KCNQ2 mutations cause approximately 13% of unexplained NEE. Patients present with a wide spectrum of severity and, although rare, infantile epilepsy onset is possible.

SUMMARYDravet syndrome (DS) is a rare and therapy-resistant epilepsy syndrome. A retrospective analysis of add-on fenfluramine treatment in 12 patients with DS was published in 2012 and provided evidence of a meaningful long-term response. Herein we present the results of a subsequent 5-year prospective observation of this original cohort. Ten patients with a mean current age of 24 years were followed prospectively from 2010 until 2014. The mean current dose of fenfluramine was 0.27 mg/kg/day, with a mean treatment duration of 16.1 years. Seizure frequency was derived from a seizure diary. Cardiac examinations and assessments of clinical effectiveness and adverse events were performed at least annually. Three patients were seizure-free for the entire 5 years, and an additional four patients experienced seizure-free intervals of at least 2 years. Fenfluramine was generally well-tolerated. Two patients had mild (stable) valve thickening on the last echocardiography that was deemed clinically insignificant. No patient had any clinical or echocardiographic signs of pulmonary hypertension. These findings support the long-term control of convulsive seizures by low-dose fenfluramine while being well tolerated in this cohort of patients with DS. After up to 27 years of treatment, no patient has developed any clinical signs or symptoms of cardiac valvulopathy or pulmonary hypertension.

Background and purposeDravet syndrome (DS) is a severe, drug‐resistant epilepsy. Fenfluramine has been reported to have a long‐term clinically meaningful anticonvulsive effect in patients with DS.MethodsThis prospective, open‐label study assessed the safety and effectiveness of low‐dose fenfluramine in a new cohort of patients with DS. Following a 3‐month baseline period, fenfluramine was added to each patient's current antiepileptic drug regimen at a dose of 0.25–1.0 mg/kg/day (max. 20 mg/day). The incidence of major motor seizures (tonic, clonic, tonic–clonic, atonic and myoclonic seizures lasting >30 s) in both the baseline and treatment periods was assessed via a seizure diary. Periodic echocardiographic examinations during the treatment period were used to assess cardiovascular safety.ResultsNine patients (aged 1.2–29.8 years) enrolled in the study and were treated with fenfluramine for a median duration of 1.5 (range, 0.3–5.1) years. Median frequency of major motor seizures was 15.0/month in the baseline period. All patients demonstrated a reduction in seizure frequency during the treatment period with a median reduction of 75% (range, 28–100%). Seven patients (78%) experienced a ≥50% reduction in major motor seizure frequency. The most common adverse events were somnolence (n = 5) and anorexia (n = 4). No evidence of cardiac valvulopathy or pulmonary hypertension was observed.ConclusionsThe effectiveness and safety of low‐dose fenfluramine as an add‐on therapy for DS in this new prospective cohort supports previous findings.

In this paper, we review the experience with fenfluramine in epileptic and other paroxysmal disorders. Since the best available data are from the treatment of Dravet syndrome, we will focus primarily on this condition. Originally fenfluramine was launched as an anorectic agent. As early as 1985, seizure reduction in children could be demonstrated in a few cases with photosensitive, self-induced epilepsy. Hereafter, a small study was launched in patients with self-induced epilepsy. Results showed a significant seizure reduction, and review of the patient data showed that 5 of the 12 patients had Dravet syndrome. During that observation period, fenfluramine was withdrawn from the market because of cardiovascular side effects associated with prescribing higher doses in combination with phentermine for weight loss. In March 2002, a Belgian Royal Decree was issued permitting further study of fenfluramine in pediatric patients with intractable epilepsy. In 2011 under the Royal Decree, a prospective study of patients with Dravet syndrome treated with low-dose fenfluramine was initiated and is currently ongoing. The initial results are promising in terms of reduction of seizure frequency and overall tolerability.