Title | Neuro-Ophthalmic Complications in Patients Treated With CTLA-4 and PD-1/PD-L1 Checkpoint Blockade |
Creator | Michel M. Sun, MD, PhD; Nicolas Seleme, MD; John J. Chen, MD, PhD; Anastasia Zekeridou, MD, PhD; Elia Sechi, MD; Ryan D. Walsh, MD; Johanna D. Beebe, MD; Osama Sabbagh, MD; Luis J. Mejico, MD; Sean Gratton, MD; Philip M. Skidd, MD; David A. Bellows, MD; Julie Falardeau, MD; Clare L. Fraser, MD; Cecilia Cappelen-Smith, MBBS, PhD; Scott R. Haines, MD; Bahareh Hassanzadeh, MD; Meagan D. Seay, DO; Prem S. Subramanian, MD, PhD; Zoë Williams, MD; Lynn K. Gordon, MD, PhD |
Affiliation | Department of Ophthalmology (MMS, NS, LKG), Jules Stein Eye Institute, David Geffen School of Medicine at the University of California Los Angeles, Los Angeles, California; Department of Ophthalmology (JJC), Mayo Clinic, Rochester, Minnesota; Department of Neurology (JJC, AZ, ES), Mayo Clinic, Rochester, Minnesota; Department of Ophthalmology & Visual Sciences (RDW), Medical College of Wisconsin, Milwaukee, Wisconsin; Department of Ophthalmology (JDB), Park Nicollet Health Services, Minneapolis, Minnesota; Department of Ophthalmology (OS), University of Kentucky/Retina Associates of Kentucky, Lexington, Kentucky; Department of Neurology (LJM), SUNY Upstate Medical Uni- versity, Syracuse, New York; Department of Ophthalmology (LJM), SUNY Upstate Medical University, Syracuse, New York; Department of Neurology (SG), University of Missouri-Kansas City, Kansas City, Missouri; Department of Ophthalmology (PMS), University of Vermont Medical Center, Burlington, Vermont; The Medical Eye Center (DAB), Manchester, New Hampshire; Department of Ophthalmology (JF), Oregon Health & Science University, Portland, Oregon; Department of Ophthalmology (CLF), University of Sydney, Sydney, Australia; Department of Neurology & Neurophysiology (CC-S), Liverpool Hospital, NSW, Australia; Department of Neurology (SRH), Virginia Commonwealth University School of Medicine, Richmond, Virginia; Department of Neurology (BH), INI Eye Center, OSF Healthcare, University of Illinois College of Medicine, Peoria, Illinois; Department of Ophthalmology (MDS), University of Utah, Salt Lake City, Utah; Department of Ophthalmology (PSS), University of Colorado, Aurora, Colorado; and Department of Ophthalmology (ZW), University of Rochester Medical Center, Rochester, New York |
Abstract | In recent years, CTLA-4 and PD-1/PD-L1 checkpoint inhibitors have proven to be effective and have become increasingly popular treatment options for meta- static melanoma and other cancers. These agents work by enhancing autologous antitumor immune responses. Immune-related ophthalmologic complications have been reported in association with checkpoint inhibitor use but remain incompletely characterized. This study seeks to investigate and further characterize the neuro-ophthalmic and ocular complications of immune checkpoint blockade treatment. |
Subject | Melanoma; Immune-Related Ophthalmology; Checkpoint Inhibitors |
OCR Text | Show Original Contribution Section Editors: Clare Fraser, MD Susan Mollan, MD Neuro-Ophthalmic Complications in Patients Treated With CTLA-4 and PD-1/PD-L1 Checkpoint Blockade Michel M. Sun, MD, PhD, Nicolas Seleme, MD, John J. Chen, MD, PhD, Anastasia Zekeridou, MD, PhD, Elia Sechi, MD, Ryan D. Walsh, MD, Johanna D. Beebe, MD, Osama Sabbagh, MD, Luis J. Mejico, MD, Sean Gratton, MD, Philip M. Skidd, MD, David A. Bellows, MD, Julie Falardeau, MD, Clare L. Fraser, MD, Cecilia Cappelen-Smith, MBBS, PhD, Scott R. Haines, MD, Bahareh Hassanzadeh, MD, Meagan D. Seay, DO, Prem S. Subramanian, MD, PhD, Zoë Williams, MD, Lynn K. Gordon, MD, PhD Background: In recent years, CTLA-4 and PD-1/PD-L1 checkpoint inhibitors have proven to be effective and have become increasingly popular treatment options for metastatic melanoma and other cancers. These agents work by enhancing autologous antitumor immune responses. Immune-related ophthalmologic complications have been reported in association with checkpoint inhibitor use but remain incompletely characterized. This study seeks to investigate and further characterize the neuro-ophthalmic and ocular complications of immune checkpoint blockade treatment. Methods: A survey was distributed through the secure electronic data collection tool REDCap to neuroophthalmology specialists in the North American NeuroOphthalmology Society listserv. The study received human subjects approval through the University of California at Los Angeles Institutional Review Board. The survey identified patients sent for neuro-ophthalmic consultation while receiving one or more of a PD-1 inhibitor (pembrolizumab, nivolumab, or cemiplimab); PD-L1 inhibitor (atezolizumab, avelumab, or durvalumab); or the CTLA-4 inhibitor ipilimumab. Thirty-one patients from 14 institutions were identified. Patient demographics, neuro-ophthalmic diagnosis, diagnostic testing, severity, treatment, clinical response, checkpoint inhibitor drug used, and cancer diagnosis was obtained. Results: The checkpoint inhibitors used in these patients included pembrolizumab (12/31), nivolumab (6/31), combined ipilimumab with nivolumab (7/31, one of whom also received pembrolizumab during their course of treatment), durvalumab (3/31), ipilimumab (2/31), and cemiplimab (1/ 31). Malignant melanoma (16/31) or nonsmall cell lung carcinoma (6/31) were the most common malignancies. The median time between first drug administration and the time of ophthalmological symptom onset was 14.5 weeks. Eleven Department of Ophthalmology (MMS, NS, LKG), Jules Stein Eye Institute, David Geffen School of Medicine at the University of California Los Angeles, Los Angeles, California; Department of Ophthalmology (JJC), Mayo Clinic, Rochester, Minnesota; Department of Neurology (JJC, AZ, ES), Mayo Clinic, Rochester, Minnesota; Department of Ophthalmology & Visual Sciences (RDW), Medical College of Wisconsin, Milwaukee, Wisconsin; Department of Ophthalmology (JDB), Park Nicollet Health Services, Minneapolis, Minnesota; Department of Ophthalmology (OS), University of Kentucky/Retina Associates of