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. 2025 Aug 25:e252949.
doi: 10.1001/jamaneurol.2025.2949. Online ahead of print.

Treatment Response to Antiseizure Medications in People With Newly Diagnosed Focal Epilepsy

Sarah N Barnard  1   2 , Zhibin Chen  1 , Manisha Holmes  3 , Andres M Kanner  4 , Manu Hegde  5 , Ruben Kuzniecky  6 , Daniel Lowenstein  5 , Jacqueline A French  7 ; Human Epilepsy Project (1) Investigators
Collaborators, Affiliations

Treatment Response to Antiseizure Medications in People With Newly Diagnosed Focal Epilepsy

Sarah N Barnard et al. JAMA Neurol. .

Abstract

Importance: Epilepsy affects approximately 65 million people worldwide, and 60% have focal seizures. Predicting seizure response and drug resistance to antiseizure medications (ASMs) in people with focal epilepsy remains difficult.

Objective: To describe the expected short- and long-term response to treatment with ASMs in people with focal epilepsy using recognized definitions by the International League Against Epilepsy.

Design, setting, and participants: The Human Epilepsy Project is an international, prospective, observational cohort study that followed up people with newly diagnosed focal epilepsy for up to 6 years between 2012 and 2020. Data were analyzed from 2023 to 2024. The Human Epilepsy Project was conducted at 34 tertiary epilepsy centers across the US, Australia, and Europe. Participants with confirmed diagnosis of focal epilepsy aged 12 to 60 years were enrolled within 4 months of treatment initiation with ASM(s). Data were analyzed from February 2024 to July 2024.

Exposure: ASM (variable).

Main outcomes and measures: The primary outcome was seizure freedom, defined as a period without seizures for 12 months or 3 times the longest pretreatment seizure-free interval, whichever was longer. Treatment response was categorized as sensitive, meaning seizure free receiving 2 or fewer adequate ASM trials; resistant, meaning having 2 or more adequate ASM trials fail; or indeterminate (neither treatment sensitive nor resistant).

Results: Among 448 enrolled participants, 267 (59.6%) were female, and median (IQR) participant age was 32 (21-44) years at treatment initiation. Median (IQR) follow-up duration was 3.13 (2.33-3.55) years. Most achieved seizure freedom (267 participants of 448 [59.6%]), largely without relapse (223 [83.5%]). There were 245 treatment-sensitive participants (54.7%), 102 treatment-resistant participants (22.8%), and 101 indeterminate participants (22.5%). Among treatment-sensitive participants, most (217 [89.3%]) responded to monotherapy and half (121 [49.4%], or 27% of total cohort) became seizure free while receiving their first ASM. In the first year of treatment, 251 participants (63%) had ongoing or worsening seizures. Median time to first seizure freedom was 12.1 months (95% CI, 9.7-16.1). This occurred earlier in those who never relapsed (median, 2.2 months; 95% CI, 0.8-3.2) than those who did (median, 7.4 months; 95% CI, 4.0-10.7). Those with infrequent pretreatment seizures were 0.41-fold more likely to be treatment resistant than those with very frequent seizures (relative risk [RR], 0.41; 95% CI, 0.18-0.89; P = .03; HB-corrected P = .02). Participants with self-reported comorbid psychological disorders were 1.78-fold more likely to be treatment resistant than those without (RR, 1.78; 95% CI, 1.26-2.52; P = .001).

Conclusions and relevance: In the Human Epilepsy Project multicenter prospective cohort study, most people with newly diagnosed focal epilepsy took more than a year and more than 1 ASM to become seizure free. Drug resistance can be identified earlier in those with frequent pretreatment seizures, and a history of psychiatric comorbidities at epilepsy diagnosis is an important prognostic factor.

