Abstract
Barnard SN, Chen Z, Holmes M, Kanner AM, Hegde M, Kuzniecky R, Lowenstein D, French JA. JAMA Neurol. 2025 Aug 25:e252949. doi: 10.1001/jamaneurol.2025.2949. Epub ahead of print. PMID: 40853673 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 0.30-fold less likely to be treatment resistant than those with very frequent seizures (hazard ratio, 0.30; 95% CI, 0.14–0.64; P = .002; Holm–Bonferroni-corrected P = .006). Participants with self-reported comorbid psychological disorders were 1.78-fold more likely to be treatment resistant than those without (relative risk, 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.
Commentary
Epilepsy affects approximately 65 million people worldwide, 1 with approximately 60% experiencing focal seizures. 2 It profoundly impacts neurological function and overall health, contributing to increased premature mortality, substantial lifetime morbidity, poorer educational and employment outcomes, higher psychiatric comorbidity, and reduced quality of life. 3 Initial management typically involves selecting antiseizure medications (ASMs) based on seizure type, guided by clinical semiology and electroencephalography—an approach that remains intuitive and practical in routine practice. 4 A major challenge is identifying the most effective ASM quickly to minimize the risks of ongoing seizures. With over 25 ASMs available, predicting individual response is difficult. 5 While genomic sequencing enables personalized therapy for certain genetic epilepsies, most patients lack treatments targeting underlying disease mechanisms, leaving optimization largely reliant on trial and error. 4
Achieving seizure freedom is the central goal of epilepsy management, yet the pathway is often unpredictable. Historically, up to two-thirds of newly diagnosed patients achieve seizure control with their first ASM, but real-world experience shows multiple trials, dose adjustments, and prolonged treatment are required. 6 Predicting ASM response in newly diagnosed focal epilepsy is challenging, highlighting the need to understand early treatment trajectories to guide decisions, set realistic expectations, and identify patients at risk of drug resistance. Barnard et al 7 addressed these challenges using data from the Human Epilepsy Project (HEP), a multicenter, prospective cohort at 34 tertiary centers in the United States, Australia, and Europe. Participants aged 12–60 years with newly diagnosed focal epilepsy were followed up to 6 years. Seizure freedom was defined as ≥12 months or 3 times the longest pretreatment seizure-free interval. Treatment response was categorized as sensitive (seizure freedom after 1 or 2 ASM trials), resistant (failure of 2 or more ASM trials), or indeterminate (neither sensitive nor resistant).
Key findings included that ∼60% of participants achieved seizure freedom, most without relapse. 7 By the end of follow-up, 55% were treatment-sensitive, 23% treatment-resistant, and 22.5% indeterminate. Among treatment-sensitive participants, 89.3% responded to monotherapy: 49.4% became seizure-free on their first ASM (27% of all participants) and 50.6% on their second (27.7%). In contrast, 20.6% of treatment-resistant patients (5% of all participants) achieved seizure freedom after 3 or more trials. Median time to seizure freedom was 12 months, and the first year was most challenging, with 63% continuing seizures, including subtle episodes. Levetiracetam was the most common first-line ASM by a considerable margin. Patients without relapse achieved seizure freedom faster (median 2.2 months) than those who relapsed (7.4 months). Most who developed resistance were identified within 6–8 months. Psychiatric comorbidity and seizure frequency predicted outcomes: participants with psychological disorders were 1.78 times more likely to be treatment-resistant, while those with infrequent seizures were 1.36 times more likely to be treatment-sensitive compared with patients experiencing weekly seizures.
Several insights emerge from the highlighted study. 7 Most individuals with newly diagnosed focal epilepsy require more than 1 ASM and over a year to achieve sustained seizure freedom. In the first 12 months, recurrent seizures and disruptions to daily functioning are common, and only about 1 in 4 patients achieve control with their initial ASM. Seizure freedom remains attainable but often requires perseverance and iterative therapy optimization. Crucially, ongoing seizures early in treatment do not necessarily indicate long-term drug resistance; half of treatment-sensitive patients achieved seizure freedom on their second adequate ASM trial. Recognizing these trajectories supports nuanced clinical decision-making, patient reassurance, and individualized management strategies.
Second, the study identifies key prognostic factors for ASM resistance: frequent pretreatment seizures and psychiatric comorbidities at diagnosis. Awareness of these factors should prompt closer monitoring, earlier consideration of alternative or adjunctive therapies, and timely referral to specialized epilepsy centers for advanced interventions, including surgical evaluation or neurostimulation. While the link between high seizure burden and resistance is expected, the association with psychiatric comorbidities reinforces the bidirectional relationship between epilepsy and psychiatric disorders, including depression, anxiety, suicidality, and psychosis. 8 Future studies using standardized psychiatric assessments are needed to clarify how these factors influence treatment response.
Third, participants who achieved sustained seizure freedom generally did so earlier than those who later relapsed, whereas most individuals who developed drug resistance were identified around 6–8 months after diagnosis. This observation suggests that clinicians should adopt a proactive approach for patients showing early signs of suboptimal response—such as persistent seizures within the first 6–12 months—rather than delaying therapy adjustments or consideration of alternative strategies.
Fourth, more than half of the participants were initially prescribed levetiracetam, yet only about 1 in 4 achieved seizure freedom on their first trial. Emerging evidence suggests that levetiracetam may not be optimal as first-line therapy for focal epilepsy.9,10 Initiating treatment with alternative ASMs, such as sodium channel modulators, could reduce resistance rates and shorten time to seizure freedom. 9 These findings underscore the limitations of a 1-size-fits-all approach and highlight the need for targeted educational initiatives to support rational, individualized ASM selection.
Finally, surprisingly, half of the indeterminate participants had undergone only a single adequate ASM trial despite ongoing seizures. Most had tried just 1 ASM, while 40% had tried multiple medications, but only 1 was considered adequate. Contributing factors may include logistical or financial barriers, patient considerations (eg, pregnancy planning), or clinical practices, such as delaying a medication switch until dose escalation or adverse effects occur. 6 In patients with infrequent seizures, this process can take months or even years, potentially delaying seizure freedom and complicating early recognition of treatment resistance.4,6
The present study provides valuable insights into patterns and predictors of ASM response among patients who ultimately achieve seizure freedom; however, several limitations warrant consideration. 7 Nearly one-quarter of participants could not be classified as treatment-sensitive or treatment-resistant, possibly reflecting incomplete follow-up, suboptimal ASM trials, or a true intermediate phenotype. These cases require deeper phenotyping to clarify trajectories, modifiable factors, and whether they differ meaningfully from defined categories. Psychiatric comorbidities were self-reported rather than clinically validated, raising the possibility of misclassification. Comparative effectiveness of first-line ASMs was not emphasized, limiting guidance for initial therapy selection. Additionally, patients with poor adherence were not excluded, and mechanistic pathways underlying ASM failure remain to be elucidated.
In conclusion, the HEP study 7 shows that achieving sustained seizure freedom in newly diagnosed focal epilepsy often requires over a year and multiple ASM trials, challenging assumptions about first-line therapy success. These findings highlight the importance of individualized care, early diagnosis, vigilant monitoring, and access to specialized expertise. Seizure frequency and psychiatric comorbidities are key predictors of treatment response, while further research into structural lesions, network pathology, and mechanistic and psychobiological pathways is needed to clarify ASM response. Until then, neurologists should embrace the principles of “Beyond the First Pill” and “The First Year,” ensuring adequate trials and careful monitoring before declaring treatment resistance.
