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

NCT07013331 | Not Yet Recruiting

• 1 other identifier: 69HCL24_1231
• Study Type: interventional
• Target: 30
• Locations: 1 country
• Sites: 1

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; Healthy Controls; Drug Resistant Epilepsy

Keywords

epilepsy; Dravet syndrome; drug-resistant focal epilepsy; serotonin; PET-MRI; MPPF; SUDEP

Outcome Measures

Primary Outcomes (1)

• Comparison of the brainstem BPND of [18F]-MPPF across patients groups (DS and focal epilepsy)

  Dynamic PET images will be modelled using a simplified reference tissue model to estimate non-displaceable binding potential (BPND) values in each voxel with reference to the cerebellar white matter excluding the vermis.

  Emission will be acquired over 90 minutes post-injection

Secondary Outcomes (4)

• Relation between the brainstem BPND of [18F]-MPPF and the total duration of central sleep apneas during total sleep time over a 24-hour period in patients with DS

  at Visit 2 (week 2)

• Comparing brainstem volume of patients with DS with the one of patients with drug-resistant focal epilepsy

  at Visit 2 (week 2)

• Relation in DS between brainstem volumes and the total duration of central sleep apneas during total sleep time over a 24-hour period

  at Visit 2 (week 2)

• Signal-noise radioactivity ratio of 5-HT1A receptors binding in healthy subjects

  at Visit 2 (week 2)

Study Arms (3)

Patients with Dravet syndrome

EXPERIMENTAL

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.

Other: [18F]MPPF PET-MRI

Patients with drug-resistant focal epilepsy

EXPERIMENTAL

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.

Other: [18F]MPPF PET-MRI

Adult healthy controls (> 18 years)

EXPERIMENTAL

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.

Other: [18F]MPPF PET-MRI

Interventions

[18F]MPPF PET-MRI 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); Patients with Dravet syndrome; Patients with drug-resistant focal epilepsy

Eligibility Criteria

• Age: 18 Years - 60 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Adult patients (≥ 18 but \< 60 years)
• 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 assent and patient (or patient's legal representative guardianship) who gave its written informed consent to participate to the study
• For women of childbearing

You may not qualify if:

• MRI contra-indication (presence of metallic elements, claustrophobia, Patients unable to maintain a minimul level of immobility during the imaging acquisition)
• Presence of Vagal Nerve Stimulation
• Patients unable to maintain a minimul level of immobility during the imaging acquisition
• Pregnant women, women in labor or breastfeeding women.
• Severe renal failure (Glomerular filtration rate \< 30 ml/min)
• Hypersensitivity to \[18F\] MPPF
• Persons deprived of their liberty by a judicial or administrative decision
• Persons under psychiatric care
• Persons not affiliated to a social security scheme or beneficiaries of a similar scheme
• Patients with drug-resistant focal epilepsy
• Adult patient (≥ 18 years)
• Patient suffering from drug-resistant focal epilepsy according to ILAE classification
• Patient in whom presurgical evaluation is considered
• No restriction related to the seizure frequency
• Patient who gave her/his written informed consent to participate to the study

Sponsors & Collaborators

• Hospices Civils de Lyon: lead

Study Sites (1)

Hôpital Neurologique Pierre Wertheimer

Bron, Rhone, 69500, France

Location

MeSH Terms

Conditions

Epilepsy; Epilepsies, Myoclonic; Drug Resistant Epilepsy; Sudden Unexpected Death in Epilepsy

Condition Hierarchy (Ancestors)

Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Epilepsy, Generalized; Epileptic Syndromes; Death, Sudden; Death; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Central Study Contacts

Sylvain Rheims, Pr

CONTACT

0472357106; Sylvain.rheims@chu-lyon.fr

Camille Giraudon, Dr

CONTACT

04 26 73 94 38; Camille.giraudon@chu-lyon.fr

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: SCREENING
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 25, 2025
• First Posted: June 10, 2025
• Study Start: April 1, 2026
• Primary Completion (Estimated): December 1, 2028
• Study Completion (Estimated): December 1, 2028
• Last Updated: February 27, 2026

Record last verified: 2026-02

Data Sharing

• IPD Sharing: Will not share

Locations

FR (1)