Paraneoplastic Autoimmune Retinopathy Associated With Non-IgM Lymphoplasmacytic Lymphoma

Clinical Correspondence Section Editors: Robert Avery, DO Karl C. Golnik, MD Caroline Froment, MD, PhD An-Guor Wang, MD Paraneoplastic Autoimmune Retinopathy Associated With Non-IgM Lymphoplasmacytic Lymphoma Andrew C. Thomson, BS, Subahari Raviskanthan, MBBS, Peter W. Mortensen, MD, Robert N. Hogan, MD, PhD, Andrew G. Lee, MD L ymphoplasmacytic lymphoma (LPL) is a non-Hodgkin B-cell tumor that often manifests as IgM-associated Waldenström macroglobulinemia (WM). Rarely, it may also present as a non-IgM secreting disease. Although most manifestations of lymphoma are hematological, visual manifestations can occur from both hyperviscosity and direct immunoglobulin deposition (1). Paraneoplastic autoimmune retinopathy (pAIR) is rare but has been reported with both solid and hematological malignancies (2). We present a case of non-IgM LPL-associated pAIR, who had improved symptoms and signs after treatment of the LPL. This, to the best of our knowledge, is the first such reported case in the English language, ophthalmic literature. A 59-year-old Caucasian man presented with a 5-month history of painless, progressive, bilateral loss of vision and positive visual phenomenon. His medical history included hypertension, depression, and an upper lip “precancerous lesion” treated with excisional biopsy. His regular medications included losartan, clonazepam, fexofenadine, sertraline, and multivitamin supplements. He was a former smokeless tobacco user and drank alcohol socially. The remainder of his history was noncontributory. He presented with bilateral photopsias described as small “light bubbles” in both eyes (OU), worse in the dark. He then developed fluctuating dyschromatopsia. His symptoms progressed further to include worsening vision in the daylight (hemeranopia) and bilateral paracentral scotomas, which affected his ability to eat (unable to see his cutlery when looking at the plate) and play golf (unable to see the putter in certain positions). McGovern Medical School (ACT), The University of Texas Health Science Center at Houston, Houston, Texas; Department of Ophthalmology (SR, PWM, AGL), Blanton Eye Institute, Houston Methodist Hospital, Houston, Texas; Departments of Ophthalmology, Pathology, Neurology, and Neurological Surgery (RNH), UT Southwestern Medical Center, Dallas, 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 Scurlock 450, Houston, TX 77030; E-mail: [e-mail] e184 He initially saw multiple providers and underwent several treatments, including artificial tears, topical steroid eye drops, and increasing refractive prescriptions without improvement. MRI of the brain only showed nonspecific T2 hyperintense foci in the bilateral cerebral white matter and a small developmental venous anomaly. On presentation to neuro-ophthalmology, his visual acuity was 20/20 in the right eye (OD) and 20/25-2 in the left eye (OS). He read 8/14 Ishihara color plates in the OD and 0/14 in the OS. Automated perimetry (automated visual field [HVF] 24-2) revealed bilateral ring scotomas, with mean deviation 213.54 dB in the OS and 213.18 in the OD, with preserved foveal thresholds (35 and 36 dB, respectively) (Fig. 1A). Further investigations for infectious, infiltrative, hereditary, inflammatory, demyelinating, nutritional, and hypercoagulable diseases were unremarkable. Electroretinogram (ERG) revealed significant cone dysfunction with mild rod dysfunction in OU (Fig. 2A). Systemic evaluation for malignancy was unremarkable except for elevated serum protein electrophoresis, which showed free kappa light chains and 2 M components identified by immunofixation as 1.66 g/dL IgA kappa (normal IgA 0–0.125 g/dL) and 0.15 g/dL IgG lambda (normal IgG 0.00114–0.01097 g/dL). Free kappa and lambda light chains were 62.54 mg/dL (normal 3.3–19.4 mg/L) and 7.53 mg/dL (normal 5.71–26.3 mg/L), respectively, with a ratio of 8.29 (normal 0.26–1.65). The optic nerve antibody panel was positive for 35 kDa and 62 kDa antibodies. No retinal antibodies were detected. Further workup by hematology revealed B-grade lymphoma on bone marrow aspirate and trephine biopsy with plasmacytic differentiation involving 20%–30% of the bone marrow. Immunohistochemistry and flow cytometry results revealed the following results: Cyclin D12, CD32, CD52, CD19+, CD20+, CD38+, CD45+, predominantly negative with few positive CD58, and kappa restriction. Fluorescence in situ hybridization panel for multiple myeloma-associated translocations and deletions was negative. Genetic testing revealed an MYD88 L265P mutation. There were no circulating plasma cells in the peripheral blood. Positron emission tomography was unremarkable. A diagnosis of pAIR secondary to a non-IgM LPL was made. He was started on a 6-month course of monthly rituximab and daily oral ibrutinib. On follow-up Thomson et al: J Neuro-Ophthalmol 2023; 43: e184-e187 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Correspondence FIG. 1. Automated perimetry (automated visual fields 24-2) showing (A) dense ring scotoma on grayscale and pattern deviation in both eyes before diagnosis and treatment of paraneoplastic autoimmune retinopathy and (B) significant improvement in ring scotoma 6 months after commencing rituximab and ibrutinib treatment. examination after 3 courses of rituximab, he reported substantial clinical improvement. On examination, his visual acuity was 20/20 OU, and he read 14/14 Ishihara plates in OU. HVF revealed significant improvement in the ring scotoma (Fig. 1B). Repeat ERG showed some improvement in cone and rod function (Fig. 2B). LPL is a non-Hodgkin B-cell neoplasm containing small lymphocytes, plasmacytoid lymphocytes, and plasma cells. It has an estimated incidence of 1,500–2,000 cases a year in the United States (3). The most common form, often used synonymously with LPL, is the IgM paraproteinassociated WM. Less than 5%–10% of cases present with non-IgM paraproteins, like our patient, or are nonsecreting (3). These seem to have lower risk of neuropathy and hyperviscosity and higher risk of extramedullary disease, either nodal or extranodal, and B symptoms (3). Vision loss associated with WM may be due to hyperviscosity, immunoglobulin deposition, or central nervous system infiltration (Bing–Neel syndrome) (1). Two cases of WM-associated autoimmune retinopathy have also been reported (1,4). Our patient did not have any typical WM or non-IgM symptoms; however, the clinical presentation, visual field, ERG findings, and response to rituximab are suggestive of pAIR. pAIR is a rare condition and has been observed in over 20 cancers. A review of serology from 441 patients by Adamus et al (2) found the most common cancers were breast (22%), melanoma (19%), and lung cancer (11%), Thomson et al: J Neuro-Ophthalmol 2023; 43: e184-e187 with lymphoma being only 4%. There is no standard therapy for AIR, but steroids, immunomodulators, biologics, intravenous immunoglobulin, and plasmapheresis have been efficacious in small studies (5). The rare incidence, lack of randomized controlled trials, and often late diagnosis of AIR are challenges in determining effective treatment. Rituximab, an anti-CD20 monoclonal antibody, has been shown in several studies to be a viable treatment for both pAIR and nonparaneoplastic AIR (5). However, of the 2 reported cases of pAIR in patients with WM, one patient developed pAIR despite being on rituximab for WM therapy, and the other patient did not improve with rituximab (1,4). This is in contrast to our patient, although the limited number of cases makes it more challenging to interpret this. Neuro-ophthalmologists should consider the diagnosis of occult retinopathy even if referred by a retina specialist with a normal fundus examination and normal optical coherence tomography of the macula. The clinical presentation of retrobulbar optic neuropathy and occult retinopathy overlap significantly, but the presence of photopsias, hemeranopia or nyctalopia, or a ring scotoma on automated perimetry is more suggestive of retinopathy than optic neuropathy. Electrophysiologic confirmation (e.g., mERG or full-field ERG) of the retinal origin for unexplained visual loss in this setting may be diagnostic and can lead to appropriate investigation and therapy for the underlying neoplasm (i.e., pAIR). Earlier diagnosis and treatment in this setting may be vision or life preserving. e185 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Correspondence FIG. 2. Full-field electroretinogram showing features of cone dystrophy with some rod dysfunction, at the time of initial diagnosis (A) and 6-month follow-up (B): (A) Left: low amplitude B wave (16 mV in the right eye and 20 mV in the left eye— normal 123 mV) and prolonged latency of the A wave. Right: 31 Hz flicker showing low amplitude 39 and 44 mV (normal for age 108 mV). B. Left: some improvement in amplitude of the B wave and normalization of the A-wave latency, Right: 31 Hz flicker showing improvement in amplitude 54 mV (normal for age 108 mV). To the best of our knowledge, this is the first case of a non-IgM LPL-associated paraneoplastic AIR reported in the English language, ophthalmic literature, with our e186 patient showing improvement both clinically and on visual fields assessment after treatment with rituximab and ibrutinib. Clinicians should consider malignancy Thomson et al: J Neuro-Ophthalmol 2023; 43: e184-e187 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Correspondence screening in the workup for unexplained retinopathy, including lymphomas, as identification and treatment of the underlying malignancy can improve the visual outcomes, even if the malignancy itself would not necessarily warrant treatment. STATEMENT OF AUTHORSHIP Conception and design: A. Thomson, S. Raviskanthan, P. Mortensen, N. Hogan, A. Lee; Acquisition of data: A. Thomson, S. Raviskanthan, P. Mortensen, N. Hogan, A. Lee; Analysis and interpretation of data: A. Thomson, S. Raviskanthan, P. Mortensen, N. Hogan, A. Lee. Drafting the manuscript: A. Thomson, S. Raviskanthan, P. Mortensen, N. Hogan, A. Lee; Revising it for intellectual content: A. Thomson, S. Raviskanthan, P. Mortensen, N. Hogan, A. Lee. Final approval of the completed manuscript: A. Thomson, S. Raviskanthan, P. Mortensen, N. Hogan, A. Lee. Thomson et al: J Neuro-Ophthalmol 2023; 43: e184-e187 REFERENCES 1. 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