Isolated Optic Neuropathy as Presenting Sign of Systemic Lymphoma

Clinical Correspondence Section Editors: Robert Avery, DO Karl C. Golnik, MD Caroline Froment, MD, PhD An-Guor Wang, MD Isolated Optic Neuropathy as Presenting Sign of Systemic Lymphoma Maya Ramachandran, BA, Jennifer E. Amengual, MD, David C. Park, MD, Mary R. Welch, MD, Gul Moonis, MD, Golnaz Moazami, MD A 65-year-old man presented with progressive painless visual loss in his right eye lasting over 9 months. His medical history was notable for sleep apnea, prediabetes, and low blood pressure. Of note, he occasionally used sildenafil. He was diagnosed with nonarteritic anterior ischemic optic neuropathy. Four months before presentation, his right eye vision worsened prompting reevaluation with MRI of the brain and orbits, carotid Doppler, and cardiac workup, which were reported as normal. In April 2018, he was seen for worsening visual acuity. At this time, acuity was 20/100 in the right eye and 20/50 in the left eye. Dilated funduscopic examination showed a swollen optic nerve without vitreous cells in the right eye and a normal-sized cup in the left eye. The patient was being followed for suspected glaucoma, and review of serial fundus photographs provided by his ophthalmologist revealed swelling of the disc in the right eye dating back to July 2017 (Fig. 1). His examination was notable for a right relative afferent pupillary defect and decreased color vision in the right eye, 0 out of 6 American Optical HardyRand-Rittler (AO-H-R-R) color plates. Humphrey visual field testing 24-2 showed temporal loss in the right eye and nasal fluctuations in the left eye. Workup included normal white blood cell count (4.62 · 103/mL), mildly elevated C-reactive protein (5.6 mg/L), normal erythrocyte sedimentation rate (4 mm/h), and hemoglobin A1c of 6.0%. A repeat MRI of the brain and orbits with gadolinium revealed enlargement of the right optic nerve with a 6mm focus of mild enlargement and enhancement of the right optic nerve at the neuro-ocular junction, without abnormal signal on T2 images or restricted diffusion (Fig. 2A, B). Neurological examination was completely intact without other stigmata of leptomeningeal disease. Cytomorphological evaluation of the cerebrospinal fluid (CSF) specimen revealed numerous small- to medium-sized mature lymphocytes, including plasmacytoid forms, and occasional plasma cells. Few Dutcher bodies were seen. Concurrent flow cytometric studies using a limited panel detected an abnormal mature B-cell population that was surface and cytoplasmic lambda light chain-restricted and negative for CD5 and CD10. A subsequent bone marrow sample revealed 30% involvement by an atypical interstitial lymphoplasmacytic proliferation with similar morphology as noted in the CSF sample in addition to admixed mast cells. Bone marrow flow cytometric studies identified a virtually identical abnormal mature B-cell population that was surface and cytoplasmic IgM lambda-restricted and negative for CD5 and CD10, whereas cytogenetic studies were negative. Comprehensive genomic profiling of the bone marrow aspirate using a panel of over 450 genes identified a sole pathogenic nonsense mutation in the ARID1A gene without mutations in MYD88 or CD79A/B; CXCR4 was not part of the panel. Comparative IgH gene rearrangement polymerase chain School of Medicine (MR), University of Missouri-Columbia, Columbia, Missouri; Division of Hematology and Oncology (JEA), Columbia University Irving Medical Center, New York, New York; Departments of Pathology and Cell Biology (DCP), Neurology (MRW), Radiology (G. Moonis), and Ophthalmology (G. Moazami), Columbia University Irving Medical Center, New York, New York. The authors report no conflicts of interest. Address correspondence to Golnaz Moazami, MD, Ophthalmology, The Edward S. Harkness Eye Institute, Columbia University Medical Center, 635 West 165th Street, Suite 304, New York, NY 10032; E-mail: [e-mail] Ramachandran et al: J Neuro-Ophthalmol 2022; 42: e341-e342 FIG. 1. Right fundus from July 2017 shows optic disc edema. e341 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Correspondence