamyltransferase (γGTP) (Table 1 and Fig. 1). Viral hepatitis was unlikely since viral markers for hepatitis A virus, hepatitis B virus, hepatitis C virus, cytomegalovirus, and Epstein–Barr virus were negative. Moreover, liver injury due to autoimmune hepatitis (AIH) or primary biliary cholangitis (PBC) was also unlikely as assessed by serum IgG levels and titers for anti-nuclear antibody (ANA) or anti-mitochondrial Ab. These blood examination data led us to consider the possibility of hepatic irAEs. No metastatic lesions were detected in the liver by abdominal contrast-enhanced CT. Moreover, magnetic resonance cholangiopancreatography did not reveal any abnormalities in the intrahepatic or extrahepatic bile ducts, suggesting that an immune-related cholangitis caused by ICIs was less likely [9]. To verify the diagnosis of hepatis irAEs, liver biopsy samples were subjected to hematoxylin and eosin (H&E) staining and immuno-histochemical analyses.Table 1 Laboratory data on admission
Hematology Blood chemistry Serological tests
WBC 6.270/μL TP 6.2 g/dL ANA (–)
RBC 346 × 104/μL Alb 3.4 g/dL AMA2 (–)
Hb 13.5 g/dL BUN 13 mg/dL IgG 697 mg/dL
Hct 39.0% Cr 0.79 mg/dL IgM 25 mg/dL
Plt 12.1 × 104/μL T-Bil 1.5 mg/dL IgE 337 IU/mL
Neutro 85.7% D-Bil 0.7 mg/dL Viral marker
Lympho 9.9% ALP 1039 U/L HBsAg (–)
Eosino 0.5% AMY 31 U/L HBsAb (–)
Endocrine LDH 679 U/L HBcAb (–)
ACTH 1.0 pg/mL AST 651 U/L HCVAb (–)
CS 6.2 μg/dL ALT 547 U/L HA-IgM (–)
TSH 1.22 μIU/mL γGTP 2718 U/L CMV-IgM (–)
FT4 1.1 ng/dL CRP 10.22 mg/dL EBVVCA-IgM (–)
Coagulation
PT 119.6%
INR 0.93
ACTH adrenocorticotropic hormone, CS cortisol, PT prothrombin time, INR international normalized ratio, AMA2 anti-mitochondrial antibody 2, ANA anti-nuclear antibody, CMV cytomegalovirus, EBV Epstein–Barr virus
Fig. 1 Clinical course of the patients. See the clinical presentation section of the text. ALT alanine aminotransferase, ALP alkaline phosphatase, AST aspartate aminotransferase, γGTP γ-glutamyltransferase, MMF mycophenolate mofetil, mPSL methylprednisolone, PSL prednisolone, UDCA ursodeoxycholic acid
Liver biopsy samples were subjected to H&E staining and immuno-histochemical analysis using mouse or rabbit anti-human CD3 antibody (Ab, Roche Diagnostics; Tokyo, Japan), CD4 Ab (Roche Diagnostics; Tokyo, Japan), CD8 Ab (Nichirei Bioscience; Tokyo, Japan), CD20 Ab (Roche Diagnostics; Tokyo, Japan), and FOXP3 Ab (Abcam; Cambridge, United Kingdom). Visualization of CD3+ T cells, CD4+ T cells, CD8+ T cells, CD20+ B cells, and FOXP3+ Tregs were performed using DakO-EnVision+ systems (Dako Japan, Tokyo, Japan) as previously described [10, 11]. The liver biopsy sample obtained from a typical patient with AIH (74-year-old female) was used as a disease control. Clinical parameters of this AIH patient were shown in Supplementary Table 1. As shown in Supplementary Table 1, serum levels of IgG and ANA titers were markedly elevated. Moreover, interface hepatitis accompanied by infiltration of plasma cells was evident. The AIH score proposed by international AIH group was 23 in this patient, and thus, this patient was diagnosed with definite AIH [12].
Although lobular as well as portal inflammation was seen in the liver specimens of this patients, immune cell infiltration was predominantly seen in the liver lobes (Fig. 2, 1st and 2nd line panels). Moreover, hyperplasia of the bile duct as well as lymphocyte infiltration into the interlobular bile duct was seen in the pathological examinations, suggesting cholestasis as well as hepatocellular injury is involved in the development of hepatic irAEs in this case [13]. These pathological findings together with elevations of serum transaminases and biliary enzymes indicated that hepatic irAEs of this case was considered to be a mixed type [13].Fig. 2 Immuno-histochemical analyses of liver biopsy specimens. Liver biopsy specimens obtained from this case with hepatic immune-related adverse effects (irAEs, 1st and 2nd line panels) and from patients with autoimmune hepatitis (AIH, 3rd and 4th line panels) were subjected to immuno-histochemical analyses using anti-CD3 Ab, anti-CD4 Ab, anti-CD8 Ab, anti-CD20 Ab, and anti-forkhead box p3 (FOXP3) Ab. Hematoxylin and eosin (H&E) staining of the portal and lobular areas (1st row). Infiltration of CD3+ T cells (2nd row), CD4+ T cells (3rd row), CD8+ T cells (4th row), CD20+ B cells (5th row), and FOXP3+ Treg cells (6th row) was visualized. Scale bar is 20 µm
Interface hepatitis accompanied by plasma cell infiltration was seen in the liver specimen with the AIH patient (Fig. 2, 3rd line panel). Thus, H&E staining in this case was compatible to hepatic irAEs rather than AIH since the former and latter disorders preferentially affect the liver lobes and portal tracts, respectively [5, 14].
We then performed characterization of immune cell infiltration in this case. As shown in Fig. 2, accumulation of CD3+ T cells was seen in the liver lobes of the patient with hepatic irAEs whereas that was seen in the portal areas of the patient with AIH. Subpopulation analysis of T cells showed predominant infiltration of CD8+ T cells rather than CD4+ T cells into the liver lobes in this case (Fig. 2, 1st line panel). AIH lesions were characterized by portal accumulation of both CD4+ and CD8+ T cells (Fig. 2, 4th line panel). Moreover, infiltration of CD20+ B cells was seen in the portal areas of AIH patients, but not those in this case. These immuno-histochemical analyses strongly suggest that liver injury arose from a manifestation of irAEs in that lesions are characterized by predominant accumulation of CD8+ T cells into the liver lobes [5]. Although Tregs expressing FOXP3 play major roles in the suppression of pro-inflammatory responses [15], their involvement in the development of hepatic irAEs has been poorly defined. Interestingly, accumulation of Tregs expressing FOXP3 was barely seen in the liver lobes of this case with hepatic irAEs whereas abundant infiltration of FOXP3+ Tregs was observed in the portal areas of the AIH patient (Fig. 2). Abundant infiltration of T cells expressing CD4, CD8, or FOXP3 was also seen in the other three cases with AIH in this study (data not shown). Taken together, these data suggest hepatic irAEs due to nivolumab might be characterized not only by predominant lobular infiltration of CD8+ T cells but also by little accumulation of FOXP3+ Tregs.
This patient was diagnosed as irAEs involving the endocrine system (G2), lung (G1), skin (G3), and the liver (G3). According to the guideline for hepatic irAEs [3], this patient was initially treated with intravenous administration of methyl PSL (mPSL, 500 mg/day) in combination with oral administration of mycophenolate mofetil (MMF, 200 mg/day, Fig. 1). mPSL was switched to oral administration of PSL (60 mg/day) with a tapering schedule as depicted in Fig. 1. His serum levels of transaminases became normalized 2 months after the treatment and then he was treated with oral administration of Tegafur/Gimeracil/Oteracil (120 mg/day) for advanced lung cancer.
Discussion
Restorement of anti-cancer immunity by ICIs has dramatically improved the prognosis of patients with metastatic cancers [1, 2]. However, the blockade of PD-1 or CTLA-4-mediated signaling pathways sometimes causes irAEs, which can affect almost every organ in the body [3, 4]. In this case, administration of nivolumab led to the development of destructive thyroiditis, primary adrenal insufficiency, interstitial pneumonia, skin eruption and liver injury. Given the fact that the endocrine systems, lung, skin, and liver are preferential organs for irAEs [3–5], this case may be considered as typical irAEs due to nivolumab.
The incidence of hepatic irAEs by nivolumab alone was reported to be 6.4% [16] and liver injury by nivolumab usually develops 8–12 weeks after the initial injection [17]. Lobular infiltration of CD8+ T cells is one of the most characteristic findings in hepatic irAEs [5, 18, 19]. Consistent with this, lobular rather than portal hepatitis accompanied by predominant accumulation of CD8+ T cells was seen in this case. In contrast, AIH lesions were characterized by interface hepatitis associated with infiltration of plasma cells, CD4+ T cells, and CD8+ T cells. Thus, AIH and hepatic irAEs are distinctive disease entities in terms of the location of inflammation and effector T cell subpopulations. It should be noted, however, that molecular mechanisms accounting for such pathological differences between these two disorders have been poorly understood. In this study, we tried to elucidate the immuno-pathogenesis underlying the development of hepatic irAEs. We found that hepatic irAE lesions, but not AIH lesions were characterized by defective accumulation of FOXP3-expressing Tregs. Therefore, we assume possible involvement of defective Treg function in the development of hepatic irAEs. However, we need to be cautious regarding the interpretation of impaired Treg accumulation into the liver of hepatic irAEs. Liver biopsy samples were obtained in the middle of PSL tapering schedule in this patient. Thus, we could not completely exclude a possibility that prior PSL treatment might have affected the function of Tregs.
As mentioned above, defective accumulation of Tregs is associated with the development of hepatic irAEs in the present case. One major question arising from the present case is the molecular link between the PD-1 blockade and Treg differentiation. In this regards, neonatal thymectomy (NTx) leads to the development of much severe hepatitis in PD-1-deficient mice than in PD-1-intact mice through concurrent loss of FOXP3-expressing Tregs [20, 21]. Moreover, transient FOXP3-expressing Treg depletion in combination with systemic administration of anti-PD-1 Ab successfully induced severe hepatic irAEs in orthotopic cancer mice [22]. Thus, these previous studies together with the present case suggest the idea that PD-1 blockade may promote the development of liver injury, i.e., hepatic irAEs, in the presence of defective Treg function. Since Tregs stably express cell-surface PD-1 [15], one might assume that neutralization of PD-1-mediated signaling pathways impair Treg function. In this regards, Asano et al. provide evidence that Tregs isolated from PD-1 deficient mice display enhanced apoptosis than those from PD-1-intact mice in the presence of low doses of IL-2, a crucial cytokine for Treg proliferation [23]. Therefore, it is likely that systemic administration of anti-PD-1 Ab reduces the number of Tregs due to enhanced apoptosis. Such defective proliferation and activation of Tregs caused by nivolumab might be involved in the development of multiorgan system irAEs involving the endocrine system, lung, skin, and the liver, as seen in this case. This idea is supported by the fact that loss of function mutations in FOXP3 causes autoimmune diseases affecting multiple organs, called IPEX syndrome [15]. Confirmation of this idea requires future studies addressing the function of FOXP3+ Tregs in patients with multiorgan system irAEs and solitary hepatic irAEs.
Another important question arising from this case is why lung, skin, and hepatic irAEs developed even after the withdrawal of nivolumab. In this regards, recent studies by Osa et al. provide evidence that the binding of nivolumab to cell-surface PD-1 can be detected by flow-cytometry around 6 months after the withdrawal of nivolumab [24]. Thus, such long-lasting neutralization of PD-1 may contribute to the development of irAEs even after the withdrawal of nivolumab.
The number of Tregs was greater in the liver of AIH than that of irAEs in this study. Based on this observation, we hypothesized that defective Treg function mediates hepatic irAEs. However, defective Treg function can also be involved in the development of AIH since impaired Treg function as assessed by the inhibition of effector T cell proliferation was demonstrated in AIH patients [25].
In conclusion, hepatic irAEs might be characterized not only by lobular infiltration of CD8+ T cells but also by defective accumulation of FOXP3+ Tregs. Lack of Treg-mediated immune suppression might underlie the immuno-pathogenesis of hepatic irAEs. Verification of this idea awaits further studies addressing a large number of hepatic irAEs and hepatic Treg function isolated from patients with this disorder.
Supplementary Information
Below is the link to the electronic supplementary material.Supplementary file1 (DOCX 17 KB)
Compliance with ethical standards
Conflict of interest
Ikue Sekai, Satoru Hagiwara, Tomohiro Watanabe and Masatoshi Kudo declare that they have no conflict of interest.
Human Rights
All procedures followed have been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments.
Informed Consent
Informed consent was obtained from all patients for being included in the study.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | RECEIVED 4 COURSES INITIALLY WITH CARBOPLATIN THEN RECEIVED MAINTENANCE MONTHERAPY | DrugDosageText | CC BY | 33665689 | 19,775,058 | 2021-08 |
What was the outcome of reaction 'Liver injury'? | A case with hepatic immune-related adverse events caused by nivolumab exhibiting impaired accumulation of regulatory T cells.
Systemic administration of anti-programmed cell death 1 (PD-1) antibody (Ab) has achieved remarkable success in metastatic cancers. The blockade of PD-1-mediated signaling pathways sometimes cause immune-related adverse events (irAEs) due to restored anti-cancer as well as anti-self immunity. Although the liver is a preferential organ for irAEs, the immuno-pathogenesis underlying hepatic irAEs has been poorly understood. We describe a 57-year-old man with Stage IV lung cancer who underwent the first-line regimen composed of carboplatin and paclitaxel. Nivolumab treatment (3.2 mg/kg, every 3 weeks) was initiated when the disease progressed after the first chemotherapy. Sequential occurrence of irAEs involving the multiorgan systems was observed. He developed hepatic irAEs (Grade 3) after endocrine, lung, and cutaneous irAEs. Lobular hepatitis characterized by predominant infiltration of CD8+ T cells was seen in the liver biopsy specimens. Interestingly, defective accumulation of regulatory T cells (Tregs) expressing forkhead box protein P3 (FOXP3) was evident in this case with hepatic irAEs as compared with typical cases with autoimmune hepatitis. This case suggests that hepatic irAEs are characterized not only by lobular infiltration of CD8+ T cells but also by defective accumulation of FOXP3+ Tregs.
Introduction
A recent remarkable success of treating advanced cancer with immune check-point inhibitors (ICIs) highlight important roles that programmed cell death protein-1 (PD-1) and cytotoxic T lymphocyte-associated protein-4 (CTLA-4) play in the suppression of anti-cancer immune responses [1, 2]. Nivolumab and ipilimumab targeting PD-1 and CTLA-4, respectively, are the representative ICIs. These ICIs restore anti-cancer immune responses through neutralization of negative regulation mediated by PD-1 or CTLA-4-mediated signaling pathways [1, 2]. In fact, introduction of nivolumab and ipilimumab into clinical practice has improved the prognosis of advanced malignancies, especially malignant melanoma [1, 2].
Despite effective restorement of anti-cancer immunity by nivolumab and ipilimumab, the blockade of PD-1 and CTLA-4, both of which are negative regulators of adaptive and innate immunity, sometimes causes excessive immune reactions in a broad range of organs, called immune-related adverse events (irAEs) [3, 4]. Liver toxicity associated with ICIs occurs in around 5–10% of patients, [5] and thus, the liver is a preferential organ targeted by ICIs in parallel to the skin, colon, endocrine system, kidney, and lung [3, 4]. Although activation and expansion of T cells through lack of negative regulation by PD-1 and CTLA-4 is considered to underlie the immuno-pathogenesis of irAEs [3–5], molecular mechanisms accounting for the development of hepatic irAEs have been poorly understood. Regulatory T cells (Tregs) expressing forkhead box protein P3 (FOXP3) are a critical component of immune systems with pivotal roles not only in the maintenance of self-tolerance but also in the suppression of anti-cancer immunity [6]. Here, we report a case with hepatic irAEs exhibiting little accumulation of FOXP3-expressing Tregs into the liver. This case suggests possible involvement of Treg deficiency in the development of hepatic irAEs.
Case reports
A 51-year-old man without any history of autoimmune diseases was diagnosed as lung adenocarcinoma (p-T3N0M0, Stage IIb) and received thoracoscopic right pneumonectomy in July 2012. Follow-up computed tomography (CT), which was performed in March 2017, revealed recurrence of his lung cancer in the left lobe accompanied by mediastinal lymph node metastasis. At this time point, he was diagnosed as Stage IV lung adenocarcinoma (p-T3N1M1). His surgical specimen was negative for epidermal growth factor receptor (EGFR) mutation or anaplastic lymphoma kinase 1 (ALK1) fusion oncogene. According to the guideline for Stage IV lung adenocarcinoma with intact EGFR and ALK1 [7], he was initially treated with the first-line regimen composed of carboplatin and paclitaxel from April 2017 for 4 courses followed by paclitaxel maintenance therapy from July 2017 to October 2017. These initial courses of chemotherapy were not successful and his lung cancer was judged as progressive disease (PD) based on computed tomography findings. Nivolumab was introduced from August 2018 at a dose of 3.2 mg/kg every 3 weeks.
Various kinds of irAEs occurred after the treatment with nivolumab and the severity was graded based on the clinical practice guideline following the Common Terminology Criteria for Adverse Events [version 5.0] [8].His initial irAEs involved the endocrine system as shown by the appearance of general fatigue caused by destructive thyroiditis. A significant elevation of serum free T3 (fT3, 6.2 pg/mL, normal range, 2.3–4) and fT4 (fT4, 2.1 ng/dL, normal range, 0.9–1.7) levels accompanied by a markedly reduced level of thyroid stimulating hormone (TSH, 0.02 μIU/mL, normal range, 0.5–5) was seen in September 2018. Three months later, thyroid hormone tests clearly showed hypothyroidism characterized by reduced fT3 and fT4 levels with elevated TSH levels. Further examination of his endocrine system revealed reduced serum levels of cortisol (3.3 μg/dL, normal range 6.2–19.4) and adrenocorticotropic hormone (ACTH 1.3 pg/mL, normal range 7.3–63.3), which suggested the presence of primary adrenal insufficiency despite normal levels of blood sugar, sodium and potassium. Oral supplementation of hydrocortisone (15 mg/day) and thyroid hormone (25 μg/day) were started for G1 primary hypothyroidism and G2 primary adrenal insufficiency, respectively. In addition to these endocrine toxicities, interstitial pneumonia (G1) was detected in February 2019 and then administration of nivolumab was discontinued. Moreover, skin rash judged as G3 irAE developed in March 2019. Prednisolone (PSL, 40 mg/day) with tapering schedule 5 mg/2 weeks was started after the appearance of irAEs involving the endocrine system, lung, and skin.
Although improvement of skin rash was achieved after the initiation of PSL treatment, he developed liver injury as shown by a marked elevation of serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), and γ-glutamyltransferase (γGTP) (Table 1 and Fig. 1). Viral hepatitis was unlikely since viral markers for hepatitis A virus, hepatitis B virus, hepatitis C virus, cytomegalovirus, and Epstein–Barr virus were negative. Moreover, liver injury due to autoimmune hepatitis (AIH) or primary biliary cholangitis (PBC) was also unlikely as assessed by serum IgG levels and titers for anti-nuclear antibody (ANA) or anti-mitochondrial Ab. These blood examination data led us to consider the possibility of hepatic irAEs. No metastatic lesions were detected in the liver by abdominal contrast-enhanced CT. Moreover, magnetic resonance cholangiopancreatography did not reveal any abnormalities in the intrahepatic or extrahepatic bile ducts, suggesting that an immune-related cholangitis caused by ICIs was less likely [9]. To verify the diagnosis of hepatis irAEs, liver biopsy samples were subjected to hematoxylin and eosin (H&E) staining and immuno-histochemical analyses.Table 1 Laboratory data on admission
Hematology Blood chemistry Serological tests
WBC 6.270/μL TP 6.2 g/dL ANA (–)
RBC 346 × 104/μL Alb 3.4 g/dL AMA2 (–)
Hb 13.5 g/dL BUN 13 mg/dL IgG 697 mg/dL
Hct 39.0% Cr 0.79 mg/dL IgM 25 mg/dL
Plt 12.1 × 104/μL T-Bil 1.5 mg/dL IgE 337 IU/mL
Neutro 85.7% D-Bil 0.7 mg/dL Viral marker
Lympho 9.9% ALP 1039 U/L HBsAg (–)
Eosino 0.5% AMY 31 U/L HBsAb (–)
Endocrine LDH 679 U/L HBcAb (–)
ACTH 1.0 pg/mL AST 651 U/L HCVAb (–)
CS 6.2 μg/dL ALT 547 U/L HA-IgM (–)
TSH 1.22 μIU/mL γGTP 2718 U/L CMV-IgM (–)
FT4 1.1 ng/dL CRP 10.22 mg/dL EBVVCA-IgM (–)
Coagulation
PT 119.6%
INR 0.93
ACTH adrenocorticotropic hormone, CS cortisol, PT prothrombin time, INR international normalized ratio, AMA2 anti-mitochondrial antibody 2, ANA anti-nuclear antibody, CMV cytomegalovirus, EBV Epstein–Barr virus
Fig. 1 Clinical course of the patients. See the clinical presentation section of the text. ALT alanine aminotransferase, ALP alkaline phosphatase, AST aspartate aminotransferase, γGTP γ-glutamyltransferase, MMF mycophenolate mofetil, mPSL methylprednisolone, PSL prednisolone, UDCA ursodeoxycholic acid
Liver biopsy samples were subjected to H&E staining and immuno-histochemical analysis using mouse or rabbit anti-human CD3 antibody (Ab, Roche Diagnostics; Tokyo, Japan), CD4 Ab (Roche Diagnostics; Tokyo, Japan), CD8 Ab (Nichirei Bioscience; Tokyo, Japan), CD20 Ab (Roche Diagnostics; Tokyo, Japan), and FOXP3 Ab (Abcam; Cambridge, United Kingdom). Visualization of CD3+ T cells, CD4+ T cells, CD8+ T cells, CD20+ B cells, and FOXP3+ Tregs were performed using DakO-EnVision+ systems (Dako Japan, Tokyo, Japan) as previously described [10, 11]. The liver biopsy sample obtained from a typical patient with AIH (74-year-old female) was used as a disease control. Clinical parameters of this AIH patient were shown in Supplementary Table 1. As shown in Supplementary Table 1, serum levels of IgG and ANA titers were markedly elevated. Moreover, interface hepatitis accompanied by infiltration of plasma cells was evident. The AIH score proposed by international AIH group was 23 in this patient, and thus, this patient was diagnosed with definite AIH [12].
Although lobular as well as portal inflammation was seen in the liver specimens of this patients, immune cell infiltration was predominantly seen in the liver lobes (Fig. 2, 1st and 2nd line panels). Moreover, hyperplasia of the bile duct as well as lymphocyte infiltration into the interlobular bile duct was seen in the pathological examinations, suggesting cholestasis as well as hepatocellular injury is involved in the development of hepatic irAEs in this case [13]. These pathological findings together with elevations of serum transaminases and biliary enzymes indicated that hepatic irAEs of this case was considered to be a mixed type [13].Fig. 2 Immuno-histochemical analyses of liver biopsy specimens. Liver biopsy specimens obtained from this case with hepatic immune-related adverse effects (irAEs, 1st and 2nd line panels) and from patients with autoimmune hepatitis (AIH, 3rd and 4th line panels) were subjected to immuno-histochemical analyses using anti-CD3 Ab, anti-CD4 Ab, anti-CD8 Ab, anti-CD20 Ab, and anti-forkhead box p3 (FOXP3) Ab. Hematoxylin and eosin (H&E) staining of the portal and lobular areas (1st row). Infiltration of CD3+ T cells (2nd row), CD4+ T cells (3rd row), CD8+ T cells (4th row), CD20+ B cells (5th row), and FOXP3+ Treg cells (6th row) was visualized. Scale bar is 20 µm
Interface hepatitis accompanied by plasma cell infiltration was seen in the liver specimen with the AIH patient (Fig. 2, 3rd line panel). Thus, H&E staining in this case was compatible to hepatic irAEs rather than AIH since the former and latter disorders preferentially affect the liver lobes and portal tracts, respectively [5, 14].
We then performed characterization of immune cell infiltration in this case. As shown in Fig. 2, accumulation of CD3+ T cells was seen in the liver lobes of the patient with hepatic irAEs whereas that was seen in the portal areas of the patient with AIH. Subpopulation analysis of T cells showed predominant infiltration of CD8+ T cells rather than CD4+ T cells into the liver lobes in this case (Fig. 2, 1st line panel). AIH lesions were characterized by portal accumulation of both CD4+ and CD8+ T cells (Fig. 2, 4th line panel). Moreover, infiltration of CD20+ B cells was seen in the portal areas of AIH patients, but not those in this case. These immuno-histochemical analyses strongly suggest that liver injury arose from a manifestation of irAEs in that lesions are characterized by predominant accumulation of CD8+ T cells into the liver lobes [5]. Although Tregs expressing FOXP3 play major roles in the suppression of pro-inflammatory responses [15], their involvement in the development of hepatic irAEs has been poorly defined. Interestingly, accumulation of Tregs expressing FOXP3 was barely seen in the liver lobes of this case with hepatic irAEs whereas abundant infiltration of FOXP3+ Tregs was observed in the portal areas of the AIH patient (Fig. 2). Abundant infiltration of T cells expressing CD4, CD8, or FOXP3 was also seen in the other three cases with AIH in this study (data not shown). Taken together, these data suggest hepatic irAEs due to nivolumab might be characterized not only by predominant lobular infiltration of CD8+ T cells but also by little accumulation of FOXP3+ Tregs.
This patient was diagnosed as irAEs involving the endocrine system (G2), lung (G1), skin (G3), and the liver (G3). According to the guideline for hepatic irAEs [3], this patient was initially treated with intravenous administration of methyl PSL (mPSL, 500 mg/day) in combination with oral administration of mycophenolate mofetil (MMF, 200 mg/day, Fig. 1). mPSL was switched to oral administration of PSL (60 mg/day) with a tapering schedule as depicted in Fig. 1. His serum levels of transaminases became normalized 2 months after the treatment and then he was treated with oral administration of Tegafur/Gimeracil/Oteracil (120 mg/day) for advanced lung cancer.
Discussion
Restorement of anti-cancer immunity by ICIs has dramatically improved the prognosis of patients with metastatic cancers [1, 2]. However, the blockade of PD-1 or CTLA-4-mediated signaling pathways sometimes causes irAEs, which can affect almost every organ in the body [3, 4]. In this case, administration of nivolumab led to the development of destructive thyroiditis, primary adrenal insufficiency, interstitial pneumonia, skin eruption and liver injury. Given the fact that the endocrine systems, lung, skin, and liver are preferential organs for irAEs [3–5], this case may be considered as typical irAEs due to nivolumab.
The incidence of hepatic irAEs by nivolumab alone was reported to be 6.4% [16] and liver injury by nivolumab usually develops 8–12 weeks after the initial injection [17]. Lobular infiltration of CD8+ T cells is one of the most characteristic findings in hepatic irAEs [5, 18, 19]. Consistent with this, lobular rather than portal hepatitis accompanied by predominant accumulation of CD8+ T cells was seen in this case. In contrast, AIH lesions were characterized by interface hepatitis associated with infiltration of plasma cells, CD4+ T cells, and CD8+ T cells. Thus, AIH and hepatic irAEs are distinctive disease entities in terms of the location of inflammation and effector T cell subpopulations. It should be noted, however, that molecular mechanisms accounting for such pathological differences between these two disorders have been poorly understood. In this study, we tried to elucidate the immuno-pathogenesis underlying the development of hepatic irAEs. We found that hepatic irAE lesions, but not AIH lesions were characterized by defective accumulation of FOXP3-expressing Tregs. Therefore, we assume possible involvement of defective Treg function in the development of hepatic irAEs. However, we need to be cautious regarding the interpretation of impaired Treg accumulation into the liver of hepatic irAEs. Liver biopsy samples were obtained in the middle of PSL tapering schedule in this patient. Thus, we could not completely exclude a possibility that prior PSL treatment might have affected the function of Tregs.