Kentucky, Lexington, Kentucky; Department of Neurology (LJM), SUNY Upstate Medical University, Syracuse, New York; Department of Ophthalmology (LJM), SUNY Upstate Medical University, Syracuse, New York; Department of Neurology (SG), University of Missouri-Kansas City, Kansas City, Missouri; Department of Ophthalmology (PMS), University of Vermont Medical Center, Burlington, Vermont; The Medical Eye Center (DAB), Manchester, New Hampshire; Department of Ophthalmology (JF), Oregon Health & Science University, Portland, Oregon; Department of Ophthalmology (CLF), University of Sydney, Sydney, Australia; Department of Neurology & Neurophysiology (CC-S), Liverpool Hospital, NSW, Australia; Department of Neurology (SRH), Virginia Commonwealth University School of Medicine, Richmond, Virginia; Department of Neurology (BH), INI Eye Center, OSF Healthcare, University of Illinois College of Medicine, Peoria, Illinois; Department of Ophthalmology (MDS), University of Utah, Salt Lake City, Utah; Department of Ophthalmology (PSS), University of Colorado, Aurora, Colorado; and Department of Ophthalmology (ZW), University of Rochester Medical Center, Rochester, New York Supported by an Unrestricted Grant from Research to Prevent Blindness, Inc. to the Department of Ophthalmology at UCLA. The use of REDCap was supported by CTSI Grant UL1TR001881. The sponsor or funding organization had no role in the design or conduct of this research. The authors report no conflicts of interest. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s Web site (www.jneuro-ophthalmology.com). Address correspondence to Lynn K.Gordon, Department of Ophthalmology, Jules Stein Eye Institute, David Geffen School of Medicine at the University of California Los Angeles, 100 Stein Plaza, Los Angeles, CA 90095‐7000; E-mail: LGordon@mednet.ucla.edu Sun et al: J Neuro-Ophthalmol 2021; 41: 519-530 519 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution patients had involvement of the optic nerve, 7 patients had inflammatory orbital or extraocular muscle involvement, 6 patients had ocular involvement from neuromuscular junction dysfunction, 4 patients had cranial nerve palsy, and 4 patients had non neuro-ophthalmic complications. Use of systemic corticosteroids with or without stopping the checkpoint inhibitor resulted in improvement of most patients with optic neuropathy, and variable improvement for the other ophthalmic conditions. Conclusion: This study describes the variable neuroophthalmic adverse events associated with use of immune checkpoint inhibitors and contributes a more thorough understanding of their clinical presentations and treatment outcomes. We expect this will increase awareness of these drug complications and guide specialists in the care of these patients. syndrome (17), hypophysitis (18), giant cell arteritis (19), and acute visual loss secondary to optic neuritis (20). The range of ocular presentations of immunotherapy complications seems to be extremely varied. Furthermore, these complications are poorly characterized, and there are no evidence-based recommendations for optimal management of these patients. Here, we detail 31 previously unreported cases of neuro-ophthalmic conditions associated with ICI use that were observed and treated by specialists in the North American NeuroOphthalmology Society (NANOS). We hope to increase awareness of ophthalmic complications that can be associated with the use of ICIs and contribute to the understanding and management of patients with these neuro-ophthalmic OirAEs. Journal of Neuro-Ophthalmology 2021;41:519–530 doi: 10.1097/WNO.0000000000001148 © 2020 by North American Neuro-Ophthalmology Society METHODS T he development of immune checkpoint inhibitors (ICIs) and other forms of cancer immunotherapy paved the way for a revolution in the field of cancer treatment. Harnessing the natural power of the immune system to detect and eliminate transformed cancerous cells led to highly effective therapy against several types of metastatic carcinomas including metastatic melanoma, small cell and non–small-cell lung cancers, and renal cell carcinoma, among others (1–3). Side effects seen with immunotherapeutic drugs are distinct from those observed with traditional chemotherapy and reflect the double-edged sword of immune enhancement and disruption of self-tolerance that allows for effective antitumor response with consequently high rates of autoimmune toxicity (4–6). Several different classes of ICIs acting on disparate immune pathways are currently available. The cytotoxic T-lymphocyte associated protein 4 (CTLA-4) pathway was the first to be targeted with the development of the drug ipilimumab in 2011. Newer generations of ICIs include pembrolizumab, nivolumab, and cemiplimab targeting the programmed cell death-1 (PD-1) receptor, and atezolizumab, avelumab, and durvalumab targeting the ligand (PDL1). The ipilimumab–nivolumab combination therapy also received FDA approval for specific cancers. Systemic autoimmune adverse effects have been well documented as a result of anti-CTLA-4 or anti-PD-1/PD-L1 use, and drugs targeting the PD-1 pathway were generally better tolerated with fewer and less severe adverse events (1,7,8). Ophthalmic immune-related adverse events (OirAEs) have also been reported and can be extremely debilitating. Classic autoimmune conditions such as uveitis were initially reported (5,9–11); however, there have been increasing cases of other ocular associations including optic neuropathy (12,13), orbital inflammation (14,15), thyroid-like ophthalmopathy (16), myasthenia gravis–like ophthalmopathy (10), orbital apex 520 Patient cases were collected through a survey distributed to neuro-ophthalmology specialists who were members of the North American Neuro-Ophthalmology Society listserv. NANOS is an approximately 700 member international society with all members having access to the listserv. Listserv subscription is voluntary, and nonmembers are able to subscribe and participate. Approval for distribution of the research survey on NANOSnet was obtained. The survey contained 17 primary