Serotonin Transporter Gene Variation and Refractory Mesial Temporal Lobe Epilepsy with Hippocampal Sclerosis

MARCELO KAUFFMAN; DAMIAN CONSALVO; SILVIA KOCHEN

NEUROLOGY

Año: 2008

0028-3878

Epilepsy typically responds well to antiepileptic drug (AED) therapy[1]. However, there are particular epileptic syndromes where patients frequently are refractory to medical treatment. Mesial Temporal Epilepsy with Hippocampal Sclerosis (MTE-HS) is such a frequent paradigmatic cause of refractory epilepsy. About 75% of these patients are candidates to surgical treatment because of the lack of response to AED[2]. In spite of this bad prognosis, about one patient in four experiments a good response to AED. There have been a number of studies looking for markers of good prognosis in this population of patients. However, none of the few markers identified so far has been of real clinical utility[3]. The interindividual variability present in the extent of response to pharmacological treatments might depend on the complex interplay between genetic and environmental factors[4]. Although a number of pharmacogenetic studies were performed in epilepsy, the results reported have been mostly inconclusive so far[5]. Nevertheless, genetics factors might be involved in the modulation of the phenotypic features of MTE-HS, including the response to AEDs. Recent evidence supports the role of serotoninergic neurotransmission in epileptogenesis[6]. Agents that elevate extracellular serotonin levels, such as 5-hydroxytryptophan[7] and serotonin reuptake blockers[8], inhibit both focal and generalized seizures. It has been shown that some anti-epileptic drugs increase endogenous extracellular serotonin concentration[6]. Furthermore, the treatment with the serotonin reuptake blocker fluoxetine might be effective in controlling seizures and recent in vivo neuroimaging studies demonstrated decreased 5-HT (1A) receptor binding in mesial temporal lobe structures of patients with MTE-HS[9, 10]. The serotonin transporter gene (SLC6A4) exhibits a functional VNTR polymorphism in intron 2. The 12 repetitions alleles seem to positively modulate the transcription of SLC6A4 gene[11]. Moreover, this polymorphism was associated with the extent of response to fluoxetine and other serotonin reuptake blocker in different conditions[12]. Since, pharmacogenetic prediction of response is one possibility for improving the efficiency of AED treatment we performed a molecular epidemiology study in a population of MTE-HS patients in order to investigate the role of the VNTR intron 2 polymorphism in the prediction of AED treatment response.