As mentioned above, defective accumulation of Tregs is associated with the development of hepatic irAEs in the present case. One major question arising from the present case is the molecular link between the PD-1 blockade and Treg differentiation. In this regards, neonatal thymectomy (NTx) leads to the development of much severe hepatitis in PD-1-deficient mice than in PD-1-intact mice through concurrent loss of FOXP3-expressing Tregs [20, 21]. Moreover, transient FOXP3-expressing Treg depletion in combination with systemic administration of anti-PD-1 Ab successfully induced severe hepatic irAEs in orthotopic cancer mice [22]. Thus, these previous studies together with the present case suggest the idea that PD-1 blockade may promote the development of liver injury, i.e., hepatic irAEs, in the presence of defective Treg function. Since Tregs stably express cell-surface PD-1 [15], one might assume that neutralization of PD-1-mediated signaling pathways impair Treg function. In this regards, Asano et al. provide evidence that Tregs isolated from PD-1 deficient mice display enhanced apoptosis than those from PD-1-intact mice in the presence of low doses of IL-2, a crucial cytokine for Treg proliferation [23]. Therefore, it is likely that systemic administration of anti-PD-1 Ab reduces the number of Tregs due to enhanced apoptosis. Such defective proliferation and activation of Tregs caused by nivolumab might be involved in the development of multiorgan system irAEs involving the endocrine system, lung, skin, and the liver, as seen in this case. This idea is supported by the fact that loss of function mutations in FOXP3 causes autoimmune diseases affecting multiple organs, called IPEX syndrome [15]. Confirmation of this idea requires future studies addressing the function of FOXP3+ Tregs in patients with multiorgan system irAEs and solitary hepatic irAEs.
Another important question arising from this case is why lung, skin, and hepatic irAEs developed even after the withdrawal of nivolumab. In this regards, recent studies by Osa et al. provide evidence that the binding of nivolumab to cell-surface PD-1 can be detected by flow-cytometry around 6 months after the withdrawal of nivolumab [24]. Thus, such long-lasting neutralization of PD-1 may contribute to the development of irAEs even after the withdrawal of nivolumab.
The number of Tregs was greater in the liver of AIH than that of irAEs in this study. Based on this observation, we hypothesized that defective Treg function mediates hepatic irAEs. However, defective Treg function can also be involved in the development of AIH since impaired Treg function as assessed by the inhibition of effector T cell proliferation was demonstrated in AIH patients [25].
In conclusion, hepatic irAEs might be characterized not only by lobular infiltration of CD8+ T cells but also by defective accumulation of FOXP3+ Tregs. Lack of Treg-mediated immune suppression might underlie the immuno-pathogenesis of hepatic irAEs. Verification of this idea awaits further studies addressing a large number of hepatic irAEs and hepatic Treg function isolated from patients with this disorder.
Supplementary Information
Below is the link to the electronic supplementary material.Supplementary file1 (DOCX 17 KB)
Compliance with ethical standards
Conflict of interest
Ikue Sekai, Satoru Hagiwara, Tomohiro Watanabe and Masatoshi Kudo declare that they have no conflict of interest.
Human Rights
All procedures followed have been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments.
Informed Consent
Informed consent was obtained from all patients for being included in the study.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | Recovered | ReactionOutcome | CC BY | 33665689 | 19,779,825 | 2021-08 |
What was the outcome of reaction 'Rash'? | A case with hepatic immune-related adverse events caused by nivolumab exhibiting impaired accumulation of regulatory T cells.
Systemic administration of anti-programmed cell death 1 (PD-1) antibody (Ab) has achieved remarkable success in metastatic cancers. The blockade of PD-1-mediated signaling pathways sometimes cause immune-related adverse events (irAEs) due to restored anti-cancer as well as anti-self immunity. Although the liver is a preferential organ for irAEs, the immuno-pathogenesis underlying hepatic irAEs has been poorly understood. We describe a 57-year-old man with Stage IV lung cancer who underwent the first-line regimen composed of carboplatin and paclitaxel. Nivolumab treatment (3.2 mg/kg, every 3 weeks) was initiated when the disease progressed after the first chemotherapy. Sequential occurrence of irAEs involving the multiorgan systems was observed. He developed hepatic irAEs (Grade 3) after endocrine, lung, and cutaneous irAEs. Lobular hepatitis characterized by predominant infiltration of CD8+ T cells was seen in the liver biopsy specimens. Interestingly, defective accumulation of regulatory T cells (Tregs) expressing forkhead box protein P3 (FOXP3) was evident in this case with hepatic irAEs as compared with typical cases with autoimmune hepatitis. This case suggests that hepatic irAEs are characterized not only by lobular infiltration of CD8+ T cells but also by defective accumulation of FOXP3+ Tregs.
Introduction
A recent remarkable success of treating advanced cancer with immune check-point inhibitors (ICIs) highlight important roles that programmed cell death protein-1 (PD-1) and cytotoxic T lymphocyte-associated protein-4 (CTLA-4) play in the suppression of anti-cancer immune responses [1, 2]. Nivolumab and ipilimumab targeting PD-1 and CTLA-4, respectively, are the representative ICIs. These ICIs restore anti-cancer immune responses through neutralization of negative regulation mediated by PD-1 or CTLA-4-mediated signaling pathways [1, 2]. In fact, introduction of nivolumab and ipilimumab into clinical practice has improved the prognosis of advanced malignancies, especially malignant melanoma [1, 2].
Despite effective restorement of anti-cancer immunity by nivolumab and ipilimumab, the blockade of PD-1 and CTLA-4, both of which are negative regulators of adaptive and innate immunity, sometimes causes excessive immune reactions in a broad range of organs, called immune-related adverse events (irAEs) [3, 4]. Liver toxicity associated with ICIs occurs in around 5–10% of patients, [5] and thus, the liver is a preferential organ targeted by ICIs in parallel to the skin, colon, endocrine system, kidney, and lung [3, 4]. Although activation and expansion of T cells through lack of negative regulation by PD-1 and CTLA-4 is considered to underlie the immuno-pathogenesis of irAEs [3–5], molecular mechanisms accounting for the development of hepatic irAEs have been poorly understood. Regulatory T cells (Tregs) expressing forkhead box protein P3 (FOXP3) are a critical component of immune systems with pivotal roles not only in the maintenance of self-tolerance but also in the suppression of anti-cancer immunity [6]. Here, we report a case with hepatic irAEs exhibiting little accumulation of FOXP3-expressing Tregs into the liver. This case suggests possible involvement of Treg deficiency in the development of hepatic irAEs.
Case reports
A 51-year-old man without any history of autoimmune diseases was diagnosed as lung adenocarcinoma (p-T3N0M0, Stage IIb) and received thoracoscopic right pneumonectomy in July 2012. Follow-up computed tomography (CT), which was performed in March 2017, revealed recurrence of his lung cancer in the left lobe accompanied by mediastinal lymph node metastasis. At this time point, he was diagnosed as Stage IV lung adenocarcinoma (p-T3N1M1). His surgical specimen was negative for epidermal growth factor receptor (EGFR) mutation or anaplastic lymphoma kinase 1 (ALK1) fusion oncogene. According to the guideline for Stage IV lung adenocarcinoma with intact EGFR and ALK1 [7], he was initially treated with the first-line regimen composed of carboplatin and paclitaxel from April 2017 for 4 courses followed by paclitaxel maintenance therapy from July 2017 to October 2017. These initial courses of chemotherapy were not successful and his lung cancer was judged as progressive disease (PD) based on computed tomography findings. Nivolumab was introduced from August 2018 at a dose of 3.2 mg/kg every 3 weeks.
Various kinds of irAEs occurred after the treatment with nivolumab and the severity was graded based on the clinical practice guideline following the Common Terminology Criteria for Adverse Events [version 5.0] [8].His initial irAEs involved the endocrine system as shown by the appearance of general fatigue caused by destructive thyroiditis. A significant elevation of serum free T3 (fT3, 6.2 pg/mL, normal range, 2.3–4) and fT4 (fT4, 2.1 ng/dL, normal range, 0.9–1.7) levels accompanied by a markedly reduced level of thyroid stimulating hormone (TSH, 0.02 μIU/mL, normal range, 0.5–5) was seen in September 2018. Three months later, thyroid hormone tests clearly showed hypothyroidism characterized by reduced fT3 and fT4 levels with elevated TSH levels. Further examination of his endocrine system revealed reduced serum levels of cortisol (3.3 μg/dL, normal range 6.2–19.4) and adrenocorticotropic hormone (ACTH 1.3 pg/mL, normal range 7.3–63.3), which suggested the presence of primary adrenal insufficiency despite normal levels of blood sugar, sodium and potassium. Oral supplementation of hydrocortisone (15 mg/day) and thyroid hormone (25 μg/day) were started for G1 primary hypothyroidism and G2 primary adrenal insufficiency, respectively. In addition to these endocrine toxicities, interstitial pneumonia (G1) was detected in February 2019 and then administration of nivolumab was discontinued. Moreover, skin rash judged as G3 irAE developed in March 2019. Prednisolone (PSL, 40 mg/day) with tapering schedule 5 mg/2 weeks was started after the appearance of irAEs involving the endocrine system, lung, and skin.
Although improvement of skin rash was achieved after the initiation of PSL treatment, he developed liver injury as shown by a marked elevation of serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), and γ-glutamyltransferase (γGTP) (Table 1 and Fig. 1). Viral hepatitis was unlikely since viral markers for hepatitis A virus, hepatitis B virus, hepatitis C virus, cytomegalovirus, and Epstein–Barr virus were negative. Moreover, liver injury due to autoimmune hepatitis (AIH) or primary biliary cholangitis (PBC) was also unlikely as assessed by serum IgG levels and titers for anti-nuclear antibody (ANA) or anti-mitochondrial Ab. These blood examination data led us to consider the possibility of hepatic irAEs. No metastatic lesions were detected in the liver by abdominal contrast-enhanced CT. Moreover, magnetic resonance cholangiopancreatography did not reveal any abnormalities in the intrahepatic or extrahepatic bile ducts, suggesting that an immune-related cholangitis caused by ICIs was less likely [9]. To verify the diagnosis of hepatis irAEs, liver biopsy samples were subjected to hematoxylin and eosin (H&E) staining and immuno-histochemical analyses.Table 1 Laboratory data on admission
Hematology Blood chemistry Serological tests
WBC 6.270/μL TP 6.2 g/dL ANA (–)
RBC 346 × 104/μL Alb 3.4 g/dL AMA2 (–)
Hb 13.5 g/dL BUN 13 mg/dL IgG 697 mg/dL
Hct 39.0% Cr 0.79 mg/dL IgM 25 mg/dL
Plt 12.1 × 104/μL T-Bil 1.5 mg/dL IgE 337 IU/mL
Neutro 85.7% D-Bil 0.7 mg/dL Viral marker
Lympho 9.9% ALP 1039 U/L HBsAg (–)
Eosino 0.5% AMY 31 U/L HBsAb (–)
Endocrine LDH 679 U/L HBcAb (–)
ACTH 1.0 pg/mL AST 651 U/L HCVAb (–)
CS 6.2 μg/dL ALT 547 U/L HA-IgM (–)
TSH 1.22 μIU/mL γGTP 2718 U/L CMV-IgM (–)
FT4 1.1 ng/dL CRP 10.22 mg/dL EBVVCA-IgM (–)
Coagulation
PT 119.6%
INR 0.93
ACTH adrenocorticotropic hormone, CS cortisol, PT prothrombin time, INR international normalized ratio, AMA2 anti-mitochondrial antibody 2, ANA anti-nuclear antibody, CMV cytomegalovirus, EBV Epstein–Barr virus
Fig. 1 Clinical course of the patients. See the clinical presentation section of the text. ALT alanine aminotransferase, ALP alkaline phosphatase, AST aspartate aminotransferase, γGTP γ-glutamyltransferase, MMF mycophenolate mofetil, mPSL methylprednisolone, PSL prednisolone, UDCA ursodeoxycholic acid
Liver biopsy samples were subjected to H&E staining and immuno-histochemical analysis using mouse or rabbit anti-human CD3 antibody (Ab, Roche Diagnostics; Tokyo, Japan), CD4 Ab (Roche Diagnostics; Tokyo, Japan), CD8 Ab (Nichirei Bioscience; Tokyo, Japan), CD20 Ab (Roche Diagnostics; Tokyo, Japan), and FOXP3 Ab (Abcam; Cambridge, United Kingdom). Visualization of CD3+ T cells, CD4+ T cells, CD8+ T cells, CD20+ B cells, and FOXP3+ Tregs were performed using DakO-EnVision+ systems (Dako Japan, Tokyo, Japan) as previously described [10, 11]. The liver biopsy sample obtained from a typical patient with AIH (74-year-old female) was used as a disease control. Clinical parameters of this AIH patient were shown in Supplementary Table 1. As shown in Supplementary Table 1, serum levels of IgG and ANA titers were markedly elevated. Moreover, interface hepatitis accompanied by infiltration of plasma cells was evident. The AIH score proposed by international AIH group was 23 in this patient, and thus, this patient was diagnosed with definite AIH [12].
Although lobular as well as portal inflammation was seen in the liver specimens of this patients, immune cell infiltration was predominantly seen in the liver lobes (Fig. 2, 1st and 2nd line panels). Moreover, hyperplasia of the bile duct as well as lymphocyte infiltration into the interlobular bile duct was seen in the pathological examinations, suggesting cholestasis as well as hepatocellular injury is involved in the development of hepatic irAEs in this case [13]. These pathological findings together with elevations of serum transaminases and biliary enzymes indicated that hepatic irAEs of this case was considered to be a mixed type [13].Fig. 2 Immuno-histochemical analyses of liver biopsy specimens. Liver biopsy specimens obtained from this case with hepatic immune-related adverse effects (irAEs, 1st and 2nd line panels) and from patients with autoimmune hepatitis (AIH, 3rd and 4th line panels) were subjected to immuno-histochemical analyses using anti-CD3 Ab, anti-CD4 Ab, anti-CD8 Ab, anti-CD20 Ab, and anti-forkhead box p3 (FOXP3) Ab. Hematoxylin and eosin (H&E) staining of the portal and lobular areas (1st row). Infiltration of CD3+ T cells (2nd row), CD4+ T cells (3rd row), CD8+ T cells (4th row), CD20+ B cells (5th row), and FOXP3+ Treg cells (6th row) was visualized. Scale bar is 20 µm
Interface hepatitis accompanied by plasma cell infiltration was seen in the liver specimen with the AIH patient (Fig. 2, 3rd line panel). Thus, H&E staining in this case was compatible to hepatic irAEs rather than AIH since the former and latter disorders preferentially affect the liver lobes and portal tracts, respectively [5, 14].
We then performed characterization of immune cell infiltration in this case. As shown in Fig. 2, accumulation of CD3+ T cells was seen in the liver lobes of the patient with hepatic irAEs whereas that was seen in the portal areas of the patient with AIH. Subpopulation analysis of T cells showed predominant infiltration of CD8+ T cells rather than CD4+ T cells into the liver lobes in this case (Fig. 2, 1st line panel). AIH lesions were characterized by portal accumulation of both CD4+ and CD8+ T cells (Fig. 2, 4th line panel). Moreover, infiltration of CD20+ B cells was seen in the portal areas of AIH patients, but not those in this case. These immuno-histochemical analyses strongly suggest that liver injury arose from a manifestation of irAEs in that lesions are characterized by predominant accumulation of CD8+ T cells into the liver lobes [5]. Although Tregs expressing FOXP3 play major roles in the suppression of pro-inflammatory responses [15], their involvement in the development of hepatic irAEs has been poorly defined. Interestingly, accumulation of Tregs expressing FOXP3 was barely seen in the liver lobes of this case with hepatic irAEs whereas abundant infiltration of FOXP3+ Tregs was observed in the portal areas of the AIH patient (Fig. 2). Abundant infiltration of T cells expressing CD4, CD8, or FOXP3 was also seen in the other three cases with AIH in this study (data not shown). Taken together, these data suggest hepatic irAEs due to nivolumab might be characterized not only by predominant lobular infiltration of CD8+ T cells but also by little accumulation of FOXP3+ Tregs.
This patient was diagnosed as irAEs involving the endocrine system (G2), lung (G1), skin (G3), and the liver (G3). According to the guideline for hepatic irAEs [3], this patient was initially treated with intravenous administration of methyl PSL (mPSL, 500 mg/day) in combination with oral administration of mycophenolate mofetil (MMF, 200 mg/day, Fig. 1). mPSL was switched to oral administration of PSL (60 mg/day) with a tapering schedule as depicted in Fig. 1. His serum levels of transaminases became normalized 2 months after the treatment and then he was treated with oral administration of Tegafur/Gimeracil/Oteracil (120 mg/day) for advanced lung cancer.
Discussion
Restorement of anti-cancer immunity by ICIs has dramatically improved the prognosis of patients with metastatic cancers [1, 2]. However, the blockade of PD-1 or CTLA-4-mediated signaling pathways sometimes causes irAEs, which can affect almost every organ in the body [3, 4]. In this case, administration of nivolumab led to the development of destructive thyroiditis, primary adrenal insufficiency, interstitial pneumonia, skin eruption and liver injury. Given the fact that the endocrine systems, lung, skin, and liver are preferential organs for irAEs [3–5], this case may be considered as typical irAEs due to nivolumab.
The incidence of hepatic irAEs by nivolumab alone was reported to be 6.4% [16] and liver injury by nivolumab usually develops 8–12 weeks after the initial injection [17]. Lobular infiltration of CD8+ T cells is one of the most characteristic findings in hepatic irAEs [5, 18, 19]. Consistent with this, lobular rather than portal hepatitis accompanied by predominant accumulation of CD8+ T cells was seen in this case. In contrast, AIH lesions were characterized by interface hepatitis associated with infiltration of plasma cells, CD4+ T cells, and CD8+ T cells. Thus, AIH and hepatic irAEs are distinctive disease entities in terms of the location of inflammation and effector T cell subpopulations. It should be noted, however, that molecular mechanisms accounting for such pathological differences between these two disorders have been poorly understood. In this study, we tried to elucidate the immuno-pathogenesis underlying the development of hepatic irAEs. We found that hepatic irAE lesions, but not AIH lesions were characterized by defective accumulation of FOXP3-expressing Tregs. Therefore, we assume possible involvement of defective Treg function in the development of hepatic irAEs. However, we need to be cautious regarding the interpretation of impaired Treg accumulation into the liver of hepatic irAEs. Liver biopsy samples were obtained in the middle of PSL tapering schedule in this patient. Thus, we could not completely exclude a possibility that prior PSL treatment might have affected the function of Tregs.
As mentioned above, defective accumulation of Tregs is associated with the development of hepatic irAEs in the present case. One major question arising from the present case is the molecular link between the PD-1 blockade and Treg differentiation. In this regards, neonatal thymectomy (NTx) leads to the development of much severe hepatitis in PD-1-deficient mice than in PD-1-intact mice through concurrent loss of FOXP3-expressing Tregs [20, 21]. Moreover, transient FOXP3-expressing Treg depletion in combination with systemic administration of anti-PD-1 Ab successfully induced severe hepatic irAEs in orthotopic cancer mice [22]. Thus, these previous studies together with the present case suggest the idea that PD-1 blockade may promote the development of liver injury, i.e., hepatic irAEs, in the presence of defective Treg function. Since Tregs stably express cell-surface PD-1 [15], one might assume that neutralization of PD-1-mediated signaling pathways impair Treg function. In this regards, Asano et al. provide evidence that Tregs isolated from PD-1 deficient mice display enhanced apoptosis than those from PD-1-intact mice in the presence of low doses of IL-2, a crucial cytokine for Treg proliferation [23]. Therefore, it is likely that systemic administration of anti-PD-1 Ab reduces the number of Tregs due to enhanced apoptosis. Such defective proliferation and activation of Tregs caused by nivolumab might be involved in the development of multiorgan system irAEs involving the endocrine system, lung, skin, and the liver, as seen in this case. This idea is supported by the fact that loss of function mutations in FOXP3 causes autoimmune diseases affecting multiple organs, called IPEX syndrome [15]. Confirmation of this idea requires future studies addressing the function of FOXP3+ Tregs in patients with multiorgan system irAEs and solitary hepatic irAEs.
Another important question arising from this case is why lung, skin, and hepatic irAEs developed even after the withdrawal of nivolumab. In this regards, recent studies by Osa et al. provide evidence that the binding of nivolumab to cell-surface PD-1 can be detected by flow-cytometry around 6 months after the withdrawal of nivolumab [24]. Thus, such long-lasting neutralization of PD-1 may contribute to the development of irAEs even after the withdrawal of nivolumab.
The number of Tregs was greater in the liver of AIH than that of irAEs in this study. Based on this observation, we hypothesized that defective Treg function mediates hepatic irAEs. However, defective Treg function can also be involved in the development of AIH since impaired Treg function as assessed by the inhibition of effector T cell proliferation was demonstrated in AIH patients [25].
In conclusion, hepatic irAEs might be characterized not only by lobular infiltration of CD8+ T cells but also by defective accumulation of FOXP3+ Tregs. Lack of Treg-mediated immune suppression might underlie the immuno-pathogenesis of hepatic irAEs. Verification of this idea awaits further studies addressing a large number of hepatic irAEs and hepatic Treg function isolated from patients with this disorder.
Supplementary Information
Below is the link to the electronic supplementary material.Supplementary file1 (DOCX 17 KB)
Compliance with ethical standards
Conflict of interest
Ikue Sekai, Satoru Hagiwara, Tomohiro Watanabe and Masatoshi Kudo declare that they have no conflict of interest.
Human Rights
All procedures followed have been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments.
Informed Consent
Informed consent was obtained from all patients for being included in the study.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | Recovering | ReactionOutcome | CC BY | 33665689 | 19,779,825 | 2021-08 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Ectopic pregnancy'. | Perampanel and pregnancy.
The objective was to summarize pregnancy and fetal/postnatal outcomes following maternal perampanel exposure using preclinical and clinical data, and to use physiologically based pharmacokinetic (PBPK) modeling to improve understanding of perampanel pharmacokinetics (PK) during pregnancy.
Preclinical developmental studies with perampanel were conducted in pregnant rats and rabbits. Clinical data were collated from the Eisai global perampanel safety database, comprising reports of perampanel exposure during pregnancy from routine clinical settings, interventional studies, and non-interventional post-marketing studies, searched for events coded to Medical Dictionary for Regulatory Activities (MedDRA) high-level group terms of Pregnancy, Labor, Delivery, and Postpartum Conditions and/or the Standardized MedDRA Query terms of Congenital, Familiar, and Genetic Disorders. A PBPK model was used to predict clinical perampanel PK throughout pregnancy.
Preclinical studies indicated that perampanel may be linked with post-implantation loss and/or some specific physical development delays but not fertility and early embryonic development. As of August 31, 2018, 96 pregnancies in 90 women receiving perampanel had been reported. No concomitant medications were reported in 26 (28.9%) women taking perampanel. Overall, 43 pregnancies reached full term (all normal live births), 28 did not reach term (induced abortion, n = 18; spontaneous miscarriage, n = 6; incomplete spontaneous miscarriage, n = 2; premature delivery, n = 1; stillbirth [Fallot's tetralogy], n = 1), 18 were lost to follow-up, and seven were ongoing at data cut-off. Adverse events were reported in five full-term neonates (low Apgar score, n = 2; fatal neonatal aspiration, n = 1; cystic fibrosis and congenital deafness, n = 1; poor sucking reflex and shallow breathing, n = 1). PK simulations predicted perampanel exposure decreases throughout pregnancy and is up to four- and three-fold lower towards the end of pregnancy compared with non-pregnant women for total and unbound perampanel, respectively.
These data provide preliminary information on perampanel use during pregnancy and should be interpreted with caution. Further outcome data are required to estimate the prevalence of adverse pregnancy outcomes with perampanel exposure.
Key Points
Preclinical data indicated that perampanel may be associated with post‐implantation loss and/or some specific physical development delays
Of 96 pregnancies evaluated in 90 women exposed to perampanel, 43 reached full term; 26 (28.9%) women reported no concomitant ASM use
Of 71 pregnancies with a known outcome, there was one report of stillbirth with Fallot’s tetralogy (concomitant levetiracetam reported)
Pharmacokinetic simulations suggested a possible three‐ to four‐fold decrease in perampanel exposure over the course of a pregnancy
The small size and 19% lost to follow‐up in this preliminary sample require more data to estimate prevalence of adverse pregnancy outcomes
1 INTRODUCTION
Women with epilepsy have been estimated to account for up to 0.7% of pregnant women. 1 Due to the likelihood of seizures and associated risks therewith, and an increased risk of pregnancy‐related complications compared with women without epilepsy, 2 , 3 women with epilepsy frequently take anti‐seizure medication (ASM) during pregnancy. 4 , 5 , 6 Therefore, it is important to assess the safety of exposure to ASMs in utero, so that treatment with ASMs during pregnancy can balance adequate seizure control with the potential risk of adverse effects on the exposed fetus. 2 Pharmacokinetic (PK) changes of ASMs during pregnancy, such as enhanced drug elimination and decreased drug exposure compared with non‐pregnant women, are important to consider, as they may impact both fetal exposure and maternal seizure control. 5 , 7 However, there is limited information about PK changes of many of the newer ASMs during pregnancy. 5 , 7 , 8
Moreover, use of ASMs in pregnant women is increasing, with a five‐fold increase in the use of newer ASMs (i.e., those approved in the United States since 1993) by pregnant women during the early‐to‐mid 2000s, whereas use of older ASMs has remained generally stable. 6 Additionally, some ASMs may also be used to treat non‐epilepsy indications, including bipolar disorder, neuropathic pain, and fibromyalgia, 9 and a substantial increase in the frequency of ASM use in pregnant women for non‐epilepsy indications, including psychiatric diagnoses and pain disorders, has been observed during the past 2 decades. 6 , 10 The prospective European Registry of Antiepileptic Drugs and Pregnancy (EURAP) registry noted marked changes in the use of different ASMs over a 14‐year period (2000–2013), with increased use of lamotrigine and levetiracetam and a decrease in the use of valproate and carbamazepine. 11 A 27% decrease in the prevalence of major congenital malformations was observed in parallel with this shift in ASM utilization, and there was no indication of an increase in the proportion of pregnancies with poor seizure control. 11 An analysis of data from the Australian Register of Antiepileptic Drugs in Pregnancy revealed that approximately half of women with epilepsy who received ASMs throughout pregnancy still experienced at least one seizure during their pregnancy. 12
Perampanel is a once‐daily ASM that has been licensed for clinical use in the United States since 2012 for focal‐onset seizures (previously known as partial‐onset seizures) with or without focal to bilateral tonic–clonic seizures (previously known as secondarily generalized seizures), and generalized tonic–clonic seizures (previously known as primary generalized tonic–clonic seizures). 13 , 14 Perampanel is eliminated primarily via cytochrome P450 3A (CYP3A) metabolism, and concomitant enzyme‐inducing ASMs reduce exposure by ~50%–67%. 14 In vitro studies have shown that at clinically relevant concentrations (20–2000 ng/ml), perampanel is ~95%–96% bound to plasma proteins. 14
There are no adequate studies specifically in pregnant women treated with perampanel to assess outcomes of pregnancies that are exposed to perampanel. 14 Additionally, unknown effects of pregnancy on perampanel PK limit our understanding of whether dose adjustments may be necessary to maintain seizure control during pregnancy and/or reduce the likelihood of fetal adverse events (AEs). The aim of the analyses presented here is to summarize pregnancy and fetal/postnatal outcomes following maternal exposure to perampanel using preclinical and clinical data, and to gain a greater understanding of how perampanel PK may be affected by pregnancy through the use of physiologically based PK (PBPK) modeling.
2 MATERIALS AND METHODS
2.1 Preclinical data in pregnancy
Preclinical studies were performed in accordance with Japanese guidelines in place at the time of study initiation. 15 , 16
Developmental studies of perampanel were conducted in pregnant animals in line with licensing requirements. Dose‐ranging (0, 10, 30, and 60 mg/kg/day) and pivotal (0, 1, 3, and 10 mg/kg/day) embryo‐fetal development studies were performed in Sprague–Dawley rats (n = 7 and n = 20 per group, respectively) and New Zealand white rabbits (n = 5 and n = 20 per group, respectively), with perampanel administered orally on gestation Days 6–17 and Days 6–18 for rats and rabbits, respectively.
Dose‐ranging and pivotal pre‐ and postnatal development studies were performed in Sprague–Dawley rats (0, 1, 3, and 10 mg/kg/day). Perampanel was administered orally from gestation Day 6 to postnatal Day 6 in the dose‐ranging study (n = 8 per group) and from gestation Day 6 to postnatal Day 20 (weaning) in the pivotal study (n = 20 per group).
2.2 Safety review in pregnancy
A search of the Eisai global safety database for perampanel was performed for events coded to the Medical Dictionary for Regulatory Activities (MedDRA) high‐level group terms of Pregnancy, Labor, Delivery, and Postpartum Conditions, and/or the Standardized MedDRA Query terms of Congenital, Familiar, and Genetic Disorders. This analysis included all reports of exposure to perampanel during pregnancy from spontaneous sources (routine clinical settings) as well as solicited reports from interventional clinical studies and non‐interventional post‐marketing studies, up until the cut‐off date of August 31, 2018. Pregnancies from interventional clinical studies where the woman was reported to be exposed to placebo rather than perampanel, or where exposure only occurred post‐partum (e.g., during breastfeeding), and unpublished reports received from EURAP were excluded (no other registry data were included in the database). Pregnancies where perampanel exposure occurred via the father were evaluated separately from those with maternal perampanel exposure. Reported pregnancies were followed up every trimester and with a form requesting details of the final pregnancy outcome (including selection of category from the following: normal, abnormal baby, congenital abnormality, and died during perinatal period). There was no specific protocol for classification of congenital malformations, nor was there a requirement for assessment by a teratologist in cases of suspected abnormal outcomes. Any additional investigation was at the discretion of the treating physician, who was also responsible for reporting the pregnancy outcome. Outcomes for pregnancies reported before August 31, 2018 were updated in line with any follow‐up reports received by May 27, 2019 (additional information related to exposure in one woman during breastfeeding was received on June 17, 2019). In cases where no outcome was recorded by May 27, 2019, these pregnancies were either considered ongoing (if last reported as ongoing any time from January 2018 onwards) or lost to follow‐up (if last reported as ongoing any time prior to January 2018, or where dates of the pregnancy were unknown).
The clinical studies with perampanel in the global safety database included data from patients with or without epilepsy (focal‐onset or generalized tonic–clonic seizures), and healthy volunteers from Phase 1 studies. Pregnancy was an exclusion criterion for all these studies. The protocols for each study required patients to be abstinent or to use at least one medically acceptable method of contraception starting at Visit 1, throughout the entire study period, and for 2 months after the last dose of study drug. Pregnancy was captured as a treatment‐emergent AE, and confirmed with urine and serum pregnancy tests.
2.3 PK modeling predictions in pregnancy
A PBPK model for perampanel was developed using Simcyp® version 15.1. A previous model developed with Simcyp® version 11 17 was used as the starting point. The previous model predicted a slightly longer half‐life for perampanel than that observed clinically; thus, the following modifications were made to correct this discrepancy: (1) a middle‐out approach was used, where clinical total drug clearance values from clinical trial data (Study 005 17 ) were escalated to intrinsic hepatic drug clearance values using the retrograde calculator, (2) the scalar for tissue‐to‐plasma partition coefficients (Kps scalar) was manually adjusted from 1.0 to 0.75 to improve fit to the clinical data, (3) active uptake into hepatocytes was changed from 1.0 to 1.5, and (4) the absorption model was changed from the advanced dissolution absorption and metabolism model 18 to a first‐order absorption model with predicted inputs. The effective permeability in vivo (Peff = 7.73 × 10−4 cm/s), the absorption rate constant (ka = 3.38 h−1), and fraction absorbed (F = 0.999) were predicted by Simcyp® with the mechanistic permeability model (MechPeff 19 , 20 ) based on perampanel's partition co‐efficient, logPoctanol:water, of 2.86. 17 The model was evaluated by simulating clinical PK of single and multiple doses of perampanel in 100 healthy volunteers (10 trials each with 10 virtual subjects aged 20–50 years; 1:1 ratio of males to females). These predictions were compared with PK profiles for single oral doses of perampanel administered at 1, 2, 4, 6, or 8 mg and once‐daily doses of oral perampanel administered at 1, 2, 4, or 6 mg for 14 days that were observed in several clinical studies.
Simcyp® supports modeling and simulations to assess potential PK‐related effects of pregnancy. The in‐built Simcyp® Pregnancy population file, with an updated CYP3A4 ontogeny (Figure S1), 21 was used to predict clinical PK in 25 pregnant women (five trials each with five virtual subjects aged 20–45 years) for single oral doses of perampanel 8 mg administered during pregnancy at Weeks 0, 10, 19, 28, and 36, and once‐daily doses of oral perampanel 8 mg administered over a 270‐day pregnancy.
3 RESULTS
3.1 Preclinical data of perampanel in pregnancy
In reproductive toxicology and developmental preclinical studies, perampanel induced developmental toxicity in pregnant rats and rabbits at clinically relevant doses, where 1 mg/kg/day is similar to 8 mg/day in humans. 14 No drug‐related effects of perampanel on fertility and early embryonic development were noted with doses of 1, 10, or 30 mg/kg/day. Dose‐dependent increases in rates of post‐implantation loss were observed with perampanel exposure following 30 and 60 mg/kg in rats and 10, 30, and 60 mg/kg in rabbits. In the pivotal embryo‐fetal development study in rats, perampanel was associated with increased rates of diverticulum of the intestine at all doses tested (1, 3, or 10 mg/kg/day).
In the dose‐ranging pre‐ and postnatal development study in rats, no developmental toxicity was observed. In the pivotal study, stillbirths were increased and the viability index was decreased for the mid‐ and high‐level doses (3 and 10 mg/kg/day). Behavioral and reproductive development of the offspring were not affected, but some parameters of physical development showed some delay (preputial separation in males and vaginal opening in females) in offspring born to mothers who received 10/mg/kg/day, which are probably secondary to the pharmacology‐based central nervous system effects of perampanel.
3.2 Clinical data of pregnancy events and outcomes with perampanel
At the data cutoff of August 31, 2018, 96 pregnancies had been reported in 90 women aged 17–48 (age was unknown in 21 women) exposed to perampanel globally, including six women who had two pregnancies each. These pregnancies included 33 from patients enrolled in clinical studies or from other solicited reports, and 63 spontaneous reports from routine clinical settings. Perampanel dosing was discontinued or modified according to clinical need during the pregnancy in some women. The demographic characteristics and sources of clinical data for the women included in this analysis are shown in Table 1. Excluding three instances of perampanel exposure via a partner, perampanel was reported to have been taken by 26 of 90 (28.9%) women with no concomitant ASM use recorded (due to limited information provided in most cases, these women cannot be confirmed as receiving monotherapy). Perampanel administered with one concomitant ASM was reported for 24 of 90 (26.7%) women, and with ≥2 concomitant ASMs for 38 of 90 (42.2%) women; concomitant ASM use was unknown in two (2.2%) women, as only the neonatal records were available. The majority of patients from clinical trials included in this analysis were from trials that enrolled patients with focal‐onset seizures. For spontaneously reported pregnancies, the seizure types that patients had were not usually recorded. An additional three pregnancies were identified following paternal exposure to perampanel.
TABLE 1 Demographic characteristics and sources of clinical data for women exposed to perampanel during pregnancy
Characteristic From clinical studies or solicited reports, n = 30 From spontaneous reports, n = 60 a Total, n = 90
Country of origin, n (%)
Japan 3 (10.0) 9 (15.0) 12 (13.3)
Spain 0 (0) 12 (20.0) 12 (13.3)
France 0 (0) 8 (13.3) 8 (8.9)
United Kingdom 1 (3.3) 7 (11.7) 8 (8.9)
Russia 1 (3.3) 6 (10.0) 7 (7.8)
United States of America 4 (13.3) 3 (5.0) 7 (7.8)
China 4 (13.3) 0 (0) 4 (4.4)
Germany 0 (0) 4 (6.7) 4 (4.4)
Australia 2 (6.7) 1 (1.7) 3 (3.3)
Austria 0 (0) 3 (5.0) 3 (3.3)
South Korea 3 (10.0) 0 (0) 3 (3.3)
Latvia 3 (10.0) 0 (0) 3 (3.3)
Other b 9 (30.0) 7 (11.7) 16 (17.8)
Age group at time of pregnancy, n (%) c
<20 years 2 (6.7) 5 (8.3) 7 (7.8)
20–24 years 7 (23.3) 6 (10.0) 13 (14.4)
25–29 years 5 (16.7) 12 (20.0) 17 (18.9)
30–34 years 5 (16.7) 8 (13.3) 13 (14.4)
35–39 years 6 (20.0) 10 (16.7) 16 (17.8)
≥40 years 3 (10.0) 0 (0) 3 (3.3)
Unknown 2 (6.7) 19 (31.7) 21 (23.3)
Number of reported concomitant ASMs, n (%)
0 5 (16.7) 21 (35.0) d 26 (28.9)
1 6 (20.0) 18 (30.0) 24 (26.7)
2 9 (30.0) e 11 (18.3) 20 (22.2)
≥3 10 (33.3) 8 (13.3) 18 (20.0)
Unknown 0 (0) 2 (3.3) 2 (2.2)
Clinical data source, n (%)
Clinical studies f 30 (100.0) 0 (0) 30 (33.3)
Spontaneous reports 0 (0) 60 (100.0) 60 (66.7)
Abbreviations: ASM, anti‐seizure medication; n, number of women with pregnancies exposed to perampanel.
a Spontaneous reports of pregnancies in routine clinical practice.
b Fewer than three patients each were from the following countries: Argentina, Belgium, Canada, Denmark, Estonia, India, Ireland, Israel, Lithuania, Mexico, and Slovakia.
c For women with multiple pregnancies, age is recorded as age during the first perampanel‐exposed pregnancy.
d No concomitant ASMs were reported; however, due to limited information being provided in most cases, monotherapy cannot be confirmed.
e Includes one woman who received two ASMs during her first pregnancy and one ASM during a second pregnancy.
f Studies 048 (NCT02279485), 207 (NCT00368472), 210 (NCT00154063), 304 (NCT00699972), 307 (NCT00735397), 332 (NCT01393743), 335 (NCT01618695), 342 (NCT03201900), 401 (NCT01871233), 402 (NCT02033902), 502 (NCT03059329), 505 (NCT02722590), and others.
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Of the 96 pregnancies reported in women receiving perampanel, 43 reached full term, 28 did not go to term, 18 were lost to follow‐up, and seven were ongoing at data cutoff (Table 2). Of the pregnancies that went to full term, all 43 resulted in normal live births. Of the pregnancies that did not go to term, 18 cases were induced abortions, six cases were spontaneous miscarriages, two cases were incomplete spontaneous miscarriages, one case resulted in premature delivery, and one resulted in stillbirth due to Fallot’s tetralogy (Table 2). The reasons for the decision to have an induced abortion were not usually known, but most were considered by the investigator or treating physician to be not related to perampanel; causality in two spontaneous reports was not reported by the treating physician, and the cases were therefore assumed to be possibly related to perampanel. Of the six women who had two perampanel‐exposed pregnancies, one woman had two full‐term normal births. Three women had one full‐term birth each, plus a spontaneous abortion, incomplete spontaneous abortion, or an unknown outcome, and two women had both an induced abortion and a spontaneous abortion. Of the three pregnancies with paternal exposure to perampanel, two resulted in normal live births; the outcome of the third pregnancy was unknown (Table 2).
TABLE 2 Pregnancy outcomes in the global safety database
Outcome From clinical studies or solicited reports From spontaneous reports a Total
Maternal exposure to perampanel n = 33 n = 63 n = 96
Reached full term 8 35 43
Normal live birth 8 35 b 43
Did not reach full term 22 6 28
Induced abortion 15 c 3 18
Spontaneous miscarriage 5 1 6
Incomplete spontaneous miscarriage 2 0 2
Premature delivery 0 1 1
Stillbirth (Fallot’s tetralogy) 0 1 1
Lost to follow‐up d 2 16 18
Ongoing pregnancy e 1 6 7
Paternal exposure to perampanel n = 2 n = 1 n = 3
Reached full term 2 0 2
Normal live birth 2 0 2
Lost to follow‐up e 0 1 1
a Spontaneous reports of pregnancies in routine clinical practice.
b Includes two cases where babies were exposed to perampanel during pregnancy and via breastfeeding.
c Includes one case of benign hydatidiform mole and one case of ectopic pregnancy.
d Cases that were last reported as ongoing any time prior to January 2018, and where no subsequent updates have been received, or where dates of pregnancy were unknown.
e Cases that were last reported as ongoing any time from January 2018 onward, and where no subsequent updates have been received.
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AEs were reported in five of the 43 babies whose mothers received perampanel that reached full term: low Apgar score in two babies, fatal neonatal aspiration in one baby, cystic fibrosis and congenital deafness in one baby, and poor sucking reflex and shallow breathing in one baby (Table 3). In the cases where the relationship of AEs to perampanel was reported, poor sucking reflex and shallow breathing (reported in one baby who was also exposed to perampanel via breastfeeding) were considered possibly related to perampanel by the treating physician, whereas fatal neonatal aspiration, congenital deafness, and cystic fibrosis were not considered by the treating physician to be related to perampanel. In the case of fatal neonatal aspiration, the mother discontinued perampanel at ~2 months of gestation following the positive pregnancy test; the baby was born by Caesarian section at 39 of weeks' gestation, and the investigator considered that “the death was probably due to aspiration of fluid during birth." The baby with cystic fibrosis and congenital deafness was born to parents with congenital deafness who were carriers of the gene for cystic fibrosis. The relationship between perampanel exposure and low Apgar score in both babies was not reported, and therefore assumed to be possibly related to perampanel. Concomitant ASM use was reported for the mothers of the babies with fatal neonatal aspiration (carbamazepine and clobazam), poor sucking reflex and shallow breathing (clonazepam), and cystic fibrosis and congenital deafness (two unspecified ASMs). No concomitant ASMs were reported for the mothers of either baby with low Apgar score. No other birth defects or fetal malformations were reported in babies who reached full term.
TABLE 3 Adverse events in babies from pregnancies with maternal exposure to perampanel that reached full term (n = 43)
Baby Outcome Causality a Perampanel dose Source b Concomitant ASMs taken by mother
1 Low Apgar score Not reported c 6 mg daily Spontaneous None reported
2 Low Apgar score Not reported c 8 mg daily Spontaneous None reported
3 Neonatal aspiration (fatal) Not related to perampanel 12 mg daily d Clinical study Carbamazepine, clobazam
4 e Cystic fibrosis Not related to perampanel Unknown Spontaneous Two unspecified ASMs
Congenital deafness Not related to perampanel
5 f Poor sucking reflex Possibly related to perampanel 2 to >12 mg daily g Spontaneous Clonazepam
Shallow breathing Possibly related to perampanel
Abbreviation: ASM, antiseizure medication.
a As considered by the investigator/reporting physician.
b Solicited reports of pregnancies from clinical studies/other solicited sources or spontaneous reports of pregnancies in routine clinical practice.
c Not reported and therefore assumed to be possibly related.
d Perampanel was discontinued at the time of positive pregnancy test (7 months prior to full‐term delivery by Caesarian section).
e Both parents had congenital deafness and were carriers of the gene for cystic fibrosis.
f This baby was also exposed to perampanel via breastfeeding.
g Perampanel dose was increased to 6 mg/day following positive pregnancy test, to 10 mg/day approximately 1 month before birth, and at the mother's own discretion exceeded 12 mg/day prior to labor before reducing to 10 mg/day after the birth. Maternal perampanel plasma concentration was increased at the time of birth (2510 ng/ml).
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The AEs related to pregnancies that did not reach full term were benign hydatidiform mole and ectopic pregnancy (one woman each, both of whom had an induced abortion; perampanel 6 mg daily and 2–4 mg daily, respectively), and stillbirth with Fallot’s tetralogy at the 30th week of pregnancy in one baby (perampanel 2–6 mg daily until the 11th week of pregnancy). None of these AEs, nor their associated induced abortions, was considered by the investigator or reporting physician to be related to perampanel, although no further explanation was provided. Use of concomitant ASM(s) was reported for all three of these mothers (benign hydatidiform mole: carbamazepine, clobazam, lamotrigine; ectopic pregnancy: lorazepam, levetiracetam, lacosamide, clonazepam; Fallot’s tetralogy: levetiracetam).
There were two cases of babies who were exposed to perampanel via breastfeeding in addition to in utero exposure to perampanel. As mentioned, poor sucking reflex and shallow breathing were reported in one of these babies. This baby was suspected to have withdrawal syndrome of perampanel and had a perampanel plasma concentration of 264 ng/ml 4 h after birth; the perampanel plasma concentration in the mother was 2510 ng/ml. Maternal concomitant clonazepam use was also reported for this pregnancy, and the baby had a clonazepam concentration of 2 mg/ml 4 h after birth. The plasma perampanel concentration in the baby decreased to 224 ng/ml 7 days after birth and to 124 ng/ml 14 days after birth; maternal plasma perampanel concentration had decreased to 845 ng/ml within approximately 2 months of the birth. No AEs were reported for the other baby who was exposed to perampanel via breastfeeding, and no information was recorded on the plasma concentrations of perampanel in that baby or its mother. No concomitant medication use was reported for the mother of this baby.
3.3 PK modeling of perampanel in pregnancy
During model evaluation, the PBPK model for perampanel generally predicted the PK profiles of perampanel well in single‐ and multiple‐dose studies in healthy volunteers (Figure S2). Single‐dose simulations of total and unbound plasma perampanel concentrations at timepoints throughout pregnancy are shown in Figure 1. These simulations predicted that total perampanel exposure is 2.5‐fold lower at the end of pregnancy (Week 36) compared with non‐pregnant women, whereas exposure for unbound (free) perampanel was predicted to be two‐fold lower (Table 4). Multiple‐dose simulations predicted that total perampanel exposure decreases over time during pregnancy, and is up to four‐fold lower toward the end of pregnancy (Week 36) compared with non‐pregnant women (Table 4 and Figure 2). Exposure for unbound perampanel was predicted to be three‐fold lower (Table 4).
FIGURE 1 Single oral dose simulations of perampanel 8 mg administered during pregnancy at Weeks 0, 10, 19, 28, and 36. (A) Mean predicted total plasma concentrations of perampanel. (B) Mean predicted unbound plasma concentrations of perampanel
TABLE 4 Total and free exposure parameters in physiologically based pharmacokinetic simulations in pregnant and non‐pregnant women
Gestational age at dosing Cmax, mg/L AUC, mg/L/h Cmax ratio AUC ratio
Total perampanel exposure for single 8‐mg doses
Not pregnant 0.180 12.83 1.00 1.00
10 weeks 0.166 10.78 0.92 0.84
19 weeks 0.152 8.12 0.84 0.63
28 weeks 0.139 6.16 0.77 0.48
36 weeks 0.128 5.07 0.71 0.40
Free perampanel exposure for single 8‐mg doses
Not pregnant 0.0090 0.657 1.00 1.00
10 weeks 0.0089 0.577 0.99 0.88
19 weeks 0.0087 0.459 0.97 0.70
28 weeks 0.0085 0.374 0.94 0.57
36 weeks .0084 0.333 0.94 0.51
Pregnancy status Cmax, mg/L AUC, mg/L/h Cmax ratio AUC ratio
Total perampanel exposure for multiple 8‐mg doses after 270 days of simulations
Not pregnant 0.53 55.51 1.00 1.00
Pregnant 0.26 14.01 0.49 0.25
Free perampanel exposure for multiple 8‐mg doses after 270 days of simulations
Not pregnant 0.027 2.84 1.00 1.00
Pregnant 0.017 0.94 0.63 0.33
Abbreviations: AUC, area under the curve; Cmax, maximum concentration.
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FIGURE 2 Predicted steady‐state pharmacokinetic profiles of perampanel 8 mg administered once daily for 240 days (5760 h) plus post‐dosing follow‐up period in pregnant and non‐pregnant women
4 DISCUSSION
In the absence of any previously published systematic summary of pregnancy outcomes with perampanel, 14 the preclinical and clinical data presented here may offer some valuable information on the effects of in utero exposure to perampanel, supplemented by PK simulations of perampanel during pregnancy.
The preclinical studies indicate that perampanel may be linked with post‐implantation loss in pregnant rats and rabbits, and with diverticulum of the intestine and specific delays in physical development when administered to pregnant rats. Preclinical data for carbamazepine, phenytoin, topiramate, and valproate, which are ASMs associated with an increased risk of congenital malformations, reveal similar types of teratogenic effects to those observed clinically, 2 , 22 , 23 , 24 , 25 highlighting the possible relevance of preclinical data for determining potential adverse pregnancy outcomes in humans. Although the risks of congenital malformations are generally considered lower in lamotrigine, levetiracetam, and oxcarbazepine (vs. carbamazepine, phenytoin, topiramate, and valproate), 2 , 26 teratogenic effects have still been observed in preclinical data for these ASMs. 27 , 28 , 29 Thus, there is an unmet need for clinical data to confirm any teratogenic effects of perampanel in human babies.
Of 71 pregnancies with a known outcome following maternal exposure to perampanel, there was one report of stillbirth with Fallot’s tetralogy and one report of fatal neonatal aspiration. Other AEs in babies included low Apgar scores in two babies, and poor sucking reflex and shallow breathing in one baby (all full‐term births). In the case of the baby with poor sucking reflex and shallow breathing, both mother and baby had elevated plasma perampanel concentrations following increased dosing of perampanel (>12 mg/day) at the mother's discretion prior to labor (concomitant clonazepam was also being taken by the mother). Additional AEs related to pregnancies that did not reach full term were benign hydatidiform mole and ectopic pregnancy (one woman each).
The conclusions that can be drawn from this safety review are limited by the low number of pregnancies included in the analysis. For example, there was a lack of information available in many of the pregnancy reports despite follow‐up at every trimester and until delivery or other outcome; this was particularly true for the reasons for induced abortions and in general for spontaneously reported pregnancies. In addition, causality with perampanel was as noted by the reporting physician, meaning that some AEs such as Fallot’s tetralogy were not attributed as related to perampanel although no alternate explanation was provided. Conversely, some AEs may have been incorrectly attributed as possibly related to perampanel due to expected effects of the drug (observer bias). A sizeable proportion of reported pregnancies (18.8%) were lost to follow‐up, which further reduces the number of pregnancy outcomes collated in this analysis. This highlights a need for the systematic collection of safety data related to epilepsy drug use during pregnancy via pregnancy registries. Finally, the mixed nature of the clinical trial and real‐world settings of perampanel administration for the patients included in this analysis meant that many patients received adjunctive perampanel rather than perampanel monotherapy. As a result, concomitant medications were administered in many, but not all, patients and some of the concomitant ASMs may have reduced perampanel exposure due to PK interactions.
The PK modeling of perampanel in pregnancy predicted that perampanel exposure may decline by two‐ to four‐fold during pregnancy, not taking into consideration any known effects of concomitant enzyme‐inducing ASMs. These differences predicted in pregnancy are a reflection of several physiological changes that are expected to occur during pregnancy, namely the two‐fold increase in CYP3A activity and an approximate 30% reduction in plasma albumin, which lead to higher free fractions in plasma and higher drug clearance. 5 , 30 Because perampanel is a low‐extraction drug, steady‐state unbound drug concentrations are independent of changes in protein binding, 31 which could explain why the predicted decrease in free perampanel exposure was smaller than that of total perampanel exposure during pregnancy.
Pregnancy can result in considerable changes to the PK of ASMs, which may have implications for seizure control and/or exposure of the fetus to ASMs. 7 Decreased serum concentrations for several ASMs, including carbamazepine, lamotrigine, levetiracetam, oxcarbazepine, phenytoin, phenobarbital, and zonisamide, have been observed during pregnancy. 7 For example, total concentration of carbamazepine, which is ~75% protein bound and metabolized similarly to perampanel (mainly via CYP3A4), 32 is reported to decrease over the course of a pregnancy, with a more limited decrease of up to 28% in unbound carbamazepine. However, reported decreases have varied widely between studies (0%–42%), 7 and some studies have reported limited or no clinically significant change in total and free carbamazepine concentrations during pregnancy. 32 , 33 Lamotrigine serum concentration is suppressed during pregnancy by 50%–60% on average, although inter‐patient variability may result in greater decreases. 7 Although total valproate concentrations are reported to fall by up to 40% during late pregnancy compared with pre‐pregnancy, the PK of valproate, an ASM that is highly protein bound (~90%), are somewhat variable, 7 , 34 and data are limited due to the known teratogenic and possible cognitive effects of valproate. 35 , 36 Based on the information presented for the PK modeling of perampanel in pregnancy, the predicted changes appear to exceed those of other ASMs. However, it should be noted that the effect of perampanel in pregnancy has not been investigated in a clinical trial and PK modeling has not been validated against observed perampanel concentrations in pregnant women. PBPK modeling has been used previously to predict the PK of other types of drugs, including dexamethasone, betamethasone, caffeine, midazolam, metoprolol, and rilpivirine, during pregnancy, and in general, the values were found to be comparable with observed PK. 21 , 37 , 38
5 CONCLUSIONS
Understanding the implications of ASM use during pregnancy is important due to an increased use in pregnant women. Although the perampanel data reported here are limited, they summarize available information on perampanel use during pregnancy and provide some insights regarding the effects of in utero exposure to perampanel. These preliminary data should be interpreted with caution, as the sample size is limited, and 18.8% of the pregnancies were lost to follow‐up. More outcome data are required to estimate the prevalence of adverse pregnancy outcomes with perampanel exposure. Physicians are encouraged to enroll pregnant women taking perampanel in a pregnancy registry, such as the North American Antiepileptic Drug Pregnancy Registry, EURAP, the UK and Irish Epilepsy & Pregnancy Registers, or the Australian Pregnancy Register, to allow more data to be collected on perampanel exposure during pregnancy. Pregnant women should also be carefully monitored, including drug‐level monitoring, where available, whilst taking perampanel as dose adjustments may be needed in order to maintain a similar level of exposure relative to a non‐pregnancy condition and to prevent the occurrence of breakthrough seizures.
CONFLICT OF INTEREST
B.V. has received research support from Biogen MA Inc., Cavion LLC, Engage Therapeutics Inc., Neurelis, Ovid Therapeutics, SK Life Science Inc., UCB Biopharma SPRL, and UCB Biosciences Inc. T.T. has received speaker's honoraria to his institution from Eisai, Sandoz, Sanofi, Sun Pharmaceutical Industries Ltd, and UCB, and research support from Bial, CURE, Eisai, the European Union (ESBACE), GlaxoSmithKline, Stockholm County Council, Teva, and UCB. C.D. and E.S. are employees of Eisai Inc. T.J.O. has received research and speaker honoraria from Eisai and UCB Pharma.
AUTHOR CONTRIBUTIONS
C.D. was involved in collating and reviewing the data relating to pregnancy events with exposure to perampanel. E.S. was responsible for developing the PBPK model for perampanel and running the pregnancy simulations. All authors were involved in the interpretation of the results, the reviewing and approval of the manuscript, and the decision to submit the article for publication. All authors also confirm accountability for the accuracy and integrity of the work.
Supporting information
Fig S1‐S2
Click here for additional data file.
ACKNOWLEDGMENTS
Funding for these analyses was provided by Eisai Inc. Rick Dabagian is thanked for assistance with review of the data. Medical writing support, under the direction of the authors, was provided by Rebekah Waters, PhD, and Kirsty Muirhead, PhD, of CMC AFFINITY, McCann Health Medical Communications, funded by, Eisai Inc., in accordance with Good Publication Practice 3 (GPP3) guidelines. | CLONAZEPAM, LACOSAMIDE, LEVETIRACETAM, LORAZEPAM | DrugsGivenReaction | CC BY-NC-ND | 33666943 | 19,058,070 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Fallot^s tetralogy'. | Perampanel and pregnancy.
The objective was to summarize pregnancy and fetal/postnatal outcomes following maternal perampanel exposure using preclinical and clinical data, and to use physiologically based pharmacokinetic (PBPK) modeling to improve understanding of perampanel pharmacokinetics (PK) during pregnancy.
Preclinical developmental studies with perampanel were conducted in pregnant rats and rabbits. Clinical data were collated from the Eisai global perampanel safety database, comprising reports of perampanel exposure during pregnancy from routine clinical settings, interventional studies, and non-interventional post-marketing studies, searched for events coded to Medical Dictionary for Regulatory Activities (MedDRA) high-level group terms of Pregnancy, Labor, Delivery, and Postpartum Conditions and/or the Standardized MedDRA Query terms of Congenital, Familiar, and Genetic Disorders. A PBPK model was used to predict clinical perampanel PK throughout pregnancy.
Preclinical studies indicated that perampanel may be linked with post-implantation loss and/or some specific physical development delays but not fertility and early embryonic development. As of August 31, 2018, 96 pregnancies in 90 women receiving perampanel had been reported. No concomitant medications were reported in 26 (28.9%) women taking perampanel. Overall, 43 pregnancies reached full term (all normal live births), 28 did not reach term (induced abortion, n = 18; spontaneous miscarriage, n = 6; incomplete spontaneous miscarriage, n = 2; premature delivery, n = 1; stillbirth [Fallot's tetralogy], n = 1), 18 were lost to follow-up, and seven were ongoing at data cut-off. Adverse events were reported in five full-term neonates (low Apgar score, n = 2; fatal neonatal aspiration, n = 1; cystic fibrosis and congenital deafness, n = 1; poor sucking reflex and shallow breathing, n = 1). PK simulations predicted perampanel exposure decreases throughout pregnancy and is up to four- and three-fold lower towards the end of pregnancy compared with non-pregnant women for total and unbound perampanel, respectively.
These data provide preliminary information on perampanel use during pregnancy and should be interpreted with caution. Further outcome data are required to estimate the prevalence of adverse pregnancy outcomes with perampanel exposure.
