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

Upadhya, M.; Kirmann, T.; Wilson, M.; Simon, C. M.; Dhangar, D.; Geis, C.; Williams, R.; Woodhall, G.; Hallermann, S.; Irani, S.; Wright, S.

doi:10.1101/2023.10.11.561725

bioRxiv · 10.1101/2023.10.11.561725

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

Upadhya, M.·Kirmann, T.·Wilson, M.·Simon, C. M.·Dhangar, D.·Geis, C.·Williams, R.·Woodhall, G.·Hallermann, S.·Irani, S.·Wright, S.

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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-mAbs), derived from patient circulating B cells. These were directed towards both major domains of LGI1, LRR (n=5) and EPTP (n=5) 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 using electrophysiology and immunostaining. By comparison to control-mAb injected rats (n=6), 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 (245{+/-}83 vs. 7.8{+/-}7.8 in controls; p=0.002). Memory was not impaired in the novel object recognition test. Local field potential recordings from postmortem brain slices showed spontaneous ictal-like spike activity in the CA3 region (p=0.03). The LGI1-mAbs bound most strongly in the hippocampal CA3 region and induced a significant reduction in Kv1.1 cluster number in this subfield (6 controls; 7 LGI1-mAbs; p=0.01) 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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Upadhya, M., Kirmann, T., Wilson, M., Simon, C. M., Dhangar, D., Geis, C., Williams, R., Woodhall, G., Hallermann, S., Irani, S., Wright, S.. 2023-10-16. Peripherally derived LGI1-reactive monoclonal antibodies cause epileptic seizures in vivo. https://doi.org/10.1101/2023.10.11.561725

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