A small follow-up report describes years of seizure reduction in four adults with genetically confirmed Dravet syndrome who were treated with cenobamate. All four remained on the treatment during follow-up, producing a 100% retention rate. The clinical picture was not uniform: one patient remained free of daytime seizures but had nighttime convulsive seizures, another went from five convulsive seizures a week to one every six months, a third later worsened during suspected aspiration pneumonia, and a fourth lost seizure freedom after nearly three years. The findings are a signal for further study, not proof that cenobamate caused the improvements, because the review used retrospective records and included only treatment responders.
The report was a multi-center retrospective follow-up based on medical records and reports from patients and caregivers. It did not include a concurrent clinical control group, so the changes observed over time cannot establish a causal treatment effect.
The clinical results varied
Patient 1 had eight generalized tonic-clonic seizures a month before treatment. At 43 months, the person had no daytime seizures but still had three to four nocturnal seizures a month. The report described this as more than 80% seizure reduction; clobazam had been stopped because of sedation, and cenobamate was continued alone.
Patient 2 began with five generalized tonic-clonic seizures a week. After 44 months on 200 milligrams a day of cenobamate, the reported frequency was one seizure every six months.
Patient 3's baseline of five to 10 seizures a month fell to two a month at 26 months. During suspected aspiration pneumonia, control worsened to three to four GTCS a month plus multiple focal seizures each day. The patient was later reported to have succumbed to SUDEP at home. Patient 4 had 20 seizures a month before treatment and was seizure-free for 34 months on 200 milligrams a day, but later had about three seizures a week. Fatigue and drowsiness prevented further dose increases.
Cell tests pointed to weaker channel function
To examine the biology behind the cases, the researchers put normal and patient-specific SCN1A channels into HEK293T cells. They used blinded immunofluorescence to see where the channel protein was located, and whole-cell patch-clamp recordings, an electrical testing method, to measure sodium currents. The localization work drew on three independent cell cultures.
Western blotting detected all three missense variants but not the truncating L780* variant, consistent with little or no detectable protein from the premature stop variant. Among the detectable missense variants, the channel signal overlapped strongly with the plasma membrane and only weakly with a marker for the endoplasmic reticulum, an internal cell compartment. The results gave no evidence of prominent ER retention, while the Patient 3 variant was not detectable in the localization analysis.
Electrical recordings classified all four variants as loss-of-function, meaning their peak sodium current was lower than the normal reference. L780, D1288Y and C1588R produced 17% or less of the current seen with WT, while Y202D retained about 62%. The spread shows that the variants impaired the channel to different degrees, even though all were functionally abnormal in this assay.
An additional experiment tested whether cenobamate immediately altered peak current density. At 300 μM, acute exposure produced no significant change in either WT or Y202D channels in paired recordings from 13 WT cells and 17 Y202D cells. This narrow result does not show what long-term treatment does in people; it shows only that the tested acute exposure did not change this one electrical measurement in the cell system.
A result that needs a larger test
The authors say cenobamate may be an option for selected adults with genetically confirmed Dravet syndrome, but they also call for larger prospective studies. The clinical evidence came from only four previously reported adults, all of whom remained on treatment and were included as responders. That design cannot show how well cenobamate would work for nonresponders or establish efficacy and safety across the wider Dravet syndrome population.
The work was supported by the Einstein Stiftung Fellowship, Sonnenfeld-Stiftung, BMBF through DZKJ, and unconditional Angelini Pharma support. Christian Boßelmann also received support from the MINT-Clinician Scientist program funded by the DFG under grant 493665037.
Paper data and sources
Original title: Cenobamate in Dravet syndrome with electrophysiologically confirmed SCN1A loss-of-function variants: long-term real-world follow-up
Authors: Fenske P, Abrahamyan A, Makridis K et al.
Journal/Repository: Frontiers in pharmacology
Status: Peer-reviewed
First online: 2026-10-08
DOI: Not available
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