A Case of Miller Fisher Syndrome Due to the Use of Cemiplimab

Clinical Correspondence Section Editors: Robert Avery, DO Karl C. Golnik, MD Caroline Froment, MD, PhD An-Gour Wang, MD A Case of Miller Fisher Syndrome Due to the Use of Cemiplimab Arko Ghosh, BS, Shruthi Harish Bindiganavile, MD, Nita Bhat, MD, Andrew G. Lee, MD A n 88-year-old Caucasian man presented with a 2-day history of acute, painless, binocular diplopia. His right eye had become progressively blurrier over the past several months. He additionally described a 2-week history of generalized weakness, shortness of breath, unsteadiness, and dysphagia. He denied recent upper respiratory infection. His past medical history was significant for cutaneous squamous cell carcinoma for which he was taking immunotherapy with cemiplimab as part of a clinical trial. He had taken a 44-mg weekly dose of intralesional cemiplimab for 4 weeks before his trial was halted because of his neurological symptoms. His past ocular history was remarkable for primary open-angle glaucoma status after selective laser trabeculectomy with stable intraocular pressure on medical therapy. Ophthalmologic examination showed a visual acuity of 20/50 in his right eye and 20/20 in his left eye. His pupils measured 3 mm in dark to 2 mm in light in both eyes, with a trace relative afferent pupillary defect in the right eye. Intraocular pressure measured 11 mm Hg in the right eye and 13 mm Hg in the left eye. He had bilateral, moderate ophthalmoplegia with a 24 deficit of elevation and depression and a 22 deficit of horizontal gaze (Fig. 1). On funduscopic examination, he had advanced asymmetric glaucomatous cupping (cup-to-disc ratio of 0.9 in the right eye and 0.7 in the left eye). The remainder of his structural eye examination was unremarkable. Neurologic examination showed ataxia, diffuse areflexia, and a bilateral ascending motor and sensory lower extremity polyneuropathy. MRI of the brain showed no brainstem lesion, but there was nonspecific age-related diffuse cerebral atrophic change with secondary ex-vacuo ventriculomegaly and diffuse chronic microvascular disease. Lumbar puncture showed normal cerebrospinal fluid cell (CSF) count and an elevated CSF protein of 69 mg/dL consistent with albuminocytoTexas A&M University College of Medicine (AG, AGL), Bryan, Texas; Department of Ophthalmology (SHB, NB, AGL), Blanton Eye Institute, Houston Methodist Hospital, Houston, Texas; Departments of Ophthalmology, Neurology, and Neurosurgery (AGL), Weill Cornell Medicine, New York, New York; Department of Ophthalmology (AGL), University of Texas Medical Branch, Galveston, Texas; University of Texas MD Anderson Cancer Center (AGL), Houston, Texas; and Department of Ophthalmology (AGL), The University of Iowa Hospitals and Clinics, Iowa City, Iowa. The authors report no conflicts of interest. Address correspondence to Andrew G. Lee, MD, Blanton Eye Institute, Houston Methodist Hospital, 6560 Fannin Street Suite 450, Houston, TX 77030; E-mail: [e-mail] Ghosh et al: J Neuro-Ophthalmol 2021; 41: e343-e345 logic dissociation. Serum anti-GQ1b antibody tested negative. Despite the negative anti-GQ1b antibody, a diagnosis of Guillain–Barre syndrome (GBS) was made, and given the ophthalmoplegia, ataxia, and areflexia, the Miller Fisher variant of GBS was suspected, which was felt to be triggered by cemiplimab. The cemiplimab was held indefinitely, and he underwent intravenous methylprednisolone and immunoglobulin therapy for 5 days, followed by a slow oral prednisone taper. The patient slowly began to see improvement of the generalized weakness and ophthalmoplegia over 7–10 days during the prednisone taper. DISCUSSION The Miller Fisher variant of GBS is an autoimmune inflammatory demyelinating polyneuropathy characterized by motor and sensory symptoms, ataxia, areflexia, and ophthalmoplegia. Patients commonly present with diplopia, gait disturbance, and dysesthesia. Signs and symptoms typically present about 1 week after exposure to a trigger, if trigger is present. Although not always present, triggers include infections, autoimmune processes, neoplasms, and, rarely, medications (1). The Miller Fisher Syndrome (MFS) typically begins to resolve with treatment and full recovery is common after 2–3 months. Plasma