Optic Perineuritis in Waldenström Macroglobulinemia-Related Cryoglobulinemic Vasculitis

Clinical Correspondence Section Editors: Robert Avery, DO Karl C. Golnik, MD Caroline Froment, MD, PhD An-Guor Wang, MD Optic Perineuritis in Waldenström Macroglobulinemia– Related Cryoglobulinemic Vasculitis Subahari Raviskanthan, MBBS, Peter W. Mortensen, MD, Patricia Chevez-Barrios, MD, Rosa Y. Kim, MD, Monica D. Desai, MD, Andrew G. Lee, MD C ryoglobulinemic vasculitis (CRV) is a relatively rare condition that typically manifests with skin, joint, renal, and peripheral nervous system manifestations (1). The most common manifestations are purpura (although there are many other dermatologic features), arthralgias, polyneuropathy, and Raynaud phenomenon (1,2). Central nervous system (CNS) involvement by CRV is rare and usually occurs with multisystem disease. Ophthalmic involvement in CRV is even rarer, and only isolated case reports of ulcerative keratitis, uveitis, and retinal vasculitis have been previously reported (2,3). Waldenström macroglobulinemia is an immunoglobulin (Ig)M plasma dyscrasia, often associated with a somatic activating mutation in the MYD88 gene (4). Common clinical manifestations include cytopenias, hyperviscosity phenomena, organomegaly, and B symptoms (4). CNS involvement in Waldenström disease is eponymously referred to as Bing–Neel syndrome—ocular manifestations are rare, but may involve retinal vein occlusions from hyperviscosity, oculomotor cranial neuropathies, optic neuropathy, and orbital infiltration (5). We report a case of ophthalmic involvement with optic neuritis and perineuritis, and retinal vasculitis as the initial Department of Ophthalmology (SR, PWM, PC-B, RK, AGL), Blanton Eye Institute, Houston Methodist Hospital, Houston, Texas; Department of Pathology and Genomic Medicine (PC-B), Houston Methodist Hospital, Houston, Texas; Department of Pathology and Laboratory Medicine, and Ophthalmology (PC-B, RK), Weill Medical College of Cornell University, New York, New York; Department of Ophthalmology (PC-B), Baylor College of Medicine, Houston, Texas; Department of Pathology and Laboratory Medicine (PC-B), The University of Texas M.D. Anderson Cancer Center, Houston, Texas; Retina Consultants of Texas (RK), Houston, Texas; Department of Oncology/Hematology (MD), Houston Methodist Cancer Center, Houston, 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; Texas A and M College of Medicine (AGL), Bryan, Texas; and Department of Ophthalmology (AGL), The University of Iowa Hospitals and Clinics, Iowa City, Iowa. The authors report no conflicts of interest. All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published. Address correspondence to Andrew G. Lee, MD, Department of Ophthalmology, Blanton Eye Institute, Houston Methodist Hospital, 6560 Fannin Street Suite 450, Houston, TX 77030; E-mail: aglee@ houstonmethodist.org e306 and primary manifestation of biopsy supported Waldenström macroglobulinemia–related CRV, which later progressed to Bing–Neel syndrome. To the best of our knowledge, this is the first such case to be reported in the English language ophthalmic literature. A 71-year-old Indian woman presented with a 2-week history of pressure in her left eye. She had recent cataract extraction with goniosynechialysis in the left eye 4 weeks earlier. Her medical history was significant for stable Waldenström macroglobulinemia, initially diagnosed on routine laboratory studies 5 years earlier with mild anemia, and hyperimmunoglobulinemia which was primarily monoclonal IgM. Bone marrow aspirate revealed Waldenström B-cell lymphoma with 50% bone marrow involvement. There was mild pelvic lymphadenopathy on staging imaging. Medical history included hypertension, iron deficiency, and asthma. Ocular history was significant for mixed mechanism glaucoma treated with previous laser peripheral iridotomy and laser trabeculoplasty. Her regular medications included aspirin, metoprolol, bimatoprost, and brinzolamide/brimonidine. She had no relevant family history. She did not smoke or drink alcohol. Two weeks after an uncomplicated cataract extraction and goniosynechiolysis procedure, the patient noted progressive “heaviness” in the left