Trial registration: ClinicalTrials.gov Identifier: NCT02126774.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Barnard reported paid employment by the Epilepsy Study Consortium Inc (ESCI) related to management of Human Epilepsy Project (HEP) operations (including maintaining the study database, data sharing, and data quality monitoring) during the conduct of the study. This work forms part of Dr Barnard’s doctoral research, which is funded by the National Health Medical Research Council of Australia. Dr Chen reported grants from The National Health and Medical Research Council of Australia and from UCB Pharma outside the submitted work. Dr Kanner reported honoraria from the Epilepsy Foundation for serving as co–Editor in Chief of Epilepsy.com and honoraria for advisory board participation from Neurelis and Xenon Laboratories outside the submitted work. Dr Lowenstein reported grants from ESCI during the conduct of the study and serving on the Scientific Advisory Board of Aligning Research to Impact Autism. Dr French reported support for the HEP study and consultation on behalf of ESCI from UCB; grants to ESCI by the Andrews Foundation, Eisai, Engage, Lundbeck, Pfizer, SK Life Science, Sunovion, UCB, and the Vogelstein Foundation during the conduct of the study; consultations on behalf of ESCI for Acadia Pharmaceuticals, Access Industries, Acuta Capital Partners, AfaSci, AgriThera, Alterity Therapeutics, Arvelle Therapeutics, Autifony Therapeutics, Axonis, Baergic Bio, Bain Capital, Beacon Biosignals, Biogen, Bloom Science, BridgeBio Pharma, Bright Minds Biosciences, CAMP4 Therapeutics Corporation, Capsida Biotherapeutics, Cerecin, Cerevel, Coda Biotherapeutics, Cognizance Biomarkers, Crossject, EcoR1 Capital, Eisai, Eliem Therapeutics, Encoded Therapeutics, Engrail, Epalex, Epihunter, Epiminder, Epitel, Equilibre BioPharmaceuticals, Genentech, Grin Therapeutics, GW Pharma, Ionis, iQure Pharma, IQVIA RDS, Janssen, Jazz Pharmaceuticals, Knopp Biosciences, Korro Bio, Leal Therapeutics, Lipocine, LivaNova, Lundbeck, Marinus, Medscape, Modulight Bio, Mosaica, Neuroelectrics USA Corporation, Neurona Therapeutics, Neuronetics, NeuroPro Therapeutics, Neuroventis, Noema, Ono Pharmaceutical Co., Otsuka Pharmaceutical Development, Ovid Therapeutics, Paladin Labs, Pfizer, PureTech, Rafa Laboratories, Receptor Holdings, Rivervest Venture Partners, Sage Therapeutics, Stoke, Stream Neuroscience, Supernus Consults, Taysha Gene Therapies, Third Rock Ventures, uniQure, Vida Ventures, and Zogenix; consultations on behalf of ESCI and travel reimbursement from Angelini Pharma S.p.A, Biohaven Pharmaceuticals, Cerebral Therapeutics, the Ceribell Clinical Education Alliance, Cowen and Company, Harmony/Epygenix, Longboard Pharmaceuticals, Neumirna Therapeutics, Neurelis, Neurocrine, Neuropace, Neurvati, Praxis, Rapport Therapeutics, SK Life Sciences, Takeda, Ventus Therapeutics, and Xenon; serving as President of and receiving travel reimbursement from ESCI; serving as Chief Medical/Innovation Officer of and receiving travel reimbursement from the Epilepsy Foundation; grants to the ESCI/Epilepsy Foundation by UCB; grants from GW/Finding A Cure for Epilepsy and Seizures/One8Foundation, Praxis, and the US National Institute of Neurological Disorders and Stroke outside the submitted work; serving on the editorial boards of Lancet Neurology and Neurology Today and as Medical Director of the Epilepsy Foundation; serving as President of and on the Board of Directors for ESCI; and receiving salary support from ESCI. No other disclosures were reported.

References

    1. Fiest KM, Sauro KM, Wiebe S, et al. Prevalence and incidence of epilepsy: a systematic review and meta-analysis of international studies. Neurology. 2017;88(3):296-303. doi: 10.1212/WNL.0000000000003509 - DOI - PMC - PubMed
    1. Thurman DJ, Logroscino G, Beghi E, et al. ; Epidemiology Commission of the International League Against Epilepsy . The burden of premature mortality of epilepsy in high-income countries: a systematic review from the Mortality Task Force of the International League Against Epilepsy. Epilepsia. 2017;58(1):17-26. doi: 10.1111/epi.13604 - DOI - PMC - PubMed
    1. Beghi E, Giussani G, Abd-Allah F, et al. ; GBD 2016 Epilepsy Collaborators . Global, regional, and national burden of epilepsy, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol. 2019;18(4):357-375. doi: 10.1016/S1474-4422(18)30454-X - DOI - PMC - PubMed
    1. Ioannou P, Foster DL, Sander JW, et al. The burden of epilepsy and unmet need in people with focal seizures. Brain Behav. 2022;12(9):e2589. doi: 10.1002/brb3.2589 - DOI - PMC - PubMed
    1. Chen Z, Brodie MJ, Liew D, Kwan P. Treatment outcomes in patients with newly diagnosed epilepsy treated with established and new antiepileptic drugs a 30-year longitudinal cohort study. JAMA Neurol. 2018;75(3):279-286. doi: 10.1001/jamaneurol.2017.3949 - DOI - PMC - PubMed

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