Opsoclonus‐Myoclonus‐Ataxia Syndrome Associated with Coexisting Anti‐N‐Methyl‐D‐Aspartate Receptor and Glial Fibrillary Acidic Protein Antibodies

Anti-N-methyl-D-aspartate receptor encephalitis (NMDARE) is a frequent autoimmune encephalitis (AE) mediated by NMDAR antibodies (NMDAR-Abs).1 In NMDARE, overlapping glial fibrillary acidic protein antibodies (GFAP-Abs) that lead to autoimmune GFAP astrocytopathy can be positive concurrent with NMDAR-Abs, although the clinical implications of NMDARE with overlapping GFAP-Abs are not fully understood.2 Here, we present the first case of a 60-year-old male patient with AE and opsoclonus-myoclonus-ataxia syndrome (OMAS) mediated by NMDAR-Abs and GFAP-Abs. A 60-year-old man presented with a 6-month history of cognitive impairment. Three months prior to admission, he developed involuntary movements of his hands and mouth accompanied by instability when walking. At his primary care clinic, essential tremor was initially suspected; he was treated with arotinolol hydrochloride and diazepam, which failed to alleviate his symptoms. He was then admitted to our hospital for a comprehensive evaluation. He had no significant familial or medical history, including autoimmune systemic disorders. Upon admission, a neurological examination revealed cognitive impairment (Mini-Mental State Examination: 16/30; Frontal Assessment Battery: 12/18), characterized by attention and executive dysfunction. He exhibited involuntary eye movements characterized by intermittent, irregular bursts, predominantly in horizontal gazes but also in multidirectional gazes, which were diagnosed as opsoclonus on the basis of nystagmometry results. His gait was abnormal with a broad-based stance, and severe limb and truncal ataxia were observed (Video 1). Involuntary movement of the mouth had already disappeared. Spasticity and hyperreflexia, along with pathological reflexes, including sucking, snout, and palmomental reflexes, were also noted. He had constipation and pollakiuria, which appeared after the onset of cognitive impairment. His blood count and chemistry, including tumor markers, were unremarkable. Antibodies against aquaporin-4, myelin oligodendrocyte glycoprotein, voltage-gated potassium channels, the NH2-terminal of alpha-enolase, and other paraneoplastic AE-related antibodies were negative. Cerebrospinal fluid (CSF) analysis showed elevated protein levels with lymphocytic pleocytosis and oligoclonal bands. In the CSF, NMDAR-Abs were positive by indirect immunofluorescence assay (BML Inc. [https://www.bml.co.jp/eng/]), and GFAP-Abs were positive by cell- and tissue-based assays.3 Brain magnetic resonance imaging (MRI) showed periventricular and juxtacortical ovoid lesions and linear perivascular radial enhancement (Fig. 1A, B). Spinal MRI depicted longitudinally extensive lesions in the cervical and thoracic spine (Fig. 1C–F). There were no specific lesions in the conus. N-isopropyl-p-(123I) iodoamphetamine single-photon emission computed tomography (IMP-SPECT) revealed hypoperfusion in the bilateral frontal and parietotemporal lobes and hyperperfusion in the cerebellum (Fig. 2). Electroencephalography showed slow-wave activity in the bilateral frontal lobe (not shown). Whole-body computed tomography and positron emission tomography did not identify neoplasms (not shown). Intravenous methylprednisolone (1000 mg for 3 days) followed by oral prednisolone with plasma exchange markedly ameliorated his symptoms (Video 2). Eight months after the treatments, the spinal lesions had resolved, and no relapse episodes occurred. Our patient exhibited symptoms of NMDARE, including involuntary movements and cognitive decline, with NMDAR-Abs detected in the CSF. However, atypical findings, including OMAS and neuroimaging features—including linear perivascular radial enhancement and longitudinally extensive spinal lesions—were observed. This is the first reported case of OMAS associated with coexisting anti-NMDAR and GFAP antibodies. Overlapping antibodies other than NMDAR-Abs may present with atypical neurological symptoms or neuroimaging in patients with NMDARE.4 Although specific MRI findings are rare for NMDARE, GFAP astrocytopathy can manifest abnormalities, such as linear perivascular radial enhancement and longitudinal spinal lesions.5 These findings suggest that overlapping antibodies may lead to atypical manifestations. Although the coexistence of NMDAR and GFAP antibodies was recently reported, OMAS has not been described, even in these overlapping cases, indicating that this manifestation is exceedingly rare (Supplementary Table S1). Although a few cases of OMAS have been reported in non-overlapping NMDAR or GFAP antibody–positive encephalitis, no overlapping cases have been documented so far (Supplementary Table S2). OMAS may result from Purkinje cell dysfunction in the cerebellum, leading to the impaired inhibition of fastigial nuclei and abnormal saccadic control.6 Although Purkinje cells lack NMDARs, granule cells that connect to Purkinje cells via parallel fibers may contribute to the pathophysiology.7 GFAP, however, is an intracellular antigen, and GFAP astrocytopathy likely results from unknown immune mechanisms rather than direct neuronal damage by GFAP-Abs.5 Despite past studies, how OMAS might be triggered by double positivity for NMDAR-Abs and GFAP-Abs remains unclear. However, in our case, IMP-SPECT revealed hyperperfusion in the cerebellum and hypoperfusion in the frontal