eye without loss of vision. Preoperative visual acuity (VA) was 20/20 in the right eye and 20/50 in the left eye. Day 1 and week 1 postoperative reviews revealed VA of 20/20 in the right eye and 20/50 in the left eye, with improving endopigment and microcystic edema in the cornea and resolving anterior chamber cells in the left eye. At her 6-week review, she was noted to have VA 20/100 in the left eye and periphlebitis along the inferotemporal arcade of the retinal vessels. Fundus fluorescein angiogram (FFA) performed revealed mild leakage from the superonasal veins, as well as mild fluorescein leakage from the optic nerve, consistent with retinal vasculitis and optic disc edema (Fig. 1A). Laboratory tests revealed an elevated erythrocyte sedimentation rate of 114 mm/hour (normal , 0–20 mm/ hour). Infectious panel was significant only for herpes simplex virus (HSV) IgM 1.49 (normal , 0.91), IgG 4,000. Vasculitis workup revealed a mildly elevated rheumatoid factor (RF) 21 international units (IU)/mL (normal 0–14 Raviskanthan et al: J Neuro-Ophthalmol 2022; 42: e306-e309 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Correspondence FIG. 1. A. Fundus fluorescein angiogram (FFA) 6 weeks after operation showing mild leakage from the large veins in the superonasal quadrant, and mild fluorescein leakage from the optic nerve, consistent with retinal vasculitis and optic neuritis in the left eye. B. Repeat FFA 8 weeks after initial shows worsening of retinal vasculitis in the left eye, involving new areas, and increased fluorescein dye leakage associated with capillary nonperfusion. The optic nerve also shows worsening of leakage. C. Repeat FFA after 4 months of treatment showing a significant improvement in retinal vasculitis and optic nerve head leakage. D. Axial MRI of the brain and orbits T1 fat-suppressed postcontrast sequence showing bilateral optic nerve sheath enhancement (arrows). E. Coronal MRI of the brain and orbits T1 fat-suppressed postcontrast sequence showing bilateral optic nerve sheath enhancement (arrows). IU/mL), positive antinuclear antibody (ANA) 1:1,280 speckled pattern, SSA, and SSB . 8.0 antibody index (AI) (normal 0–0.9 AI). Anterior chamber tap with intravitreal foscarnet was negative, and she was started on trimethoprim/sulfamethoxazole and valganciclovir for presumed infectious retinitis. Her VA worsened to counting fingers at 3 feet in the left eye, and she was admitted to hospital for further workup. Repeat FFA showed worsening of retinal vasculitis in the left eye, involving new areas and with increased fluorescein dye leakage, capillary nonperfusion, and worsening optic nerve leakage (Fig. 1B). MRI of the brain and orbits with contrast revealed bilateral perineural enhancement at the optic nerve sheath complexes (Fig. 1D, E). Computerized tomography of the chest, abdomen, and pelvis revealed stable mediastinal and inguinal lymphadenopathy. Hematology laboratory investigations were stable (elevated IgM 2,708 [normal 33–255], kappa:lambda ratio 48.83 [normal , 1.65], kappa light chain 523 [normal , 19.40], serum viscosity 1.88 [normal 1.1–1.8]). She was empirically treated with 3 days of intravenous methylprednisolone with rapid improvement in her VA to 20/100 within 3 weeks and was continued on an oral steroid taper. Lumbar puncture revealed 2 white blood cells, protein 50 mg/dL (normal 15–45 mg/dL). Cytology was negative. Flow cytometry showed a small population of kappa light chain–restricted CD5- and CD10-negative B cells that matched peripheral flow cytometry. Temporal artery biopsy showed irregular intimal hyperplasia with focal absence of elastic lamina, focal duplication of the lamina, and focal fibrinous thrombi. The small arterioles Raviskanthan et al: J Neuro-Ophthalmol 2022; 42: e306-e309 had more significant damage with marked intimal hyperplasia, absent elastic lamina, and focal hemorrhage into the muscularis layer. Although there was no lymphocytic or giant cell infiltrate in the fall of the artery, there were several macrophages disclosed by immunohistochemistry (CD163) at the level of the elastic lamina. IgG, IgM, and kappa light chain by immunohistochemistry highlighted the fibrinous thrombi and the intravascular