Neuropathology of a human hippocampus following long-term treatment with vigabatrin: lack of microvacuoles

doi:10.1016/0920-1211(90)90092-A

Epilepsy Research

Volume 6, Issue 2, July 1990, Pages 166-170

https://doi.org/10.1016/0920-1211(90)90092-A Get rights and content

Abstract

Vigabatrin (gamma-vinyl-GABA), an irreversible inhibitor of gamma-aminobutyric acid transaminase, has been reported to be effective in the treatment of refractory epilepsies. Animal toxicology studies have shown that long-term application of vigabatrin induces intramyelinic edema and microvacuolation of the white matter in non-primate species. However, clinical and neuropathological studies of patients exposed to long-term vigabatrin treatment have, so far, provided no evidence for microvacuolation in the human brain.

We report on the histopathological findings of selective amygdalohippocampectomy specimens from a 36-year-old female patient treated with vigabatrin for a period of 11.5 months, and from 2 control patients with chronic refractory temporal lobe seizures. All specimens showed changes associated with chronic epileptic seizures including focal neuronal loss and hippocampal gliosis. Microvacuoles, intramyelinic edema or other manifestations of neurotoxic damage were not observed in vigabatrin exposed tissue, supporting the view that this compound may not exert hippocampal neurotoxicity in humans.

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Cited by (33)

The vigabatrin-associated brain abnormalities on MRI and their differential diagnosis
2024, Clinical Radiology
Vigabatrin is an anti-epileptic drug that inhibits the enzyme γ-aminobutyric acid (GABA)-transaminase. The anticonvulsant effect of vigabatrin involves increasing GABA levels and attenuating glutamate–glutamine cycling. Vigabatrin indications include infantile spasms and refractory focal seizures. Despite having a significant role in paediatric epileptology, vigabatrin has adverse effects, such as retinal toxicity, in up to 30% of patients after 1 year of use and brain abnormalities on magnetic resonance imaging (MRI). The percentage of patients with brain abnormalities on MRI varies between 22–32% of children using vigabatrin to treat infantile spasms. Risk factors for presenting these imaging abnormalities are cryptogenic infantile spasms, age <12 months old, high dosage, and possible concomitant hormonal therapy. Clinically, these abnormalities are usually asymptomatic. Histopathological analysis reveals white matter vacuolation and intramyelinic oedema. The typical findings of vigabatrin-associated brain abnormalities on MRI are bilateral and have a symmetrical hyperintense signal on T2-weighted imaging, with diffusion restriction, that often compromise the globi pallidi, thalami, subthalamic nuclei, cerebral peduncles, midbrain, dorsal brainstem, including the medial longitudinal fasciculi, and dentate nuclei of the cerebellum. In this article, the authors intend to review the clinical manifestations, histopathological features, imaging aspects, and differential diagnosis of vigabatrin-associated brain abnormalities on MRI.
Brain MRI findings with vigabatrin therapy: Case report and literature review
2016, Clinical Imaging
Citation Excerpt :
Several reports that have analyzed the effect of administering the drug long term to animals have found the development of intramyelinic edema, manifesting as microvacuoles in the visual pathways, fornix column, and white matter of the cerebellum [17–21]. It is important to note that these changes have not been seen in human patients [17,22]. Cocito et al. [13] used MRI to examine the white matter of 11 epileptic patients who received vigabatrin for more than 5 years.
Infantile spasm or West syndrome is a pediatric epileptic disorder characterized by flexor and/or extensor spasms beginning in childhood. Vigabatrin is an effective medical therapy for infantile spasm but has pronounced, potentially worrisome imaging findings in patients receiving therapy. We present the case of an 8-month-old infant with such brain magnetic resonance imaging findings after treatment initiation. In this article, we highlight the imaging changes and discuss the differential diagnosis along with the required follow-up.
Temporal lobe epilepsy
2005, Magnetic Resonance in Epilepsy
Temporal Lobe Epilepsy
2004, Magnetic Resonance in Epilepsy: Neuroimaging Techniques: Second Edition
A comparison of the neuropathological effects of vigabatrin and carbamazepine in patients with newly diagnosed localization-related epilepsy using MR-based cerebral T2 relaxation time measurements
1998, Epilepsy Research
Background: Magnetic resonance (MR)-based T2 relaxation time measurement is a sensitive technique to detect neuropathological changes such as intramyelinic edema in vivo. Objective: To determine whether vigabatrin (VGB) causes an increase in T2 relaxation time in patients with newly diagnosed localization-related epilepsy over 1 year. Methods: Patients with newly diagnosed localization-related epilepsy who participated in a VGB-carbamazepine (CBZ) monotherapy trial were included. All were scanned on a 1.5 T Siemens SP63 Magnetom scanner. T2 maps of the brain were obtained at baseline and at follow-up 1 year later. Nine control subjects had repeated hippocampal T2 maps with a median interval of ≈2 years. Results: 23 patients (12 on VGB and 11 on CBZ) were included. There were no increased T2 relaxation times in the VGB treated group at follow-up and no significant differences between the two antiepileptic drug groups. There was a trend for the temporal and frontal white matter T2 relaxation times to be lower on follow-up in the patients compared to the control subjects. Conclusion: The findings do not suggest that intramyelinic edema occurs in patients taking monotherapy VGB for 1 year.
Quantitative MR relaxometry study of effects of vigabatrin on the brains of patients with epilepsy
1994, Epilepsy Research
Neurotoxic changes have been found in the brains of dogs and rats treated with the antiepileptic drug vigabatrin, and these can be demonstrated in vivo by MRI. Quantification of T2 signal by relaxometry is more sensitive than visual assessment of T2-weighted images in revealing changes in T2 signal. We have therefore undertaken a quantitative MR study of 45 patients with refractory partial seizures during a prospective, randomised, double-blind trial of vigabatrin (1.5 g twice daily), followed by open treatment. T2 relaxometry was performed during a baseline period, after 20 weeks vigabatrin or placebo treatment and again in those who continued the drug for at least 35 weeks. Twenty weeks' vigabatrin treatment was not associated with a significant change in T2 relaxation time in any brain area. There were no significant T2 signal changes in the follow-up study and no correlation between change in T2 and duration of vigabatrin treatment. There was no quantitative MR evidence of vigabatrin-related changes in the white matter of these patients similar to those which have been found in animals treated with the drug.

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Short communicationNeuropathology of a human hippocampus following long-term treatment with vigabatrin: lack of microvacuoles

Abstract

Biochem. Pharmacol.

Epilepsy Res.

Lancet

J. Epilepsy

Surg. Neurol.

Case report of surgical brain sample after 2.5 years of vigabatrin therapy (abstract)

Epilepsia

Vigabatrin bei therapieresistenten Epilepsien. Vorläufige Ergebnisse

Akt. Neurol.

Vigabatrin for refractory complex partial seizures: multicenter single-blind study with long-term follow-up

Neurology

The neuropathology of vigabatrin

Epilepsia

A study of the effects of vigabatrin in the central nervous system and retina of Sprague Dawley and Lister-hooded rats

Toxicol. Pathol.

Short communication
Neuropathology of a human hippocampus following long-term treatment with vigabatrin: lack of microvacuoles