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

Обзор

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.

Вмешательства

• Процедура Video-EEG monitoring
  Video-EEG monitoring
• Процедура 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)
• Процедура 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
• Процедура 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.
• Процедура 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.
• Другое Questionnaires
  Questionnaire to assess caffeine consumption habits Quality of life questionnaires QOLIE-31 Anxiety and depression questionnaires HADS

Первичные конечные точки

• End tidal CO2 (PETCO2) value at arousal in patients with epilepsy and in healthly subjects [Срок оценки: the night of hospitalization]

Вторичные конечные точки (8)

• Value of the HCVR slope during sleep in patients with epilepsy and in healthy subjects [Срок оценки: one night of hospitalization]
• Value of the awake HCVR slope in patients with epilepsy and in healthly subjects [Срок оценки: will be measured during hypercapnic challenges on awakening on the first day of hospitalization.]
• Value of the ventilatory recruitment threshold (VRT) in patients with epilepsy and in healthly subjects [Срок оценки: will be measured during hypercapnic challenges on awakening on the first day of hospitalization.]
• Number of focal to bilateral tonic-clonic seizures during the 3 months preceding the polysomnography in patients with epilepsy [Срок оценки: Will be collected during the first day of hospitalization]
• Central apnea index and Obstructive Apnea Hypopnea Index [Срок оценки: one night of hospitalization]
• Sound intensity (dB) required to induced awakening [Срок оценки: one night of hospitalization]
• Current and past mean daily intake of caffeine (mg/day) [Срок оценки: Will be collected between inclusion and the first day of hospitalization]
• Presence of subjective experience of awakenings [Срок оценки: one night of hospitalization]

Критерии участия

Критерии включения

Patients :

• Written informed consent obtained from study subject and ability for study subject to comply with the requirements of the study
• Aged 18 to 55 years old
• Diagnosis of focal epilepsy
• Epilepsy is refractory to treatment, as defined by the International League Against Epilepsy
• Patients with ≥3 focal to bilateral tonic-clonic seizure (FBTCS) during the past 18 months
• Patients who had undergone long-term video-EEG (VEEG) monitoring for presurgical evaluation in the past ten years within the Department of Functional Neurology and Epileptology at Hospices Civils de Lyon, ensuring access to detailed information about:

• occurrence of transient respiratory dysfunction during the focal seizures, transient hypoxemia during strictly focal seizures being observed in 40% of patients(39) and in 87% of patients with at least one FBTCS during the VEEG monitoring(46)
• localization of the epileptogenic zone, the risk of peri-ictal respiratory dysfunction being greater in seizures of temporal lobe origin than in extra-temporal seizures, even after FBTCS

Healthy subjects

• Written informed consent obtained from study subject and ability for study subject to comply with the requirements of the study
• Aged 18 to 55 years old

Критерии исключения

Patients

• Ongoing or chronic respiratory and/or cardiac insufficiency
• Obstructive sleep-apnea syndrome
• Ongoing treatment with selective serotonin reuptake inhibitor
• Patient treated with vagal nerve stimulation
• Pregnant women or breastfeeding women, based on declarations at V0
• Persons receiving psychiatric care
• Persons deprived of their liberty by a judicial or administrative decision
• Adults subject to a legal protection measure (guardianship, curatorship)
• Persons not affiliated to a social security scheme or beneficiaries of a similar scheme
• Positive urine pregnancy test at V1, if applicable

Healthy subjects

• History of epilepsy
• Ongoing or chronic respiratory and/or cardiac insufficiency
• Obstructive sleep-apnea syndrome
• Pregnant women, women in labor or breastfeeding women, based on declarations at V0
• Persons receiving psychiatric care
• Persons deprived of their liberty by a judicial or administrative decision
• Adults subject to a legal protection measure (guardianship, curatorship)
• Persons not affiliated to a social security scheme or beneficiaries of a similar scheme
• Positive urine pregnancy test at V1, if applicable

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Да

Дизайн исследования

Распределение

Нерандомизированное

Модель

Параллельные группы

Маскирование

Открытое

Основная цель

Фундаментальное исследование

Центры проведения

Франция · 1 центр

• Hôpital Pierre Wertheimer — Bron

Идентификаторы

NCT: NCT06545214 · 69HCL23_1350

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

Открыть это исследование на ClinicalTrials.gov ↗