Seizures Induce Hypoxia, and Hypoxia Induces Seizures: A Perverse Relationship That Increases the Risk of Sudden Unexpected Death in Epilepsy (SUDEP)

Abstract

Hypoxia can promote both rescue-survival mechanisms and irreversibleevents leading to cell death. How many types of hypoxia are known, and what is the severity of the hypoxic state when more than one type of hypoxia is acting simultaneously? Assuming convulsive seizures as hypoxic-ischemic phenomena that can trigger new seizures, repetitive seizures will contribute to the development of cerebral ischemia with cell death and neurodegeneration. Generalized tonic–clonic seizures (GTCS) or status epilepticus will induce a systemic hypoxic repercussion affecting peripheral organs such as the cardiovascular system. This cumulative hypoxic–ischemic insult to the heart may develop into heart failure in patients withrefractory epilepsy (RE). Uncontrolled GTCS increases the risk of sudden unexpected death in epilepsy (SUDEP), with a 24-fold increased risk relative to the normal population. Recently, an epileptic heart has been described as “a heart and coronary vasculature damaged by chronic epilepsy as a result of repeated hypoxemia” that can induce heart failure with fatal arrhythmia (bradycardia). Hypoxia induces overexpression of P-glycoprotein (P-gp), downregulation of inward rectifier potassium channels (Kir), and activation of ferroptosis, all related to membrane depolarization. These mechanisms associated with epileptogenesis and heart failure can be detected by noninvasive methods that help prevent SUDEP.