{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T00:55:15Z","timestamp":1791334515518,"version":"4.3.1"},"reference-count":30,"publisher":"Oxford University Press (OUP)","issue":"8","license":[{"start":{"date-parts":[[2024,4,25]],"date-time":"2024-04-25T00:00:00Z","timestamp":1714003200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,8,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>One striking clinical hallmark in patients with autoantibodies to leucine-rich glioma inactivated 1 (LGI1) is the very frequent focal seizure semiologies, including faciobrachial dystonic seizures (FBDS), in addition to the amnesia. Polyclonal serum IgGs have successfully modelled the cognitive changes in vivo but not seizures. Hence, it remains unclear whether LGI1-autoantibodies are sufficient to cause seizures.<\/jats:p>\n                  <jats:p>We tested this with the molecularly precise monoclonal antibodies directed against LGI1 [LGI1-monoclonal antibodies (mAbs)], derived from patient circulating B cells. These were directed towards both major domains of LGI1, leucine-rich repeat and epitempin repeat, and infused intracerebroventricularly over 7 days into juvenile male Wistar rats using osmotic pumps. Continuous wireless EEG was recorded from a depth electrode placed in hippocampal CA3 plus behavioural tests for memory and hyperexcitability were performed. Following infusion completion (Day 9), post-mortem brain slices were studied for antibody binding and effects on Kv1.1.<\/jats:p>\n                  <jats:p>The LGI1-mAbs bound most strongly in the hippocampal CA3 region and induced a significant reduction in Kv1.1 cluster number in this subfield. By comparison to control-Ab injected rats video-EEG analysis over 9 days revealed convulsive and non-convulsive seizure activity in rats infused with LGI1-mAbs, with a significant number of ictal events. Memory was not impaired in the novel object recognition test.<\/jats:p>\n                  <jats:p>Peripherally-derived human LGI1-mAbs infused into rodent CSF provide strong evidence of direct in vivo epileptogenesis with molecular correlations. These findings fulfill criteria for LGI1-antibodies in seizure causation.<\/jats:p>","DOI":"10.1093\/brain\/awae129","type":"journal-article","created":{"date-parts":[[2024,4,23]],"date-time":"2024-04-23T07:32:02Z","timestamp":1713857522000},"page":"2636-2642","source":"Crossref","is-referenced-by-count":24,"title":["Peripherally-derived LGI1-reactive monoclonal antibodies cause epileptic seizures\n                    <i>in vivo<\/i>"],"prefix":"10.1093","volume":"147","author":[{"given":"Manoj","family":"Upadhya","sequence":"first","affiliation":[{"name":"Institute of Health and Neurodevelopment, School of Health and Life Sciences, Aston University , Birmingham, B4 7ET , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toni","family":"Kirmann","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Carl-Ludwig-Institute of Physiology, Leipzig University , Leipzig 04103 , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3317-9433","authenticated-orcid":false,"given":"Max A","family":"Wilson","sequence":"additional","affiliation":[{"name":"Institute of Health and Neurodevelopment, School of Health and Life Sciences, Aston University , Birmingham, B4 7ET , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian M","family":"Simon","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Carl-Ludwig-Institute of Physiology, Leipzig University , Leipzig 04103 , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Divya","family":"Dhangar","sequence":"additional","affiliation":[{"name":"Institute of Health and Neurodevelopment, School of Health and Life Sciences, Aston University , Birmingham, B4 7ET , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Geis","sequence":"additional","affiliation":[{"name":"Department of Neurology, Section Translational Neuroimmunology, Jena University Hospital , Jena 07747 , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robyn","family":"Williams","sequence":"additional","affiliation":[{"name":"Oxford