Chronobiology of epilepsy and sudden unexpected death in epilepsy

Epilepsy is a neurological disease characterized by spontaneous, unprovoked seizures. Various insults render the brain hyperexcitable and susceptible to seizure. Despite there being dozens of preventative anti-seizure medications available, these drugs fail to control seizures in nearly 1 in 3 patients with epilepsy. Over the last century, a large body of evidence has demonstrated that internal and external rhythms can modify seizure phenotypes. Physiologically relevant rhythms with shorter periodic rhythms, such as endogenous circadian rhythms and sleep-state, as well as rhythms with longer periodicity, including multidien rhythms and menses, influence the timing of seizures through poorly understood mechanisms. The purpose of this review is to discuss the findings from both human and animal studies that consider the effect of such biologically relevant rhythms on epilepsy and seizure-associated death. Patients with medically refractory epilepsy are at increased risk of sudden unexpected death in epilepsy (SUDEP). The role that some of these rhythms play in the nocturnal susceptibility to SUDEP will also be discussed. While the involvement of some of these rhythms in epilepsy has been known for over a century, applying the rhythmic nature of such phenomenon to epilepsy management, particularly in mitigating the risk of SUDEP, has been underutilized. As our understanding of the physiological influence on such rhythmic phenomenon improves, and as technology for chronic intracranial epileptiform monitoring becomes more widespread, smaller and less invasive, novel seizure-prediction technologies and time-dependent chronotherapeutic seizure management strategies can be realized.