Synergistic seizure reduction in patient with persistently elevated N-desmethylclobazam levels, CYP450 genetic polymorphism, and responsive neurostimulator targeting centromedian nuclei of bilateral thalami

Abstract

Clobazam (CLB) and cenobamate (CNB) are commonly used antiseizure medications (ASMs) in the treatment of patients with drug-resistant epilepsy (DRE). However, concomitant use of these two ASMs may lead to significant treatment-related adverse events (TRAE). Furthermore, these TRAE may be exacerbated in individuals with genetic polymorphisms involving the P450 system. In patients with DRE, epilepsy surgery, including neuromodulation, may lead to improved seizure control and a reduction in systemic TRAE from ASMs. This case report describes a patient with drug-resistant idiopathic generalized epilepsy (IGE) who experienced persistent excessive somnolence correlated with elevated N-desmethylclobazam (N-CLB) levels. Pharmacogenetic testing revealed poor metabolism of CYP2C19, and N-CLB levels remained elevated and detectable for nearly one year after the discontinuation of treatment with CLB and CNB. Responsive neurostimulator (RNS) implantation within the bilateral centromedian nuclei (CMN) of the thalamus resulted in seizure freedom until N-CLB levels fell, after which there was an 83-93 % reduction in the frequency of generalized tonic-clonic seizures (GTC).

Keywords: Cenobamate; Clobazam; Idiopathic generalized epilepsy; Pharmacogenetics; Responsive neurostimulator.

Fig. 1

A–D: Scalp EEG. This figure provides representative scalp EEG epileptiform abnormalities from inpatient video-EEG monitoring. A–C are 15 s epochs of EEG, while Fig. 1D is a 30 s EEG epoch. The scalp EEG settings are as follows: Sensitivity – 7 uV, HFF – 70 Hz, LFF – 0.53 Hz. Fig. 1A is a burst of 3 Hz generalized spike/polyspike-and-wave discharges during wakefulness that is not associated with a change in clinical behavior. Fig. 1B is interictal epileptiform activity embedded within physiologic sleep architecture. Fig. 1C illustrates an interictal epileptiform discharge with features suggestive of a generalized polyspike train, which has been associated with drug-resistant IGE [24]. Fig. 1D is a 30 s EEG epoch of the onset of a GTC.

Fig. 2

Clinical Course. This figure illustrates the clinical course of GTC with respect to treatment with LTG, CLB, and CNB as well as corresponding CLB and N-CLB. The average number of GTC is represented on the Y-axis, and the months are delineated on the X-axis. The dose of LTG remained relatively constant during this time. Treatment with CLB was discontinued in September 2023, and treatment with CNB was discontinued in October 2023. Note the persistently elevated N-CLB corresponded to prolonged freedom from GTC. As the N-CLB began to significantly decrease in March 2024, GTC recurred. Prior to RNS implantation in August 2023, she could have up to 3–7 GTC per month. After RNS implantation and nondetectable N-CLB levels, in November 2024 she averaged 1 GTC every other month.

Fig. 3

A–B: Responsive neurostimulator (RNS) Electrocorticography (ECoG). The recorded GTC was her first GTC after RNS implantation, nearly 9 months after RNS implantation. Fig. 3A is the 90-second ECoG, while 3B is a 10 s viewing window of the GTC onset. The red outline in both Fig. 3A and 3B represents the GTC onset, while the red arrow illustrates these time points between different viewing windows. Note, Fig. 3B scale is 4 times that Fig. 3A to better illustrate the GTC onset. The blue boxes labeled Tx are treatment delivered by RNS. The boxes labeled A1 and A2 are the RNS detections, while the box LE corresponds to RNS long episode. In this GTC, RNS detection and therapy occur within approximately 1 s of the electrographic onset. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)