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Neuro-ophthalmic Complications of Immune Checkpoint Inhibitors: A Systematic Review

Authors Yu CW , Yau M, Mezey N , Joarder I , Micieli JA 

Received 20 August 2020

Accepted for publication 24 September 2020

Published 3 November 2020 Volume 2020:12 Pages 139—167


Checked for plagiarism Yes

Review by Single anonymous peer review

Peer reviewer comments 2

Editor who approved publication: Professor Margaret Wong-Riley

Caberry W Yu,1 Matthew Yau,2 Natalie Mezey,1 Ishraq Joarder,3 Jonathan A Micieli4,5

1Faculty of Medicine, Queen’s University, Kingston, Canada; 2Faculty of Medicine, University of Toronto, Toronto, Canada; 3Faculty of Science, University of Toronto, Scarborough, Ontario, Canada; 4Department of Ophthalmology and Vision Sciences and Division of Neurology, Department of Medicine, University of Toronto, Toronto, Canada; 5Kensington Vision and Research Centre, Toronto, Canada

Correspondence: Jonathan A Micieli
Kensington Vision and Research Centre, 340 College Street, Suite 501, Toronto, Ontario M5T 3A9, Canada
Tel +1(416) 928-1335
Fax +1(416) 928-5075
Email [email protected]

Objective: Immune checkpoint inhibitors (ICIs) are novel cancer therapies that may be associated with immune-related adverse events (IRAEs) and come to the attention of neuro-ophthalmologists. This systematic review aims to synthesize the reported ICI-associated IRAEs relevant to neuro-ophthalmologists to help in the diagnosis and management of these conditions.
Methods: A systematic review of the literature indexed by MEDLINE, Embase, CENTRAL, and Web of Science databases was searched from inception to May 2020. Reporting followed the Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) guidelines. Primary studies on ICIs and neuro-ophthalmic complications were included. Outcomes included number of cases and incidence of neuro-ophthalmic IRAEs.
Results: Neuro-ophthalmic complications of ICIs occurred in 0.46% of patients undergoing ICI and may affect the afferent and efferent visual systems. Afferent complications include optic neuritis (12.8%), neuroretinitis (0.9%), and giant cell arteritis (3.7%). Efferent complications include myasthenia gravis (MG) (45.0%), thyroid-like eye disease (11.9%), orbital myositis (13.8%), general myositis with ptosis (7.3%), internuclear ophthalmoplegia (0.9%), opsoclonus-myoclonus-ataxia syndrome (0.9%), and oculomotor nerve palsy (0.9%). Pembrolizumab was the most common causative agent for neuro-ophthalmic complications (32.1%). Mortality was highest for MG (19.8%). Most patients (79.8%) experienced improvement or complete resolution of neuro-ophthalmic symptoms due to cessation of ICI and immunosuppression with systemic corticosteroids.
Conclusion: While incidence of neuro-ophthalmic IRAEs is low, clinicians involved in the care of cancer patients must be aware of their presentation to facilitate prompt recognition and management. Collaboration between oncology and neuro-ophthalmology teams is required to effectively manage patients and reduce morbidity and mortality.

Keywords: immune checkpoint inhibitors, cancer immunotherapy, CTLA-4 inhibitors, PD-1 inhibitors, PD-L1 inhibitors


Immune checkpoint inhibitors (ICIs) are novel immunologic monoclonal antibodies that block inhibitory receptors of the immune system, such as cytotoxic T-lymphocyte associated antigen-4 (CTLA-4), programmed death-1 receptor (PD-1), and programmed death ligand-1 (PD-L1).1 They are increasingly used as cancer therapies for cancers such as melanoma due to their activation of specific antitumor T-cell immune responses.2 These immune checkpoint molecules maintain immune homeostasis and prevent autoimmunity, but are also used by cancers to suppress normal antitumor immune responses.1,2 CTLA-4, located on T-cells, regulates T-cell activity in the priming phase by preferentially binding to B7 on antigen-presenting cells. CTLA-4 inhibitors decrease the preferential binding between CTLA-4 and cluster of differentiation 28 (CD28) to allow binding of CD28 to B7 to occur and activate T-cells, thereby enhancing antitumor activity.3 PD-1 and PD-L1 inhibitors work by inhibiting the PD-1 (expressed on T or B cells) and the PD-L1 (expressed on cells like tumor cells) interaction that dampens immune response.4 There are currently seven ICIs approved by the US Food and Drug Administration, ipilimumab, pembrolizumab, nivolumab, cemiplimab, atezolizumab, avelumab, and durvalumab.

