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

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

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.

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 as failure of adequate trials of two tolerated, appropriately chosen and used antiseizure drug schedules (whether as monotherapies or in combination) to achieve sustained seizure freedom
  5. Patients with ≥3 focal to bilateral tonic-clonic seizure (FBTCS) or generalized tonic-clonic seizure (GTCS) during the past 18 months
  6. For women of childbearing potential, use highly effective contraception until the end of relevant systemic exposure (V2)

• 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 highly effective contraception until the end of relevant systemic exposure (V2)

Exclusion Criteria:

• For patients

  1. Ongoing or chronic respiratory insufficiency defined as breathlessness Grade ≥ 2 using the modified Medical Research Council Dyspnea Scale and/or patient treated by a pneumologist for respiratory insufficiency
  2. Cardiac insufficiency defined as symptoms Grade ≥ 2 using New York Heart Association Functional Classification and/or patient treated by a cardiologist for chronic heart failure
  3. Ischaemic heart disease defined as history of myocardial ischemia and/or of typical angina confirmed by a cardiologist.
  4. Obstructive sleep-apnea syndrome, defined as participant who had been diagnosed for Obstructive sleep apnoea by polysomnography, whether a dedicated therapy is ongoing or not
  5. Ongoing treatment with selective serotonin reuptake inhibitor (Selective Serotonin Reuptake Inhibitors): Citalopram, Escitalopram, Fluoxetine, Fluvoxamine, Paroxetine, Sertraline and SNRIs (Serotonin-Norepinephrine Reuptake Inhibitors): Duloxetine, Milnacipran, Venlafaxine
  6. Hypercapnic challenges contra-indication (History of stroke in the last 5 years, space-occupying lesion in the brain associated with brain oedema and/or mass effect on MRI/CT scan)
  7. MRI contra-indication (presence of metallic elements, claustrophobia)
  8. Patient treated with vagal nerve stimulation or deep brain stimulation
  9. Pregnant women, women in labor or breastfeeding women, based on declarations at V0
  10. Patients suffering from a psychiatric disorder, regardless of its etiology, whose care is provided under compulsory measures
  11. Persons deprived of their liberty by a judicial or administrative decision
  12. Adults subject to a legal protection measure (guardianship, curatorship)
  13. Persons not affiliated to a social security scheme or beneficiaries of a similar scheme
  14. Positive urine pregnancy test at V2, if applicable
  15. Hypersensitivity to [18F]-CPFPX

• For healthy volunteers

  1. History of epilepsy
  2. Ongoing or chronic respiratory insufficiency defined as breathlessness Grade ≥ 2 using the modified Medical Research Council Dyspnea Scale and/or patient treated by a pneumologist for respiratory insufficiency
  3. Cardiac insufficiency defined as symptoms Grade ≥ 2 using New York Heart Association Functional Classification and/or patient treated by a cardiologist for chronic heart failure
  4. Ischaemic heart disease defined as history of myocardial ischemia and/or of typical angina confirmed by a cardiologist.
  5. Obstructive sleep-apnea syndrome, defined as participant who had been diagnosed for Obstructive sleep apnoea by polysomnography, whether a dedicated therapy is ongoing or not
  6. Ongoing treatment with selective serotonin reuptake inhibitor : SSRIs (Selective Serotonin Reuptake Inhibitors) : Citalopram, Escitalopram, Fluoxetine, Fluvoxamine, Paroxetine, Sertraline and SNRIs (Serotonin-Norepinephrine Reuptake Inhibitors) : Duloxetine, Milnacipran, Venlafaxine
  7. Hypercapnic challenges contra-indication (History of stroke in the last 5 years, space-occupying lesion in the brain associated with brain oedema and/or mass effect on MRI/CT scan)
  8. MRI contra-indication (presence of metallic elements, claustrophobia)
  9. Pregnant women, women in labor or breastfeeding women, based on declarations at V0
  10. Patients suffering from a psychiatric disorder, regardless of its etiology, whose care is provided under compulsory measures
  11. Persons deprived of their liberty by a judicial or administrative decision
  12. Adults subject to a legal protection measure (guardianship, curatorship)
  13. Persons not affiliated to a social security scheme or beneficiaries of a similar scheme
  14. Positive urine pregnancy test at V2, if applicable
  15. Hypersensitivity to [18F]-CPFPX