2023 American Academy of Neurology Abstract Website

J Helen Cross¹, Orrin Devinsky², Antonio Gil-Nagel³, Berten Ceulemans⁴, Lieven Lagae⁵, Kelly Knupp⁶, An-Sofie Schoonjans⁴, Philippe Ryvlin⁷, Elizabeth Thiele⁸, Rima Nabbout⁹, Amélie Lothe¹⁰, Shikha Polega¹¹
¹UCL NIHR BRC Great Ormond Street Institute of Child Health, ²NYU Epilepsy Center, ³Hospital Ruber Internacional, ⁴University of Antwerp, ⁵University Hospital Gasthuisberg, University of Leuven, ⁶Children's Hospital Colorado, ⁷University of Lausanne, ⁸Massachusetts General Hospital, ⁹Paris Descartes University, ¹⁰Zogenix International (now a part of UCB), ¹¹Zogenix, Inc. (now a part of UCB)

Objective:

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

Background:

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.

Design/Methods:

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.

Results:

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.

Conclusions:

These results indicate that FFA led to a clinically significant reduction in GTCS (or TCS) frequency in patients with rare epilepsy syndromes, suggesting it may also reduce SUDEP rates in these disorders. Further research is needed to determine the impact of FFA on SUDEP in those patient populations.