Effect of fenfluramine on seizures and comorbidities in SCN8A‐developmental and epileptic encephalopathy: A case series

Abstract

SCN8A‐developmental and epileptic encephalopathy is caused by pathogenic variants in the SCN8A gene encoding the Nav1.6 sodium channel, and is characterized by intractable multivariate seizures and developmental regression. Fenfluramine is a repurposed drug with proven antiseizure efficacy in Dravet syndrome and Lennox–Gastaut syndrome. The effect of fenfluramine treatment was assessed in a retrospective series of three patients with intractable SCN8A epilepsy and severe neurodevelopmental comorbidity (n = 2 females; age 2.8–13 years; 8–16 prior failed antiseizure medications [ASM]; treatment duration: 0.75–4.2 years). In the 6 months prior to receiving fenfluramine, patients experienced multiple seizure types, including generalized tonic–clonic, focal and myoclonic seizures, and status epilepticus. Overall seizure reduction was 60%–90% in the last 3, 6, and 12 months of fenfluramine treatment. Clinically meaningful improvement was noted in ≥1 non‐seizure comorbidity per patient after fenfluramine, as assessed by physician‐ratings of ≥“Much Improved” on the Clinical Global Impression of Improvement scale. Improvements included ambulation in a previously non‐ambulant patient and better attention, sleep, and language. One patient showed mild irritability which resolved; no other treatment‐related adverse events were reported. There were no reports of valvular heart disease or pulmonary arterial hypertension. Fenfluramine may be a promising ASM for randomized clinical trials in SCN8A‐related disorders.

Carvedilol increases seizure resistance in a mouse model of SCN8A-derived epilepsy

“…While a recent study reported that fenfluramine was able to significantly reduce seizure frequency in three patients with SCN8Aderived epilepsy (Aledo-Serrano et al, 2022), we did not observe any significant effect on susceptibility to 6 Hz-induced seizures in RL/+ mutants treated with fenfluramine (Figure 2E). We did not test higher doses of fenfluramine in the RL/+ mutants as a higher dose of fenfluramine (30 mg/kg) in CF1 WT mice was associated with increased seizure susceptibility and significant side effects were observed in the RL/+ mutants and WT littermates.…”

“…In addition, fenfluramine has garnered interest for its ability to significantly reduce seizure frequency in several severe pediatric forms of epilepsy. A recent study also reported a significant reduction in seizure frequency in three patients with SCN8A epilepsy mutations who were treated with fenfluramine ( Aledo-Serrano et al, 2022 ).…”

“…We selected amitriptyline (AMI), carvedilol (CVD), and nilvadipine for testing in the Scn8a R1620L/+ (RL/+) mouse line based on a previous in vitro screen that suggested these drugs might be efficacious in SCN8A -derived epilepsy due to their ability to inhibit sodium influx ( Atkin et al, 2018 ). Fenfluramine (FF) was selected because it is efficacious in patients with Dravet syndrome and Lennox-Gastaut syndrome ( Ceulemans et al, 2012 ; Ceulemans et al, 2016 ; Knupp et al, 2022 ; Knupp et al, 2023 ), and was recently reported to reduce seizure frequency in three patients with SCN8A -derived epilepsy ( Aledo-Serrano et al, 2022 ).…”

“…Previously used in the treatment of depression and obesity, fenfluramine recently received Food and Drug Administration (FDA) approval for the treatment of Dravet syndrome, Lennox-Gastaut syndrome, and Tuberous Sclerosis Complex. In a recent case report, fenfluramine was found to decrease seizure frequency by 60%–90% in three patients with SCN8A -associated epilepsy ( Aledo-Serrano et al, 2022 ).…”

SCN8A epileptic encephalopathy: literature review and own observation

“…Возможно наличие апноэ во сне, что может влиять на частоту приступов, поведение и когнитивные функции. При подозрении на обструктивное или центральное апноэ во сне следует провести полисомнографию [20,5].…”