A PET-MRI Study of Serotoninergic Brainstem Pathway in Patients With Dravet Syndrome

NCT ID: NCT07013331

Last Updated: 2025-06-10

Basic Information

• Recruitment Status: NOT_YET_RECRUITING
• Clinical Phase: NA
• Total Enrollment: 30 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2025-09-01
• Study Completion Date: 2027-06-01

Brief 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

Conditions

Epilepsy; Dravet Syndrome; Drug Resistant Epilepsy; Healthy Controls

Study Design

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

Study Groups

Patients with Dravet syndrome

Adult patients with Dravet syndrome (\> 18 and \< 60 years). Diagnosis of Dravet syndrome will be confirmed based on medical history, type of seizures, EEG data and results of genetic testing. Ten DS patients will be recruited and will be passed the PET-IRM with injection of the tracer \[18F\]MPPF.

Group Type: EXPERIMENTAL

[18F]MPPF PET-MRI

Intervention Type: OTHER

Patients will be seen during an first inclusion visit during which a review of eligibility criteria, medical history and a clinical examination will be done. Participants will be scheduled for a PET-MRI scan within 2 to 8 weeks. For all women of childbearing age a urine pregnancy test will be performed before the PET-MRI.

Anatomical MR imaging will be first acquired for anatomical co-registration and morphometry analyses (Neuromelanin sensitive images and 3D anatomical T1-weighted covering the whole brain volume with 1mm3 cubic voxels) After i.v. injection of a bolus of 180 MBq ± 10%, with a maximum of 198 MBq MBq, of [18F]-MPPF, a dynamic emission scan consisting of 35 frames of increasing duration (20s to 5min) will be acquired over 90-min post-injection

Patients with drug-resistant focal epilepsy

Adult patients (\> 18 years) with drug-resistant focal epilepsy, as defined by the ILAE, and whom presurgical evaluation is considered. Ten patients will be recruited and will be passed the PET-IRM with injection of the tracer \[18F\]MPPF.

Group Type: EXPERIMENTAL

[18F]MPPF PET-MRI

Intervention Type: OTHER

Patients will be seen during an first inclusion visit during which a review of eligibility criteria, medical history and a clinical examination will be done. Participants will be scheduled for a PET-MRI scan within 2 to 8 weeks. For all women of childbearing age a urine pregnancy test will be performed before the PET-MRI.

Anatomical MR imaging will be first acquired for anatomical co-registration and morphometry analyses (Neuromelanin sensitive images and 3D anatomical T1-weighted covering the whole brain volume with 1mm3 cubic voxels) After i.v. injection of a bolus of 180 MBq ± 10%, with a maximum of 198 MBq MBq, of [18F]-MPPF, a dynamic emission scan consisting of 35 frames of increasing duration (20s to 5min) will be acquired over 90-min post-injection

Adult healthy controls (> 18 years)

Ten healthy controls will be recruited and will be passed the PET-IRM with injection of the tracer \[18F\]MPPF. Participants must be of legal age.

Group Type: EXPERIMENTAL

[18F]MPPF PET-MRI

Intervention Type: OTHER

Patients will be seen during an first inclusion visit during which a review of eligibility criteria, medical history and a clinical examination will be done. Participants will be scheduled for a PET-MRI scan within 2 to 8 weeks. For all women of childbearing age a urine pregnancy test will be performed before the PET-MRI.

Anatomical MR imaging will be first acquired for anatomical co-registration and morphometry analyses (Neuromelanin sensitive images and 3D anatomical T1-weighted covering the whole brain volume with 1mm3 cubic voxels) After i.v. injection of a bolus of 180 MBq ± 10%, with a maximum of 198 MBq MBq, of [18F]-MPPF, a dynamic emission scan consisting of 35 frames of increasing duration (20s to 5min) will be acquired over 90-min post-injection

Interventions

[18F]MPPF PET-MRI

Patients will be seen during an first inclusion visit during which a review of eligibility criteria, medical history and a clinical examination will be done. Participants will be scheduled for a PET-MRI scan within 2 to 8 weeks. For all women of childbearing age a urine pregnancy test will be performed before the PET-MRI.

Anatomical MR imaging will be first acquired for anatomical co-registration and morphometry analyses (Neuromelanin sensitive images and 3D anatomical T1-weighted covering the whole brain volume with 1mm3 cubic voxels) After i.v. injection of a bolus of 180 MBq ± 10%, with a maximum of 198 MBq MBq, of [18F]-MPPF, a dynamic emission scan consisting of 35 frames of increasing duration (20s to 5min) will be acquired over 90-min post-injection

Intervention Type: OTHER

Eligibility Criteria

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

• 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

• 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

• 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

• 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

• 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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 60 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

Hospices Civils de Lyon

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Locations

Hôpital Neurologique Pierre Wertheimer

Bron, Rhone, France

Countries

France

Central Contacts

Sylvain Rheims, Pr

Role: CONTACT

Sylvain.rheims@chu-lyon.fr

0472357106 ext. +33

Camille Giraudon, Dr

Role: CONTACT

Camille.giraudon@chu-lyon.fr

04 26 73 94 38 ext. +33

Facility Contacts

Sylvain Rheims, Pr

Role: primary

Sylvain.rheims@chu-lyon.fr

0472357106 ext. +33

Camille Giraudon

Role: backup

Camille.giraudon@chu-lyon.fr

04 26 73 94 38 ext. +33

Other Identifiers

69HCL24_1231

Identifier Type: -

Identifier Source: org_study_id