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NCT Number: NCT07013331

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

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

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Key information

Conditions

Epilepsy Brain Diseases Central Nervous System Diseases Death Death, Sudden Dravet Syndrome Drug Resistant Epilepsy Epilepsies, Myoclonic Epilepsy, Generalized Epileptic Syndromes Healthy Controls Nervous System Diseases Pathologic Processes Pathological Conditions, Signs and Symptoms Sudden Unexpected Death in Epilepsy

Age range

18 year–60 year

Sex eligibility

All sexes

Study type

Interventional

Phase

Not applicable

Primary location

Who can participate

Healthy volunteers accepted: Yes

Only the study team can determine whether someone qualifies for participation.

Patients with DS

  • Inclusion criteria
  • 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
  • Exclusion criteria
  • Subject in exclusion period of another study
  • 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

  • Inclusion criteria
  • 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
  • For women of childbearing potential, use highly effective contraception during study participation
  • Exclusion criteria
  • Subject in exclusion period of another study
  • MRI contra-indication (presence of metallic elements, claustrophobia)
  • Presence of Vagal Nerve Stimulation
  • Ongoing serotoninergic treatment, including selective serotonin reuptake inhibitor
  • 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 admitted to a health or social institution for purposes other than research
  • Adults subject to a legal protection measure (guardianship, curatorship)
  • Persons not affiliated to a social security scheme or beneficiaries of a similar scheme

Healthy controls

  • Inclusion criteria
  • 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)
  • 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 admitted to a health or social institution for purposes other than research
  • Adults subject to a legal protection measure (guardianship, curatorship)
  • Persons not affiliated to a social security scheme or beneficiaries of a similar scheme
  • Exclusion criteria
  • 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)
  • 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 admitted to a health or social institution for purposes other than research
  • Adults subject to a legal protection measure (guardianship, curatorship)
  • Persons not affiliated to a social security scheme or beneficiaries of a similar scheme

Treatment and study plan

[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

Primary outcomes

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

    Time frame: Emission will be acquired over 90 minutes post-injection

    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.

Secondary outcomes

  1. 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

    Time frame: at Visit 2 (week 2)

    The total duration of central sleep apnea has been preferred to the total number of episodes of central sleep apnea as primary endpoint in order to take into account both the occurrence rate and the severity of episodes. To take into account the variability of the total sleep time across patients, the total duration of central sleep apneas will be expressed as the percentage of the total sleep time for each patient. Sleep apneas can classified as obstructive, central or both central sleep apnea, Apnea will be defined as a decrease in peak nasal pressure of >90% of baseline, lasting at least 10 s. Hypopnea was defined as a decrease of >30% of the baseline nasal pressure, lasting at least 10 s and associated with ≥4% drop in SpO2. Central apnea will be defined by cessation > 10 seconds of airflow with simultaneous cessation of respiratory effort. The respiratory events are scored in clinical routine according to the 2007 American Academy of Sleep Medicine guidelines.

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

    Time frame: at Visit 2 (week 2)

    Comparing VBM on the brainstem parcels of patients with DS with the one of patients with drug-resistant focal epilepsy

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

    Time frame: at Visit 2 (week 2)

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

    Time frame: at Visit 2 (week 2)

    Comparing the signal-noise radioactivity ratio of 5-HT1A receptors binding in healthy subjects with the one observed with the old PET camera used to develop the CERMEP normative database of 5-HT1A receptors binding in adults

Study contacts

Contact information is provided by the study sponsor or research team.

Camille Giraudon, Dr

CONTACT

[email protected]

04 26 73 94 38 ext. +33

Sylvain Rheims, Pr

CONTACT

[email protected]

0472357106 ext. +33

Sponsors and collaborators

Lead sponsor

Hospices Civils de Lyon

Other

Registry information

Acronym: DRAPETONINE

Important dates

Study start
2026
Primary completion
2028
Study completion
2028
First posted
Jun 10, 2025
Registry last updated
May 8, 2026

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

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This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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