MRI monitoring of vigabatrin‐induced intramyelinic edema in dogs

Weiss, Kenneth L.; Schroeder, Charles E.; Kastin, S. J.; Gibson, John P.; Yarrington, J. T.; Heydorn, William E.; McBride, R. G.; Sussman, Neil M.; Arezzo, J. C.

doi:10.1212/wnl.44.10.1944

Cited by 43 publications

(29 citation statements)

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“…Although the nucleus basalis is enriched in GABA-ergic input (47), we did not observe any abnormalities in this area in MR images or histologic sections. We speculate that VGB-induced toxicity is related to tissue-specific effects on the white matter (7,8). Axonal damage also might result from loss of normal interaction with oligodendrocytes.…”

Section: Discussionmentioning

confidence: 93%

Effect of Long‐Term Vigabatrin Administration on the Immature Rat Brain

et al. 2000

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Summary:Purpose: To determine whether the neuropathologic changes produced by vigabatrin (VGB; y-vinyl GABA) administration in the developing rat brain are reversible.Methods: We injected rats daily with VGB (2540 mglkgl day, s.c.) from age 12 days for 2 weeks followed by 2 weeks of a drug-free period. Behavioral testing, magnetic resonance (MR) imaging, biochemical assays, and histologic technique were used to assess the adverse effect of VGB in developing brain and its reversibility.Results: At the end of 2 weeks' VGB administration: (a) there was a hyperactivity and a shortened latency to escape out of cool water; (b) white matter appeared hyperintense in T, and diffusion-weighted MR images with 4-15% increases in T,; (c) microvacuolation, TUNEL-positive nuclei, and swollen axons were observed in the corpus callosum; (d) myelin staining indicated a reduction in myelination, as did the reduction in activities of myelin and oligodendrocyte-associated enzymes and the decrease in myelin basic protein on Western blots. Two weeks after stopping VGB administration: (a) MR images were normal, and microvacuolation was no longer in the white matter; (b) reduction in myelination reversed partially; (c) the T, relaxation time remained elevated in the hypothalamus; and (d) the behavioral response remained abnormal.Conclusions: Long-term VGB administration to young rats causes brain injury, which recovers partially on its cessation. The observed cell death, disrupted myelination, and alterations in behavior indicate a need for further safety assessment in infants and children. Key Words: Development-Magnetic resonance imaging-Vigabatrin-White matter.Vigabatrin (VGB; y-vinyl-aminobutyric acid) elevates tissue levels of GABA by irreversibly binding to GABA transaminase, thereby inhibiting GABA degradation. VGB is considered an effective and safe antiepileptic drug (AED) in both adults and children and now is the preferred treatment for infantile spasms (1 4). However, Holmes ( 5 ) has emphasized that the detrimental effects of AEDs may be greater in the developing brain than in the mature brain. In addition, Marson et al. (6) have drawn attention to the paucity of information on the "new" AEDs in childhood epilepsy and advocated the need for randomized clinical trials at an earlier stage of drug development than is currently the case. Although prolonged administration of VGB to adult animals causes potentially reversible intramyelinic edema or microvacuolation (7,8), we demonstrated recently (9) that the adverse effects of VGB may be greater in immature than mature brains. Treatment of rats at age 12-16 days Accepted February 8, 2000. Address correspondence and reprint requests to Dr. U. Tuor at Institute for Biodiagnostics, National Research Council of Canada, 435 Ellice Ave., Winnipeg, Manitoba R3B 1Y6, Canada. E-mail: Ursula. Tuor@ nrc.ca with 15-50 mglkg of VGB daily for 5 days caused decreased myelin staining, axonal degeneration, glial cell death in the white matter, and reactive astrogliosis in the frontal cortex. Whe...

