Kreitlow Benjamin L, Novella-Maciel Ana T, Vázquez Ariana M Hernández, Buchanan Gordon F
Department of Neurology, University of Iowa Carver College of Medicine, Iowa City, IA, USA.
Iowa Neuroscience Institute, University of Iowa Carver College of Medicine, Iowa City, IA, USA.
J Physiol. 2025 Jun;603(12):3571-3587. doi: 10.1113/JP288697. Epub 2025 Jun 2.
Sudden unexpected death in epilepsy (SUDEP) is the most extreme consequence of epilepsy. SUDEP typically occurs at night. Because humans sleep at night, these nighttime deaths are often attributed to seizures arising from sleep. Nocturnal mice also experience more seizure-associated deaths during the nighttime. This could represent timing that is under circadian control. To examine this, male and female Scn1a mice, a model of the epileptic encephalopathy Dravet syndrome, in which patients experience spontaneous seizures that often result in death, were housed in constant darkness and the timing of seizure associated death was assessed. We found that the timing of sudden death following seizures persists in constant darkness and peaks during the subjective nighttime. This circadian rhythm of death was independent of the timing of potentially fatal seizures and more frequently occurred while awake. Potentially fatal seizures resulted in prolonged unconsciousness, which also exhibited a circadian rhythm peaking during the subjective night. These findings provide support for circadian regulation, independent of seizure timing and sleep, in the nighttime risk of seizure-associated death. Nighttime seizures may increase risk of SUDEP via multiple mechanisms, as evident by peak spontaneous sudden death and profoundly impaired consciousness following seizures during the subjective night. KEY POINTS: Sudden unexpected death in epilepsy, or SUDEP, is a devastating outcome of intractable epilepsy. Converging lines of evidence indicate that there is a time-of-day preference for SUDEP, with more SUDEP occurring during the night. Several animal models of the epileptic encephalopathy Dravet syndrome (DS), including the one employed in our study, recapitulate key features of DS in patients, including a high rate of seizure-related death and more of the deaths occurring at night. Here, we removed light/dark photocycles, by housing animals in constant darkness, and identify nighttime preponderance of death, suggesting that this is under circadian regulation. We further carefully characterize fatal vs. non-fatal seizures in our animals and identify features that may prove to be useful biomarkers to predict which seizures may become fatal.
癫痫性猝死（SUDEP）是癫痫最严重的后果。SUDEP通常发生在夜间。由于人类在夜间睡眠，这些夜间死亡常被归因于睡眠中出现的癫痫发作。夜间的小鼠在夜间也会经历更多与癫痫发作相关的死亡。这可能代表了受昼夜节律控制的时间安排。为了对此进行研究，将雄性和雌性Scn1a小鼠（一种癫痫性脑病——德雷维特综合征的模型，该综合征患者会出现常导致死亡的自发性癫痫发作）饲养在持续黑暗的环境中，并评估与癫痫发作相关的死亡时间。我们发现，癫痫发作后猝死的时间在持续黑暗环境中依然存在，且在主观夜间达到峰值。这种死亡的昼夜节律独立于潜在致命性癫痫发作的时间，且更常发生在清醒时。潜在致命性癫痫发作会导致长时间昏迷，而昏迷也呈现出在主观夜间达到峰值的昼夜节律。这些发现为昼夜节律调节提供了支持，即在与癫痫发作相关的夜间死亡风险中，昼夜节律调节独立于癫痫发作时间和睡眠。夜间癫痫发作可能通过多种机制增加SUDEP的风险，主观夜间癫痫发作后出现的自发性猝死峰值以及意识严重受损就证明了这一点。要点：癫痫性猝死（SUDEP）是难治性癫痫的一个毁灭性后果。越来越多的证据表明，SUDEP存在一天中的特定时段偏好，夜间发生的SUDEP更多。癫痫性脑病德雷维特综合征（DS）的几种动物模型，包括我们研究中使用的模型，重现了DS患者的关键特征，包括癫痫发作相关的高死亡率以及更多在夜间发生的死亡。在这里，我们通过将动物饲养在持续黑暗环境中消除了光/暗光周期，并确定了死亡在夜间占优势，这表明这受昼夜节律调节。我们进一步仔细描述了动物中致命性与非致命性癫痫发作的特征，并确定了可能成为有用生物标志物的特征，以预测哪些癫痫发作可能会致命。
