Caracterization of the Combined Alterations in Respiration and AROUSal in Patients with Drug-resistant EpiLepsy

Not Applicable

Recruiting

• Conditions: Epilepsy
• Interventions: Procedure: Video-EEG monitoring; Procedure: Respiratory monitoring and polysomnography; Procedure: 1 Hypercapnic challenge while participant is awake; Procedure: 2 Hypercapnic challenges while participant is sleeping; Procedure: Auditory stimulus; Other: Questionnaires

• Registration Number: NCT06545214
• Lead Sponsor: Hospices Civils de Lyon

Brief 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.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2024-08-01
• Study First Submitted QC: 2024-08-06
• Study First Posted: 2024-08-09
• Study Start: 2024-11-04
• Status Verified: 2025-01
• Last Update Submitted: 2025-01-03
• Last Update Posted: 2025-01-06
• Primary Completion: 2027-01-04
• Study Completion: 2027-01-04

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 60

Inclusion Criteria

Patients :

1. Written informed consent obtained from study subject and ability for study subject to comply with the requirements of the study

2. Aged 18 to 55 years old

3. Diagnosis of focal epilepsy

4. Epilepsy is refractory to treatment, as defined by the International League Against Epilepsy

5. Patients with ≥3 focal to bilateral tonic-clonic seizure (FBTCS) during the past 18 months

6. 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

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

Exclusion Criteria

Patients

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

Healthy subjects

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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Patients with drug-resistant focal epilepsy	1 Hypercapnic challenge while participant is awake	Patients with \>3 focal to bilateral tonic-clonic seizure per year and who had undergone long-term video-EEG (VEEG) monitoring for presurgical evaluation. After a prospective baseline, which will allow to ensure prospective seizure count for patients with epilepsy, all participants will undergo a 24-hours hospitalization. The following procedures will be carried out as part of the research: * Video-EEG recordings * Respiratory monitoring * Full-night polysomnography * 1 Hypercapnic challenge while participant is awake * 2 Hypercapnic challenges while participant is sleeping * Auditory stimulus All the medical devices used in this study are already in routine use at Hospices Civils de Lyon
Healthy subjects	Respiratory monitoring and polysomnography	Selection of healthy subjects will be performed to ensure age-matching. After a prospective baseline, which will allow to ensure prospective seizure count for patients with epilepsy, all participants will undergo a 24-hours hospitalization. The following procedures will be carried out as part of the research: * Video-EEG recordings * Respiratory monitoring * Full-night polysomnography * 1 Hypercapnic challenge while participant is awake * 2 Hypercapnic challenges while participant is sleeping * Auditory stimulus All the medical devices used in this study are already in routine use at Hospices Civils de Lyon
Patients with drug-resistant focal epilepsy	Video-EEG monitoring	Patients with \>3 focal to bilateral tonic-clonic seizure per year and who had undergone long-term video-EEG (VEEG) monitoring for presurgical evaluation. After a prospective baseline, which will allow to ensure prospective seizure count for patients with epilepsy, all participants will undergo a 24-hours hospitalization. The following procedures will be carried out as part of the research: * Video-EEG recordings * Respiratory monitoring * Full-night polysomnography * 1 Hypercapnic challenge while participant is awake * 2 Hypercapnic challenges while participant is sleeping * Auditory stimulus All the medical devices used in this study are already in routine use at Hospices Civils de Lyon
Patients with drug-resistant focal epilepsy	Respiratory monitoring and polysomnography	Patients with \>3 focal to bilateral tonic-clonic seizure per year and who had undergone long-term video-EEG (VEEG) monitoring for presurgical evaluation. After a prospective baseline, which will allow to ensure prospective seizure count for patients with epilepsy, all participants will undergo a 24-hours hospitalization. The following procedures will be carried out as part of the research: * Video-EEG recordings * Respiratory monitoring * Full-night polysomnography * 1 Hypercapnic challenge while participant is awake * 2 Hypercapnic challenges while participant is sleeping * Auditory stimulus All the medical devices used in this study are already in routine use at Hospices Civils de Lyon
Patients with drug-resistant focal epilepsy	2 Hypercapnic challenges while participant is sleeping	Patients with \>3 focal to bilateral tonic-clonic seizure per year and who had undergone long-term video-EEG (VEEG) monitoring for presurgical evaluation. After a prospective baseline, which will allow to ensure prospective seizure count for patients with epilepsy, all participants will undergo a 24-hours hospitalization. The following procedures will be carried out as part of the research: * Video-EEG recordings * Respiratory monitoring * Full-night polysomnography * 1 Hypercapnic challenge while participant is awake * 2 Hypercapnic challenges while participant is sleeping * Auditory stimulus All the medical devices used in this study are already in routine use at Hospices Civils de Lyon
