Autoimmune encephalitis

Marienke A A M de Bruijn^{1

2}, Frank Leypoldt^{3

4}, Josep Dalmau^{5

6

7

8}, Soon-Tae Lee⁹, Jerome Honnorat¹⁰, Stacey L Clardy¹¹, Sarosh R Irani¹², Ava Easton^{13

14}, Amy Kunchok¹⁵, Maarten J Titulaer¹⁶

Affiliations

¹ Department of Neurology, Erasmus University Medical Center, Rotterdam, The Netherlands.
² Department of Neurology, Elisabeth-Tweesteden Hospital, Tilburg, The Netherlands.
³ Neuroimmunology, Institute of Clinical Chemistry, University Hospital Schleswig-Holstein Kiel, Kiel, Germany.
⁴ Department of Neurology, Christian-Albrechts University, Kiel, Germany.
⁵ Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain.
⁶ Neurology Department, Institute of Neuroscience, Hospital Clínic de Barcelona, University of Barcelona, Barcelona, Spain.
⁷ Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
⁸ Catalan Institution for Research and Advanced Studies (ICREA), Barcelona, Spain.
⁹ Department of Neurology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, South Korea.
¹⁰ French Reference Centre for Paraneoplastic Neurological Syndromes and Autoimmune Encephalitis, Hospices Civils de Lyon, MeLiS - UCBL-CNRS UMR 5284 - INSERM U1314, Université Claude Bernard Lyon 1, Lyon, France.
¹¹ Department of Neurology, University of Utah, Salt Lake City, UT, USA.
¹² Departments of Neurology and Neurosciences, Mayo Clinic, Jacksonville, FL, USA.
¹³ Department of Clinical Infection, Microbiology and Immunology, University of Liverpool, Liverpool, UK.
¹⁴ Encephalitis International, Malton, UK.
¹⁵ Mellen Center for Multiple Sclerosis Treatment and Research, Cleveland Clinic Foundation, Cleveland, OH, USA.
¹⁶ Department of Neurology, Erasmus University Medical Center, Rotterdam, The Netherlands. m.titulaer@erasmusmc.nl.

PMID: 40935848
DOI: 10.1038/s41572-025-00650-1

Review

Autoimmune encephalitis

Marienke A A M de Bruijn et al. Nat Rev Dis Primers. 2025.

. 2025 Sep 11;11(1):65.

doi: 10.1038/s41572-025-00650-1.

Authors

Affiliations

¹ Department of Neurology, Erasmus University Medical Center, Rotterdam, The Netherlands.
² Department of Neurology, Elisabeth-Tweesteden Hospital, Tilburg, The Netherlands.
³ Neuroimmunology, Institute of Clinical Chemistry, University Hospital Schleswig-Holstein Kiel, Kiel, Germany.
⁴ Department of Neurology, Christian-Albrechts University, Kiel, Germany.
⁵ Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain.
⁶ Neurology Department, Institute of Neuroscience, Hospital Clínic de Barcelona, University of Barcelona, Barcelona, Spain.
⁷ Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
⁸ Catalan Institution for Research and Advanced Studies (ICREA), Barcelona, Spain.
⁹ Department of Neurology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, South Korea.
¹⁰ French Reference Centre for Paraneoplastic Neurological Syndromes and Autoimmune Encephalitis, Hospices Civils de Lyon, MeLiS - UCBL-CNRS UMR 5284 - INSERM U1314, Université Claude Bernard Lyon 1, Lyon, France.
¹¹ Department of Neurology, University of Utah, Salt Lake City, UT, USA.
¹² Departments of Neurology and Neurosciences, Mayo Clinic, Jacksonville, FL, USA.
¹³ Department of Clinical Infection, Microbiology and Immunology, University of Liverpool, Liverpool, UK.
¹⁴ Encephalitis International, Malton, UK.
¹⁵ Mellen Center for Multiple Sclerosis Treatment and Research, Cleveland Clinic Foundation, Cleveland, OH, USA.
¹⁶ Department of Neurology, Erasmus University Medical Center, Rotterdam, The Netherlands. m.titulaer@erasmusmc.nl.

PMID: 40935848
DOI: 10.1038/s41572-025-00650-1

Abstract

Autoimmune encephalitis (AE) is a treatable neuro-inflammatory disorder that is increasing in incidence. AE can be associated with malignancy (paraneoplastic), but in many patients no tumour is present. The disease presentation of AE can be heterogeneous depending on the type of antibody involved. AE is often caused by neuronal antibodies that bind to extracellular autoantigens (that is, N-methyl-D-aspartate receptor (NMDAR) and LGI1). Binding of these antibodies causes dysfunction of synaptic receptors, which leads to neurological symptoms. In these patients, treatment with immunosuppressive therapies is believed to decrease inflammation and deplete antibodies, and is essential for recovery. AE can also occur in patients with antibodies against intracellular antigens (such as Hu and Ri), often in the setting of malignancy. In these patients, tumour treatment is essential for stabilization or improvement. The most frequent symptoms of AE are cognitive problems, behavioural changes and seizures. Rapid recognition of AE syndromes is essential as earlier treatment of AE leads to better outcomes. For a definite diagnosis, the identification of an autoantibody is essential; however, some patients have seronegative AE. Most patients are severely affected during the acute disease stage, but long-term functional recovery is often good, particularly for patients without cancer. Nevertheless, residual anxiety, fatigue and cognitive problems can considerably affect quality of life. Research focuses on improving the understanding of pathophysiological processes, establishing patient-tailored outcome measures, optimizing treatment prediction models and studying different therapeutic regimens, all aiming to improve treatment and long-term outcomes.

