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Pitfalls in clinical diagnosis of anti-NMDA receptor encephalitis

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Abstract

Objectives

To report pitfalls in the clinical diagnosis of anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis.

Methods

We retrospectively reviewed the clinical information of 221 patients with clinically suspected autoimmune neurological disorders who underwent testing for autoantibodies against neuronal cell-surface antigens between January 1, 2007 and September 10, 2017. Forty-one patients met the diagnostic criteria for probable anti-NMDAR encephalitis (probable criteria), but one was excluded because neither serum nor CSF was examined at the active stage. Thus, in 220 patients, sensitivity and specificity of the probable criteria were assessed.

Results

NMDAR-antibodies were detected in 34 of 40 patients (85%) with the probable criteria; however, 2 of the 6 antibody-negative patients had ovarian teratoma. The median age at onset was higher in antibody-negative patients than those with antibodies (49 vs. 27 years, p = 0.015). The age at onset was associated with the probability of antibody detection (p = 0.014); the probability was less than 50% in patients aged 50 years or older. NMDAR-antibodies were also detected in 5 of 180 patients who did not fulfill the probable criteria; these patients presented with isolated epileptic syndrome (n = 2), atypical demyelinating syndrome (n = 2; one with aquaporin 4 antibodies), and autoimmune post-herpes simplex encephalitis (post-HSE) (n = 1). Sensitivity and specificity of the probable criteria was 87.2 and 96.7%, respectively.

Conclusion

The probable criteria are valid, but the diversity of clinical phenotype should be taken into account in diagnosing anti-NMDAR encephalitis particularly in patients aged 50 years or older, or with isolated epileptic syndrome, atypical demyelinating syndrome, or post-HSE.

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Acknowledgements

We particularly thank Professor Josep Dalmau in Service of Neurology, IDIBAPS Hospital Clínic, University of Barcelona, Casanova (Spain) for examining antibodies against neuronal cell-surface antigens, and MOG and AQP4 antibodies. We are extremely grateful to all participants and physicians for their contribution to this study, and acknowledge the efforts of research staffs, who worked on the clinical, and neuroimaging data collection.

Funding

This work was supported in part by a grant from Japan Epilepsy Research Foundation (JERFTENKAN 17002).

Author information

Authors and Affiliations

  1. Department of Neurology, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa, 252-0374, Japan

    Atsushi Kaneko, Juntaro Kaneko, Naomi Tominaga, Naomi Kanazawa, Daisuke Ishima, Eiji Kitamura, Kazutoshi Nishiyama & Takahiro Iizuka

  2. Department of Neurology, School of Medicine, Fukushima Medical University, Fukushima, Japan

    Kasumi Hattori & Yoshikazu Ugawa

  3. Japanese Red Cross Fukushima Hospital, Fukushima, Japan

    Arata Moriya

  4. Department of Neurology, Chikamori Hospital, Kochi, Japan

    Daisuke Kuzume

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  1. Atsushi Kaneko
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Contributions

Atsushi Kaneko: Study concept or design, data acquisition, analysis or interpretation of the data, drafting/revising the manuscript. Juntaro Kaneko: Data acquisition, analysis or interpretation of the data, drafting/revising the manuscript. Naomi Tominaga: Data acquisition, analysis or interpretation of the data, drafting/revising the manuscript. Naomi Kanazawa: Data acquisition, analysis or interpretation of the data, statistical analysis, drafting/revising the manuscript. Kasumi Hattori: Data acquisition, analysis or interpretation of the data, drafting/revising the manuscript. Yoshikazu Ugawa: Data acquisition, analysis or interpretation of the data, drafting/revising the manuscript. Arata Moriya: Data acquisition, analysis or interpretation of the data, drafting/revising the manuscript. Daiske Kuzume: Data acquisition, analysis or interpretation of the data, drafting/revising the manuscript. Daisuke Ishima: Data acquisition, analysis or interpretation of the data, drafting/revising the manuscript. Eiji Kitamura: Data acquisition, analysis or interpretation of the data, drafting/revising the manuscript. Kazutoshi Nishiyama: Data acquisition, analysis or interpretation of the data, drafting/revising the manuscript. Takahiro Iizuka: Study concept or design, data acquisition, analysis or interpretation of the data, statistical analysis, drafting/revising the manuscript.

Corresponding author

Correspondence to Takahiro Iizuka.

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Ethical approval

This study was approved by Institutional Review Boards of Kitasato University (B17-144).

Conflicts of interest

A. Kaneko, J. Kaneko, N. Tominaga, N. Kanazawa, and K. Hattori report no disclosures; Y. Ugawa received grants from the Ministry of Education, Culture, Sports, Science and Technology of Japan, the Ministry of Health, Labour and Welfare of Japan, the Support Center for Advanced Telecommunications Technology Research, the Association of Radio Industries Businesses, Ministry of Internal Affairs and Communications/grants from the Committee of the Study of Human Exposure to EMF, and the Novartis Foundation (Japan) for the Promotion of Science, Nihon Kohden, Ltd., Takeda Pharmaceutical Company Limited, Nippon Boehringer Ingelheim Co., Ltd., Mitsubishi Tanabe Pharma Corporation received honoraria from the Taiwan Movement Disorders Society, Chinese Neurology Society, Astellas Pharma Inc., Eisai Co., Ltd., FP Pharmaceutical Corporation, Otsuka Pharmaceutical Co., Ltd., Elsevier Japan K. K., Kissei Pharmaceutical Co., Ltd., Kyorin Pharmaceutical Co., Ltd., Kyowa Hakko Kirin Co., Ltd., GlaxoSmithKline K. K., Sanofi-Aventis K.K., Daiichi Sankyo Co., Ltd., Dainippon Sumitomo Pharma Co., Ltd., Takeda Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Teijin Pharma Ltd., Nippon Chemiphar Co., Ltd., Nihon Pharmaceutical Co., Ltd., Nippon Boehringer Ingelheim Co., Ltd., Novartis Pharma K.K., Bayer Yakuhin, Ltd., and Mochida Pharmaceutical Co., Ltd. Y. Ugawa also received royalties from CHUGAI-IGAKUSHA, Igaku-Shoin Ltd., Medical View Co. Ltd., and Blackwell Publishing K.K.; A. Moriya, D. Kuzume, D. Ishima, and E. Kitamura reports no disclosures; K. Nishiyama received grants from Nippon Boehringer Ingelheim Co., Ltd., Daiichi Sankyo Co., Ltd., Astellas Pharma Inc., Otsuka Pharmaceutical Co., Ltd., Kyorin Pharmaceutical Co., Ltd., Dainippon Sumitomo Pharma Co., Ltd., Teijin Pharma Limited., Nihon Pharmaceutical Co., Ltd., Pfizer Inc., Bristol-Myers Squibb, Japan Blood Products Organization, MSD, and Nihon Medi-Physics Co., Ltd; T. Iizuka is an editorial board member for Current Treatment Options in Neurology, and Rinsho Shinkeigaku, and received a grant from Japan Epilepsy Research Foundation.

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Kaneko, A., Kaneko, J., Tominaga, N. et al. Pitfalls in clinical diagnosis of anti-NMDA receptor encephalitis. J Neurol 265, 586–596 (2018). https://doi.org/10.1007/s00415-018-8749-3

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  • DOI: https://doi.org/10.1007/s00415-018-8749-3

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