Despite ocular adverse events from immune checkpoint inhibitors being uncommon, they are still important complications to be aware of. We present the case of metastatic melanoma on ipilimumab/nivolumab in a patient who developed immunotherapy complications with delayed diagnosis because the only presenting symptom was unilateral ptosis. We reviewed the literature for relevant and important ocular and neurological complications of immune checkpoint inhibitors.

The use of immunotherapy continues to expand within the field of oncology. Over the past few years immune checkpoint inhibitors (ICIs) have been approved for use in the systemic treatment of cancer such as melanoma, lung cancer, breast cancer, esophageal cancer, and others. With increased use of ICIs (e.g., anti-programmed cell death protein 1 [PD1], PD-ligand 1 [PD-L1], and anti-cytotoxic T-lymphocyte associated protein 4 [CTLA4]), as well as use of the novel inhibitors (lymphocyte-activation gene 3 [LAG3]), there has been the challenge of increased immunotherapy toxicity.

It is well known that ICIs cause an array of immune-related adverse effects (irAEs) that are distinct from toxicity associated with other systemic antineoplastic therapy. Data suggest that between 30% and 70% of patients receiving immunotherapy will at some point develop an irAE, and approximately 10–15% of them will develop grade 3 or grade 4 immune-mediated toxicity with anti-PD1/anti-PD-L1 therapy alone that would preclude these patients from further use of immunotherapy.[1–4] The rate of grade 3–5 irAEs is higher when anti-PD1/PD-L1 treatment is combined with CTLA4 blockade. The side effects commonly involve colitis, pneumonitis, dermatitis, hepatitis, and endocrinopathies such as hypothyroidism and adrenal insufficiency. Occasionally, patients develop inflammation of other organ systems, including myocarditis and myositis that can cause life-threatening respiratory muscle compromise or arrythmias.

Ocular toxicity is rare, with rates of ocular adverse events (oAEs) at 3–7%.[5,6] The most common oAEs include uveitis, retinal disorders, lacrimal disorders, and ophthalmoplegia including ptosis. Awareness of the rare side effects and appropriate patient monitoring while on ICIs is essential for oncology providers.

ICIs are the cornerstone of melanoma management. Systemic treatment for stage 4 melanoma typically involves inhibitors of PD1/PD-L1, alone or in combination with inhibitors of LAG-3 or CTLA4. Ipilimumab is an anti-CTLA4 monoclonal antibody, and nivolumab is a targeted monoclonal antibody against PD-1. The combination of the two has been associated with a more than 50% response rate. Albeit it is often the preferred first-line regimen for patients with advanced melanoma,[7] it is associated with grade 3 or 4 adverse events in more than 50% of patients. Recently, the addition of relatlimab, a LAG3-blocking antibody, to nivolumab has also been found to be more effective for metastatic melanoma compared with nivolumab alone, but at the expense of significant increase in grade 3 or 4 irAEs.[8]

We present the case of a patient with metastatic melanoma treated with ipilimumab and nivolumab who developed a potentially dangerous immune-mediated toxicity, but diagnosis was delayed as his only symptom was unilateral eye ptosis. We have obtained signed consent from the patient to publish the details of his case and the included photo.

The patient is a 65-year-old man who presented to our oncology clinic with metastatic melanoma. His medical history included hypertension and benign prostatic hypertrophy. In 2014, he had a history of cutaneous melanoma with a Breslow thickness of 1.4 mm of his left cheek without ulceration. He underwent wide local excision with sentinel lymph node biopsy that was negative for residual disease and lymph node involvement. He followed up with dermatology for skin checks. In the summer of 2022, he felt a right axillary lump. He underwent fine-needle aspiration of an enlarged axillary lymph node, and pathology revealed metastatic melanoma. Testing was negative for BRAF V600E or KIT mutation. Staging imaging revealed multiple sites of metastases, including the lungs, liver, brain, and multiple lymph nodes.

