Opsoclonus-Myoclonus Syndrome in Primary Central Nervous System Lymphoma

Adult-onset opsoclonus-myoclonus syndrome (OMS) has been associated with multiple cancers, most commonly small-cell lung carcinoma and breast adenocarcinoma. A 53-year-old woman who presented with OMS was found to have primary central nervous system (CNS) diffuse large B-cell lymphoma. OMS has been described in only 5 cases with non-Hodgkin lymphoma (NHL), and this is only the third reported case of OMS in NHL limited to the CNS. Although the paraneoplastic antibody panel was negative, we presume that the OMS was a paraneoplastic manifestation. Antineoplastic and anti-immune therapy had no effect on the neurologic manifestations.

Clinical Observation Opsoclonus-Myoclonus Syndrome in Primary Central Nervous System Lymphoma Joseph Grubbs Jr, MD, MPH, Jonathan D. Trobe, MD, Amanda Fisher-Hubbard, MD Abstract: Adult-onset opsoclonus-myoclonus syndrome (OMS) has been associated with multiple cancers, most commonly small-cell lung carcinoma and breast adenocarcinoma. A 53-year-old woman who presented with OMS was found to have primary central nervous system (CNS) diffuse large B-cell lymphoma. OMS has been described in only 5 cases with non-Hodgkin lymphoma (NHL), and this is only the third reported case of OMS in NHL limited to the CNS. Although the paraneoplastic antibody panel was negative, we presume that the OMS was a paraneoplastic manifestation. Antineoplastic and anti-immune therapy had no effect on the neurologic manifestations. Journal of Neuro-Ophthalmology 2016;36:408-411 doi: 10.1097/WNO.0000000000000359 © 2016 by North American Neuro-Ophthalmology Society A dult-onset opsoclonus-myoclonus syndrome (OMS) is a rare neurologic manifestation that is thought to be of autoimmune origin. The underlying etiology is usually idiopathic, but in approximately 1/5 of cases, an underlying cancer is present or eventually identified, in which autoimmunity is based on crossreactivity between cancer cell surface antigens and central nervous system (CNS) pathways that control eye movements (1,2). OMS has been reported in a variety of cancers (1) but in only 2 cases of primary central system lymphoma (3,4). We report an additional case. Departments of Ophthalmology and Visual Sciences (JG, JDT), Neurology (JDT) and Pathology (Neuropathology) (AFH), Kellogg Eye Center, University of Michigan Medical System, Ann Arbor, Michigan. The authors report no conflicts of interest. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the full text and PDF versions of this article on the journal's Web site (www. jneuro-ophthalmology.com). Address correspondence to Jonathan D. Trobe, MD, Kellogg Eye Center, 1000 Wall Street, Ann Arbor, MI 48105; E-mail: jdtrobe@ umich.edu 408 CASE REPORT A 53-year-old woman developed "fluttering" eye movements that gradually became more intense. Two months later, she had jerking movements in her extremities, together with imbalance, slurred speech, and cognitive decline. Initial laboratory work-up showed hypercalcemia of 13.9 mg/dL (normal: 8.6-10.3 mg/dL) and an elevated parathyroid hormone level of 189 pg/mL (normal: 10-65 pg/mL) with subsequent thyroid ultrasound revealing a 1.8-cm right superior parathyroid mass. Two months later, this mass was surgically removed and the patient's hypercalcemia resolved. Her symptoms, however, continued to worsen, and she gradually lost all speech. The patient subsequently was admitted to the hospital for progressive functional decline, and examination on admission disclosed that she was mute and only responded to painful stimuli. She had intermittent myoclonic movements of all 4 extremities and rapid conjugate eye movements in multiple directions of gaze that persisted even with eyes closed (See Supplemental Digital Content, Video, http://links.lww.com/WNO/A196). Brain magnetic resonance imaging revealed multiple enhancing lesions in the cerebrum, thalamus, and basal ganglia bilaterally (Fig. 1). Lumbar puncture revealed acellular fluid with an elevated protein level of 115 mg/dL (normal: 15-45 mg/dL) and negative flow cytometry and cytology. Computed tomography of the chest, abdomen, and pelvis; ultrasound of breast and bladder; and Mayo Medical Laboratories paraneoplastic panel (5) were negative. A repeat lumbar puncture was again negative for malignant cells. Right frontal lobe biopsy showed perivascular collections of neoplastic lymphocytes that were immunoreactive for the B-cell marker CD20. There were numerous scattered CD68-positive reactive T-cell lymphocytes throughout the tissue (Fig. 2). Stains for bacteria, fungi, and acid-fasts microorganisms were negative. These features were consistent with the diagnosis of diffuse large B-cell lymphoma. For a diagnosis of paraneoplastic OMS, the patient received 0.04 mg/kg intravenous immunoglobulin (IVIG) Grubbs et al: J Neuro-Ophthalmol 2016; 36: 408-411 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Observation FIG. 1. A. Postcontrast axial T1 magnetic resonance imaging shows enhancing foci in the pons and left temporal lobe. B. The axial fluid-attenuated inversion recovery (FLAIR) image