Cenobamate and Clobazam Combination as Personalized Medicine in Autoimmune-Associated Epilepsy With Anti-Gad65 Antibodies

Pedro J Serrano-Castro; Juan J Rodríguez-Uranga; Pablo Cabezudo-García; Guillermina García-Martín; Jorge Romero-Godoy; Guillermo Estivill-Torrús; Nicolás Lundahl Ciano-Petersen; Begoña Oliver; Jesús Ortega-Pinazo; Yolanda López-Moreno; Maria J Aguilar-Castillo; Antonio L Gutierrez-Cardo; Teresa Ramírez-García; Lorenzo Sanchez-Godoy; Mar Carreño

doi:10.1212/NXI.0000000000200151

Cenobamate and Clobazam Combination as Personalized Medicine in Autoimmune-Associated Epilepsy With Anti-Gad65 Antibodies

Neurol Neuroimmunol Neuroinflamm. 2023 Aug 22;10(6):e200151. doi: 10.1212/NXI.0000000000200151. Print 2023 Nov.

Authors

Pedro J Serrano-Castro¹, Juan J Rodríguez-Uranga², Pablo Cabezudo-García¹, Guillermina García-Martín², Jorge Romero-Godoy², Guillermo Estivill-Torrús², Nicolás Lundahl Ciano-Petersen², Begoña Oliver², Jesús Ortega-Pinazo², Yolanda López-Moreno², Maria J Aguilar-Castillo², Antonio L Gutierrez-Cardo², Teresa Ramírez-García², Lorenzo Sanchez-Godoy², Mar Carreño²

Affiliations

¹ From the Epilepsy Unit, Regional University Hospital of Málaga (P.J.S.-C., P.C.-G., G.G.-M., Y.L.-M); Institute for Biomedical Research of Málaga (IBIMA-Plataforma Bionand), Málaga (P.J.S.-C., P.C.-G., G.G.-M., N.L.C.-P., B.O., G.E.-T., J.O.-P., T.R.-G., L.S.-G.); Andalusian Network for Clinical and Translational Research in Neurology (Neuro-RECA), Spain (P.J.S.-C., J.J.R.-U., P.C.-G., G.G.-M., B.O.) University of Málaga (P.J.S.-C., B.O.); Vithas Hospital of Málaga, Spain (P.J.S.-C., P.C.-G.); Epilepsy Unit, Center for Avanced Neurology of Seville (J.J.R.-U.); Epilepsy Unit, Virgen de la Victoria University Hospital of Málaga (J.R.-G.), Biotechnology Unit, Regional University Hospital of Málaga (M.J.A.-C., L.S.-G.); Nuclear Medicina Unit, Regional University Hospital of Málaga (A.L.G.-C.); Epilepsy Unit, Clinic Hospital of Barcelona (M.C.), August Pi i Sunyer Biomedical Research Institute, Barcelona (M.C.), European Reference Network for Rare and Complex Epilepsies (EPICARE) (M.C.), Spain. pedro.serrano.c@gmail.com pablocabezudo@gmail.com.
² From the Epilepsy Unit, Regional University Hospital of Málaga (P.J.S.-C., P.C.-G., G.G.-M., Y.L.-M); Institute for Biomedical Research of Málaga (IBIMA-Plataforma Bionand), Málaga (P.J.S.-C., P.C.-G., G.G.-M., N.L.C.-P., B.O., G.E.-T., J.O.-P., T.R.-G., L.S.-G.); Andalusian Network for Clinical and Translational Research in Neurology (Neuro-RECA), Spain (P.J.S.-C., J.J.R.-U., P.C.-G., G.G.-M., B.O.) University of Málaga (P.J.S.-C., B.O.); Vithas Hospital of Málaga, Spain (P.J.S.-C., P.C.-G.); Epilepsy Unit, Center for Avanced Neurology of Seville (J.J.R.-U.); Epilepsy Unit, Virgen de la Victoria University Hospital of Málaga (J.R.-G.), Biotechnology Unit, Regional University Hospital of Málaga (M.J.A.-C., L.S.-G.); Nuclear Medicina Unit, Regional University Hospital of Málaga (A.L.G.-C.); Epilepsy Unit, Clinic Hospital of Barcelona (M.C.), August Pi i Sunyer Biomedical Research Institute, Barcelona (M.C.), European Reference Network for Rare and Complex Epilepsies (EPICARE) (M.C.), Spain.

Abstract

Background and objectives: Autoimmune-associated epilepsy (AAE) with antiglutamic acid decarboxylase 65 (GAD65) antibodies is considered a T-cell-mediated encephalitis that evolves to drug-resistant epilepsy. We do not have an effective therapeutic strategy for these patients. Because the GAD enzyme is primarily responsible for the conversion of glutamate to GABA, the mechanism of epileptogenesis in this condition predicts decreased levels of GABA content in synaptic vesicles. Cenobamate (CNB) acts as a positive allosteric modulator at synaptic and extra synaptic GABAA receptors, producing increased inhibitory neurotransmission in the brain. This mechanism could be especially beneficial in AAE with anti-GAD65 antibodies because it would be able to correct the imbalance due to the GABAergic stimulation deficit in postsynaptic neurons.

Methods: We recruit a retrospective multicentric consecutive case series of AAE with anti-GAD65 antibodies from 5 epilepsy units in Spain who have received treatment with CNB.

Results: A total of 8 patients were recruited. This cohort of highly refractory patients have failed a mean of 9.50 (SD = 3.20) ASM without control of seizures for sustained periods of time. The average number of seizures per month during the previous 3 months before CNB treatment was 19.63 (SD = 17.03). After the introduction of CNB improvement was achieved in all our patients, with a median reduction in the number of seizures of 92.22% (interquartile range [IQR]: 57.25-98.75). The mean follow-up was 156.75 days (SD = 68.23). In patients with concomitant treatment with clobazam (CLB), the median percentage of seizure reduction was higher than those not taking CLB: 94.72% (IQR: 87.25-100) vs 41.50% (p = 0.044) and also higher than the control group of patients with refractory epilepsy not related to anti-GAD65 treated with the same combination: 94.72% (IQR: 87.25-100) vs 45.00% (IQR: 25.00-87.00) (p = 0.019).

Discussion: Treatment with the combination CNB + CLB could be a type of personalized medicine in patients with AAE with anti-GAD65. Our preliminary data will need to be endorsed with new prospective and controlled studies.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Clobazam
Drug Resistant Epilepsy*
Epilepsy* / drug therapy
Humans
Precision Medicine
Prospective Studies
Retrospective Studies
Seizures
gamma-Aminobutyric Acid

Substances

Clobazam
Cenobamate
gamma-Aminobutyric Acid