Seizure Reduction with Cenobamate in a Pediatric Patient with Refractory Generalized Epilepsy: A Case Report

doi:10.21203/rs.3.rs-5321423/v1

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Case Report

Seizure Reduction with Cenobamate in a Pediatric Patient with Refractory Generalized Epilepsy: A Case Report

https://doi.org/10.21203/rs.3.rs-5321423/v1

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Cenobamate (CNB) is a newer anti-seizure medication (ASM) approved by Food and Drug Administration (FDA) for adjunctive treatment of focal onset seizures in adults. Preclinical data indicates that CNB may have broad spectrum anti-seizure properties. A recently published small case study has reported that CNB led to improvement in seizure frequency in patients with generalized epilepsy. We present a pediatric patient with refractory generalized epilepsy who presented to our institution in status epilepticus consisting of bilateral facial and upper extremity twitching. After a prolonged hospitalization for refractory status epilepticus, he experienced a clinically significant reduction in seizure frequency with utilization of CNB. Our case adds to sparse literature available for the efficacy of utilizing CNB in a patient with refractory generalized epilepsy.

Neurology

Cenobamate

generalized epilepsy

refractory seizures

Cenobamate (CNB) is a relatively new anti-seizure medication (ASM) that has received approval from the Food and Drug Administration (FDA) for the adjunctive treatment of focal onset seizures in adults. Emerging preclinical data suggests that CNB may also be effective in the management of generalized epilepsy [1]. Recent clinical evidence supports this potential, with a case study demonstrating that CNB can lead to a significant reduction in seizure frequency, with patients experiencing a reduction greater than 50% [2]. Moreover, a retrospective data analysis has indicated that CNB can significantly improve seizure control in intellectually disabled patients with drug-resistant epilepsy, allowing for a reduction in drug load [3]. In another study, CNB showed promise in older adults with uncontrolled focal seizures, suggesting its benefits may extend across different patient demographics [4]. We present a case of a pediatric patient with refractory generalized epilepsy who, upon initiation of CNB treatment, experienced a clinically meaningful decrease in seizure frequency, aligning with the broader trends observed in recent research.

The patient is a 17-year-old Hispanic right-handed male with refractory genetic generalized epilepsy with multiple seizure types including eyelid myoclonia and absence seizures. His seizures began at 9 months old with staring spells and behavioral arrest with eyelid myoclonia, occurring at least 10 times per day. Around age 14, his seizures progressed to episodes of impaired awareness with facial and upper extremity twitching. He was found to have variants of uncertain significance in PECX5, SPTAN1, SZT2 on genetic testing and microcephaly identified on MRI brain.

In 2023, the patient was presented to our institution in status epilepticus with bilateral facial and upper extremity twitching. At the time of admission, the patient was taking six anti-seizure medications: valproic acid, levetiracetam, lacosamide, ethosuximide, clobazam, and zonisamide. During this admission, long-term video EEG (vEEG) monitoring revealed frequent electro-clinical seizures. These seizures manifested as eyelid myoclonia and impaired awareness, accompanied by generalized spike wave and polyspike wave discharges. Various anti-seizure medication (ASM) combinations were attempted during his admission, including his home ASMs, perampanel, phenobarbital, and lamotrigine. Minimal improvement occurred until cenobamate was initiated. After 20 days of admission, the patient was discharged on a regimen of levetiracetam, phenobarbital, topiramate, clobazam, perampanel, and a titration package of cenobamate.

Initially post discharge, he continued to have 6–8 typical seizures per day, each lasting 10–13 minutes. Upon reaching optimal dose of cenobamate 200mg, he began experiencing greater than 50% seizure reduction with average 1–2 seizure a day, including periods of up to 3–4 days with complete seizure freedom. He currently remains on cenobamate 200mg daily in addition to maximum doses of levetiracetam, clobazam, topirmate. He was able to successfully wean off of phenobarbital and perampanel in the outpatient setting. He will be undergoing implantation of a responsive neurostimulation (RNS) device in the bilateral centromedian nuclei in hopes to optimize his seizure control.

Currently, CNB is approved for treating focal onset seizures in the USA and Europe. Randomized controlled trials have demonstrated a ≥ 50% reduction in seizure frequency when CNB is used as an adjunctive treatment at a dosage of 200 mg/day [5]. Currently, the efficacy of CNB in primary generalized epilepsy syndromes is unknown and in the process of being studied in clinical trial.

The proposed mechanism of action for cenobamate is via blockage of persistent sodium channel currents as well as positive allosteric modulator of the γ-aminobutyric acid-A (GABA-A) receptor [6, 7]. Previous preclinical studies of CNB have demonstrated the potential for it to be a broad-spectrum anti-seizure medication useful for the treatment of both focal and generalized epilepsies [5, 7].

In a recent small case study, 5 out of 6 patients with frequent generalized tonic-clonic (GTC) seizures experienced a ≥ 50% reduction in seizures. The study included a total of 13 patients: 4 with genetic generalized epilepsy (GGE) and 9 with combined generalized focal epilepsy (CGFE). Within the same study, a 16-year-old patient with eyelid myoclonia and absence seizures experienced a 30% reduction in seizures. Additionally, a 20-year-old patient with eyelid myoclonia, absence seizures, and GTC experienced a 100% reduction in GTC [2].

Our case demonstrates the efficacy of utilizing CNB in a patient with refractory generalized epilepsy. Although the patient did not experience complete seizure freedom, he did however have a significant reduction in seizures that has improved his quality of life allowing him to resume his education and partake in extracurricular activities. Our case report adds to existing sparse literature of CNB use in generalized epilepsy. A larger randomized controlled trial is warranted to confirm efficacy of CNB in generalized epilepsy.

"Informed consent has been obtained from the patient. The patient also consented to publish the case report."

Sharma R, Nakamura fM, Neupane C et al (2020) Positive allosteric modulation of GABAA receptors by a novel antiepileptic drug cenobamate. Eur J Pharmacol 879:173117. 10.1016/j.ejphar.2020.173117
Agashe S, Worrell G, Britton J (2023) Cenobamate in Generalized Epilepsy and Combined Generalized and Focal Epilepsy. Neurol Clin Pract 13:200133–200110. 10.1212/CPJ.000000000020013
Friedo AL, Greshake B, Makridis KL, Straub HB (2023) Cenobamate significantly improves seizure control in intellectually disabled patients with drug-resistant epilepsy and allows drug load reduction. Front Neurol 17:1209487. 10.3389/fneur.2023.1209487
O’Dwyer R, Stern S, Wade Safety and Efficacy of Cenobamate for the Treatment of Focal Seizures in Older Patients: Post Hoc Analysis of a Phase III, Multicenter, Open-Label Study. Drugs Aging 41:251–260. 10.1007/s40266-024-01102-3
Chung SS, French JA, Kowalski J (2020) Randomized phase 2 study of adjunctive cenobamate in patients with uncontrolled focal seizures. Neurology 2:2311–2322. 10.1212/WNL.0000000000009530
Rissardo JP, Fornari Caprara AL (2023) Cenobamate (YKP3089) and Drug-Resistant Epilepsy: A Review of the Literature. Medicina 59:1389. 10.3390/medicina5908138
Löscher W, Klein P The Pharmacology and Clinical Efficacy of Antiseizure Medications: From Bromide Salts to Cenobamate and Beyond. CNS Drugs 35:935–963. 10.1007/s40263-021-00827-8

The authors declare no competing interests.

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Seizure Reduction with Cenobamate in a Pediatric Patient with Refractory Generalized Epilepsy: A Case Report

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