Pembrolizumab-Associated Optic Neuritis With an Unusual Manifestation of Monocular Optic Disc Edema

Clinical Correspondence Section Editors: Robert Avery, DO Karl C. Golnik, MD Caroline Froment, MD, PhD An-Guor Wang, MD Pembrolizumab-Associated Optic Neuritis With an Unusual Manifestation of Monocular Optic Disc Edema Roxana Teodorescu, MD, Henry Liu, MD, Alfredo A. Sadun, MD, PhD A 67-year-old Caucasian woman was referred for a neuroophthalmologic examination after an initial diagnosis of papillitis in the left eye by her ophthalmologist. She complained of bilateral floaters for 3 months, and previously had 3 cycles of pembrolizumab therapy (200 mg every 3 weeks) for metastatic Merkel cell carcinoma, which was otherwise well-tolerated. The patient denied eye pain, blurry vision, or change in color perception. Pembrolizumab was discontinued because of concerns about papillitis, and she was referred for further evaluation. Examination revealed a visual acuity of 20/20, normal color vision in both eyes, and a trace relative afferent pupillary defect in the left eye. Ocular motility was full without painful eye movements. Anterior segment examination was unremarkable except for the presence of a 2+ nuclear sclerotic cataract. On fundus examination, the optic disc of the right eye appeared normal (Fig. 1A), whereas the left eye demonstrated grade 3+ disc edema with peripapillary vessel obscuration (Fig. 1B). The clinical features were not consistent with the diagnosis of papillitis. Both eyes showed posterior vitreous detachment, mild epiretinal membrane, and a few macular drusen. Optical coherence tomography (OCT) was congruent with examination findings and confirmed optic disc edema with retinal nerve fiber layer (RNFL) swelling and marked rim elevation of the left eye. Visual field testing demonstrated mild arcuate superior visual field defects in both eyes (Fig. 2A). The differential diagnosis of a swollen optic disc includes optic neuritis, papilledema, anterior ischemic neuropathy, pseudopapilledema, central retinal vein occlusion, and neuroretinitis. Less common causes include uveitis, papillitis, diabetic papillopathy, malignant hypertension, optic nerve infiltration, and Leber’ hereditary optic neuropathy (1). Typical optic neuritis (ON) is frequently associated with multiple sclerosis and presents itself in young, Caucasian women with eye pain, dyschromatopsia, decreased visual acuity, scotoma, and demyelinating lesions on neuroimaging. Atypical ON is because of causes other than multiple sclerosis, is seen in children under 12 years old or Doheny Eye Institute (RT, HL, AAS), Los Angeles, California; and Department of Ophthalmology (AAS), David Geffen School of Medicine at University of California, Los Angeles, California. The authors report no conflicts of interest. Address correspondence to Henry Liu, Doheny Eye Center-UCLA, 800 S. Fairmount Avenue, Suite 215, Pasadena, CA 91105; E-mail: [e-mail] e246 adults over 50 years old, and occurs more in men. This type of ON presents with severe eye pain, progressive vision loss, and MRI may show extensive involvement of the optic nerve, optic chiasm, and optic tracts (2). MRI of the brain was unremarkable with no demyelinating, metastatic, or intracranial compressive lesions; only nonspecific T2/FLAIR hyperintensities were noted. Lumbar puncture revealed a normal opening pressure of 110 mm H2O and normal cerebrospinal fluid analysis with exception of oligoclonal bands concluded to be nonspecific. Serologies were normal and without evidence of infection, autoimmune or granulomatous disease. Neuromyelitis optica and myelin oligodendrocyte glycoprotein antibody disease were excluded based on the patient’s clinical profile. The patient was diagnosed with bilateral optic neuritis and monocular optic disc edema (left eye) as a probable pembrolizumab-related adverse event, according to the Naranjo Nomogram (score 6). At follow-up, her visual acuity and color vision remained normal. The left optic disc swelling decreased to grade 2+, along with the RNFL thickness on OCT. Pembrolizumab was then resumed, and the patient was reassessed 2 months later. Her visual acuity was normal without left relative afferent pupillary defect and optic disc edema of the left eye resolved (Fig. 1C). The visual field was normal in both eyes (Fig. 2B), as was the RFNL thickness on OCT. Immune checkpoint inhibitor (ICI)-associated ON has clinical features that are not entirely consistent with the classical triad (unilateral decreased vision, dyschromatopsia, and painful eye movements) of ON secondary to other causes. The relative lack of pain with ICI-associated ON is a distinct feature but without a clear explanation (3). This patient was challenging, because of the initial presentation, and that the diagnosis was, in effect, incidental. Her bilateral ON only presented with mild visual field defects, and the presence of optic disc edema was not part of this. Cancer immunotherapy relies on the strategy of