Efficacy of stiripentol, fenfluramine, and their combination on clinical outcomes in Dravet syndrome: A preliminary report.

objectiveStiripentol and fenfluramine are approved treatments for Dravet syndrome (DS), but real-world data comparing their effectiveness and combined use remain limited. Our study aims to explore associations between treatment with stiripentol, fenfluramine, and their combination and clinical outcomes in patients with DS.

methodsWe retrospectively reviewed medical records of patients with genetically confirmed DS. Patients were classified into four treatment groups: stiripentol, fenfluramine, stiripentol + fenfluramine, other antiseizure medications. Seizure frequency, cognitive outcome, neuropsychiatric disorders, and movement disorders were compared across groups and according to age at treatment initiation and SCN1A genetic variant. Statistical analyses included Fisher's exact tests and Welch's one-way Analysis of Variance (p < 0.05). Post hoc analyses were conducted only for variables with a significant overall test (p < 0.05), using standardized residuals to identify which categories contributed most. We performed exploratory multivariable and sensitivity analyses to assess the consistency of our findings. Given the retrospective design and small subgroup sizes, analyses were considered exploratory.

resultsSixty-six patients were included: stiripentol (n = 15), fenfluramine (n = 29), stiripentol + fenfluramine (n = 7), other antiseizure medications (n = 13). Exploratory analyses showed differences in seizure frequency distribution across treatment groups (p = 0.021), with lower seizure burden observed among patients receiving fenfluramine-containing regimens. This association remained significant after adjustment for age at last follow-up and disease duration (global p = 0.022). Differences in movement disorders observed in unadjusted analyses (p = 0.006) were attenuated after adjustment. No significant differences were observed for cognitive outcome (p = 0.081) or neuropsychiatric disorders (p = 0.152). Earlier initiation of stiripentol was descriptively associated with lower rates of movement disorders (p = 0.003), neuropsychiatric disorders (p = 0.013), and better cognitive outcomes (p = 0.013). Similarly, earlier initiation of fenfluramine was descriptively associated with more favorable cognitive outcomes (p < 0.001) and a lower prevalence of movement disorders (p = 0.028). These associations were substantially attenuated in sensitivity analyses accounting for age at assessment, disease duration and treatment era. SIGNIFICANCE: These preliminary findings suggest that fenfluramine-based regimens are associated with lower seizure burden in patients with DS. Associations between earlier initiation of syndrome-specific therapies and long-term developmental outcomes should be interpreted cautiously because of potential confounding by disease stage, treatment era, and non-random treatment allocation. Larger prospective studies are required to determine whether earlier treatment directly influences long-term developmental outcomes. PLAIN LANGUAGE SUMMARY: Patients receiving fenfluramine-based regimens had a lower seizure burden than those receiving other antiseizure medications. Earlier initiation of stiripentol or fenfluramine was associated with better cognitive and motor outcomes, but these associations were substantially influenced by age, disease duration, and treatment era. Larger prospective studies are needed to determine whether earlier treatment independently influences long-term developmental outcomes.