Metabolism and epilepsy: Ketogenic diets as a homeostatic link

•Most seizures are unpredictable and/or caused by factors that are not quantifiable.•Metabolic dysfunction can underlie sporadic seizures.•There is a clear therapeutic link between metabolism and neuronal activity.•Metabolic treatment can stabilize the brain network and promote homeostasis.•A ketogenic diet can mitigate unpredictable and sporadic seizures. Metabolic dysfunction can underlie seizure disorders, and metabolism-based treatments can afford seizure control and promote homeostasis. This relationship between metabolism and the risk of sporadic seizures was observed historically with the clinical success of a low-carbohydrate, high-fat, ketosis-inducing ketogenic diet – a treatment that remains relevant today, and one that has been shown to be effective against medically refractory epilepsy. Mechanisms underlying the success of the ketogenic diet are a topic of intense research efforts – not only because of proven success in arresting treatment-resistant seizures, but also because recent evidence suggests that altering metabolism with a ketogenic diet enables a homeostatic state in the brain that is less excitable, and hence raises the threshold for seizure genesis. Metabolic therapy with a ketogenic diet has been shown to normalize a range of abnormal physiological and behavioral parameters and may also make the central nervous system more resilient to other insults or physiological stresses. Because the therapeutic ability of such a diet may be more limited than a drug because of a dose “ceiling”, investigations are underway to develop and test analogous or supplemental approaches. In addition, significant efforts have been made to demonstrate broader applications of metabolic therapy in promoting health and preventing disease, including conditions where epileptic seizures manifest in a comorbid fashion.