Barnard Sarah N, Chen Zhibin, Holmes Manisha, Kanner Andres M, Hegde Manu, Kuzniecky Ruben, Lowenstein Daniel, French Jacqueline A
School of Translational Medicine, Monash University, Melbourne, Victoria, Australia.
Alfred Health, Melbourne, Victoria, Australia.
JAMA Neurol. 2025 Aug 25. doi: 10.1001/jamaneurol.2025.2949.
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.
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.
ASM (variable).
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).
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).
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.
ClinicalTrials.gov Identifier: NCT02126774.
癫痫影响着全球约6500万人，其中60%患有局灶性癫痫发作。预测局灶性癫痫患者对抗癫痫药物（ASM）的癫痫发作反应和耐药性仍然很困难。
使用国际抗癫痫联盟认可的定义，描述局灶性癫痫患者接受ASM治疗的预期短期和长期反应。
设计、背景和参与者：人类癫痫项目是一项国际前瞻性观察性队列研究，在2012年至2020年间对新诊断的局灶性癫痫患者进行了长达6年的随访。2023年至2024年对数据进行了分析。人类癫痫项目在美国、澳大利亚和欧洲的34个三级癫痫中心开展。确诊为局灶性癫痫、年龄在12至60岁之间的参与者在开始使用ASM治疗的4个月内入组。2024年2月至2024年7月对数据进行了分析。
ASM（变量）。
主要结局是无癫痫发作，定义为无癫痫发作12个月或最长治疗前无癫痫发作间隔的3倍，以较长者为准。治疗反应分为敏感，即接受2次或更少充分的ASM试验后无癫痫发作；耐药，即2次或更多充分的ASM试验失败；或不确定（既非治疗敏感也非耐药）。
在448名入组参与者中，267名（59.6%）为女性，治疗开始时参与者的年龄中位数（四分位间距）为32（21 - 44）岁。随访时间中位数（四分位间距）为3.13（2.33 - 3.55）年。大多数人实现了无癫痫发作（448名参与者中的267名[59.6%]），且大多无复发（223名[83.5%]）。有245名治疗敏感的参与者（54.7%），102名治疗耐药的参与者（22.8%），以及101名不确定的参与者（22.5%）。在治疗敏感的参与者中，大多数（217名[89.3%]）对单药治疗有反应，一半（121名[49.4%]，占总队列的27%）在接受首次ASM治疗时实现了无癫痫发作。在治疗的第一年，251名参与者（63%）有持续或恶化的癫痫发作。首次无癫痫发作的中位时间为12.1个月（95%置信区间，9.7 - 16.1）。这在从未复发的参与者中出现得更早（中位数，2.2个月；95%置信区间，0.8 - 3.2），而在复发的参与者中则为（中位数，7.4个月；95%置信区间，4.0 - 10.7）。治疗前癫痫发作不频繁的参与者比癫痫发作非常频繁的参与者耐药的可能性高0.41倍（相对风险[RR]，0.41；95%置信区间，0.18 - 0.89；P = 0.03；经HB校正的P = 0.02）。自我报告有合并心理障碍的参与者比没有的参与者耐药的可能性高1.78倍（RR，1.78；95%置信区间，1.26 - 2.52；P = 0.001）。
在人类癫痫项目多中心前瞻性队列研究中，大多数新诊断的局灶性癫痫患者需要一年多时间且使用超过1种ASM才能实现无癫痫发作。在治疗前癫痫发作频繁的患者中可以更早地识别出耐药性，并且癫痫诊断时的精神疾病合并史是一个重要的预后因素。
ClinicalTrials.gov标识符：NCT02126774。