questions with additional 4–9 disease specific questions (See Supplemental Digital Content, Supplemental Data E1, http://links.lww.com/WNO/ A448). Physicians were asked to identify patients who developed a neuro-ophthalmic complication after treatment with 1 of the 3 commercially available PD-1 inhibitors (pembrolizumab, nivolumab, and cemiplimab), 3 available PD-L1 inhibitors (atezolizumab, avelumab, and durvalumab), or the CTLA-4 inhibitor (ipilimumab). Participating physicians submitted HIPAA compliant, deidentified information including patient demographics, neuro-ophthalmic diagnosis, diagnostic testing, severity, treatment, clinical response, checkpoint inhibitor drug used, and cancer diagnosis for each patient. This research was conducted under IRB approval through the University of California, Los Angeles (IRB #17-001861) for multicenter collection of deidentified patient data from specialists in the North American Neuro-Ophthalmology Society. The online survey was designed and distributed through the secure electronic data collection tool REDCap and responses saved in HIPAA compliant data backup in house. Numeric data were exported and basic statistical analyses were performed. Text responses were aggregated and edited for consistency, style, and removal of potentially identifiable information. RESULTS A total of 31 individuals from 14 different institutions were submitted for inclusion in this study (Table 1). The median age was 63 years at the time of diagnosis, with a range from 34 Sun et al: J Neuro-Ophthalmol 2021; 41: 519-530 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution TABLE 1. Patient demographics, drug regimen, cancer, and ophthalmic complication Case No. Age Gender Race/ Ethnicity Checkpoint Inhibitor Regimen 1 2 3 4 5 6 7 8 9 62 52 67 45 60 49 50 52 57 Female Male Male Male Female Male Male Male Male White N/A White White White White White N/A White 10 11 12 40 72 82 Female Male Female White White White Ipilimumab Ipilimumab Ipilimumab/nivolumab Ipilimumab/nivolumab Ipilimumab/nivolumab Ipilimumab/nivolumab Ipilimumab/nivolumab Ipilimumab/nivolumab Ipilimumab/nivolumab/ pembrolizumab* Nivolumab Nivolumab Nivolumab 13 84 Male White Nivolumab 14 15 65 77 Male Male White White Nivolumab Nivolumab 16 49 Male Pembrolizumab 17 74 Male Hispanic/ Latino White Pembrolizumab 18 76 Male White Pembrolizumab 19 79 Male White Pembrolizumab 20 21 22 56 34 54 Male Female Male White White White Pembrolizumab Pembrolizumab Pembrolizumab 23 60 Male White Pembrolizumab 24 25 77 68 Female Male White White Pembrolizumab Pembrolizumab 26 64 Male White Pembrolizumab 27 78 Male White Pembrolizumab 28 64 Male White Durvalumab 29 66 Male White Durvalumab 30 63 Male White Durvalumab 31 50 Female White Cemiplimab Cancer Diagnosis Malignant Malignant Malignant Malignant Malignant Malignant Malignant Malignant Malignant melanoma melanoma melanoma melanoma melanoma melanoma melanoma melanoma melanoma Malignant melanoma Malignant melanoma Renal cell carcinoma Ophthalmic Involvement Unilateral vs Bilateral Muscle/orbit Cranial nerve Retina Optic nerve Optic nerve Uveitis Optic nerve Cranial nerve Optic nerve Unilateral Bilateral Bilateral Bilateral Bilateral Bilateral Bilateral Bilateral Unilateral Cranial nerve Optic nerve Neuromuscular junction Amaurosis fugax Muscle/orbit Neuromuscular junction Optic nerve Unilateral Bilateral N/A Non–small-cell lung cancer Malignant melanoma Squamous cell carcinoma of the lung Metastatic gastric cancer Non–small-cell lung Optic nerve cancer Squamous cell Optic nerve carcinoma of head and neck Non–small-cell lung Neuromuscular cancer junction Malignant melanoma Optic nerve Ductal breast cancer Muscle/orbit Non-Hodgkin’s Muscle/orbit lymphoma Metastatic GEJ Retina adenocarcinoma Malignant melanoma Muscle/orbit Metastatic esophageal Muscle/orbit adenocarcinoma Malignant melanoma Neuromuscular junction Malignant melanoma Neuromuscular junction Non–small-cell lung can- Muscle/orbit cer Non–small-cell lung can- Neuromuscular cer junction Non–small-cell lung can- Cranial nerve cer Squamous cell Optic nerve carcinoma of the head and neck Unilateral Bilateral Bilateral Bilateral Bilateral Bilateral Bilateral Bilateral Bilateral Bilateral Bilateral Bilateral Bilateral Bilateral Unilateral Unilateral Bilateral Unilateral Bilateral *Other medications: dabrafenib/trametinib/vemurafenib. Sun et al: J Neuro-Ophthalmol 2021; 41: 519-530 521 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution to 84 years. The majority of subjects were male (70.4%), and race/ethnicity were reported in 29 patients, 28 of whom identified as Caucasian, and only 1 patient identified as Hispanic/ Latino. Treatment with the PD-1 inhibitors nivolumab and pembrolizumab was the most common, with a total of 13 patients treated with either nivolumab alone (19.4%) or a combination of ipilimumab and nivolumab (22.6%), with 1 of these patients also having previously received pembrolizumab (Case 9), and a total of 12 patients who received pembrolizumab monotherapy (38.7%). Six patients underwent other monotherapy treatments; 3 with durvalumab (9.6%), 2 with ipilimumab (6.5%), and 1 with cemiplimab (3.2%). Most patients had a cancer diagnosis of skin malignant melanoma (16 patients, 51.6%), with other reported cancers including non–small-cell carcinoma of the lung (6 patients), squamous cell carcinoma of head and neck (2 patients), and renal cell carcinoma, squamous cell carcinoma of lung, nonHodgkin’s lymphoma, metastatic gastric cancer, metastatic adenocarcinoma, metastatic esophageal adenocarcinoma, and ductal breast cancer (1 patient with each). Neuroophthalmologic conditions were observed affecting the optic nerve in 32.3% of cases, neuromuscular junction in 19.3%, muscle/orbit in 22.6%, cranial nerve in 12.9%, and others (retina, uvea, and amaurosis fugax). There was no relationship between the checkpoint inhibitor regimen used and specific complications (Table 1). Onset of the ophthalmic side effects occurred fairly quickly after initial dosing of the checkpoint inhibitor, with a median time of less than 3.5 