Impact of Epilepsy on the Brainstem Adenosine Pathway and Its Relation With Arousal and Respiratory Reactivity

NCT ID: NCT07249034

Last Updated: 2025-11-25

Basic Information

• Recruitment Status: NOT_YET_RECRUITING
• Clinical Phase: NA
• Total Enrollment: 50 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2026-01-01
• Study Completion Date: 2028-03-01

Brief Summary

Despite the continuous development of new antiseizure medications over the past 25 years, 30% of patients with epilepsy suffer from drug-resistant seizures and are at risk of epilepsy-related complications, like cognitive dysfunctions, sleep-disordered breathing or Sudden and Unexpected Death in Epilepsy (SUDEP). 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.

Post-mortem data in SUDEP patients showed alteration of neuronal populations involved in respiratory control in the medulla. Accordingly, pharmacologic strategies aimed at reducing the severity of postictal respiratory dysfunction has appeared as one of the most promising way to prevent SUDEP. However, no encouraging result has hitherto been reported.

Interconnections between the complex network that regulates arousal and sleep and the respiratory network are numerous. They primarily include the relation between chemosensitive regulation and arousal system to ensure asphyxia-induced arousal (i.e. arousal to elevated CO2), especially through serotonin (5HT)-dependent connections in brain stem. The link between alterations of the brainstem networks involved in arousal regulation and respiratory dysfunction has not been characterized in patients with epilepsy yet.

Like 5HT, adenosine is deeply implicated in the regulation of sleep and central respiratory control.

Seizures transiently increase adenosine extracellular levels. Adenosine physiological effects in the brain are mediated through the activation of two types of Adenosine receptors (ARs), A1Rs and A2ARs. Extracellular adenosine promotes sleep via A1R-dependant inhibition of glutamatergic neurons in the basal forebrain, but also via A2AR-dependant activation of neurons in the nucleus accumbens. Respiration is also inhibited by A1R and A2AR. Most importantly, it has been shown that drug-resistant epilepsy is associated with long-term alterations of ARs cortical expression. However, whether or not a similar epilepsy-related plasticity of ARs occurs in the brainstem and may participate to chronic arousal and respiratory dysfunction in epilepsy has never been investigated.

Considering the tight interplay between central respiratory control, arousal regulation and brainstem adenosine, the main hypothesis of the BRAVE study is that epilepsy might result in alterations of the distribution of A1Rs in the brainstem structures involved in respiratory regulation and/or arousal control, especially in the brainstem structures involved in respiratory regulation under hypercapnic condition.

The study combines clinical respiratory characterization, morphological, functional and metabolic imaging, using the hybrid simultaneous 3T MRI-PET scanner (Siemens Biograph mMR) of the CERMEP. Combining PET with anatomical and functional MR imaging enables non-invasively in vivo mapping of receptor binding and functional neuronal assessment of a physiological task in the entire brain with high spatial resolution.

Investigators already performed fMRI study of respiratory centers, showing number of functional changes in brainstem regions participating to the central control of respiration, including reduced activation during breath-holding fMRI, in patients with epilepsy. The BRAVE study will use the same respiratory paradigm as the one used in this past study.

PET imaging will be focused on A1R, using [18F]CPFPX, a selective A1R antagonist.

Conditions

Epilepsy; Drug-resistant Focal Epilepsy; Healthy Controls

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: BASIC_SCIENCE
• Blinding Strategy: NONE

Study Groups

Patients with drug-resistant epilepsy

Diagnosis of refractory focal epilepsy or of refractory idiopathic generalized epilepsy, as defined by the International League Against Epilepsy.

The following procedures will be carried out as part of the research:

• Hypercapnic challenge
• PET/MRI acquisition with [18F]-CPFPX Baseline (0-70 min) Hypercapnic challenge (Breath holding) (70-100 min) Return to equilibrium (100-120 min)

Group Type: EXPERIMENTAL

1 Hypercapnic challenge while participant is awake

Intervention Type: PROCEDURE

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

PET/MRI acquisition

Intervention Type: PROCEDURE

The PET/MRI acquisition will be organized into 3 parts for a total duration of 120 minutes from the injection of the radiotracer

1. Baseline (0-70 min)

2. Respiratory challenge (70-100 min) :

Subjects will perform three series of expiratory breath holds (six repeats during each run). A green dot will be shown for 30 seconds, indicating that the patient can still breathe normally for 30 seconds. Then, a yellow dot appears for two seconds, indicating that the patient needs to prepare himself for an expiratory BH that shall start at the end of an expiration, and at the end of the two seconds. Then a red dot appears indicating that the patient must hold his breath while being in full expiration or inspiration. The red dot remains until the patient decides to breath again and push a button to alert us of re-breathing. Screen turns black for 60 seconds before another sequence starts (30 sec. green dot).

3. Return to equilibrium (100-120 min).

Healthy subjects

Selection of healthy subjects will be performed to ensure age and sex matching.

The following procedures will be carried out as part of the research:

• Hypercapnic challenge
• PET/MRI acquisition with [18F]-CPFPX Baseline (0-70 min) Hypercapnic challenge (Breath holding) (70-100 min) Return to equilibrium (100-120 min)

Group Type: EXPERIMENTAL

1 Hypercapnic challenge while participant is awake

Intervention Type: PROCEDURE

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

PET/MRI acquisition

Intervention Type: PROCEDURE

The PET/MRI acquisition will be organized into 3 parts for a total duration of 120 minutes from the injection of the radiotracer

1. Baseline (0-70 min)

2. Respiratory challenge (70-100 min) :

Subjects will perform three series of expiratory breath holds (six repeats during each run). A green dot will be shown for 30 seconds, indicating that the patient can still breathe normally for 30 seconds. Then, a yellow dot appears for two seconds, indicating that the patient needs to prepare himself for an expiratory BH that shall start at the end of an expiration, and at the end of the two seconds. Then a red dot appears indicating that the patient must hold his breath while being in full expiration or inspiration. The red dot remains until the patient decides to breath again and push a button to alert us of re-breathing. Screen turns black for 60 seconds before another sequence starts (30 sec. green dot).

3. Return to equilibrium (100-120 min).

Interventions

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

Intervention Type: PROCEDURE

PET/MRI acquisition

The PET/MRI acquisition will be organized into 3 parts for a total duration of 120 minutes from the injection of the radiotracer

1. Baseline (0-70 min)

2. Respiratory challenge (70-100 min) :

Subjects will perform three series of expiratory breath holds (six repeats during each run). A green dot will be shown for 30 seconds, indicating that the patient can still breathe normally for 30 seconds. Then, a yellow dot appears for two seconds, indicating that the patient needs to prepare himself for an expiratory BH that shall start at the end of an expiration, and at the end of the two seconds. Then a red dot appears indicating that the patient must hold his breath while being in full expiration or inspiration. The red dot remains until the patient decides to breath again and push a button to alert us of re-breathing. Screen turns black for 60 seconds before another sequence starts (30 sec. green dot).

3. Return to equilibrium (100-120 min).

Intervention Type: PROCEDURE

Eligibility Criteria

Inclusion Criteria

• For 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 or of idiopathic generalized epilepsy, as defined by the International League Against Epilepsy

4. Diagnosis of refractory epilepsy, 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. For women of childbearing potential, use effective contraception during study participation

• For healthy volunteers

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. For women of childbearing potential, use effective contraception during study participation

Exclusion Criteria

• For patients

1. Ongoing or chronic respiratory and/or cardiac insufficiency

2. Obstructive sleep-apnea syndrome

3. Ongoing treatment with selective serotonin reuptake inhibitor

4. MRI contra-indication (presence of metallic elements, claustrophobia)

5. Patient treated with vagal nerve stimulation or deep brain stimulation

6. Pregnant women, women in laboror breastfeeding women, based on declarations at V0

7. Persons under psychiatric care

8. Persons deprived of their liberty by a judicial or administrative decision

9. Adults subject to a legal protection measure (guardianship, curatorship)

10. Persons not affiliated to a social security scheme or beneficiaries of a similar scheme

11. Positive urine pregnancy test at V2, if applicable

12. Hypersensitivity to [18F]-CPFPX

• For healthy volunteers

1. History of epilepsy

2. Ongoing or chronic respiratory and/or cardiac insufficiency

3. Obstructive sleep-apnea syndrome

4. Ongoing treatment with selective serotonin reuptake inhibitor

5. MRI contra-indication (presence of metallic elements, claustrophobia)

6. Pregnant women, women in labor or breastfeeding women, based on declarations at V0

7. Persons under psychiatric care

8. Persons deprived of their liberty by a judicial or administrative decision

9. Adults subject to a legal protection measure (guardianship, curatorship)

10. Persons not affiliated to a social security scheme or beneficiaries of a similar scheme

11. Positive urine pregnancy test at V2, if applicable

12. Hypersensitivity to [18F]-CPFPX

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 55 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

Hospices Civils de Lyon

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Sylvain RHEIMS, PUPH

Role: PRINCIPAL_INVESTIGATOR

Hospices Civils de Lyon

Locations

Hospices Civils de Lyon

Bron, , France

Countries

France

Central Contacts

Sylvain RHEIMS, PUPH

Role: CONTACT

sylvain.rheims@chu-lyon.fr

+33472357106

Mathilde LECLERCQ, CP

Role: CONTACT

Mathilde.leclercq@chu-lyon.fr

+33472355838

Facility Contacts

Sylvain RHEIMS, PH PH

Role: primary

sylvain.rheims@chu-lyon.fr

+33472357106

Mathilde LECLERCQ, CP

Role: backup

Mathilde.leclercq@chu-lyon.fr

+33472355838

Other Identifiers

2025-A01888-41

Identifier Type: -

Identifier Source: org_study_id