Due to their efficacious antitumor responses in advanced malignancies, ICIs are increasingly used, and potential new ICIs are investigated in clinical trials. However, there are frequent toxicities associated with their use that can lead to their discontinuation. The toxicities that occur due to immune system activation are termed immune-related adverse events (IRAEs), which can occur in 70–90% of patients and affect any organ system.5,6 The skin and gastrointestinal systems are most affected by ICIs and usually involve low-grade IRAEs such as rashes, diarrhea, and nausea.7,8 ICIs have also been associated with de novo endocrinopathies or exacerbations of existing ones.9 Ophthalmic IRAEs have been reported in less than 1% of patients, common examples include anterior uveitis and dry eye.1012

Neuro-ophthalmic complications warrant their own investigation and can present with higher morbidity and mortality than IRAEs of other systems.7 Currently, established guidelines for the management of IRAEs contain very few neuro-ophthalmic conditions (eg myasthenia gravis (MG), general myositis and thyroid eye disease) and have been nonspecific in describing the unique complications in neuro-ophthalmology.13 While there have been systematic reviews on ophthalmic10,14 and neurologic1517 complications alone, they focus on complications like uveitis or central nervous system disorders that may not involve the visual pathways. No systematic reviews exist on neuro-ophthalmic IRAEs specifically. Thus, the present review was conducted to investigate the neuro-ophthalmic IRAEs of ICIs to collate information on presentation, treatment, and outcome to guide diagnosis and management.


This systematic review and meta-analysis were performed in accordance with the Cochrane Handbook for Systematic Reviews of Interventions18 and the reporting followed the Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) guidelines.19

Search Methods

MEDLINE, Embase, CENTRAL, and Web of Science databases were comprehensively searched from inception to May 8, 2020 (complete search strategy available in Table S1). Articles were limited to English language with no year restrictions. A manual search of references in original studies and reviews and editorials was also conducted. When full-texts were unavailable, library copies were requested. Covidence was used to manage records identified by the literature search.20

Eligibility Criteria and Study Selection

All published articles on ICIs and neuro-ophthalmic outcomes were considered for inclusion. Reviews were used to identify potential eligible articles, but excluded from final analysis. The primary outcomes of the review were the number of cases and incidence of neuro-ophthalmic IRAEs. These included complications of the afferent visual system (eg, optic neuritis; giant cell arteritis, GCA; neuroretinitis), efferent visual system (eg, MG, thyroid-like eye disease, orbital myositis, orbital apex syndrome, oculomotor nerve palsies), and other disorders (eg Tolosa–Hunt Syndrome, neuromyelitis optica). Neurological conditions such as MG were only included if ocular symptoms were involved.

Each study was reviewed by two reviewers, independently and in duplicate, by title and abstract, and subsequently by full text, with discrepancies resolved by an independent third reviewer. During abstract screening, all clinical trials, cohort studies, and case series on side effects not specific to neuro-ophthalmology with ICIs were included for full-text review to ensure that papers that only mentioned neuro-ophthalmic outcomes in the full-text were included.

Data Collection and Synthesis

Data extraction occurred for each study using predefined data abstraction forms in accordance with PRISMA. Extracted data included study characteristics (eg, author, publication year, country, study design), patient demographics (eg, age, sex, cancer type), intervention (eg ICI name, cycles and duration prior to onset), and outcome (eg, neuro-ophthalmic diagnosis, presentation, treatment, and final outcome). Prevalence was also collected for observational studies and clinical trials. Risk of bias was not assessed due to the higher number of case reports and series included. Qualitative analysis was carried out for each neuro-ophthalmic diagnosis reported. Quantitative analysis was performed using Microsoft Excel to calculate mean incidence or mortality of diagnoses when more than one pharmacovigilance or clinical trial reported such data. Overall prevalence of neuro-ophthalmic complications was calculated by dividing the number of cases of neuro-ophthalmic complications in included clinical trials and observational studies by the total number of patients who received ICIs in these studies.


