a pet-mri study of serotoninergic brainstem pathway in patients with dravet syndrome

Conditions: Epilepsy; Dravet Syndrome; Drug Resistant Epilepsy; Healthy Controls

Summary: dravet syndrome (ds) is a severe neurodevelopmental disease, which is predominantly caused by mutations of scn1a, the gene coding for nav1.1 voltage-gated sodium channels. ds is characterized by infancy onset, severe cognitive deficit and drug-resistant seizures, including several generalized convulsive seizures per day and frequent status epilepticus, often triggered by fever or hyperthermia. among the causes of premature deaths in patients with epilepsy, sudden and unexpected death in epilepsy (sudep) represents a major cause. sudep is a non-traumatic and non-drowning death in patients with epilepsy, unrelated to a documented status epilepticus. the risk of sudep is particularly high in patients suffering from ds, reaching about 9/1000-person-year, as compared to about 1/1000-person-year in people with epilepsy including all disease types. the main clinical risk factor of sudep is the frequency of convulsive seizures. beyond improving seizure control, which we showed to mitigate the sudep risk, more specific preventive treatment strategies are still lacking. experimental and clinical data suggest that most sudep cases result from postictal brainstem dysfunction, including central respiratory arrest there is a body of evidence suggesting involvement of serotonin (5ht) dysfunction both in the pathogenesis of epilepsy in ds and in seizure-related respiratory dysfunction. serotonin indeed plays a key role in the regulation of respiration. population firing of serotoninergic neurons in the medullary raphe is significantly decreased during the ictal and post-ictal periods, in association with decreased breathing and heart rate during and after seizures. most importantly, post-mortem data in patients, including ds, showed alteration of neuronal populations in the medulla in sudep cases with evidence for greater reduction in neuromodulatory neuropeptidergic and monoaminergic, including serotoninergic, systems. sudep in ds might therefore be the result of a seizure-induced fatal apnea in a patient who has developed epilepsy-related vulnerability to central respiratory dysfunction favored by 5ht dysfunction. however, several issues remain to be addressed to identify detailed mechanisms and effective therapies. among them, a key issue is the exact relation between the alterations of the 5ht pathway observed in ds and epilepsy-related respiratory dysfunction in the present study, the hypothesis is that adult patients with ds might demonstrate specific alterations of the 5ht pathway within the brainstem as assessed by pet imaging. the drapetotine study will thus focus on imaging 5ht brainstem pathway with pet and mri in patients with ds to assess if abnormalities can be observed and through comparison with data collected in patients drug-resistant focal epilepsy whether these abnormalities are ds specficic or reflect the consequence on brainstem 5ht pathway of refractory seizures. this study will involve 20 adult patients, including 10 adults with established diagnosis of dravet syndrome and 10 patients with drug-resistant focal epilepsy. ten healthy adults will also be included. participants will be recruited over a period of 18 months and the duration of participation for each participant will be 2 weeks to 8 weeks


Eligibility criteria:
patients with ds * inclusion criteria * adult patients (≥ 18 but \< 60 years) with established diagnosis of dravet syndrome * adults protected by a guardianship or curatorship * diagnosis of dravet syndrome will be confirmed based on medical history, type of seizures, eeg data and results of genetic testing * no restriction related to the seizure frequency * patient (or patient's legal representative) who gave its written informed consent to participate to the study * patient and/or legal representative understanding and speaking national language * absence of known current pregnancy and breastfeeding * patient affiliated to the french national health care system * exclusion criteria * subject in exclusion period of another study * mri contra-indication (presence of metallic elements) * presence of vagal nerve stimulation * claustrophobia * patients unable to maintain a minimul level of immobility during the imaging acquisition patients with drug-resistant focal epilepsy * inclusion criteria * adult patient (≥ 18 years) suffering from drug-resistant focal epilepsy according to ilae classification * patients in whom presurgical evaluation is considered * patient who gave her/his written informed consent to participate to the study * no restriction related to the seizure frequency * absence of known current pregnancy and breastfeeding * patient affiliated to french health care system * exclusion criteria * subject in exclusion period of another study * adults protected by a guardianship or curatorship * mri contra-indication (presence of metallic elements) * presence of vagal nerve stimulation * claustrophobia * ongoing serotoninergic treatment, including selective serotonin reuptake inhibitor healthy controls * inclusion criteria * adult (≥ 18 years) * without history of neurological disorders and/or psychiatric disorders, and/or general medical disorders * subject who gave her/his written informed consent to participate to the study * subject affiliated to the french health care system * absence of known current pregnancy and breastfeeding * exclusion criteria * age \< 18 years * presence of the symptoms of anxiety and/or depression as defined by a score ≥ 11 at the french version of the hospital anxiety and depression scale (hads) * ongoing treatment with selective serotonin reuptake inhibitor * mri contra-indication (presence of metallic elements) * claustrophobia

Keywords: epilepsy dravet syndrome drug-resistant focal epilepsy serotonin pet-mri mppf sudep