Recent Advances in the Drug Treatment of Dravet Syndrome.

Abstract

Dravet syndrome is a rare but severe epilepsy syndrome that begins in the first year of life with recurrent seizures triggered by fever that are typically prolonged and hemiclonic. The epilepsy is highly drug resistant. Although development is normal at onset, over time, most patients develop moderate-to-severe intellectual disability, behavior disorders, and a characteristic crouch gait. There is a significant mortality, predominantly owing to sudden unexpected death in epilepsy. Complete seizure control is rarely attainable. Initial therapy includes valproic acid and clobazam, but response is typically inadequate. The results of new drugs for Dravet syndrome, including stiripentol, cannabidiol, and fenfluramine, are very promising. Stiripentol was associated with a greater than 50% reduction in convulsive seizure frequency in 71% of cases, when added to valproic acid and clobazam, and also markedly reduced status epilepticus. Pharmaceutical-grade cannabidiol resulted in a median change in monthly motor seizures from baseline of -36.5%. Fenfluramine was associated with a greater than 50% reduction in seizures of 70%, with one quarter of cases achieving near seizure freedom over the duration of the trial. These agents are generally well tolerated, with few patients discontinuing for adverse effects. There is limited evidence to date regarding improvement in cognition with these newer agents; however, a meaningful change is challenging to assess over short trial periods and requires longer follow-up studies. While current treatments focus predominantly on seizure control, newer therapies including genetic treatments and antisense oligonucleotides can target the SCN1A channelopathy, and thus, may also significantly impact the important co-morbidities associated with this syndrome.