Stress, seizures, and hypothalamic–pituitary–adrenal axis targets for the treatment of epilepsy

Abstract Epilepsy is a heterogeneous condition with varying etiologies including genetics, infection, trauma, vascular, neoplasms, and toxic exposures. The overlap of psychiatric comorbidity adds to the challenge of optimal treatment for people with epilepsy. Seizure episodes themselves may have varying triggers; however, for decades, stress has been commonly and consistently suspected to be a trigger for seizure events. This paper explores the relationship between stress and seizures and reviews clinical data as well as animal studies that increasingly corroborate the impact of stress hormones on neuronal excitability and seizure susceptibility. The basis for enthusiasm for targeting glucocorticoid receptors for the treatment of epilepsy and the mixed results of such treatment efforts are reviewed. In addition, this paper will highlight recent findings identifying a regulatory pathway controlling the body's physiological response to stress which represents a novel therapeutic target for modulation of the hypothalamic–pituitary–adrenal (HPA) axis. Thus, the HPA axis may have important clinical implications for seizure control and imply use of anticonvulsants that influence this neuronal pathway. This article is part of a Special Issue entitled “The Future of Translational Epilepsy Research”.