months (Fig. 1). There seems to be some variability in onset by class of ophthalmic side effect, with optic nerve involvement and neuromuscular junction involvement tending to occur later than orbit/ muscle involvement, cranial nerve palsy, or retinal involvement. Most patients experienced ophthalmic side effects between 7 days and 275 days after checkpoint inhibitor initiation, with a single outlier having ophthalmic symptom onset at 854 days after initial drug exposure (Fig. 1). Optic Nerve Involvement A total of 10 patients had optic nerve involvement, all of whom had edema of the optic disc (Table 2). Nine patients had bilateral optic nerve involvement, variably characterized as having optic neuropathy, optic neuritis, optic disc edema, or papilledema. Four patients had concomitant inflammatory ophthalmic and/or neurologic findings: 1 had anterior uveitis, 1 had choroiditis, 1 had posterior uveitis as well as encephalopathy, and 1 had hypophysitis. One patient (Case 9) subsequently developed transverse myelitis, with negative tests for myelin oligodendrocyte (MOG) or aquaporin 4 (AQP4) antibodies. Information about the initial visual acuity was available for 16 eyes of 8 patients. Nine eyes of 5 patients had bestcorrected visual acuity at presentation of better than or equal to 20/30, and none had worsening of vision at the time of followup. Seven eyes of 4 patients had best-corrected or pinhole 522 FIG. 1. Time to diagnosis of OirAE after initiation of ICI. The time interval (days) from first documented administration of ICI to diagnosis of ophthalmic complication was determined and analyzed by ophthalmic diagnosis category. The initial immune checkpoint inhibitor administration date and diagnosis date of the ophthalmic complication were reported for 28 of 31 patients; 10/10 optic nerve involvement, 6/6 neuromuscular junction involvement, 7/7 orbit/muscle involvement, 3/4 cranial nerve palsy, and 2/2 retina involvement. Case 15 with neuromuscular junction involvement was diagnosed 854 days after initial ICI use and is removed off scale. Case 6 with uveitis and Case 13 with amaurosis fugax are not included. Data are presented as mean time interval (days) with SEM. One-way analysis of variance P-value 0.2239, not significant by Tukey’s multiple comparisons test. visual acuity at presentation of worse than or equal to 20/50. After treatment, all 7 eyes demonstrated improvement in visual acuity, with 4 eyes of 3 patients achieving better than or equal to 20/30, 1 eye of 1 patient improved to 20/40, and 2 eyes of 1 patient had final visual acuity measurements of 20/100 in the right eye and 20/70 (pinhole to 20/50-2) in the left eye. Pain was reported in 2 patients and a deficit of color perception in 5 patients. Results from formal visual field tests were available for 9 patients and were described as altitudinal for 3 patients, arcuate in 4 patients, enlargement of the blind spot in 3 patients, and inferotemporal depression in 1 patient. The mean deviation was available for 10 eyes from 5 patients. The average mean deviation at the time of OirAE presentation was 29.90 dB (range 21.22 to 226.92 dB) and at the time of follow-up, there was improvement in each of the mean deviations with an average of 26.782 dB (range 20.74 to 222.74 dB). MRI findings were provided for 7 patients, 3 of which were reported as normal and 4 demonstrated optic nerve hyperintensity or enhancement at the optic nerve head or just behind the globe. Spinal fluid analysis was available for 2 Sun et al: J Neuro-Ophthalmol 2021; 41: 519-530 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution TABLE 2. Optic nerve involvement Case No. Diagnosis per 31 Optic neuropathy 18 Optic neuropathy 17 Optic neuritis 20 Optic neuritis/posterior uveitis/encephalopathy 16 Optic neuritis 11 5 Optic neuritis Left optic nerve disc edema/ bilateral choroiditis 4 Optic neuritis/anterior uveitis 9 Optic neuritis 7 Bilateral papilledema/ hypophysitis Case No. Checkpoint Inhibitor Status Vision at presentation/Mean Deviation on First HVF OD: 20/30 OD: 20/100 OD: 20/125 (NIPH) OS: 20/100-2 (PH 20/80-1) OD: 226.92 dB OS: 225.20 dB OD: 20/60 (PH 20/50) OS: 20/80 (PH 20/50) OD: 213.53 dB OS: 212.93 dB OD: 20/20 OS: 20/20 OD: 27.14 dB OS: 24.39 dB OD: 20/25 OS: 20/25+1 OD: 24.75 dB OS: 23.18 dB OD: 20/20 OS: 20/30 OD: 21.22 dB OS: 24.58 dB OD: 20/70 OS: 20/70 OD: 20/15 OS: 20/30 Final Vision/Mean Deviation on Final HVF 31 Cemiplimab held OD: 20/25 OS: 20/30 18 Pembrolizumab held OD: 20/100 (NIPH) OS: 20/70 (PH 20/50-2) OD: 222.74 dB OS: 220.46 dB 17 Pembrolizumab discontinued OD: 20/25 OS: 20/40 OD: 28.18 dB OS: 27.58 dB OD: 20/20 OS: 20/20 OD: 25.39 dB OS: 23.18 dB 20 Sun et al: J Neuro-Ophthalmol 2021; 41: 519-530 Neuro-Ophthalmic Outcome Improvement in the visual acuity over 3 days of treatment Improvement in the visual acuity, with residual temporalpredominant pallor bilaterally. No residual edema or heme Vision, visual fields, and optic nerve edema improved significantly in both eyes Good response. Residual optic nerve pallor and constricted visual fields with good visual acuity and color vision Treatment Methylprednisolone; prednisone Methylprednisolone; prednisone Prednisone IV steroids; rituximab Prednisone Prednisone Prednisone Difluprednate; atropine Methylprednisolone; prednisone Hydrocortisone Clinical Outcome Significant improvement Significant improvement Significant improvement Complete resolution of encephalopathy and other neurologic symptoms 523 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution (Continued ) Case No. Checkpoint Inhibitor Status OD: 20/20-1 OS: 20/25+2 OD: 22.57 dB OS: 20.92 dB OD: 20/20 OS: 20/20 16 11 5 4 Nivolumab discontinued 9 7 Final Vision/Mean Deviation on Final HVF OD: 20/20 OS: 20/20 OD: 21.21 dB OS: 20.74 dB OD: 20/25 OS: 20/20 OD: 20/15 OS: 20/15 Nivolumab and ipilimumab both discontinued patients, both of which were unremarkable. Recurrence of optic neuropathy occurred in 1 patient (Case 9) when oral prednisone was decreased to 15 mg per day, at which time the patient also reported hypoesthesia in their