Neurodevelopmental Impact of Epilepsy on Autonomic Function in Dravet Syndrome

Dravet Syndrome (DS) is a severe epileptic encephalopathy, which main cause is mutations of SCN1A, the gene coding for the Nav1.1 voltage-gated sodium channel. DS is characterized by childhood onset, severe cognitive deficit and drug-resistant seizures, including several generalized convulsive seizures per day, frequent status epilepticus and high seizure-related mortality rate. Sudden and unexpected death in epilepsy (SUDEP) represents the major cause of premature deaths. The risk of SUDEP is thus about 9/1000-person-year in comparison with about 5/1000-person-year in the whole population of patients with drug-resistant epilepsies.

Experimental and clinical data suggest that SUDEP primarily result from a postictal central respiratory dysfunction. SUDEP in DS, might be the result of a seizure-induced fatal apnea in a patient who had developed epilepsy-related vulnerability to central autonomic and/or respiratory dysfunction. However, a key clinical issue which remains to be addressed is the temporal dynamics of the onset and evolution of the autonomic vulnerability in these patients. The main clinical risk factor of SUDEP is the frequency of convulsive seizures and the SUDEP risk can vary along the evolution of epilepsy. Although non-fatal seizure-induced ataxic breathing can be observed in patients with DS, whether or not repetition of seizures results in long-term alterations of breathing remains unclear.

In the AUTONOMIC project, it will be investigate in a homogenous population of patients with DS the exact interplay between epilepsy-related cardiac and respiratory alterations on the one hand and the relation between the underlying neurodevelopmental disease, the repetition of seizure per se and these epilepsy-related autonomic alterations on the other hand.

Autonomic functions will be investigated in the inter-ictal period (i.e. in the absence of immediate seizures, Work Package 1 (WP1)) and in the peri-ictal period, i.e. in the immediate time before, during (if possible) and after seizures (WP2). A multicenter cohort will be constituted, allowing to collect the inter-ictal and ictal cardio-respiratory data required in the 2 WP. The study will be sponsored by the Lyon's University Hospital.

Patients will be recruited over a period of 24 months in one of the three participating clinical center. All patients will first enter in a prospective baseline period of 3 to 6 months duration in order to collect seizure frequency. After this period, all patients will then undergo a 24-48 hours video-EEG recordings as part of the routine clinical care. The monitoring will also include a full-night polysomnography. This patients will be eligible for inclusion in an extension follow-up study will monitor vital status every year in order to investigate long-term mortality, including SUDEP.

The AUTONOMIC project will provide important results which will pave the way to develop and eventually validate therapeutic intervention to prevent SUDEP. By deciphering the exact interplay between epilepsy-related cardiac and respiratory alterations on the one hand and the relation between the underlying neurodevelopmental disease, the repetition of seizure per se and these epilepsy-related autonomic alterations on the other hand, the project will primarily deliver clinically relevant biomarkers.