The patient was initiated on systemic immunotherapy with nivolumab and ipilimumab. He received nivolumab 3 mg/kg and ipilimumab 1 mg/kg every 3 weeks. Two weeks after receiving his second cycle, he noticed drooping of his left eyelid. It was significant enough to cover his left pupil and block vision of his left eye (Fig. 1). He had no ocular symptoms in his right eye. He did not have any other symptoms such as eye pain or redness, muscle weakness, difficulty with speech or swallowing, sensory deficits, skin rash, shortness of breath, cough, or diarrhea. He reached out to his oncology team and subsequently sent a picture of his eye, which documented the ptosis. Based on this, he was sent to his local emergency room out of concern that this was ICI-related myasthenia gravis.

Figure 1

Left-sided ptosis noted on physical examination. Photograph is courtesy of Mayo Foundation for Medical Education and Research, all rights reserved.

Figure 1

Left-sided ptosis noted on physical examination. Photograph is courtesy of Mayo Foundation for Medical Education and Research, all rights reserved.

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At the emergency room, he was evaluated by an ophthalmologist and on examination he was noted to have isolated ptosis of the left eyelid. There was no evidence of scleritis or uveitis, his pupils were normal in appearance and reactive to light, and the remainder of the ophthalmological examination was unremarkable. Because of his known central nervous system (CNS) disease, he was also evaluated with a CT scan of the head, which was not concerning for changes in his CNS involvement by melanoma. The ophthalmologist suspected this ptosis was due to levator dehiscence.

He presented to the oncology clinic a few days later for regular follow-up. His left ptosis was still present and significant enough to obstruct the vision from his left eye, but he was starting to notice drooping of his right eyelid as well, with some ptosis of the right eye noted on examination. He was otherwise asymptomatic. Laboratory evaluation demonstrated a creatine kinase level of 2359 U/L (upper limit of normal [ULN] is 308), alanine aminotransferase of 119 U/L (ULN is 55), aspartate aminotransferase of 118 U/L (ULN is 43), and troponin T of 330 ng/L (ULN is 15). He was admitted to the hospital for suspected myositis, myocarditis, and possible myasthenia gravis (“triple M” syndrome) secondary to ICI use and was managed in a multidisciplinary fashion with guidance and input from oncology, neurology, and cardiology teams.

Workup for “triple M” syndrome included an electromyogram done in the hospital that showed evidence of myopathy without evidence of any superimposed neuromuscular transmission disorder. Screening for myasthenia gravis and other myopathies with MuSK autoantibodies, anti-Ach receptor antibodies, HMG-CoA reductase antibodies, anti-Jo, and anti-U1 RNP antibodies was negative. His brain MRI demonstrated interval reduction in the size of a previously noted enhancing right occipital metastatic lesion with near complete interval resolution of the surrounding edema. No acute intracranial findings or new enhancing lesions were seen. He underwent an echocardiogram that was unremarkable with a left ventricular ejection fraction of 61%. His cardiac rhythm remained stable on telemetry monitoring. In addition, he underwent a cardiac MRI that showed no evidence of myocarditis, and the elevated troponin was felt to be “troponin leak” from his skeletal muscles. The presenting symptom of eye ptosis was attributed to grade 2 ICI myositis, and based on transaminases he was diagnosed with a grade 1 ICI-induced hepatitis.[9,10] Other etiologies of myositis and rhabdomyolysis, including uncontrolled hypothyroidism, alcohol use disorder, and toxicity from other medications were ruled out.

Given the initial suspicion for myocarditis, he was started on 1000 mg of IV methylprednisolone daily for 3 days, then was transitioned to oral prednisone at 1 mg/kg daily dosing (100 mg). He started noticing improvement in his ptosis within 48 hours of initiating the IV steroids. Thankfully, his symptoms did not progress beyond ptosis, and he never had noticeable extremity weakness or chest pain. His labs also demonstrated rapid improvement over the next few days. His prednisone was tapered weekly over the course of 2 months, and all his laboratory abnormalities had normalized except for his troponin T, which remained at 44 (Fig. 2). Rechallenge with ICI was not attempted, and the patient remains free of progression 14 months later and without any recurrence of his ICI toxicities.

Figure 2

Trends in abnormal labs following treatment. ALT, alanine aminotransferase; AST, aspartate aminotransferase; CK, creatine kinase; IV, intravenous; PO, per oral; ULN, upper limit of normal.

Figure 2

Trends in abnormal labs following treatment. ALT, alanine aminotransferase; AST, aspartate aminotransferase; CK, creatine kinase; IV, intravenous; PO, per oral; ULN, upper limit of normal.