reveals high-intensity signal involving the thalamus, basal ganglia bilaterally, and right frontal lobe. daily for 5 days. For the CNS lymphoma, she received intravenous dexamethasone 4 mg every 6 hours for 1 week followed by an oral dexamethasone taper and 2 cycles of methotrexate 8 g/m2 IV, vincristine 2 mg IV, and rituximab 700 mg IV. Thirty-nine days later, her clinical status was unimproved, and she was transferred to hospice care. DISCUSSION Our patient had primary CNS lymphoma and OMS, an autoimmune disorder characterized by involuntary, repetitive, and rapid conjugate ocular saccades that occur in irregular amplitudes and frequencies in all directions of gaze and "shock-like," sudden, short, involuntary movements (myoclonus) caused by muscular inhibitions or contractions (1,6). Although we acknowledge that the lymphoma involved brainstem centers implicated in the generation of saccades, we believe that the OMS was a paraneoplastic phenomenon because OMS is much more commonly associated with indirect than direct effects of cancer on the CNS, and non-Hodgkin lymphoma (NHL) has been widely implicated in other types of paraneoplastic syndromes (1,7). For example, up to 20% of patients with NHL are reported to develop a presumed paraneoplastic endocarditis (7). A smaller percentage develop other paraneoplastic phenomena, including hemolytic anemias, glomerulonephritis, and multiple neurologic syndromes including chronic demyelinating polyneuropathy, Guillain-Barré syndrome, motor and sensory neuropathies, and autonomic dysfunction (7). In their case report of a primary leptomeningeal NHL causing OMS, Briongos-Figuero et al (3) argued that direct brainstem involvement by NHL likely caused OMS. However, given that other paraneoplastic phenomena occur in patients with NHL and the fact that OMS also occurs in NHL outside the brain (6,8,9), we believe that OMS was a paraneoplastic manifestation in that case and ours. However, we acknowledge that in both cases it is plausible that direct brainstem involvement by NHL could be the primary cause of the OMS. FIG. 2. Brain biopsy. A. There is a perivascular collection of atypical neoplastic lymphoid cells with round to irregular nuclei and prominent nucleoli (hematoxylin and eosin; ·400). B. Immunohistochemical stain for CD20 highlights the neoplastic B-cells (·400). Grubbs et al: J Neuro-Ophthalmol 2016; 36: 408-411 409 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. 410 Comfort care 53/F CNS, central nervous system; DLBCL, diffuse large B-cell lymphoma; F, female; M, male; N/A, not available; OMS, opsoclonus-myoclonus syndrome. Yes Yes No N/A Deceased Yes No 46/F 50/F Primary CNS DLBCL Primary diffuse leptomeningeal non-Hodgkin T-cell lymphoma Primary CNS DLBCL Yes Yes Yes No Deceased Deceased Deceased No No N/A Yes Yes Yes N/A Yes N/A T-cell mediastino-cervical lymphoma Mediastinal DLBCL Digestive lymphoma Ducrocq (8) Kumar et al (6) Gabaldon-Torres et al (9) Tsuzaka et al (4) Briongos-Figuero et al (3) Our patient 66/F 69/M N/A Immunotherapy Report Age/Gender Diagnosis Antineoplastic Treatment TABLE 1. Summary of reported cases of opsoclonus-myoclonus syndrome associated with non-Hodgkin lymphoma Improvement in OMS Symptoms After Treatment Outcome Clinical Observation Paraneoplastic disorders likely account for 20% of cases of OMS (1,2), the more common etiology being a presumed prior viral infection ("postviral OMS") (1). Among 60 cases of paraneoplastic OMS reported in the English literature from 1967 to 2011, nearly half were caused by small-cell lung carcinoma and slightly more than 10% by breast adenocarcinoma (1). OMS is an extremely rare manifestation of NHL, with only 5 reported cases (Table 1). Of these 5 patients, just 2 were associated with primary CNS lymphoma; 1 involving the brain parenchyma (4), the other the leptomeninges (3). The average survival in primary CNS lymphoma is 1.5 months if untreated and approximately 4 years if treated (10). Treatment of paraneoplastic OMS consists of intravenous corticosteroids or IVIG, together with anticancer regimens (1,11). In one case series (2), 5 of 6 patients with paraneoplastic OMS treated only with immunotherapy and without an anticancer regimen experienced worsening of their OMS symptoms and died within 6 months of treatment, whereas 8 of 8 patients who received anticancer treatments with or without immunotherapy experienced improvement in their OMS symptoms, and 6 survived for a minimum of 1.5 years. As shown in Table 1, the 5 reported patients with OMS associated with NHL had a very poor prognosis and did not improve with immunotherapy and/or antineoplastic therapy. STATEMENT OF AUTHORSHIP Category 1: a. Conception and design: J. Grubbs, Jr and J. D. Trobe; b. Acquisition of data: J. Grubbs, Jr, J. D. Trobe, and Amanda FisherHubbard; c. Analysis and interpretation of data: Joseph Grubbs, Jr, Jonathan D. Trobe, and A. Fisher-Hubbard. Category 2: a. Drafting the manuscript: J. Grubbs, Jr and J. D. Trobe; b. Revising it for intellectual content: J. Grubbs, Jr and J. D. Trobe. Category 3: a. 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