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

Overview

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.

Interventions

• 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
• 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

Primary outcome measures

• Comparison of the [18F]-CPFPX BPND in the brainstem structures involved in respiratory regulation under hypercapnic condition in patients with drug-resistant epilepsy with the one of healthy subjects [Time frame: Emission will be acquired over 90 minutes post-injection]

Secondary outcome measures (7)

• Comparison of the [18F]-CPFPX BPND in the cortical structures involved in respiratory regulation under hypercapnic condition in patients with drug-resistant epilepsy with the one of healthy subjects [Time frame: Emission will be acquired over 90 minutes post-injection]
• Evaluating the relation between [18F]-CPFPX BPND in the brainstem structures involved in respiratory regulation under hypercapnic condition and the HCVR slope in patients with drug-resistant epilepsy and in healthy subjects [Time frame: Emission will be acquired over 90 minutes post-injection]
• Comparison of the HCVR slope in patients with drug-resistant epilepsy and in heathly subjects [Time frame: will be measured during hypercapnic challenges between Day 15 and Day 60 after inclusion]
• Evaluating the relation between the HCVR slope and the pattern of BOLD activation during BH in patients with drug-resistant epilepsy and in heathly subjects [Time frame: will be measured during fMRI acquisition (30 minutes)]
• Comparing brainstem regional volumes on MRI of patients with drug-resistant epilepsy with the one of healthy subjects [Time frame: Will ne measured during structural MRI protocol which will include 10 minutes of anatomical imaging]
• Evaluating the relation between the brainstem regional volumes on MRI and the HCVR slope in patients with drug-resistant epilepsy and in heathly subjects [Time frame: Will be measured during structural MRI protocol which will include 10 minutes of anatomical imaging]
• Evaluating the relation between mean daily intake of caffeine (mg/day) and the [18F]-CPFPX BPND in the brainstem and cortical structures [Time frame: Emission will be acquired over 90 minutes post-injection]

Eligibility criteria

Inclusion criteria

• For 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 or of idiopathic generalized epilepsy, as defined by the International League Against Epilepsy
• Diagnosis of refractory epilepsy, as defined by the International League Against Epilepsy
• Patients with ≥3 focal to bilateral tonic-clonic seizure (FBTCS) during the past 18 months
• For women of childbearing potential, use effective contraception during study participation
• For healthy volunteers

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

Exclusion criteria

• For patients

• Ongoing or chronic respiratory and/or cardiac insufficiency
• Obstructive sleep-apnea syndrome
• Ongoing treatment with selective serotonin reuptake inhibitor
• MRI contra-indication (presence of metallic elements, claustrophobia)
• Patient treated with vagal nerve stimulation or deep brain stimulation
• Pregnant women, women in laboror breastfeeding women, based on declarations at V0
• Persons under 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 V2, if applicable
• Hypersensitivity to \[18F\]-CPFPX
• For healthy volunteers

• History of epilepsy
• Ongoing or chronic respiratory and/or cardiac insufficiency
• Obstructive sleep-apnea syndrome
• Ongoing treatment with selective serotonin reuptake inhibitor
• MRI contra-indication (presence of metallic elements, claustrophobia)
• Pregnant women, women in labor or breastfeeding women, based on declarations at V0
• Persons under 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 V2, if applicable
• Hypersensitivity to \[18F\]-CPFPX

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: Yes

Study design

Allocation

Non-randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Basic science

Study locations

France · 1 center

• Hospices Civils de Lyon — Bron

Identifiers

NCT: NCT07249034 · 2025-A01888-41

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