lower extremities, and there was neuroradiologic evidence for transverse myelitis; however, AQP4-IgG and MOG-IgG were both negative. Additional systemic symptoms consisting of headache was reported in 1 patient and encephalopathy in a second patient. All patients with optic nerve involvement received corticosteroids. Five received high dose intravenous methylprednisolone at up to 1 gm/day for 1–7 days followed by oral tapering over a period of several months, 5 received oral prednisone with an initial dose up to 80 mg per day or hydrocortisone, and 1 with severe uveitis received topical difluprednate. The checkpoint inhibitor regimen was discontinued in 5 patients. One of the 10 patients was lost to follow-up, and 1 patient died from cancer 26 months after the initial neuro-ophthalmic examination. Muscle/Orbit Involvement Seven patients were categorized in the subgroup of muscle/ orbit involvement (Table 3). All presented with an ophthalmic complaint of diplopia; 3 had restrictive strabismus and 2 had ptosis. Four patients reported additional systemic symptoms 524 Neuro-Ophthalmic Outcome Clinical Outcome Improving disc edema and visual field defects Ongoing course Rapid decrease/ resolution of bilateral optic disc edema. Rapid improvement in visual field testing Complete resolution of symptoms, optic disc edema, and choroiditis resolved Vision returned to normal but uveitis still persistent Had one recurrence of optic neuritis. Near complete resolution of ocular symptoms, mild inferior depression remains on visual field Papilledema improved but never completely resolved; hypophysitis resolved; known CNS metastatic disease Excellent, rapid improvement Excellent Lost to follow-up Developed AQP4 and MOG negative transverse myelitis in the thoracic region. In remission Disease progression. Patient deceased including weakness, fatigue, bulbar myopathy, dysphonia, dysphagia, and/or myocarditis. Five of the patients had electromyography (EMG) evidence for myopathy without evidence for neuromuscular junction involvement (4 patients), and/or pathologic evidence on muscle biopsy for myopathy, myositis, or muscle fiber necrosis (3 patients). Two patients had positive titers for striated muscle antibodies, and the following tests were negative when reported: antinuclear antibodies (3 patients), acetylcholine receptor antibodies (2 patients), and antithyroid antibodies together with antineutrophil cytoplasmic antibodies (1 patient). One patient (Case 24) had elevated levels of creatine kinase (1284 U/L) and aldolase (42.9 U/L) (data not shown). One patient (Case 1) presented with an orbital inflammatory syndrome with ophthalmoparesis, ptosis, and optic neuropathy with mild optic atrophy and count fingers vision at presentation. MRI of this patient demonstrated optic perineuritis; enlargement and enhancement of inferior, medial, and lateral rectus muscles; proptosis; enlargement of the pituitary gland; and thickening of the infundibulum (not shown). Laboratory evaluation showed increased erythrocyte sedimentation rate, C reactive protein, thyrotropic receptor antibodies, and thyroglobulin antibodies. After treatment with intravenous methylprednisolone at 1 gm/day for 7 days Sun et al: J Neuro-Ophthalmol 2021; 41: 519-530 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Sun et al: J Neuro-Ophthalmol 2021; 41: 519-530 Case No. Ocular Signs/Symptoms 25 Diplopia; ptosis 14 Diplopia; extraocular muscle restriction 22 21 24 Diplopia; extraocular muscle restriction Diplopia; extraocular muscle restriction Diplopia; ptosis 28 1 Diplopia Ophthalmoparesis, ptosis, and decreased visual acuity to count fingers OD Case No. EMG 25 14 Proximal myopathy Diffuse myopathy 22 Myopathic process Muscle Biopsy Necrotizing myopathy Myopathy and microvasculopathy 21 Proximal myopathic process 28 1 Not performed Systemic Symptoms Generalized weakness, myocarditis, ventricular tachycardia, complete heart block Weakness of bulbar, axial and proximal upper limb muscles Bulbar myopathy with dysphagia Striated muscle antibody titer elevated at 1:7,680 Bulbar symptoms, dysphonia, dysphagia Striated muscle antibody titer elevated at 1:61,400 None Thyrotropin receptor antibody elevated at 22.49 and thyroglobulin antibody elevated at 42 Treatment High-dose steroids; PLEX Prednisone; methylprednisolone; IVIG Neuro-Ophthalmic Outcome Incomplete recovery of ophthalmoparesis Prednisone Partial diplopia improvement Prednisone; IVIG Partial diplopia improvement No improvement Focal muscle fiber necrosis Prednisone Immune-related myositis Prednisone Not performed Methylprednisolone; prednisone IVIG, intravenous immunoglobulin; PLEX, plasma exchange. Antibody Testing Persistent diplopia and exotropia of left eye Improvement of the visual acuity to 20/40 with mild optic atrophy and double vision that incompletely improved Clinical Outcome Significant improvement in myopathy Significant response and improvement of weakness, fatigue. Mild residual dysphonia. Deceased from metastatic cancer Significant improvement in dysphagia and diplopia in response to prednisone Bulbar symptoms worsened. Deceased No obvious improvement Clinical improvement Original Contribution 24 525 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. TABLE 3. Muscle/orbit involvement Original Contribution followed by a slow prednisone taper, the vision showed dramatic improvement to 20/40 in the affected eye; however, the diplopia did not completely resolve. All patients with muscle/orbit involvement were treated with either oral or intravenous corticosteroids, with additional intravenous immunoglobulin (IVIG) in 2 patients and plasma exchange (PLEX) in 1 patient. Clinical outcome was variable; 5 patients experienced partial improvement in double vision or eye movements, and 2 patients had no neuro-ophthalmic improvement. Two patients in this group died from progression of their metastatic cancer. Cranial Nerve Palsies Four patients were observed to have a cranial nerve palsy at presentation. Two patients had a unilateral third nerve palsy, and 2 additional patients had leptomeningeal