Noebels Jeffrey L.
Sudden unexpected death in epilepsy (SUDEP) is the most common cause of premature mortality among young adults with refractory seizures. A sharp increase in clinical and forensic awareness over the last decade has accelerated the search to identify predictive risk biomarkers, clarify underlying cellular mechanisms, and develop effective interventions. In monitored nocturnal cases, available evidence points to a consistent pattern of postictal bradycardia with rapid collapse of brainstem cardiorespiratory pacemaking within minutes following termination of a generalized tonic-clonic seizure. Single gene discovery leading to SUDEP phenotypes in humans and mouse models now promises to speed the validation of candidate SUDEP genetic biomarkers and pinpoint malignant cellular excitability defects. The diverse biology and shared expression in brainstem pathways delineate distinct survival trajectories and molecular targets to mitigate SUDEP risk. Conditional deletion models confirm that SUDEP is a neurogenic, not cardiogenic, event and that brainstem involvement is both necessary and sufficient. SUDEP gene mutations lower the threshold for spreading depolarization (SD), a slow, self-regenerative pathological wave that silences neurons in critical brainstem networks. SD can occur independently of seizures, but can also be tightly coupled to their co-occurrence, offering molecular insight into a latent excitability threshold mechanism, a “second hit” that can explain why only some tonic-clonic seizures are lethal. While the role of brainstem SD awaits human confirmation, gene mutations that lower SD threshold in mice are found in clinical populations with elevated SUDEP risk. More research on modulating brainstem SD threshold could lead to lifesaving interventions in individuals at risk.
癫痫猝死（SUDEP）是难治性癫痫的年轻成年人过早死亡的最常见原因。在过去十年中，临床和法医意识的急剧提高加速了对预测性风险生物标志物的寻找、对潜在细胞机制的阐明以及有效干预措施的开发。在夜间监测的病例中，现有证据表明，在全身强直阵挛性发作终止后的几分钟内，存在发作后心动过缓的一致模式，同时脑干心肺起搏功能迅速衰竭。在人类和小鼠模型中导致SUDEP表型的单基因发现，有望加快对候选SUDEP遗传生物标志物的验证，并确定恶性细胞兴奋性缺陷。脑干通路中多样的生物学特性和共享的表达描绘了不同的生存轨迹和分子靶点，以降低SUDEP风险。条件性基因敲除模型证实，SUDEP是一种神经源性而非心源性事件，且脑干受累既是必要的也是充分的。SUDEP基因突变降低了扩散性去极化（SD）的阈值，SD是一种缓慢的、自我再生的病理波，可使关键脑干网络中的神经元沉默。SD可独立于癫痫发作而发生，但也可与其同时发生紧密相关，这为潜在的兴奋性阈值机制提供了分子层面的见解，即一种“二次打击”，可以解释为什么只有一些强直阵挛性发作是致命的。虽然脑干SD的作用有待人类研究证实，但在SUDEP风险升高的临床人群中发现了降低小鼠SD阈值的基因突变。对调节脑干SD阈值的更多研究可能会为有风险的个体带来挽救生命的干预措施。
