Dose-dependent Absence Status Epilepticus Associated with Cenobamate Treatment
Abstract number :
2.391
Submission category :
7. Anti-seizure Medications / 7D. Drug Side Effects
Year :
2024
Submission ID :
1137
Source :
www.aesnet.org
Presentation date :
12/8/2024 12:00:00 AM
Published date :
Authors :
Presenting Author: Gurpreet Seehra, MD – UCLA Mattel Children's Hospital, David Geffen School of Medicine
Jacqueline Ngo, MD – UCLA Mattel Children's Hospital, David Geffen School of Medicine
Catherine Stanecki, DO, MS – University of California Los Angeles Medical Center
Nicole Cobo, MD – Miller Children's Hospital
Shaun Hussain, MD, MS – UCLA Mattel Children's Hospital, David Geffen School of Medicine
Raman Sankar, MD, PhD – University of California, Los Angeles
Rationale: Treatment of focal-onset seizures with cenobamate (CBM) is supported by controlled clinical trials, and several small retrospective studies have suggested favorable efficacy in children, as well as patients with Lennox-Gastaut syndrome (LGS) and Dravet syndrome. From a tolerability standpoint, few side effects have been reported aside from dose-dependent sedation, and drug reaction with eosinophilia and systemic symptoms (DRESS) in the setting of rapid dose titration. In this case series, we describe four patients with treatment-emergent absence status epilepticus.
Methods: This study is a retrospective case series. All patients were identified informally through the course of routine clinical care. Clinical presentations, electroencephalography (EEG) data, and attributes of CBM exposure were extracted from the electronic medical record.
Results: We identified four children with fulminant presentation of absence status epilepticus, all in the setting of CBM. During this span in which these four cases presented, no other cases of absence status epilepticus were identified at either participating medical center. A representative sample of EEG from patient 1 is presented in the Figure. EEG confirmation of absence status epilepticus was documented in each case. For each patient, absence status epilepticus appeared to be dose dependent, and resolution of absence seizures occurred in all patients without complete discontinuation of CBM. However, in all cases, efficacy of CBM was compromised by dose reduction.
Conclusions: This report signals potential dose-dependent risk of absence status epilepticus associated with CBM. The mechanisms of action of CBM include a selective blockade of persistent sodium currents over transient sodium currents which are important on fast-spiking, parvalbumin-positive, GABAergic interneurons (Nakamura et al, 2019) and a selective positive allosteric modulation of GABA-mediated tonic chloride currents (Sharma et al, 2020). Phasic currents mediated by synaptic GABA receptors are reversed by flumazenil; flumazenil had no effect on CBM-enhanced tonic currents. We hypothesize that in susceptible individuals the increase in tonic current, especially in thalamo-cortical circuits, likely involving the nucleus reticularis thalami, lowers the membrane potential to the range that triggers low-threshold calcium currents which in turn trigger the EPSPs triggering spike-waves (Crunelli et al, 2002; Leresche et al, 2012). The role of low-threshold calcium currents in generalized spike-wave epilepsy dates back to the description of the mode of action of specific petit-mal anticonvulsants (Coulter et al, 1989). Further study is warranted to better quantify the risk of absence status epilepticus and identify other risk factors.
Funding: None
Anti-seizure Medications