The path to post-traumatic epilepsy: A review of emerging biomarkers and therapeutic targets

Background Post-traumatic epilepsy (PTE) is a common, disabling sequela of traumatic brain injury (TBI), contributing to long-term morbidity. Short-term antiseizure prophylaxis reduces early provoked seizures, but no interventions prevent late unprovoked seizures or PTE. This gap arises from limited understanding of underlying mechanisms. Objective This review synthesizes PTE pathophysiology and emerging mechanism-based prevention strategies, emphasizing a shift from reactive management to personalized prophylaxis. Evidence Synthesis PTE develops via epileptogenesis—a latent, multifactorial process distinct from acute seizure triggers—involving chronic neuroinflammation (e.g., IL-1β, NLRP3 pathways), blood-brain barrier dysfunction, maladaptive gliosis with glutamate dysregulation, and aberrant plasticity (e.g., mTOR signaling, interneuron loss). These insights identify targets for intervention. Promising repurposed agents include IL-1 receptor antagonists (anakinra), mTOR inhibitors (rapamycin), and glutamate modulators (ceftriaxone), with preclinical data showing reduced seizure burden. Predictive biomarkers (neuroimaging, EEG, cytokines, microRNAs) are essential for risk stratification in prophylactic trials. Conclusions The field is pivoting toward disease prevention through targeted therapies and precision medicine. Translating these advances could yield the first PTE-preventive treatment, altering TBI outcomes for survivors.