Key Points
Preclinical data indicated that perampanel may be associated with post‐implantation loss and/or some specific physical development delays
Of 96 pregnancies evaluated in 90 women exposed to perampanel, 43 reached full term; 26 (28.9%) women reported no concomitant ASM use
Of 71 pregnancies with a known outcome, there was one report of stillbirth with Fallot’s tetralogy (concomitant levetiracetam reported)
Pharmacokinetic simulations suggested a possible three‐ to four‐fold decrease in perampanel exposure over the course of a pregnancy
The small size and 19% lost to follow‐up in this preliminary sample require more data to estimate prevalence of adverse pregnancy outcomes
1 INTRODUCTION
Women with epilepsy have been estimated to account for up to 0.7% of pregnant women. 1 Due to the likelihood of seizures and associated risks therewith, and an increased risk of pregnancy‐related complications compared with women without epilepsy, 2 , 3 women with epilepsy frequently take anti‐seizure medication (ASM) during pregnancy. 4 , 5 , 6 Therefore, it is important to assess the safety of exposure to ASMs in utero, so that treatment with ASMs during pregnancy can balance adequate seizure control with the potential risk of adverse effects on the exposed fetus. 2 Pharmacokinetic (PK) changes of ASMs during pregnancy, such as enhanced drug elimination and decreased drug exposure compared with non‐pregnant women, are important to consider, as they may impact both fetal exposure and maternal seizure control. 5 , 7 However, there is limited information about PK changes of many of the newer ASMs during pregnancy. 5 , 7 , 8
Moreover, use of ASMs in pregnant women is increasing, with a five‐fold increase in the use of newer ASMs (i.e., those approved in the United States since 1993) by pregnant women during the early‐to‐mid 2000s, whereas use of older ASMs has remained generally stable. 6 Additionally, some ASMs may also be used to treat non‐epilepsy indications, including bipolar disorder, neuropathic pain, and fibromyalgia, 9 and a substantial increase in the frequency of ASM use in pregnant women for non‐epilepsy indications, including psychiatric diagnoses and pain disorders, has been observed during the past 2 decades. 6 , 10 The prospective European Registry of Antiepileptic Drugs and Pregnancy (EURAP) registry noted marked changes in the use of different ASMs over a 14‐year period (2000–2013), with increased use of lamotrigine and levetiracetam and a decrease in the use of valproate and carbamazepine. 11 A 27% decrease in the prevalence of major congenital malformations was observed in parallel with this shift in ASM utilization, and there was no indication of an increase in the proportion of pregnancies with poor seizure control. 11 An analysis of data from the Australian Register of Antiepileptic Drugs in Pregnancy revealed that approximately half of women with epilepsy who received ASMs throughout pregnancy still experienced at least one seizure during their pregnancy. 12
Perampanel is a once‐daily ASM that has been licensed for clinical use in the United States since 2012 for focal‐onset seizures (previously known as partial‐onset seizures) with or without focal to bilateral tonic–clonic seizures (previously known as secondarily generalized seizures), and generalized tonic–clonic seizures (previously known as primary generalized tonic–clonic seizures). 13 , 14 Perampanel is eliminated primarily via cytochrome P450 3A (CYP3A) metabolism, and concomitant enzyme‐inducing ASMs reduce exposure by ~50%–67%. 14 In vitro studies have shown that at clinically relevant concentrations (20–2000 ng/ml), perampanel is ~95%–96% bound to plasma proteins. 14
There are no adequate studies specifically in pregnant women treated with perampanel to assess outcomes of pregnancies that are exposed to perampanel. 14 Additionally, unknown effects of pregnancy on perampanel PK limit our understanding of whether dose adjustments may be necessary to maintain seizure control during pregnancy and/or reduce the likelihood of fetal adverse events (AEs). The aim of the analyses presented here is to summarize pregnancy and fetal/postnatal outcomes following maternal exposure to perampanel using preclinical and clinical data, and to gain a greater understanding of how perampanel PK may be affected by pregnancy through the use of physiologically based PK (PBPK) modeling.
2 MATERIALS AND METHODS
2.1 Preclinical data in pregnancy
Preclinical studies were performed in accordance with Japanese guidelines in place at the time of study initiation. 15 , 16
Developmental studies of perampanel were conducted in pregnant animals in line with licensing requirements. Dose‐ranging (0, 10, 30, and 60 mg/kg/day) and pivotal (0, 1, 3, and 10 mg/kg/day) embryo‐fetal development studies were performed in Sprague–Dawley rats (n = 7 and n = 20 per group, respectively) and New Zealand white rabbits (n = 5 and n = 20 per group, respectively), with perampanel administered orally on gestation Days 6–17 and Days 6–18 for rats and rabbits, respectively.
Dose‐ranging and pivotal pre‐ and postnatal development studies were performed in Sprague–Dawley rats (0, 1, 3, and 10 mg/kg/day). Perampanel was administered orally from gestation Day 6 to postnatal Day 6 in the dose‐ranging study (n = 8 per group) and from gestation Day 6 to postnatal Day 20 (weaning) in the pivotal study (n = 20 per group).
2.2 Safety review in pregnancy
A search of the Eisai global safety database for perampanel was performed for events coded to the Medical Dictionary for Regulatory Activities (MedDRA) high‐level group terms of Pregnancy, Labor, Delivery, and Postpartum Conditions, and/or the Standardized MedDRA Query terms of Congenital, Familiar, and Genetic Disorders. This analysis included all reports of exposure to perampanel during pregnancy from spontaneous sources (routine clinical settings) as well as solicited reports from interventional clinical studies and non‐interventional post‐marketing studies, up until the cut‐off date of August 31, 2018. Pregnancies from interventional clinical studies where the woman was reported to be exposed to placebo rather than perampanel, or where exposure only occurred post‐partum (e.g., during breastfeeding), and unpublished reports received from EURAP were excluded (no other registry data were included in the database). Pregnancies where perampanel exposure occurred via the father were evaluated separately from those with maternal perampanel exposure. Reported pregnancies were followed up every trimester and with a form requesting details of the final pregnancy outcome (including selection of category from the following: normal, abnormal baby, congenital abnormality, and died during perinatal period). There was no specific protocol for classification of congenital malformations, nor was there a requirement for assessment by a teratologist in cases of suspected abnormal outcomes. Any additional investigation was at the discretion of the treating physician, who was also responsible for reporting the pregnancy outcome. Outcomes for pregnancies reported before August 31, 2018 were updated in line with any follow‐up reports received by May 27, 2019 (additional information related to exposure in one woman during breastfeeding was received on June 17, 2019). In cases where no outcome was recorded by May 27, 2019, these pregnancies were either considered ongoing (if last reported as ongoing any time from January 2018 onwards) or lost to follow‐up (if last reported as ongoing any time prior to January 2018, or where dates of the pregnancy were unknown).
The clinical studies with perampanel in the global safety database included data from patients with or without epilepsy (focal‐onset or generalized tonic–clonic seizures), and healthy volunteers from Phase 1 studies. Pregnancy was an exclusion criterion for all these studies. The protocols for each study required patients to be abstinent or to use at least one medically acceptable method of contraception starting at Visit 1, throughout the entire study period, and for 2 months after the last dose of study drug. Pregnancy was captured as a treatment‐emergent AE, and confirmed with urine and serum pregnancy tests.
2.3 PK modeling predictions in pregnancy
A PBPK model for perampanel was developed using Simcyp® version 15.1. A previous model developed with Simcyp® version 11 17 was used as the starting point. The previous model predicted a slightly longer half‐life for perampanel than that observed clinically; thus, the following modifications were made to correct this discrepancy: (1) a middle‐out approach was used, where clinical total drug clearance values from clinical trial data (Study 005 17 ) were escalated to intrinsic hepatic drug clearance values using the retrograde calculator, (2) the scalar for tissue‐to‐plasma partition coefficients (Kps scalar) was manually adjusted from 1.0 to 0.75 to improve fit to the clinical data, (3) active uptake into hepatocytes was changed from 1.0 to 1.5, and (4) the absorption model was changed from the advanced dissolution absorption and metabolism model 18 to a first‐order absorption model with predicted inputs. The effective permeability in vivo (Peff = 7.73 × 10−4 cm/s), the absorption rate constant (ka = 3.38 h−1), and fraction absorbed (F = 0.999) were predicted by Simcyp® with the mechanistic permeability model (MechPeff 19 , 20 ) based on perampanel's partition co‐efficient, logPoctanol:water, of 2.86. 17 The model was evaluated by simulating clinical PK of single and multiple doses of perampanel in 100 healthy volunteers (10 trials each with 10 virtual subjects aged 20–50 years; 1:1 ratio of males to females). These predictions were compared with PK profiles for single oral doses of perampanel administered at 1, 2, 4, 6, or 8 mg and once‐daily doses of oral perampanel administered at 1, 2, 4, or 6 mg for 14 days that were observed in several clinical studies.
Simcyp® supports modeling and simulations to assess potential PK‐related effects of pregnancy. The in‐built Simcyp® Pregnancy population file, with an updated CYP3A4 ontogeny (Figure S1), 21 was used to predict clinical PK in 25 pregnant women (five trials each with five virtual subjects aged 20–45 years) for single oral doses of perampanel 8 mg administered during pregnancy at Weeks 0, 10, 19, 28, and 36, and once‐daily doses of oral perampanel 8 mg administered over a 270‐day pregnancy.
3 RESULTS
3.1 Preclinical data of perampanel in pregnancy
In reproductive toxicology and developmental preclinical studies, perampanel induced developmental toxicity in pregnant rats and rabbits at clinically relevant doses, where 1 mg/kg/day is similar to 8 mg/day in humans. 14 No drug‐related effects of perampanel on fertility and early embryonic development were noted with doses of 1, 10, or 30 mg/kg/day. Dose‐dependent increases in rates of post‐implantation loss were observed with perampanel exposure following 30 and 60 mg/kg in rats and 10, 30, and 60 mg/kg in rabbits. In the pivotal embryo‐fetal development study in rats, perampanel was associated with increased rates of diverticulum of the intestine at all doses tested (1, 3, or 10 mg/kg/day).
In the dose‐ranging pre‐ and postnatal development study in rats, no developmental toxicity was observed. In the pivotal study, stillbirths were increased and the viability index was decreased for the mid‐ and high‐level doses (3 and 10 mg/kg/day). Behavioral and reproductive development of the offspring were not affected, but some parameters of physical development showed some delay (preputial separation in males and vaginal opening in females) in offspring born to mothers who received 10/mg/kg/day, which are probably secondary to the pharmacology‐based central nervous system effects of perampanel.
3.2 Clinical data of pregnancy events and outcomes with perampanel
At the data cutoff of August 31, 2018, 96 pregnancies had been reported in 90 women aged 17–48 (age was unknown in 21 women) exposed to perampanel globally, including six women who had two pregnancies each. These pregnancies included 33 from patients enrolled in clinical studies or from other solicited reports, and 63 spontaneous reports from routine clinical settings. Perampanel dosing was discontinued or modified according to clinical need during the pregnancy in some women. The demographic characteristics and sources of clinical data for the women included in this analysis are shown in Table 1. Excluding three instances of perampanel exposure via a partner, perampanel was reported to have been taken by 26 of 90 (28.9%) women with no concomitant ASM use recorded (due to limited information provided in most cases, these women cannot be confirmed as receiving monotherapy). Perampanel administered with one concomitant ASM was reported for 24 of 90 (26.7%) women, and with ≥2 concomitant ASMs for 38 of 90 (42.2%) women; concomitant ASM use was unknown in two (2.2%) women, as only the neonatal records were available. The majority of patients from clinical trials included in this analysis were from trials that enrolled patients with focal‐onset seizures. For spontaneously reported pregnancies, the seizure types that patients had were not usually recorded. An additional three pregnancies were identified following paternal exposure to perampanel.
TABLE 1 Demographic characteristics and sources of clinical data for women exposed to perampanel during pregnancy
Characteristic From clinical studies or solicited reports, n = 30 From spontaneous reports, n = 60 a Total, n = 90
Country of origin, n (%)
Japan 3 (10.0) 9 (15.0) 12 (13.3)
Spain 0 (0) 12 (20.0) 12 (13.3)
France 0 (0) 8 (13.3) 8 (8.9)
United Kingdom 1 (3.3) 7 (11.7) 8 (8.9)
Russia 1 (3.3) 6 (10.0) 7 (7.8)
United States of America 4 (13.3) 3 (5.0) 7 (7.8)
China 4 (13.3) 0 (0) 4 (4.4)
Germany 0 (0) 4 (6.7) 4 (4.4)
Australia 2 (6.7) 1 (1.7) 3 (3.3)
Austria 0 (0) 3 (5.0) 3 (3.3)
South Korea 3 (10.0) 0 (0) 3 (3.3)
Latvia 3 (10.0) 0 (0) 3 (3.3)
Other b 9 (30.0) 7 (11.7) 16 (17.8)
Age group at time of pregnancy, n (%) c
<20 years 2 (6.7) 5 (8.3) 7 (7.8)
20–24 years 7 (23.3) 6 (10.0) 13 (14.4)
25–29 years 5 (16.7) 12 (20.0) 17 (18.9)
30–34 years 5 (16.7) 8 (13.3) 13 (14.4)
35–39 years 6 (20.0) 10 (16.7) 16 (17.8)
≥40 years 3 (10.0) 0 (0) 3 (3.3)
Unknown 2 (6.7) 19 (31.7) 21 (23.3)
Number of reported concomitant ASMs, n (%)
0 5 (16.7) 21 (35.0) d 26 (28.9)
1 6 (20.0) 18 (30.0) 24 (26.7)
2 9 (30.0) e 11 (18.3) 20 (22.2)
≥3 10 (33.3) 8 (13.3) 18 (20.0)
Unknown 0 (0) 2 (3.3) 2 (2.2)
Clinical data source, n (%)
Clinical studies f 30 (100.0) 0 (0) 30 (33.3)
Spontaneous reports 0 (0) 60 (100.0) 60 (66.7)
Abbreviations: ASM, anti‐seizure medication; n, number of women with pregnancies exposed to perampanel.
a Spontaneous reports of pregnancies in routine clinical practice.
b Fewer than three patients each were from the following countries: Argentina, Belgium, Canada, Denmark, Estonia, India, Ireland, Israel, Lithuania, Mexico, and Slovakia.
c For women with multiple pregnancies, age is recorded as age during the first perampanel‐exposed pregnancy.
d No concomitant ASMs were reported; however, due to limited information being provided in most cases, monotherapy cannot be confirmed.
e Includes one woman who received two ASMs during her first pregnancy and one ASM during a second pregnancy.
f Studies 048 (NCT02279485), 207 (NCT00368472), 210 (NCT00154063), 304 (NCT00699972), 307 (NCT00735397), 332 (NCT01393743), 335 (NCT01618695), 342 (NCT03201900), 401 (NCT01871233), 402 (NCT02033902), 502 (NCT03059329), 505 (NCT02722590), and others.
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Of the 96 pregnancies reported in women receiving perampanel, 43 reached full term, 28 did not go to term, 18 were lost to follow‐up, and seven were ongoing at data cutoff (Table 2). Of the pregnancies that went to full term, all 43 resulted in normal live births. Of the pregnancies that did not go to term, 18 cases were induced abortions, six cases were spontaneous miscarriages, two cases were incomplete spontaneous miscarriages, one case resulted in premature delivery, and one resulted in stillbirth due to Fallot’s tetralogy (Table 2). The reasons for the decision to have an induced abortion were not usually known, but most were considered by the investigator or treating physician to be not related to perampanel; causality in two spontaneous reports was not reported by the treating physician, and the cases were therefore assumed to be possibly related to perampanel. Of the six women who had two perampanel‐exposed pregnancies, one woman had two full‐term normal births. Three women had one full‐term birth each, plus a spontaneous abortion, incomplete spontaneous abortion, or an unknown outcome, and two women had both an induced abortion and a spontaneous abortion. Of the three pregnancies with paternal exposure to perampanel, two resulted in normal live births; the outcome of the third pregnancy was unknown (Table 2).
TABLE 2 Pregnancy outcomes in the global safety database
Outcome From clinical studies or solicited reports From spontaneous reports a Total
Maternal exposure to perampanel n = 33 n = 63 n = 96
Reached full term 8 35 43
Normal live birth 8 35 b 43
Did not reach full term 22 6 28
Induced abortion 15 c 3 18
Spontaneous miscarriage 5 1 6
Incomplete spontaneous miscarriage 2 0 2
Premature delivery 0 1 1
Stillbirth (Fallot’s tetralogy) 0 1 1
Lost to follow‐up d 2 16 18
Ongoing pregnancy e 1 6 7
Paternal exposure to perampanel n = 2 n = 1 n = 3
Reached full term 2 0 2
Normal live birth 2 0 2
Lost to follow‐up e 0 1 1
a Spontaneous reports of pregnancies in routine clinical practice.
b Includes two cases where babies were exposed to perampanel during pregnancy and via breastfeeding.
c Includes one case of benign hydatidiform mole and one case of ectopic pregnancy.
d Cases that were last reported as ongoing any time prior to January 2018, and where no subsequent updates have been received, or where dates of pregnancy were unknown.
e Cases that were last reported as ongoing any time from January 2018 onward, and where no subsequent updates have been received.
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AEs were reported in five of the 43 babies whose mothers received perampanel that reached full term: low Apgar score in two babies, fatal neonatal aspiration in one baby, cystic fibrosis and congenital deafness in one baby, and poor sucking reflex and shallow breathing in one baby (Table 3). In the cases where the relationship of AEs to perampanel was reported, poor sucking reflex and shallow breathing (reported in one baby who was also exposed to perampanel via breastfeeding) were considered possibly related to perampanel by the treating physician, whereas fatal neonatal aspiration, congenital deafness, and cystic fibrosis were not considered by the treating physician to be related to perampanel. In the case of fatal neonatal aspiration, the mother discontinued perampanel at ~2 months of gestation following the positive pregnancy test; the baby was born by Caesarian section at 39 of weeks' gestation, and the investigator considered that “the death was probably due to aspiration of fluid during birth." The baby with cystic fibrosis and congenital deafness was born to parents with congenital deafness who were carriers of the gene for cystic fibrosis. The relationship between perampanel exposure and low Apgar score in both babies was not reported, and therefore assumed to be possibly related to perampanel. Concomitant ASM use was reported for the mothers of the babies with fatal neonatal aspiration (carbamazepine and clobazam), poor sucking reflex and shallow breathing (clonazepam), and cystic fibrosis and congenital deafness (two unspecified ASMs). No concomitant ASMs were reported for the mothers of either baby with low Apgar score. No other birth defects or fetal malformations were reported in babies who reached full term.
TABLE 3 Adverse events in babies from pregnancies with maternal exposure to perampanel that reached full term (n = 43)
Baby Outcome Causality a Perampanel dose Source b Concomitant ASMs taken by mother
1 Low Apgar score Not reported c 6 mg daily Spontaneous None reported
2 Low Apgar score Not reported c 8 mg daily Spontaneous None reported
3 Neonatal aspiration (fatal) Not related to perampanel 12 mg daily d Clinical study Carbamazepine, clobazam
4 e Cystic fibrosis Not related to perampanel Unknown Spontaneous Two unspecified ASMs
Congenital deafness Not related to perampanel
5 f Poor sucking reflex Possibly related to perampanel 2 to >12 mg daily g Spontaneous Clonazepam
Shallow breathing Possibly related to perampanel
Abbreviation: ASM, antiseizure medication.
a As considered by the investigator/reporting physician.
b Solicited reports of pregnancies from clinical studies/other solicited sources or spontaneous reports of pregnancies in routine clinical practice.
c Not reported and therefore assumed to be possibly related.
d Perampanel was discontinued at the time of positive pregnancy test (7 months prior to full‐term delivery by Caesarian section).
e Both parents had congenital deafness and were carriers of the gene for cystic fibrosis.
f This baby was also exposed to perampanel via breastfeeding.
g Perampanel dose was increased to 6 mg/day following positive pregnancy test, to 10 mg/day approximately 1 month before birth, and at the mother's own discretion exceeded 12 mg/day prior to labor before reducing to 10 mg/day after the birth. Maternal perampanel plasma concentration was increased at the time of birth (2510 ng/ml).
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The AEs related to pregnancies that did not reach full term were benign hydatidiform mole and ectopic pregnancy (one woman each, both of whom had an induced abortion; perampanel 6 mg daily and 2–4 mg daily, respectively), and stillbirth with Fallot’s tetralogy at the 30th week of pregnancy in one baby (perampanel 2–6 mg daily until the 11th week of pregnancy). None of these AEs, nor their associated induced abortions, was considered by the investigator or reporting physician to be related to perampanel, although no further explanation was provided. Use of concomitant ASM(s) was reported for all three of these mothers (benign hydatidiform mole: carbamazepine, clobazam, lamotrigine; ectopic pregnancy: lorazepam, levetiracetam, lacosamide, clonazepam; Fallot’s tetralogy: levetiracetam).
There were two cases of babies who were exposed to perampanel via breastfeeding in addition to in utero exposure to perampanel. As mentioned, poor sucking reflex and shallow breathing were reported in one of these babies. This baby was suspected to have withdrawal syndrome of perampanel and had a perampanel plasma concentration of 264 ng/ml 4 h after birth; the perampanel plasma concentration in the mother was 2510 ng/ml. Maternal concomitant clonazepam use was also reported for this pregnancy, and the baby had a clonazepam concentration of 2 mg/ml 4 h after birth. The plasma perampanel concentration in the baby decreased to 224 ng/ml 7 days after birth and to 124 ng/ml 14 days after birth; maternal plasma perampanel concentration had decreased to 845 ng/ml within approximately 2 months of the birth. No AEs were reported for the other baby who was exposed to perampanel via breastfeeding, and no information was recorded on the plasma concentrations of perampanel in that baby or its mother. No concomitant medication use was reported for the mother of this baby.
3.3 PK modeling of perampanel in pregnancy
During model evaluation, the PBPK model for perampanel generally predicted the PK profiles of perampanel well in single‐ and multiple‐dose studies in healthy volunteers (Figure S2). Single‐dose simulations of total and unbound plasma perampanel concentrations at timepoints throughout pregnancy are shown in Figure 1. These simulations predicted that total perampanel exposure is 2.5‐fold lower at the end of pregnancy (Week 36) compared with non‐pregnant women, whereas exposure for unbound (free) perampanel was predicted to be two‐fold lower (Table 4). Multiple‐dose simulations predicted that total perampanel exposure decreases over time during pregnancy, and is up to four‐fold lower toward the end of pregnancy (Week 36) compared with non‐pregnant women (Table 4 and Figure 2). Exposure for unbound perampanel was predicted to be three‐fold lower (Table 4).
FIGURE 1 Single oral dose simulations of perampanel 8 mg administered during pregnancy at Weeks 0, 10, 19, 28, and 36. (A) Mean predicted total plasma concentrations of perampanel. (B) Mean predicted unbound plasma concentrations of perampanel
TABLE 4 Total and free exposure parameters in physiologically based pharmacokinetic simulations in pregnant and non‐pregnant women
Gestational age at dosing Cmax, mg/L AUC, mg/L/h Cmax ratio AUC ratio
Total perampanel exposure for single 8‐mg doses
Not pregnant 0.180 12.83 1.00 1.00
10 weeks 0.166 10.78 0.92 0.84
19 weeks 0.152 8.12 0.84 0.63
28 weeks 0.139 6.16 0.77 0.48
36 weeks 0.128 5.07 0.71 0.40
Free perampanel exposure for single 8‐mg doses
Not pregnant 0.0090 0.657 1.00 1.00
10 weeks 0.0089 0.577 0.99 0.88
19 weeks 0.0087 0.459 0.97 0.70
28 weeks 0.0085 0.374 0.94 0.57
36 weeks .0084 0.333 0.94 0.51
Pregnancy status Cmax, mg/L AUC, mg/L/h Cmax ratio AUC ratio
Total perampanel exposure for multiple 8‐mg doses after 270 days of simulations
Not pregnant 0.53 55.51 1.00 1.00
Pregnant 0.26 14.01 0.49 0.25
Free perampanel exposure for multiple 8‐mg doses after 270 days of simulations
Not pregnant 0.027 2.84 1.00 1.00
Pregnant 0.017 0.94 0.63 0.33
Abbreviations: AUC, area under the curve; Cmax, maximum concentration.
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FIGURE 2 Predicted steady‐state pharmacokinetic profiles of perampanel 8 mg administered once daily for 240 days (5760 h) plus post‐dosing follow‐up period in pregnant and non‐pregnant women
4 DISCUSSION
In the absence of any previously published systematic summary of pregnancy outcomes with perampanel, 14 the preclinical and clinical data presented here may offer some valuable information on the effects of in utero exposure to perampanel, supplemented by PK simulations of perampanel during pregnancy.
The preclinical studies indicate that perampanel may be linked with post‐implantation loss in pregnant rats and rabbits, and with diverticulum of the intestine and specific delays in physical development when administered to pregnant rats. Preclinical data for carbamazepine, phenytoin, topiramate, and valproate, which are ASMs associated with an increased risk of congenital malformations, reveal similar types of teratogenic effects to those observed clinically, 2 , 22 , 23 , 24 , 25 highlighting the possible relevance of preclinical data for determining potential adverse pregnancy outcomes in humans. Although the risks of congenital malformations are generally considered lower in lamotrigine, levetiracetam, and oxcarbazepine (vs. carbamazepine, phenytoin, topiramate, and valproate), 2 , 26 teratogenic effects have still been observed in preclinical data for these ASMs. 27 , 28 , 29 Thus, there is an unmet need for clinical data to confirm any teratogenic effects of perampanel in human babies.
Of 71 pregnancies with a known outcome following maternal exposure to perampanel, there was one report of stillbirth with Fallot’s tetralogy and one report of fatal neonatal aspiration. Other AEs in babies included low Apgar scores in two babies, and poor sucking reflex and shallow breathing in one baby (all full‐term births). In the case of the baby with poor sucking reflex and shallow breathing, both mother and baby had elevated plasma perampanel concentrations following increased dosing of perampanel (>12 mg/day) at the mother's discretion prior to labor (concomitant clonazepam was also being taken by the mother). Additional AEs related to pregnancies that did not reach full term were benign hydatidiform mole and ectopic pregnancy (one woman each).
The conclusions that can be drawn from this safety review are limited by the low number of pregnancies included in the analysis. For example, there was a lack of information available in many of the pregnancy reports despite follow‐up at every trimester and until delivery or other outcome; this was particularly true for the reasons for induced abortions and in general for spontaneously reported pregnancies. In addition, causality with perampanel was as noted by the reporting physician, meaning that some AEs such as Fallot’s tetralogy were not attributed as related to perampanel although no alternate explanation was provided. Conversely, some AEs may have been incorrectly attributed as possibly related to perampanel due to expected effects of the drug (observer bias). A sizeable proportion of reported pregnancies (18.8%) were lost to follow‐up, which further reduces the number of pregnancy outcomes collated in this analysis. This highlights a need for the systematic collection of safety data related to epilepsy drug use during pregnancy via pregnancy registries. Finally, the mixed nature of the clinical trial and real‐world settings of perampanel administration for the patients included in this analysis meant that many patients received adjunctive perampanel rather than perampanel monotherapy. As a result, concomitant medications were administered in many, but not all, patients and some of the concomitant ASMs may have reduced perampanel exposure due to PK interactions.
The PK modeling of perampanel in pregnancy predicted that perampanel exposure may decline by two‐ to four‐fold during pregnancy, not taking into consideration any known effects of concomitant enzyme‐inducing ASMs. These differences predicted in pregnancy are a reflection of several physiological changes that are expected to occur during pregnancy, namely the two‐fold increase in CYP3A activity and an approximate 30% reduction in plasma albumin, which lead to higher free fractions in plasma and higher drug clearance. 5 , 30 Because perampanel is a low‐extraction drug, steady‐state unbound drug concentrations are independent of changes in protein binding, 31 which could explain why the predicted decrease in free perampanel exposure was smaller than that of total perampanel exposure during pregnancy.
Pregnancy can result in considerable changes to the PK of ASMs, which may have implications for seizure control and/or exposure of the fetus to ASMs. 7 Decreased serum concentrations for several ASMs, including carbamazepine, lamotrigine, levetiracetam, oxcarbazepine, phenytoin, phenobarbital, and zonisamide, have been observed during pregnancy. 7 For example, total concentration of carbamazepine, which is ~75% protein bound and metabolized similarly to perampanel (mainly via CYP3A4), 32 is reported to decrease over the course of a pregnancy, with a more limited decrease of up to 28% in unbound carbamazepine. However, reported decreases have varied widely between studies (0%–42%), 7 and some studies have reported limited or no clinically significant change in total and free carbamazepine concentrations during pregnancy. 32 , 33 Lamotrigine serum concentration is suppressed during pregnancy by 50%–60% on average, although inter‐patient variability may result in greater decreases. 7 Although total valproate concentrations are reported to fall by up to 40% during late pregnancy compared with pre‐pregnancy, the PK of valproate, an ASM that is highly protein bound (~90%), are somewhat variable, 7 , 34 and data are limited due to the known teratogenic and possible cognitive effects of valproate. 35 , 36 Based on the information presented for the PK modeling of perampanel in pregnancy, the predicted changes appear to exceed those of other ASMs. However, it should be noted that the effect of perampanel in pregnancy has not been investigated in a clinical trial and PK modeling has not been validated against observed perampanel concentrations in pregnant women. PBPK modeling has been used previously to predict the PK of other types of drugs, including dexamethasone, betamethasone, caffeine, midazolam, metoprolol, and rilpivirine, during pregnancy, and in general, the values were found to be comparable with observed PK. 21 , 37 , 38
5 CONCLUSIONS
Understanding the implications of ASM use during pregnancy is important due to an increased use in pregnant women. Although the perampanel data reported here are limited, they summarize available information on perampanel use during pregnancy and provide some insights regarding the effects of in utero exposure to perampanel. These preliminary data should be interpreted with caution, as the sample size is limited, and 18.8% of the pregnancies were lost to follow‐up. More outcome data are required to estimate the prevalence of adverse pregnancy outcomes with perampanel exposure. Physicians are encouraged to enroll pregnant women taking perampanel in a pregnancy registry, such as the North American Antiepileptic Drug Pregnancy Registry, EURAP, the UK and Irish Epilepsy & Pregnancy Registers, or the Australian Pregnancy Register, to allow more data to be collected on perampanel exposure during pregnancy. Pregnant women should also be carefully monitored, including drug‐level monitoring, where available, whilst taking perampanel as dose adjustments may be needed in order to maintain a similar level of exposure relative to a non‐pregnancy condition and to prevent the occurrence of breakthrough seizures.
CONFLICT OF INTEREST
B.V. has received research support from Biogen MA Inc., Cavion LLC, Engage Therapeutics Inc., Neurelis, Ovid Therapeutics, SK Life Science Inc., UCB Biopharma SPRL, and UCB Biosciences Inc. T.T. has received speaker's honoraria to his institution from Eisai, Sandoz, Sanofi, Sun Pharmaceutical Industries Ltd, and UCB, and research support from Bial, CURE, Eisai, the European Union (ESBACE), GlaxoSmithKline, Stockholm County Council, Teva, and UCB. C.D. and E.S. are employees of Eisai Inc. T.J.O. has received research and speaker honoraria from Eisai and UCB Pharma.
AUTHOR CONTRIBUTIONS
C.D. was involved in collating and reviewing the data relating to pregnancy events with exposure to perampanel. E.S. was responsible for developing the PBPK model for perampanel and running the pregnancy simulations. All authors were involved in the interpretation of the results, the reviewing and approval of the manuscript, and the decision to submit the article for publication. All authors also confirm accountability for the accuracy and integrity of the work.
Supporting information
Fig S1‐S2
Click here for additional data file.
ACKNOWLEDGMENTS
Funding for these analyses was provided by Eisai Inc. Rick Dabagian is thanked for assistance with review of the data. Medical writing support, under the direction of the authors, was provided by Rebekah Waters, PhD, and Kirsty Muirhead, PhD, of CMC AFFINITY, McCann Health Medical Communications, funded by, Eisai Inc., in accordance with Good Publication Practice 3 (GPP3) guidelines. | LEVETIRACETAM | DrugsGivenReaction | CC BY-NC-ND | 33666943 | 19,056,286 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Pemphigoid'. | IgE blockade with omalizumab reduces pruritus related to immune checkpoint inhibitors and anti-HER2 therapies.
Immunoglobulin E (IgE) blockade with omalizumab has demonstrated clinical benefit in pruritus-associated dermatoses (e.g. atopic dermatitis, bullous pemphigoid, urticaria). In oncology, pruritus-associated cutaneous adverse events (paCAEs) are frequent with immune checkpoint inhibitors (CPIs) and targeted anti-human epidermal growth factor receptor 2 (HER2) therapies. Thus, we sought to evaluate the efficacy and safety of IgE blockade with omalizumab in cancer patients with refractory paCAEs related to CPIs and anti-HER2 agents.
Patients included in this multicenter retrospective analysis received monthly subcutaneous injections of omalizumab for CPI or anti-HER2 therapy-related grade 2/3 pruritus that was refractory to topical corticosteroids plus at least one additional systemic intervention. To assess clinical response to omalizumab, we used the Common Terminology Criteria for Adverse Events version 5.0. The primary endpoint was defined as reduction in the severity of paCAEs to grade 1/0.
A total of 34 patients (50% female, median age 67.5 years) received omalizumab for cancer therapy-related paCAEs (71% CPIs; 29% anti-HER2). All had solid tumors (29% breast, 29% genitourinary, 15% lung, 26% other), and most (n = 18, 64%) presented with an urticarial phenotype. In total 28 of 34 (82%) patients responded to omalizumab. The proportion of patients receiving oral corticosteroids as supportive treatment for management of paCAEs decreased with IgE blockade, from 50% to 9% (P < 0.001). Ten of 32 (31%) patients had interruption of oncologic therapy due to skin toxicity; four of six (67%) were successfully rechallenged following omalizumab. There were no reports of anaphylaxis or hypersensitivity reactions related to omalizumab.
IgE blockade with omalizumab demonstrated clinical efficacy and was well tolerated in cancer patients with pruritus related to CPIs and anti-HER2 therapies.
pmcINTRODUCTION
Immune checkpoint inhibitor (CPI) and anti-human epidermal growth factor receptor 2 (anti-HER2) targeted therapies have improved the survival of patients with various malignancies.1,2 However, these agents [e.g. anti-programmed cell death protein 1/ligand 1 (PD-1/PD-L1), anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), anti-HER2] are frequently associated with skin toxicity and represent a substantial burden on quality of life in cancer patients.3,4 Dermatologic reactions of CPIs and anti-HER2 monoclonal antibodies (mAbs) include pruritus and pruritus-associated cutaneous adverse events (paCAEs), such as urticaria, eczema, and bullous pemphigoid (BP) rash.5 The percentage of pruritus reported ranges from 14% to 47% among patients receiving CPIs and from 10% to 18% in those treated with anti-HER2 agents.6–8
Hitherto, therapeutic recommendations for paCAEs were based on anecdotal reports and expert opinion,9–13 with upto 25% of patients not responding to standard-of-care anti-pruritus measures, such as topical corticosteroids (TCS), oral antihistamines (OAHs), and gamma-aminobutyric acid analogs [GABAlogs (e.g. gabapentin, pregabalin)].5 Because higher total serum immunoglobulin E (IgE) levels have been reported in higher-grade immune-related cutaneous adverse events (AEs),5 we hypothesized that IgE blockade represents an actionable therapeutic target to block immune mediators of pruritus. Omalizumab, an anti-IgE mAb approved for chronic idiopathic urticaria (CIU) refractory to OAHs,14,15 is cited in the National Comprehensive Cancer Network® (NCCN®) Clinical Practice Guidelines in Oncology for consideration in the management of refractory cases of CPI-related dermatologic AEs in which anti-IgE therapy has demonstrated therapeutic benefit (e.g. pruritus, urticaria). However, its efficacy for this indication has not been investigated yet. Here, we summarize the characteristics and outcomes of oncology patients treated with omalizumab for paCAEs that remained refractory to prior treatments.
METHODS
Patients
Cancer patients from two institutions [Memorial Sloan Kettering Cancer Center (MSK) in New York, NY (n = 32); MD Anderson Cancer Center (MDA) in Houston, TX (n = 2)] who were referred to the oncodermatology clinic between 23 April 2018 and 6 September 2019 for grade ≥ 2 pruritus related to CPI or anti-HER2 treatment refractory to TCS plus at least one additional systemic intervention [e.g. OAH, oral GABAlog, oral corticosteroid (OCS)] and who were subsequently managed with monthly subcutaneous injections of omalizumab were included in the analysis. Patients were identified and their electronic medical record (EMR) was retrospectively reviewed using an institutional health information and data management system. This study was conducted under institutional review board approval protocols for each participating institution (MSK Protocol #16–458 and MDA Protocol #PA-15–0959).
Study outcomes
Our primary aim was to assess the rate of clinical response to treatment with omalizumab. The primary endpoint (reduction in severity of paCAEs from grade 3/2 to grade 0/1) was evaluated either in person at patients’ follow-up visits (which occurred approximately every 30 days) or via telephone calls made to patients by either dermatology or oncology clinicians following each administration of omalizumab (also approximately every 30 days). Response outcome data were retrospectively evaluated using the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 toxicity grading scale16 and defined a priori. Positive clinical responses to IgE blockade with omalizumab were further subclassified as either complete (reduction from grade 3/2 to grade 0) or partial (reduction from grade 3/2 to grade 1). Patients were considered non-responders if the severity of their paCAEs changed from grade 3/2 to grade ≥ 2.
As a secondary aim, we examined outcomes of clinical safety, including AEs reported by patients and documented by clinicians during treatment with omalizumab. When specified in the EMR, attribution categories of unrelated, unlikely related, possibly related, probably related, or definitely related were assigned to each AE. Demographics, clinicopathologic characteristics, and laboratory measures were described and compared across response groups.
Statistical methods
Data were summarized using descriptive statistics with Excel (Microsoft, Redmond, WA) and SPSS Statistics version 25 (IBM, Armonk, NY). Categorical data are reported as counts (percentages). Unless otherwise specified, all continuous variables are reported as median and range (minimum-maximum) values. We utilized Fisher’s exact and paired t-tests to determine differences in categorical variables and normally distributed ordinal data, respectively; and Wilcoxon ManneWhitney U and median tests for analysis of nonparametric independent continuous samples. To detect change in related categorical and ordinal variables, McNemar’s and Wilcoxon signed rank tests were carried out. All analyses were two-tailed tests based on α = 0.05, with results reaching statistical significance if P < 0.05.
RESULTS
Demographics and oncologic history
A total of 34 patients [median age 67.5 years (37–84), 50% female] with solid tumors undergoing treatment with CPIs (n = 24, 71%) and anti-HER2 therapies (n = 10, 29%) were included (Table 1). All received omalizumab for paCAEs that remained refractory to other anti-pruritic or rash management strategies. Nearly half of paCAEs (n = 16, 47%) were attributed to anti-PD-1 agents, namely pembrolizumab (n = 8, 24%) or nivolumab (n = 8, 24%). Other CPI regimens associated with paCAEs included combination anti-CTLA-4/anti-PD-1 treatment with ipilimumab plus nivolumab (n = 5, 15%) and the single-agent PD-L1 blockers atezolizumab (n = 2, 6%) or durvalumab (n = 1, 3%).
Clinicopathologic characteristics
In total, 22 (64%) patients were diagnosed with urticaria (Figure 1A and B), 9 (26%) with BP (Figure 1C and D) using direct immunofluorescence and/or an enzyme-linked immunosorbent assay to detect and measure BP 180 and BP 230 serum antibodies (Supplementary Table S1, available at https://doi.org/10.1016/j.annonc.2021.02.016), and 3 (9%) with eczema (Figure 1E and F). paCAEs were of moderate-severe clinical severity: 25 (74%) were classified as CTCAE grade 2 and 9 (26%) as grade 3. From the onset of paCAEs to the first dose of omalizumab, the median duration of pruritic skin disease was 93 days (4–820 days) in 32 patients (Figure 2). Of 17 patients with a cutaneous biopsy carried out before receiving anti-IgE therapy, 16 (94%) had eosinophils identified on hematoxyline—eosin (H&E) histologic evaluation. Twelve of 16 patients (75%) with eosinophils on skin biopsy were responders: 6 (50%) partial, 6 (50%) complete. Four were non-responders. The patient without eosinophils identified on H&E was a partial responder. Ten of 13 patients (77%), all of whom were receiving CPI treatment, had abundance of eosinophils (>10 per 5 consecutive high-power fields).
Clinical response to omalizumab
Twenty-eight of 34 patients (82%) responded to omalizumab. Among the 28 responders, 16 (57%) had partial response (reduction of CTCAE grade 2/3 to grade 1 paCAEs) and 12 (43%) had complete response (reduction to grade 0). A relatively younger age was characteristic of omalizumab responders in comparison to non-responders (65 versus 71 years), and the proportion of females in the responder group significantly outweighed that found in the non-responder group (n = 17, 61% versus 0, 100%, P = 0.018). All non-responders (n = 6, 100%) were male, and most of them (n = 4, 67%) had genitourinary neoplasms (2 renal, 2 urothelial) that were being treated with CPIs. Anti-PD-1 agents (n = 5, 83%) predominated in the non-responder group. All 10 patients with paCAEs related to anti-HER2 therapies and 18 of 24 (75%) with paCAEs related to CPIs responded to omalizumab (Table 2).
The majority of patients with urticaria (18/22; 82%) (Figure 1A) and BP (7/9, 78%) (Figure 1C) derived clinical benefit from omalizumab (Figure 3A and B). IgE blockade was also effective in patients with eczema (n = 3, 100%; Figure 1E). Four of 22 (28%) patients with urticaria and 2 of 9 (22%) with BP did not respond to omalizumab.
The median duration of treatment with IgE blockade was 62 days (0–440 days), and the median time to response was 28 days (0–77 days): 25 days (0–65 days) in partial responders (n = 16) versus 53 days (5–77 days) in complete responders (n = 12) (Figure 2). The average number of doses of omalizumab that patients received before report of maximum clinical response was greater in complete responders than in partial responders (1.5 versus 1.0, P = 0.007).
Changes in supportive management of paCAEs
Before intervention with IgE blockade, the majority of patients (n = 27, 80%) failed three or more different types of treatments, and nearly 25% failed four or more (n = 8, 24%). All 34 (100%) patients failed TCS (e.g. clobetasol, fluocinonide, triamcinolone) and also at least one additional intervention of a different therapeutic class. Other failed supportive treatment categories included GABAlogs (n = 26, 77%) such as pregabalin, OAHs (n = 21, 62%) such as hydroxyzine, OCS (n = 17, 50%) such as prednisone, immunomodulators (IMs) (n = 10, 29%) such as aprepitant, and biologic agents (n = 4, 12%) such as dupilumab. After the introduction of anti-IgE therapy with omalizumab, patients used an average of 1.6 supportive treatments, which was significantly lower than 2.3, the average number before omalizumab (P = 0.005). Fewer patients continued to use
TCS concurrently with omalizumab (n = 23, 68% versus 34, 100%, P = 0.001) (Figure 4). The greatest reduction rates were observed with OCS (50% to 9%, P < 0.001), followed by GABAlogs (77% to 41%, P < 0.001), OAHs (62% to 32%, P = 0.006), and IMs (29% to 0%, P = 0.002). Of note, two (6%) patients did not require additional supportive medications concurrently with omalizumab.
Impact of omalizumab on interruption of cancer therapy
Ten of 32 (31%) patients had interruption of cancer therapy as a result of paCAEs, which were related exclusively to CPIs. Oncologic treatments were stopped within a median of 140 days (1–500 days) before receiving omalizumab. Six of these 10 (60%) patients responded to IgE blockade and were rechallenged with their respective regimen; four (67%) of the six were able to resume oncologic therapy without recurrence or worsening of skin toxicity. Among the two (33%) responders whose cancer therapy was discontinued, both had developed grade 3 BP during treatment with PD-1 inhibitors (one with prembrolizumab, the other with nivolumab). One of the two patients had progression of his lung malignancy; the other, whose baseline total serum IgE was recorded at 20 380 kU/l, died; he had renal cancer.
Safety of omalizumab
Overall (n = 34), the median total number of omalizumab injections administered was 3 (1–14), which was the same in responders and non-responders. An initial 300-mg injection was administered subcutaneously once per month in most (n = 30, 88%) cases. Four (12%) patients had one 150-mg monthly injection as their first dose, three of whom went on to receive the standard 300-mg monthly injections thereafter. There were no reports of AEs related to omalizumab. All AEs reported by oncologists and dermatologists during treatment with omalizumab are published as supplementary material (Supplementary Table S2, available at https://doi.org/10.1016/j.annonc.2021.02.016).
Changes in total serum IgE
Among 18 patients with blood drawn within 30 days pre-omalizumab, the median total serum IgE was 150 kU/l (7.9–20 380.0 kU/l). Seven (39%) of those 18 patients had levels >213 kU/l [median 390 kU/l (229–20 380 kU/l)], which is the upper limit of normal (ULN). Median values at baseline were 263 kU/l in complete responders (n = 5), 79.5 kU/l in partial responders (n = 9), and 208 kU/l in non-responders (n = 4). In 15 patients with both pre- and post-omalizumab IgE measured within a median of 71 days (12–501 days) following their first dose, the median total serum IgE at first follow-up was 213 kU/l (10–1156 kU/l) (Figure 5). The ratio of total serum baseline IgE/follow-up IgE was 0.5 in these 15 patients (0.4 in 12 responders versus 0.9 in 3 non-responders).
Characteristics of patients with abnormally elevated total serum IgE pre-omalizumab
Pre-omalizumab (baseline), there were 11 (34%) of 32 patients with total serum IgE above the ULN, 8 (73%) of whom had a positive response to IgE blockade [5 (62.5%) with partial response; 3 (37.5%) with complete response]. Three patients with IgE above the ULN did not respond to omalizumab. Among the 11 patients with abnormally high total serum IgE, the median was higher in omalizumab responders (629 kU/l, n = 8) compared to non-responders (300 kU/l, n = 3), P = 0.048. Genitourinary malignancy (n = 5, 45%) and BP (n = 4, 36%) were more prevalent in these patients. Most (n = 10, 91%) were on CPIs; one (9%) was on anti-HER2 treatment (Supplementary Table S3, available at https://doi.org/10.1016/j.annonc.2021.02.016).
Changes in blood eosinophils
Among 34 patients with blood eosinophils (absolute count, abs eos) measured pre-omalizumab, the median was 200 cells/μl (0–3800 cells/μl); 6 (18%) patients had ≥700 cells/μl with a median of 950 cells/μl (800–3800 cells/μl) (Supplementary Table S4, available at https://doi.org/10.1016/j.annonc.2021.02.016). Median values at baseline were 200 in complete responders (n = 12), 250 in partial responders (n = 16), and 100 in non-responders (n = 6). Post-omalizumab (n = 30), the overall median was 300 cells/μl (0–9300 cells/μl), with an increase of 100 cells/μl (−1400 to +5500 cells/μl) pre- to post-IgE blockade. Overall, the ratio of baseline abs eos/follow-up abs eos was equivalent (0.5) to that observed with total serum IgE (Figure 5).
DISCUSSION
Omalizumab as a therapeutic option for paCAEs related to CPIs and anti-HER2 therapies
Our assessment of cancer patients receiving omalizumab for pruritus associated with urticaria, BP, and eczema related to CPIs and anti-HER2 therapies resulted in positive outcomes of clinical efficacy. In concordance with the high response rates reported in randomized clinical trials and case series that have evaluated omalizumab for CIU,15 BP,17 and pediatric atopic dermatitis,18 our study demonstrated a response rate of 82%, which is clinically highly impactful.
In our study, whereas a significantly greater proportion of females were found in the responder group, males exclusively populated the non-responder group. This difference may be explained by the types of cancer and treatments that predominated in each group. Compared to CPIs, anti-HER2 mAbs were more frequently observed among responders, which were utilized exclusively by females for breast cancer. Thus, differences in degree of clinical response to omalizumab may be dependent on the target of mAbs and CPIs.
All BP and eczema lesions appeared under CPIs. While maculopapular rash remains one of the most common AEs observed in patients treated with CPIs,19 there is also increasing evidence to suggest that BP eruptions occur frequently among those receiving PD-1/PD-L1 inhibitors20,21 and that treatment is challenging. Although we observed a high degree of response among BP patients, additional controlled clinical studies with large samples are warranted to characterize the mechanisms responsible for recalcitrant pruritus in this population.
Reduction in the proportion of patients requiring additional supportive management during treatment with omalizumab
Both the average number of supportive treatments and the proportion of patients requiring their use concurrently with omalizumab decreased significantly. Before IgE blockade, >40% of our patients were prescribed supportive OCS and/or other IM measures to manage pruritus related to CPIs and anti-HER2 mAbs. However, the utilization of OCS and IMs decreased by 82% and 100%, respectively, which has clinical implications in the prevention of serious infections in those who are already immunocompromised.
While management of most paCAEs with TCS and/or oral antipruritics such as GABAlogs and OAHs is successful, there are patients who fail to demonstrate sustained clinical improvement, ultimately requiring OCS, IMs, or biologics. Pregabalin is often considered in patients with recalcitrant pruritus; however, its utilization is limited by sedation, dizziness and drowsiness, drug interactions, withdrawal seizures, and need for renal dosing.22–24 It is also not universally effective, as anecdotally many patients fail to improve. As refractory cases of paCAEs emerge, with up to 25% of patients not responding to symptom-directed dermatologic interventions,5 many will lead to anticancer therapy dosing interruptions and/or discontinuation.
Reduction of cancer therapy interruption with omalizumab
A substantial proportion (31%) of patients had interruption of oncologic therapy due to severe pruritus exclusively related to CPIs. Thus, as both CPI and anti-HER2-related dermatologic toxicities may result in dosing alterations and permanent discontinuation of cancer treatment,11,25 successful control of paCAEs related to these life-saving therapeutic mechanisms remains a priority. More than half of the patients who resumed oncologic treatment after receiving omalizumab did not have recurrence or worsening of skin toxicity, which further highlights the potentially beneficial therapeutic role of IgE blockade in cancer care.
Omalizumab as a safe treatment option for paCAEs related to CPIs and anti-HER2 therapies
The omalizumab dosing strategies and safety profile herein were similar to those in the CIU study,15 with the majority of patients receiving 300-mg monthly injections and a low reported incidence of AEs related to the anti-IgE agent. However, whereas the rate of serious AEs in the pivotal trial ranged between 1% and 6% across the intervention groups,15 there were zero cases in our study attributed to omalizumab, potentially due to uncontrolled AE reporting and a smaller study sample size.
Predictors of clinical response to omalizumab
Consistent with previous data, our study findings suggest that a lower ratio of total serum baseline IgE/follow-up IgE is a good predictor of response to omalizumab,26 with a lower total serum baseline IgE/follow-up IgE ratio resulting from a slower elimination rate of omalizumabeIgE complexes (compared to free IgE).24 Additionally, we observed better response outcomes in patients with greater abnormally high pre-omalizumab total serum IgE levels, which clinical studies on omalizumab for CIU have also reported.26,27 However, as evidenced in this study and in the previous CIU literature, the majority of patients with normal baseline IgE levels responded to omalizumab. Thus, our data would not justify a particular threshold of total serum IgE before the administration of omalizumab for its use in oncology patients.
Limitations
Conclusions drawn from this investigation are limited primarily by its retrospective design, moderate sample size, and lack of matched placebo-treated controls. Hence, all statistical inferences have been taken with these concerns into account. While omalizumab appeared to be beneficial in this moderately sized cohort of cancer patients with grade 2/3 paCAEs resistant to TCS plus at least one additional systemic treatment, this group may not be representative, and thus not generalizable to all oncology patients with toxicities of similar phenotype and severity related to CPI and anti-HER2 agents.
Despite the clinically meaningful response rate observed in our study, important questions remain to be addressed regarding the efficacy and safety of omalizumab for paCAEs related to CPIs and anti-HER2 targeted therapies. Firstly, characterization of additional blood markers, such as free serum IgE, autoantibodies to IgE, thyroid hormone, tryptase, and estrogen/progesterone, in women treated with anti-HER2 therapies for breast cancer would add to our understanding of the mechanism through which omalizumab improves pruritus related to anti-HER2 mAbs compared to CPIs. Secondly, the question of optimal dosing and when, if ever, therapy with omalizumab should be stopped while patients continue to undergo anticancer treatment with CPIs and anti-HER2 agents remains unanswered. As stipulated by Navarro-Triviño and colleagues,28 it may be possible that in certain patients with cancer, such as the ones we encountered with CPI-related BP and a lack of response to omalizumab, the use of higher doses (>300 mg/month) or even a shorter therapeutic interval (300 mg every 2 or 3 weeks) may be necessary to optimize the full effect of IgE blockade.
Conclusions
The results of our study suggest that blockade of IgE may represent a novel intervention for patients with pruritus related to CPIs and anti-HER2 therapies. Importantly, omalizumab appears to reduce the need for additional supportive medications, including OCS. Omalizumab has the potential to safely and effectively improve severity of paCAEs, as well as provide the opportunity for successful rechallenge and continuation of anticancer treatment. However, these observations require further evaluation and characterization in a prospective clinical trial. Also, given this initial signal of potential efficacy in pruritus related to CPIs and anti-HER2 agents, the investigation of anti-IgE therapy among a broader class of pruritus-inducing targeted anticancer therapies is warranted.
Supplementary Material
1
ACKNOWLEDGEMENTS
We acknowledge Ms Bernadette Murphy for her assistance with photography.
FUNDING
This work was supported in part by the National Cancer Institute at the National Institutes of Health [grant number P30 CA008748] to MEL and by the National Institute of Arthritis and Musculoskeletal and Skin Diseases at the National Institutes of Health [grant number U01 AR077511] to MEL and DYML. The funders/sponsors had no role in the design and conduct of the study; in the collection, analysis, and interpretation of data; or in the preparation, review, or approval of the manuscript. The content is solely the responsibility of the authors and does not necessarily represent the official views of funders/sponsors.
DISCLOSURE
AM has an advisory board role in AstraZeneca, receives research funding from Incyte, and is supported by a Dermatology Foundation Career Development Award. EQ receives royalties from UpToDate. SAF receives research funding from AstraZeneca and Genentech/Roche, has a consulting/advisory relationship with Merck, and has ownership interests in Urogen, Allogene Therapeutics, Neogene Therapeutics, Kronos Bio, InconOVir and Vida Ventures. MHV reports receiving commercial research support from Pfizer and honoraria from Pfizer, Exelixis, Eisai, Calithera Biosciences, and Corvus Pharmaceuticals. AD discloses honoraria/advisory board participation for Ignyta/Genentech/Roche, Loxo/Bayer/Lilly, Takeda/Ariad/Millennium, TP Therapeutics, AstraZeneca, Pfizer, Blueprint Medicines, Helsinn, Beigene, BergenBio, Hengrui Therapeutics, Exelixis, Tyra Biosciences, Verastem, and MORE Health; associated research funding paid to the institution from Pfizer, Exelixis, GlaxoSmithKline, Teva, Taiho, and Pharma-Mar; research for Foundation Medicine; royalties from Wolters Kluwer; expenses from Merck and Puma; and CME honoraria from Medscape, OncLive, PeerVoice, Physicians Education Resources, Targeted Oncology, and Research to Practice. MDH receives research funding from Bristol Myers Squibb; is a paid consultant to Merck, Bristol Myers Squibb, AstraZeneca, Genentech/Roche, Nektar, Syndax, Mirati, Blueprint, Achilles Therapeutics, PACT Pharma, Immunai, and Shattuck Labs; receives travel support/honoraria from AstraZeneca, Eli Lilly, Merck, and BMS; and a patent has been filed by MSK related to the use of tumor mutation burden to predict response to immunotherapy (PCT/US2015/062208), which has received licensing fees from PGDx. EAC reports consultancy fees from Pfizer, Novartis, Bristol Myers Squibb, COTA, Genentech-Roche, and Heron Therapeutics. DYML has been a consultant for Genentech and Novartis. MEL has a consultant role with Johnson and Johnson, Novocure, QED, Bicara, Janssen, Novartis, F. Hoffmann-La Roche AG, EMD Serono, Astrazeneca, Innovaderm, Deciphera, DFB, Azitra, Kintara, RBC/La Roche Posay, Trifecta, Varsona, Genentech, Loxo, Seattle Genetics, Lutris, OnQuality, Azitra, Roche, NCODA, Apricity, Oncoderm Labs, Hoth Therapeutics. Dr. Lacouture also receives research funding from Lutris, Paxman, Novocure, J&J, US Biotest, OQL, Novartis and AZ. All other authors have declared no conflicts of interest.
Figure 1. Clinicopathologic features of patients receiving IgE blockade with omalizumab for pruritus related to immune checkpoint inhibitors and anti-HER2 therapies.
(A) Urticaria with (B) interface dermatitis and superficial perivascular lymphoeosinophilic infiltrate (×200 magnification). (C) Bullous pemphigoid with (D) subepidermal vesicle with eosinophils and lymphocytes (×100 magnification). (E) Eczema with (F) slight spongiosis with superficial perivascular lymphoeosinophilic infiltrate (×200 magnification).
Anti-HER2, anti-human epidermal growth factor receptor 2; IgE, immunoglobulin E.
Figure 2. Time course and efficacy of IgE blockade in patients receiving omalizumab for pruritus related to CPIs and anti-HER2 therapies.