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Section: Discussionmentioning

confidence: 93%

Effect of Long‐Term Vigabatrin Administration on the Immature Rat Brain

et al. 2000

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“…However, significant differences based on group averages were not observed until 8-10 wk of dosing (32). MRI changes were also detectable after 4-7 wk (37). Thus, functional disturbances of the vigabatrin-treated dog brain appear to occur at about the same time or slightly after the intramyelinic edema becomes distinguishable from the background vacuolation of controls.…”

Section: Histopczthologymentioning

confidence: 84%

“…Toxicity studies with vigabatrin have demonstrated microscopic brain vacuolation, most notably in white matter tracts, as the main toxic effect in mice, rats, and dogs given dosages of 30-300 mg/ kg/day in subacute and chronic tests (1,4,5,9,10,32,37). Cynomolgus monkeys treated with 300 mg/ kg/day for 16 mo exhibited minimal microvacuolation, which was considered equivocal since it was not noticeably different from background observed in controls (4,9,10).…”

Section: Introductionmentioning

confidence: 99%

Sequential Neuropathology of Dogs Treated with Vigabatrin, a GABA-Transaminase Inhibitor

Yarrington¹,

Gibson²,

Dillberger³

et al. 1993

Toxicol Pathol

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Vigabatrin (Sabril®) is a γ-aminobutyric acid-transaminase (GABA-T) inhibitor that is effective in the treatment of certain types of drug-resistant or uncontrolled epilepsy but is known to cause microscopic vacuolation (intramyelinic edema) in the brains of treated rats, mice, and dogs. The effects of high oral doses (300 mg/kg/day) of vigabatrin administered orally to Beagle dogs were studied during treatment weeks 1-12 and recovery weeks 13, 14, 16, 20, 24, and 28. Emesis, loose stools, and anorexia and 3 drug-related deaths were observed during the first 4 wk of treatment but were virtually nonexistent thereafter because of adaptation to the drug aided by food supplementation. In more sensitive areas of the brain (columns of the fomix, thalamus, and hypothalamus), microscopic quantitative differences between background vacuolation in controls and drug-related vacuolation in treated dogs could be delineated after 4 wk, generally reached highest levels of severity between 8 and 12 wk, and were reversible upon cessation of dosing. Inhibition of brain GABA-T and elevation of brain GABA were noted after 1 wk of treatment. During the course of treatment vigabatrin ranged between 4-17 nmol/ml (plasma) and 42-1,570 nmol/ml [cerebrospinal fluid (CSF)] while CSF GABA concentrations were 4-32 nmol/ml (treated dogs) and 0.1-0.6 nmol/ml (control dogs). Although the cause of vigabatrin-induced microvacuolation is unknown, the results of the study demonstrated that GABA-T inhibition with subsequent GABA elevation occurred within the first week of treatment and was followed by the onset of detectable microvacuolation several weeks later.

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“…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.…”

Section: Magnetic Resonance Imaging In Animalsmentioning

confidence: 92%

The Potential for Vigabatrin‐Induced Intramyelinic Edema in Humans

Cohen¹,

Fisher²,

Brigell³

et al. 2000

Epilepsia

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Purpose: Vigabatrin (Sabril, Hoechst Marion Roussel) is an antiepilepsy drug (AED) presently marketed in 64 countries for the treatment of partial and secondarily generalized seizures. Vigabatrin (VGB) is marketed in a subset of these countries for the treatment of infantile spasms. Clinical experience in humans has shown that VGB provides effective seizure control with a wide margin of safety. However, animal toxicity studies raised concern when prolonged administration of VGB was shown to induce intramyelinic edema (IME) in some laboratory animal species. Methods: Animal and human data were reviewed with respect to the potential for VGB-induced IME. Surveillance of patients receiving VGB in clinical trials or by prescription has been conducted for >15 years to identify patients developing clinical abnormalities that might be IME related. Results: The histologic lesions of VGB-induced IME in animals are reliably reproduced and correlate with changes in multimodality evoked potentials (EPs) and magnetic resonance imaging (MRI). Numerous studies of the effects of VGB on EP and MRI in epilepsy patients have demonstrated no clear-cut IME-related changes in these modalities. Additionally, autopsy and surgical brain samples from VGB-treated patients have been scrutinized for potential IME histopathology. In an estimated 350,000 patient-years of VGB exposure (-1 75,000 pa

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MRI monitoring of vigabatrin‐induced intramyelinic edema in dogs

Cited by 43 publications

References 0 publications

Effect of Long‐Term Vigabatrin Administration on the Immature Rat Brain

Effect of Long‐Term Vigabatrin Administration on the Immature Rat Brain

Sequential Neuropathology of Dogs Treated with Vigabatrin, a GABA-Transaminase Inhibitor

The Potential for Vigabatrin‐Induced Intramyelinic Edema in Humans

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