Study Highlights Predictive Factors for Treatment Response in Focal Epilepsy

A large international study from the Human Epilepsy Project (HEP) offers insight into how patients with newly diagnosed focal epilepsy respond to antiseizure medications (ASMs), revealing both the time frame and clinical factors that influence seizure outcomes. The findings underscore persistent challenges in managing focal epilepsy and point to opportunities for earlier identification of drug resistance, which could inform clinical and coverage decisions.

Epilepsy affects about 65 million people globally, with focal seizures accounting for 60% of cases. Predicting how patients will respond to ASMs or develop treatment resistance remains a longstanding clinical challenge. The HEP study, a multicenter, prospective, observational cohort conducted across 34 epilepsy centers in the US, Europe, and Australia, followed 448 individuals with newly diagnosed focal epilepsy for up to 6 years between 2012 and 2020. Data were analyzed from February to July 2024 using definitions of seizure freedom and drug resistance established by the International League Against Epilepsy (ILAE).

The study evaluated short- and long-term responses to ASMs, the time required to reach seizure freedom, and key predictors of treatment outcomes. Participants were between 12 and 60 years old and enrolled within 4 months of starting ASM treatment.

Results showed that nearly 60% (267 of 448) achieved seizure freedom during the study, with most maintaining that status without relapse. Among those, 89% of treatment-sensitive patients responded to monotherapy, and about half became seizure free on their first ASM. Despite these encouraging findings, early treatment failure was common: 63% experienced ongoing or worsening seizures during the first year, and the median time to seizure freedom was 12.1 months.

Participants were categorized as treatment sensitive (54.7%), resistant (22.8%), or indeterminate (22.5%). The analysis revealed that pretreatment seizure frequency and psychiatric comorbidities were significant predictors of treatment outcomes. Those with infrequent pretreatment seizures were 70% less likely to develop treatment resistance than those with frequent seizures, while patients with comorbid psychological disorders were 1.78 times more likely to experience resistance.

The authors noted, “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.”

These findings have practical implications for both clinical management and payer policy. The data highlight that seizure freedom often requires multiple medication trials and substantial time, suggesting that early reassessment and potential therapy adjustments should be supported within care frameworks and reimbursement models. The first year after diagnosis represents a critical period for intervention, as most patients fail their initial ASM and remain vulnerable to ongoing seizures.

Despite the availability of newer-generation ASMs, the study found that overall prognosis for focal epilepsy has not improved significantly. Many patients did not fit neatly into defined treatment phenotypes, complicating decisions about long-term therapy. The researchers emphasize that ongoing seizures do not always indicate treatment resistance, reinforcing the need for nuanced clinical evaluation and longitudinal monitoring.

For payers and managed care professionals, these results underscore the importance of coverage policies that facilitate early specialist evaluation, timely ASM adjustments, and comprehensive management of comorbidities. Optimizing initial treatment strategies and supporting rapid escalation or alternative therapy when indicated may improve seizure control rates and reduce long-term health care costs associated with drug-resistant epilepsy.

Reference

Barnard SN, Chen Z, Holmes M, et al. Treatment Response to Antiseizure Medications in People With Newly Diagnosed Focal Epilepsy. JAMA Neurol. 2025;82(10):1022-1030. doi: 10.1001/jamaneurol.2025.2949