Clinical trial NCT05472389: Neurodevelopmental Impact of Epilepsy on Autonomic Function in Dravet Syndrome
Official title: Neurodevelopmental Impact of Epilepsy on Autonomic Function in Dravet Syndrome
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Dravet Syndrome
Epilepsy
Keywords: Dravet Syndrome
Epilepsy
Lead sponsor: Hospices Civils de Lyon
Sponsor class: OTHER
First posted: 2022-07-25
Enrollment: 100
Sex: ALL
Minimum age (years): 2
Maximum age (years): 60
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: OTHER

Brief summary: 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.


Eligibility criteria: Inclusion Criteria:

* Children (\> 2 years and \< 18 years) and adult patients (\< 60 years) with established diagnosis of Dravet Syndrome
* Adults protected by a guardianship or curatorship
* Diagnosis of Dravet syndrome will be confirmed by PI of each study center based on medical history, type of seizures, EEG data and results of genetic testing
* No restriction related to the seizure frequency
* Patient (or patient's parents or legal representative) who gave its written informed consent to participate to the study
* At least one of the parents and/or legal representative understanding and speaking national language
* Written consent form signed by both parents
* Absence of known current pregnancy and breastfeeding
* Patient affiliated to its national health care system

Exclusion Criteria:

* Patients (children or adults) unable to tolerate at least 24 hours of video-EEG recordings (behavioural problems resulting in technical issues for appropriate EEG recordings)
* Patients with congenital heart or lung disease
* Patients with congenital abnormalities or diseases, other than the epilepsy, which could interfere with sleep
* Subject in exclusion period of another study

