A Case of Pembrolizumab-Induced Papillitis With Transverse Myelitis

Clinical Correspondence Section Editors: Robert Avery, DO Karl C. Golnik, MD Caroline Froment, MD, PhD An-Guor Wang, MD A Case of Pembrolizumab-Induced Papillitis With Transverse Myelitis Nathan A. Lambert-Cheatham, DO, Ragha C. Sakuru, MD, Melody Merati, DO, Sophia T. Tessema, MD, MPH, Luke R. Salbert, MD, Jayne H. Ward, DO, Lina Nagia, DO P embrolizumab is a monoclonal antibody that inhibits the programmed cell death-1 (PD-1) pathway, thereby enhancing the antitumor immune response. Currently, pembrolizumab is an approved treatment for various types of cancers including cutaneous melanoma (1). Very few patients (,1%) on pembrolizumab will develop severe ocular complications, such as uveitis, papillitis, and ocular myositis (2,3). In addition to the ocular complications, neurologic immune– related adverse events also have been reported in the literature (4). In these cases, cessation of pembrolizumab with or without the addition of steroids generally improves symptoms. Because of the wide variety of presentations, diagnosing pembrolizumab-related complications can be elusive. Below, we describe the diagnosis and treatment of a patient with pembrolizumab-induced bilateral papillitis and transverse myelitis mimicking neuromyelitis optica spectrum disorder (NMOSD). A 48-year-old woman presents with a new right eye floater. Her medical history is significant for noninvasive malignant melanoma of the upper back which was treated with surgical excision 1 year before and ongoing adjuvant pembrolizumab (Keytruda, Merck). On presentation, the patient had normal visual acuity, color plates, extraocular movements, and did not have a relative afferent pupillary defect. Funduscopic examination revealed Frisen Grade 2–3 bilateral disc edema and a small superior retinal tear in the right eye, which was subsequently treated with laser therapy. Retinal Nerve Fiber Layer Optical Coherence Tomography (RNFL OCT) was consistent with bilateral disc edema (Fig. 1A). Automated visual fields 30-2 demon- FIG. 1. Color fundus and OCT retinal nerve fiber layer images of the patient on Day 0 (A) and Day 31 (B) of follow-up. Address correspondence to Nathan Lambert-Cheatham, DO, Department of Neurology & Ophthalmology, Michigan State University, 804 Service Drive, Suite A217, East Lansing, MI 48824; E-mail: [e-mail] strated enlarged blind spots. MRI of the brain and orbits was unremarkable (Fig. 2A). The patient did not have symptoms of increased intracranial pressure including pulsatile tinnitus, headaches, or transient visual obscurations. On follow-up examination, the patient was noted to have mild lower extremity weakness prompting further workup. An MRI spine was ordered which demonstrated Lambert-Cheatham et al: J Neuro-Ophthalmol 2023; 43: e131-e133 e131 Department of Neurology and Ophthalmology, Michigan State University, East Lansing, Michigan. The authors report no conflicts of interest. Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Correspondence FIG. 2. A. Pregadolinium (left) and postgadolinium fat-saturated (right) MRI orbits images. No contrast enhancement was seen along the length of the optic nerve. B, C. T1 sagittal MRI images of the cervical (B) and thoracic (C) spine. Left images demonstrate enhancement (yellow arrows) consistent with long segment demyelination found during initial evaluation. Right images demonstrate resolution of enhancement on Day 96 of follow-up. enhancement along the cervical and thoracic regions suggestive of demyelination (Fig. 2B). The patient was admitted to the hospital where she underwent a lumbar puncture. Cerebrospinal Fluid (CSF) analysis revealed elevated protein (118 mg/dL) and WBCs (59/cu mm). CSF immunophenotyping demonstrated a predominance of lymphocytes (69%) mostly composed of T cells (90%). CSF analysis was normal for glucose (63 mg/dL), Red Blood Cells (0/ cu mm), oligoclonal bands, and ACE (20 U/L). CSF cultures revealed no growth. An opening pressure was not recorded. Serum analysis by flow cytometry was negative for Aquaporin 4 and Myelin Oligodendrocyte antibodies. Given the unclear etiology, there were concerns for pembrolizumab toxicity. Pembrolizumab was discontinued. The patient was started on 1-g Intravenous (IV) methylprednisolone for 5 days followed by 70-mg oral prednisone with a 3-month taper. Her lower extremity weakness e132 improved 5 days status post steroids. Close follow-up revealed progressive reduction of disc edema on fundus examination and RNFL OCT, which fully resolved on Day 31 of follow-up (Fig. 1B). Repeat MRI spine on Day 96 revealed complete resolution of enhancement (Fig. 2C). We describe a case of pembrolizumab-induced bilateral papillitis and transverse myelitis. Notably, these findings mimicked the presentation of NMOSD. However, evaluation for NMOSD, including antibodies and MRI brain/ orbits, was not supportive of this diagnosis. The patient’s symptoms were minimal. Her disc edema and spinal inflammation fully resolved with discontinuation of pembrolizumab and IV steroid therapy. After excluding all other possibilities, pembrolizumab-induced toxicity was deemed to be the likely cause of her symptoms. The large range of inflammatory-related and immunerelated side effects from pembrolizumab therapy is well recognized in the literature. Although the cause of pembrolizumab’s inflammatory side effects is not definitely known, they are hypothesized to result from disinhibition of cytotoxic T cells. PD-1, the protein targeted by pembrolizumab, acts by downregulating cytotoxic T cells. PD-1 is activated by PD receptor ligand (PD-L1). The expression of PD-L1 can be increased by various cancers, such as melanoma, which aids in immune evasion. Pembrolizumab, by inhibiting PD-1, counters this neoplastic adaptation. As an unfortunate consequence, pembrolizumab has the potential to lead to overactivation and proliferation of T cells causing various immune-mediated side effects. Indeed, this correlates to the increased T cells seen in our patient’s CSF immunophenotypic analysis. Usually, these immune-mediated side effects are mild. Especially in the case of transverse myelitis, reports show patients typically only become symptomatic after additional proinflammatory therapies such as radiotherapy. This may explain why our patient was minimally symptomatic at presentation. Like our case, reports have shown a rapid response to pembrolizumab discontinuation with the addition of steroid therapy (1,2). In conclusion, pembrolizumab toxicity may present with a unique combination of symptoms that can easily mimic more significant immunologic conditions. To the best of our knowledge, a combination of papillitis with transverse myelitis due to pembrolizumab has not been previously reported in the literature. We hope to increase awareness and add to the growing body of literature exploring the inflammatory side effects of pembrolizumab. STATEMENT OF AUTHORSHIP Conception and design: N. Lambert-Cheatham, R. C. Sakuru, S. Tessema, L. Nagia; Acquisition of data: R. C. Sakuru, M. Merati, L. Salbert, J. Ward, L. Nagia; Analysis and interpretation of data: N. Lambert-Cheatham, R. C. Sakuru, S. Tessema, L. Nagia. Drafting the manuscript: N. Lambert-Cheatham, R. C. Sakuru; Revising it for intellectual content: J. Ward, L. Nagia. Final approval of the Lambert-Cheatham et al: J Neuro-Ophthalmol 2023; 43: e131-e133 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Correspondence completed manuscript: N. Lambert-Cheatham, R. C. Sakuru, M. Merati, S. Tessema, L. Salbert, J. 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