Dead in the Night: Sleep-Wake and Time-Of-Day Influences on Sudden Unexpected Death in Epilepsy

Abstract

Sudden unexpected death in epilepsy (SUDEP) is the leading cause of epilepsy-related death in patients with refractory epilepsy. Convergent lines of evidence suggest that SUDEP occurs due to seizure induced perturbation of respiratory, cardiac, and electrocerebral function as well as potential predisposing factors. It is consistently observed that SUDEP happens more during the night and the early hours of the morning. The aim of this review is to discuss evidence from patient cases, clinical studies, and animal research which is pertinent to the nocturnality of SUDEP. There are a number of factors which might contribute to the nighttime predilection of SUDEP. These factors fall into four categories: influences of (1) being unwitnessed, (2) lying prone in bed, (3) sleep-wake state, and (4) circadian rhythms. During the night, seizures are more likely to be unwitnessed; therefore, it is less likely that another person would be able to administer a lifesaving intervention. Patients are more likely to be prone on a bed following a nocturnal seizure. Being prone in the accouterments of a bed during the postictal period might impair breathing and increase SUDEP risk. Sleep typically happens at night and seizures which emerge from sleep might be more dangerous. Lastly, there are circadian changes to physiology during the night which might facilitate SUDEP. These possible explanations for the nocturnality of SUDEP are not mutually exclusive. The increased rate of SUDEP during the night is likely multifactorial involving both situational factors, such as being without a witness and prone, and physiological changes due to the influence of sleep and circadian rhythms. Understanding the causal elements in the nocturnality of SUDEP may be critical to the development of effective preventive countermeasures.

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

Figure 1

(A) Numbers of SUDEP cases in different vigilance states captured by EEG in the mortality in epilepsy monitoring units study (MORTEMUS: redrawn with permission from Ryvlin et al. (10). (B) numbers of sleep-related definite, possible, and probable SUDEP cases [redrawn with permission from Ali et al. (13)]; (C) numbers of witnessed and unwitnessed SUDEP cases in sleep and wakefulness [redrawn with permission from Lamberts et al. (12)]. (D) numbers of definite, possible, and probable SUDEP cases in sleep and wakefulness and in different body positions [redrawn with permission from Ali et al. (13)].

Figure 2

Temporal distribution of spontaneous seizure induced death in Kv1.1 knockout mice [redrawn with permission from Moore et al. (133)].

Figure 3

Quantification of seizure induced suppression of breathing (RR; respiratory rate, V_T; tidal volume, V_E; minute ventilation) following maximal electroshock seizures induced during wakefulness or non-rapid eye movement sleep (NREM) at different times of day [redrawn with permission from Purnell et al. (134)]. ^*P < 0.05.

Figure 4

(A) Double plotted day/night differences in serotonin (5-HT) levels in different tissues of humans and rodents [redrawn with permission from Rao et al. (141); Mateos et al. (142); Agren et al. (132)]. (B) Double plotted day/night differences in norepinephrine (NE) and Monoamine oxidase A (MAOA) in different tissues of humans and rodents [redrawn with permission from (, –145)]. (C) Double plotted day/night differences in adenosine (ADO) and its metabolizing agents in different tissues of humans and rodents [redrawn with permission from (–148)].

Figure 5

A schematic representation of how different factors relevant to the night might alter the likelihood that a seizure results in SUDEP.