Peripherally-derived LGI1-reactive monoclonal antibodies cause epileptic seizures in vivo

Manoj Upadhya; Toni Kirmann; Max A. Wilson; Christian M. Simon; Divya Dhangar; Christian Geis; Robyn Williams; Gavin Woodhall; Stefan Hallermann; Sarosh R. Irani; Sukhvir K. Wright

doi:10.1093/brain/awae129

Peripherally-derived LGI1-reactive monoclonal antibodies cause epileptic seizures in vivo

Manoj Upadhya
, Toni Kirmann
, Max A. Wilson
, Christian M. Simon
, Divya Dhangar
, Christian Geis
, Robyn Williams
, Gavin Woodhall
, Stefan Hallermann
, Sarosh R. Irani
, Sukhvir K. Wright

Faculty of Medicine, Carl-Ludwig-Institute of Physiology, Leipzig University , Leipzig 04103 , Germany
Department of Neurology, Section Translational Neuroimmunology, Jena University Hospital , Jena 07747 , Germany
Departments of Neurology and Neuroscience, Mayo Clinic , Jacksonville, Florida 32224 , USA

Research output: Contribution to journal › Article › peer-review

15 Citations (Scopus)

22 Downloads (Pure)

Abstract

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. 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. 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. 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.

Original language	English
Pages (from-to)	2636-2642
Number of pages	7
Journal	Brain
Volume	147
Issue number	8
Early online date	25 Apr 2024
DOIs	https://doi.org/10.1093/brain/awae129
Publication status	Published - 1 Aug 2024

Bibliographical note

Copyright © The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.

Data Access Statement

Data are available on request

Funding

This was supported by a Wellcome Trust Fellowship [216613/Z/19/Z] to S.K.W; a senior clinical fellowship from the Medical Research Council [MR/V007173/1] and Wellcome Trust Fellowship [104079/Z/14/Z] to S.R.I., the German Research Foundation [FOR3004 SYNABS, HA6386/9-2, HA6386/10-2 to S.H. and GE2519/8-1 and GE2519/9-1 to C.G.] and the European Research Council [ERC CoG 865634] to S.H., the Schilling Foundation to C.G., the German Research Foundation (SI-1969/2-1, SI-1969/3-1) and SMA Europe to C.M.S., 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.

Funders	Funder number
National Institute for Health and Care Research
SMA Europe
European Research Council
Wellcome Trust	216613/Z/19/Z
Wellcome Trust
Medical Research Council	MR/V007173/1, 104079/Z/14/Z
Medical Research Council
ERC	865634
Hermann und Lilly Schilling-Stiftung für Medizinische Forschung	SI-1969/3-1, SI-1969/2-1
Hermann und Lilly Schilling-Stiftung für Medizinische Forschung
German Research Foundation	FOR3004, HA6386/9–2, GE2519/8-1, GE2519/9-1, HA6386/10-2

Keywords

LGI1-Ab encephalitis
autoimmune-associated epilepsy
faciobrachial dystonic seizures (FBDS)
k 1 1
seizures

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10.1093/brain/awae129Licence: CC BY 4.0

M Upadhya et al_Peripherally-derived LGI1-reactive monoclonal antibodies cause epileptic seizures in vivo
Copyright © The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
Final published version, 709 KBLicence: CC BY 4.0

Cite this

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title = "Peripherally-derived LGI1-reactive monoclonal antibodies cause epileptic seizures in vivo",

abstract = "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. 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. 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. 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.",

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note = "Copyright {\textcopyright} The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.",

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AU - Upadhya, Manoj

AU - Kirmann, Toni

AU - Wilson, Max A.

AU - Simon, Christian M.

AU - Dhangar, Divya

AU - Geis, Christian

AU - Williams, Robyn

AU - Woodhall, Gavin

AU - Hallermann, Stefan

AU - Irani, Sarosh R.

AU - Wright, Sukhvir K.

N1 - Copyright © The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.

PY - 2024/8/1

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N2 - 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. 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. 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. 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.

AB - 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. 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. 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. 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.

KW - LGI1-Ab encephalitis

KW - autoimmune-associated epilepsy

KW - faciobrachial dystonic seizures (FBDS)

KW - k 1 1

KW - seizures

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DO - 10.1093/brain/awae129

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SN - 1460-2156

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JO - Brain

JF - Brain

IS - 8

ER -

Peripherally-derived LGI1-reactive monoclonal antibodies cause epileptic seizures in vivo

Abstract

Bibliographical note

Data Access Statement

Funding

Keywords

Access to Document

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