Anti-HER2, anti-human epidermal growth factor receptor 2; CPI, checkpoint inhibitor (e.g. PD-1, PD-L1, CTLA-4); CTLA-4, cytotoxic T-lymphocyte-associated protein 4; paCAEs, pruritus-associated cutaneous adverse events; PD-1, programmed cell death protein 1; PD-L1, programmed cell death-ligand 1.
a Median (min-max), 93 days (4–820 days) in 32 patients.
b median (min-max), 62 days (0–440 days) in 34 patients.
Figure 3. Clinical manifestation of paCAEs before (left) and after (right) IgE blockade with omalizumab.
(A) Patient with metastatic breast cancer and CTCAE grade 2 dermatographic urticaria related to anti-HER2 therapy (resistant to alclometasone dipropionate, clobetasol, diphenhydramine, hydroxyzine, levocetirizine, pregabalin). Two subcutaneous 300-mg doses of omalizumab resulted in complete response with reduction of paCAE to CTCAE grade 0. (B) Patient with advanced melanoma and CTCAE grade 3 bullous pemphigoid related to anti-PD-1 + anti-CTLA-4 immune checkpoint inhibition (resistant to cetirizine, diphenhydramine, mycophenolate mofetil, rituximab, prednisone, pregabalin). One subcutaneous 300-mg injection of omalizumab resulted in partial response with reduction of paCAE to CTCAE grade 1.
Anti-HER2, anti-human epidermal growth factor receptor 2; CTCAE, Common Terminology Criteria for Adverse Events; CTLA-4, cytotoxic T-lymphocyte-associated protein 4; IgE, immunoglobulin E; paCAEs, pruritus-associated cutaneous adverse events; PD-1, programmed cell death protein 1.
Figure 4. Pre- to post-omalizumab changes in the proportion of patients requiring supportive treatments to manage paCAEs related to immune checkpoint inhibitors and anti-HER2 therapies.
Anti-HER2, anti-human epidermal growth factor receptor 2; CTLA-4, cytotoxic T-lymphocyte-associated protein 4; GABAlogs, gamma-aminobutyric acid analogs; IMs, immunomodulators; OAH, oral antihistamine; OCS, oral corticosteroids; paCAEs, pruritus-associated cutaneous adverse events; PD-1, programmed cell death protein 1; PD-L1, programmed cell death-ligand 1; TCS, topical corticosteroids.
Figure 5. Pre- to post-omalizumab changes in total serum IgE and blood eosinophils of patients with paCAEs related to immune checkpoint inhibitors and anti-HER2 therapies.
Measured analytes correspond to total serum IgE and absolute count of blood eosinophils. The upper limit of normal (ULN) values were established a priori at 213 kU/l and 699 cells/μl, respectively, as per our institutional laboratory services provider (Mayo Clinic Laboratories, Rochester, MN).
Anti-HER2, anti-human epidermal growth factor receptor 2; IgE, immunoglobulin E; paCAEs, pruritus-associated cutaneous adverse events.
Table 1. Characteristics of cancer patients receiving IgE blockade with omalizumab for pruritus related to immune checkpoint inhibitors and anti-HER2 therapies
All patients Omalizumab respondersa
Reduction from baseline to CTCAE grade 0/1 Omalizumab non-respondersa
No reduction from baseline to CTCAE grade 0/1 P valueb,c
n (%)a 34 (100) 28 (82) 6 (18)
Age, years
Median(range) 67.5 (37–84) 65 (37–84) 71 (65–84) 0.177
≤50 8 (24) 8 (29) 0 (0) 0.434
51–69 11 (32) 9 (32) 2 (33)
≥70 15 (44) 11 (39) 4 (67)
Sex
Female 17 (50) 17 (61) 0 (0) 0.018
Male 17 (50) 11 (39) 6 (100)
Race
White 23 (68) 19 (68) 4 (67) 0.641
Asian 4 (12) 4 (14) 0 (0)
Otherd 7 (21) 5 (18) 2 (33)
Ethnicity
Non-Hispanic 28 (82) 22 (79) 6 (100) 0.562
Hispanic 6 (18) 6 (21) 0 (0)
Cancer diagnosis
Breast 10 (29) 10 (36) 0 (0) 0.114
Genitourinarye 10 (29) 6 (21) 4 (67)
Lung 5 (15) 4 (14) 1 (17)
Otherf 9 (26) 8 (29) 1 (17)
Cancer therapy type
Anti-PD-1 16 (47) 11 (39) 5 (83) 0.098
Anti-HER2 10 (29) 10 (36) 0 (0)
Anti-PD-1 + CTLA-4 5 (15) 5 (18) 0 (0)
Anti-PD-L1 3 (9) 2 (7) 1 (17)
paCAE phenotype
Urticaria 22 (64) 81 (64) 4 (67) 0.678
Bullous pemphigoid 9 (26) 7 (25) 2 (33)
Eczema 3 (9) 3 (11) 0 (0)
Baseline CTCAE v5.0 severity gradeb
Grade 2 25 (74) 21 (75) 4 (67) 0.644
Grade 3 9 (26) 7 (25) 2 (33)
CTCAE v5.0, Common Terminology Criteria for Adverse Events version 5.0; CTLA-4, cytotoxic T-lymphocyte-associated protein 4; IgE, immunoglobulin E; PD-1, programmed cell death protein 1; PD-L1, programmed cell death-ligand 1; paCAEs, pruritus-associated cutaneous adverse events.
a Clinical response to omalizumab was evaluated retrospectively by clinicians using the CTCAE version 5.0 toxicity grading scale.
b Fisher’s exact test for categorical variables.
c ManneWhitney U test for continuous variables.
d Other races include unknown and undisclosed.
e Genitourinary cancer diagnoses include renal cell carcinoma (n = 7, 21%) and urothelial tumors (n = 3, 9%).
f Other malignancies include head and neck (n = 2, 6%), melanoma (n = 2, 6%), glioblastoma (n = 1, 3%), angiosarcoma (n = 1, 3%), gastric (n = 1, 3%), ovarian (n = 1, 3%), and laryngeal (n = 1, 3%) cancer.
Table 2. Characteristics of cancer patients responding to IgE blockade with omalizumab for pruritus related to immune checkpoint inhibitors and anti-HER2 therapies
All responders n = 28 Patients with CPI-related paCAEs n = 18 Patients with anti-HER2-related paCAEs n = 10
Partial respondersa Complete respondersb Partial respondersa Complete respondersb
n (%) 28 (100) 10 (56) 8 (44) 6 (60) 4 (40)
Age, years
Median(range) 65 (37–84) 67 (50–81) 75 (66–84) 47 (37–68) 52 (43–63)
≤50 8 (29) 1 (10) 0 (0) 5 (83) 2 (50)
51–69 9 (32) 4 (40) 2 (25) 1 (17) 2 (50)
≥70 11 (39) 5 (50) 6 (75) 0 (0) 0 (0)
Sex
Female 17 (61) 4 (40) 3 (38) 6 (100) 4 (100)
Male 11 (39) 6 (60) 5 (63) 0 (0) 0 (0)
Race
White 19 (68) 6 (60) 6 (75) 5 (83) 2 (50)
Asian 4 (14) 0 (0) 2 (25) 1 (17) 1 (25)
Other 5 (18) 4 (40) 0 (0) 0 (0) 1 (25)
Ethnicity
Non-Hispanic 22 (79) 7 (70) 7 (88) 5 (83) 3 (75)
Hispanic 6 (21) 3 (30) 1 (13) 1 (17) 1 (25)
Cancer diagnosis
Breast 10 (36) 0 (0) 0 (0) 6 (100) 4 (100)
Genitourinary 6 (21) 4 (40) 2 (25) 0 (0) 0 (0)
Lung 4 (14) 2 (20) 2 (25) 0 (0) 0 (0)
Other 8 (29) 4 (40) 4 (50) 0 (0) 0 (0)
paCAE phenotype
Urticaria 18 (64) 4 (40) 4 (51) 6 (100) 4 (100)
Bullous pemphigoid 7 (25) 4 (40) 3 (38) 0 (0) 0 (0)
Eczema 3 (11) 2 (20) 1 (13) 0 (0) 0 (0)
Baseline CTCAE v5.0 severity grade
Grade 2 21 (75) 7 (70) 4 (50) 6 (100) 4 (100)
Grade 3 7 (25) 3 (30) 4 (50) 0 (0) 0 (0)
Anti-HER2, anti-human epidermal growth factor receptor 2; CPI, immune checkpoint inhibitor; CTCAE v5.0, Common Terminology Criteria for Adverse Events version 5.0; IgE, immunoglobulin E; paCAE, pruritus-associated cutaneous adverse events.
a Partial responders = reduction in severity of paCAEs from baseline CTCAE grade 2/3 to grade 1/2.
b Complete responders = reduction in severity of paCAEs from baseline CTCAE grade 2/3 to grade 0/1. | IPILIMUMAB, NIVOLUMAB | DrugsGivenReaction | CC BY-NC-ND | 33667669 | 19,956,572 | 2021-06 |
What was the outcome of reaction 'Pemphigoid'? | IgE blockade with omalizumab reduces pruritus related to immune checkpoint inhibitors and anti-HER2 therapies.
Immunoglobulin E (IgE) blockade with omalizumab has demonstrated clinical benefit in pruritus-associated dermatoses (e.g. atopic dermatitis, bullous pemphigoid, urticaria). In oncology, pruritus-associated cutaneous adverse events (paCAEs) are frequent with immune checkpoint inhibitors (CPIs) and targeted anti-human epidermal growth factor receptor 2 (HER2) therapies. Thus, we sought to evaluate the efficacy and safety of IgE blockade with omalizumab in cancer patients with refractory paCAEs related to CPIs and anti-HER2 agents.
Patients included in this multicenter retrospective analysis received monthly subcutaneous injections of omalizumab for CPI or anti-HER2 therapy-related grade 2/3 pruritus that was refractory to topical corticosteroids plus at least one additional systemic intervention. To assess clinical response to omalizumab, we used the Common Terminology Criteria for Adverse Events version 5.0. The primary endpoint was defined as reduction in the severity of paCAEs to grade 1/0.
A total of 34 patients (50% female, median age 67.5 years) received omalizumab for cancer therapy-related paCAEs (71% CPIs; 29% anti-HER2). All had solid tumors (29% breast, 29% genitourinary, 15% lung, 26% other), and most (n = 18, 64%) presented with an urticarial phenotype. In total 28 of 34 (82%) patients responded to omalizumab. The proportion of patients receiving oral corticosteroids as supportive treatment for management of paCAEs decreased with IgE blockade, from 50% to 9% (P < 0.001). Ten of 32 (31%) patients had interruption of oncologic therapy due to skin toxicity; four of six (67%) were successfully rechallenged following omalizumab. There were no reports of anaphylaxis or hypersensitivity reactions related to omalizumab.
IgE blockade with omalizumab demonstrated clinical efficacy and was well tolerated in cancer patients with pruritus related to CPIs and anti-HER2 therapies.
pmcINTRODUCTION
Immune checkpoint inhibitor (CPI) and anti-human epidermal growth factor receptor 2 (anti-HER2) targeted therapies have improved the survival of patients with various malignancies.1,2 However, these agents [e.g. anti-programmed cell death protein 1/ligand 1 (PD-1/PD-L1), anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), anti-HER2] are frequently associated with skin toxicity and represent a substantial burden on quality of life in cancer patients.3,4 Dermatologic reactions of CPIs and anti-HER2 monoclonal antibodies (mAbs) include pruritus and pruritus-associated cutaneous adverse events (paCAEs), such as urticaria, eczema, and bullous pemphigoid (BP) rash.5 The percentage of pruritus reported ranges from 14% to 47% among patients receiving CPIs and from 10% to 18% in those treated with anti-HER2 agents.6–8
Hitherto, therapeutic recommendations for paCAEs were based on anecdotal reports and expert opinion,9–13 with upto 25% of patients not responding to standard-of-care anti-pruritus measures, such as topical corticosteroids (TCS), oral antihistamines (OAHs), and gamma-aminobutyric acid analogs [GABAlogs (e.g. gabapentin, pregabalin)].5 Because higher total serum immunoglobulin E (IgE) levels have been reported in higher-grade immune-related cutaneous adverse events (AEs),5 we hypothesized that IgE blockade represents an actionable therapeutic target to block immune mediators of pruritus. Omalizumab, an anti-IgE mAb approved for chronic idiopathic urticaria (CIU) refractory to OAHs,14,15 is cited in the National Comprehensive Cancer Network® (NCCN®) Clinical Practice Guidelines in Oncology for consideration in the management of refractory cases of CPI-related dermatologic AEs in which anti-IgE therapy has demonstrated therapeutic benefit (e.g. pruritus, urticaria). However, its efficacy for this indication has not been investigated yet. Here, we summarize the characteristics and outcomes of oncology patients treated with omalizumab for paCAEs that remained refractory to prior treatments.
METHODS
Patients
Cancer patients from two institutions [Memorial Sloan Kettering Cancer Center (MSK) in New York, NY (n = 32); MD Anderson Cancer Center (MDA) in Houston, TX (n = 2)] who were referred to the oncodermatology clinic between 23 April 2018 and 6 September 2019 for grade ≥ 2 pruritus related to CPI or anti-HER2 treatment refractory to TCS plus at least one additional systemic intervention [e.g. OAH, oral GABAlog, oral corticosteroid (OCS)] and who were subsequently managed with monthly subcutaneous injections of omalizumab were included in the analysis. Patients were identified and their electronic medical record (EMR) was retrospectively reviewed using an institutional health information and data management system. This study was conducted under institutional review board approval protocols for each participating institution (MSK Protocol #16–458 and MDA Protocol #PA-15–0959).
Study outcomes
Our primary aim was to assess the rate of clinical response to treatment with omalizumab. The primary endpoint (reduction in severity of paCAEs from grade 3/2 to grade 0/1) was evaluated either in person at patients’ follow-up visits (which occurred approximately every 30 days) or via telephone calls made to patients by either dermatology or oncology clinicians following each administration of omalizumab (also approximately every 30 days). Response outcome data were retrospectively evaluated using the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 toxicity grading scale16 and defined a priori. Positive clinical responses to IgE blockade with omalizumab were further subclassified as either complete (reduction from grade 3/2 to grade 0) or partial (reduction from grade 3/2 to grade 1). Patients were considered non-responders if the severity of their paCAEs changed from grade 3/2 to grade ≥ 2.
As a secondary aim, we examined outcomes of clinical safety, including AEs reported by patients and documented by clinicians during treatment with omalizumab. When specified in the EMR, attribution categories of unrelated, unlikely related, possibly related, probably related, or definitely related were assigned to each AE. Demographics, clinicopathologic characteristics, and laboratory measures were described and compared across response groups.
Statistical methods
Data were summarized using descriptive statistics with Excel (Microsoft, Redmond, WA) and SPSS Statistics version 25 (IBM, Armonk, NY). Categorical data are reported as counts (percentages). Unless otherwise specified, all continuous variables are reported as median and range (minimum-maximum) values. We utilized Fisher’s exact and paired t-tests to determine differences in categorical variables and normally distributed ordinal data, respectively; and Wilcoxon ManneWhitney U and median tests for analysis of nonparametric independent continuous samples. To detect change in related categorical and ordinal variables, McNemar’s and Wilcoxon signed rank tests were carried out. All analyses were two-tailed tests based on α = 0.05, with results reaching statistical significance if P < 0.05.
RESULTS
Demographics and oncologic history
A total of 34 patients [median age 67.5 years (37–84), 50% female] with solid tumors undergoing treatment with CPIs (n = 24, 71%) and anti-HER2 therapies (n = 10, 29%) were included (Table 1). All received omalizumab for paCAEs that remained refractory to other anti-pruritic or rash management strategies. Nearly half of paCAEs (n = 16, 47%) were attributed to anti-PD-1 agents, namely pembrolizumab (n = 8, 24%) or nivolumab (n = 8, 24%). Other CPI regimens associated with paCAEs included combination anti-CTLA-4/anti-PD-1 treatment with ipilimumab plus nivolumab (n = 5, 15%) and the single-agent PD-L1 blockers atezolizumab (n = 2, 6%) or durvalumab (n = 1, 3%).
Clinicopathologic characteristics
In total, 22 (64%) patients were diagnosed with urticaria (Figure 1A and B), 9 (26%) with BP (Figure 1C and D) using direct immunofluorescence and/or an enzyme-linked immunosorbent assay to detect and measure BP 180 and BP 230 serum antibodies (Supplementary Table S1, available at https://doi.org/10.1016/j.annonc.2021.02.016), and 3 (9%) with eczema (Figure 1E and F). paCAEs were of moderate-severe clinical severity: 25 (74%) were classified as CTCAE grade 2 and 9 (26%) as grade 3. From the onset of paCAEs to the first dose of omalizumab, the median duration of pruritic skin disease was 93 days (4–820 days) in 32 patients (Figure 2). Of 17 patients with a cutaneous biopsy carried out before receiving anti-IgE therapy, 16 (94%) had eosinophils identified on hematoxyline—eosin (H&E) histologic evaluation. Twelve of 16 patients (75%) with eosinophils on skin biopsy were responders: 6 (50%) partial, 6 (50%) complete. Four were non-responders. The patient without eosinophils identified on H&E was a partial responder. Ten of 13 patients (77%), all of whom were receiving CPI treatment, had abundance of eosinophils (>10 per 5 consecutive high-power fields).
Clinical response to omalizumab
Twenty-eight of 34 patients (82%) responded to omalizumab. Among the 28 responders, 16 (57%) had partial response (reduction of CTCAE grade 2/3 to grade 1 paCAEs) and 12 (43%) had complete response (reduction to grade 0). A relatively younger age was characteristic of omalizumab responders in comparison to non-responders (65 versus 71 years), and the proportion of females in the responder group significantly outweighed that found in the non-responder group (n = 17, 61% versus 0, 100%, P = 0.018). All non-responders (n = 6, 100%) were male, and most of them (n = 4, 67%) had genitourinary neoplasms (2 renal, 2 urothelial) that were being treated with CPIs. Anti-PD-1 agents (n = 5, 83%) predominated in the non-responder group. All 10 patients with paCAEs related to anti-HER2 therapies and 18 of 24 (75%) with paCAEs related to CPIs responded to omalizumab (Table 2).
The majority of patients with urticaria (18/22; 82%) (Figure 1A) and BP (7/9, 78%) (Figure 1C) derived clinical benefit from omalizumab (Figure 3A and B). IgE blockade was also effective in patients with eczema (n = 3, 100%; Figure 1E). Four of 22 (28%) patients with urticaria and 2 of 9 (22%) with BP did not respond to omalizumab.
The median duration of treatment with IgE blockade was 62 days (0–440 days), and the median time to response was 28 days (0–77 days): 25 days (0–65 days) in partial responders (n = 16) versus 53 days (5–77 days) in complete responders (n = 12) (Figure 2). The average number of doses of omalizumab that patients received before report of maximum clinical response was greater in complete responders than in partial responders (1.5 versus 1.0, P = 0.007).
Changes in supportive management of paCAEs
Before intervention with IgE blockade, the majority of patients (n = 27, 80%) failed three or more different types of treatments, and nearly 25% failed four or more (n = 8, 24%). All 34 (100%) patients failed TCS (e.g. clobetasol, fluocinonide, triamcinolone) and also at least one additional intervention of a different therapeutic class. Other failed supportive treatment categories included GABAlogs (n = 26, 77%) such as pregabalin, OAHs (n = 21, 62%) such as hydroxyzine, OCS (n = 17, 50%) such as prednisone, immunomodulators (IMs) (n = 10, 29%) such as aprepitant, and biologic agents (n = 4, 12%) such as dupilumab. After the introduction of anti-IgE therapy with omalizumab, patients used an average of 1.6 supportive treatments, which was significantly lower than 2.3, the average number before omalizumab (P = 0.005). Fewer patients continued to use
TCS concurrently with omalizumab (n = 23, 68% versus 34, 100%, P = 0.001) (Figure 4). The greatest reduction rates were observed with OCS (50% to 9%, P < 0.001), followed by GABAlogs (77% to 41%, P < 0.001), OAHs (62% to 32%, P = 0.006), and IMs (29% to 0%, P = 0.002). Of note, two (6%) patients did not require additional supportive medications concurrently with omalizumab.
Impact of omalizumab on interruption of cancer therapy
Ten of 32 (31%) patients had interruption of cancer therapy as a result of paCAEs, which were related exclusively to CPIs. Oncologic treatments were stopped within a median of 140 days (1–500 days) before receiving omalizumab. Six of these 10 (60%) patients responded to IgE blockade and were rechallenged with their respective regimen; four (67%) of the six were able to resume oncologic therapy without recurrence or worsening of skin toxicity. Among the two (33%) responders whose cancer therapy was discontinued, both had developed grade 3 BP during treatment with PD-1 inhibitors (one with prembrolizumab, the other with nivolumab). One of the two patients had progression of his lung malignancy; the other, whose baseline total serum IgE was recorded at 20 380 kU/l, died; he had renal cancer.
Safety of omalizumab
Overall (n = 34), the median total number of omalizumab injections administered was 3 (1–14), which was the same in responders and non-responders. An initial 300-mg injection was administered subcutaneously once per month in most (n = 30, 88%) cases. Four (12%) patients had one 150-mg monthly injection as their first dose, three of whom went on to receive the standard 300-mg monthly injections thereafter. There were no reports of AEs related to omalizumab. All AEs reported by oncologists and dermatologists during treatment with omalizumab are published as supplementary material (Supplementary Table S2, available at https://doi.org/10.1016/j.annonc.2021.02.016).
Changes in total serum IgE
Among 18 patients with blood drawn within 30 days pre-omalizumab, the median total serum IgE was 150 kU/l (7.9–20 380.0 kU/l). Seven (39%) of those 18 patients had levels >213 kU/l [median 390 kU/l (229–20 380 kU/l)], which is the upper limit of normal (ULN). Median values at baseline were 263 kU/l in complete responders (n = 5), 79.5 kU/l in partial responders (n = 9), and 208 kU/l in non-responders (n = 4). In 15 patients with both pre- and post-omalizumab IgE measured within a median of 71 days (12–501 days) following their first dose, the median total serum IgE at first follow-up was 213 kU/l (10–1156 kU/l) (Figure 5). The ratio of total serum baseline IgE/follow-up IgE was 0.5 in these 15 patients (0.4 in 12 responders versus 0.9 in 3 non-responders).
Characteristics of patients with abnormally elevated total serum IgE pre-omalizumab
Pre-omalizumab (baseline), there were 11 (34%) of 32 patients with total serum IgE above the ULN, 8 (73%) of whom had a positive response to IgE blockade [5 (62.5%) with partial response; 3 (37.5%) with complete response]. Three patients with IgE above the ULN did not respond to omalizumab. Among the 11 patients with abnormally high total serum IgE, the median was higher in omalizumab responders (629 kU/l, n = 8) compared to non-responders (300 kU/l, n = 3), P = 0.048. Genitourinary malignancy (n = 5, 45%) and BP (n = 4, 36%) were more prevalent in these patients. Most (n = 10, 91%) were on CPIs; one (9%) was on anti-HER2 treatment (Supplementary Table S3, available at https://doi.org/10.1016/j.annonc.2021.02.016).
Changes in blood eosinophils
Among 34 patients with blood eosinophils (absolute count, abs eos) measured pre-omalizumab, the median was 200 cells/μl (0–3800 cells/μl); 6 (18%) patients had ≥700 cells/μl with a median of 950 cells/μl (800–3800 cells/μl) (Supplementary Table S4, available at https://doi.org/10.1016/j.annonc.2021.02.016). Median values at baseline were 200 in complete responders (n = 12), 250 in partial responders (n = 16), and 100 in non-responders (n = 6). Post-omalizumab (n = 30), the overall median was 300 cells/μl (0–9300 cells/μl), with an increase of 100 cells/μl (−1400 to +5500 cells/μl) pre- to post-IgE blockade. Overall, the ratio of baseline abs eos/follow-up abs eos was equivalent (0.5) to that observed with total serum IgE (Figure 5).
DISCUSSION
Omalizumab as a therapeutic option for paCAEs related to CPIs and anti-HER2 therapies
Our assessment of cancer patients receiving omalizumab for pruritus associated with urticaria, BP, and eczema related to CPIs and anti-HER2 therapies resulted in positive outcomes of clinical efficacy. In concordance with the high response rates reported in randomized clinical trials and case series that have evaluated omalizumab for CIU,15 BP,17 and pediatric atopic dermatitis,18 our study demonstrated a response rate of 82%, which is clinically highly impactful.
In our study, whereas a significantly greater proportion of females were found in the responder group, males exclusively populated the non-responder group. This difference may be explained by the types of cancer and treatments that predominated in each group. Compared to CPIs, anti-HER2 mAbs were more frequently observed among responders, which were utilized exclusively by females for breast cancer. Thus, differences in degree of clinical response to omalizumab may be dependent on the target of mAbs and CPIs.
All BP and eczema lesions appeared under CPIs. While maculopapular rash remains one of the most common AEs observed in patients treated with CPIs,19 there is also increasing evidence to suggest that BP eruptions occur frequently among those receiving PD-1/PD-L1 inhibitors20,21 and that treatment is challenging. Although we observed a high degree of response among BP patients, additional controlled clinical studies with large samples are warranted to characterize the mechanisms responsible for recalcitrant pruritus in this population.
Reduction in the proportion of patients requiring additional supportive management during treatment with omalizumab
Both the average number of supportive treatments and the proportion of patients requiring their use concurrently with omalizumab decreased significantly. Before IgE blockade, >40% of our patients were prescribed supportive OCS and/or other IM measures to manage pruritus related to CPIs and anti-HER2 mAbs. However, the utilization of OCS and IMs decreased by 82% and 100%, respectively, which has clinical implications in the prevention of serious infections in those who are already immunocompromised.
While management of most paCAEs with TCS and/or oral antipruritics such as GABAlogs and OAHs is successful, there are patients who fail to demonstrate sustained clinical improvement, ultimately requiring OCS, IMs, or biologics. Pregabalin is often considered in patients with recalcitrant pruritus; however, its utilization is limited by sedation, dizziness and drowsiness, drug interactions, withdrawal seizures, and need for renal dosing.22–24 It is also not universally effective, as anecdotally many patients fail to improve. As refractory cases of paCAEs emerge, with up to 25% of patients not responding to symptom-directed dermatologic interventions,5 many will lead to anticancer therapy dosing interruptions and/or discontinuation.
Reduction of cancer therapy interruption with omalizumab
A substantial proportion (31%) of patients had interruption of oncologic therapy due to severe pruritus exclusively related to CPIs. Thus, as both CPI and anti-HER2-related dermatologic toxicities may result in dosing alterations and permanent discontinuation of cancer treatment,11,25 successful control of paCAEs related to these life-saving therapeutic mechanisms remains a priority. More than half of the patients who resumed oncologic treatment after receiving omalizumab did not have recurrence or worsening of skin toxicity, which further highlights the potentially beneficial therapeutic role of IgE blockade in cancer care.
Omalizumab as a safe treatment option for paCAEs related to CPIs and anti-HER2 therapies
The omalizumab dosing strategies and safety profile herein were similar to those in the CIU study,15 with the majority of patients receiving 300-mg monthly injections and a low reported incidence of AEs related to the anti-IgE agent. However, whereas the rate of serious AEs in the pivotal trial ranged between 1% and 6% across the intervention groups,15 there were zero cases in our study attributed to omalizumab, potentially due to uncontrolled AE reporting and a smaller study sample size.
Predictors of clinical response to omalizumab
Consistent with previous data, our study findings suggest that a lower ratio of total serum baseline IgE/follow-up IgE is a good predictor of response to omalizumab,26 with a lower total serum baseline IgE/follow-up IgE ratio resulting from a slower elimination rate of omalizumabeIgE complexes (compared to free IgE).24 Additionally, we observed better response outcomes in patients with greater abnormally high pre-omalizumab total serum IgE levels, which clinical studies on omalizumab for CIU have also reported.26,27 However, as evidenced in this study and in the previous CIU literature, the majority of patients with normal baseline IgE levels responded to omalizumab. Thus, our data would not justify a particular threshold of total serum IgE before the administration of omalizumab for its use in oncology patients.
Limitations
Conclusions drawn from this investigation are limited primarily by its retrospective design, moderate sample size, and lack of matched placebo-treated controls. Hence, all statistical inferences have been taken with these concerns into account. While omalizumab appeared to be beneficial in this moderately sized cohort of cancer patients with grade 2/3 paCAEs resistant to TCS plus at least one additional systemic treatment, this group may not be representative, and thus not generalizable to all oncology patients with toxicities of similar phenotype and severity related to CPI and anti-HER2 agents.
