Dravet syndrome: Advances in etiology, clinical presentation, and treatment

Dravet syndrome (DS) is a form of genetic refractory epilepsy. More than 80 % of DS patients carry pathogenic SCN1A mutations, and this percentage is actually higher due to false-negative results in gene testing. Potential genotype-phenotype correlations may exist but require further confirmation. "SCN1A mutation-mediated dysfunction of NaV1.1 affects GABAergic inhibitory interneurons" is currently the most accepted pathogenesis. Besides SCN1A, there are other genes associated with DS-like phenotypes, among which GABA_A-receptor subunit genes have recently received more attention. Most DS patients experience prolonged, hemiclonic or tonic-clonic seizures triggered by fever during the first year of life, followed by the gradual onset of other seizure types, including myoclonic, atypical absence, and focal seizures. Over time, seizures tend to become less frequent and severe but generalized tonic-clonic seizures remain. DS also has many comorbidities, including motor, cognitive, behavior, and sleep impairments, which cause poor quality of life and impact the long-term course. The electroencephalography and neuroimaging of DS lack specificity, but the evolution of electroencephalography may help to identify DS. Current treatments for DS are symptomatic and difficult to control seizures. The combination of valproic acid, clobazam and stiripentol is a commonly used clinical treatment option, fenfluramine and cannabidiol have been used as second- and third-line drugs, respectively. Later therapeutic options include other anti-seizure medications, the ketogenic diet, and vagus nerve stimulation, whereas sodium channel blockers should be avoided in DS. Furthermore, several promising drugs including soticlestat are in development, and genetic therapies are beginning to emerge, representing future treatment directions.