Glutamic acid decarboxylase antibody-associated neurological syndromes: Clinical and antibody characteristics and therapy response

Marie Madlener; Christine Strippel; Franziska S Thaler; Kathrin Doppler; Klaus P Wandinger; Jan Lewerenz; Marius Ringelstein; Rosa Roessling; Til Menge; Jonathan Wickel; Christoph Kellingshaus; Sigrid Mues; Andrea Kraft; Andreas Linsa; Simone C Tauber; Florian Then Berg; Stefan T Gerner; Asterios Paliantonis; Alexander Finke; Josef Priller; Ingo Schirotzek; Marie Süße; Kurt W Sühs; Christian Urbanek; Makbule Senel; Claudia Sommer; Tania Kuempfel; Harald Pruess; Gereon R Fink; Frank Leypoldt; Nico Melzer; Michael P Malter; German Network for Research on Autoimmune Encephalitis (GENERATE)

doi:10.1016/j.jns.2022.120540

Glutamic acid decarboxylase antibody-associated neurological syndromes: Clinical and antibody characteristics and therapy response

J Neurol Sci. 2023 Feb 15:445:120540. doi: 10.1016/j.jns.2022.120540. Epub 2022 Dec 29.

Authors

Marie Madlener¹, Christine Strippel², Franziska S Thaler³, Kathrin Doppler⁴, Klaus P Wandinger⁵, Jan Lewerenz⁶, Marius Ringelstein⁷, Rosa Roessling⁸, Til Menge⁹, Jonathan Wickel¹⁰, Christoph Kellingshaus¹¹, Sigrid Mues¹², Andrea Kraft¹³, Andreas Linsa¹⁴, Simone C Tauber¹⁵, Florian Then Berg¹⁶, Stefan T Gerner¹⁷, Asterios Paliantonis¹⁸, Alexander Finke¹⁹, Josef Priller²⁰, Ingo Schirotzek²¹, Marie Süße²², Kurt W Sühs²³, Christian Urbanek²⁴, Makbule Senel⁶, Claudia Sommer⁴, Tania Kuempfel³, Harald Pruess⁸, Gereon R Fink²⁵, Frank Leypoldt²⁶, Nico Melzer²⁷, Michael P Malter²⁸; German Network for Research on Autoimmune Encephalitis (GENERATE)

Affiliations

¹ Department of Neurology, University of Cologne, Faculty of Medicine and University Hospital Cologne, Kerpener Str. 62, Cologne 50937, Germany. Electronic address: marie.madlener@uk-koeln.de.
² Department of Neurology with Institute of Translational Neurology, University Hospital Muenster, Albert-Schweitzer-Campus 1, Muenster 48149, Germany.
³ Institute of Clinical Neuroimmunology, University Hospital and Biomedical Center, Ludwig-Maximilians University Munich, Marchioninistrasse 15, Munich 81377, Germany.
⁴ Department of Neurology, University of Wuerzburg, Josef-Schneider-Straße 2, Würzburg 97080, Germany.
⁵ Institute of Clinical Chemistry, University Hospital Schleswig-Holstein, Campus Luebeck, Ratzeburger Allee 160, Luebeck 23538, Germany.
⁶ Department of Neurology, Ulm University, Albert-Einstein-Allee 23, Ulm 89081, Germany.
⁷ Department of Neurology, Medical Faculty, Heinrich-Heine-University Duesseldorf, Moorenstraße 5, Duesseldorf 40225, Germany; Department of Neurology, Center for Neurology and Neuropsychiatry, LVR-Klinikum, Heinrich-Heine-University Duesseldorf, Bergische Landstraße 2, Duesseldorf 40629, Germany.
⁸ Department of Neurology and Experimental Neurology, Charité-Universitaetsmedizin Berlin, German Center for Neurodegenerative Diseases (DZNE) Berlin, Charitéplatz 1, Berlin 10117, Germany.
⁹ Department of Neurology, Center for Neurology and Neuropsychiatry, LVR-Klinikum, Heinrich-Heine-University Duesseldorf, Bergische Landstraße 2, Duesseldorf 40629, Germany.
¹⁰ Section Translational Neuroimmunology, Department of Neurology, University Hospital Jena, Am Klinikum1, Jena 07747, Germany.
¹¹ Department of Neurology, Klinikum Osnabrueck, Am Finkenhügel 1, Osnabrueck 49076, Germany.
¹² Department of Neurology, University Hospital, Technische Universitaet Dresden, Fetscherstraße 74, Dresden 01307, Germany.
¹³ Department of Neurology, Martha-Maria Hospital Halle, Röntgenstraße 1, Halle (Saale) 06120, Germany.
¹⁴ Department of Neurology, Carl-Thiem Klinikum Cottbus, Thiemstraße 111, Cottbus 03048, Germany.
¹⁵ Department of Neurology, RWTH Aachen University, Templergraben 55, Aachen 52062, Germany.
¹⁶ Department of Neurology, University of Leipzig, Liebigstraße 20, Leipzig 04103, Germany.
¹⁷ Department of Neurology, University Hospital Erlangen, Maximiliansplatz 2, Erlangen 91054, Germany.
¹⁸ Department of Neurology, Alfried Krupp Krankenhaus Essen, Alfried-Krupp-Straße 21, Essen 45131, Germany.
¹⁹ Department of Neurology, Hospital Lueneburg, Bögelstraße 1, Lueneburg 21339, Germany.
²⁰ Department of Neuropsychiatry and Laboratory of Molecular Psychiatry, Charité-Universitaetsmedizin Berlin, Charitéplatz 1, Berlin 10117, Germany.
²¹ Department of Neurology, University Hospital Giessen and Marburg, Rudolf-Buchheim-Straße 8, Giessen 35392, Germany; Department of Neurology and Neurointensive Care, Klinikum Darmstadt, Grafenstraße 9, Darmstadt 64283, Germany.
²² Department of Neurology, University Medicine Greifswald, Fleischmannstraße 8, Greifswald 17475, Germany.
²³ Department of Neurology, University Hospital Hannover, Carl-Neuberg-Straße 1, Hannover 30625, Germany.
²⁴ Department of Neurology, Hospital Ludwigshafen, Bremserstraße 79, Ludwigshafen am Rhein 67063, Germany.
²⁵ Department of Neurology, University of Cologne, Faculty of Medicine and University Hospital Cologne, Kerpener Str. 62, Cologne 50937, Germany; Cognitive Neuroscience, Institute of Neuroscience and Medicine (INM-3), Research Center Juelich, Wilhelm-Johnen-Straße, Juelich 52428, Germany.
²⁶ Institute of Clinical Chemistry and Department of Neurology, University Kiel and University Hospital Schleswig-Holstein, Arnold-Heller-Straße 3, Kiel 24105, Germany.
²⁷ Department of Neurology with Institute of Translational Neurology, University Hospital Muenster, Albert-Schweitzer-Campus 1, Muenster 48149, Germany; Department of Neurology, Medical Faculty, Heinrich-Heine-University Duesseldorf, Moorenstraße 5, Duesseldorf 40225, Germany.
²⁸ Department of Neurology, University of Cologne, Faculty of Medicine and University Hospital Cologne, Kerpener Str. 62, Cologne 50937, Germany.