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This is a case of a patient with grade 2 myositis and unusual initial presentation of unilateral ptosis. ICI-related myositis frequently occurs concomitantly with myasthenia gravis and myocarditis (“triple M”), which can be life threatening.[11,12] ICI-related myositis similarly has a high fatality rate of 20–40%, whereas the mortality rate of ICI-induced myocarditis is approximately 50% or more.[13–15] Fortunately, our patient did not develop myocarditis or myasthenia gravis. This case illustrates some of the diagnostic challenges in the evaluation of patients with immune-related myositis, as early aggressive treatment with corticosteroids can be critical at a time when the clinical syndrome may have not fully developed yet. Here, the decision to treat as an inpatient with high-dose intravenous (IV) corticosteroids was made on the basis of a troponin leak and before the findings of the full cardiologic workup, including a cardiac MRI, were made available.

Mazharuddin et al[16] demonstrated that ipilimumab/nivolumab combination had the highest rates of oAEs, with the most common being corneal and neuro-ophthalmic toxicities. Unsurprisingly, patients with metastatic melanoma were the most likely to develop irAEs among the solid tumors in their cohort analysis. Optic nerve injury (neuritis or atrophy) was the most common neuro-ophthalmic diagnosis, followed by immune-related myasthenia gravis (3%). In a study assessing ICI use in patients with lung cancer, ophthalmoplegia (40.5%), uveitis (20.3%), and dry eye (17.7%) were the most common oAEs, and among ophthalmoplegias, ptosis was the most common (53.1%).[6] Importantly, ophthalmoplegia was unilateral in 11 patients. The median onset for ophthalmoplegia was 35 days. Those with ptosis often had ICI-induced myasthenia gravis, which had a 40% mortality rate despite discontinuing ICIs and initiating immunosuppression.

The workup conducted here, including the lab tests, electromyography, myopathy and myasthenia gravis panel screening, and cardiac MRI, as well as the management via steroid therapy and discontinuation of ICI were based on recommendations found in American Society of Clinical Oncology and European Society for Medical Oncology guidelines.[9,10] For ICI toxicities requiring hospitalization, guidelines typically recommend high-dose steroids (1–2 mg/kg of prednisone or equivalent), consideration of other immunosuppressants, and close monitoring and multidisciplinary care. If concerned for myocarditis, even higher doses of 500–1000 mg of methylprednisolone should be used for the first few days. Pyridostigmine should be considered if there is concern for myasthenia gravis. Once the ICI toxicity has demonstrated steroid responsiveness, the steroids should be tapered over a matter of weeks. Should the toxicity not respond sufficiently to steroids, other immunosuppressants that can be used include tocilizumab, mycophenolate mofetil, infliximab, and anti-thymocyte globulin.

Of note, our patient remains disease free more than a year out from his last ICI dose, despite having only received two cycles of treatment. The relationship between ICI toxicity and antitumor efficacy has been an area of research interest, with several studies suggesting the irAEs are correlated with increased ICI responses.[17,18] In a meta-analysis including 21 melanoma studies by Hussaini et al,[17] the development of irAEs was associated with better average overall survival (15.24 months versus 8.94 months, hazard ratio = 0.46, 95% CI 0.35–0.62, p < 0.00001). The robust immune response in this case that resulted in ICI toxicity may explain the sustained melanoma response as well.

This case demonstrates that it is important to be vigilant regarding any new symptoms that develop while a patient is on an ICI, and to recognize that unilateral ptosis, although uncommon, is still a potential side effect of immunotherapy. As with all other ICI-related adverse events, discontinuing therapy and initiating immunosuppression is the mainstay of treatment.

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Source of Support: None.

Conflicts of Interest: Anastasios Dimou reports honoraria from Intellisphere and Roche/Genentech; advisory board for TP Therapeutics, Guardant Health, AnHeart Therapeutics, and ChromaCode; and clinical trial support from Syntrix Pharmaceuticals, Novartis, Merck, AnHeart Therapeutics, Sorrento Therapeutics, Guardant Health, Philogen, and AstraZeneca. The other authors have no conflicts of interest.

This work is published under a CC-BY-NC-ND 4.0 International License.