From 3507 abstracts obtained from the search strategy, 2469 abstracts were screened after de-duplication, and 394 full texts were reviewed. Of these, 115 papers met our inclusion criteria. Figure 1 depicts a PRISMA flow diagram.

Figure 1 PRISMA chart for screening process, PRISMA figure adapted from Liberati A, Altman D, Tezlaff J, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. Journal of clinical epidemiology. 2009;62(10). Creative Commons.

Study Characteristics

Of the 115 included studies, 98 were case reports or series and 17 were retrospective chart reviews or clinical trials that reported incidence of neuro-ophthalmic complications. Table 1 provides a summary of these observational or pharmacovigilance studies.2138 Tables 26 detail 109 individual cases (including cases described in observational studies) of optic neuritis/neuroretinitis, neuromuscular disorders, orbital disorders, GCA, and other diseases. A breakdown of the diagnoses can be found in Table 7. Of the cases, 31.2% of all patients with a neuro-ophthalmic complication were female. The mean (range) age at presentation was 66.5 (9–87) years. Cutaneous melanoma was the most common indication for ICI treatment for (48/109, 44.0%), followed by non-squamous cell lung cancer (NSCLC) (19/109, 17.4%). Pembrolizumab was the most common causative agent for neuro-ophthalmic complications (35/109, 32.1%), followed by nivolumab (27/109, 24.8%), ipilimumab (23/109, 21.1%), combination of ICIs (17/109, 15.6%), and atezolizumab (4/109, 3.7%). One case was reported for each of tremelimumab, durvalumab, and sintilimab. There were no reports on neuro-ophthalmic IRAEs for dostarlimab.

Table 1 Summary of Observational Studies or Clinical Trials

Table 2 Summary of Cases—Optic Neuritis or Neuroretinitis

Table 3 Summary of Cases – Neuromuscular

Table 4 Summary of Cases— Orbit

Table 5 Summary of Cases— Giant Cell Arteritis

Table 6 Summary of Cases— Other

Table 7 Breakdown of Neuro-ophthalmic Diagnoses. Excludes Pharmacovigilance or Observational Trials That Do Not Include Details of the Patients

The overall incidence of neuro-ophthalmic outcomes following ICI therapy was 0.46%. The median time to symptom onset was two cycles and ranged from one to 51 doses. ICIs were terminated in most patients following neuro-ophthalmic complication (67/109, 61.5%). They were held in 12 patients (11.0%) and continued in 13 patients (11.9%). Death occurred in 20 of 109 patients (18.3%) due to various causes, including worsening symptoms or other causes prior to improvement of neuro-ophthalmic symptoms. Improvement in neuro-ophthalmic symptoms with persistent deficits (eg, ptosis, diplopia) at last follow-up was seen in 45 of 109 (41.3%) patients, while 42 of 109 (38.5%) patients experienced complete resolution of neuro-ophthalmic symptoms. Outcome was not reported in two patients.

Optic Neuritis

Optic neuritis11,23,26,30,31,34,36,3947 (n=12 case reports, n=9 in larger studies) and neuroretinitis48 (n=1) have been associated with various ICIs, most commonly with ipilimumab (60%). Pharmacovigilance studies showed a combined incidence of 9/2094 (0.43%) for ICI-associated optic neuritis. Of cases that reported laterality, optic neuritis was bilateral in most cases (9/12, 75.0%). While corticosteroids form the mainstay of the treatment, four of 14 patients (28.6%) required additional interventions: intravenous immunoglobulin (IVIg), plasma exchange (PLEX), infliximab, and/or mycophenolate mofetil. All cases experienced resolution (4/14) or improvement with residual symptoms or signs (eg, visual defects, disc pallor) (10/14). Hahn and Pepple reported a patient with neuroretinitis, which involved optic disc and macular edema that resolved with topical and systemic corticosteroids.48

