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 and EPTP 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.

中文翻译：

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外周源性 LGI1 反应性单克隆抗体在体内引起癫痫发作

富含亮氨酸灭活胶质瘤 1 (LGI1) 自身抗体的患者的一个显着临床特征是非常频繁的局灶性癫痫发作症状，除了健忘症之外，还包括面臂肌张力障碍性癫痫发作 (FBDS)。多克隆血清 IgG 已成功模拟体内认知变化，但不能模拟癫痫发作。因此，目前尚不清楚 LGI1 自身抗体是否足以引起癫痫发作。我们使用源自患者循环 B 细胞的针对 LGI1 的分子精确单克隆抗体 (LGI1-mAb) 对此进行了测试。这些药物针对 LGI1、LRR 和 EPTP 的两个主要结构域，并使用渗透泵在 7 天的时间内将其注入幼年雄性 Wistar 大鼠的脑室内。通过放置在海马 CA3 中的深度电极记录连续无线脑电图，并进行记忆和过度兴奋行为测试。输注完成后（第 9 天），研究死后脑切片的抗体结合和对 Kv1.1 的影响。 LGI1-mAb 在海马 CA3 区域结合最强，并导致该亚区 Kv1.1 簇数量显着减少。与注射对照抗体的大鼠相比，9 天的视频脑电图分析显示，注射 LGI1-mAb 的大鼠出现惊厥和非惊厥癫痫发作活动，并伴有大量发作事件。在新奇物体识别测试中，记忆没有受到损害。将外周来源的人 LGI1-mAb 注入啮齿动物 CSF 中，提供了直接体内癫痫发生与分子相关性的有力证据。这些发现符合 LGI1 抗体在癫痫发作原因中的标准。