Prolonged vigabatrin treatment modifies developmental changes of GABA(A)-receptor binding in young children with epilepsy.
OBJECTIVE
To determine whether prolonged treatment with vigabatrin (VGB), an antiepileptic drug (AED) that acts by elevating brain gamma-aminobutyric acid (GABA) levels, interferes with age-related changes of in vivo GABA(A)-receptor binding in children with epilepsy.


METHODS
Using [11C]flumazenil (FMZ)-positron emission tomography (PET) imaging, 15 children (aged 1-8 years) with medically intractable epilepsy were studied. Seven of these children were treated with VGB (1,000-2,500 mg/day) for > or =3 months before the FMZ-PET study. The remaining eight patients were medicated with other drugs that are known not to act directly on the GABAergic system. Absolute quantification of PET data was performed by using the volume of distribution (VD) of FMZ in brain tissue representing FMZ ligand binding.


RESULTS
After controlling for age, hemispheric FMZ VD values were significantly lower in children treated with VGB as compared with the non-VGB group (p = 0.012). Regional FMZ VD values of the VGB-treated patients were significantly lower in all cortical regions and the cerebellum, whereas the difference was not significant in the thalamus and basal ganglia. No significant drug effect or drug-by-region interaction could be determined when the patients were separated according to treatment with carbamazepine (p = 0.97) or valproate (p = 0.55).


CONCLUSIONS
VGB induces a decrease in GABA(A)-receptor binding in the cortex and cerebellum of the developing epileptic brain. A similar effect of other drugs and substances of abuse targeting the GABAergic system may be hypothesized. Because of the important role of the GABAergic system in developmental plasticity, the reversibility and functional consequences of this age-specific drug effect should be further studied.
Juhász
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C
Department of Pediatrics, Children's Hospital of Michigan, The Detroit Medical Center, Wayne State University School of Medicine, Detroit, Michigan 48201, USA.
Muzik
O
O
Chugani
D C
DC
Shen
C
C
Janisse
J
J
Chugani
H T
HT
D000367:Age Factors; D001921:Brain / Q000000981:diagnostic imaging / Q000187:drug effects / Q000503:physiopathology; D001931:Brain Mapping; D002250:Carbon Radioisotopes; D002648:Child; D002675:Child, Preschool; D004827:Epilepsy / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000503:physiopathology; D005260:Female; D005442:Flumazenil / Q000493:pharmacokinetics*; D006801:Humans; D007223:Infant; D008297:Male; D009473:Neuronal Plasticity / Q000187:drug effects / Q000502:physiology; D011869:Radioligand Assay; D011963:Receptors, GABA-A / Q000187:drug effects*; D014055:Tomography, Emission-Computed; D020888:Vigabatrin / Q000009:adverse effects* / Q000627:therapeutic use
D002250:Carbon Radioisotopes; D011963:Receptors, GABA-A; D005442:Flumazenil; D020888:Vigabatrin