Dravet Syndrome: Inroads into Understanding Epileptic Encephalopathies

Abstract

ravet syndrome is a severe childhood epilepsy characterized by intractable seizures and neurodevelopmental delay. First described in 1978 by Dravet as severe myoclonic epilepsy of infancy (SMEI), the syndrome was renamed in light of the widening spectrum of clinical phenotypes associated with the more-recently discovered underlying genetic basis. Based on clinical diagnostic criteria, Dravet syndrome has been estimated to affect 1 in 40 000 children, accounting for about 7% of severe epilepsy occurring in children under age 3 years. These numbers likely underestimate the actual incidence, given that genetic testing has dramatically increased diagnosis of this disorder. Dravet syndrome has been mainly associated with mutations in a neuronal voltage-gated sodium channel gene, SCN1A (sodium channel subunit 1A). SCN1A mutations also have been associated with febrile seizures (FS) and milder forms of epilepsy, and more recently, SCN1A polymorphisms have been implicated in susceptibility to FS. Unravelling the mechanisms of epileptic seizures in Dravet syndrome is of great importance, because SCN1A mutations confer varying degrees of seizure susceptibility, in part determining the seizure threshold. The recent association of this childhood epilepsy with the occurrence of vaccine-related seizures and encephalopathy has led to a reexamination of this historically charged medicolegal controversy. An animal model for Dravet syndrome has reproduced many of the clinical features and has expanded our understanding of how seizures occur in this syndrome. The most greatly affected neurons appear to be interneurons, which serve as part of the inhibitory circuitry in the brain. The emerging concept of epilepsy resulting from interneuron dysfunction, or ‘‘interneuronopathy,’’ has been useful in understanding the mechanisms of seizures in Dravet syndrome. Dravet syndrome is recognized as an epileptic encephalopathy because of the association between frequent seizures and cognitive impairment and poor developmental outcome. The effect of seizures on the developing brain is of great interest and critical importance in the field of pediatric epilepsy.