Optimizing the diagnostic timing for drug-resistant epilepsy: balancing timeliness and stability with an antiseizure medication waiting period

Background: While drug-resistant epilepsy (DRE) is defined by the failure of two antiseizure medications (ASM), the optimal duration to confirm such resistance remains controversial. Clinical delays intended for treatment optimization may postpone life-changing nonpharmacological interventions and increase risks associated with uncontrolled seizures, highlighting the need for standardized diagnostic timing. Objective: We aimed to identify the optimal waiting period that balances the consistency, stability, and timeliness of DRE diagnosis. Design: Retrospective observational cohort study. Methods: This study evaluated a modified DRE definition featuring a structured “ASM waiting period” against the original criteria. Outpatients with epilepsy received initial ASM at a tertiary center in a self-paired diagnostic simulation design. A B-spline linear model verified the inflection point at which the DRE revision proportion plateaued. A trade-off score for DRE (TOS_DRE) was developed to identify the optimal waiting period by balancing diagnostic stability and delay. Results: This study included 1573 patients. We used 28-, 219-, and 364-days as waiting periods for the analyses. The diagnostic consistency with the original standard was high (κ ⩾ 0.879, p < 0.001). A significant increase in diagnostic delay was observed across waiting periods ( p < 0.001), except for the 0- and 28-day strategies ( p = 0.290). Kaplan–Meier analysis, truncated on day 540, revealed higher DRE maintenance possibility for the 219- (hazard ratio (HR) = 0.29, 95% confidence interval (CI) 0.10–0.87, p = 0.028), and 364-day criteria (HR = 0.33, 95% CI 0.11–0.98, p = 0.046) than those for the 0-day criterion. The TOS_DRE indicated a 219-day optimal waiting period for diagnostic accuracy ( w 1 = 0.7). Subgroup analyses confirmed the robustness of the 219-day strategy in most scenarios. Conclusion: We propose a 219-day waiting period to operationalize an “adequate trial” of DRE. This timeframe may inform DRE diagnosis and evaluation of nonpharmacological therapy.