The emerging role of trace elements in epilepsy and metabolic disorders: a new frontier in neurotherapeutics

Studies investigating the relationship between trace element status and disease variability in humans are steadily increasing. Experimental and clinical data suggest that normal brain function critically depends on the homeostasis of several trace elements, and that disturbances in this balance may contribute to epileptogenesis. Trace elements in epilepsy have therefore emerged as a growing field of research, with numerous studies exploring the mechanisms by which different metal ions influence epileptic seizures in both animal models and patients. This review summarizes current evidence on the trace elements most frequently associated with epilepsy, including selenium, iron, copper, zinc and manganese, and highlights inherited metabolic disorders Menkes diseases and Congenital Hypomagnesemia, as well as selected mitochondrial syndromes, in which profound trace element imbalances converge with epileptic phenotypes. In addition, we discuss how antiepileptic drugs and the ketogenic diet can modify trace element levels in serum and other biological matrices. We performed a bibliographical synthesis to examine the correlation between epilepsy and abnormal concentrations of trace elements; namely zinc, copper, iron, selenium, manganese, magnesium and phosphorus, in blood and brain. Overall, available evidence suggests that trace element dysregulation may influence epileptogenesis, seizure susceptibility, and response to antiepileptic therapies.