The effect of time‐of‐day and circadian phase on vulnerability to seizure‐induced death in two mouse models

Abstract

Key points Sudden unexpected death in epilepsy (SUDEP) is the leading cause of premature death in patients with refractory epilepsy. SUDEP typically occurs during the night, although the reason for this is unclear. We found that, in normally entrained mice, time‐of‐day alters vulnerability to seizure‐induced death. We found that, in free‐running mice, circadian phase alters the vulnerability to seizure‐induced death. These findings suggest that circadian rhythmicity may be responsible for the increased night‐time prevalence of SUDEP Abstract Sudden unexpected death in epilepsy (SUDEP) is the leading cause of epilepsy‐related death. SUDEP typically occurs during the night following a seizure. Many aspects of mammalian physiology are regulated by circadian rhythms in ways that might make seizures occuring during the night more dangerous. Using two mouse models of seizure‐induced death, we demonstrate that time‐of‐day and circadian rhythms alter vulnerability to seizure‐induced death. We exposed normally entrained DBA/1 mice to a potentially seizure‐inducing acoustic stimulus at different times of day and compared the characteristics and outcomes of the seizures. Time‐of‐day did not alter the probability of a seizure but it did alter the probability of seizure‐induced death. To determine whether circadian rhythms alter vulnerability to seizure‐induced death, we induced maximal electroshock seizures in free‐running C57BL/6J mice at different circadian time points at the same time as measuring breathing via whole body plethysmography. Circadian phase did not affect seizure severity but it did alter postictal respiratory outcomes and the probability of seizure‐induced death. By contrast to our expectations, in entrained and free‐running mice, vulnerability to seizure‐induced death was greatest during the night and subjective night, respectively. These findings suggest that circadian rhythmicity may be responsible for the increased night‐time prevalence of SUDEP and that the underlying mechanism is phase conserved between nocturnal and diurnal mammals. All of the seizures in the present study were induced during wakefulness, indicating that the effect of time point on vulnerability to seizure‐induced death was not the result of sleep. Understanding why SUDEP occurs more frequently during the night may inform future preventative countermeasures.

Elucidation of a proposed cardiorespiratory circadian rhythm impacting survival in SUDEP

“…In summary, the study by Purnell et al . (2021) offers supporting evidence for a proposed cardiorespiratory circadian rhythm impacting survival outcomes during nocturnal seizure events. The results clearly illustrate a greater susceptibility to nocturnal seizures and plethysmography illustrates that respiratory response differs throughout the day.…”

“…The strength of study by Purnell et al . (2021) lies in its impact on future mice models of epilepsy. The finding that non‐primed DBA/1 mice experience seizure‐induced death at a rate of 71.1% during the night‐time as a result of audiogenic stimulus has the potential to greatly impact the use of mice models in future studies of epilepsy.…”

And when I die … What time should I expect it?

“…In this issue of the The Journal of Physiology , Purnell et al . (2021) use two different mouse models of convulsive seizure activity with significant seizure‐associated mortality rates to show (i) additional strong evidence that these mouse models have relevance for SUDEP research; (ii) consistent variance in mortality rates as a function of the time of day; and (iii) a clear separation of circadian rhythm from sleep as the determinant of sudden death variance. Importantly, Purnell et al .…”

“…Importantly, Purnell et al . (2021) make a discussion point that the circadian wake/sleep cycle of the mouse is reversed from the human wake/sleep cycle, whereas circadian serotonin level variations, as one example, are not reversed. This points squarely at a brain state that impacts seizure intensity and/or its spread pattern to alter the cardiorespiratory impact of an individual seizure.…”

“…What is the practical utility of the results reported by Purnell et al . (2021)? First, the results help to increase clinical awareness of what to expect in a person with epilepsy and their risks of sudden death.…”