hemorrhage (Fig. 2). Serum cryoglobulins were confirmatory, with a marked cryoprecipitate of 1.8%, consisting of IgM kappa monoclonal protein as well as polyclonal IgG, IgM, suggesting a unifying diagnosis of type 2 CRV, most likely secondary to Waldenström macroglobulinemia. She was commenced on rituximab and commenced steroid weaning. At subsequent review, her VA was 20/30 in the left eye. Repeat FFA showed marked improvement (Fig. 1C). Two months later, she represented with delirium, rightsided facial droop and limb weakness, and falls. A repeat cranial MRI revealed multiple diffusion restricted T2 fluidattenuated inversion recovery hyperintense confluent lesions, most prominent in the left frontal subcortical white matter, as well as the right temporal occipital gyrus, left basal ganglia, and splenium of the corpus callosum (Fig. 3). Lumbar puncture was repeated and showed 12 white blood cells, with flow cytometry again showing a population of kappa light chain–restricted B cells was identified, negative for CD5 and CD10, compatible with CNS infiltration from Waldenström macroglobulinemia, the Bing–Neel syndrome. She was commenced on twice weekly intrathecal methotrexate and oral ibrutinib. e307 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Correspondence FIG. 2. Temporal artery biopsy: (A) medium size artery with moderate intimal hyperplasia and a loose fibrin thrombus in the lumen (*). Notice no active inflammation is seen (hematoxylin and eosin stain, original magnification ·10). B. The internal elastic lamina (black) shows segmental absence, and there is focal fibrosis of media and intima (blue/green). The lumen of the temporal artery and the small arterioles and venules are clotted with blood and fibrin (*) (Movat pentachrome, original magnification ·10). C. An arteriole, branch of the temporal artery, has total absence of the elastic lamina and marked intimal hyperplasia with obliterated lumen (*). Notice the adjacent temporal artery to the left with residual elastic lamina (black) (Movat pentachrome, original magnification ·10). D. Few epithelioid histiocytes are seen in contact with residual elastic lamina from the muscularis side (circle) (immunohistochemistry using CD163 antibody, DAB chromogen. Original magnification ·40). E. Closeup of a branch of the temporal artery shows hemorrhage in the wall of the artery (red blood cells in superior portion). There is irregular fibrin deposits in the lumen, and smaller arterioles also show fibrin thrombus in the lumen (*) (hematoxylin and eosin stain, original magnification ·20). F. Irregular fibrosis of the wall (blue/green) with absent elastic lamina is seen. Lumen shows fibrinous deposits (*) (Movat pentachrome, original magnification ·10). G. Immunoglobulin M (IgM) is seen deposited in the wall of the artery and in the perivascular tissues and concentrated in the fibrinous thrombi of the lumen of vessels (*) (IgM antibody, DAB chromogen. Original magnification ·20). H. Kappa light chain is deposited in the wall of the artery and concentrated in the fibrinous thrombi of the lumen of vessels (*) (kappa light chain antibody, DAB chromogen. Original magnification ·20). DAB, diaminobenzidine. CRV is a multisystem condition affecting the arterioles and venules (1). Cryoglobulins are circulating proteins, typically immunoglobulins, that aggregate in cold temperatures, typically depositing in small blood vessels in the skin, joints, peripheral nervous system, and kidneys (1). CNS manifestations of CRV are uncommon, occurring in approximately 2% of patients, and are typically associated with other systemic manifestations of the disease (1). The diagnostic criteria for CRV require the presence of cryoglobulinemia twice within a 12-week period, as well as skin, clinical, and laboratory evidence of systemic dysfunction (1). Ophthalmic manifestations of CRV include scleritis or uveitis. There is only 1 previous case report of retinal vasculitis in the setting of type II mixed cryoglobulinemia— this patient also had no other systemic manifestations and was managed with oral nonsteroidal anti-inflammatory medications and topical dexamethasone with good clinical improvement at 3-month review (2). The presence of CRV in this patient is the only indication for this patient to currently be on rituximab treatment—the rest of her Waldenström-related clinical and laboratory findings would not fulfill criteria for pharmacotherapy. Pharmacotherapy for Waldenström-related CRV is different from pharmacotherapy of Waldenström macroglobulin disease, with a better e308 prognosis being yielded with rituximab in the former, but consideration required for combination chemotherapy in the latter (6). Other differential diagnoses were considered for this patient—although she had other antibodies positive, including RF, ANA, SSA, and SSB, she did not have other manifestations to meet the diagnostic criteria for systemic lupus erythematosus, Sjögren syndrome. She was reviewed by rheumatology who agreed that her symptoms were more consistent with her hematological diagnosis. Although her initial HSV serology showed a positive IgG and IgM, testing of the aqueous humor twice returned negative for viral etiologies. Aqueous humor polymerase chain reaction testing is reported to have 80% sensitivity for viral etiologies in patients with presumed infectious uveitis (7). She was also treated with a prolonged course of oral, intravenous, and intravitreal antivirals without any clear improvement in symptoms, making this diagnosis less likely. The subsequent deterioration in the patient’s clinical state is most suggestive of Bing–Neel syndrome, Waldenström-related infiltration into the CNS. Bing–Neel syndrome is uncommon, with estimated prevalence as low as 0.8% of patients in retrospective reviews (5). Clinical presentation is variable, but where cranial neuropathies are noted, they are typically of the oculomotor nerve and facial Raviskanthan et al: J Neuro-Ophthalmol 2022; 42: e306-e309 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Correspondence FIG. 3. MRI of the brain, axial fluid-attenuated inversion recovery sequence, showing hyperintense confluent lesions, seen in the left frontal subcortical white matter, left basal ganglia, and splenium of the corpus callosum. nerve, with optic neuritis not being a key manifestation (5). Gold standard diagnostic testing involves biopsy of an affected area of brain/meninges, although CSF analysis may also be suggestive. At the time of her assessment, our patient fit the diagnostic criteria for CRV, and was treated with rituximab, with the aim of targeting both the cryoglobulins and the Waldenström macroglobulinemia. Because both Bing–Neel syndrome and CRV are rare, it is not possible to definitively state that her initial manifestations were from CRV which progressed to Bing–Neel syndrome, or whether her whole presentation was related to Bing–Neel syndrome with slow progression, initial response, and then rapid deterioration. To the best of our knowledge, this patient is the first reported case in the English language ophthalmic literature of the neuro-ophthalmic clinical (optic disc edema and retinal vasculitis) and radiographic (optic perineuritis) features associated with biopsy-proven Waldenström macroglobulinemia–related CRV and Bing–Neel syndrome and only the second reported case of retinal vasculitis in CRV. Clinicians should remain aware of the neuroophthalmic manifestations of CRV, and of Bing–Neel syndrome, as well as the possible overlap that may make diagnosis and treatments more challenging. STATEMENT OF AUTHORSHIP Category 1: a. Conception and design: S. Raviskanthan, P. W. Mortensen, P. Chevez-Barrios, R. Kim, M. Desai, and A. G. Lee; b. Acquisition of data: S. Raviskanthan, P. W. Mortensen, P. Chevez- Raviskanthan et al: J Neuro-Ophthalmol 2022; 42: e306-e309 Barrios, R. Kim, M. Desai, and A. G. Lee; c. Analysis and interpretation of data: S. Raviskanthan, P. W. Mortensen, P. Chevez-Barrios, R. Kim, M. Desai, and A. G. Lee. Category 2: a. Drafting the manuscript: S. Raviskanthan, P. W. Mortensen, P. Chevez-Barrios, R. Kim, M. Desai, and A. G. Lee; b. Revising it for intellectual content: S. Raviskanthan, P. W. Mortensen, P. ChevezBarrios, R. Kim, M. Desai, and A. G. Lee. Category 3: a. Final approval of the completed manuscript: S. Raviskanthan, P. W. Mortensen, P. 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