Patients were only confirmed to have optic neuritis if abnormalities in optic nerve enhancement were shown on MRI and clinical presentation was consistent with optic neuritis as highlighted in a previous paper.49 This could not be confirmed for several cases.26,41,44,45

Neuromuscular Disorders

The most common disorder of neuromuscular transmission reported with ICI was MG. Only one case of Lambert–Eaton Myasthenic Syndrome (LEMS) occurred with nivolumab, with symptoms improving with amifampridine.50 Forty-nine case reports of MG were found in the literature.5196 Pharmacovigilance studies suggested that ICI-associated MG has a combined incidence of 303/64,828 (0.47%).25,28,35 However, milder cases of MG may be underdiagnosed due to nonspecific symptoms such as weakness and fatigue. While few cases involved exacerbation of underlying MG (4/49, 8.2%), the rest were de novo (45/49, 91.8%).

Among the 49 cases, most (38/49, 77.6%) occurred with anti-PD-1 (eg, pembrolizumab, nivolumab). Pharmacovigilance studies also supported that MG occurred more commonly in anti-PD-1 (eg, pembrolizumab or nivolumab) or anti-PD-L1 (eg, atezolizumab) compared to anti-CTLA-4 (eg, ipilimumab) therapy (ROR: 3.9, 95%CI: 2.3–6.8).28 Suzuki et al found no cases of MG with ipilimumab.35

There was a shorter time to onset (median 29 days) for ICI-associated MG compared to other neurologic IRAEs (61–80 days).25 The median number of cycles prior to symptom onset amongst all cases was two cycles and ranged from three days after the first dose to three months after the sixth dose. The neuro-ophthalmic symptoms of MG included ptosis and diplopia. In comparison to idiopathic MG, ICI-associated MG patients were more likely to experience bulbar symptoms, specifically dysphagia, dysarthria, and dyspnea, as well as myasthenic crisis.35 ICI-associated MG was also more frequently associated with undetectable or lower acetylcholine receptor antibodies compared to idiopathic MG.28,97,98

ICI-associated MG overlapped with myositis (myalgia and/or elevated creatine kinase, CK) in 24 of 49 cases (49.0%). These results were lower than findings in larger studies—MG was associated with myositis in 85% and myocarditis in 8% of patients.28 There may be an underdiagnosis of concurrent myositis as many cases with elevated CK levels were not formally assessed. Few studies performed skeletal muscle biopsy, but five of seven tested patients had inflammatory infiltrates.28

ICI-associated MG presented with a more common life-threatening fulminant presentation than idiopathic MG.28 Myasthenic crisis had a weighted incidence of 35/78 (46.7%) in larger studies.28,35 In contrast, idiopathic MG has around 15% to 20% lifetime risk of myasthenic crisis in the literature.99 Median onset from presentation to respiratory failure requiring intubation was one week for ICI-associated MG.28

A wide spectrum of clinical severity existed for MG, however, aggressive treatment led to improvement of symptoms in 55.5% and complete remission in 18.9% of patients in larger studies.28,35 While corticosteroids are appropriate for MG, IVIg or PLEX used as a first-line therapy for patients presenting with severe respiratory or bulbar symptoms showed better MG outcomes compared to those who received steroids alone (95% vs 63% symptom improvement).28 However, none of those who had respiratory failure following first-line corticosteroids showed clinical improvement with secondary IVIg or PLEX, unlike patients with idiopathic MG.28

A fatality rate of 19.8% (70/354) was found in case reports and larger studies.25,28,35 Outcomes were worse in patients with concurrent myositis and/or myocarditis, with highest mortality in patients with both (5/8, 62.5%) compared with MG alone (29/179, 16.2%), or with myositis only (6/29; 20.7%).25,28 Overall, complete recovery of MG symptoms occurred in (28/123, 22.8%) of patients. Most patients were maintained on prolonged steroid tapers and showed improvement (63/123, 51.2%).

