Successful seizure control with cenobamate in juvenile myoclonic epilepsy

Juvenile myoclonic epilepsy (JME) is the most common form of idiopathic generalized epilepsy (IGE).¹ Although 80%–92% of patients can achieve long-term seizure freedom with pharmacotherapy, pharmacoresistance still remains a major challenge.^{1, 2} We present a patient's case with severe drug-resistant JME, who became seizure-free after the administration of a new antiseizure medication (ASM), cenobamate^{3, 4} as a rescue therapy with a follow-up of 2 years. This is the first report on the application of cenobamate in JME, and a noteworthy thereof, since a 100% reduction rate could be reached regarding generalized tonic–clonic seizures (GTCS).

The patient is a 28-year-old female with normal birth and psychomotor development, with no known epilepsy risk factors. Family history regarding epilepsy is negative. Apart from congenital divergent strabism, neurological physical examination is normal. Seizure onset was at the age of 18 years, when she suffered a GTCS. Shortly after, upper extremity myoclonic seizures appeared upon awakening on a daily basis. Triggering factors were menstruation, flickering lights, sleep deprivation, and alcohol consumption. Routine EEG was normal. EEG after sleep deprivation showed normal background activity and sleep structure with infrequent interictal 1–2 s long and even prolonged (5–10 s long) bursts with 3–3.5 Hz spike–wave and polyspike–wave complexes (Figure 1). Epilepsy protocol brain MRI was normal. The diagnosis of JME was established, slow titration of lamotrigine was started together with valproate. Reaching the therapeutic dose of lamotrigine, valproate was tapered off; however, it had to be re-added due to incomplete seizure control, without any significant improvement, though. In the subsequent years, levetiracetam, brivaracetam, zonisamide, felbamate, clobazam, and acetazolamide were introduced as either monotherapy or as add-on medication (Table S1); the patient was hospitalized repeatedly because of GTCSs. Regarding myoclonic seizures, no significant seizure reduction could be achieved with either medication. Average frequency of GTCSs was 2-3/month, myoclonic seizures appeared every day. In 2022, she was admitted to our video-EEG monitoring unit for further evaluation. During monitoring, normal background activity and physiological sleep structure were recorded with infrequent interictal 3–3.5 Hz spike–wave paroxysms and photomyoclonic response during photic stimulation. GTCS did not occur. Repeatedly performed epilepsy protocol brain MRI was normal. These results fortified a diagnosis of pharmacoresistant JME. Given the frequently occurring GTCS-associated increased risk of injury and sudden unexpected death, and since the patient preferred a last pharmacological attempt before neuromodulation therapy and perampanel was unavailable in Hungary that time, the off-label use of cenobamate as add-on therapy to lamotrigine–valproate–acetazolamide combination was initiated in October 2022. With a slow titration rate, the target dose of 200 mg could be reached in 11 weeks, resulting in seizure freedom in terms of GTCS, enabling valproate to be tapered off. As of October 2024, only infrequent myoclonic seizures are present.

Eight to twenty per cent of patients with JME become drug resistant, that is seizure freedom cannot be obtained with two adequately chosen and dosed, broad-spectrum ASM (valproate, lamotrigine, and levetiracetam as first-line, and brivaracetam, zonisamide, felbamate, and perampanel as second-line therapy).^{1, 5} The issue of drug resistance in JME is of great importance since GTCSs carry serious risk for injuries and sudden unexpected death (SUDEP). The mechanism of pharmacoresistence is still unclear: the role of pharmacogenetic-based changes in pharmacokinetics, altered cortico-cortico and cortico-subcortical networks, and minor focal lesions have been suggested,⁶ the latter corresponding with our previous study on increased number of minor physical anomalies in drug-resistant JME patients.⁷ EEG biomarkers, including focal discharges, asymmetric spike–wave and polyspike–wave discharges, generalized polyspike train, and generalized paroxysmal fast activity, also carry great importance.⁸

Cenobamate is a promising new ASM, approved as add-on treatment in patients with pharmacoresistant focal epilepsies,^{3, 4} although it showed a broad-spectrum antiseizure activity in animal models, which can be attributed to the synergistic effect of its mechanisms of action: the inhibition of non-inactivating sodium channels, and allosteric modulation of synaptic and extrasynaptic GABAA receptors.⁹ It has been detected that cenobamate suppresses photoparoxysmal response in patients with photosensitive epilepsy, a hallmark feature of IGEs.¹⁰ In a retrospective case series, two patients with juvenile absence epilepsy experienced significant reduction of GTCSs.¹¹

Our case highlights the important issue of therapy resistance in JME, arising from the risk of SUDEP, moreover serves as an example of possibly reaching therapy resistance with a promising new ASM.

None of the authors has any conflict of interest to declare.