Advances and challenges in experimental models of posttraumatic epilepsy for therapeutic interventions

Epilepsy affects over 80 million people worldwide, with approximately 40% experiencing refractory seizures. Despite some progress in deciphering the complex process of epileptogenesis, which transforms a healthy brain into one susceptible to epilepsy, there are still no therapies available to prevent this condition. Traumatic brain injury (TBI) is a leading cause of epilepsy in both military and civilian populations, often leading to the complex condition of posttraumatic epilepsy (PTE). Defined as recurrent seizures following TBI, PTE lacks effective treatment options, highlighting the need for improved experimental models and translational interventions. Unveiling disease-modifying therapeutics for epilepsy is a top priority in the field of neurology research. One major obstacle in PTE research is the lack of robust models that accurately reflect the multifaceted and heterogeneous nature of human PTE. Hence, developing disease-modifying treatments requires innovative models that facilitate the identification of novel therapeutic approaches. Establishing clinically relevant animal models is critical for elucidating the pathophysiological mechanisms of epileptogenesis and identifying effective therapies for PTE management. This article describes the opportunities and challenges associated with advances in PTE experimental models, including the call for common data elements to be developed for PTE. Inspired by insights from a 2023 workshop supported by the American Epilepsy Society, this review explores progress in animal models, experimental protocols, biomarkers, and principles of therapeutic interventions for TBI-induced seizures and posttraumatic epileptogenesis. It evaluates the PTE research landscape and critically discusses current strategies, innovations, hurdles and future directions for establishing models that ultimately lead to the development of disease-modifying agents and targeted therapeutic approaches for PTE prevention. SIGNIFICANCE STATEMENT: Posttraumatic epilepsy (PTE) lacks specific therapies due to limited experimental models. Here, we outline the proceedings of the 2023 American Epilepsy Society-supported National Workshop on PTE, covering small and large animal models for PTE research. This article provides insights into recent advancements in experimental paradigms and analyzes the validity and application of these models in identifying interventions to prevent epileptogenesis following traumatic brain injury. We address challenges and obstacles in discovering PTE therapies, offering clinical data context and common themes.