Despite the clinically meaningful response rate observed in our study, important questions remain to be addressed regarding the efficacy and safety of omalizumab for paCAEs related to CPIs and anti-HER2 targeted therapies. Firstly, characterization of additional blood markers, such as free serum IgE, autoantibodies to IgE, thyroid hormone, tryptase, and estrogen/progesterone, in women treated with anti-HER2 therapies for breast cancer would add to our understanding of the mechanism through which omalizumab improves pruritus related to anti-HER2 mAbs compared to CPIs. Secondly, the question of optimal dosing and when, if ever, therapy with omalizumab should be stopped while patients continue to undergo anticancer treatment with CPIs and anti-HER2 agents remains unanswered. As stipulated by Navarro-Triviño and colleagues,28 it may be possible that in certain patients with cancer, such as the ones we encountered with CPI-related BP and a lack of response to omalizumab, the use of higher doses (>300 mg/month) or even a shorter therapeutic interval (300 mg every 2 or 3 weeks) may be necessary to optimize the full effect of IgE blockade.
Conclusions
The results of our study suggest that blockade of IgE may represent a novel intervention for patients with pruritus related to CPIs and anti-HER2 therapies. Importantly, omalizumab appears to reduce the need for additional supportive medications, including OCS. Omalizumab has the potential to safely and effectively improve severity of paCAEs, as well as provide the opportunity for successful rechallenge and continuation of anticancer treatment. However, these observations require further evaluation and characterization in a prospective clinical trial. Also, given this initial signal of potential efficacy in pruritus related to CPIs and anti-HER2 agents, the investigation of anti-IgE therapy among a broader class of pruritus-inducing targeted anticancer therapies is warranted.
Supplementary Material
1
ACKNOWLEDGEMENTS
We acknowledge Ms Bernadette Murphy for her assistance with photography.
FUNDING
This work was supported in part by the National Cancer Institute at the National Institutes of Health [grant number P30 CA008748] to MEL and by the National Institute of Arthritis and Musculoskeletal and Skin Diseases at the National Institutes of Health [grant number U01 AR077511] to MEL and DYML. The funders/sponsors had no role in the design and conduct of the study; in the collection, analysis, and interpretation of data; or in the preparation, review, or approval of the manuscript. The content is solely the responsibility of the authors and does not necessarily represent the official views of funders/sponsors.
DISCLOSURE
AM has an advisory board role in AstraZeneca, receives research funding from Incyte, and is supported by a Dermatology Foundation Career Development Award. EQ receives royalties from UpToDate. SAF receives research funding from AstraZeneca and Genentech/Roche, has a consulting/advisory relationship with Merck, and has ownership interests in Urogen, Allogene Therapeutics, Neogene Therapeutics, Kronos Bio, InconOVir and Vida Ventures. MHV reports receiving commercial research support from Pfizer and honoraria from Pfizer, Exelixis, Eisai, Calithera Biosciences, and Corvus Pharmaceuticals. AD discloses honoraria/advisory board participation for Ignyta/Genentech/Roche, Loxo/Bayer/Lilly, Takeda/Ariad/Millennium, TP Therapeutics, AstraZeneca, Pfizer, Blueprint Medicines, Helsinn, Beigene, BergenBio, Hengrui Therapeutics, Exelixis, Tyra Biosciences, Verastem, and MORE Health; associated research funding paid to the institution from Pfizer, Exelixis, GlaxoSmithKline, Teva, Taiho, and Pharma-Mar; research for Foundation Medicine; royalties from Wolters Kluwer; expenses from Merck and Puma; and CME honoraria from Medscape, OncLive, PeerVoice, Physicians Education Resources, Targeted Oncology, and Research to Practice. MDH receives research funding from Bristol Myers Squibb; is a paid consultant to Merck, Bristol Myers Squibb, AstraZeneca, Genentech/Roche, Nektar, Syndax, Mirati, Blueprint, Achilles Therapeutics, PACT Pharma, Immunai, and Shattuck Labs; receives travel support/honoraria from AstraZeneca, Eli Lilly, Merck, and BMS; and a patent has been filed by MSK related to the use of tumor mutation burden to predict response to immunotherapy (PCT/US2015/062208), which has received licensing fees from PGDx. EAC reports consultancy fees from Pfizer, Novartis, Bristol Myers Squibb, COTA, Genentech-Roche, and Heron Therapeutics. DYML has been a consultant for Genentech and Novartis. MEL has a consultant role with Johnson and Johnson, Novocure, QED, Bicara, Janssen, Novartis, F. Hoffmann-La Roche AG, EMD Serono, Astrazeneca, Innovaderm, Deciphera, DFB, Azitra, Kintara, RBC/La Roche Posay, Trifecta, Varsona, Genentech, Loxo, Seattle Genetics, Lutris, OnQuality, Azitra, Roche, NCODA, Apricity, Oncoderm Labs, Hoth Therapeutics. Dr. Lacouture also receives research funding from Lutris, Paxman, Novocure, J&J, US Biotest, OQL, Novartis and AZ. All other authors have declared no conflicts of interest.
Figure 1. Clinicopathologic features of patients receiving IgE blockade with omalizumab for pruritus related to immune checkpoint inhibitors and anti-HER2 therapies.
(A) Urticaria with (B) interface dermatitis and superficial perivascular lymphoeosinophilic infiltrate (×200 magnification). (C) Bullous pemphigoid with (D) subepidermal vesicle with eosinophils and lymphocytes (×100 magnification). (E) Eczema with (F) slight spongiosis with superficial perivascular lymphoeosinophilic infiltrate (×200 magnification).
Anti-HER2, anti-human epidermal growth factor receptor 2; IgE, immunoglobulin E.
Figure 2. Time course and efficacy of IgE blockade in patients receiving omalizumab for pruritus related to CPIs and anti-HER2 therapies.
Anti-HER2, anti-human epidermal growth factor receptor 2; CPI, checkpoint inhibitor (e.g. PD-1, PD-L1, CTLA-4); CTLA-4, cytotoxic T-lymphocyte-associated protein 4; paCAEs, pruritus-associated cutaneous adverse events; PD-1, programmed cell death protein 1; PD-L1, programmed cell death-ligand 1.
a Median (min-max), 93 days (4–820 days) in 32 patients.
b median (min-max), 62 days (0–440 days) in 34 patients.
Figure 3. Clinical manifestation of paCAEs before (left) and after (right) IgE blockade with omalizumab.
(A) Patient with metastatic breast cancer and CTCAE grade 2 dermatographic urticaria related to anti-HER2 therapy (resistant to alclometasone dipropionate, clobetasol, diphenhydramine, hydroxyzine, levocetirizine, pregabalin). Two subcutaneous 300-mg doses of omalizumab resulted in complete response with reduction of paCAE to CTCAE grade 0. (B) Patient with advanced melanoma and CTCAE grade 3 bullous pemphigoid related to anti-PD-1 + anti-CTLA-4 immune checkpoint inhibition (resistant to cetirizine, diphenhydramine, mycophenolate mofetil, rituximab, prednisone, pregabalin). One subcutaneous 300-mg injection of omalizumab resulted in partial response with reduction of paCAE to CTCAE grade 1.
Anti-HER2, anti-human epidermal growth factor receptor 2; CTCAE, Common Terminology Criteria for Adverse Events; CTLA-4, cytotoxic T-lymphocyte-associated protein 4; IgE, immunoglobulin E; paCAEs, pruritus-associated cutaneous adverse events; PD-1, programmed cell death protein 1.
Figure 4. Pre- to post-omalizumab changes in the proportion of patients requiring supportive treatments to manage paCAEs related to immune checkpoint inhibitors and anti-HER2 therapies.
Anti-HER2, anti-human epidermal growth factor receptor 2; CTLA-4, cytotoxic T-lymphocyte-associated protein 4; GABAlogs, gamma-aminobutyric acid analogs; IMs, immunomodulators; OAH, oral antihistamine; OCS, oral corticosteroids; paCAEs, pruritus-associated cutaneous adverse events; PD-1, programmed cell death protein 1; PD-L1, programmed cell death-ligand 1; TCS, topical corticosteroids.
Figure 5. Pre- to post-omalizumab changes in total serum IgE and blood eosinophils of patients with paCAEs related to immune checkpoint inhibitors and anti-HER2 therapies.
Measured analytes correspond to total serum IgE and absolute count of blood eosinophils. The upper limit of normal (ULN) values were established a priori at 213 kU/l and 699 cells/μl, respectively, as per our institutional laboratory services provider (Mayo Clinic Laboratories, Rochester, MN).
Anti-HER2, anti-human epidermal growth factor receptor 2; IgE, immunoglobulin E; paCAEs, pruritus-associated cutaneous adverse events.
Table 1. Characteristics of cancer patients receiving IgE blockade with omalizumab for pruritus related to immune checkpoint inhibitors and anti-HER2 therapies
All patients Omalizumab respondersa
Reduction from baseline to CTCAE grade 0/1 Omalizumab non-respondersa
No reduction from baseline to CTCAE grade 0/1 P valueb,c
n (%)a 34 (100) 28 (82) 6 (18)
Age, years
Median(range) 67.5 (37–84) 65 (37–84) 71 (65–84) 0.177
≤50 8 (24) 8 (29) 0 (0) 0.434
51–69 11 (32) 9 (32) 2 (33)
≥70 15 (44) 11 (39) 4 (67)
Sex
Female 17 (50) 17 (61) 0 (0) 0.018
Male 17 (50) 11 (39) 6 (100)
Race
White 23 (68) 19 (68) 4 (67) 0.641
Asian 4 (12) 4 (14) 0 (0)
Otherd 7 (21) 5 (18) 2 (33)
Ethnicity
Non-Hispanic 28 (82) 22 (79) 6 (100) 0.562
Hispanic 6 (18) 6 (21) 0 (0)
Cancer diagnosis
Breast 10 (29) 10 (36) 0 (0) 0.114
Genitourinarye 10 (29) 6 (21) 4 (67)
Lung 5 (15) 4 (14) 1 (17)
Otherf 9 (26) 8 (29) 1 (17)
Cancer therapy type
Anti-PD-1 16 (47) 11 (39) 5 (83) 0.098
Anti-HER2 10 (29) 10 (36) 0 (0)
Anti-PD-1 + CTLA-4 5 (15) 5 (18) 0 (0)
Anti-PD-L1 3 (9) 2 (7) 1 (17)
paCAE phenotype
Urticaria 22 (64) 81 (64) 4 (67) 0.678
Bullous pemphigoid 9 (26) 7 (25) 2 (33)
Eczema 3 (9) 3 (11) 0 (0)
Baseline CTCAE v5.0 severity gradeb
Grade 2 25 (74) 21 (75) 4 (67) 0.644
Grade 3 9 (26) 7 (25) 2 (33)
CTCAE v5.0, Common Terminology Criteria for Adverse Events version 5.0; CTLA-4, cytotoxic T-lymphocyte-associated protein 4; IgE, immunoglobulin E; PD-1, programmed cell death protein 1; PD-L1, programmed cell death-ligand 1; paCAEs, pruritus-associated cutaneous adverse events.
a Clinical response to omalizumab was evaluated retrospectively by clinicians using the CTCAE version 5.0 toxicity grading scale.
b Fisher’s exact test for categorical variables.
c ManneWhitney U test for continuous variables.
d Other races include unknown and undisclosed.
e Genitourinary cancer diagnoses include renal cell carcinoma (n = 7, 21%) and urothelial tumors (n = 3, 9%).
f Other malignancies include head and neck (n = 2, 6%), melanoma (n = 2, 6%), glioblastoma (n = 1, 3%), angiosarcoma (n = 1, 3%), gastric (n = 1, 3%), ovarian (n = 1, 3%), and laryngeal (n = 1, 3%) cancer.
Table 2. Characteristics of cancer patients responding to IgE blockade with omalizumab for pruritus related to immune checkpoint inhibitors and anti-HER2 therapies
All responders n = 28 Patients with CPI-related paCAEs n = 18 Patients with anti-HER2-related paCAEs n = 10
Partial respondersa Complete respondersb Partial respondersa Complete respondersb
n (%) 28 (100) 10 (56) 8 (44) 6 (60) 4 (40)
Age, years
Median(range) 65 (37–84) 67 (50–81) 75 (66–84) 47 (37–68) 52 (43–63)
≤50 8 (29) 1 (10) 0 (0) 5 (83) 2 (50)
51–69 9 (32) 4 (40) 2 (25) 1 (17) 2 (50)
≥70 11 (39) 5 (50) 6 (75) 0 (0) 0 (0)
Sex
Female 17 (61) 4 (40) 3 (38) 6 (100) 4 (100)
Male 11 (39) 6 (60) 5 (63) 0 (0) 0 (0)
Race
White 19 (68) 6 (60) 6 (75) 5 (83) 2 (50)
Asian 4 (14) 0 (0) 2 (25) 1 (17) 1 (25)
Other 5 (18) 4 (40) 0 (0) 0 (0) 1 (25)
Ethnicity
Non-Hispanic 22 (79) 7 (70) 7 (88) 5 (83) 3 (75)
Hispanic 6 (21) 3 (30) 1 (13) 1 (17) 1 (25)
Cancer diagnosis
Breast 10 (36) 0 (0) 0 (0) 6 (100) 4 (100)
Genitourinary 6 (21) 4 (40) 2 (25) 0 (0) 0 (0)
Lung 4 (14) 2 (20) 2 (25) 0 (0) 0 (0)
Other 8 (29) 4 (40) 4 (50) 0 (0) 0 (0)
paCAE phenotype
Urticaria 18 (64) 4 (40) 4 (51) 6 (100) 4 (100)
Bullous pemphigoid 7 (25) 4 (40) 3 (38) 0 (0) 0 (0)
Eczema 3 (11) 2 (20) 1 (13) 0 (0) 0 (0)
Baseline CTCAE v5.0 severity grade
Grade 2 21 (75) 7 (70) 4 (50) 6 (100) 4 (100)
Grade 3 7 (25) 3 (30) 4 (50) 0 (0) 0 (0)
Anti-HER2, anti-human epidermal growth factor receptor 2; CPI, immune checkpoint inhibitor; CTCAE v5.0, Common Terminology Criteria for Adverse Events version 5.0; IgE, immunoglobulin E; paCAE, pruritus-associated cutaneous adverse events.
a Partial responders = reduction in severity of paCAEs from baseline CTCAE grade 2/3 to grade 1/2.
b Complete responders = reduction in severity of paCAEs from baseline CTCAE grade 2/3 to grade 0/1. | Recovering | ReactionOutcome | CC BY-NC-ND | 33667669 | 19,956,572 | 2021-06 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Off label use'. | Survival of large volume recurrent endometrial cancer with peritoneal metastases treated by cytoreductive surgery, HIPEC and EPIC. Report of a case.
Endometrial cancer may disseminate through lymphatic channels to pelvic and retroperitoneal lymph nodes, through the bloodstream to the lungs, or through the peritoneal space to peritoneal surfaces. However, not all endometrial cancers involve all 3 sites for metastatic disease.
METHODS
A patient with large volume of symptomatic recurrence of peritoneal metastases from endometrial cancer was subjected to additional surgery and both regional and systemic chemotherapy. All aspects of her disease and its treatment were studied.
The primary malignancy was treated by a laparoscopic hysterectomy and bilateral salpingo-oophorectomy followed by intravaginal radiation. Large volume recurrent disease limited to the abdomen and pelvis was treated by complete cytoreductive surgery (CRS), hyperthermic intraperitoneal chemotherapy (HIPEC) and early postoperative intraperitoneal chemotherapy (EPIC). After recovery from surgery, systemic chemotherapy with cisplatin and paclitaxel was administered. The patient is now 25 months following treatment for recurrent cancer and free of disease.
CONCLUSIONS
The possibility of complete resection of recurrent endometrial cancer combined with HIPEC, EPIC and systemic chemotherapy is a treatment option for selected patients.
1 Introduction
Endometrial cancer is confined to the corpus uteri at the time of diagnosis in a large majority of patients [1,2]. Also, most of these patients are cured of disease by hysterectomy with or without pelvic and para-aortic lymph node dissection. Radiation therapy, usually recommended in the past, is less frequently or not used at all [3]. Combination chemotherapy is increasingly used by systemic administration. A regional (intraperitoneal chemotherapy) treatment has seldom been used in the past. This lack of enthusiasm for a regional route of administration may be questioned in that the most common sites of disease dissemination in patients thought to have uterine-confine disease is the peritoneal space. Positive peritoneal cytology was documented in 12%, 5% had adnexal involvement and 6% had gross intraperitoneal metastases [4]. These patients with early peritoneal disease at the time of primary resection will most commonly fail treatment within the peritoneal cavity [5]. Therapies may be individualized by determining the most likely sites for metastatic disease documented by careful follow-up [6].
Although not mentioned in the standard textbooks, surgery for recurrent endometrial cancer has been reported with some success. Papadia and coworkers reported a 5-year disease-free survival of 42% in 42 patients with optimal cytoreduction [7]. Cornali and coworkers added HIPEC with cisplatin to a cytoreductive surgery for 33 patients with peritoneal metastases from recurrent endometrial cancer. The 5-year overall survival was 30% (median survival was 33.1 months) [8]. The completeness of cytoreduction was the only significant factor independently influencing overall survival (p = 0.016). Goere et al. reported on 20 patients who underwent CRS and HIPEC for recurrent endometrial cancer [9].
In this case report, a patient with extensive recurrent endometrial cancer confined to the abdomen and pelvis was treated with a complete CRS, multiagent HIPEC and EPIC paclitaxel. She remains disease-free at 25 months after her intervention for recurrent disease. The ramifications of this outcome for patients who have a high propensity for progression of peritoneal metastases is discussed.
2 Patient presentation
Data on this patient was prospectively recorded and then retrospectively reviewed at an academic institution. This research work has been reported in line with the SCARE 2020 criteria [10]. This study was registered as a case report on the www.researchregistry.com website with UIN 6481.
September 2016: At age 57, this woman developed postmenopausal bleeding. A Pap smear revealed malignant cells.
January 2017: A laparoscopic total abdominal hysterectomy and bilateral salpingo-oophorectomy was performed by a gynecologic oncologist. Right and left sentinel pelvic lymph nodes were negative as were biopsies from right and left para-aortic lymph nodes. The endometrioid adenocarcinoma of the endometrium was FIGO grade 2 of 3. The tumor size was 3.5 cm in diameter. The histologic type was endometrioid adenocarcinoma with focal squamous differentiation. The patient underwent 5 cycles of intravaginal chemotherapy.
September 2018: The patient had an episode of urinary retention with severe discomfort upon urination. A CT scan showed disease within the greater omentum (Fig. 1), a mass associated with the transverse colon (Fig. 2) and a nodule between right and left common iliac vessels thought to be a para-aortic lymph node (Fig. 3).Fig. 1 CT scan through the upper abdomen shows cancer infiltration of the greater omentum.
Fig. 1
Fig. 2 At the level of the umbilicus, CT shows an 8 cm mass associated with the mid-transverse colon. No bowel obstruction is evident.
Fig. 2
Fig. 3 A nodule interpreted as a lymph node at the bifurcation of the aorta is seen between the right and left common iliac vessels.
Fig. 3
An encounter summary performed in the Cancer Institute recorded no drug history, no family history of cancer, and a totally normal psychosocial history.
Physical examination showed a prominent mass in the left upper quadrant which extended transversely along the abdominal wall. On pelvic exam, there were masses on the left side of the pelvis and at the apex of the vagina.
The results of the evaluation for recurrent endometrial cancer including the masses by physical examination and the marked progression of disease by CT were discussed with the patient. The possible options for treatment were discussed at a combined surgical oncology/gynecologic oncology multidisciplinary team (MDT) meeting. Given the patient’s young age and lack of comorbid conditions, a reoperative surgery plus HIPEC was recommended. This information was again, at a separate visit, communicated to the patient and her family. The possibility for adverse events and their incidence were discussed. The patient elected to move toward the cytoreductive surgery which was scheduled within 10 days. The patient was treated as part of an ongoing performance improvement project with extensive data monitoring.
October 2018: An 11-h cytoreductive surgery was performed with HIPEC by a surgical oncologist (PHS). Procedures performed included greater omentectomy, splenectomy, cholecystectomy, lesser omentectomy, peritonectomy of the undersurface of the right hemidiaphragm, partial peritonectomy of the left hemidiaphragm, transverse colectomy with anastomosis, pelvic peritonectomy and bilateral ureterolysis. The apex of the vagina was resected for approximately 4 cm because of disease at that site [11]. All specimens except the gallbladder were positive for metastatic high-grade carcinoma. The nodule at the bifurcation of the aorta was removed and submitted as a separate specimen. It was a nodule of high-grade carcinoma but was not thought to be within a lymph node. Fig. 4 shows the peritoneal cancer index.Fig. 4 The peritoneal cancer index (PCI). The PCI combines size and distribution parameters to determine a numerical score. The lesion size (LS) is used to quantitate the size of the peritoneal nodules with the 13 abdomino-pelvic regions. LS-0 indicates no tumor seen, LS-1 indicates tumor implants up to 0.5 cm, LS-2 indicates tumor implants between 0.5 and 5 cm, and LS-3 indicates tumor implants larger than 5 cm or a layering of cancer. The PCI in a 59-year-old woman undergoing surgery for recurrent endometrial high-grade carcinoma is shown in the diagram. The PCI was 20.
Fig. 4
The patient received hyperthermic intraperitoneal chemotherapy for 90 min with cisplatin 80 mg, doxorubicin 24 mg, and intravenous ifosfamide 2080 mg. Mesna was given prior to ifosfamide infusion, 4 h after completion of chemotherapy and 8 h after completion of chemotherapy at 416 mg. Temperature within the peritoneal space was approximately 42.5–43.5 °C [12].
Postoperatively, the patient received EPIC paclitaxel at 32 mg/day in 1 L of hetastarch solution for 5 consecutive days. The total dose of paclitaxel was 160 mg [12]. The patient developed a wound infection which was treated with antibiotics and opening of the lower 3 cm of the abdominal incision. The patient was discharged on her 21st postoperative day. There were no class 3 or 4 adverse events. The HIPEC and EPIC were well tolerated.
The patient received 5 cycles of systemic chemotherapy using cisplatin and paclitaxel delivered by a medical oncologist. A planned sixth cycle of systemic chemotherapy was withheld because of cumulative cisplatin toxicity.
Postoperatively, CT have been performed on a 6 monthly basis.
At 25 months postoperatively, a CT scan of the chest, abdomen and pelvis showed no progression of disease. CA-125 tumor marker was negative prior to surgery and has not shown elevation. The patient is maintained on oral nutrition without supplements and is maintaining here preoperative weight. No pain medicines are required.
3 Discussion
3.1 Treatment and prevention of peritoneal spread is possible
This case report illustrates that peritoneal metastases from endometrial cancer, even of large volume, can be controlled with a combination of complete resection and combined regional and systemic chemotherapy. Other reports attempt to convey the same message [8,9]. It is important to realize that the timing of the two components of this treatment strategy are crucial to its success. The surgery must remove all visible evidence of disease using a combination of peritonectomy procedures and visceral resections [11]. Then before stray cancer cells have the opportunity to become fixed within a fibrinous matrix, they must be washed by a chemotherapy solution to remove them mechanically and initiate chemotherapy-induced apoptosis. The current treatment option to supplement complete cytoreduction is HIPEC or HIPEC plus EPIC as was used in this patient [12]. Success in the management of peritoneal metastases from endometrial cancer is possible.
3.2 Careful study of the primary cancer may reveal the natural history of treatment failure
As published by Creasman and coworkers in a Gynecologic Oncology Group study, positive peritoneal cytology and/or peritoneal metastases are present in approximately 20% of primary endometrial cancers. The extent of the peritoneal spread and its documentation is not available from the pathologist for approximately one week following the surgical procedure. Morrow and coworkers have suggested that there is a relationship between the surgical-pathologic risk factors and the patient’s outcome [13]. Also, Mariani and coworkers more specifically showed that the findings within the resected endometrial cancer specimen can predict later progression of peritoneal metastases [5]. If CRS and HIPEC were utilized to eliminate peritoneal dissemination in patients at high risk for this type of treatment failure, an improved outcome is expected.
3.3 A new and expanded role for the pathologist in patients with endometrial cancer
Currently, a large amount of crucial information regarding the outcome of cancer patients is provided by the pathologist. The resected specimen is placed in formalin to be prosected by the pathologist at a later and convenient time. For interventions that occur at the time of cancer resection, such as CRS and HIPEC, this information is “after the fact.” Of course, very interesting, but not of benefit to the patient who may be in need of preventative treatment for subsequent progression of peritoneal disease. For peritonectomy procedures to be used to resect peritoneal metastases at a particular site, the anatomic site of disease must be documented histopathologically in the operating theater. Return to perform a second-look at a later time is not a realistic plan. Also, results of peritoneal cytology are needed while the patient is in the operating room to make a decision regarding HIPEC or HIPEC with EPIC.
3.4 Intraoperative surgical-pathological collaboration
In order to make the prediction of high risk for peritoneal recurrence/progression relevant to an individual patient, information must be made available in the operating theater. Immediately after the specimen is removed, it must be oriented by the surgeon for the pathologist. All peritoneal or Fallopian tube biopsies suspicious for peritoneal metastases must be presented to the pathologist. The peritoneal cytology results must be determined. The uterus specimen must be examined for peritoneal infiltration. Together the surgeon and pathologist need to make a decision regarding the subsequent risk of the individual patient for peritoneal metastases. If there is a risk, peritonectomy of selected anatomic sites may be required. Also, HIPEC or HIPEC plus EPIC administration requires an intraoperative judgment to proceed. In addition, prior consent for these interventions are required. By cryostat sections, the histopathological information needs to be available in the operating theater to administer the individualized treatments that are indicated in a timely manner.
3.5 CRS and HIPEC failures despite treatment
In the patient in this case report, the small bowel and its mesentery were observed to be free of peritoneal metastases. This is a favorable observation that indicates long-term success may be possible even with large masses of tumor distributed on the parietal peritoneum. Cytoreduction of small bowel and its mesentery is especially difficult. Extensive resection of small bowel is to be avoided. Also, tumor nodule removal on the bowel surface places the patient at risk for postoperative fistula. Removal of tumor from the mesentery creates a risk for small bowel ischemia. This is a major concern if tumor nodules are at the junction of small bowel with its mesentery. The mechanism for persistence and then subsequent progression of peritoneal metastases on visceral peritoneum has not been elucidated. However, incomplete resection combined with rapid removal of cancer chemotherapy with a generous blood supply within the small bowel may combine to cause the poor result. Small bowel sparing is important to the long-term success of CRS and HIPEC.
3.6 Bidirectional chemotherapy with HIPEC and EPIC for prevention or treatment of resected endometrial cancer with peritoneal metastases
For the chemotherapy agents used in this patient with peritoneal metastases from endometrial cancer, drugs with known response for this disease were selected. For HIPEC, the intraperitoneal drugs were moderate dose cisplatin and doxorubicin. Both of these drugs have activity for endometrial cancer and both are augmented in their cytotoxicity by heat. Both drugs have a favorable area under the curve ratio of intraperitoneal to systemic drug concentration. They are both acute phase agents and produce their full cytotoxic effect within the 90-minute HIPEC treatment [14]. A single systemic agent is ifosfamide. Our pharmacologic studies show that the same concentrations of intravenous and intraperitoneal ifosfamide are present almost immediately after intravenous infusion [15]. The intravenous ifosfamide has been shown to gain access to peritoneal tumor nodules.
For EPIC, paclitaxel was selected. This drug has a prolonged dwell time within the peritoneal space because of its large molecular weight. Also, it is a non-vesicant drug and well tolerated by the peritoneum without causing fibrosis [16]. Markman and coworkers demonstrated a 61% complete response rate in 28 patients with microscopic residual disease [17].
Declaration of Competing Interest
Paul H. Sugarbaker has no conflicts of interest to declare.
Funding
Data management and secretarial support provided by Foundation for Applied Research in Gastrointestinal Oncology.
Ethical approval
MedStar Health Institutional Review Board has determined that a case report of less than three (3) patients does not meet the DHHS definition of research (45 CFR 46.102(d)(pre-2018)/45 CFR46.102(l)(1/19/2017)) or the FDA definition of clinical investigation (21 CFR 46.102(c)) and therefore are not subject to IRB review requirements and do not require IRB approval.
Consent
Written and signed consent was obtained from the patient.
Author contribution
Paul H. Sugarbaker: study concept or design, data collection, data analysis or interpretation, writing the paper.
Registration of research studies
This study was registered as a case report on the www.researchregistry.com website with UIN 6481.
Guarantor
Paul H. Sugarbaker, MD
Provenance and peer review
Not commissioned, externally peer-reviewed. | CISPLATIN, DOXORUBICIN, IFOSFAMIDE, MESNA, PACLITAXEL | DrugsGivenReaction | CC BY-NC-ND | 33667906 | 19,025,392 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Wound infection'. | Survival of large volume recurrent endometrial cancer with peritoneal metastases treated by cytoreductive surgery, HIPEC and EPIC. Report of a case.