Autoimmune Neurology Group, Nuffield Department of Clinical Neurosciences, University of Oxford , Oxford, OX3 9DU , UK"},{"name":"Departments of Neurology and Neuroscience, Mayo Clinic , Jacksonville, FL 32224 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1281-9008","authenticated-orcid":false,"given":"Gavin","family":"Woodhall","sequence":"additional","affiliation":[{"name":"Institute of Health and Neurodevelopment, School of Health and Life Sciences, Aston University , Birmingham, B4 7ET , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefan","family":"Hallermann","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Carl-Ludwig-Institute of Physiology, Leipzig University , Leipzig 04103 , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7667-9748","authenticated-orcid":false,"given":"Sarosh R","family":"Irani","sequence":"additional","affiliation":[{"name":"Oxford Autoimmune Neurology Group, Nuffield Department of Clinical Neurosciences, University of Oxford , Oxford, OX3 9DU , UK"},{"name":"Departments of Neurology and Neuroscience, Mayo Clinic , Jacksonville, FL 32224 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5464-3779","authenticated-orcid":false,"given":"Sukhvir K","family":"Wright","sequence":"additional","affiliation":[{"name":"Institute of Health and Neurodevelopment, School of Health and Life Sciences, Aston University , Birmingham, B4 7ET , UK"},{"name":"Department of Neurology, Birmingham Women\u2019s and Children\u2019s Hospital NHS Trust , Birmingham, B4 6NH , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2024,4,25]]},"reference":[{"key":"2024080113024431400_awae129-B1","doi-asserted-by":"crossref","first-page":"2734","DOI":"10.1093\/brain\/awq213","article-title":"Antibodies to kv1 potassium channel-complex proteins leucine-rich, glioma inactivated 1 protein and contactin-associated protein-2 in limbic encephalitis, Morvan\u2019s syndrome and acquired neuromyotonia","volume":"133","author":"Irani","year":"2010","journal-title":"Brain"},{"key":"2024080113024431400_awae129-B2","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1016\/j.seizure.2017.05.017","article-title":"LGI1-antibody encephalitis is characterised by frequent, multifocal clinical and subclinical seizures","volume":"50","author":"Aurangzeb","year":"2017","journal-title":"Seizure"},{"key":"2024080113024431400_awae129-B3","doi-asserted-by":"crossref","first-page":"892","DOI":"10.1002\/ana.22307","article-title":"Faciobrachial dystonic seizures precede lgi1 antibody limbic encephalitis","volume":"69","author":"Irani","year":"2011","journal-title":"Ann Neurol"},{"key":"2024080113024431400_awae129-B4","doi-asserted-by":"crossref","first-page":"348","DOI":"10.1093\/brain\/awx323","article-title":"The importance of early immunotherapy in patients with faciobrachial dystonic seizures","volume":"141","author":"Thompson","year":"2018","journal-title":"Brain"},{"key":"2024080113024431400_awae129-B5","doi-asserted-by":"crossref","first-page":"1212","DOI":"10.1093\/brain\/awx070","article-title":"Focal CA3 hippocampal subfield atrophy following LGI1 VGKC-complex antibody limbic encephalitis","volume":"140","author":"Miller","year":"2017","journal-title":"Brain"},{"key":"2024080113024431400_awae129-B6","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1016\/j.yebeh.2018.08.019","article-title":"Clinical and electrographic characteristics of seizures in LGI1-antibody encephalitis","volume":"88","author":"Li","year":"2018","journal-title":"Epilepsy Behav"},{"key":"2024080113024431400_awae129-B7","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1016\/j.seizure.2018.06.021","article-title":"Electroclinical features of seizures associated with autoimmune encephalitis","volume":"60","author":"Steriade","year":"2018","journal-title":"Seizure"},{"issue":"Pt 4","key":"2024080113024431400_awae129-B8","doi-asserted-by":"crossref","first-page":"1079","DOI":"10.1093\/brain\/aww012","article-title":"Motor cortex and hippocampus are the two main