enhancement seen on MRI in addition to bilateral sixth nerve palsy (Case 8) and left facial nerve palsy with a reported skew deviation (Case 2) (Table 4). All of these patients presented with a complaint of diplopia. Specific antibody laboratory testing was performed in 2 patients, including acetylcholine receptor antibody (AChR), antimuscle specific kinase antibody, and rheumatoid factor, with negative results (data not shown). All patients were treated with oral or intravenous corticosteroids, with 1 patient also receiving IVIG. The immune checkpoint treatment discontinuation status was reported for 1 patient in whom durvalumab was held, whereas prednisone was used at a dose of 60 mg/day, which resolved the double vision and ptosis but symptoms recurred during steroid taper (Case 30). The patients with the sixth nerve palsy (Case 8) and facial nerve palsy (Case 2) had significant clinical improvement in symptoms and resolution of MRI findings including leptomeningeal enhancement. One patient was documented to have died of metastatic cancer. Neuromuscular Junction Dysfunction Six patients presented with ptosis and diplopia, 4 of whom had other, non-ophthalmic muscle complaints, and are included in the neuromuscular junction subgroup (Table 5). AChR antibodies were positive in 3 patients, and electromyography (EMG) studies were consistent with neuromuscular junction involvement in 4 patients (3 single fiber EMG and 1 repetitive nerve stimulation test). All of the 6 patients reported had either positive muscle-AChR antibody, EMG that showed a postsynaptic neuromuscular junction defect, or both. In addition, an ice test was reported to be positive in 2 patients and elevation of creatine kinase was noted in another 2 patients. Treatment was varied; 5 patients received pyridostigmine (Mestinon), 3 patients were given corticosteroids, and a combination of IVIG and PLEX was used in 2 patients. One patient did not receive targeted therapy for the neuromuscular junction involvement. Checkpoint inhibitor regimen was discontinued in 2 patients, with no information provided about continued use in the others. Response to 526 treatment was variable. One patient improved without specific therapy; 2 patients responded with use of pyridostigmine alone or pyridostigmine and corticosteroids. One patient responded after IVIG and methylprednisolone and did not further respond to PLEX. One patient continued to worsen despite therapy with intravenous corticosteroids, IVIG, and PLEX. The clinical outcome was overall poor, with 3 of the 6 patients succumbing to their metastatic cancer. Among the 17 patients who experienced involvement of the neuromuscular junction, a cranial nerve palsy, or involvement of the extraocular muscles and/or orbit, 6 were noted to die from cancer-related causes. Other Ocular Manifestations We briefly report several other ocular manifestations reported by neuro-ophthalmologists that reflect the variety of presentations that may be related to underlying OirAEs or complications from the primary cancer. One patient had a Vogt–Koyanagi–Harada-like syndrome (Case 6), and another patient experienced episodes of amaurosis fugax and was believed to have a vasculitic type of syndrome (Case 13). One patient developed melanoma-associated retinopathy (MAR), with decreased visual acuity, photopsias, visual field defects, color vision defects, and visual distortions (Case 3). This patient exhibited a normal fundus examination, diffuse visual field loss, peripapillary RNFL thinning on OCT, and an ERG that demonstrated an absent scotopic response. Antiretinal antibodies were positive. The patient initially responded to oral prednisone and withdrawal of ICI therapy. However, the patient died 3 months after the onset of visual complaints. The final patient developed bilateral diffuse uveal melanocytic proliferation (BDUMP) with visual field defects and a fundus examination that demonstrated diffuse choroidal thickening with subretinal fluid in both eyes abutting the inferior aspect of the optic nerve, multiple choroidal lesions with overlying subretinal fluid and orange pigment (Case 23). Use of IVIG and PLEX correlated with improvement in macular subretinal fluid. Checkpoint inhibitor status was not documented; however, there was overall clinical improvement, and the patient survived. DISCUSSION This study characterizes the largest cohort of patients with neuro-ophthalmic conditions after the use of an ICIs. Because of the largely temporal association between the start of ICI and development of the neuro-ophthalmic condition, these are termed neuro-ophthalmic ocular immune-related adverse events (OirAEs). We expect that this study will increase awareness of these drug complications and guide the development of evidence-based recommendations for monitoring and treatment. Sun et al: J Neuro-Ophthalmol 2021; 41: 519-530 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution TABLE 4. Cranial nerve palsy Case No. Cranial Nerve Presentation Signs/Symptoms 8 30 10 2 Bilateral sixth nerve palsy Third nerve palsy Third nerve palsy Left facial nerve palsy Intermittent horizontal diplopia Diplopia; ptosis Diplopia Diplopia; skew deviation Case No. Treatment 8 Methylprednisolone; prednisone 30 Prednisone 10 Prednisone 2 High-dose steroids; IVIG Checkpoint Inhibitor Status Durvalumab held MRI Leptomeningeal enhancement Multifocal leptomeningeal/pachymeningeal enhancement, likely inflammatory Neuro-Ophthalmic Outcome Resolution of leptomeningeal enhancement. Improved abduction and intermittent esotropia Resolution of symptoms, followed by recurrence. Minimal improvement after recurrence Stable Significant improvement. Residual minimal weakness in the orbicularis oculi Clinical Outcome Good response to steroid therapy Continues under active management Continues under active management Residual paresthesias in the feet; deceased from metastatic cancer IVIG, intravenous immunoglobulin. The ICIs used to treat patients in this study included inhibitors targeting CTLA-4 (ipilimumab), PD-1 (pembrolizumab, nivolumab, and cemiplimab), and PD-L1 (durvalumab) molecules. Most patients were submitted by neuro-ophthalmologists from tertiary care facilities. Most patients were Caucasian, which may reflect in part the fact that malignant melanoma was the most common cancer diagnosis in this cohort of patients (51.6%), and the known relationship between lighter skinned Caucasians and increased risk of malignant melanoma on UV exposed skin (21). The data on race predilection in neuro-ophthalmologic complications with checkpoint inhibitors are scarce (12,17). The lack of racial diversity in this cohort may be explained in part by the underlying race association in malignant melanoma; however, additional factors may include differential event reporting among practitioners or differential access to cancer immunotherapy. Pembrolizumab and nivolumab, in combination or alone, were the most frequently reported ICIs associated with OirAEs in this study. These PD-1 inhibitors were introduced in 2014 and have previously demonstrated good antitumor efficacy with lower rates of irAEs than the anti-CTLA-4 inhibitor, ipilimumab (22). Combination therapy using both a CTLA-4 and a PD-1 inhibitor is increasing in clinical practice (23), and the use of PD-1 inhibitors is expanding in a larger number of clinical indications (24,25). The fact that most OirAEs in this study were reported with the use of PD-1 inhibitors is likely a reflection of the volume of prescriptions, with PD-1 inhibitors being the fastest growing checkpoint inhibitor regime currently in use (24). There is evidence Sun et al: J Neuro-Ophthalmol 2021; 41: 519-530 that CTLA-4 and PD-1 inhibitors may have different irAE profiles (26); however, an association between individual drugs or classes of drugs and specific types of neuro-ophthalmic irAEs remains to be determined. Consistent with previous studies (9), skin malignant melanoma was the most common diagnosis associated with the development of ophthalmic complications (51.6%) in this report. Melanoma was the first indication to receive FDA approval for treatment with checkpoint inhibitors in 2011 and is still the most common indication for use of these drugs. Our findings may simply be a reflection of the sequence of FDA approvals for specific cancers; however, it is also possible that there may be an association between the type of cancer and increased risk of OirAEs that because of our low numbers of other malignancies we could not investigate in this cohort. Most patients developed their ocular complication between 1 and 6 months after the initiation of the checkpoint inhibitor, with a median for all groups of 101.5 days. Interestingly, there seemed to be a difference in onset between groups of diseases, with ocular complications occurring earlier in the case of orbit/muscle and cranial nerve involvement, whereas patients with optic nerve involvement patients tended to present later. These results are in agreement with previous case reports of neuro-ophthalmic complications (14–18,20), uveitis complications (9), and nonocular irAEs (27–29), all of which have highest risk within the first 6 months after ICI initiation. It must be noted, however, that some of the neuro-ophthalmic conditions could have been secondary to the cancer itself, through either direct or 527 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution TABLE 5. Neuromuscular junction involvement Anti-Ach Receptor Antibody Titer Case No. Ocular Signs/Symptoms 27 29 Ptosis; diplopia Ptosis; diplopia 19 26 Ptosis; strabismus Ptosis; diplopia Positive Negative; anti-titin antibody positive Positive Positive 15 Ptosis; diplopia Negative 12 Ptosis; diplopia Negative Case No. 27 29 Checkpoint Inhibitor Status Pembrolizumab discontinued Durvalumab discontinued Treatment EMG Repetitive stimulation/Single fiber EMG negative, EMG—myositis Repetitive nerve stimulation test positive Repetitive nerve stimulation test positive; single fiber EMG positive Single fiber EMG positive Neuro-Ophthalmic Outcome Pyridostigmine Pyridostigmine; prednisolone; IVIG; mycophenolate 19 Pyridostigmine; IVIG; prednisone; methylprednisolone; PLEX 26 None 15 12 Pyridostigmine Pyridostigmine; prednisone; IVIG; hydrocortisone; PLEX Resolution of diplopia and left sided ptosis Resolution of ptosis, restoration of eye movements. Resolution of generalized weakness Improvement in eyelid closure and improved pulmonary mechanics after IVIG and methylprednisolone. Minimal to no clinical improvement after PLEX Improvement over time without treatment. Some residual weakness Unknown No significant improvement with treatment. Clinical Outcome Stable Deceased from metastatic cancer Deceased from metastatic cancer Deceased from metastatic cancer Developed worsening ptosis and diplopia, bulbar weakness and proximal extremity weakness IVIG, intravenous immunoglobulin; PLEX, plasma exchange. indirect effect, and not a result of the ICI therapy, which is a potential confounder of the results. Most patients in the optic nerve involvement subgroup, the most common of the OirAEs, had bilateral involvement, which is consistent with a systemic etiology. Most also presented with optic disc edema. Pain was largely absent in this group, differing significantly from the classical presentation of typical optic neuritis in adults, where the retrobulbar, unilateral, and painful presentation is more common (30). Most of these patients had mild visual loss with excellent visual outcome after steroid treatment and 528 only 1 patient died during follow-up. Taken together, these data suggest that patients presenting with optic nerve involvement alone may have better ocular and systemic prognosis than those with other OirAEs; however, further investigation is needed to determine a definitive association. It is possible that discontinuation of the checkpoint inhibitor may not be necessary in these patients, possibly facilitating a better systemic outcome in terms of their cancer therapy. We propose that these patients should be treated with high dose systemic steroids with close follow-up. Continued use of the checkpoint inhibitor should be based on Sun et