PMID: 36608627
DOI: 10.1016/j.jns.2022.120540

Abstract

Background: Antibodies against glutamic acid decarboxylase (GAD-abs) at high serum levels are associated with diverse autoimmune neurological syndromes (AINS), including cerebellar ataxia, epilepsy, limbic encephalitis and stiff-person syndrome. The impact of low serum GAD-ab levels in patients with suspected AINS remains controversial. Specific intrathecal GAD-ab synthesis may serve as a marker for GAD-ab-associated nervous system autoimmunity. We present characteristics of a multicentric patient cohort with suspected AINS associated with GAD antibodies (SAINS-GAD+) and explore the relevance of serum GAD-ab levels and intrathecal GAD-ab synthesis.

Methods: All patients with SAINS-GAD+ included in the registry of the German Network for Research on Autoimmune Encephalitis (GENERATE) from 2011 to 2019 were analyzed. High serum GAD-ab levels were defined as RIA>2000 U/mL, ELISA>1000 U/mL, or as a positive staining pattern on cell-based assays.

Results: One-hundred-one patients were analyzed. In descending order they presented with epilepsy/limbic encephalitis (39%), cerebellar ataxia (28%), stiff person syndrome (22%), and overlap syndrome (12%). Immunotherapy was administered in 89% of cases with improvements in 46%. 35% of SAINS-GAD+ patients had low GAD-ab serum levels. Notably, unmatched oligoclonal bands in CSF but not in serum were more frequent in patients with low GAD-ab serum levels. GAD-ab-levels (high/low) and intrathecal GAD-ab synthesis (present or not) did not impact clinical characteristics and outcome.

Conclusions: Overall, immunotherapy in SAINS-GAD+ was moderately effective. Serum GAD-ab levels and the absence or presence of intrathecal GAD-ab synthesis did not predict clinical characteristics or outcomes in SAINS-GAD+. The detection of unmatched oligoclonal bands might outweigh low GAD-ab serum levels.

Keywords: Autoantibodies; Autoimmune encephalitis; GAD; GENERATE; Glutamic acid decarboxylase.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Autoantibodies
Cerebellar Ataxia* / drug therapy
Glutamate Decarboxylase
Humans
Limbic Encephalitis* / therapy
Oligoclonal Bands
Stiff-Person Syndrome* / therapy

Substances

Glutamate Decarboxylase
Autoantibodies
Oligoclonal Bands