FIG. 2. A. Postgadolinium fat-saturated T1 coronal image of the orbits demonstrates enhancement of the right optic nerve near the neuro-ocular junction (arrow). B. On the corresponding T2 coronal image with fat saturation, there is increased size of the right optic nerve (arrow) compared with the left but no abnormal signal. reaction assays confirmed that the lymphoid populations seen in the CSF and bone marrow were clonally related. IgA levels were 105 mg/dL, IgG was 621 mg/dL, and IgM was 35 mg/ dL. Serum protein electrophoresis was normal. Whole-body positron emission tomography/computed tomography (PET/ CT) demonstrated non–18F-fluorodeoxyglucose-avid splenomegaly (spleen was 17 cm long) and mildly enlarged 18Ffluorodeoxyglucose-avid cervical, axillary, and retroperitoneal lymph nodes. Taken together, the clinicopathologic features were compatible with a systemic MYD88WT nonsecreting IgM lambda-restricted lymphoplasmacytic lymphoma involving the bone marrow and central nervous system (CNS) mimicking Bing–Neel syndrome. The patient was prescribed 20 mg of prednisone to halt disease progression and visual loss. Rituximab was given weekly for 1 month at 750 mg/m2. The patient also received low-dose radiation therapy to the right optic nerve and was started on 420 mg of ibrutinib. After 4 months of treatment, his vision improved to 20/40 in his right eye with improvement in his visual field and color vision (1 out of 6 AO-H-R-R color plates). Funduscopic examination, however, now showed optic atrophy in the right eye. On a whole-body PET/CT in June 2020, the spleen was 14 cm long and there was no evidence of disease. CSF and bone marrow studies were not repeated as the patient showed significant clinical improvement. Previous studies have shown that non-Hodgkin lymphoma (NHL) affects the CNS in approximately 10% of cases and only 3% of cases of indolent NHL (1). Very few cases of indolent NHL involve only the optic nerve (1,2). For patients with lymphomatous optic nerve infiltration, visual loss is severe and is associated with disc swelling, as in this case; peripapillary hemorrhage has also been noted in a few cases (1,3). The majority of patients with lymphoplasmacytic lymphoma have Waldenström macroglobulinemia, which is defined by circulating monoclonal IgM paraprotein. Our patient did not have IgM gammopathy. For approximately 1% of patients with Waldenström macro- e342 globulinemia, malignant lymphoplasmacytic cells infiltrate the CNS and cause Bing–Neel syndrome (1,4). MYD88 mutations, which frequently occur in both aggressive and indolent CNS lymphomas, were not detected in this case. A nonsense mutation was detected in the epigenetic tumor suppressor gene ARID1A. In indolent B-cell lymphomas, ARID1A mutations are associated with increased bone marrow disease infiltration (5). Ibrutinib, a Bruton tyrosine kinase inhibitor, is associated with improved clinical outcomes for patients with lymphoplasmacytic lymphoma and many other types of indolent B-cell lymphomas. Ibrutinib was chosen because of increasing evidence that it can penetrate the blood–brain barrier (4). A multicenter study of 28 patients found ibrutinib to be an effective treatment for Bing–Neel syndrome–associated symptoms and MRI abnormalities (4). Due to the CNS involvement, this case of lymphoplasmacytic lymphoma clinically and morphologically resembles Bing–Neel syndrome. Our case is significant in that isolated optic neuropathy without other neurological findings has rarely been reported as the presenting sign for patients with lymphoplasmacytic lymphoma (1). REFERENCES 1. Hughes MS, Atkins EJ, Cestari DM, Stacy RC, Hochberg F. Isolated optic nerve, chiasm, and tract involvement in bing–neel syndrome. J Neuroophthalmol. 2014;34:340–345. 2. Kim JL, Mendoza PR, Rashid A, Hayek B, Grossniklaus HE. Optic nerve lymphoma: report of two cases and review of the literature. Surv Ophthalmol. 2014;60:153–165. 3. Wong D, Danesh-Meyer H, Pon JA. Infiltrative lymphomatous optic neuropathy in non-Hodgkin lymphoma. J Clin Neurosci. 2015;22:1513–1515. 4. 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