Cenobamate Efficacy in Individuals With Autoimmune Epilepsy

Autoimmune Epilepsy

cenobamate, autoimmune epilepsy, epilepsy

Over the last decades, multiple neuronal autoantibodies directed against intracellular or cell-surface antigens have been identified in association with epilepsy and encephalopathy. In some patients with immune-mediated brain disorders, seizures persist and become chronic despite treatment with antiseizure medications (ASMs) and immunotherapy. This condition is particularly common in patients with antibodies against glutamic acid decarboxylase 65 (GAD65) or onconeural antigens (e.g., Hu, Ma2, and CRMP5/CV2). The persistence of seizures despite immunotherapy suggests the development of a sustained epileptogenic predisposition, consistent with the current conceptual definition of epilepsy. Cenobamate (CNB) is a recently approved antiseizure medication for the treatment of focal-onset seizures, with or without secondary generalization, in adults whose epilepsy remains uncontrolled despite prior treatment with at least two ASMs. CNB has demonstrated broad antiseizure efficacy, likely due to its dual mechanism of action: inhibition of the persistent component of voltage-gated sodium currents and positive allosteric modulation of GABAA receptors through a non-benzodiazepine mechanism. Recent retrospective data suggest that CNB may be effective in patients with anti-GAD65 autoimmune encephalitis, potentially compensating for impaired GABAergic neurotransmission associated with these antibodies. Other studies have also suggested that GABA-enhancing ASMs, such as benzodiazepines and barbiturates, may be beneficial in anti-GABAAR encephalitis, whereas sodium channel blockers may be effective in LGI1/CASPR2 antibody-associated encephalitis by reducing repetitive neuronal firing through interactions with voltage-gated sodium channels. The primary objective of this study is to determine the proportion of patients achieving a ≥50% reduction in seizure frequency during the 24 weeks following initiation of cenobamate compared with baseline seizure frequency. Secondary objectives include: evaluating the proportion of patients achieving ≥75% and 100% seizure reduction, assessing the safety and tolerability of cenobamate by documenting the frequency and severity of adverse events, analyzing the impact of CNB treatment on quality of life using validated scales such as the Clinical Global Impression (CGI) and the Hospital Anxiety and Depression Scale (HADS), exploring treatment efficacy according to the specific autoantibody subtype associated with autoimmune epilepsy.

In recent decades, multiple neuronal autoantibodies directed against cell-surface or intracellular antigens associated with epilepsy and/or encephalopathy have been discovered \[2\]. Some patients with immune-mediated brain diseases experience seizures that become chronic and are resistant to both antiseizure medications (ASMs) and immunotherapy. This occurs more frequently in patients with antibodies directed against glutamic acid decarboxylase 65 (GAD65) and against onconeural proteins (e.g., Hu, Ma2, collapsing response mediator protein 5/CV2). In this context, the persistence of seizures despite immunotherapy suggests a lasting predisposition, consistent with the current conceptual definition of epilepsy \[4\]. Cenobamate (CNB) is an antiseizure medication (ASM) recently approved for the treatment of focal-onset seizures, with or without secondary generalization, in adult patients with epilepsy inadequately controlled despite a history of treatment with at least two ASMs \[5\]. CNB has demonstrated broad-spectrum efficacy, exerting its antiseizure effect through a dual mechanism of action. In addition to inhibiting the persistent component of voltage-gated sodium currents, CNB also acts as a non-benzodiazepine positive allosteric modulator of GABAA channels \[6\]. The efficacy of CNB in the treatment of patients with anti-GAD65 encephalitis has been suggested by a recent retrospective study, hypothetically compensating for the deficit in GABAergic neurotransmission observed in autoimmune encephalitis associated with anti-GAD65 antibodies \[7\]. Furthermore, other studies have indicated that ASMs that enhance GABA transmission, such as benzodiazepines and barbiturates, may be beneficial in patients with anti-GABAAR encephalitis, whereas sodium channel blockers have demonstrated efficacy in the treatment of LGI1/CASPR2 antibody-associated encephalitis, reducing repetitive neuronal firing through interaction with voltage-gated sodium channels \[8\]. Primary objective: To determine the percentage of patients achieving a ≥50% reduction in seizure frequency during the 24 weeks following initiation of cenobamate treatment compared with the pre-treatment baseline. Secondary objectives: * To evaluate the proportion of patients achieving a ≥75% and 100% reduction in seizure frequency compared with baseline. * To evaluate the safety and tolerability of CNB by documenting the frequency and severity of adverse events. * To analyze the impact of CNB treatment on patients' quality of life using validated scales such as the Clinical Global Impression (CGI) and the Hospital Anxiety and Depression Scale (HADS). * To examine the efficacy of CNB according to the specific type of antibody associated with autoimmune epilepsy.

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