Bilateral Optic Neuritis Secondary to Immune Etiology by anti-PD-L1 Antibody

Clinical Correspondence Section Editors: Robert Avery, DO Karl C. Golnik, MD Caroline Froment, MD, PhD An-Gour Wang, MD Bilateral Optic Neuritis Secondary to Immune Etiology by anti-PD-L1 Antibody Mikel Vicente-Pascual, MD, Cristina Molins-Rojas, MD, Katiuska Rosas-Soto, MD, Eleonor P. Murata-Yonamine, MD, Daniel Vázquez-Justes, MD, Francisco Purroy, MD, PhD, Alicia Traveset-Maeso, MD C heckpoint inhibitors (CPIs) have been established as a promising alternative treatment for various cancers, including renal cancer. Among these drugs are nivolumab, a human monoclonal antibody immunoglobulin type G4 (IgG4) that binds to the programmed death receptor 1 (PD1) and blocks its interaction with PD-L1 and PD-L2. This enhances the responses of T-lymphocytes, including antitumor responses. However, this increase in T-cell responsiveness leads to toxicity and adverse effects on any target organ, including the central nervous system. We present a new case of neurological toxicity. The patient is a woman affected of a renal carcinoma, in treatment with nivolumab as a second-line treatment. She presented a decrease in bilateral visual acuity, which was diagnosed with optic neuritis. The neurological and ophthalmological study discarded other neurological or ophthalmological diseases, considering the possibility of optic neuritis immune-related associated with nivolumab. The patient was a 70-year-old woman with history of hypertension and clear cell renal carcinoma, diagnosed in 2016, treated with nephroureterectomy and adjuvant chemotherapy with sunitinib. After 2 years, treatment with sunitinib was discontinued due to symptomatic hypothyroidism and neutropenia, leading to a disease progression, appearing retrocaval tumor recurrence and perisplenic tumor implants. Consequently the patient started a new therapy with nivolumab. After the third cycle, the patient experienced bilateral visual loss with no headache or ocular pain with eye movements. The ophthalmic examination evidenced a visual acuity of 7/10 and 6/10 (right eye and left eye, respectively), and central vision defect with increased blind spot (Fig. 1) and bilateral disc optic edema (Fig. 2A). The fluorescein Department of Neurology (MV-P, DV-J, FP), Arnau de Vilanova Hospital, Lleida, Spain; Primary Care Medical Center (CM-R), Balàfia-Pardinyes Basic Health Area, Lleida, Spain; Department of Neurosurgery (KR-S), Arnau de Vilanova Hospital, Lleida, Spain; Department of Oncology (EPM-Y), Arnau de Vilanova Hospital, Lleida, Spain; and Department of Ophthalmology (AT-M), Arnau de Vilanova Hospital, Lleida, Spain. The authors report no conflicts of interest. Address correspondence to Mikel Vicente-Pascual, MD, Department of Neurology, Hospital Universitari Arnau de Vilanova, Av. Alcalde Rovira Roure, 80, 25198, Lleida, Spain; E-mail: [e-mail] Vicente-Pascual et al: J Neuro-Ophthalmol 2021; 41: e177-e179 angiography showed bilateral papillary hyperfluorescence, without evidence of vascular abnormalities (Fig. 2B), and the optical coherence tomography showed thickening of ganglion fibers. These results were compatible with bilateral optic neuritis immune-related by nivolumab. The neurological examination did not get any pathological signs. The brain MRI showed no space-occupying lesions and the lumbar puncture got a clear fluid, without biochemical alterations, negative serology, and normal opening pressure (17 cm H2O). Visual-evoked potentials registered axonal and demyelinating involvement of both optic nerves. Autoimmunity objectivated positive antinuclear antibodies, on 1/320 title, with mottled staining pattern, and negative anti-MOG, anti-NMO antibodies, and oligoclonal bands. With all these results, she was diagnosed with bilateral optic neuritis secondary to nivolumab. Steroid pulse therapy was initiated, at dose of 1 g of intravenous methylprednisolone for 3 days, followed by oral