cortical targets in LGI1-antibody encephalitis","volume":"139","author":"Navarro","year":"2016","journal-title":"Brain"},{"key":"2024080113024431400_awae129-B9","doi-asserted-by":"crossref","first-page":"e155","DOI":"10.1111\/epi.13436","article-title":"Subclinical temporal EEG seizure pattern in LGI1-antibody-mediated encephalitis","volume":"57","author":"Steriade","year":"2016","journal-title":"Epilepsia"},{"key":"2024080113024431400_awae129-B10","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1002\/ana.25666","article-title":"Human cerebrospinal fluid monoclonal LGI1 autoantibodies increase neuronal excitability","volume":"87","author":"Kornau","year":"2020","journal-title":"Ann Neurol"},{"key":"2024080113024431400_awae129-B11","doi-asserted-by":"crossref","first-page":"18161","DOI":"10.1523\/JNEUROSCI.3506-13.2013","article-title":"Autoantibodies to epilepsy-related LGI1 in limbic encephalitis neutralize LGI1-ADAM22 interaction and reduce synaptic AMPA receptors","volume":"33","author":"Ohkawa","year":"2013","journal-title":"J Neurosci"},{"key":"2024080113024431400_awae129-B12","doi-asserted-by":"crossref","DOI":"10.1523\/ENEURO.0267-22.2023","article-title":"In vivo injection of anti-LGI1 antibodies into the rodent M1 Cortex and hippocampus is ineffective in inducing seizures","volume":"10","author":"Baudin","year":"2023","journal-title":"eNeuro"},{"key":"2024080113024431400_awae129-B13","first-page":"3144","article-title":"LGI1 antibodies alter kv1.1 and AMPA receptors changing synaptic excitability, plasticity and memory","volume":"141","author":"Petit-Pedrol","year":"2018","journal-title":"Brain"},{"key":"2024080113024431400_awae129-B14","doi-asserted-by":"crossref","first-page":"1731","DOI":"10.1093\/brain\/awaa104","article-title":"Distinctive binding properties of human monoclonal LGI1 autoantibodies determine pathogenic mechanisms","volume":"143","author":"Ramberger","year":"2020","journal-title":"Brain"},{"key":"2024080113024431400_awae129-B15","doi-asserted-by":"crossref","first-page":"1106","DOI":"10.1038\/s42003-021-02635-8","article-title":"Multimodal electrophysiological analyses reveal that reduced synaptic excitatory neurotransmission underlies seizures in a model of NMDAR antibody-mediated encephalitis","volume":"4","author":"Wright","year":"2021","journal-title":"Commun Biol"},{"key":"2024080113024431400_awae129-B16","first-page":"e20210012","article-title":"Encephalitis patient-derived monoclonal GABAA receptor antibodies cause epileptic seizures","volume":"218","author":"Kreye","year":"2021","journal-title":"J Exp Med"},{"issue":"Pt 11","key":"2024080113024431400_awae129-B17","doi-asserted-by":"crossref","first-page":"3159","DOI":"10.1093\/brain\/awv257","article-title":"Epileptogenic effects of NMDAR antibodies in a passive transfer mouse model","volume":"138","author":"Wright","year":"2015","journal-title":"Brain"},{"key":"2024080113024431400_awae129-B18","doi-asserted-by":"crossref","first-page":"e0147265","DOI":"10.1371\/journal.pone.0147265","article-title":"A low mortality, high morbidity reduced intensity Status epilepticus (RISE) model of epilepsy and epileptogenesis in the rat","volume":"11","author":"Modebadze","year":"2016","journal-title":"PLoS One"},{"key":"2024080113024431400_awae129-B19","doi-asserted-by":"crossref","first-page":"107462","DOI":"10.1016\/j.yebeh.2020.107462","article-title":"Electroencephalographic findings in antileucine-rich glioma-inactivated 1 (LGI1) autoimmune encephalitis: A systematic review","volume":"112","author":"Roberto","year":"2020","journal-title":"Epilepsy Behav"},{"key":"2024080113024431400_awae129-B20","doi-asserted-by":"crossref","first-page":"426","DOI":"10.1016\/0167-5699(93)90244-F","article-title":"Defining criteria for autoimmune diseases (witebsky\u2019s postulates revisited)","volume":"14","author":"Rose","year":"1993","journal-title":"Immunol Today"},{"key":"2024080113024431400_awae129-B21","doi-asserted-by":"crossref","first-page":"831","DOI":"10.4103\/aian.aian_626_23","article-title":"LGI1 