Patients with drug-resistant focal epilepsy	Auditory stimulus	Patients with \>3 focal to bilateral tonic-clonic seizure per year and who had undergone long-term video-EEG (VEEG) monitoring for presurgical evaluation. After a prospective baseline, which will allow to ensure prospective seizure count for patients with epilepsy, all participants will undergo a 24-hours hospitalization. The following procedures will be carried out as part of the research: * Video-EEG recordings * Respiratory monitoring * Full-night polysomnography * 1 Hypercapnic challenge while participant is awake * 2 Hypercapnic challenges while participant is sleeping * Auditory stimulus All the medical devices used in this study are already in routine use at Hospices Civils de Lyon
Patients with drug-resistant focal epilepsy	Questionnaires	Patients with \>3 focal to bilateral tonic-clonic seizure per year and who had undergone long-term video-EEG (VEEG) monitoring for presurgical evaluation. After a prospective baseline, which will allow to ensure prospective seizure count for patients with epilepsy, all participants will undergo a 24-hours hospitalization. The following procedures will be carried out as part of the research: * Video-EEG recordings * Respiratory monitoring * Full-night polysomnography * 1 Hypercapnic challenge while participant is awake * 2 Hypercapnic challenges while participant is sleeping * Auditory stimulus All the medical devices used in this study are already in routine use at Hospices Civils de Lyon
Healthy subjects	Video-EEG monitoring	Selection of healthy subjects will be performed to ensure age-matching. After a prospective baseline, which will allow to ensure prospective seizure count for patients with epilepsy, all participants will undergo a 24-hours hospitalization. The following procedures will be carried out as part of the research: * Video-EEG recordings * Respiratory monitoring * Full-night polysomnography * 1 Hypercapnic challenge while participant is awake * 2 Hypercapnic challenges while participant is sleeping * Auditory stimulus All the medical devices used in this study are already in routine use at Hospices Civils de Lyon
Healthy subjects	1 Hypercapnic challenge while participant is awake	Selection of healthy subjects will be performed to ensure age-matching. After a prospective baseline, which will allow to ensure prospective seizure count for patients with epilepsy, all participants will undergo a 24-hours hospitalization. The following procedures will be carried out as part of the research: * Video-EEG recordings * Respiratory monitoring * Full-night polysomnography * 1 Hypercapnic challenge while participant is awake * 2 Hypercapnic challenges while participant is sleeping * Auditory stimulus All the medical devices used in this study are already in routine use at Hospices Civils de Lyon
Healthy subjects	Questionnaires	Selection of healthy subjects will be performed to ensure age-matching. After a prospective baseline, which will allow to ensure prospective seizure count for patients with epilepsy, all participants will undergo a 24-hours hospitalization. The following procedures will be carried out as part of the research: * Video-EEG recordings * Respiratory monitoring * Full-night polysomnography * 1 Hypercapnic challenge while participant is awake * 2 Hypercapnic challenges while participant is sleeping * Auditory stimulus All the medical devices used in this study are already in routine use at Hospices Civils de Lyon
Healthy subjects	2 Hypercapnic challenges while participant is sleeping	Selection of healthy subjects will be performed to ensure age-matching. After a prospective baseline, which will allow to ensure prospective seizure count for patients with epilepsy, all participants will undergo a 24-hours hospitalization. The following procedures will be carried out as part of the research: * Video-EEG recordings * Respiratory monitoring * Full-night polysomnography * 1 Hypercapnic challenge while participant is awake * 2 Hypercapnic challenges while participant is sleeping * Auditory stimulus All the medical devices used in this study are already in routine use at Hospices Civils de Lyon
Healthy subjects	Auditory stimulus	Selection of healthy subjects will be performed to ensure age-matching. After a prospective baseline, which will allow to ensure prospective seizure count for patients with epilepsy, all participants will undergo a 24-hours hospitalization. The following procedures will be carried out as part of the research: * Video-EEG recordings * Respiratory monitoring * Full-night polysomnography * 1 Hypercapnic challenge while participant is awake * 2 Hypercapnic challenges while participant is sleeping * Auditory stimulus All the medical devices used in this study are already in routine use at Hospices Civils de Lyon

Primary Outcome Measures

Name	Time	Method
End tidal CO2 (PETCO2) value at arousal in patients with epilepsy and in healthly subjects	the night of hospitalization	PETCO2 corresponds to the value taken at the end of a breath of the partial pressure of CO2. Two hypercapnic challenges will be performed the same night. The first will start once unequivocal N3 stage of NREM will be observed, as determined online by polysomnography data. After the termination of the first test, the patient/subject will go back to sleep and a second procedure will be performed once she/he will reach N3 stage of NREM again. Data from the two procedures will be averaged for each subject.

Secondary Outcome Measures

Name	Time	Method
Value of the awake HCVR slope in patients with epilepsy and in healthly subjects	will be measured during hypercapnic challenges on awakening on the first day of hospitalization.	As detailed in section 6.1.3, a hypercapnic challenge will be performed awake after arrival of the patient/subject in the epilepsy monitoring unit. Calculation of the awake HCVR slope wil be performed as described for HCVR slope during sleep
Value of the HCVR slope during sleep in patients with epilepsy and in healthy subjects	one night of hospitalization	HCVR measures the increase in minute ventilation (VE) induced by an increase of PETCO2. The HCVR slope, expressed in L/min/mmHg, will be calculated from the linear regression of VE and PETCO2. Data from the two procedures per night described aboves will be averaged for each subject.; will be measured during hypercapnic sleep challenges during the night of hospitalization.
Central apnea index and Obstructive Apnea Hypopnea Index	one night of hospitalization	Sleep apneas can classified as obstructive, central or both central sleep apnea, Apnea will be defined as a decrease in peak nasal pressure of \>90% of baseline, lasting at least 10 s. Hypopnea was defined as a decrease of \>30% of the baseline nasal pressure, lasting at least 10 s and associated with ≥4% drop in SpO2. Central apnea will be defined by cessation \> 10 seconds of airflow with simultaneous cessation of respiratory effort. The respiratory events will be scored according to the 2007 American Academy of Sleep Medicine guidelines. Apnea index will correspond to total number of each apnea type divided by total sleep time over a 24-hour period.
Value of the ventilatory recruitment threshold (VRT) in patients with epilepsy and in healthly subjects	will be measured during hypercapnic challenges on awakening on the first day of hospitalization.	VRT reflects the PCO2 value at which the central chemoreflex is initiated and corresponds to the onset of compensatory and progressive rise in VE during hypercapnic challenge. The determination of VRT requires a hyperventilation baseline period during which the measured VE is the one required to maintain hypopnea under resting metabolic conditions; termed basal ventilation or the "wakefulness drive" to drive. To determine VRT, it is therefore required that the subject breathes deeply for few minutes, raising her/his tidal volume such that she/he rapidly achieves and maintaines a PETCO2 of 20-25 mmHg. Then the hypercapnic challenge can be performed. In this context, VRT can not be determined during sleep.
Number of focal to bilateral tonic-clonic seizures during the 3 months preceding the polysomnography in patients with epilepsy	Will be collected during the first day of hospitalization
Sound intensity (dB) required to induced awakening	one night of hospitalization	The paradigm will be the one proposed by Martin et al. 1996 ; Philip et al. 1994 . The stimulation will be manually delivered using earphone inserts and will consist in pure sounds of 1000Hz, from 40dB to 110dB, duration 5s. Stimulation starts after 5 min of unequivocal NREM, as assessed with continuous EEG montoring. The stimulation will start with intensity I1=50dB. If complete behavioral arousal (=awakening): stop stimulation and wait until 2 min of stable sleep (defined by re-apparition of a spindle, a K complex or REM) and next trial with I1-10dB. If arousal but no awakening: wait until 2 min of stable sleep and next trial with sound +10dB. If no Arousal : wait 10s and deliver sound +10dB or longer sound (10s)
Current and past mean daily intake of caffeine (mg/day)	Will be collected between inclusion and the first day of hospitalization	Current usual caffeine intake and the one over the last ten years will be assessed by a validated self-survey (Simonin et al., Neuroobiology of Disease 2013) filled-in at home by the patient and, if needed, the help of the caregiver filled between the inclusion visit and the polysomnography. Its reliability, assessed by retest (mean interval: 37.5 ± 5.5 days) in 31 patients, was excellent (intraclass correlation coefficient by Fleiss method: 0.97 \[95% CI: 0.94-0.98\]). The mean daily intake of caffeine containing items (coffee, tea, chocolate, sodas) will be reported, along with any changes of consumption over the 10 year period. All data will be then confirmed by interview perfomed during the stay in epilepsy monitoring unit.

Trial Locations

Locations (1)

Hôpital Pierre Wertheimer; 🇫🇷 Bron, Rhone, France