treatment. Visual loss did not progress, and the fundus was normalized without any other abnormalities in the optical coherence tomography. CPIs are increasingly used as chemotherapeutic agents. They exert their function by activating the immune system to attack tumor cells. Because of this, new adverse effects related to the immune system are being known. It is estimated that ocular symptoms occur in slightly more than 1% of patients, being in most cases affectations of the anterior segment (1). Nervous system involvement is a rare condition, occurring in less than 1%. Among them, the most frequent are peripheral neuritis, encephalitis, myasthenia gravis, and acute and chronic demyelinating polyradiculoneuropathy. Recently, new cases of the secondary effects of nivolumab have been described; one was an optic neuromyelitis with positive anti-NMO antibodies (2). Two other cases were similar to our patient. The first one presented a child with glioblastoma multiforme, who developed optic neuritis 3 days after the second cycle of treatment (3). The second was about an adult with lung carcinoma. This patient presented a left optic neuritis, associated with hypopituitarism. Visual symptoms began one year after e177 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Correspondence FIG. 1. Visual field: A central vision defect with increased blind spot is observed. treatment with nivolumab (4). In both cases of optic neuritis, visual loss improved after intravenous steroids treatment, which was early started after the onset of symptoms. The authors assumed that this drug reduces the self-tolerance of the immune system, stimulating the autoimmune phenomena. In a phase 1 study of 90 patients with ipilimumab refractory melanoma or naive melanoma in treatment with nivolumab, one patient presented bilateral optic neuritis, which was resolved after treatment with oral steroids (5). In our case, there was no improvement in visual acuity, which may be explained by the axonal involvement of the optic nerve. The positivity of antinuclear antibodies, without systemic symptomatology, reinforces the diagnosis of immune-related disease. We reported another case of optic neuritis, possibly immune-related by anti-PD-L1 antibody treatment. Axonal involvement in visual-evoked potentials implies a worse prognostic, concluding that an early recognition of symptomatology is essential to avoid disability, by discontinuing the drug and starting the steroids therapy. FIG. 2. A. Fundus showing bilateral optic disc edema. B. Fluorescein angiography shows bilateral papillary hyperfluorescence. e178 Vicente-Pascual et al: J Neuro-Ophthalmol 2021; 41: e177-e179 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Correspondence REFERENCES 1. Dalvin LA, Shields CL, Orlof M, Sato T, Shields JA. Checkpoint inhibitor immune therapy: systemic indications and ophthalmic side efects. Retina. 2018;38:1063–1078. 2. Narumi Y, Yoshida R, Minami Y, Yamamoto Y, Takeguchi S, Kano K, Takahashi K, Saito T, Sawada J, Terui H, Katayama T, Sasaki T, Ohsaki Y. Neuromyelitis optica spectrum disorder secondary to treatment with anti-PD-1 antibody nivolumab: the first report. BMC Cancer. 2018;18:95. 3. Mori S, Kurimoto T, Ueda K, Enomoto H, Sakamoto M, Keshi Y, Yamada Y, Nakamura M. Optic neuritis possibly induced by Vicente-Pascual et al: J Neuro-Ophthalmol 2021; 41: e177-e179 anti-PD-L1 antibody treatment in a patient with non-small cell lung carcinoma. Case Rep Ophthalmol. 2018;9:348–356. 4. Kartal Ö, Ataş E. Bilateral optic neuritis secondary to nivolumab therapy: a case report. Medicina (Kaunas). 2018;6:54. 5. Weber JS, Kudchadkar RR, Yu B, Gallenstein D, Horak CE, Inzunza HD, Zhao X, Martinez AJ, Wang W, Gibney G, Kroeger J, Eysmans C, Sarnaik AA, Chen YA. Safety, efficacy, and biomarkers of nivolumab with vaccine in ipilimumabrefractory or -naive melanoma. J Clin Oncol. 2013;31:4311– 4318. e179 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited.