PET Study of the Nicotinic System in Epilepsy (NICOPET)

Mutations in neuronal nicotinic acetylcholine receptors (nAChRs) have been identified in the autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE). Despite the demonstration of a gain of function of the mutated receptors, the precise mechanisms leading to this nocturnal epilepsy are still unknown. In 2006 the investigators studied the nAChR cerebral distribution in a group of patients with ADNFLE carrying a nAChR mutation, by a PET-scan using [18F]-F-A-85380, a ligand with a high affinity and specificity for alpha4beta2 nicotinic receptors. The study showed a different pattern of brain distribution of the radiotracer in the ADNFLE patients when compared to a group of control subjects, with a significant increase of nicotinic receptor density in the patients in mesencephalon and cerebellum (Picard et al., Brain 2006). Based on the known biochemical and cellular circuits in the brainstem, these results suggest that the nAChR density increase in mesencephalon is involved in the pathophysiology of ADNFLE through the role of brainstem ascending cholinergic systems in arousal. The follow-up step consists of extending this examination to other forms of epilepsy, in order to verify the specificity of the hyperfixation pattern for ADNFLE, and search for a potential involvement of nicotinic receptors in other forms of epilepsy. The investigators aim to study 5 groups of subjects: control subjects (Group 1, 20 subjects); patients with a non lesional partial epilepsy and a predominance of diurnal seizures (Group 2, 12 subjects); patients with an idiopathic generalized epilepsy (Group 3, 12 subjects); patients with nocturnal frontal lobe epilepsy (Group 4, 3 subjects) and epileptic patients with vagal nerve stimulation (Group 5, 1 subject). For each patient, a cerebral MRI, [18F]- fluorodeoxyglucose (FDG) PET/CT and [18F]-F-A-85380 PET/CT examinations are planned. The investigators will perform data analyses on volume of distribution (Vt) parametric images which will be based on the ratio of brain tissue to unchanged F-A-85380 plasma at equilibrium. Statistical parametric mapping (SPM2) will be used to further study the parametric PET images. This study is primarily dedicated to demonstrate that the pattern of hyperfixation that was obtained in ADNFLE patients is specific for this disorder and does not constitute a common pattern to various forms of epilepsy. The investigators will also search for a possible involvement of the nAChRs in other forms of epilepsy.

Study Overview

• Status: Completed
• Conditions: Epilepsy
• Intervention / Treatment: Radiation: MRI of the brain; Radiation: PET scan [18F]F-A-85380; Radiation: PET scan [18F]FDG

• Study Type: Interventional
• Enrollment (Actual): 48
• Phase: Not Applicable

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 60 years (Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: Male

Description

Inclusion Criteria:

• males
• 18-60 years old
• non-smokers

Exclusion Criteria:

• smoking during the past twelve months
• contraindications to MRI
• brain lesions on MRI (including hippocampal atrophy)
• neurological disorder (other than epilepsy) or psychiatric disorder
• neoplasia or coronary disease
• blood test showing : creatinine clearance < 50 ml/min, or platelet < 100 G/l, or leucocytes < 3.8 G/l, or ALT or AST > 2 x upper standard, or gamma-GT > 3 x upper standard, or albumin < 35 g/l or > 48 g/l .
• patients only : nuclear imaging during the past twelve months
• healthy volunteers only : ionising radiation exam during the past five years

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Control group	Radiation: MRI of the brain; to eliminate a structural intra-cerebral lesion; Radiation: PET scan [18F]F-A-85380; exam performed after iv injection of 200 MBq [18F]F-A-85380; Radiation: PET scan [18F]FDG; exam performed after iv injection of 200 MBq [18F]FDG
Experimental: Non lesional diurnal partial epilepsy	Radiation: MRI of the brain; to eliminate a structural intra-cerebral lesion; Radiation: PET scan [18F]F-A-85380; exam performed after iv injection of 200 MBq [18F]F-A-85380; Radiation: PET scan [18F]FDG; exam performed after iv injection of 200 MBq [18F]FDG
Experimental: Idiopathic generalized epilepsy	Radiation: MRI of the brain; to eliminate a structural intra-cerebral lesion; Radiation: PET scan [18F]F-A-85380; exam performed after iv injection of 200 MBq [18F]F-A-85380; Radiation: PET scan [18F]FDG; exam performed after iv injection of 200 MBq [18F]FDG
Experimental: Nocturnal frontal lobe epilepsy	Radiation: MRI of the brain; to eliminate a structural intra-cerebral lesion; Radiation: PET scan [18F]F-A-85380; exam performed after iv injection of 200 MBq [18F]F-A-85380; Radiation: PET scan [18F]FDG; exam performed after iv injection of 200 MBq [18F]FDG
Experimental: Epileptic patients with Vagus Nerve Stimulation (VNS)	Radiation: PET scan [18F]F-A-85380; exam performed after iv injection of 200 MBq [18F]F-A-85380; Radiation: PET scan [18F]FDG; exam performed after iv injection of 200 MBq [18F]FDG

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Comparison of the cerebral distribution of the neuronal nicotinic acetylcholine receptors (nAChR) in the 5 groups of individuals by means of voxelwise and regional 18F-FA binding potential measurements	Parametric 18F-FA and 18F-FDG binding potential measurements will be compared between the different groups of patients with epilepsy and the control group in order to find specific changes in the cerebral distribution of the nicotinic receptors in the different types of epilepsy, by using a voxel-wise (SPM) and a volume of interest (VOI) analysis.	1 month

Collaborators and Investigators

• Sponsor: Fabienne PICARD

Publications and helpful links

General Publications

• Picard F, Bruel D, Servent D, Saba W, Fruchart-Gaillard C, Schollhorn-Peyronneau MA, Roumenov D, Brodtkorb E, Zuberi S, Gambardella A, Steinborn B, Hufnagel A, Valette H, Bottlaender M. Alteration of the in vivo nicotinic receptor density in ADNFLE patients: a PET study. Brain. 2006 Aug;129(Pt 8):2047-60. doi: 10.1093/brain/awl156. Epub 2006 Jun 30.

Study record dates

Study Major Dates

• Study Start (Actual): February 1, 2012
• Primary Completion (Actual): November 1, 2015
• Study Completion (Actual): November 1, 2015

Study Registration Dates

• First Submitted: August 24, 2017
• First Submitted That Met QC Criteria: August 30, 2017
• First Posted (Actual): August 31, 2017

Study Record Updates

• Last Update Posted (Actual): August 31, 2017
• Last Update Submitted That Met QC Criteria: August 30, 2017
• Last Verified: August 1, 2017

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Epilepsy
• Other Study ID Numbers: 10-041

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No