Orbital Disorders

ICIs were associated with both thyroid-like eye disease (TED)100108 (n=10) and idiopathic orbital myositis103,109119 (n=16). TED may develop in patients on ipilimumab, nivolumab, pembrolizumab, or tremelimumab, even in the absence of existing thyroid dysfunction. In TED, patients generally presented with proptosis, chemosis, and thickening of extra-ocular muscles. They were associated with Graves' disease in 6/10 (60%) of case reports. Labs usually showed abnormal thyroid function, but up to 5% of patients with TED can be euthyroid or hypothyroid.107 Orbital myositis occurred in 15 patients, either from pembrolizumab or ipilimumab with or without nivolumab therapy. The median number of cycles prior to onset of symptoms for TED and myositis was three doses and ranged from one to 51 doses. In TED, orbital imaging showed thickening and enlargement of extraocular muscles without involvement of tendons, while in orbital myositis, tendons were involved. For TED, 9/10 patients (90%) showed improvement or resolution of TED with systemic corticosteroids, while one patient required canthotomy/cantholysis.100 Outcomes were worse for orbital myositis, with nine of 16 patients requiring additional therapy beyond systemic steroids (IVIg, methotrexate, PLEX, mycophenolate mofetil). Thirteen of 16 patients improved or experienced resolution, while two patients died from respiratory failure111,114 and one did not experience improvement before dying from unknown causes.116

In addition, one case each of orbital apex syndrome120 and Tolosa–Hunt syndrome22 occurred with ipilimumab. The former presented with painless vision loss, ptosis, ophthalmoplegia as a result of simultaneous dysfunction of the optic nerve and cranial nerves, and showed improvement on systemic steroids, albeit with persistent esotropia.120 The latter presented with severe unilateral periorbital pain and ophthalmoplegia, which improved with systemic steroids and local radiotherapy.22

Giant Cell Arteritis (GCA)

Five cases of GCA were reported following nivolumab, ipilimumab, combination of both, or pembrolizumab with one to 30 cycles of therapy.121125 Patients presented similar to idiopathic GCA with blurry vision, diplopia, transient vision loss, along with headache, scalp tenderness, and jaw claudication. One patient presented with sudden onset loss of vision alone, while another had no visual symptoms.124,125 Three of five cases also had polymyalgia rheumatica.121,123,124 Most cases resolved with discontinuation of ICI and high-dose corticosteroids between two and four days, while one case persisted with low-grade symptoms and worsened upon starting another ICI.124 No larger trials existed to evaluate incidence of ICI-associated GCA.

Other Neuro-ophthalmic Disorders

Eight cases of generalized myositis with ptosis were reported in literature, most commonly following pembrolizumab therapy (3/8, 37.5%).126133 A high rate of mortality was seen with general myositis (4/8, 50%). The remaining cases improved or resolved with corticosteroids alone or with IVIg. Other neuro-ophthalmic disorders included one case of oculomotor nerve palsy in 526 patients receiving nivolumab.24 This followed three cycles of nivolumab and resolved with a prednisone taper. Another study showed one case of bilateral internuclear ophthalmoplegia following nivolumab of 347 patients, which also improved with corticosteroids.38 One case of opsoclonus-myoclonus-ataxia syndrome was reported following ipilimumab and nivolumab therapy, which resolved with systemic corticosteroids and IVIg.134


Neuro-ophthalmic complications may occur in patients being treated with ICIs. These include afferent disorders including optic neuritis, neuroretinitis, and GCA, and efferent disorders such as TED, MG, LEMS, orbital apex syndrome, oculomotor nerve palsy, orbital myositis, myositis with ptosis, Tolosa–Hunt Syndrome, and bilateral internuclear ophthalmoplegia. In general, ICIs may be held or discontinued for neuro-ophthalmic IRAEs, this decision should be made in consultation with the oncology team and appropriate guidelines, in particular, for more common IRAEs such as myasthenia gravis and myositis.13,135 Almost all patients require initial therapy with high-dose corticosteroids and may require other immunomodulatory therapy. Most afferent visual disorders (12/20, 60.0%) were treated with intravenous corticosteroids while others were treated orally. Out of all the afferent and efferent complications, four of 20 (20.0%) and 40 of 89 (44.9%), respectively, required additional immunomodulatory therapy, most commonly single therapy of IVIg. ICI re-challenge can be considered in cases of mild symptoms that resolve. In our review, 19 cases had either continued or held and then were re-challenged with ICI. Of these cases, four had recurrence or worsening of the same IRAE.84,106,124,136 In cases refractory to corticosteroids and recurrence of IRAE occurs to tapering of corticosteroids, IVIg and plasma exchange have been useful in the acute setting. Given the severity of symptoms and concern for new neuro-ophthalmic symptoms in patients with cancer, hospitalization is often necessary in patients with severe symptoms and multidisciplinary care involving oncology, ophthalmology, neurology, and neuro-ophthalmology is often required.

