Review and meta-analysis of neuropsychological findings in autoimmune limbic encephalitis with autoantibodies against LGI1, CASPR2, and GAD65 and their response to immunotherapy

Christoph Mueller, Saskia Elben, Gregory S. Day, Pedro Alves, Julien Hebert, David F. Tang-Wai, Olga Holtmann, Raffaele Iorio, Daniela Perani, Maarten J. Titulaer, Niels Hansen, Thorsten Bartsch, Andreas Johnen, Zslot Illes, Leah Borm, Alice G. Willison, Heinz Wiendl, Sven G. Meuth, Stjepana Kovac, Jens BölteNico Melzer*

*Corresponding author for this work

Research output: Contribution to journalReview articlePopular

3 Citations (Scopus)
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Objectives: It is assumed that autoimmune limbic encephalitis (ALE) demonstrates distinct neuropsychological manifestations with differential responses to immunotherapy according to which associated autoantibody (AAB), if any, is identified. Towards investigating whether this is the case, this study aims to summarize respective findings from the primary literature on ALE with AABs binding to cell surface neural antigens and ALE with AABs against intracellular neural antigens. Methods: We chose ALE with AABs against leucine-rich, glioma inactivated protein 1 (LGI1) and contactin-associated protein-like 2 (CASPR2) as the most frequent cell surface membrane antigens, and ALE with AABs to Embryonic Lethal, Abnormal Vision, Like 1 (ELAVL) proteins (anti-Hu) and glutamic acid decarboxylase 65 (GAD65) as the most frequent intracellular neural antigens. The PubMed and Scopus databases were searched on March 1st, 2021 for neuropsychological test and -screening data from patients with ALE of these AAB-types. Findings were reviewed according to AAB-type and immunotherapy status and are presented in a review section and are further statistically evaluated and presented in a meta-analysis section in this publication. Results: Of the 1304 initial hits, 32 studies on ALE with AABs against LGI1, CASPR2, and GAD65 reporting cognitive screening data could be included in a review. In ALE with AABs against LGI1, CASPR2 and GAD65, memory deficits are the most frequently reported deficits. However, deficits in attention and executive functions including working memory, fluency, and psychological function have also been reported. This review shows that ALE patients with AABs against both LGI1 and CASPR2 show higher percentages of neuropsychological deficits compared to ALE patients with AABs against GAD65 before and after initiation of immunotherapy. However, the methodologies used in these studies were heterogenous, and longitudinal studies were not comparable. Moreover, 21 studies including ALE patients with AABs against LGI1 and GAD65 were also suitable for meta-analysis. No suitable study on ALE with AABs against ELAVL proteins could be identified. Meta-Analyses could be executed for cognitive screening data and only partially, due to the small number of studies. However, in statistical analysis no consistent effect of AAB or immunotherapy on performance in cognitive screening tests could be found. Conclusion: Currently, there is no definite evidence supporting the notion that different AAB-types of ALE exhibit distinct neuropsychological manifestations and respond differently to immunotherapy. Overall, we could not identify evidence for any effect of immunotherapy on cognition in ALE. More systematic, in-depth and longitudinal neuropsychological assessments of patients with different AAB-types of ALE are required in the future to investigate these aspects.

Original languageEnglish
Article number107559
JournalClinical Neurology and Neurosurgery
Publication statusPublished - Jan 2023

Bibliographical note

Funding Information:
This project was supported by the German Federal Ministry of Education and Research (Comprehensive, Orchestrated, National Network to Explain, Categorize and Treat autoimmune encephalitis and allied diseases within the German Network for Research on Autoimmune Encephalitis – CONNECT GENERATE ; 01GM1908 ).

Publisher Copyright:
© 2022 The Authors


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