Neurodevelopmental Impact of Epilepsy on Autonomic Function in Dravet Syndrome

NCT05472389 | Active Not Recruiting

• 1 other identifier: 69HCL22_0370
• Study Type: interventional
• Target: 92
• Locations: 3 countries
• Sites: 4

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.

Conditions

Dravet Syndrome; Epilepsy

Keywords

Dravet Syndrome; Epilepsy

Outcome Measures

Primary Outcomes (4)

• 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

  Total duration of central sleep apneas during total sleep time over a 24-hour period at Visit 2

  Data collected during 24 hours of video-EEG.

• Cardiac primary outcome for the inter-ictal period: ratio's calculation of root mean square of successive differences (RMSSD) during wakefulness and sleep

  Ratio of root mean square of successive differences (RMSSD) during wakefulness and sleep

  Data collected during 24 hours of video-EEG at Visit 2

• 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

  Occurrence of post-convulsive central apnea

  Between 30 seconds and 10 minutes after the end of the convulsive seizure at Visit 2

• 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

  Ictal QTc-lengthening, ≥60 ms

  Between 30 seconds and 10 minutes after the end of the convulsive seizure at visit 2

Secondary Outcomes (23)

• Respiratory secondary outcomes for the inter-ictal period : calculation of central apnea index

  Data collected during 24 hours of video-EEG.

• 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)

  Data collected during 24 hours of video-EEG.

• Respiratory secondary outcomes for the inter-ictal period : calculation of Obstructive Apnea Hypopnea Index

  Data collected during 24 hours of video-EEG.

• 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)

  Data collected during 24 hours of video-EEG.

• 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

  Data collected during 24 hours of video-EEG.

Study Arms (1)

Patients, adults and children, with Dravet Syndrome

OTHER

An homogenous population of patients with DS. The patients will have 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 and a full-night polysomnography

Other: Video-electroencephalography; Other: Blood Samples

Interventions

Video-electroencephalography OTHER

All patients will be monitored 24 hours. Whenever possible, duration of the long-term monitoring will be extended to 48 hours, including a second full night polysomnography. These recordings will also allow us to assess sleep architecture and to capture seizures in some patients video , EEEG, EKG, respiration and other polysomnography data will be centralized at Hospices Civils de Lyon. A copy of the EEG-EKG data required to address the objectives related to cardiac features will then be electronically transferred to Partner 2 (Bonn) Evaluation will be performed blind to other data by the Partner 1 (Lyon) for the respiratory data and by the Partner 2 (Bonn) for the EKG data All primary outcomes and secondary outcomes will be assessed with respect to duration of epilepsy and frequency of convulsive seizures during the baseline period.

Patients, adults and children, with Dravet Syndrome

Blood Samples OTHER

Blood samples will be collected at V2 in all patients. A total of seven blood samples of 4 ml each will be collected, including five EDTA and two dry. Samples EDTA plasma and serum will then be prepared after centrifugation. In children \< 10 kg, only 5 samples of 4 ml each (22 ml in total), including four EDTA and one dry.

Patients, adults and children, with Dravet Syndrome

Eligibility Criteria

• Age: 2 Years - 60 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Hospices Civils de Lyon: lead

Study Sites (4)

Department of Paediatrics and Paediatric Neurology, Antwerp University Hospital

Edegem, 2650, Belgium

Location

HFME Hospices Civils de Lyon

Bron, Rhone, 69500, France

Location

Hôpital Neurologique Pierre Wertheimer Hospices Civils de Lyon

Bron, Rhone, 69500, France

Location

Klinik und Poliklinik für Epileptologie, Universitätsklinikum

Bonn, 53127, Germany

Location

MeSH Terms

Conditions

Epilepsies, Myoclonic; Epilepsy

Interventions

Blood Specimen Collection

Condition Hierarchy (Ancestors)

Epilepsy, Generalized; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Epileptic Syndromes

Intervention Hierarchy (Ancestors)

Specimen Handling; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Punctures; Surgical Procedures, Operative; Investigative Techniques

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NA
• Masking: NONE
• Purpose: OTHER
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 16, 2022
• First Posted: July 25, 2022
• Study Start: October 14, 2022
• Primary Completion: September 11, 2025
• Study Completion (Estimated): September 11, 2035
• Last Updated: January 14, 2026

Record last verified: 2026-01

Data Sharing

• IPD Sharing: Will not share

Locations

DE (1); FR (2); BE (1)