While ICIs are highly effective in stimulating the immune system to lead to a robust antitumor response, our study supports existing literature that ICIs have significant IRAEs that must be properly managed. In the literature, combination therapies have been discontinued more frequently than monotherapy.137 The mechanisms of induction of IRAEs is not fully elucidated, but are hypothesized to involve decreased peripheral tolerance and induction of organ-specific inflammatory processes.

In our review, several IRAEs occurred with a long duration after ICI administration and occurred with various doses and cycles of ICI. The earliest complication was TED, which arose after one dose (three days) of ipilimumab and pembrolizumab combination therapy,106 while the latest complication of orbital myositis arose after 51 doses (three years) of ipilimumab.115 Thus, the potential dose effects of ICIs on toxicity is difficult to determine at this time. There are key differences between neuro-ophthalmic and ophthalmic complications, our study found that neuro-ophthalmic ones were more likely to be associated with pembrolizumab, while ocular side effects were more common with ipilimumab in literature, likely due to differences in reporting adverse events between the two ICIs.14 In addition, the mean age of patients with neuro-ophthalmic complications was 66.5 years, higher than the mean age of 54 years for ophthalmic complications like uveitis.46 Ophthalmic complications generally had more favorable clinical outcomes compared to neuro-ophthalmic complications such as MG, which had a fatality rate of 19.8%.46

It is also unknown currently if neuro-ophthalmic IRAE severity can be used to predict treatment efficacy. An early study suggested that IRAE such as enterocolitis could signify response to treatment for metastatic melanoma;138 however, other studies have shown that occurrence of IRAE did not correlate with survival outcome or ICI treatment failure.139,140 Horvat et al also reported that the use of corticosteroids for IRAEs (primarily diarrhea, hepatitis, and dermatitis) did not impair overall survival in patients receiving ipilimumab for melanoma.140 This finding was supported by a recent systematic review of nine studies.141 There are currently a large number of novel ICIs, including two anti-CTLA-4, nine anti-PD-1, and four anti-PD-L1 currently in late-stage clinical studies for cancer indications.142

There are several limitations in this review. Data largely consisted of case series, which do not prove cause and effect between ICI and neuro-ophthalmic IRAEs. This link has not been firmly established, especially for conditions such as GCA where prevalence is higher in the patient demographics reported. We have reviewed each case to ensure that other common entities have been excluded in diagnostic consideration. Epidemiologic data on ICI complications were limited by the few number of studies that had neuro-ophthalmic complications. Some conditions may be under-reported due to nonspecific symptoms. While some diseases render a resemblance to established disorders, such as TED, it is possible that ICI-associated disorders (eg, inflammatory orbitopathy) is a distinct clinical syndrome. Future studies should aim to evaluate syndromes consistently (eg, tested for thyroid receptor antibody, thyroglobulin antibody, and thyroid peroxidase antibody). We have described misdiagnosis in previous reports of optic neuritis and emphasized the importance of proper investigations to confirm the diagnosis (eg, use of orbital MRI to detect optic nerve enhancement postgadolinium administration for optic neuritis, anti-aquaporin-4 antibodies for neuromyelitis optica).49 Efforts must be made to exclude common entities.

With the growing number of ICIs and increasing number of indications, it is important for neuro-ophthalmologists to be aware of potential adverse events. Future directions will include identifying minimum active doses for ICIs to achieve antitumor responses while minimizing IRAEs. The rapid identification and initiation of immunosuppression can improve patient outcomes. A collaborative approach and open communication with oncology is necessary in management of these IRAEs.


There is no funding to report.


The authors report no conflicts of interest in this work.


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