Myasthenia Gravis Associated With Orbital Marginal Zone Lymphoma

A 78-year-old man with hypertension and chronic sinusitis developed diplopia and left eyelid ptosis 2 months after endoscopic sinus surgery. He reported that his diplopia fluctuated throughout the day and was often absent early in the morning. MRI of the brain without contrast revealed soft-tissue nodules within the orbits abutting both globes. Complete blood count with differential showed mild anemia but was otherwise unremarkable. His sedimentation rate was 107 mm/hour, and other hematological studies are summarized in Table 1. He denied constitutional symptoms of giant cell arteritis. He was evaluated by a hematologist for the elevated protein gap and found to have 2 monoclonal spikes on serum protein electrophoresis that did not meet criteria for multiple myeloma. Computed tomography of the chest, abdomen, and pelvis was unremarkable. He was diagnosed with a monoclonal gammopathy of unknown significance. The patient was referred for neuro-ophthalmic evaluation.

Clinical Correspondence Myasthenia Gravis Associated With Orbital Marginal Zone Lymphoma Shu Feng, MD, Ryan E. Dodge III, BS, Courtney E. Francis, MD A 78-year-old man with hypertension and chronic sinusitis developed diplopia and left eyelid ptosis 2 months after endoscopic sinus surgery. He reported that his diplopia fluctuated throughout the day and was often absent early in the morning. MRI of the brain without contrast revealed softtissue nodules within the orbits abutting both globes. Complete blood count with differential showed mild anemia but was otherwise unremarkable. His sedimentation rate was 107 mm/hour, and other hematological studies are summarized in Table 1. He denied constitutional symptoms of giant cell arteritis. He was evaluated by a hematologist for the elevated protein gap and found to have 2 monoclonal spikes on serum protein electrophoresis that did not meet criteria for multiple myeloma. Computed tomography of the chest, abdomen, and pelvis was unremarkable. He was diagnosed with a monoclonal gammopathy of unknown significance. The patient was referred for neuro-ophthalmic evaluation. Visual acuity, pupillary testing, visual fields by confrontation, and intraocular pressures were normal. Ocular motility showed moderate limitation in upgaze and slight limitation in downgaze of the right eye, and in primary gaze there was a right hypertropia of 10 prism diopters. He had 8-9 mm of left ptosis with mild lid fatigue and minimal improvement after an ice test. Antibody testing demonstrated elevated striated muscle antibody of 1:7,680 (normal , 1:120) acetylcholine binding receptor antibody of 8.29 nmol/L (normal #0.02 nmol/L) and acetylcholine receptor modulating antibody of 85% (normal: 0%-20%). He was diagnosed with ocular myasthenia gravis (MG) and started on pyridostigmine. This led to less diplopia but there was a persistent left ptosis. Repeat MRI showed bilateral orbital masses which were T1 and T2 isointense. There was robust enhancement of the orbital masses which spanned from the extraconal to the intraconal space (Fig. 1A). The left orbital mass was biopsied. Flow cytometry of the specimen demonstrated an abnormal mature B-cell population with lambda light chain restriction and normal expression of CD19, CD20, CD38, and CD45 without CD5 or CD10. Immunohistochemistry showed CD20 B cell predominance. Bone marrow biopsy showed hypercellular marrow with 10%-15% involvement of low-grade B-cell neoplasm with plasmacytic differentiation. The combined histomorphologic and flow cytometric findings were consistent with extranodal marginal zone lymphoma, and the patient received orbital radiation therapy of 25.2 Gy fractionated over 14 sessions. Computed tomography of the chest showed no evidence of thymus tissue, and the patient was prescribed 40-mg prednisone daily for improved control of his MG. TABLE 1. Laboratory findings in a patient with myasthenia gravis and orbital marginal zone lymphoma Patient Results Reference Range White blood cell count Hemoglobin Platelet count Creatinine Total protein plasma Albumin ESR Serum protein electrophoresis 7·103 12.3 373·103 1.11 8.7 3.6 107 Beta 1.2 4.3-10.0·103/mL 13.0-18.0 g/dL 150-400·103/mL 0.72-1.24 mg/dL 6.1-8.0 g/dL 3.4-4.8 g/dL 0-38 mm/hr 0.6-1.0 g/dL Supported by an unrestricted grant from Research to Prevent Blindness. The funding organization had no role in the design or conduct of this research. The authors report no conflicts of interest. Gamma 1.7 95 1,056 2,876 Positive 1:7,680 ACh receptor binding Ab 8.29 ACh receptor 85% modulating Ab Address correspondence to Courtney E. Francis, MD, Department of Ophthalmology, University of Washington, Box 359608, 325 Ninth Avenue, Seattle, WA 98104; E-mail: [e-mail] ACh, acetylcholine; Ab, antibody; ESR, erythrocyte sedimentation rate. Department of Ophthalmology, University of Washington, Seattle, Washington. 