A comprehensive review of evolving treatment strategies for Dravet syndrome: Insights from randomized trials, meta-analyses, real-world evidence, and emerging therapeutic approaches

Abstract

Dravet syndrome (DS) is a severe genetic developmental and epileptic encephalopathy, primarily caused by SCN1A gene mutations. Historically, treatments like clobazam and valproate have been used without evidence from randomized controlled trials (RCTs). However, the therapeutic landscape of DS has evolved with multiple RCTs demonstrating the efficacy and safety of three antiseizure medications (ASMs): stiripentol, cannabidiol (CBD), and fenfluramine. In the absence of direct comparisons between these therapies, several network meta-analyses have been conducted to compare the ASMs, while expert consensus has independently been developed to formulate treatment guidelines. While these three ASMs show promise in reducing seizures, increasing awareness of non-seizure outcomes—such as cognitive development and quality of life—has shifted the focus of evaluation. Some recent real-world studies of these ASMs have reported improvements in these non-seizure outcomes, alongside sustained efficacy and safety. However, natural history studies continue to underscore persistent deficits in these areas and highlight suboptimal long-term seizure control despite the use of these therapies. This review addresses these gaps by first discussing network meta-analyses and treatment guidelines, along with the practical limitations of these approaches. It then examines the long-term efficacy, safety, non-seizure effects, and cost-effectiveness from real-world studies of these ASMs. Finally, emerging research on novel therapeutic approaches, including genetic and serotonergic modulation, is explored. By evaluating these developments, this review aims to guide clinical decision-making and propose future directions for optimizing DS care.