Poster Number: 3.419

Rationale: Dravet syndrome (DS) is a genetic epilepsy syndrome associated with pathogenic variants in the SCN1A gene leading to dysfunction of Naᵥ1.1 sodium channel, which is present in both excitatory and inhibitory neurons. ASMs relying on nonselective sodium channel blockade are associated with worsening seizures. Cenobamate (CNB), a relatively new ASM, selectively targets the non-inactivating persistent component of the sodium current and modulates GABA-A receptors [1].


Methods: This single-center retrospective case series includes four DS patients treated with CNB. Seizure frequency, episodes of status epilepticus and side effects were evaluated following addition of CNB to their ASM regimen.


Results: Case 1: Case 1: A 21-year-old female with DS, with refractory epilepsy with recurrent episodes of status epilepticus despite various combinations of 8 ASMs. CNB was then added to her regimen of divalproex, clobazam, and fenfluramine and titrated over 12 months to 200mg daily without any serious side effects. After addition of CNB, her generalized tonic-clonic seizures decreased from 8-12 per month to 1 per month. She had seizure-free periods of up to 7 weeks. Non-convulsive seizures which used to happen almost daily has also reduced significantly.

Case 2: An 18-year-old male with DS, with frequent nocturnal generalized tonic-clonic seizures (12-20 per month) as well as recurrent episodes of status epilepticus despite various combinations of 8 ASMs. CNB was then added to his regimen of oral diazepam and was slowly titrated to 100 mg daily without any side effects. With addition of CNB, his seizure frequency decreased to 10-15 per month, with less clustering and reduced nocturnal seizures. No significant changes were reported in terms of frequency of status epilepticus.

Case 3: A 17-year-old male with DS, with seizures refractory to various combinations of five ASMs and VNS implantation. CNB, added to valproic acid, clobazam, and stiripentol, and was gradually titrated to 100 mg daily. His baseline seizure frequency was 1-4 generalized tonic-clonic seizures per month. Initially he had brief improvement in his seizures, achieving a 2-month seizure-free period. However, his seizure frequency returned to baseline after couple months. Additionally, CNB doses above 75 mg daily was associated with side effects including dizziness and balance issues.

Case 4: A 7-year-old female with DS, with refractory focal and generalized seizures as well as recurrent episodes of status epilepticus. Seizures were refractory to multiple ASMs in including topiramate and cannabidiol. CNB was added to her regimen of divalproex, clobazam and levetiracetam and titrated to 50 mg daily over the course of one month and continued at this dose. Patient’s baseline seizure frequency of 2-3 per month decreased with a 7-month seizure-free period before two breakthrough seizures due to febrile illness. No status epilepticus episodes were reported while on CNB.


Conclusions:This case series suggests that CNB effectively reduces seizure frequency and severity in DS patients without serious side effects. Three of our patients from different age groups, presenting with intractable epilepsy with various seizure types and severity, experienced significant improvement after addition of CNB. For one of our patients, response to therapy seemed to be transient and CNB dose titration was limited by side effects. CNB's targeted action on the non-inactivating persistent component of the sodium channels in excitatory neurons appears to provide significant therapeutic benefits while minimizing side effects. Further investigations with larger cohorts warranted to better understand clinical outcomes.

References:
1. Sankar, R., Treatment of status epilepticus: Physiology, pharmacology, and future directions. Epilepsia Open, 2023. 8: p. S141-S148.



Funding: None