Fenfluramine in developmental and epileptic encephalopathies: An age- and syndrome-stratified systematic review and meta-analysis.

PURPOSE: Developmental and epileptic encephalopathies (DEEs) are heterogeneous developmental encephalopathies in which ongoing epileptic activity contributes to worsening of pre-existing cognitive, behavioral, and motor impairment. Fenfluramine evidence is strongest in Dravet syndrome (DS), but limited in Lennox-Gastaut syndrome (LGS), other DEEs, and adults. We evaluated efficacy by syndrome and age, considering follow-up for durability.

METHODS

We conducted a systematic review and meta-analysis (PROSPERO CRD420251161054). PubMed, Embase, and CENTRAL were searched from inception to 15 September 2025. Eligible studies enrolled individuals with DEE treated with fenfluramine. Subgroup analy

RESULTS

Twenty studies (4 randomized, 16 observational) comprising 1387 patients met criteria. Pooled estimates were 16.7% (95% CI 10.3-25.8) for minimal/no benefit, 64.8% (56.1-72.7) for ≥50% response, 41.6% (32.1-51.8) for ≥70% reduction, and 11.4% (7.2-17.6) for seizure freedom. Syndrome-stratified analyses strengthened the signal of differential efficacy: response was consistently attenuated in LGS compared with DS in ≥50% and ≥70% thresholds, with significant subgroup interactions, supporting a credible between-syndrome difference. Other DEEs showed higher point estimates (e.g.: ≥50%=100%; ≥70%=77.8%) but were informed by few studies. Adults had higher seizure-freedom estimates (38.2%vs 11.3% mixed and 8.2% pediatric); this signal is clinically relevant but should be interpreted in light of DS predominance and the age-related evolution of seizure burden in DS. Follow-up was heterogeneous; long-term data, mainly from DS cohorts, did not suggest systematic loss of efficacy.

CONCLUSION

Fenfluramine provides clinically meaningful seizure reduction across DEEs, with differential efficacy by syndrome and encouraging long-term durability, particularly in DS.