Abstracts

RATIONALE: Increased serotonin (5-HT) innervation and synthesis have been demonstrated in human epileptogenic malformations of cortical development (MCD), using immunocytochemistry study of surgically resected tissue (Trottier et al. 1996), and more recently, in vivo PET study of [alpha][11C]methyl-L-tryptophan (AMT) brain distribution (Chugani et al. 1998). In patients with tuberous sclerosis and multiple brain lesions, AMT captation appears to be specifically increased in the epileptogenic tuber (Chugani et al. 1998). In experimental models of epilepsy, serotonin receptors, and in particular 5-HT1A receptors, are modulated in various ways, depending on the model considered. Based on the above data, we have hypothetized that 5-HT1A receptors changes might also occurred in human epileptogenic MCD.
METHODS: Five patients were selected for this study, including two with bilateral nodular periventricular heterotopia, and three with a localized malformation of cortical organization. One of the latter patient also had a single nodular periventricular heterotopia contralateral to its cortical malformation. All patients, as well as 24 control subjects, underwent a 3D-mpr MRI and a 70 minutes duration dynamic [18F]-MPPF PET study. [18F]-MPPF (2[ssquote]-methoxyphenyl-(N-2[ssquote][ssquote]-pyridinyl)-p-fluoro-benzamido-ethyl-piperazin) is a validated selective antagonist of 5-HT1A receptors. PET images were coregistrated with MRI, and quantified using the model of Gunn et al. (Neuroimage, 1998), considering the cerebellum as a reference for non-specific binding. We obtained binding potential (BP) parametric images which were then processed in order to perform a comparison between each individual patients and their respective sex and age matched control group, using the ANCOVA function of SPM 99. We also traced regions of interest (ROIs) over all MCD, as well as over various ipsilateral and contralateral cortical areas.
RESULTS: All five patients demonstrated significant focal 5-HT1A changes. Some, but not all heterotopia, were associated with an increased BP, which remained however lower than that of adjacent cortical structures. Within the same patient, major BP differences were observed between the multiple heterotopic nodules. Malformations of cortical organization could be associated with a significant increased (N=2), or decreased (N=1) BP. Other distant cortical and subcortical areas, which appeared normal on MRI, also demonstrated significant increased or decreased BP. Among the latter, the raphe nuclei of the mesencephalon and/or of the medulla, showed an increased BP in all five patients.
CONCLUSIONS: Our preliminary data suggest that epileptic patients with MCD have significant 5-HT1A receptor changes. The latter involve the MCD as well as other cortical and subcortical regions, including the raphe nuclei. The major 5-HT1A BP differences observed between the various MCD, both among and within individuals, raise the issue of the relation between 5-HT1A BP changes and the epileptogenicity of the MCD. This issue will need to be further addressed. Finally, the very consistent increased BP observed within the raphe nuclei suggests a general modulation of the serotoninergic system in epileptic patients with MCD , and might represent a potential therapeutic target.
[Supported by: Claude Bernard Lyon 1 University, Hospices Civils de Lyon]