exchange or intravenous immunoglobulin (IVIg) may speed recovery (2). The Miller Fisher syndrome is often associated with antiganglioside antibodies (e.g., GQ1b). Anti-GQ1b antibodies may develop through molecular mimicry after a trigger. These antibodies localize in the motor nuclei of cranial nerves III, IV, and VI, causing extraocular motor dysfunction. Anti-GQ1b antibodies also target the cerebellum and neuromuscular junctions causing ataxia and areflexia, respectively. The presence of anti-GQ1b antibodies is a highly sensitive laboratory finding, found in 85% of patients with MFS. Despite the high sensitivity of this laboratory value, MFS remains a clinical diagnosis (1). GQ1b antibodies were negative in our patient but the clinical picture still reflected MFS. A recent case series reviewed 5 patients with GBS secondary to immunomodulating treatment, 3 of whom died or failed to improve (3). Cemiplimab is a monoclonal antibody used for the treatment of cutaneous squamous cell carcinoma (4). Cemiplimab acts as a checkpoint inhibitor by targeting PD-1, an important T-cell regulator protein. e343 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Correspondence FIG. 1. Extraocular motility examination showing 15 prism diopter exotropia in primary gaze and limited ductions in all cardinal positions of gaze. PD-1 guards against autoimmunity by inducing apoptosis of T cells that recognize self-antigens. By blocking PD-1, cemiplimab augments the T-cell response against cancer cells (5). Cemiplimab, like other checkpoint inhibitors, can cause immune-related adverse effects (IRAEs) in multiple organ systems (6). Although neurological adverse effects are less common, they can be serious and include myasthenia gravis, multiple sclerosis, encephalitis, and inflammatory polyneuropathies, such as GBS. Ophthalmological complications of checkpoint inhibitors are rare but include blepharitis, conjunctivitis, keratitis, iritis, uveitis, optic disc edema, papillitis, neuroretinitis, and orbital inflammation or myositis (3). Although GBS has been documented as a complication of the use of checkpoint inhibitors, the Miller Fisher syndrome is an unusual IRAE. There have been only 2 previous documented cases of Miller Fisher syndrome presumed secondary to the use of checkpoint inhibitors. Both cases involved nivolumab, a PD-1 inhibitor similar to cemiplimab. Both of these cases were effectively managed with cessation of the immunomodulator and commencement of intravenous corticosteroid and IVIg therapy (7,8). To the best of our knowledge, this is the first case of cemiplimab causing MFS as an IRAE in the English language ophthalmic literature. Clinicians should be aware of the possibility of ophthalmoplegia and diplopia from IRAE (e.g., myasthenia gravis, thyroid ophthalmopathy, and MFS) in patients on immunotherapy with checkpoint inhibitors, including cemiplimab. e344 STATEMENT OF AUTHORSHIP Category 1: a. Conception and design: A. G. Lee, S. H. Bindiganavile, and A. Ghosh; b. Acquisition of data: S. H. Bindiganavile, A. Ghosh, and A. G. Lee; c. Analysis and interpretation of data: S. H. Bindiganavile, A. Ghosh, A. G. Lee, and N. Bhat. Category 2: a. Drafting the manuscript: S. H. Bindiganavile, A. Ghosh, and A. G. Lee; b. Revising it for intellectual content: S. H. Bindiganavile, A. Ghosh, and A. G. Lee. Category 3: a. Final approval of the completed manuscript: S. H. Bindiganavile, A. Ghosh, A. G. Lee, and N. Bhat. REFERENCES 1. Teener JW. Miller Fisher’s syndrome. Semin Neurol. 2012;32:512–516. 2. Mori M, Kuwabara S, Fukutake T, Hattori T. Intravenous immunoglobulin therapy for Miller Fisher syndrome. Neurology. 2007;68:1144–1146. 3. Haugh AM, Probasco JC, Johnson DB. Neurologic complications of immune checkpoint inhibitors. Expert Opin Drug Saf. 2020;19:479–488. 4. Migden MR, Khushalani NI, Chang ALS, Lewis KD, Schmults CD, Hernandez-Aya L, Meier F, Schadendorf D, Guminski A, Hauschild A, Wong DJ, Daniels GA, Berking C, Jankovic V, Stankevich E, Booth J, Li S, Weinreich DM, Yancopoulos GD, Lowy I, Fury MG, Rischin D. Cemiplimab in locally advanced cutaneous squamous cell carcinoma: results from an open-label, phase 2, single-arm trial. Lancet Oncol. 2020;21:294–305. 5. 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