lobe, consistent with cerebellar inflammation.8 Therefore, we speculated that OMAS might be triggered by cerebellar inflammation in association with NMDAR-Abs and GFAP-Abs. Further research is needed to elucidate the mechanisms by which the coexistence of these two antibodies leads to the development of OMAS. This study had several limitations. First, undetected antibodies may have contributed to AE and OMAS. Second, there was insufficient evidence to conclude that hyperperfusion on IMP-SPECT was definitively associated with inflammation because follow-up imaging was not performed. However, the improvement in cerebellar symptoms after immunotherapy suggests that the hyperperfusion may be related to NMDAR-Abs and GFAP-Abs. In conclusion, we report a case of OMAS with double positivity for NMDAR-Abs and GFAP-Abs. Our report highlights the importance of considering coexisting antibodies when OMAS is seen in AE patients. (1) Research project: A. Conception, B. Organization, C. Execution; (2) Statistical Analysis: A. Design, B. Execution, C. Review and Critique; (3) Manuscript Preparation: A. Writing of the first draft, B. Review and Critique. E.I.: 1C, 3A. Y.O.: 1A, 1B, 1C, 3B. A.Y.: 1C, 3B. S.U.: 1C, 3B. Y.T.: 1A, 1B, 1C, 3B. T.T.: 1A, 3B. T.H.: 1A, 1B, 3B. N.H.: 1A, 1B, 3B. We thank the patient and his family for kindly permitting the publication of his case. We are sincerely grateful to Professor Takayoshi Shimohata and his colleagues at the Department of Neurology at Gifu University for measuring GFAP antibodies and to Professor Tatsuro Misu and his colleagues at the Department of Neurology at Tohoku University for measuring myelin oligodendrocyte glycoprotein antibodies. We thank J. Ludovic Croxford, PhD, from Edanz (https://jp.edanz.com/ac) for editing the draft English text of this manuscript. Ethical Compliance Statement: The authors confirm that approval from the Institutional Review Board was not required for this study. Written informed consent was obtained from the patient. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines. Funding Sources and Conflict of Interest: No specific funding was received for this work. The authors declare that there are no conflicts of interest relevant to this work. Financial Disclosures for the previous 12 months: E.I. declares that there are no additional disclosures to report. Y.O. reports receiving grants from Japan Society for the Promotion of Science-Kakenhi (no: 23K14762), the Japan Agency for Medical Research and Development (grant number 24wm0625309h0001), and speakers’ honoraria from Takeda Pharmaceutical Co., Ltd., Eisai Co., Ltd., Ono Pharmaceutical Co., Ltd., and AbbVie GK. A.Y. declares that there are no additional disclosures to report. S.U. declares that there are no additional disclosures to report. Y.T. declares that there are no additional disclosures to report. T.T. reports receiving grants from the Japan Society for the Promotion of Science, Grant-in-Aid for Scientific Research, and speaker honoraria from Eisai Co., Ltd., Kyowa Kirin Co., Ltd., Kyowa Pharmaceutical Industry Co., Ltd., Otsuka Pharmaceutical Co., Ltd., UCB Japan, Mitsubishi Tanabe Pharma Corporation, and Fondazione Prada. T.H. reports receiving grants from the Japan Agency for Medical Research and Development, Japan Agency for Medical Research and Development (no: 25wm0625127, 25wm0625503, 25dk0207072, 24wm0425015, 24wm0425019), and the Japan Society for the Promotion of Science, Japan Society for the Promotion of Science-Kakenhi (no: 24 K02373), and speaker's honoraria from Sumitomo Pharma Co., Ltd., Takeda Pharmaceutical Co., Ltd., Kyowa Kirin Co., Ltd., Eisai Co., Ltd., Kowa Company, Ltd., EA Pharma Co., Ltd., Viatris Inc., and AbbVie Inc. N.H. reports receiving the following grants and fees unrelated to this research during the conduct of the study: grants from the Japan Society for the Promotion of Science, the Japan Agency for Medical Research and Development, the Japan Science and Technology Agency, a Health Labour Sciences Research Grant, IPMDS, and MJFF; personal fees for speaker's honoraria from Sumitomo Dainippon Pharma Co., Ltd., Takeda Pharmaceutical Co., Ltd., Kyowa Kirin Co., Ltd., AbbVie GK, Otsuka Pharmaceutical Co., Ltd., Novartis Pharma Co., Ltd., Ono Pharmaceutical Co., Ltd., Eisai Co., Ltd., Teijin Pharma, Daiichi Sankyo Co., Ltd., and FP Pharmaceutical Corporation; personal fees for consultancies and advisory boards from Sumitomo Dainippon Pharma Co., Ltd., Takeda Pharmaceutical Co. Ltd., Kyowa Kirin Co., Ltd., Ono Pharmaceutical Co., Ltd., Teijin Pharma, and PARKINSON Laboratories Co., Ltd.; and owns shares in the PARKINSON Laboratories Co., Ltd., (equity stock 8%). The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions. TABLE S1. Previously reported cases of dual positivity for anti–N-methyl-D-aspartate receptor (NMDAR) and glial fibrillary acidic protein (GFAP) antibodies. This table summarizes the clinical, radiological, and therapeutic features of previously reported patients with dual positivity for NMDAR and GFAP antibodies Table S2. Previously reported cases of opsoclonus in patients with anti–N-methyl-D-aspartate receptor (NMDAR) or glial fibrillary acidic protein (GFAP) antibodies. This table summarizes the clinical and radiological characteristics of patients reported in the literature who exhibited opsoclonus or abnormal ocular movement in association with NMDAR or GFAP antibodies Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.