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Conflict of interest statement

Competing interests: F.L. is supported by E-Rare Joint Transnational research support (ERA-Net, LE3064/2-1), European Joint Program for Neurodegenerative Diseases (EJPRD) IGNITEMIND (01ED2506B), ERA-Net MICE-AE (01EW2507B), Stiftung Pathobiochemie of the German Society for Laboratory Medicine and HORIZON MSCA 2022 Doctoral Network 101119457 — IgG4-TREAT and discloses speaker honoraria from Grifols, Teva, Biogen, Bayer, Roche, Novartis, Fresenius, travel funding from Merck, Grifols and Bayer and serving on advisory boards for Roche, Biogen and Alexion. J.D. declares research funding to the institution from Instituto de Salud Carlos III, La Caixa Foundation, Edmond J. Safra Foundation, Department of Health, Generalitat de Catalunya; a research contract from Sage Therapeutics; unrestricted research support from Euroimmun, Inc; and royalties paid to the author from Euroimmun, Inc. for the use of NMDAR, GABAa, GABAb, DPPX and IgLOn5 as antibody tests. S.-T.L. is a steering committee member of the CIELO trial (Roche/Genentech) and has served on advisory boards for Argenx, Arialys Therapeutics, Advanced Neural Technologies and Piehealthcare. He is a named inventor of the CASE score. S.L.C. is a principal investigator of the ExTINGUISH Trial for NMDAR Encephalitis, supported by the National Institute of Neurological Disorders and Stroke of the National Institutes of Health under award number U01NS120901. Additional support was provided by Amgen for this investigator-initiated trial. This report does not represent the official view of the National Institute of Neurological Disorders and Stroke (NINDS), the National Institutes of Health (NIH) or any part of the US Federal Government. No support or endorsement of this article by the NINDS or NIH is intended or should be inferred. S.L.C. is editorial board member for Neurology: Neuroimmunology & Neuroinflammation. S.R.I. has performed this research funded in whole or in part by a senior clinical fellowship from the Medical Research Council (MR/V007173/1) and Wellcome Trust Fellowship (104079/Z/14/Z), the Kogod Centre on Aging and by the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre (BRC). For the purpose of Open Access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript (AAM) version arising from this submission. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. S.R.I. has received honoraria/research support from Amgen, Argenx, UCB, Roche, Janssen, IQVIA, Clarivate, Slingshot Insights, Cerebral therapeutics, BioHaven therapeutics, CSL Behring and ONO Pharma. S.R.I. receives licensed royalties on patent application WO/2010/046716 entitled ‘Neurological Autoimmune Disorders’, and has filed two other patents entitled ‘Diagnostic method and therapy’ (WO2019211633 and US app 17/051,930; PCT application WO202189788A1) and ‘Biomarkers’ (WO202189788A1, US App 18/279,624; PCT/GB2022/050614). M.J.T. has received research funds for serving on a scientific advisory board of AmGen, UCB, Arialys and ArgenX; received funds from Dioraphte (2001 0403); filed a patent for methods for typing neurologic disorders and cancer, and devices for use therein; obtained a copyright (on behalf of Erasmus MC) for the PROSE, an AE-specific patient-reported outcome measure; received research funds for consultation at Guidepoint Global LLC, an unrestricted research grant from CSL Behring (Interlaken Leadership Award) and an unrestricted research grant from Euroimmun. He was supported by an E-RARE3 grant (UltraAIE, ZonMW), ACT-MD (ZonMW), PARADE-VIMP (ZonMW) and ItsME. M.J.T. has received publishing royalties from UpToDate Inc. M.J.T. served as an associate editor for the Dutch Journal of Neurology and Neurosurgery (Tijdschrift voor Neurologie en Neurochirurgie, TNN) and as editorial board member for Neurology: Neuroimmunology & Neuroinflammation. M.J.T. is a scientific advisory board member for Encephalitis International, Autoimmune Encephalitis Alliance and ItsME (patient advocacy foundations). The other authors declare no competing interests.

References

1. Dalmau, J. & Graus, F. Antibody-mediated encephalitis. N. Engl. J. Med. 378, 840–851 (2018). - PubMed - DOI
1. Leypoldt, F. et al. Herpes simplex virus-1 encephalitis can trigger anti-NMDA receptor encephalitis: case report. Neurology 81, 1637–1639 (2013). - PubMed - PMC - DOI
1. Abboud, H. et al. Autoimmune encephalitis: proposed best practice recommendations for diagnosis and acute management. J. Neurol. Neurosurg. Psychiatry 92, 757–768 (2021). - PubMed - DOI
1. Dalmau, J. et al. Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies. Lancet Neurol. 7, 1091–1098 (2008). - PubMed - PMC - DOI
1. Titulaer, M. J. et al. Treatment and prognostic factors for long-term outcome in patients with anti-NMDA receptor encephalitis: an observational cohort study. Lancet Neurol. 12, 157–165 (2013). This study is the first large cohort description, depicting anti-NMDAR encephalitis, showing the effects of different treatments on long-term outcomes. - PubMed - PMC - DOI

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Autoimmune encephalitis

Affiliations

Autoimmune encephalitis

Authors

Affiliations

Abstract

Conflict of interest statement

References

Publication types

MeSH terms

Substances

Supplementary concepts