Fenfluramine reduces hard-to-treat seizures in 3 girls with Rett syndrome
Improvements in functional abilities, quality of life also reported for 2 patients
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Fenfluramine, an add-on medication already approved for certain types of epilepsy, may also help to reduce the frequency of hard-to-treat seizures in children with Rett syndrome, according to a new case series.
The therapy specifically reduced seizures in three out of four girls with Rett syndrome who had not responded to several prior anti-seizure medications. In two of those patients, the treatment also led to improvements in functional abilities and quality of life, as reported by caregivers.
“Fenfluramine shows promise as add-on therapy in severe [Rett] epilepsy and should be assessed in adequately powered controlled trials,” the researchers wrote.
The findings were published in the study “Use of fenfluramine in MECP2-related Rett syndrome: Findings from a retrospective multicenter pediatric case series” in the journal Epilepsy & Behavior.
More treatment options needed for drug-resistant epilepsy in Rett
In most cases of Rett syndrome, mutations in the MECP2 gene disrupt the production of a protein critical for brain development, leading to a range of debilitating symptoms. Seizures are a core manifestation of Rett, affecting an estimated 60% or more of those diagnosed.
Despite the range of anti-epileptic drugs available, roughly 1 in 3 patients will continue to have seizures that don’t respond to treatment.
Fenfluramine is currently approved as an add-on therapy for Dravet syndrome and Lennox-Gastaut syndrome, two other conditions characterized by seizures. Across both conditions, fenfluramine has been shown to reduce seizure frequency and improve cognitive function.
“Given the high prevalence of drug-resistant epilepsy in [Rett] and the substantial unmet therapeutic need, [fenfluramine] represents a rational candidate for investigation in this population,” the researchers wrote.
In this study, a team of scientists in Italy reviewed the outcomes of four girls, ages 9-14, with MECP2-related Rett and drug-resistant epilepsy who were treated with fenfluramine.
3 of 4 girls had fewer seizures on fenfluramine
The first patient had been experiencing multiple seizures every day despite trying more than nine different medications, vagus nerve stimulation, and a ketogenic diet.
Vagus nerve stimulation uses electrical impulses to stimulate the vagus nerve — a major nerve that runs from the brain to the heart, lungs, and digestive tract — and is approved to treat seizures that do not respond to medications. A ketogenic diet is one rich in fats and low in carbohydrates that is often used in children with uncontrolled epilepsy.
The girl started fenfluramine at age 8, and within a few days, tonic-clonic seizures — characterized by full-body stiffening (tonic) followed by rhythmic jerking (clonic), and described by caregivers as the most distressing type — were cut in half. Tonic seizures, a type of seizure that affects only one side of the body, disappeared entirely. The benefits were sustained for at least nine months.
Her parents also noticed she was more engaged in daily activities and less irritable. No side effects were reported.
The reduction of seizures and the potential simplification of drug treatment through the use of [fenfluramine] could also improve the cognitive aspects and life quality of patients and caregivers.
The second girl was also dealing with multiple seizures daily, even after trying several medications and a ketogenic diet. After starting fenfluramine at age 9, her seizures fell from around 40 per month to 10-12, a 70% reduction.
Both tonic-clonic and atypical absence seizures (brief episodes of staring or unresponsiveness) decreased, and her participation in activities and communication also improved. These gains held steady at 13 months of follow-up, with no side effects reported.
The third patient had multiple daily seizures that had not responded to many previous therapies and a ketogenic diet.
She did show some response to fenfluramine starting at age 13, with a 10%-12% reduction in seizures. However, the ideal dose for her body weight was never reached because side effects appeared — including apathy and slowed physical movements and mental processing. Although these effects resolved, and she restarted fenfluramine, seizure reduction remained limited.
The fourth patient began fenfluramine at the age of 7 after several other therapies, vagus nerve stimulation, and a ketogenic diet had failed. After one year, the medication had not reduced her seizures, and treatment was discontinued.
Across all four cases, caregivers reported no meaningful changes in sleep patterns. All patients received regular heart monitoring, including electrocardiograms and echocardiograms every six to 12 months, with consistently normal results.
“We hypothesize that the reduction of seizures and the potential simplification of drug treatment through the use of [fenfluramine] could also improve the cognitive aspects and life quality of patients and caregivers,” the researchers wrote.
“Future studies should include prospective controlled trials with larger cohorts of patients with [Rett] and long-term monitoring of seizure control and cognitive-behavioral outcomes,” they concluded.
