Fenfluramine's Broader Potential: A Second Notable Electroencephalogram Response in Developmental Epileptic Encephalopathy With Spike-Wave Activation in Sleep

Fenfluramine, a serotonergic agent, was first identified in the 1980s for its potential antiseizure properties, particularly in photosensitive epilepsy and later in Dravet syndrome [1]. Although it was withdrawn from the market in the 1990s due to concerns over cardiovascular adverse effects, including pulmonary arterial hypertension associated with high doses, subsequent studies have demonstrated that low-dose fenfluramine can be both efficacious and well-tolerated in managing refractory epilepsies [2, 3].

We present a second pediatric patient with developmental and epileptic encephalopathy with spike-wave activation in sleep (DEE-SWAS) in which fenfluramine was associated with marked electroencephalographic and clinical improvements, supporting its potential role as an adjunctive therapy in this challenging epilepsy phenotype.

This 6-year-old right-handed boy with DEE-SWAS was admitted to the epilepsy monitoring unit for further evaluation. He had been experiencing seizures since age 2 years, occurring multiple times daily and lasting only a few seconds. The seizure semiology was consistent with myoclonic seizures, characterized by eyelid myoclonia and bilateral arm jerks.

Initial electroencephalography (EEG) revealed a diffusely slowed background with abundant multifocal epileptiform discharges, most prominent in the bilateral temporal regions. During wakefulness, several electroclinical seizures with eyelid myoclonia were recorded. In sleep, EEG demonstrated bilaterally synchronous spike-and-wave discharges, with a spike-wave index exceeding 85% during non–rapid eye movement (NREM) sleep.

Comprehensive genetic testing—including chromosomal microarray analysis, mitochondrial DNA analysis, and whole-exome sequencing—did not identify any pathogenic variants. Magnetic resonance imaging (MRI) of the brain was also unremarkable.

At the time of admission, the patient was receiving levetiracetam, valproic acid, clobazam, and diazepam. Despite this regimen, he exhibited significant developmental regression, particularly in motor and language skills, accompanied by severe sleep disturbances that negatively impacted his overall quality of life. Previous treatments, including high-dose intravenous methylprednisolone, intravenous immunoglobulin (IVIG), and acetazolamide, had been discontinued due to ineffectiveness or uncertain benefit.

During his epilepsy monitoring unit stay, fenfluramine was initiated at a dose of 0.2 mg/kg/day, divided into two daily administrations, as an adjunct to his ongoing antiseizure medications. In parallel, the ketogenic diet was introduced as an additional therapeutic strategy for seizure control. Within 24–48 h of initiating fenfluramine, the patient's EEG exhibited a marked improvement compared with baseline (Figure 1).

This second pediatric patient with refractory epilepsy and DEE-SWAS demonstrated significant EEG improvement following initiation of fenfluramine (0.2 mg/kg/day) [4]. After starting fenfluramine, the boy experienced only one seizure day within 6 months and has now remained seizure-free for 9 months. His most recent EEG (November 2024) showed a spike-wave index below 1%, with only rare left central discharges. Valproic acid was discontinued after the tremors resolved, and the patient continues to improve in both receptive and expressive speech, as well as motor skills.

The ketogenic diet was initiated around the same time as fenfluramine, which may have contributed synergistically to seizure control and cognitive improvements. However, the rapid EEG and clinical improvement observed shortly after fenfluramine initiation occurred before achieving therapeutic ketosis. The combined therapy was safe and well-tolerated, and the patient continues on fenfluramine.

We present a novel observation of fenfluramine's therapeutic effect in a second pediatric patient with DEE-SWAS. When considered alongside previously documented patients, these findings suggest that fenfluramine may have broader clinical utility beyond its current approved indications for Dravet syndrome and Lennox–Gastaut syndrome [3]. Although the small number of patients precludes definitive conclusions, the consistent clinical and electrographic improvements observed highlight the need for further investigation into fenfluramine's mechanisms of action and its potential role in a wider range of developmental and epileptic encephalopathies.

Abigail Arroyo: writing – original draft, writing – review and editing, resources, data curation. Douglas R. Nordli III: writing – original draft, writing – review and editing, resources, data curation. Fernando Galan: writing – original draft, writing – review and editing, data curation, supervision, resources.

The authors declare no conflicts of interest.