Beyond seizure control: Functional and caregiver-reported outcomes of long-term fenfluramine treatment in Dravet syndrome

Objective: To evaluate caregiver-reported perceptions of functional change during long-term fenfluramine (FFA) therapy in Dravet syndrome (DS) and to explore associations with cognitive, adaptive, and clinical variables. Methods: This single-center, cross-sectional study included 21 individuals with DS (mean age 16.1 ± 7.2 years; 62% female) receiving FFA as adjunctive therapy for a median of 3.0 years (IQR 2–6). Standardized cognitive and adaptive assessments (WISC-IV, WAIS-IV, Leiter-R, Vineland-II) were combined with a purpose-designed 13-item caregiver questionnaire evaluating perceived changes across communication, attention, behavior, and daily functioning (Likert 1–5; Cronbach's α = 0.83). Non-parametric statistics were used to explore associations with seizure outcomes and clinical predictors. Results: Over the previous 12 months, 52.4% achieved ≥ 50% seizure reduction and 19.0% were seizure-free. Standardized tests confirmed profound cognitive and adaptive impairment (IQ range 39–51; Vineland composite median = 20), consistent with floor effects. In contrast, caregivers reported consistent functional improvements in expressive language, attention, environmental alertness, and behavioral regulation (median global improvement = 4 [IQR 4–5]). Younger age (ρ = –0.48, p = 0.029) and higher rehabilitation frequency (ρ = 0.50, p = 0.022) were associated with greater perceived improvement, whereas earlier seizure onset predicted poorer outcomes (ρ = –0.52, p = 0.015). Significance: Despite severe baseline impairment, caregivers perceived ecologically meaningful functional gains during long-term FFA therapy. Functional improvements did not strictly parallel seizure reduction, suggesting broader neuromodulatory and developmental effects. Findings highlight the need to integrate caregiver-informed measures with standardized assessments and to combine pharmacological and rehabilitative strategies to optimize outcomes in DS. Plain language summary: This study explored how caregivers of people with Dravet syndrome perceived everyday changes during long-term treatment with fenfluramine. Although standard tests confirmed severe cognitive and adaptive impairments, caregivers noticed meaningful improvements in communication, attention, alertness, and behavior. These changes were more evident in younger patients and in those receiving regular rehabilitation. Importantly, improvements were reported even when seizures did not markedly decrease, suggesting that fenfluramine may have broader effects on brain function beyond seizure control. Combining medication with early and continuous rehabilitative care may help maximize quality of life for individuals with Dravet syndrome and their families.