Development of vigabatrin-induced lesions in the rat brain studied by magnetic resonance imaging, histology, and immunocytochemistry

Vigabatrin, the γ-aminobutyric acid transaminase (GABA-T)-inhibiting anticonvulsant drug, was given orally at a dose of 275 mg/kg/day to rats (n = 6) in their feed for a period of 12 weeks, during which T₂-weighted magnetic resonance images (MRIs) and diffusion-weighted MRIs (DWIs) were collected at weeks 1, 3, 6, 9, and 12. Half the rats (n = 3; and half their age-matched littermate controls; n = 3) were then killed for histopathological confirmation of the observed VGB-induced cerebellar and cortical white-matter lesions. VGB was removed from the diet and additional MRIs of the remaining rats taken at weeks 14, 17, 20, and 24, at which time they (n = 3), along with remaining controls (n = 3), were also killed for histopathology. The T₂-weighted MRIs acquired were used to compute T₂ relaxation time maps. Statistically significant VGB-induced T₂ increases were observed in the frontal and occipital cortices and in the cerebellar white matter (CWM). The cerebellar lesions were more clearly discerned by eye in the DWIs than by T₂-contrast alone. During the recovery period the VGB-treatment group CWM-T₂ and CWM-DWI hyperintensity greatly decreased as the reversible lesion disappeared. As expected, histological and immunocytochemical examinations demonstrated the presence of intra-myelinic edema, microvacuolation, and reactive astrocytosis in the CWM and cortex after 12 weeks VGB-treatment. In the remaining animals microvacuolation of the white matter had not completely resolved during the 12-week recovery phase. The data show that quantitative MRI T₂-relaxometry can be used to detect VGB-induced CNS pathology, and also suggest that DWI is particularly sensitive to the cerebellar lesion. The reversible neurotoxicity of global GABA-elevation in experimental animals is discussed. Synapse 53:36–43, 2004. © 2004 Wiley-Liss, Inc.