Abstracts

Rationale: The gamma-aminobutyric acidA (GABAA) receptor complex undergoes major developmental changes from birth to adulthood. These changes might be associated with modifications in physiological properties of GABAA receptors influencing seizure susceptibility. Some antiepileptic drugs increase brain GABA levels but accompanying changes of in vivo GABAA receptor function in children with epilepsy are not known. [11C]Flumazenil (FMZ) positron emission tomography (PET) is a sensitive tool for detecting epileptic foci and may be used to assess GABAA receptor function during neurodevelopment. Methods: In vivo FMZ binding was quantified in 27 children (age: 1.4-18 years) with intractable focal epilepsy using FMZ PET. Following compartmental analysis of dynamic FMZ PET and using metabolite-corrected arterial blood data, hemispheric and regional FMZ binding were measured on parametric images of volume of distribution (VD, a macroparameter representing Bmax/KD) on the side contralateral to the epileptic focus. Similar data from 15 adults were used for comparison. Results: In children who used anticonvulsants which do not increase GABA concentration in brain (N=20), regional FMZ VD values were 40-60% higher at age two years than in adults. An exponential age-related decline was found reaching adult levels between 14-22 years of age. Children using vigabatrin (N=7, age <8 years) had significantly lower FMZ VD values than children of similar age from the other group (N=8, P=.048). There were no FMZ VD differences between children with vs. without carbamazepine, phenytoin or valproate of the same age-group. Conclusions: Age-related decline of in vivo FMZ binding reflects developmental ontogeny of GABAA receptor function in epileptic children. Since previous studies reported no significant changes in GABAA receptor binding in adults taking vigabatrin, our preliminary data suggest that there are developmental differences in the down-regulation of the GABAA receptor complex in response to chronic vigabatrin treatment. FMZ PET can be a powerful tool to assess age-related changes and effects of GABAergic drugs on GABAA receptor function.