Use of Ex Vivo Magnetic Resonance Imaging to Detect Onset of Vigabatrin‐Induced Intramyelinic Edema in Canine Brain

Abstract

Vigabatrin (VGB) causes intramyelinic edema (microvacuolation) in brain of dogs and rodent, which has encouraged development of noninvasive methods to monitor for this effect during clinical trials. We report the qualitative ex vivo magnetic resonance imaging (MRI) changes observed in a neuropathology study in dogs to detect time of onset and regression of VGB-induced intramyelinic edema. Beagles were randomly assigned 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 after discontinuation of drug treatment. Myelin microvacuolation in thalamus, hypothalamus, and fornix were noted histologically after 4-5 weeks of treatment. Increases in MRI T2 intensity were observed in hypothalamus after 4 weeks and in thalamus and columns of the fornix after 7 weeks. Both MRI T2 intensity and microvacuolation continued to increase during 12-week VGB treatment. When VGB treatment was discontinued after 12 weeks, both MRI T2 intensity and microvacuolation began to decrease. Sixteen weeks after VGB discontinuation, histopathology had returned to normal and MRI examination demonstrated a marked trend toward reversal of the increased T2 signal intensity. MRI thus has potential as a noninvasive surveillance technique in certain experimental and clinical conditions associated with intramyelinic edema.

Abnormal Axial Diffusivity in the Deep Gray Nuclei and Dorsal Brain Stem in Infantile Spasm Treated with Vigabatrin

“…The MR imaging signal intensity increased with the duration of the treatment and normalized 16 weeks after the drug was discontinued. 4 Myelin vacuolation has been reported in the myelinated white matter tracts of mice exposed to vigabatrin. 2 Further study of rats that have been treated with vigabatrin showed lesions in the cerebellar white matter and increased T2 relaxation on MR imaging, which correlated with microvacuolation on postmortem examination.…”

“…A randomized placebo-control study of 108 dogs given vigabatrin for Յ12 weeks demonstrated myelin vacuolation in the thalamus, hypothalamus, and fornix on histology 4 -5 weeks after treatment. 4 The ages of the dogs were not stated. MR imaging changes were present in these animals several weeks after histologic changes.…”

“…In addition, animal studies have raised concerns that prolonged administration of vigabatrin induced intramyelin edema. [2][3][4] Recently, human studies have described reversible MR imaging abnormalities characterized by T2-weighted hyperintensities and/or restricted diffusion in the globi pallidi, thalami, dorsal pons, and midbrain in approximately 20%-30% of patients with infantile spasm. [5][6][7] Young age and high dose appeared to be risk factors for the development of these reversible changes in the deep gray nuclei and brain stem.…”

Succinic Semialdehyde Dehydrogenase: Biochemical–Molecular–Clinical Disease Mechanisms, Redox Regulation, and Functional Significance

“…Vigabatrin, however, has not been a consistently helpful therapeutic for these patients, and there have been many reports of lack of effect or, worse, worsening of symptoms ranging from seizure control to alertness. Further, there have been concerns regarding vigabatrin, resulting thus far in absence of U.S. Food and Drug Administration approval, initially because of intramyelinic edema and white matter vacuolation in rats and dogs (22,148,153). In clinical trials, 30% of patients treated with vigabatrin for epilepsy report visual field defects after 1 year of treatment (103,181,190).…”

The Potential for Vigabatrin‐Induced Intramyelinic Edema in Humans

“…Increased signal on T,-weighted images and histologic changes of IME were closely correlated. In dogs, regions with IME demonstrated increased signal on T,-weighted images and decreased signal on T, -weighted images (16,48). The development of the T, signal abnormality followed the time-course and anatomic distribution of pathologic changes.…”