We aim to describe the effectiveness of fenfluramine (FFA) on generalized tonic-clonic seizures (GTCS) in patients with rare epilepsy syndromes.

Seizure refractoriness and frequent GTCS are hallmarks of developmental and epileptic encephalopathies (DEEs) and are 2 major risk factors for sudden unexpected death in epilepsy (SUDEP). Patients with 1-3 GTCS/year have up to a 16-fold greater risk of SUDEP. An analysis of SUDEP rates in patients with Dravet syndrome (DS) found a 5-fold lower SUDEP mortality rate in FFA-treated patients compared to historical controls. FFA has demonstrated reduced seizure burden in other rare epilepsies.

Studies where FFA was used to manage convulsive seizures associated with rare epilepsy syndromes were included. Initial FFA doses, duration of treatment (exposure) and reduction in GTCS or tonic-clonic seizures (TCS) are reported. Descriptive statistics were used. 

We included data from 13 studies: 4 randomized-controlled trials (RCTs), 4 observational studies, 4 open-label studies, and 1 case series. In these studies, 561 patients were treated with FFA for DS (n=360), LGS (n=176), Sunflower syndrome (n=10), CDKL5 deficiency disorder (n=6), SCN8A-related disorder (n=3), and other DEEs (n=6). Of these, 396 (70.6%) patients experienced GTCS or TCS at baseline. FFA was generally initiated at 0.2 mg/kg/day and titrated per protocol or physician discretion; FFA exposure: 14 weeks-27 years. In 8 studies, the median percent reduction in GTCS ranged from 45.7%-90.8%. Among 8 studies, 7 reported at least half of the patients experienced ≥75% reduction in GTCS (or TCS); five studies reported more than half of patients were GTCS-free after FFA treatment.