Primary outcomes:
measure: Respiratory primary outcome for the inter-ictal period : measure of the total duration of central sleep apnea (sec/min/hours) during total sleep time over a 24-hour period
timeFrame: Data collected during 24 hours of video-EEG.
measure: Cardiac primary outcome for the inter-ictal period: ratio's calculation of root mean square of successive differences (RMSSD) during wakefulness and sleep
timeFrame: Data collected during 24 hours of video-EEG at Visit 2
measure: Respiratory primary outcome for the peri-ictal period :occurrence's measure of post-convulsive central apnea during the 30 sec to 10 min after the end of convulsive seizure
timeFrame: Between 30 seconds and 10 minutes after the end of the convulsive seizure at Visit 2
measure: Cardiac primary outcome for the peri-ictal period : measurement of ictal QTc-lengthening ≥60 ms during the 30 sec to 10 min after the end of convulsive seizure
timeFrame: Between 30 seconds and 10 minutes after the end of the convulsive seizure at visit 2
Secondary outcomes:
measure: Respiratory secondary outcomes for the inter-ictal period : calculation of central apnea index
timeFrame: Data collected during 24 hours of video-EEG.
measure: Respiratory secondary outcomes for the inter-ictal period : measurement of Total duration of central sleep apneas during each sleep stage over a 24-hour period (sec/min)
timeFrame: Data collected during 24 hours of video-EEG.
measure: Respiratory secondary outcomes for the inter-ictal period : calculation of Obstructive Apnea Hypopnea Index
timeFrame: Data collected during 24 hours of video-EEG.
measure: Respiratory secondary outcomes for the inter-ictal period : measurement of total duration of periods with tcCO2 >50 mmHg during total sleep time over a 24-hour period (sec/min)
timeFrame: Data collected during 24 hours of video-EEG.
measure: Respiratory secondary outcomes for the inter-ictal period : measurement of total duration of periods with pulse oximetry <90% during total sleep time over a 24-hour period
timeFrame: Data collected during 24 hours of video-EEG.
measure: Cardiac secondary outcomes for the inter-ictal period calculation of standard deviation of R-R intervals
timeFrame: Data collected during 24 hours of video-EEG.
measure: Cardiac secondary outcomes for the inter-ictal period : percentage's calculation of consecutive R-R intervals differing by > 50 milliseconds (pNN50) during sleep and during wakefulness (%)
timeFrame: Data collected during 24 hours of video-EEG.
measure: Cardiac secondary outcomes for the inter-ictal period : calculation of ratio between the low frequency and high frequency spectrum (LF/HF ratio) of the RR-interval. (Hz)
timeFrame: Data collected during 24 hours of video-EEG.
measure: Cardiac secondary outcomes for the inter-ictal period : analysis of ration of sleep to wakefulness for each HRV variables
timeFrame: Data collected during 24 hours of video-EEG.
measure: Cardiac secondary outcomes for the inter-ictal period : measurement of the evolution of Heart Rate Variability variable during hyperventilation procedure
timeFrame: Data collected during 24 hours of video-EEG.
measure: Cardiac secondary outcomes for the inter-ictal period : analysis of T wave alternans (V)
timeFrame: Data collected during 24 hours of video-EEG.
measure: Respiratory secondary outcomes for the peri-ictal period : duration's measurement of post-convulsive central apnea (sec/min)
timeFrame: Between 30 seconds and 10 minutes after the end of the convulsive seizure.
measure: Respiratory secondary outcomes for the peri-ictal period : occurrence's measurement of ataxic breathing
timeFrame: Between 30 seconds and 10 minutes after the end of the convulsive seizure.
measure: Respiratory secondary outcomes for the peri-ictal period : occurrence and duration's measurement of period of tcCO2 >50 mm Hg in the post-ictal period (sec/min)
timeFrame: Between 30 seconds and 10 minutes after the end of the convulsive seizure.
measure: Respiratory secondary outcomes for the peri-ictal period : measurement of Delay between the end of the seizure and recovery of oxygen saturation (SpO2) ≥90% (sec/min)
timeFrame: Between 30 seconds and 10 minutes after the end of the convulsive seizure.
measure: Respiratory secondary outcomes for the peri-ictal period : measurement of desaturation nadir
timeFrame: Between 30 seconds and 10 minutes after the end of the convulsive seizure.
measure: Cardiac secondary outcomes for the peri-ictal period : occurrence's measurement of peri-ictal asystole
timeFrame: Between 30 seconds and 10 minutes after the end of the convulsive seizure.
measure: Cardiac secondary outcomes for the peri-ictal period : occurrence's measurement of peri-ictal bradycardia
timeFrame: Between 30 seconds and 10 minutes after the end of the convulsive seizure.
measure: Cardiac secondary outcomes for the peri-ictal period : measurement of all Heart Rate Variability (HRV)
timeFrame: Between 30 seconds and 10 minutes after the end of the convulsive seizure.
measure: Cardiac secondary outcomes for the peri-ictal period : measurement of T wave alternans
timeFrame: Between 30 seconds and 10 minutes after the end of the convulsive seizure.
measure: Additional features : measurement of the the postictal generalized EEG suppression (V)
timeFrame: All measurements will take place during hospitalization for 24/48 hours at Visit 2 after the baseline period
measure: Additional features : measurement of the total duration of the postictal coma (sec/min/hours)
timeFrame: During hospitalization for 24/48 hours at Visit 2 after the baseline period
measure: Additional features : measurement of the total duration of the postictal immobility (sec/min/hours)
timeFrame: During hospitalization for 24/48 hours at Visit 2 after the baseline period
Other outcomes:
Locations:
city: Edegem
country: Belgium
facility: Department of Paediatrics and Paediatric Neurology, Antwerp University Hospital
city: Bron
country: France
facility: HFME Hospices Civils de Lyon
state: Rhone
city: Bron
country: France
facility: Hôpital Neurologique Pierre Wertheimer Hospices Civils de Lyon
state: Rhone
city: Bonn
country: Germany
facility: Klinik und Poliklinik für Epileptologie, Universitätsklinikum
Study officials:
References: