Overwhelming evidence indicates that sudden unexpected death in epilepsy (SUDEP) is attributable to a seizure causing a primary defect in either cardiovascular or respiratory control or, less commonly, in both
From a research perspective, respiratory dysfunction in SUDEP has received less attention than cardiac mechanisms, despite the fact that peri-ictal hypoventilation is common and can lead to severe oxygen desaturation
Postictal impairment of wakefulness and arousal probably contributes to the inability of a patient to respond to an external stressor, such as lying prone in bed
SUDEP shares many similarities with sudden infant death syndrome, which has been linked to a defect in the 5-hydroxytryptamine (5-HT) system
Currently available preventive treatments for SUDEP are designed to decrease seizure frequency; potential approaches that need to be further investigated include targeting of the 5-HT and adenosine systems
Routine respiratory monitoring should probably be performed on every patient admitted to an epilepsy monitoring unit
Sudden unexpected death in epilepsy (SUDEP) is the leading cause of death in patients with refractory epilepsy, with an estimated 35% lifetime risk in this patient population. There is a surprising lack of awareness among patients and physicians of this increased risk of sudden death: in a recent survey, only 33% of Canadian paediatricians who treated patients with epilepsy knew the term SUDEP. Controversy prevails over whether cardiac arrhythmia or respiratory arrest is more important as the primary cause of death. Effective preventive strategies in high-risk patients will rely on definition of the mechanisms that lead from seizures to death. Here, we summarize evidence for the mechanisms that cause cardiac, respiratory and arousal abnormalities during the ictal and postictal period. We highlight potential cellular mechanisms underlying these abnormalities, such as a defect in the serotonergic system, ictal adenosine release, and changes in autonomic output. We discuss genetic mutations that cause Dravet and long QT syndromes, both of which are linked with increased risk of sudden death. We then highlight possible preventive interventions that are likely to decrease SUDEP incidence, including respiratory monitoring in epilepsy monitoring units and overnight supervision. Finally, we discuss treatments, such as selective serotonin reuptake inhibitors, that might be personalized to a specific genetic or pathological defect.
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C.A.M. and G.B.R. have received funding from the Beth L. Tross Epilepsy Research Fund. L.P.S. is funded by a T32 Multidisciplinary Lung Research Career Development Program Training Grant from the National Heart, Lung, and Blood Institute at NIH. G.B.R. has received funding from the National Institute of Neurological Disorders and Stroke (grant P20NS076916) and the National Institute of Child Health and Human Development (grants R01HD052772 and P01HD36379).
The authors declare no competing financial interests.
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Massey, C., Sowers, L., Dlouhy, B. et al. Mechanisms of sudden unexpected death in epilepsy: the pathway to prevention. Nat Rev Neurol 10, 271–282 (2014). https://doi.org/10.1038/nrneurol.2014.64
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