Case of autoantibodies against N‐methyl‐D‐aspartate receptor+/antibodies against myelin‐oligodendrocyte glycoprotein+ multiphasic acute disseminated encephalomyelitis (ADEM)

Abstract

Autoantibodies against N-methyl-D-aspartate receptor (anti-NMDAR) are found in patients with limbic encephalitis (LE). The initial case series reported by Dalmau et al.1 had anti-NMDAR+ LE with ovarian teratoma in young patients, but a significant proportion of anti-NMDAR+ cases do not have associated tumors, suggesting that patients with disruption of immune tolerance could also develop such antibodies.2 Recently, the same research group reported that some patients with anti-NMDAR+ LE and demyelinating episodes or abnormal magnetic resonance imaging (MRI) findings were positive for antibodies against myelin-oligodendrocyte glycoprotein (anti-MOG) or aquaporin 4 (anti-AQP4).3 Anti-AQP4 antibody-positive cases had features compatible with neuromyelitis optica, but anti-MOG-positive cases were associated with demyelinating episodes characterized by diplopia, motor paresis, sensory disturbance, gait disturbance and/or brain lesions on the MRI suggestive of demyelinating disease. However, the great majority of the patients were analyzed in a cross-sectional study with autoantibody testing carried out only once. We herein report the MRI features of a young woman with multiphasic ADEM who was positive to anti-NMDAR and anti-MOG. Our patient was a 27-year-old Japanese woman who presented with headache and abnormal behavior during the 7th month of pregnancy. The brain MRI was normal and her clinical symptoms improved spontaneously after premature delivery. Three months later, she had new episodes of headaches and stupor. During this admission, the brain MRI showed abnormal findings as seen in Fig. 1a–c. Cerebrospinal fluid showed pleocytosis (8 cells/mm3) with elevated protein (44 mg/dL). No tumor was found, including ovarian teratoma. She improved after intravenous methylprednisolone 1 g/day for 3 days (IVMP), and the brain lesions on the MRI disappeared. Low-dose oral prednisone was commenced to prevent recurrences. Three years later, she presented with confusion, memory impairment, unstable gait, saccadic eye movements and hyperreflexia after oral prednisone discontinuation. The brain MRI showed new multiple lesions (Fig. 1d–i), and she received IVMP with good recovery. Then, 15 months later, the patient became irritated, and there was a worsening of behavioral symptoms after she had discontinued oral prednisone. The brain MRI showed a new lesion, as seen in Fig. 1j–l. She was treated with IVMP with good recovery, and oral prednisone was resumed. Multiple serum and CSF samples collected throughout the disease course were positive to anti-NMDAR and anti-MOG, using cell-based assays with NR1/NR2b and full-length MOG transfected HEK cells, respectively.4 Anti-MOG titers measured post-IVMP treatment during one exacerbation in the serum and CSF were reduced compared with pretreatment levels (1:16 384 to 1:8192, and 1:256 to 1:64, serum and CSF, pre- and post-treatment, respectively). The reduction in anti-MOG titers post-IVMP was associated with improvement of brain MRI lesions. In contrast, serum and CSF anti-NMDAR titers were slowly reduced overtime with long-term oral corticosteroid treatment, while maintaining a higher CSF:serum ratio (1:1 to 1:10), suggesting a higher intrathecal synthesis compared with anti-MOG. Further studies are required to clarify the predisposing factors to develop autoantibodies to multiple central nervous system antigens, but anti-MOG antibodies should be suspected in anti-NMDAR+ LE patients who develop demyelinating lesions. This study was supported by KAKENHI (22229008) of The Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan, and by the Health and Labor Sciences Research Grant on Intractable Diseases (Neuroimmunological Diseases) from the Ministry of Health, Labor and Welfare of Japan. The funding sources had no role in the design, collection, analysis or interpretation of the study, nor in the writing of the article or decision to submit. Dr Kaneko has nothing to disclose. Dr Sato is an associate editor of the Arquivos de Neuropsiquiatria (official journal of the Brazilian Academy of Neurology); has received a scholarship from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan; and speaker honoraria from Novartis. Dr Kurosawa has nothing to disclose. Dr Misu has received speaker honoraria from Bayer Schering Pharma, Biogen Idec Japan, Mitsubishi Tanabe Pharma Corporation, Asahi Kasei Medical Co. and Astellas Pharma Inc.; has received research support from Bayer Schering Pharma, Biogen Idec Japan, Asahi Kasei Kuraray Medical Co., The Chemo-Sero-Therapeutic Research Institute, Teva Pharmaceutical K.K., Mitsubishi Tanabe Pharma Corporation and Teijin Pharma; and Grants-in-Aid for Scientific Research from the Ministry of Education, Science and Technology, and the Ministry of Health, Labor and Welfare of Japan. Dr Nakashima reports grants from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan, and from the Ministry of Health, Labor and Welfare of Japan; personal fees from Mitsubishi Tanabe Pharma Corporation, Biogen Idec Japan, Novartis Pharmaceuticals Japan, Bayer Yakuhin, Ltd; and grants from LSI Medience Corporation. Dr Fujihara serves on scientific advisory boards for Bayer Schering Pharma, Biogen Idec, Mitsubishi Tanabe Pharma Corporation, Novartis Pharma, Chugai Pharmaceutical, Ono Pharmaceutical, Nihon Pharmaceutical, Merck Serono, Alexion Pharmaceuticals, Medimmune and Medical Review; has received funding for travel and speaker honoraria from Bayer Schering Pharma, Biogen Idec, Eisai Inc., Mitsubishi Tanabe Pharma Corporation, Novartis Pharma, Astellas Pharma Inc., Takeda Pharmaceutical Company Limited, Asahi Kasei Medical Co., Daiichi Sankyo, and Nihon Pharmaceutical; serves as an editorial board member of Clinical and Experimental Neuroimmunology (2009-present); is a advisory board member of Sri Lanka Journal of Neurology; has received research support from Bayer Schering Pharma, Biogen Idec Japan, Asahi Kasei Medical, The Chemo-Sero-Therapeutic Research Institute, Teva Pharmaceutical, Mitsubishi Tanabe Pharma, Teijin Pharma, Chugai Pharmaceutical, Ono Pharmaceutical, Nihon Pharmaceutical and Genzyme Japan; is funded as the secondary investigator (#22229008, 2010-2015) by the Grants-in-Aid for Scientific Research from the Ministry of Education, Science and Technology of Japan, and as the secondary investigator by the Grants-in-Aid for Scientific Research from the Ministry of Health, Welfare and Labor of Japan (2010-present). Dr Aoki has nothing to disclose.