Sudden unexpected death in dravet syndrome.

Commentary Sudden unexpected death in epilepsy (SUDEP) is a rare, fatal complication of epilepsy defined as sudden death in an individual with epilepsy, in the absence of an obvious cause of death (1). The cause of SUDEP is unknown; however, it is hypothesized that there may be a disruption in respiration, heart rhythm, or cerebral shutdown (1). The population incidence of SUDEP in individuals with epilepsy is estimated to be 0.9 per 1,000 in adults and 0.4 per 1,000 in children (2). The risk of SUDEP in children with Dravet syndrome is estimated to be 15-fold greater than other childhood-onset epilepsies, making this a major concern for families and caregivers (3). Dravet syndrome is a severe epileptic encephalopathy that begins in infancy with prolonged hemiclonic or tonic–clonic seizures, often precipitated by fever. As the syndrome progresses, other seizure types emerge along with developmental and cognitive delays, behavioral impairments, and ataxia (4). In more than 80% of cases, Dravet syndrome is caused by mutation of the SCN1A gene that encodes the voltage-gated sodium channel Na v 1.1 (5). A mouse model of Dravet syndrome was generated by heterozygous deletion of the Scn1a gene. This mouse model recapitulates many features of Dravet syndrome, including spontaneous seizures, sensitivity to hyperthermia-induced seizures, cognitive deficits, and ataxia (6–8). Dravet mice also have a high rate of premature death that peaks in the juvenile period between 3–5 weeks of age (6). In the current study, Kalume and colleagues more fully characterize the premature lethality phenotype in Dravet mice and begin to unravel the underlying mechanism. To more fully understand the relationship between seizures and premature lethality, they used continuous video monitoring during the period of highest lethality risk (postnatal days 23–27). They found a strong correlation between mortality risk and the number of generalized tonic–clonic seizures in the 24 hours preceding death, while the duration of each individual seizure was not correlated. All recorded sudden deaths occurred following a generalized tonic–clonic seizure of relatively short duration. Although they did observe mice that experienced lethal status epilepticus, these were excluded from the study in order to focus on sudden death in Dravet mice as a model of SUDEP in Dravet syndrome patients. In addition to being expressed in the brain, Na v 1.1 is also expressed in the sinoatrial node of the heart, where it contributes to control of heart rate (9). Thus, a key question is …