USE OF EX-VIVO MAGNETIC-RESONANCE-IMAGING TO DETECT ONSET OF VIGABATRIN-INDUCED INTRAMYELINIC EDEMA IN CANINE BRAIN

Vigabatrin (VGB) causes intramyelinic edema (microvacuolation) in brai n of dogs and rodent, which has encouraged development of noninvasive methods to monitor for this effect during clinical trials. We report t he qualitative ex vivo magnetic resonance imaging (MRI) changes observ ed in a neuropathology study in dogs to detect time of onset and regre ssion of VGB-induced intramyelinic edema. Beagles were randomly assign ed to 18 groups of 6 dogs per group and administered vigabatrin orally (p.o.) at a dose of 300 mg/kg/day (2 males, 2 females) or placebo (1 male, 1 female). Animals were killed and examined at weekly intervals during the 12 weeks of treatment and at 1, 2, 4, 8, 12, and 16 weeks a fter discontinuation of drug treatment. Myelin microvacuolation in tha lamus, hypothalamus, and fornix were noted histologically after 4-5 we eks of treatment. Increases in MRI T-2 intensity were observed in hypo thalamus after 4 weeks and in thalamus and columns of the fornix after 7 weeks. Both MRI T-2 intensity and microvacuolation continued to inc rease during 12-week VGB treatment. When VGB treatment was discontinue d after 12 weeks, both MRI T-2 intensity and microvacuolation began to decrease. Sixteen weeks after VGB discontinuation, histopathology had returned to normal and MRI examination demonstrated a marked trend to ward reversal of the increased T-2 signal intensity. MRT thus has pote ntial as a noninvasive surveillance technique in certain experimental and clinical conditions associated with intramyelinic edema.