242 IgA serum IgG serum IgM serum Striated muscle Ab 0.4-1.4 g/dL 101-645 mg/dL 540-1822 mg/dL 22-240 mg/dL ,1:120 titer #0.02 nmol/L 0%-20% Feng et al: J Neuro-Ophthalmol 2019; 39: 242-243 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Correspondence FIG. 1. Orbital T1 MRI. A. Following intravenous contrast, the lesion in the right orbit is crescentric and intimately associated with the right posterolateral aspect of the superior globe. On the left, the lesion is more globular and located at the superomedial margin of the globe. Each lesion involves both the extraconal and intraconal spaces. B. Follow-up MRI reveals a marked decrease in the size of the orbital lesions. The patient noticed complete resolution of ptosis and diplopia a week after starting radiation therapy. He self-tapered off prednisone after 1 week and lowered his pyridostigmine to 60 mg twice a day with no recurrence of diplopia. Over the following month, the patient's examination revealed full extraocular movements and resolution of left ptosis. Pyridostigmine was discontinued. Orbital MRI disclosed decrease in the size of the lymphomatous masses (Fig. 1B), and the patient has remained stable over 8 months of follow-up. MG is associated with various types of malignancies, classically thymoma. In addition, there are reports linking lymphoid malignancies and MG (1). In their study, Yeh et al (2) found a 2.27-fold increased risk of lymphoid malignancies among patients with MG. Although Karlin et al (3) described a patient with orbital mantle cell lymphoma presenting as MG, we are unaware of an association of marginal cell lymphoma and MG. In some patients, there is a close temporal relationship of onset between the 2 diseases, whereas in others, there is no temporal relationship, and the 2 diseases may occur years apart (synchronous and asynchronous, respectively). It is believed that synchronous MG may be a paraneoplastic syndrome associated with lymphoid malignancies due, in part, to the resolution of myasthenic symptoms with the treatment of the malignancy (4), as occurred in our patient. It has long been postulated that an immunologic disorder may contribute to the formation of both MG and lymphoid malignancies, either by impairment of immuno- Feng et al: J Neuro-Ophthalmol 2019; 39: 242-243 logic surveillance or by dysfunctional regulation of the immune system caused by autoantibodies (4). In conclusion, clinicians should maintain a high index of suspicion for malignancy when caring for patients with MG. Depending on the mode of presentation, evaluation for malignancies other than thymoma may be warranted. STATEMENT OF AUTHORSHIP Category 1: a. conception and design: C. E. Francis; b. acquisition of data: S. Feng, R. E. Dodge, and C. E. Francis; c. analysis and interpretation of data: S. Feng and C. E. Francis. Category 2: a. drafting the manuscript: S. Feng and R. E. Dodge; b. revising it for intellectual content: S. Feng and C. E. Francis. Category 3: a. final approval of the completed manuscript: C. E. Francis. REFERENCES 1. Davis S, Schumacher MJ. Myasthenia gravis and lymphoma in clinical and immunological association. JAMA. 1979;242:2096-2097. 2. Yeh JH, Lin CC, Chen YK, Sung FC, Chiu HC. Excessive risk of cancer and in particular lymphoid malignancy in myasthenia gravis patients: a population-based cohort study. Neuromuscul Disord. 2014;24:245-249. 3. Karlin J, Peck T, Prenshaw K, Portell CA, Kirzhner M. Orbital mantle cell lymphoma presenting as myasthenia gravis. Orbit. 2017;36:365-369. 4. Yi Q, Pirskanen R, Lefvert AK. Human muscle acetylcholine receptor reactive T and B lymphocytes in the peripheral blood of patients with myasthenia growth. J Neuroimmunol. 1993;42:215-222. 243 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited.