{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T14:47:40Z","timestamp":1789138060556,"version":"build-2803163510"},"reference-count":68,"publisher":"Oxford University Press (OUP)","issue":"4","license":[{"start":{"date-parts":[[2022,10,31]],"date-time":"2022-10-31T00:00:00Z","timestamp":1667174400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Austrian Science Fund","award":["P 26936-B27"],"award-info":[{"award-number":["P 26936-B27"]}]},{"name":"Austrian Science Fund","award":["P 34864-B"],"award-info":[{"award-number":["P 34864-B"]}]},{"name":"Austrian Science Fund","award":["DOC 33-B27"],"award-info":[{"award-number":["DOC 33-B27"]}]},{"name":"Austrian Science Fund","award":["I4685-B SYNABS"],"award-info":[{"award-number":["I4685-B SYNABS"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,4,19]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Temporal lobe epilepsy (TLE) is one of the syndromes linked to antibodies against glutamic acid decarboxylase (GAD). It has been questioned whether \u2018limbic encephalitis with GAD antibodies\u2019 is a meaningful diagnostic entity. The immunopathogenesis of GAD-TLE has remained enigmatic. Improvement of immunological treatability is an urgent clinical concern.<\/jats:p>\n               <jats:p>We retrospectively assessed the clinical, MRI and CSF course as well as brain tissue of 15 adult patients with GAD-TLE who underwent temporal lobe surgery. Brain tissue was studied by means of immunohistochemistry, multiplex fluorescent microscopy and transcriptomic analysis for inflammatory mediators and neuronal degeneration.<\/jats:p>\n               <jats:p>In 10 patients, there was a period of mediotemporal swelling and T2 signal increase; in nine cases this occurred within the first 6 years after symptom onset. This resulted in unilateral or bilateral hippocampal sclerosis; three cases developed hippocampal sclerosis within the first 2 years. All CSF studies done within the first year (n = 6) revealed intrathecal synthesis of immunoglobulin G. Temporal lobe surgeries were done after a median disease duration of 9 years (range 3 weeks to 60 years). Only two patients became seizure-free. Brain parenchyma collected during surgery in the first 6 years revealed high numbers of plasma cells but no signs of antibody-mediated tissue damage. Even more dense was the infiltration by CD8+ cytotoxic T lymphocytes (CTLs) that were seen to locally proliferate. Further, a portion of these cells revealed an antigen-specific resident memory T cell phenotype. Finally, CTLs with cytotoxic granzyme B+ granules were also seen in microglial nodules and attached to neurons, suggesting a CTL-mediated destruction of these cells. With longer disease duration, the density of all lymphocytes decreased. Whole transcriptome analysis in early\/active cases (but not in late\/inactive stages) revealed \u2018T cell immunity\u2019 and \u2018Regulation of immune processes\u2019 as the largest overrepresented clusters. To a lesser extent, pathways associated with B cells and neuronal degeneration also showed increased representation.<\/jats:p>\n               <jats:p>Surgically treated patients with GAD-TLE go through an early active inflammatory, \u2018encephalitic\u2019 stage (\u22646 years) with CTL-mediated, antigen-driven neuronal loss and antibody-producing plasma cells but without signs of complement-mediated cell death. Subsequently, patients enter an apparently immunologically inactive or low-active stage with ongoing seizures, probably caused by the structural damage to the temporal lobe. \u2018Limbic encephalitis\u2019 with GAD antibodies should be subsumed under GAD-TLE. The early tissue damage explains why immunotherapy does not usually lead to freedom from seizures.<\/jats:p>","DOI":"10.1093\/brain\/awac404","type":"journal-article","created":{"date-parts":[[2022,10,31]],"date-time":"2022-10-31T08:27:36Z","timestamp":1667204856000},"page":"1436-1452","source":"Crossref","is-referenced-by-count":85,"title":["Temporal lobe epilepsy with GAD antibodies: neurons killed by T cells not by complement membrane attack complex"],"prefix":"10.1093","volume":"146","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3003-4677","authenticated-orcid":false,"given":"Anna R","family":"Tr\u00f6scher","sequence":"first","affiliation":[{"name":"Department of Neuroimmunology, Centre for Brain Research, Medical University of Vienna , Vienna , Austria"},{"name":"Department of Neurology I, Neuromed Campus, Kepler University Hospital , Linz , Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3339-0714","authenticated-orcid":false,"given":"Katharina M","family":"Mair","sequence":"additional","affiliation":[{"name":"Department of Neuroimmunology, Centre for Brain Research, Medical University of Vienna , Vienna , Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3173-2768","authenticated-orcid":false,"given":"Laia","family":"Verd\u00fa de Juan","sequence":"additional","affiliation":[{"name":"Department of Neuroimmunology, Centre for Brain Research, Medical University of Vienna , Vienna , Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ulrike","family":"K\u00f6ck","sequence":"additional","affiliation":[{"name":"Department of Neuroimmunology, Centre for Brain Research, Medical University of Vienna , Vienna , Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2389-1892","authenticated-orcid":false,"given":"Anja","family":"Steinmaurer","sequence":"additional","affiliation":[{"name":"Department of Neuroimmunology, Centre for Brain Research, Medical University of Vienna , Vienna , Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hartmut","family":"Baier","sequence":"additional","affiliation":[{"name":"Epilepsy Centre Bodensee , Ravensburg , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2661-3705","authenticated-orcid":false,"given":"Albert","family":"Becker","sequence":"additional","affiliation":[{"name":"Section for Translational Epilepsy Research Department of Neuropathology, University Hospital Bonn , Bonn , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8676-0788","authenticated-orcid":false,"given":"Ingmar","family":"Bl\u00fcmcke","sequence":"additional","affiliation":[{"name":"Department of Neuropathology, Universit\u00e4tsklinikum Erlangen , Erlangen , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Finzel","sequence":"additional","affiliation":[{"name":"Epilepsy Centre Kleinwachau , Radeberg , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9859-581X","authenticated-orcid":false,"given":"Christian","family":"Geis","sequence":"additional","affiliation":[{"name":"Section Translational Neuroimmunology, Department of Neurology, University Hospital Jena , Jena , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5769-1100","authenticated-orcid":false,"given":"Romana","family":"H\u00f6ftberger","sequence":"additional","affiliation":[{"name":"Division of Neuropathology and Neurochemistry, Department of Neurology, Medical University of Vienna , Vienna , Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6677-3124","authenticated-orcid":false,"given":"Christian","family":"Mawrin","sequence":"additional","affiliation":[{"name":"Department of Neuropathology, University Hospital Magdeburg , Magdeburg , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2164-7842","authenticated-orcid":false,"given":"Tim J","family":"von Oertzen","sequence":"additional","affiliation":[{"name":"Department of Neurology I, Neuromed Campus, Kepler University Hospital , Linz , Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6688-4916","authenticated-orcid":false,"given":"Julika","family":"Pitsch","sequence":"additional","affiliation":[{"name":"Department of Epileptology, University Hospital Bonn , Bonn , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3177-8582","authenticated-orcid":false,"given":"Rainer","family":"Surges","sequence":"additional","affiliation":[{"name":"Department of Epileptology, University Hospital Bonn , Bonn , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0556-9565","authenticated-orcid":false,"given":"Berthold","family":"Voges","sequence":"additional","affiliation":[{"name":"Hamburg Epilepsy Centre, Protestant Hospital Alsterdorf, Department of Neurology and Epileptology , Hamburg , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6750-2599","authenticated-orcid":false,"given":"Serge","family":"Weis","sequence":"additional","affiliation":[{"name":"Division of Neuropathology, Department of Pathology and Molecular Pathology, Neuromed Campus, Kepler University Hospital Linz , Linz , Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4938-7827","authenticated-orcid":false,"given":"Michael","family":"Winklehner","sequence":"additional","affiliation":[{"name":"Division of Neuropathology and Neurochemistry, Department of Neurology, Medical University of Vienna , Vienna , Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Friedrich","family":"Woermann","sequence":"additional","affiliation":[{"name":"Department of Neuroimmunology, Centre for Brain Research, Medical University of Vienna , Vienna , Austria"},{"name":"Epilepsy Centre Bodensee , 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