Metabolic Correlates of Sleep and Seizures: The Basis for a Unified Concept of Seizure Onset and Termination

Abstract

Two questions of fundamental clinical importance in epilepsy research continue to resist scientific inquiry: when and why does a seizure begin; and when and why does a seizure end? The answers may be embedded in the counter-intuitive relationship between sleep and seizures. Deep sleep (NREM) and seizures, seemingly disparate conditions, share two distinctive features: altered consciousness, and electroencephalograph (EEG) slow waves of synchronized neuronal activity. Both altered consciousness and EEG slow waves are induced by elevated levels of adenosine, a breakdown product of the biological energy source, adenosine triphosphate (ATP). The common bond between sleep and seizures is neuronal energy homeostasis. Sleep replenishes glial energy reserves that support neuronal activity during wakefulness. This glial energy resource is accessed when neurons are deprived of the critical nutrients, glucose and oxygen, that are required to generate neuronal mitochondrial ATP. If nutrient deficiency and energy debt continue unabated, a primitive reflex mechanism, a seizure is activated in a final, desperate attempt to restore neuronal energy homeostasis. A teleological, Darwinian perspective is offered to explain the primordial link between the full tonic-clonic seizure and neuronal energy metabolism, and why this relationship has persisted through the eons. In summary: a seizure starts when normal energy reserve mechanisms fail to meet increased neuronal energy demands and terminates when glucose and oxygen, critical nutrients for the synthesis of mitochondrial ATP, are delivered to deprived neurons by an intense cerebral-hemodynamic response associated with the seizure itself.