The purpose of this systematic review was to compare the efficacy and tolerability of two FDA-approved antiseizure medications, fenfluramine (Fintepla®) and cannabidiol (Epidiolex®), to that of vagal nerve stimulation (VNS) for severe, refractory seizures in Lennox-Gastaut syndrome (LGS).

LGS is an early-onset epilepsy syndrome characterized by multiple seizure types, cognitive impairment, and characteristic EEG pattern of generalized slow spike-and-wave discharges. Seizures associated with LGS are often refractory to various antiseizure medications (ASMs), and VNS therapy has been utilized for years in treatment of refractory LGS without FDA approval. Recently, two newer ASMs, fenfluramine and cannabidiol, gained FDA approval for LGS. The benefits of VNS when compared to these newly-approved ASMs remain unclear. 

A systematic search of PubMed and Embase databases was conducted using “VNS” “Cannabidiol” “Fenfluramine” and “Lennox-Gastaut” as search terms. Only clinical trials with sufficient sample size and study period were included in our review. We used a random effects model to compare seizure frequency dependent on treatment modality in SPSS.

We identified two open-label clinical studies of VNS therapy for refractory LGS. One randomized double-blinded study was found with fenfluramine and two with cannabidiol for refractory LGS. From these studies, the median reduction of drop seizures (tonic, atonic, tonic-clonic seizures with falls) was 60.3% for VNS, 36.3% for patients on 0.7mg/kg/day of fenfluramine (p=0.481), and 50.3% for patients on 20 mg/day of cannabidiol (p=0.772).  Most frequently reported adverse effects for VNS were transient dysphonia, hoarseness, and drooling; for fenfluramine: decreased appetite and fatigue; for cannabidiol: somnolence, diarrhea, and decreased appetite.

While VNS therapy continues to be utilized off-label for LGS, it provides comparable efficacy with different adverse effect profiles from fenfluramine and cannabidiol based on current open-label trials. Direct comparative studies may provide superior insight into the treatment of patients with refractory LGS.