actively manipulating 1 of the 3 basic steps in the generation and regulation of antitumor immunity. Instead of an immunomodulatory role, ICIs activate the immune system by blocking the inhibitory pathways activated by cancer cells. Pembrolizumab targets programmed cell death protein 1 (PD-1) in the tumor microenvironment, which normally functions to limit T-cell expansion and prevent tissue damage from inflammation. Anti-PD-1 antibodies release this inhibitory blockade, allowing for continued T-cell Teodorescu et al: J Neuro-Ophthalmol 2024; 44: e246-e248 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Correspondence FIG. 2. Humphrey visual field, total deviation plots. A. HVF 24-2 initial examination demonstrates mild arcuate superior visual field defect in both eyes. B. HVF 30-2 follow-up examination at 4 months demonstrates complete resolution of visual field defect in both eyes. HVF indicates Humphrey visual field; MD, mean deviation; PSD, pattern standard deviation. FIG. 1. Fundus photographs. A. Initial examination of right eye: normal optic disc. B. Initial examination of left eye: 3+ optic disc edema with vessel obscuration at the elevation base. C. Follow-up examination of left eye at 4 months: complete remission of optic disc edema. Teodorescu et al: J Neuro-Ophthalmol 2024; 44: e246-e248 activation, with the potential for clinical responses across a wide variety of tumor types. The eye has special mechanisms to prevent against the invasion of infectious agents and inflammation. The lack of efferent lymphatics and the presence of the blood–retinal barrier are all special ocular features, whereas immune mechanisms, such as upregulation of tumor growth factor-beta and Fas ligand, prevent ocular inflammation by causing immune cell death and converting T cells into regulatory T cells. Retinal pigmental epithelial cells express CD86 and PD-L1, which interact with CTLA4 and PD-1, respectively, to downregulate inflammatory T-cell activity. The effect of checkpoint inhibitor therapy on this unique microenvironment is currently not wellunderstood. PD-1 inhibitors are most frequently associated with dry eyes and uveitis, and for pembrolizumab, specifically, are associated with myasthenia gravis, retinal vasculitis, macular edema, papillitis, and melanoma-associated retinopathy with chorioretinal lesions (4). According to a review of the cases recorded in the literature, neuro-ophthalmic complications occurred in 0.46% of patients undergoing ICI. Pembrolizumab was the most common causative agent for neuro-ophthalmic complications during chemotherapy (32.1%). The mechanisms of e247 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Correspondence induction of immune-related adverse events (IRAEs) are not fully elucidated, but are hypothesized to involve decreased peripheral tolerance and induction of organ-specific inflammatory processes (5). Typically, IRAEs with immune checkpoint inhibitors, including the neuro-ophthalmological ones, present weeks to months after treatment initiation (4) and that timeframe coincides with our case. Patients receiving PD-1 inhibitors are advised to have a baseline ophthalmologic examination before treatment initiation, and prompt evaluation for any visual signs or symptoms that appear, both during and after treatment, as toxicity may occur long after the end of treatment. Further research is necessary regarding rare adverse effects of ICIs with the possibility of proving the causal relationship between this medication-toxic effect described. Toxicities frequently require discontinuation of therapy, which may be life-threatening. STATEMENT OF AUTHORSHIP Conception and design: R. Teodorescu, A. A. Sadun; Acquisition of data: H. Liu; Analysis and interpretation of data: R. Teodorescu, e248 H. Liu, A. A. Sadun. Drafting the manuscript: R. Teodorescu, H. Liu; Revising the manuscript for intellectual content: R. Teodorescu, H. Liu, A. A. Sadun. Final approval of the completed manuscript: R. Teodorescu, H. Liu, A. A. Sadun. REFERENCES 1. Liu GT, Volpe NJ, Galetta SL. Liu, Volpe, and Galetta’s NeuroOphthalmology: Diagnosis and Management. 3rd edition. Philadelphia: Elsevier, 2019. 2. Nassar A, Rivera N, Mora J, Martinez A. A bilateral optic neuritis side effect of biological treatment with pembrolizumab in a patient with metastatic melanoma. J Neurol Stroke. 2020;10:177–181. 3. Francis JH, Jaben K, Santomasso BD, Canestraro J, Abramson DH, Chapman PB, Berkenstock M, Aronow ME. Immune checkpoint inhibitor-associated optic neuritis. Ophthalmology. 2020;127:1585–1589. 4. Dalvin LA, Shields CL, Orloff M, Sato T, Shields JA. Checkpoint inhibitor immune therapy: systemic indications and ophthalmic side effects. Retina. 2018;38:1063–1078. 5. Yu CW, Yau M, Mezey N, Joarder I, Micieli JA. Neuro-ophthalmic complications of immune checkpoint inhibitors: a systematic review. Eye Brain. 2020;12:139–167. Teodorescu et al: J Neuro-Ophthalmol 2024; 44: e246-e248 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited.