Journal of Neuro-Ophthalmology, December 2014, Volume 34, Issue 4

Isolated Optic Nerve, Chiasm, and Tract Involvement in BingNeel Syndrome

Isolated Optic Nerve, Chiasm, and Tract Involvement in Bing-Neel Syndrome Michael S. Hughes, HSD, Edward J. Atkins, MD, FRCPC, Dean M. Cestari, MD, Rebecca C. Stacy, MD, PhD, Fred Hochberg, MD Abstract: Central nervous system infiltration of Waldenström's macroglobulinemia is referred to as Bing-Neel Syndrome. We describe 2 patients whose clinical presentation was due to isolated involvement of the anterior visual pathways. The mech-anism of visual failure in Bing-Neel Syndrome may involve both infiltrative and autoimmune processes. Journal of Neuro-Ophthalmology 2014;34:340-345 doi: 10.1097/WNO.0000000000000138 © 2014 by North American Neuro-Ophthalmology Society Waldenström's macroglobulinemia (WM), or lympho-plasmacytic lymphoma, is a chronic lymphoprolifer-ative disorder characterized by infiltrates of lymphoplasmacytic (LMP) cells including B-cell lymphocytes (1-3). These infil-trates are associated with elevated serum concentrations of immunoglobulin M (IgM) (1-4). Rarely, patients with WM develop central nervous system (CNS) involvement, termed Bing-Neel Syndrome (BNS) (2-6). BNS includes patients with LMP cells invading the brain, cranial nerves, or their coverings, and those whose neurologic deficits reflect the ef-fects of IgM deposition (7). Although hyperviscosity can occur in WM, CNS involvement in BNS is not related to hypervis-cosity (1,2). LMP cells can often be detected by examining the cerebrospinal fluid (CSF) or observing nodular masses on brain magnetic resonance imaging (MRI). Patients with BNS may have LMP cells evident in the CSF or masses seen on MRI or may have white matter involvement because of IgM deposition (7,8). Patients with BNS usually present with confusion or focal neurological deficits but rarely with visual complaints (3,4,9). We report 2 patients with WM who presented with visual loss secondary to involvement of the anterior visual pathways. REPORT OF CASES Case 1 A 54-year-old previously healthy man was found to have lymphocytosis with mature lymphoid cells and splenomegaly. Bone marrow biopsy demonstrated 50% LMP lymphoma cells producing IgM-k, and serum monoclonal IgM-k para-protein 5000 mg/dL (normal upper limit: 334 mg/dL). No treatment was prescribed. Two years later, the patient experi-enced headaches, blurred vision, and transient visual obscura-tions. Visual acuity was 20/20 in both eyes with a left relative afferent pupillary defect (RAPD). The patient recognized 12.5/ 14 Ishihara plates right eye, and 6/14 left eye. Automated visual field testing was abnormal bilaterally (Fig. 1), and both optic discs were swollen (Fig. 2). Neuroimaging studies includ-ing computed tomography, MRI with contrast, and magnetic resonance venography were normal. Examination of the CSF showed normal cell concentration and cytologically atypical lymphocytes. CSF glucose, protein, and cell counts were nor-mal. No treatment was given. Forty months after initial visual symptoms, the patient's visual acuity was 20/70, right eye, and 20/25, left eye, with progressive visual field loss bilaterally. CSF analysis dis-closed 7 cells/mm3 with atypical lymphocytes similar to the lymphocytes found in the peripheral blood. With flow cytometry, CSF cells were monotypic B-cells expressing IgM-k. Six months later, visual acuity was 20/30 right eye and 20/50 left eye with a left RAPD. Color vision was unchanged. Optic discs were edematous, and there was progression of field deficits. MRI revealed enlarged and enhancing optic nerves and optic nerve sheaths bilaterally Harvard University (MSH); University of Saskatchewan (EJA); Massachusetts Eye and Ear Infirmary (DMC, RCS); and Massachusetts General Hospital (FH), Boston, Massachusetts. The authors report no conflicts of interest. All authors drafted and revised the manuscript for content. M. S. Hughes, D. M. Cestari, and F. Hochberg analyzed and interpreted data. E. J. Atkins, D. M. Cestari, R. C. Stacy, and F. Hochberg performed the clinical examinations. Address correspondence to Fred Hochberg, MD, Massachusetts General Hospital, 55 Fruit Street, Boston, MA 02114. 340 Hughes et al: J Neuro-Ophthalmol 2014; 34: 340-345 Original Contribution Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. (Fig. 3). Peripheral blood lymphocytosis was noted (4.56 · 109/L) consistent with LMP lymphoma. Monoclonal serum paraprotein was 480 mg/dL rising to 700 mg/dL over 9 days. CSF contained 10 cells/mm3 (95% lymphocytes and 5% macrophages), which included atypical lymphoplasma-cytoid IgM-k cells. Flow cytometry revealed monotypic cells in both CSF and peripheral blood. The patient was given dexamethasone (8 mg) orally with weekly intrathecal lumbar injections of methotrexate (15 mg) for 5 cycles during a 6-month period. Two months later, visual acuity was 20/20 right eye, and 20/100 left eye with a left RAPD. Visual fields were unchanged in left eye and somewhat improved in right eye (Fig. 4), and both optic discs were pale without edema. CSF lymphocytosis and serum parapro-tein slowly decreased, and chemotherapy with R-CHOP (rituximab/cyclophosphamide/vincristine) was provided. Visual acuity, visual fields, and optic nerve appearance have remained stable for more than 1 year since discontin-uation of treatment. Forty-six months after his initial neuro-ophthalmic assessment, brain MRI showed interval decrease in the size of the optic nerves with the left being more atrophic. There was an increased T2 signal in the intra-orbital portions of the optic nerves but no abnormal enhancement. The systemic disease has not progressed nor have new neurologic symptoms developed. Case 2 A 67-year-old woman