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.

Keywords: SUDEP; breathing; circadian; epilepsy; sleep.

Figure 1

Potential risk factors associated with seizures emerging from sleep vs. nocturnal seizures and how they may facilitate SUDEP by modulating epilepsy, seizures, and respiration as well as seizure-induced death itself.

Figure 2

Circadian and sleep state-dependent effects on ventilation. (A) 72-h traces of average minute ventilation (top), tidal volume (middle) and breathing frequency (bottom) in adult male rats housed under a 12:12 h light:dark cycle and receiving room air (21% O₂, balance N₂). Solid horizontal bars at the bottom indicate periods where lights were off. (B) 24-h trace of average minute ventilation in rats during wake, non-rapid eye movement (NREM) sleep, and rapid-eye movement (REM) sleep as indicated. All animals housed in a 12:12 h light:dark cycle. (A) Redrawn with permission from Seifert and Mortola (2002). (B) Redrawn with permission from Stephenson et al. (2001).

Figure 3

Circadian and sleep state-dependent effects on the hypercapnic ventilatory response (HCVR). (A) 48-h trace of circadian variations in HCVR in adult humans. (B) Sleep state-dependent differences in HCVR in adult males. (A) Redrawn with permission from Spengler et al. (2000). (B) Redrawn with permission from Bulow (1963).

Figure 4

Time-of-day and circadian probability of seizure-induced death in mouse models of epilepsy. Temporal distribution of spontaneous seizure-induced death in (C) SCN1A^R1407X/+ and (D) Kv1.1 knockout mice housed in a 12:12 h light:dark cycle. (A) Percentage of audiogenic seizures resulting in death in DBA/1 mice housed in a 12:12 h light:dark cycle. (B) Percentage of maximal electroshock (MES) seizures resulting in death in mice housed in constant darkness. Redrawn with permission from (C) Teran et al. (2019), (D) Moore et al. (2014), (A,B) Purnell et al. (2021b).