Arousal and respiratory co-dysfunction in drug-resistant epilepsy: from mechanisms to therapy

Introduction

Both seizures and their complications are modulated by patients’ vigilance states. Several epilepsy complications are associated with sleep, including Sudden and Unexpected Death in Epilepsy (SUDEP). SUDEP primarily results from a fatal postictal central apnea after nocturnal generalized convulsive seizures.

Seizure-Related Respiratory Dysfunction

While transient seizure-related respiratory dysfunction is frequent in patients, current hypotheses suggest that in some of them, repetition of seizures may induce a chronic alteration of respiratory regulation, increasing the risk of fatal apnea. Reducing the severity of postictal respiratory dysfunction has thus appeared as one of the most promising ways to prevent SUDEP.

However, no encouraging results have been reported yet, suggesting that epilepsy-related respiratory dysfunction may only be the tip of the iceberg.

Hypothesis

Given the numerous interconnections between the network that regulates arousal and sleep and the respiratory network, I hypothesize that some patients with drug-resistant epilepsy might combine this well-known seizure-related respiratory dysfunction with a chronic alteration of arousal regulation, resulting in abnormal asphyxia-induced arousal.

Role of the Adenosine System

The adenosine system is deeply implicated in the regulation of sleep and central respiratory control and is modulated by seizures. Epilepsy-related alteration of the brainstem adenosine pathway may play a key role in the development of arousal and respiratory co-dysfunction.

Research Objectives

Using both experimental and clinical studies, EPIAROUSAL will investigate:

1. The exact interplay between epilepsy-related respiratory dysfunction and arousal regulation.
2. The relation between long-term repetition of seizures, brainstem adenosine pathway, and the respiratory and arousal co-dysfunction.

Final Objective

The final objective is to validate that adenosine-targeted therapy can restore normal asphyxia-induced arousal in drug-resistant epilepsy, paving the way for a first clinical trial of SUDEP prevention.