Immune Checkpoint Inhibitor-Induced Ptosis in a Patient With Prostate Cancer

Clinical Correspondence Section Editors: Robert Avery, DO Karl C. Golnik, MD Immune Checkpoint Inhibitor–Induced Ptosis in a Patient With Prostate Cancer Katherine J. Williams, MD, Richard C. Allen, MD, PhD, FACS Downloaded from http://journals.lww.com/jneuro-ophthalmology by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCywCX1AWnYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC4/OAVpDDa8KKGKV0Ymy+78= on 05/04/2022 T he development of checkpoint inhibitors has advanced the treatment of multifocal metastatic cancer. In this case, we describe a novel complication as a result of the side effects of these increasingly used chemotherapeutic agents. Although autoimmune complications associated with immunotherapy are becoming better delineated, it is important for ophthalmologists and neuro-ophthalmologists to recognize these symptoms in practice, in both establishing diagnosis and guiding management. Our patient presented with ptosis and was found to have myopathy. A 69-year-old man with metastatic prostate adenocarcinoma presented with a 1-week history of acute painless blepharoptosis on the left eye greater than the right eye. Oncologic history was notable for castrate-resistant prostate cancer with multifocal metastatic disease. The patient had recently completed 2 cycles separated by 3 weeks of ipilimumab and nivolumab. The patient denied previous episodes of ptosis and also denied any trauma or additional symptoms, including diplopia or dysphagia. Visual acuity was 20/20 in the right eye and 20/25 in the left eye; the pupil motility, confrontational fields (with eyelids elevated), intraocular pressure, and anterior and posterior segment examinations were normal. External examination showed ptosis on the left eye greater than the right eye (Fig. 1A), with a margin reflex distance of 0 mm in the right eye and 4 mm in the left eye as well as a levator function of 10 mm in the right eye and 2 mm in the left eye. The ice test showed no significant change in the lid position. MRI of the brain and orbits with and without contrast was normal, without vascular, metastatic, or compressive lesions. Four days after evaluation, the patient developed urinary incontinence with elevated creatine kinase from 1,402 units/L at initial presentation to 4,516 units/L, with associated transaminitis with alanine transaminase (ALT) 207 units/L and aspartate transaminase (AST) 304 units/L (reference range for creatine kinase 22–198 units/L; the patient’s previous baseline ALT was 25 units/L and AST 33 units/L). The patient was admitted and initiated on therapy with 1 g of intravenous (IV) Solu-Medrol twice daily because of a concern for adverse reactions from cycles of ipilimumab and nivolumab, given the new-onset urinary incontinence and transaminitis. Serologic results showed a positive striated muscle antibody and calcium channel– binding antibody. Acetylcholine receptor binding and modulating antibodies and anti-MuSK antibodies were negative. Electromyography and muscle biopsy showed mild generalized myopathy of the skeletal muscle with inflammatory infiltrates, including macrophages, scattered B cells, and abundant T cells. These changes were believed to be nonspecific, but suggestive of acute myositis in the setting of ipilimumab and nivolumab use, with changes in the upper extremities, septal evidence of neuromuscular junction disorder, and inflammation with B and T cells. These findings are suggestive of immunotherapy-induced myositis. The patient underwent plasmapheresis because of the concern for immune-related hepatitis, followed by 4 cycles of IV immunoglobulin and mycophenolate mofetil with Department of Ophthalmology (KJW, RCA), Baylor College or Medicine, Houston, Texas; and Section of Ophthalmology (RCA), Department of Head and Neck Surgery, University of Texas MD Anderson Cancer Center, Houston, Texas. The authors report no conflicts of interest. Address correspondence to Katherine J. Williams, MD, 1977 Butler Boulevard, Houston, TX 77004; E-mail: [e-mail] Williams and Allen: J Neuro-Ophthalmol 2021; 41: e71-e72 FIG. 1. External photographs of the patient at presentation (A), 8-week follow-up (B), and 6-month follow-up (C). e71 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Correspondence improvement in creatine kinase and liver function tests. The patient was discharged with a slow corticosteroid taper; at 8week follow-up after the initial presentation, there was a slow improvement of ptosis (Fig. 1B). At 6 months, ptosis had resolved (Fig. 1C). Immunotherapy with ipilimumab and nivolumab was not restarted, and the patient died of his disease approximately 1 year later. Immunotherapy with checkpoint inhibitors has been a recent and remarkable development in cancer treatment (1,2). However, the use of immune checkpoint inhibitors has been marked by a significant side-effect profile, most commonly related to unwanted inflammation, that is, autoimmune disease. Ophthalmic side effects of checkpoint inhibitors include uveitis and orbital inflammation (including dacryoadenitis and myositis). Our patient experienced both myositis and myasthenic syndrome. The patient presented received 2 novel immunotherapy agents: ipilimumab, an anti–cytotoxic T-lymphocyte– associated protein 4 (CTLA-4) monoclonal antibody, and nivolumab, an anti–programmed cell death protein 1 (PD-1) monoclonal antibody. Ipilimumab targets the CTLA-4 pathway, leading to T-cell activation. Treatment with CTLA-4 inhibitors has been previously reported to cause myasthenia gravis in mouse models (3); immunerelated adverse events have been reported previously in up to 35% of patients (1). Nivolumab blocks the PD-1 immune checkpoint on T lymphocytes to affect the negative regulation of T-cell signaling; blockade of PD-1 leads to T-cell–mediated antitumor response. Myasthenia gravis has been previously reported with the use of nivolumab (4,5). Serologic results are negative for autoantibodies typically found in myasthenia gravis; 73.7% of the previously reported cases were de novo (2,4,5). In our patient, AChR Abs were negative, and the currently published reports suggest the significance of these antibodies in immunotherapy-induced myasthenia gravis remains indeterminate (5). Of note, the use of dual immune checkpoint e72 inhibitor therapies may lead to an overall increase in toxicity and subsequent increase in the amplitude of the symptoms experienced by patients, as compared to side effects observed with either immune checkpoint inhibitor used independently (1). Although myasthenia symptoms are relatively rare in comparison with other immune-related adverse events, there is specifically a 30.4% myasthenia gravis–related mortality (5). The previously reported cases of immunotherapyinduced myasthenic syndrome have been treated with low-dose acetylcholinesterase inhibitors, pyridostigmine and IV immunoglobulin combined together; pyridostigmine alone provides minimal benefits (5). As a diagnostic tool, the role of pyridostigmine, as well as ice and rest testing in diagnosis, requires further evaluation. Reports on treatment with exclusive acetylcholinesterase inhibitors, including pyridostigmine, are limited, and most published reports to date involve immunomodulatory therapy (5). As the utilization of immune checkpoint inhibitors becomes more common, it is important for ophthalmologists to be aware of these potential side effects to ensure prompt recognition and treatment. REFERENCES 1. Farkona S, Diamandis EP, Blasutig IM. Cancer immunotherapy: the beginning of the end of cancer? BMC Med. 2016;14:73. 2. Stone JB, DeAngelis LM. Cancer treatment-induced neurotoxicity: a focus on newer treatments. Nat Rev Clin Oncol. 2016;13:92–105. 3. Wang HB, Shi FD, Li H, Chambers BJ, Link H, Ljunggren HG. AntiCTLA-4 antibody treatment triggers determinant spreading and enhances murine myasthenia gravis. J Immunol. 2001;166:6430–6436. 4. Chen YH, Liu FC, Hsu CH, Chian CF. Nivolumab-induced myasthenia gravis in a patient with squamous cell lung carcinoma: case report. Sinnberg. T, ed. Medicine (Baltimore). 2017;96:e7350. 5. Makarious D, Horwood K, Coward JIG. Myasthenia gravis: an emerging toxicity of immune checkpoint inhibitors. Eur J Cancer. 2017;82:128–136. Williams and Allen: J Neuro-Ophthalmol 2021; 41: e71-e72 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited.