Stress and Epilepsy: Towards Understanding of Neurobiological Mechanisms for Better Management

Stress has been identified as a major contributor to human disease and is postulated to play a substantial role in epileptogenesis. In a significant proportion of individuals with epilepsy, sensitivity to stressful events contributes to dynamic symptomatic burden, notably seizure occurrence and frequency, and presence and severity of psychiatric comorbidities [anxiety, depression, posttraumatic stress disorder (PTSD)]. Here, we review this complex relationship be-tween stress and epilepsy using clinical data and highlight key neurobiological mechanisms including the hypothalamic-pituitary-adrenal (HPA) axis dysfunction, altered neuroplasticity within limbic system structures, and alterations in neurochemical pathways such as brain-derived neurotrophic factor (BNDF) linking epilepsy and stress. We discuss current clinical management approaches of stress that help optimize seizure control and prevention, as well as psychiatric comorbidities associated with epilepsy. We propose that various shared mechanisms of stress and epilepsy present multiple avenues for the development of new symptomatic and preventative treatments, including disease modifying therapies aimed at reducing epileptogenesis. This would require close collaborations between clinicians and basic scientists to integrate data across multiple scales, from genetics to systems biology, from clinical observations to fundamental mechanistic insights. In future, advances in machine learning approaches and neuromodulation strategies will enable personalized and targeted interventions to manage and ultimately treat stress-related epileptogenesis.