The role of sleep state and time of day in modulating breathing in epilepsy: implications for sudden unexpected death in epilepsy

Abstract

Sudden unexpected death in epilepsy (SUDEP) is the leading cause of death among patients with refractory epilepsy. While the exact etiology of SUDEP is unknown, mounting evidence implicates respiratory dysfunction as a precipitating factor in cases of seizure-induced death. Dysregulation of breathing can occur in epilepsy patients during and after seizures as well as interictally, with many epilepsy patients exhibiting sleep-disordered breathing (SDB), such as obstructive sleep apnea (OSA). The majority of SUDEP cases occur during the night, with the victim found prone in or near a bed. As breathing is modulated in both a time-of-day and sleep state-dependent manner, it is relevant to examine the added burden of nocturnal seizures on respiratory function. This review explores the current state of understanding of the relationship between respiratory function, sleep state and time of day, and epilepsy. We highlight sleep as a particularly vulnerable period for individuals with epilepsy and press that this topic warrants further investigation in order to develop therapeutic interventions to mitigate the risk of SUDEP.

Sudden unexpected death in epilepsy

“…In MORTEMUS, SUDEP followed a seizure that occurred during sleep in seven of the 10 patients for which there was sufficient data to determine sleep-wake state [48]. Animal studies demonstrate a differential role for sleep and wake in seizure-induced mortality and on effects of seizures on breathing, cardiac function and PGES [30,57,60,106,136 ▪ ,137,138], and progressive sleep dysregulation preceding death in certain genetic models for seizures and seizure-related death [137,139]. Death is more common during the night in several animal models including a model of Dravet Syndrome [63], Kcna1 knockout mice [140], audiogenic seizures in DBA/1 mice and MES-induced seizures in C57BL/6J mice [60].…”

Peri-ictal activation of dorsomedial dorsal raphe serotonin neurons reduces mortality associated with maximal electroshock seizures

“…Cardiorespiratory failure and impairment of arousal are implicated in SUDEP. 3 , 5 Seizures can provoke apnoeas, 6 which cause oxygen desaturation 7 and increase end-tidal CO 2 . 8 Tachycardia, 9 bradycardia 10 and cardiac arrythmias 10 are also provoked by seizures.…”