Seizure-related death exhibits a circadian rhythm independent of seizure timing or sleep in a mouse model of Dravet syndrome.
Seizure-related deaths in Dravet syndrome mice peak at night due to circadian rhythms, not seizure timing or sleep, suggesting new angles for SUDEP risk research.
Where it sits
this study against the rest of the cartalax (aed peptide) corpusSummary and findings
The study investigated the circadian rhythm of seizure-related deaths in a mouse model of Dravet syndrome under constant darkness. It found that sudden death following seizures peaks during the subjective nighttime, independent of seizure timing or sleep. This suggests a circadian regulation of seizure-associated death risk.
Abstract
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<sup>R1407X/+</sup> 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.
Background
Sudden unexpected death in epilepsy (SUDEP) is a severe consequence of epilepsy, often occurring at night and attributed to seizures during sleep. This study addresses whether the timing of seizure-related deaths is influenced by circadian rhythms, independent of sleep or seizure timing. Understanding this could help identify risk factors and mechanisms underlying SUDEP.
Methods
The study used male and female Scn1aR1407X/+ mice, a model for Dravet syndrome, housed in constant darkness to assess the timing of seizure-associated deaths. The primary outcome was the timing of sudden death following seizures, with secondary outcomes including the duration of unconsciousness post-seizure.
Results
The primary finding was that sudden death following seizures peaks during the subjective nighttime, suggesting a circadian influence. This pattern persisted even in constant darkness, indicating that the timing of death is independent of seizure timing and sleep. Prolonged unconsciousness after seizures also exhibited a circadian rhythm, peaking at night.
Interpretation
The study suggests that circadian rhythms, rather than seizure timing or sleep, may regulate the risk of seizure-related death in Dravet syndrome. While statistically significant, the clinical relevance is uncertain due to the use of a mouse model. These findings may guide future research on SUDEP risk factors and prevention strategies.
Key findings
- Sudden death following seizures peaks during the subjective nighttime.
- Circadian rhythm of death persists in constant darkness.
- Prolonged unconsciousness after seizures also peaks during the subjective night.
- Nighttime seizures may increase SUDEP risk via multiple mechanisms.
- Study used male and female Scn1aR1407X/+ mice.
Limitations
- mouse model, not human data
- constant darkness conditions
- mechanistic insights may not translate to clinical practice
- no direct human SUDEP data