encephalitis: Autoimmune epilepsy or movement disorder","volume":"26","author":"Jagtap","year":"2023","journal-title":"Ann Indian Acad Neurol"},{"key":"2024080113024431400_awae129-B22","doi-asserted-by":"crossref","first-page":"1792","DOI":"10.1126\/science.1129947","article-title":"Epilepsy-related ligand\/receptor complex LGI1 and ADAM22 regulate synaptic transmission","volume":"313","author":"Fukata","year":"2006","journal-title":"Science"},{"key":"2024080113024431400_awae129-B23","doi-asserted-by":"crossref","first-page":"e200096","DOI":"10.1212\/NXI.0000000000200096","article-title":"Comparative effects of domain-specific human monoclonal antibodies against LGI1 on neuronal excitability","volume":"10","author":"Sell","year":"2023","journal-title":"Neurol Neuroimmunol Neuroinflamm"},{"key":"2024080113024431400_awae129-B24","doi-asserted-by":"crossref","first-page":"E9916","DOI":"10.1073\/pnas.1804846115","article-title":"NMDA-receptor antibodies alter cortical microcircuit dynamics","volume":"115","author":"Rosch","year":"2018","journal-title":"Proc Natl Acad Sci U S A"},{"key":"2024080113024431400_awae129-B25","doi-asserted-by":"crossref","first-page":"1449","DOI":"10.1212\/WNL.0000000000003173","article-title":"Anti-LGI1 encephalitis: Clinical syndrome and long-term follow-up","volume":"87","author":"van Sonderen","year":"2016","journal-title":"Neurology"},{"key":"2024080113024431400_awae129-B26","doi-asserted-by":"crossref","first-page":"551","DOI":"10.1006\/exnr.1998.6948","article-title":"Differences in kindling development in seven outbred and inbred rat strains","volume":"154","author":"Loscher","year":"1998","journal-title":"Exp Neurol"},{"key":"2024080113024431400_awae129-B27","doi-asserted-by":"crossref","first-page":"697","DOI":"10.1016\/j.neuron.2006.01.033","article-title":"The epilepsy-linked lgi1 protein assembles into presynaptic kv1 channels and inhibits inactivation by kv\u03b21","volume":"49","author":"Schulte","year":"2006","journal-title":"Neuron"},{"key":"2024080113024431400_awae129-B28","doi-asserted-by":"crossref","first-page":"2836","DOI":"10.1111\/epi.16736","article-title":"LGI1 downregulation increases neuronal circuit excitability","volume":"61","author":"Lugar\u00e0","year":"2020","journal-title":"Epilepsia"},{"key":"2024080113024431400_awae129-B29","doi-asserted-by":"crossref","first-page":"102262","DOI":"10.1016\/j.pneurobio.2022.102262","article-title":"Kv1.1 channels inhibition in the rat motor cortex recapitulates seizures associated with anti-LGI1 encephalitis","volume":"213","author":"Baudin","year":"2022","journal-title":"Prog Neurobiol"},{"key":"2024080113024431400_awae129-B30","doi-asserted-by":"crossref","first-page":"e2","DOI":"10.1136\/jnnp-2022-abn2.111","article-title":"067 One Health: Clinical characteristics of spontaneously-arising feline LGI1- autoantibody limbic encephalitis in a large international cohort","volume":"93","author":"Binks","year":"2022","journal-title":"J Neurol Neurosurg Psychiatry."}],"container-title":["Brain"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/brain\/advance-article-pdf\/doi\/10.1093\/brain\/awae129\/58476579\/awae129.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/brain\/article-pdf\/147\/8\/2636\/58712451\/awae129.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/brain\/article-pdf\/147\/8\/2636\/58712451\/awae129.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,8,1]],"date-time":"2024-08-01T17:44:24Z","timestamp":1722534264000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/brain\/article\/147\/8\/2636\/7658324"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,4,25]]},"references-count":30,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2024,4,25]]},"published-print":{"date-parts":[[2024,8,1]]}},"URL":"https:\/\/doi.org\/10.1093\/brain\/awae129","relation":{},"ISSN":["0006-8950","1460-2156"],"issn-type":[{"value":"0006-8950","type":"print"},{"value":"1460-2156","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2024,8]]},"published":{"date-parts":[[2024,4,25]]}}}