Post-traumatic epilepsy: An historical review from ancient observations to modern molecular mechanisms

Post-traumatic epilepsy (PTE) represents a significant neurological complication of traumatic brain injury (TBI), accounting for approximately 5% of all epilepsies and 10-20% of structural/symptomatic epilepsies in population studies. This review traces the evolution of PTE research from ancient medical observations through 140+ years of modern scientific investigation, with emphasis on the historical, epidemiological and clinical-trial literature that established the field's current conceptual and diagnostic framework. Molecular and cellular mechanisms are introduced only briefly as a bridge to this historical narrative, as they are addressed in-depth elsewhere in this special issue. Thus, this review will focus upon the transition from purely observational studies in the late 19th century through epidemiological investigations of wartime injuries, the development of animal models, molecular mechanistic discoveries, and contemporary prevention trials. Recent meta-analytic data (2022-2025) indicate that modern-era severe TBI cohorts show higher long-term PTE incidence than older estimates suggested. Despite substantial progress, PTE remains largely unpreventable, representing a critical unmet medical need, though a maturing pipeline of biomarker-enriched antiepileptogenesis trials offers genuine hope for the coming decade.