Successful use of fenfluramine as an add‐on treatment for Dravet syndrome

Abstract

Summary Purpose: Despite the development of new antiepileptic drugs, Dravet syndrome frequently remains therapy resistant and is a catastrophic epilepsy syndrome. Fenfluramine is an amphetamine‐like drug that has been used in the past as a part of antiobesity treatments. Because of the possible cardiac adverse effects (valve thickening, pulmonary hypertension) associated with use of fenfluramine, it was withdrawn from the market in 2001. In Belgium, a Royal Decree permitted examination of the potential anticonvulsive effects of fenfluramine in a clinical trial consisting of a small group of patients diagnosed with Dravet syndrome. Methods: Herein, we report 12 patients, 7 female and 5 male, with a genetically proven (11 of 12) diagnosis of Dravet syndrome who received fenfluramine as add‐on therapy. Key Findings: Their ages at their last evaluation ranged from 3–35 years. The mean dosage of fenfluramine was 0.34 (0.12–0.90) mg/kg/day. Exposure duration to fenfluramine ranged from 1–19 years. Seven of the patients who were still receiving the fenfluramine treatment at the time of the last visit had been seizure‐free for at least 1 year. In total, patients had been seizure‐free for a mean of 6 (1–19) years. In seven patients, the fenfluramine treatment was interrupted once during the follow‐up; seizures reappeared in three of the seizure‐free patients. Subsequent reintroduction of fenfluramine controlled the seizures in these three patients again. Only two patients exhibited a mild thickening of one or two cardiac valves without clinical significance. Significance: Compared with a recent long‐term follow‐up series in which a maximum of 16% of patients with Dravet syndrome were seizure‐free, our result of 70% of patients with Dravet syndrome remaining seizure‐free is noteworthy. Given the limitations of this observational study, a larger prospective study should be undertaken to confirm these promising results.

Molecular Targets of Cannabidiol in Neurological Disorders

“…CBD exhibits reasonable affinity at plausible concentration for 5-HT 1A and 5-HT 2A receptors, and 5-HT 2A receptors act as a target for fenfluramine, a drug for which some evidence exists supporting efficacy in drug-resistant epilepsies such as Dravet syndrome [144]. A very limited number of studies have reported changes in 5-HT receptor expression and function in people with epilepsy, although it remains unclear whether this is a consequence of the disease or a component of pathogenesis.…”

Low-dose fenfluramine in the treatment of neurologic disorders: experience in Dravet syndrome

“…Retrospective data Ceulemans and colleagues reported on the effect of fenfluramine in 12 patients with Dravet syndrome [Ceulemans et al 2012], retrospectively analyzed in 2010. The patient population included five patients from a study reported by Boel and Casaer [Boel and Casaer, 1996] who after review of their files and genetic testing were diagnosed with Dravet syndrome.…”

“…In 2012, 12 patients were included of which 10 from the retrospective study and two new patients. Of the seven of 10 patients from the retrospective study [Ceulemans et al 2012] who had been seizurefree in the year prior to the initiation of this prospective study, four have continued to be free of seizures and three have exhibited rare seizure episodes (3-7 tonic-clonic convulsions) during the two additional years of observation. In three of them there was a provocative factor like fever, a stressful situation or intensive physical exercise explaining the seizures.…”

Audit of use of stiripentol in adults with Dravet syndrome

“…Lamotrigine can also cause seizure exacerbation,10 although has been reported to be beneficial in some cases 11. Effective treatment strategies include valproic acid, clobazam, topiramate, levetiracetam, fenfluramine and bromides,12, 13, 14 or dietary therapies (ketogenic or modified Atkins diet) 15. There are ongoing studies on the use of cannabidiol in children with DS 16.…”