complained of blurred vision 12 years after being diagnosed with WM on the basis of IgM proteinuria and bone marrow biopsy showing 10% infil-tration by small CD20 lymphocytes. Four years before, she had been placed on sildenafil for WM. On examination, visual acuity was 20/20 in each eye, with intact color vision and normal pupillary responses. Automated visual field testing demonstrated an incongruous left homonymous hemianopia (Fig. 5). The optic discs were pale. FIG. 1. Case 1. Automated visual fields demonstrate marked field loss in left eye and arcuate defects in right eye. FIG. 2. Case 1. Bilateral optic disc edema is present. Hughes et al: J Neuro-Ophthalmol 2014; 34: 340-345 341 Original Contribution Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Brain MRI showed enlargement and enhancement of the prechiasmatic optic nerves, optic chiasm, and optic tracts (Fig. 6). There was no meningeal enhancement. CSF con-tained no white blood cells or malignant cells and no evi-dence of immunoglobulin gene rearrangement. Opening pressure was not recorded. Hematologic flow cytometry studies revealed only T-cell staining for CD4 and CD8. Serum IgM levels were elevated at 1300-1988 mg/dL (nor-mal upper limit: 334 mg/dL). The patient was treated with dexamethasone over 1 month with improvement in the appearance of her optic nerves and chiasm on MRI. Repeat CSF analysis failed to reveal malignant cells. Intravenous MTX (8 g/m2) was administered every 10 to 14 days for 6 cycles, with IV rituximab (375 mg/m2) every week for 4 weeks. After 3 cycles of MTX, visual field defects were somewhat improved (Fig. 7). After 12 cycles of MTX, her bone marrow contained minimal WM infiltration significantly improved compared with initial biopsy findings. Six cycles of bend-amustine and rituximab were then administered. After 1 year of therapy, visual acuity was 20/20 bilaterally, and visual fields were stable. Enhancement of the optic nerves, chiasm, and optic tracts were no longer seen on MRI. The patient is being maintained on rituximab therapy. FIG. 3. Case 1. Postcontrast T1 fat suppressed axial (A) and coronal (B) MRI shows enlargement and enhancement of both optic nerves (arrows). FIG. 4. Case 1. After treatment, there is no significant change in left eye visual field with improvement in the right eye. 342 Hughes et al: J Neuro-Ophthalmol 2014; 34: 340-345 Original Contribution Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. DISCUSSION WM is a lymphoproliferative disorder of LMP cells with monoclonal B-cell or T-cell markers (10), associated with production of excessive IgM (1-6). Its incidence has been reported at 5.7-9.5 cases per million for males, 1.3-3.7 cases per million for females (11). WM is associated with IgM-related hyperviscosity in both the CNS and other organs (1,5,12). In addition, WM-associated IgM can act as an auto-antibody with demyelinating properties affecting peripheral nerves (7). Encephalopathy or myelopathy reflects LMP infil-tration of brain, dura, or CSF (1) and paraneoplastic anti-bodies or brain deposition of IgM (12) believed to damage cerebral white matter. Peripheral demyelinative and axonal neuropathies occur in up to 50% of patients with WM (1,2). Similar IgM deposition may occur in the CNS (13). BNS is a rare form of WM that involves the CNS (2,3,5,6,8). Patients may present with seizures, encephalitis, cognitive decline, blurry vision, diplopia, numbness, paresthe-sias, headache, confusion, stupor, coma, cranial neuropathy, FIG. 5. Case 2. Automated visual fields reveal an incomplete left homonymous hemianopia. FIG. 6. Case 2. Postcontrast axial spoiled gradient recall MRI shows enhancement (arrows) of the optic chiasm (A) and optic tracts (B). Hughes et al: J Neuro-Ophthalmol 2014; 34: 340-345 343 Original Contribution Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. or weakness. Tissue analysis is required to confirm a definitive BNS diagnosis (2,5). Treatment of BNS includes chemother-apy, high-dose steroids, cranial radiation, and plasmapheresis (1,3,5-8). When the LMP cells infiltrate brain or CSF, the outcome is poor (2). LMP cell infiltration (8) is associated with CSF under increased opening pressure, lymphocytic pleocytosis, and/or increased CSF protein concentration. There are increased CSF levels of IgM-k or l, CD20+ lym-phoplasmacytoid cells, and IgH rearrangement anomalies on polymerase chain reaction studies. When these changes are not present, an autoimmune mechanism is thought to cause tissue damage. Patients with BNS with cranial nerve V, VII, and VIII and with orbital findings have been reported (4,9,10). Our two cases are rare examples of BNS with isolated visual symptoms secondary to involvement of the anterior visual pathways without other manifestations of CNS involve-ment. We are unaware of similar reports. Our Case 2 also raises the possibility of paraneoplastic optic neuropathy (14). IgM may alter and cross the blood- brain barrier through anti-HNK-1 function (15,16). Demy-elination has been associated with IgM deposition in WM as well as other diseases (15-21) and, with autoimmune disorders of the CNS, the visual pathways may be targeted (14,22). WM and other malignant lymphomas may be accompanied by autoimmune markers (23) and associated with autoimmune and inflammatory syndromes (24,25), including autoimmune hemolytic anemia (26,27). Our 2 patients represent novel forms of BNS because of their focal clinical findings. They share features of visual pathway involvement in the setting of stable WM without malignant transformation. Each patient demonstrated improvement of clinical and MRI findings with therapy to reduce both WM cellular infiltrates and possible IgM deposition. 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