Endometrial cancer may disseminate through lymphatic channels to pelvic and retroperitoneal lymph nodes, through the bloodstream to the lungs, or through the peritoneal space to peritoneal surfaces. However, not all endometrial cancers involve all 3 sites for metastatic disease.
METHODS
A patient with large volume of symptomatic recurrence of peritoneal metastases from endometrial cancer was subjected to additional surgery and both regional and systemic chemotherapy. All aspects of her disease and its treatment were studied.
The primary malignancy was treated by a laparoscopic hysterectomy and bilateral salpingo-oophorectomy followed by intravaginal radiation. Large volume recurrent disease limited to the abdomen and pelvis was treated by complete cytoreductive surgery (CRS), hyperthermic intraperitoneal chemotherapy (HIPEC) and early postoperative intraperitoneal chemotherapy (EPIC). After recovery from surgery, systemic chemotherapy with cisplatin and paclitaxel was administered. The patient is now 25 months following treatment for recurrent cancer and free of disease.
CONCLUSIONS
The possibility of complete resection of recurrent endometrial cancer combined with HIPEC, EPIC and systemic chemotherapy is a treatment option for selected patients.
1 Introduction
Endometrial cancer is confined to the corpus uteri at the time of diagnosis in a large majority of patients [1,2]. Also, most of these patients are cured of disease by hysterectomy with or without pelvic and para-aortic lymph node dissection. Radiation therapy, usually recommended in the past, is less frequently or not used at all [3]. Combination chemotherapy is increasingly used by systemic administration. A regional (intraperitoneal chemotherapy) treatment has seldom been used in the past. This lack of enthusiasm for a regional route of administration may be questioned in that the most common sites of disease dissemination in patients thought to have uterine-confine disease is the peritoneal space. Positive peritoneal cytology was documented in 12%, 5% had adnexal involvement and 6% had gross intraperitoneal metastases [4]. These patients with early peritoneal disease at the time of primary resection will most commonly fail treatment within the peritoneal cavity [5]. Therapies may be individualized by determining the most likely sites for metastatic disease documented by careful follow-up [6].
Although not mentioned in the standard textbooks, surgery for recurrent endometrial cancer has been reported with some success. Papadia and coworkers reported a 5-year disease-free survival of 42% in 42 patients with optimal cytoreduction [7]. Cornali and coworkers added HIPEC with cisplatin to a cytoreductive surgery for 33 patients with peritoneal metastases from recurrent endometrial cancer. The 5-year overall survival was 30% (median survival was 33.1 months) [8]. The completeness of cytoreduction was the only significant factor independently influencing overall survival (p = 0.016). Goere et al. reported on 20 patients who underwent CRS and HIPEC for recurrent endometrial cancer [9].
In this case report, a patient with extensive recurrent endometrial cancer confined to the abdomen and pelvis was treated with a complete CRS, multiagent HIPEC and EPIC paclitaxel. She remains disease-free at 25 months after her intervention for recurrent disease. The ramifications of this outcome for patients who have a high propensity for progression of peritoneal metastases is discussed.
2 Patient presentation
Data on this patient was prospectively recorded and then retrospectively reviewed at an academic institution. This research work has been reported in line with the SCARE 2020 criteria [10]. This study was registered as a case report on the www.researchregistry.com website with UIN 6481.
September 2016: At age 57, this woman developed postmenopausal bleeding. A Pap smear revealed malignant cells.
January 2017: A laparoscopic total abdominal hysterectomy and bilateral salpingo-oophorectomy was performed by a gynecologic oncologist. Right and left sentinel pelvic lymph nodes were negative as were biopsies from right and left para-aortic lymph nodes. The endometrioid adenocarcinoma of the endometrium was FIGO grade 2 of 3. The tumor size was 3.5 cm in diameter. The histologic type was endometrioid adenocarcinoma with focal squamous differentiation. The patient underwent 5 cycles of intravaginal chemotherapy.
September 2018: The patient had an episode of urinary retention with severe discomfort upon urination. A CT scan showed disease within the greater omentum (Fig. 1), a mass associated with the transverse colon (Fig. 2) and a nodule between right and left common iliac vessels thought to be a para-aortic lymph node (Fig. 3).Fig. 1 CT scan through the upper abdomen shows cancer infiltration of the greater omentum.
Fig. 1
Fig. 2 At the level of the umbilicus, CT shows an 8 cm mass associated with the mid-transverse colon. No bowel obstruction is evident.
Fig. 2
Fig. 3 A nodule interpreted as a lymph node at the bifurcation of the aorta is seen between the right and left common iliac vessels.
Fig. 3
An encounter summary performed in the Cancer Institute recorded no drug history, no family history of cancer, and a totally normal psychosocial history.
Physical examination showed a prominent mass in the left upper quadrant which extended transversely along the abdominal wall. On pelvic exam, there were masses on the left side of the pelvis and at the apex of the vagina.
The results of the evaluation for recurrent endometrial cancer including the masses by physical examination and the marked progression of disease by CT were discussed with the patient. The possible options for treatment were discussed at a combined surgical oncology/gynecologic oncology multidisciplinary team (MDT) meeting. Given the patient’s young age and lack of comorbid conditions, a reoperative surgery plus HIPEC was recommended. This information was again, at a separate visit, communicated to the patient and her family. The possibility for adverse events and their incidence were discussed. The patient elected to move toward the cytoreductive surgery which was scheduled within 10 days. The patient was treated as part of an ongoing performance improvement project with extensive data monitoring.
October 2018: An 11-h cytoreductive surgery was performed with HIPEC by a surgical oncologist (PHS). Procedures performed included greater omentectomy, splenectomy, cholecystectomy, lesser omentectomy, peritonectomy of the undersurface of the right hemidiaphragm, partial peritonectomy of the left hemidiaphragm, transverse colectomy with anastomosis, pelvic peritonectomy and bilateral ureterolysis. The apex of the vagina was resected for approximately 4 cm because of disease at that site [11]. All specimens except the gallbladder were positive for metastatic high-grade carcinoma. The nodule at the bifurcation of the aorta was removed and submitted as a separate specimen. It was a nodule of high-grade carcinoma but was not thought to be within a lymph node. Fig. 4 shows the peritoneal cancer index.Fig. 4 The peritoneal cancer index (PCI). The PCI combines size and distribution parameters to determine a numerical score. The lesion size (LS) is used to quantitate the size of the peritoneal nodules with the 13 abdomino-pelvic regions. LS-0 indicates no tumor seen, LS-1 indicates tumor implants up to 0.5 cm, LS-2 indicates tumor implants between 0.5 and 5 cm, and LS-3 indicates tumor implants larger than 5 cm or a layering of cancer. The PCI in a 59-year-old woman undergoing surgery for recurrent endometrial high-grade carcinoma is shown in the diagram. The PCI was 20.
Fig. 4
The patient received hyperthermic intraperitoneal chemotherapy for 90 min with cisplatin 80 mg, doxorubicin 24 mg, and intravenous ifosfamide 2080 mg. Mesna was given prior to ifosfamide infusion, 4 h after completion of chemotherapy and 8 h after completion of chemotherapy at 416 mg. Temperature within the peritoneal space was approximately 42.5–43.5 °C [12].
Postoperatively, the patient received EPIC paclitaxel at 32 mg/day in 1 L of hetastarch solution for 5 consecutive days. The total dose of paclitaxel was 160 mg [12]. The patient developed a wound infection which was treated with antibiotics and opening of the lower 3 cm of the abdominal incision. The patient was discharged on her 21st postoperative day. There were no class 3 or 4 adverse events. The HIPEC and EPIC were well tolerated.
The patient received 5 cycles of systemic chemotherapy using cisplatin and paclitaxel delivered by a medical oncologist. A planned sixth cycle of systemic chemotherapy was withheld because of cumulative cisplatin toxicity.
Postoperatively, CT have been performed on a 6 monthly basis.
At 25 months postoperatively, a CT scan of the chest, abdomen and pelvis showed no progression of disease. CA-125 tumor marker was negative prior to surgery and has not shown elevation. The patient is maintained on oral nutrition without supplements and is maintaining here preoperative weight. No pain medicines are required.
3 Discussion
3.1 Treatment and prevention of peritoneal spread is possible
This case report illustrates that peritoneal metastases from endometrial cancer, even of large volume, can be controlled with a combination of complete resection and combined regional and systemic chemotherapy. Other reports attempt to convey the same message [8,9]. It is important to realize that the timing of the two components of this treatment strategy are crucial to its success. The surgery must remove all visible evidence of disease using a combination of peritonectomy procedures and visceral resections [11]. Then before stray cancer cells have the opportunity to become fixed within a fibrinous matrix, they must be washed by a chemotherapy solution to remove them mechanically and initiate chemotherapy-induced apoptosis. The current treatment option to supplement complete cytoreduction is HIPEC or HIPEC plus EPIC as was used in this patient [12]. Success in the management of peritoneal metastases from endometrial cancer is possible.
3.2 Careful study of the primary cancer may reveal the natural history of treatment failure
As published by Creasman and coworkers in a Gynecologic Oncology Group study, positive peritoneal cytology and/or peritoneal metastases are present in approximately 20% of primary endometrial cancers. The extent of the peritoneal spread and its documentation is not available from the pathologist for approximately one week following the surgical procedure. Morrow and coworkers have suggested that there is a relationship between the surgical-pathologic risk factors and the patient’s outcome [13]. Also, Mariani and coworkers more specifically showed that the findings within the resected endometrial cancer specimen can predict later progression of peritoneal metastases [5]. If CRS and HIPEC were utilized to eliminate peritoneal dissemination in patients at high risk for this type of treatment failure, an improved outcome is expected.
3.3 A new and expanded role for the pathologist in patients with endometrial cancer
Currently, a large amount of crucial information regarding the outcome of cancer patients is provided by the pathologist. The resected specimen is placed in formalin to be prosected by the pathologist at a later and convenient time. For interventions that occur at the time of cancer resection, such as CRS and HIPEC, this information is “after the fact.” Of course, very interesting, but not of benefit to the patient who may be in need of preventative treatment for subsequent progression of peritoneal disease. For peritonectomy procedures to be used to resect peritoneal metastases at a particular site, the anatomic site of disease must be documented histopathologically in the operating theater. Return to perform a second-look at a later time is not a realistic plan. Also, results of peritoneal cytology are needed while the patient is in the operating room to make a decision regarding HIPEC or HIPEC with EPIC.
3.4 Intraoperative surgical-pathological collaboration
In order to make the prediction of high risk for peritoneal recurrence/progression relevant to an individual patient, information must be made available in the operating theater. Immediately after the specimen is removed, it must be oriented by the surgeon for the pathologist. All peritoneal or Fallopian tube biopsies suspicious for peritoneal metastases must be presented to the pathologist. The peritoneal cytology results must be determined. The uterus specimen must be examined for peritoneal infiltration. Together the surgeon and pathologist need to make a decision regarding the subsequent risk of the individual patient for peritoneal metastases. If there is a risk, peritonectomy of selected anatomic sites may be required. Also, HIPEC or HIPEC plus EPIC administration requires an intraoperative judgment to proceed. In addition, prior consent for these interventions are required. By cryostat sections, the histopathological information needs to be available in the operating theater to administer the individualized treatments that are indicated in a timely manner.
3.5 CRS and HIPEC failures despite treatment
In the patient in this case report, the small bowel and its mesentery were observed to be free of peritoneal metastases. This is a favorable observation that indicates long-term success may be possible even with large masses of tumor distributed on the parietal peritoneum. Cytoreduction of small bowel and its mesentery is especially difficult. Extensive resection of small bowel is to be avoided. Also, tumor nodule removal on the bowel surface places the patient at risk for postoperative fistula. Removal of tumor from the mesentery creates a risk for small bowel ischemia. This is a major concern if tumor nodules are at the junction of small bowel with its mesentery. The mechanism for persistence and then subsequent progression of peritoneal metastases on visceral peritoneum has not been elucidated. However, incomplete resection combined with rapid removal of cancer chemotherapy with a generous blood supply within the small bowel may combine to cause the poor result. Small bowel sparing is important to the long-term success of CRS and HIPEC.
3.6 Bidirectional chemotherapy with HIPEC and EPIC for prevention or treatment of resected endometrial cancer with peritoneal metastases
For the chemotherapy agents used in this patient with peritoneal metastases from endometrial cancer, drugs with known response for this disease were selected. For HIPEC, the intraperitoneal drugs were moderate dose cisplatin and doxorubicin. Both of these drugs have activity for endometrial cancer and both are augmented in their cytotoxicity by heat. Both drugs have a favorable area under the curve ratio of intraperitoneal to systemic drug concentration. They are both acute phase agents and produce their full cytotoxic effect within the 90-minute HIPEC treatment [14]. A single systemic agent is ifosfamide. Our pharmacologic studies show that the same concentrations of intravenous and intraperitoneal ifosfamide are present almost immediately after intravenous infusion [15]. The intravenous ifosfamide has been shown to gain access to peritoneal tumor nodules.
For EPIC, paclitaxel was selected. This drug has a prolonged dwell time within the peritoneal space because of its large molecular weight. Also, it is a non-vesicant drug and well tolerated by the peritoneum without causing fibrosis [16]. Markman and coworkers demonstrated a 61% complete response rate in 28 patients with microscopic residual disease [17].
Declaration of Competing Interest
Paul H. Sugarbaker has no conflicts of interest to declare.
Funding
Data management and secretarial support provided by Foundation for Applied Research in Gastrointestinal Oncology.
Ethical approval
MedStar Health Institutional Review Board has determined that a case report of less than three (3) patients does not meet the DHHS definition of research (45 CFR 46.102(d)(pre-2018)/45 CFR46.102(l)(1/19/2017)) or the FDA definition of clinical investigation (21 CFR 46.102(c)) and therefore are not subject to IRB review requirements and do not require IRB approval.
Consent
Written and signed consent was obtained from the patient.
Author contribution
Paul H. Sugarbaker: study concept or design, data collection, data analysis or interpretation, writing the paper.
Registration of research studies
This study was registered as a case report on the www.researchregistry.com website with UIN 6481.
Guarantor
Paul H. Sugarbaker, MD
Provenance and peer review
Not commissioned, externally peer-reviewed. | CISPLATIN, DOXORUBICIN, IFOSFAMIDE, MESNA, PACLITAXEL | DrugsGivenReaction | CC BY-NC-ND | 33667906 | 19,025,392 | 2021-03 |
What was the administration route of drug 'CISPLATIN'? | Survival of large volume recurrent endometrial cancer with peritoneal metastases treated by cytoreductive surgery, HIPEC and EPIC. Report of a case.
Endometrial cancer may disseminate through lymphatic channels to pelvic and retroperitoneal lymph nodes, through the bloodstream to the lungs, or through the peritoneal space to peritoneal surfaces. However, not all endometrial cancers involve all 3 sites for metastatic disease.
METHODS
A patient with large volume of symptomatic recurrence of peritoneal metastases from endometrial cancer was subjected to additional surgery and both regional and systemic chemotherapy. All aspects of her disease and its treatment were studied.
The primary malignancy was treated by a laparoscopic hysterectomy and bilateral salpingo-oophorectomy followed by intravaginal radiation. Large volume recurrent disease limited to the abdomen and pelvis was treated by complete cytoreductive surgery (CRS), hyperthermic intraperitoneal chemotherapy (HIPEC) and early postoperative intraperitoneal chemotherapy (EPIC). After recovery from surgery, systemic chemotherapy with cisplatin and paclitaxel was administered. The patient is now 25 months following treatment for recurrent cancer and free of disease.
CONCLUSIONS
The possibility of complete resection of recurrent endometrial cancer combined with HIPEC, EPIC and systemic chemotherapy is a treatment option for selected patients.
1 Introduction
Endometrial cancer is confined to the corpus uteri at the time of diagnosis in a large majority of patients [1,2]. Also, most of these patients are cured of disease by hysterectomy with or without pelvic and para-aortic lymph node dissection. Radiation therapy, usually recommended in the past, is less frequently or not used at all [3]. Combination chemotherapy is increasingly used by systemic administration. A regional (intraperitoneal chemotherapy) treatment has seldom been used in the past. This lack of enthusiasm for a regional route of administration may be questioned in that the most common sites of disease dissemination in patients thought to have uterine-confine disease is the peritoneal space. Positive peritoneal cytology was documented in 12%, 5% had adnexal involvement and 6% had gross intraperitoneal metastases [4]. These patients with early peritoneal disease at the time of primary resection will most commonly fail treatment within the peritoneal cavity [5]. Therapies may be individualized by determining the most likely sites for metastatic disease documented by careful follow-up [6].
Although not mentioned in the standard textbooks, surgery for recurrent endometrial cancer has been reported with some success. Papadia and coworkers reported a 5-year disease-free survival of 42% in 42 patients with optimal cytoreduction [7]. Cornali and coworkers added HIPEC with cisplatin to a cytoreductive surgery for 33 patients with peritoneal metastases from recurrent endometrial cancer. The 5-year overall survival was 30% (median survival was 33.1 months) [8]. The completeness of cytoreduction was the only significant factor independently influencing overall survival (p = 0.016). Goere et al. reported on 20 patients who underwent CRS and HIPEC for recurrent endometrial cancer [9].
In this case report, a patient with extensive recurrent endometrial cancer confined to the abdomen and pelvis was treated with a complete CRS, multiagent HIPEC and EPIC paclitaxel. She remains disease-free at 25 months after her intervention for recurrent disease. The ramifications of this outcome for patients who have a high propensity for progression of peritoneal metastases is discussed.
2 Patient presentation
Data on this patient was prospectively recorded and then retrospectively reviewed at an academic institution. This research work has been reported in line with the SCARE 2020 criteria [10]. This study was registered as a case report on the www.researchregistry.com website with UIN 6481.
September 2016: At age 57, this woman developed postmenopausal bleeding. A Pap smear revealed malignant cells.
January 2017: A laparoscopic total abdominal hysterectomy and bilateral salpingo-oophorectomy was performed by a gynecologic oncologist. Right and left sentinel pelvic lymph nodes were negative as were biopsies from right and left para-aortic lymph nodes. The endometrioid adenocarcinoma of the endometrium was FIGO grade 2 of 3. The tumor size was 3.5 cm in diameter. The histologic type was endometrioid adenocarcinoma with focal squamous differentiation. The patient underwent 5 cycles of intravaginal chemotherapy.
September 2018: The patient had an episode of urinary retention with severe discomfort upon urination. A CT scan showed disease within the greater omentum (Fig. 1), a mass associated with the transverse colon (Fig. 2) and a nodule between right and left common iliac vessels thought to be a para-aortic lymph node (Fig. 3).Fig. 1 CT scan through the upper abdomen shows cancer infiltration of the greater omentum.
Fig. 1
Fig. 2 At the level of the umbilicus, CT shows an 8 cm mass associated with the mid-transverse colon. No bowel obstruction is evident.
Fig. 2
Fig. 3 A nodule interpreted as a lymph node at the bifurcation of the aorta is seen between the right and left common iliac vessels.
Fig. 3
An encounter summary performed in the Cancer Institute recorded no drug history, no family history of cancer, and a totally normal psychosocial history.
Physical examination showed a prominent mass in the left upper quadrant which extended transversely along the abdominal wall. On pelvic exam, there were masses on the left side of the pelvis and at the apex of the vagina.
The results of the evaluation for recurrent endometrial cancer including the masses by physical examination and the marked progression of disease by CT were discussed with the patient. The possible options for treatment were discussed at a combined surgical oncology/gynecologic oncology multidisciplinary team (MDT) meeting. Given the patient’s young age and lack of comorbid conditions, a reoperative surgery plus HIPEC was recommended. This information was again, at a separate visit, communicated to the patient and her family. The possibility for adverse events and their incidence were discussed. The patient elected to move toward the cytoreductive surgery which was scheduled within 10 days. The patient was treated as part of an ongoing performance improvement project with extensive data monitoring.
October 2018: An 11-h cytoreductive surgery was performed with HIPEC by a surgical oncologist (PHS). Procedures performed included greater omentectomy, splenectomy, cholecystectomy, lesser omentectomy, peritonectomy of the undersurface of the right hemidiaphragm, partial peritonectomy of the left hemidiaphragm, transverse colectomy with anastomosis, pelvic peritonectomy and bilateral ureterolysis. The apex of the vagina was resected for approximately 4 cm because of disease at that site [11]. All specimens except the gallbladder were positive for metastatic high-grade carcinoma. The nodule at the bifurcation of the aorta was removed and submitted as a separate specimen. It was a nodule of high-grade carcinoma but was not thought to be within a lymph node. Fig. 4 shows the peritoneal cancer index.Fig. 4 The peritoneal cancer index (PCI). The PCI combines size and distribution parameters to determine a numerical score. The lesion size (LS) is used to quantitate the size of the peritoneal nodules with the 13 abdomino-pelvic regions. LS-0 indicates no tumor seen, LS-1 indicates tumor implants up to 0.5 cm, LS-2 indicates tumor implants between 0.5 and 5 cm, and LS-3 indicates tumor implants larger than 5 cm or a layering of cancer. The PCI in a 59-year-old woman undergoing surgery for recurrent endometrial high-grade carcinoma is shown in the diagram. The PCI was 20.
Fig. 4
The patient received hyperthermic intraperitoneal chemotherapy for 90 min with cisplatin 80 mg, doxorubicin 24 mg, and intravenous ifosfamide 2080 mg. Mesna was given prior to ifosfamide infusion, 4 h after completion of chemotherapy and 8 h after completion of chemotherapy at 416 mg. Temperature within the peritoneal space was approximately 42.5–43.5 °C [12].
Postoperatively, the patient received EPIC paclitaxel at 32 mg/day in 1 L of hetastarch solution for 5 consecutive days. The total dose of paclitaxel was 160 mg [12]. The patient developed a wound infection which was treated with antibiotics and opening of the lower 3 cm of the abdominal incision. The patient was discharged on her 21st postoperative day. There were no class 3 or 4 adverse events. The HIPEC and EPIC were well tolerated.
The patient received 5 cycles of systemic chemotherapy using cisplatin and paclitaxel delivered by a medical oncologist. A planned sixth cycle of systemic chemotherapy was withheld because of cumulative cisplatin toxicity.
Postoperatively, CT have been performed on a 6 monthly basis.
At 25 months postoperatively, a CT scan of the chest, abdomen and pelvis showed no progression of disease. CA-125 tumor marker was negative prior to surgery and has not shown elevation. The patient is maintained on oral nutrition without supplements and is maintaining here preoperative weight. No pain medicines are required.
3 Discussion
3.1 Treatment and prevention of peritoneal spread is possible
This case report illustrates that peritoneal metastases from endometrial cancer, even of large volume, can be controlled with a combination of complete resection and combined regional and systemic chemotherapy. Other reports attempt to convey the same message [8,9]. It is important to realize that the timing of the two components of this treatment strategy are crucial to its success. The surgery must remove all visible evidence of disease using a combination of peritonectomy procedures and visceral resections [11]. Then before stray cancer cells have the opportunity to become fixed within a fibrinous matrix, they must be washed by a chemotherapy solution to remove them mechanically and initiate chemotherapy-induced apoptosis. The current treatment option to supplement complete cytoreduction is HIPEC or HIPEC plus EPIC as was used in this patient [12]. Success in the management of peritoneal metastases from endometrial cancer is possible.
3.2 Careful study of the primary cancer may reveal the natural history of treatment failure
As published by Creasman and coworkers in a Gynecologic Oncology Group study, positive peritoneal cytology and/or peritoneal metastases are present in approximately 20% of primary endometrial cancers. The extent of the peritoneal spread and its documentation is not available from the pathologist for approximately one week following the surgical procedure. Morrow and coworkers have suggested that there is a relationship between the surgical-pathologic risk factors and the patient’s outcome [13]. Also, Mariani and coworkers more specifically showed that the findings within the resected endometrial cancer specimen can predict later progression of peritoneal metastases [5]. If CRS and HIPEC were utilized to eliminate peritoneal dissemination in patients at high risk for this type of treatment failure, an improved outcome is expected.
3.3 A new and expanded role for the pathologist in patients with endometrial cancer
Currently, a large amount of crucial information regarding the outcome of cancer patients is provided by the pathologist. The resected specimen is placed in formalin to be prosected by the pathologist at a later and convenient time. For interventions that occur at the time of cancer resection, such as CRS and HIPEC, this information is “after the fact.” Of course, very interesting, but not of benefit to the patient who may be in need of preventative treatment for subsequent progression of peritoneal disease. For peritonectomy procedures to be used to resect peritoneal metastases at a particular site, the anatomic site of disease must be documented histopathologically in the operating theater. Return to perform a second-look at a later time is not a realistic plan. Also, results of peritoneal cytology are needed while the patient is in the operating room to make a decision regarding HIPEC or HIPEC with EPIC.
3.4 Intraoperative surgical-pathological collaboration
In order to make the prediction of high risk for peritoneal recurrence/progression relevant to an individual patient, information must be made available in the operating theater. Immediately after the specimen is removed, it must be oriented by the surgeon for the pathologist. All peritoneal or Fallopian tube biopsies suspicious for peritoneal metastases must be presented to the pathologist. The peritoneal cytology results must be determined. The uterus specimen must be examined for peritoneal infiltration. Together the surgeon and pathologist need to make a decision regarding the subsequent risk of the individual patient for peritoneal metastases. If there is a risk, peritonectomy of selected anatomic sites may be required. Also, HIPEC or HIPEC plus EPIC administration requires an intraoperative judgment to proceed. In addition, prior consent for these interventions are required. By cryostat sections, the histopathological information needs to be available in the operating theater to administer the individualized treatments that are indicated in a timely manner.
3.5 CRS and HIPEC failures despite treatment
In the patient in this case report, the small bowel and its mesentery were observed to be free of peritoneal metastases. This is a favorable observation that indicates long-term success may be possible even with large masses of tumor distributed on the parietal peritoneum. Cytoreduction of small bowel and its mesentery is especially difficult. Extensive resection of small bowel is to be avoided. Also, tumor nodule removal on the bowel surface places the patient at risk for postoperative fistula. Removal of tumor from the mesentery creates a risk for small bowel ischemia. This is a major concern if tumor nodules are at the junction of small bowel with its mesentery. The mechanism for persistence and then subsequent progression of peritoneal metastases on visceral peritoneum has not been elucidated. However, incomplete resection combined with rapid removal of cancer chemotherapy with a generous blood supply within the small bowel may combine to cause the poor result. Small bowel sparing is important to the long-term success of CRS and HIPEC.
3.6 Bidirectional chemotherapy with HIPEC and EPIC for prevention or treatment of resected endometrial cancer with peritoneal metastases
For the chemotherapy agents used in this patient with peritoneal metastases from endometrial cancer, drugs with known response for this disease were selected. For HIPEC, the intraperitoneal drugs were moderate dose cisplatin and doxorubicin. Both of these drugs have activity for endometrial cancer and both are augmented in their cytotoxicity by heat. Both drugs have a favorable area under the curve ratio of intraperitoneal to systemic drug concentration. They are both acute phase agents and produce their full cytotoxic effect within the 90-minute HIPEC treatment [14]. A single systemic agent is ifosfamide. Our pharmacologic studies show that the same concentrations of intravenous and intraperitoneal ifosfamide are present almost immediately after intravenous infusion [15]. The intravenous ifosfamide has been shown to gain access to peritoneal tumor nodules.
For EPIC, paclitaxel was selected. This drug has a prolonged dwell time within the peritoneal space because of its large molecular weight. Also, it is a non-vesicant drug and well tolerated by the peritoneum without causing fibrosis [16]. Markman and coworkers demonstrated a 61% complete response rate in 28 patients with microscopic residual disease [17].
Declaration of Competing Interest
Paul H. Sugarbaker has no conflicts of interest to declare.
Funding
Data management and secretarial support provided by Foundation for Applied Research in Gastrointestinal Oncology.
Ethical approval
MedStar Health Institutional Review Board has determined that a case report of less than three (3) patients does not meet the DHHS definition of research (45 CFR 46.102(d)(pre-2018)/45 CFR46.102(l)(1/19/2017)) or the FDA definition of clinical investigation (21 CFR 46.102(c)) and therefore are not subject to IRB review requirements and do not require IRB approval.
Consent
Written and signed consent was obtained from the patient.
Author contribution
Paul H. Sugarbaker: study concept or design, data collection, data analysis or interpretation, writing the paper.
Registration of research studies
This study was registered as a case report on the www.researchregistry.com website with UIN 6481.
Guarantor
Paul H. Sugarbaker, MD
Provenance and peer review
Not commissioned, externally peer-reviewed. | Intraperitoneal | DrugAdministrationRoute | CC BY-NC-ND | 33667906 | 19,025,392 | 2021-03 |
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