al: J Neuro-Ophthalmol 2021; 41: 519-530 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution the degree of visual detriment, the responsiveness of the visual function to steroid treatment, and the discretion of the treating physicians. Specific diagnostic testing methods were consistent and clear enough to allow proper division and characterization of the neuromuscular junction and muscle/orbit involvement subgroups. All patients in the neuromuscular junction subgroup presented with diplopia and ptosis, and most had involvement of other nonocular muscular groups. Response to treatment was variable, with some patients demonstrating good response to standard treatment, whereas others showed no clinical response to use of pyridostigmine, and others required corticosteroids, IVIG, or PLEX. Notably, half of the patients in this group (3/6) died from metastatic cancer during follow-up. Similar outcomes for both the OirAE and cancer were noted in the muscle/orbit involvement group. This group shared some features in their clinical presentation with the neuromuscular junction patients but differed in diagnostic evaluation. Six of 7 patients had either elevated striated muscle antibodies titers, muscle biopsy showing myositis, and/or EMG consistent with a myopathic process. Ocular outcome in these patients was poor, with incomplete recovery or no improvement in most cases (6/7). Two patients in this group died of their underlying cancer during follow-up. Similarly, patients in the cranial nerve involvement subgroup also showed variable response to steroid treatment; 1 of 4 patients died during follow-up. The data suggest that patients presenting with either neuromuscular junction, muscle/ orbit, or cranial nerve complications may be more likely to have poorer ocular prognosis. It is also possible that some of these cases, similar to the patients with MAR and BDUMP, may be secondary to either the underlying cancer or a paraneoplastic response, rather than truly representative of an OirAE secondary to the ICI. This study emphasizes that multiple distinct neuroophthalmologic complications can occur in patients treated with ICIs. Symptoms including loss of vision, diplopia, and ptosis should warrant prompt referral for subspecialty care. This study also serves as an excellent example of the utility of scientific organizations such as NANOS, allowing for the recruitment and investigation of larger numbers of patients with uncommon diseases through coordinated research efforts within the member community. This study has several limitations that also must be acknowledged. The questionnaire format used to collect cases allows for ease of data acquisition from physicians from different centers, but potentially limits the thoroughness of the data submitted. There can be inconsistent reporting of cases, missing data, and variability in diagnosis criteria and scoring. In addition, the retrospective nature precludes standardized treatment regimens in the setting of OirAEs, which can preclude determination of best therapy for these conditions. This study does not Sun et al: J Neuro-Ophthalmol 2021; 41: 519-530 allow determination of the incidences of the OirAEs in association with use of ICI, nor does it allow for the ability to make associations between specific types of OirAE complications and specific checkpoint inhibitors or drug classes. There are many factors that can affect tumor prognosis and act as potential confounders, particularly tumor type and stage and differences in follow-up time. The design of this study does not address these cancer-related factors. In addition, causality beyond a close temporal relationship cannot be confirmed between the neuro-ophthalmic adverse events and ICI use, and it is possible some neuro-ophthalmic events may be related specifically to the cancer or alternatively may be unrelated to either the cancer or use of ICI. There was variable reporting about whether ICI use was active at the time of neuro-ophthalmic diagnosis, which is also limits interpretation. Although the current data provides insights regarding treatment response among different types of complications, recommendations for the best therapeutic modalities for each neuro-ophthalmologic complication remain to be determined. A wider variety of neuro-ophthalmologic complications than previously appreciated can occur in patients on checkpoint inhibitors. Most complications occur within 6 months of initiating ICI treatment, suggesting that early and close coordination with oncology colleagues is critical for optimal patient care. We observed that patients with optic nerve involvement generally did well, with generally good visual outcome with steroid treatment, and overall low mortality rate. By contrast, patients with neuromuscular junction, muscle/orbit, or cranial nerve involvement had a more variable and unpredictable ophthalmic outcome, with higher mortality rate. Whether development of these complications may predict poorer survival remains to be confirmed. Oncologists should be aware of the range of these complications and the need for prompt evaluation by an appropriate ophthalmic specialist. STATEMENT OF AUTHORSHIP Category 1: a. Conception and design: M. M. Sun, N. Seleme, and L. K. Gordon; b. Acquisition of data: J. J. Chen, A. Zekeridou, E. Sechi, R. D. Walsh, J. D. Beebe, O. Sabbagh, L. J. Mejico, S. Gratton, P. M. 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Date | 2021-12 |
Language | eng |
Format | application/pdf |
Type | Text |
Publication Type | Journal Article |
Source | Journal of Neuro-Ophthalmology, December 2021, Volume 41, Issue 4 |
Collection | Neuro-Ophthalmology Virtual Education Library: Journal of Neuro-Ophthalmology Archives: https://novel.utah.edu/jno/ |
Publisher | Lippincott, Williams & Wilkins |
Holding Institution | Spencer S. Eccles Health Sciences Library, University of Utah |
Rights Management | © North American Neuro-Ophthalmology Society |
ARK | ark:/87278/s6y8wq6x |
Setname | ehsl_novel_jno |
ID | 2116248 |
Reference URL | https://collections.lib.utah.edu/ark:/87278/s6y8wq6x |