Caracterization of the Combined Alterations in Respiration and aROUSal in Patients With Drug-resistant EpiLepsy

Summary

30% of patients with epilepsy suffer from drug-resistant seizures and are at risk of epilepsy-related complications, from cognitive dysfunctions to premature mortality. Both seizures and their complications are modulated by patients' vigilance states, with a tight and bi-directional interplay between sleep and epilepsy. Several epilepsy complications are associated with sleep, such as sleep-disordered breathing or Sudden and Unexpected Death in Epilepsy (SUDEP). SUDEP is a non-traumatic death, unrelated to a documented status epilepticus, which accounts for up 50% of premature deaths in epilepsy, with a cumulative risk of ≈ 10% at 40 years in patients with childhood-onset epilepsy. SUDEP typically occurs during sleep, after a nocturnal seizure, and primarily results from a postictal central respiratory dysfunction in patients with generalized convulsive seizure (GCS), suggesting that interaction between respiratory dysfunction and sleep state may play a role in its pathophysiology.

Most of patients with drug-resistant seizures demonstrate transient peri-ictal apnea and hypoxemia, especially in the aftermath of a GCS. Experimental and clinical data suggest that most SUDEP primarily result from a fatal seizure-related respiratory arrest. In patients whose SUDEP had occurred during long-term video-EEG monitoring, we observed fatal postictal central apnea after a nocturnal GCS in all SUDEP. Accordingly, it is currently hypothesized that in a subgroup of patients, repetition of seizures may contribute to chronic alteration of respiratory regulation which may increase the risk of fatal postictal central respiratory arrest. Finally, post-mortem data in SUDEP patients showed alteration of neuronal populations involved in respiratory control in the medulla.

The complex network that regulates arousal and sleep and the respiratory network are strongly interconnected. Impairment of the interaction between central respiratory control and arousal systems has been reported in several clinical situations, including sleep apnea syndrome, sudden infant death syndrome or Prader-Willi Syndrome. In epilepsy, preclinical data in rodents indirectly support a role for 5HT in the impairment of the interactions between the arousal and respiratory systems in the cascade of events leading to SUDEP. However, no direct evidence is available, and the link between alterations of the brainstem networks involved in arousal regulation and respiratory dysfunction has not been characterized in patients with epilepsy yet.

Conditions

• Epilepsy

Interventions

PROCEDURE

Video-EEG monitoring

Video-EEG monitoring

PROCEDURE

Respiratory monitoring and polysomnography

heart rate, pulse oximetry (oxygen levels in the blood), nasal airflow, respiratory effort (thoracic and abdominal) and capnography (carbon dioxide (CO2) levels in exhaled air)

PROCEDURE

1 Hypercapnic challenge while participant is awake

The healthy patient/subject breathes through the mouth, using a mouthpiece and a nose clip, through a device fitted with a hermetically sealed bag that measures the various parameters of his/her breathing. At the start of the test, the healthy patient/subject breathes ambient air and his or her breathing is measured. Then, after a few minutes, the healthy patient/subject is connected to the bag, breathing in a closed circuit. This causes a gradual increase in carbon dioxide (CO2) in the inspired air. During this time, breathing parameters will be measured and gas exchanges studied with each breath. The test is stopped when the end-tidal carbon dioxide pressure (PetCO2) reaches 60 mm Hg, or in the event of intolerance.

PROCEDURE

2 Hypercapnic challenges while participant is sleeping

In the evening, as soon as the doctor detects on the EEG that the patient/subject is in deep sleep, various tests will be carried out to assess reactivity to wakefulness. Two hypercapnic challenges will be carried out during sleep, using the same procedure as for wakefulness. The test will be stopped when the healthy patient/subject wakes up, or when the end-tidal carbon dioxide pressure (PetCO2) reaches 60 mm Hg, or in case of intolerance.

PROCEDURE

Auditory stimulus

Two auditory stimulus tests will be carried out during the patient's sleep. Using headphones, the investigator will administer auditory stimuli at regular, progressively louder intervals to determine the ability of the patient/ healthy subject to awaken to an auditory stimulus.

OTHER

Questionnaires

Questionnaire to assess caffeine consumption habits Quality of life questionnaires QOLIE-31 Anxiety and depression questionnaires HADS

Sponsors & Collaborators

• Hospices Civils de Lyon

  lead OTHER

Study Design

Allocation

NON_RANDOMIZED

Purpose

BASIC_SCIENCE

Masking

NONE

Model

PARALLEL

Eligibility

Min Age

18 Years

Max Age

55 Years

Sex

ALL

Healthy Volunteers

Yes

Timeline & Regulatory

Start

2024-11-04

Primary Completion

2027-01-04

Completion

2027-01-04

Countries

• France

Study Locations