A unified hypothesis of SUDEP: Seizure-induced respiratory depression induced by adenosine may lead to SUDEP but can be prevented by autoresuscitation and other restorative respiratory response mechanisms mediated by the action of serotonin on the periaqueductal gray

Abstract

Sudden unexpected death in epilepsy (SUDEP) is a major cause of death in people with epilepsy (PWE). Postictal apnea leading to cardiac arrest is the most common sequence of terminal events in witnessed cases of SUDEP, and postconvulsive central apnea has been proposed as a potential biomarker of SUDEP susceptibility. Research in SUDEP animal models has led to the serotonin and adenosine hypotheses of SUDEP. These neurotransmitters influence respiration, seizures, and lethality in animal models of SUDEP, and are implicated in human SUDEP cases. Adenosine released during seizures is proposed to be an important seizure termination mechanism. However, adenosine also depresses respiration, and this effect is mediated, in part, by inhibition of neuronal activity in subcortical structures that modulate respiration, including the periaqueductal gray (PAG). Drugs that enhance the action of adenosine increase postictal death in SUDEP models. Serotonin is also released during seizures, but enhances respiration in response to an elevated carbon dioxide level, which often occurs postictally. This effect of serotonin can potentially compensate, in part, for the adenosine-mediated respiratory depression, acting to facilitate autoresuscitation and other restorative respiratory response mechanisms. A number of drugs that enhance the action of serotonin prevent postictal death in several SUDEP models and reduce postictal respiratory depression in PWE. This effect of serotonergic drugs may be mediated, in part, by actions on brainstem sites that modulate respiration, including the PAG. Enhanced activity in the PAG increases respiration in response to hypoxia and other exigent conditions and can be activated by electrical stimulation. Thus, we propose the unifying hypothesis that seizure-induced adenosine release leads to respiratory depression. This can be reversed by serotonergic action on autoresuscitation and other restorative respiratory responses acting, in part, via the PAG. Therefore, we hypothesize that serotonergic or direct activation of this brainstem site may be a useful approach for SUDEP prevention.

Keywords: adenosine; amygdala; periaqueductal gray; serotonin; sudden unexpected death in epilepsy.

Fig. 1

A generalized tonic-clonic seizure (1) causes release of neuroactive substances (2), including adenosine (3). Adenosine induces respiratory depression by actions on the neurons in the rostral ventral lateral medulla (RVLM) (4), which in turn diminishes the central drive to the lungs and causes apnea (5). The apnea causes elevated pCO₂, which activates raphe neurons (6) to increase the release of serotonin (5-HT), which activates periaqueductal gray (PAG) neurons (7). PAG activation triggers autoresuscitation and other restorative respiratory responses mechanisms (8). If these mechanisms are not sufficient to overcome the apnea, it results in SUDEP. Enhancement of PAG neuronal activation by exogenous agents that increase the action of 5-HT may prevent SUDEP.