Abstracts

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 Naᵥ1.6 channels and modulates GABA-A receptors [1].


Methods: This single-center retrospective case series presents 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: A 21-year-old female with DS, with refractory epilepsy despite various combinations of 8 ASMs. CNB was then added to divalproex, clobazam, and fenfluramine and titrated over 12 months to 200mg daily. After addition of CNB, her generalized tonic-clonic seizures (GTC) decreased from 8-12 per month to 1 per month. She had seizure-free periods of up to 7 weeks.

Case 2: An 18-year-old male with DS, with frequent GTC seizures (12-20 per month) as well as recurrent status epilepticus (SE) despite various combinations of 8 ASMs. CNB was then added to oral diazepam and was slowly titrated to 100 mg daily. With addition of CNB, his seizure frequency decreased to 10-15 per month, with less clustering. No significant changes were noted in frequency of SE.

Case 3: A 17-year-old male with DS, with seizures refractory to various combinations of five ASMs and VNS. CNB added to valproic acid, clobazam, and stiripentol, and was gradually titrated to 100 mg daily. His baseline seizure frequency was 1-4 GTC seizures per month. He initially achieved a 2-month seizure-free period, however his seizure frequency returned to baseline after couple months. Additionally, CNB doses above 75 mg daily was reported to cause side effects.

Case 4: A 7-year-old female with DS, with frequent seizures as well as recurrent SE, refractory to multiple ASMs. CNB was added to her regimen of divalproex, clobazam and levetiracetam and titrated to 50 mg daily gradually. Patient had improvement of her baseline seizure frequency of 2-3 per month with a 7-month seizure-free period before two breakthrough seizures due to febrile illness. Patient then remained seizure free and no SE were reported while on CNB.


Conclusions: This case series suggests that CNB might be an effective alternative for the treatment of seizures in DS patients without serious side effects. Three of our patients from different age groups experienced significant improvement in their seizure control 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 Naᵥ1.6 channels in excitatory neurons appears to provide significant therapeutic benefits while minimizing side effects. Further investigations with larger cohorts warranted to better understand further clinical benefits and risks.

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



Funding: None