Vigabatrin is generally well tolerated, with approximately 5% to 15% of patients withdrawing from clinical trials due to unwanted side effects. Most of the adverse effects involve the nervous system and are possibly due to raised GABA concentration. Drowsiness is the most frequent complaint. Other CNS complaints include dizziness, headache, confusion, ataxia, diplopia, memory impairment, and insomnia. There is a low incidence of depression and psychoses as well. A more detailed listing of adverse reactions is given in the Physicians Desk Reference. White matter spongiosis, defined by electron microscopy as intramyelinic edema, has been previously reported as an adverse effect of vigabatrin therapy in various animal models and has been confirmed on autopsy of an epileptic child following sudden death (17). Vigabatrin is associated with transient, asymptomatic MRI abnormalities in infants treated for infantile spasms, but most of these resolveeven in subjects who remain on vigabatrin therapy. There is a case report of a patient with infantile spasms who developed ataxic movements following treatment with vigabatrin, and MRI demonstrated a symmetrical pattern of thalamic and globi pallidi diffusion restriction, which resolved (24). However, there is another case report of an infant with infantile spasms treated with adrenocorticotropic hormone and vigabatrin who presented with a movement disorder and encephalopathy with MRI changes that had not been seen with hormone therapy alone (15). Encephalopathy resolved after discontinuation of vigabatrin.
There are reports of children with early myoclonic encephalopathy owing to nonketotic hyperglycinemia who were treated with vigabatrin and deteriorated, likely due to enhancement of the encephalopathy by elevated GABA concentration together with the elevated levels of glycine. Caution should be exercised in using vigabatrin in children with elevated glycine levels.
Visual field defects. Vigabatrin-induced optic neuropathy manifested by visual field defects has been reported and is due to reversible myelin edema in the optic nerves. Another explanation is retinal cone system dysfunction. Vigabatrin also affects foveal cone electroretinographic amplitudes and rod-derived visual fields. The mechanism of vigabatrin-mediated retinal degeneration is accumulation of the amino acid taurine in retinal cells, and deficiency of this amino acid may be involved in phototoxicity (11). In a meta-analysis of studies of patients with epilepsy who received vigabatrin treatment, peripapillary retinal nerve fiber layer thickness was reduced, and optical coherence tomography was found to be a useful tool to help clinicians for assessing retinal toxicity and guiding the dosage (19).
Perimetry seemed to be the most sensitive modality for identifying vigabatrin toxicity. Visual field loss resulting from vigabatrin is usually not reversible. However, visual acuity, color vision, and electroretinogram amplitude loss may be reversible in patients with minimal or no field loss. Visual field defects were found in 34% of children treated with vigabatrin for infantile spasms in an international multicenter study, and the rate increased from 9% to 63% as duration of treatment was prolonged (21). There is some evidence that visual field defects remain stable with continuous treatment. These data give support to the hypothesis that the pathogenesis of vigabatrin-associated visual field defects may be an idiosyncratic adverse drug reaction rather than dose-dependent toxicity. It is, therefore, feasible to continue treatment with vigabatrin in these cases, provided regular visual field monitoring is done. Reversibility of visual field loss after withdrawal of vigabatrin has been reported in some cases. White sphere kinetic perimetry has the potential to detect visual field constriction associated with vigabatrin use in young children. Electrophysiologic testing is more accurate than the visual field testing to monitor the direct vigabatrin effect on the outer retina. Wide-field multifocal electroretinogram is useful for assessment of retinal function in vigabatrin-treated patients. Optical coherence tomography can detect attenuation of the retinal nerve fiber layer in patients exposed to vigabatrin and correlates with reduced full-field electroretinography parameters as well as constricted visual fields, indicating retinotoxicity at several levels (14).
A comparative, open-label, parallel-group, multicenter study associated frequency of vigabatrin-attributed visual field loss in patients with epilepsy to duration of treatment and recommended visual field examination at least every six months for the duration of treatment (29). According to a systematic review, the relative risk for field loss in vigabatrin-exposed patients was 4.0, and it was recommended that vigabatrin be reserved for epilepsy patients for whom there is no alternative or for patients for whom the benefit of ongoing treatment outweighs the risk of vigabatrin-associated visual field loss (16).
In view of the concern for visual field complications, a prospective study on adult patients with refractory complex partial seizures conducted ophthalmologic examination prior to initiation of vigabatrin therapy and documented several patients with preexisting visual field defects (25). Up to one year of adjunctive vigabatrin treatment did not significantly change near visual fields in the treated patients. The limitations of this study were single-arm, open-label design and limited duration of exposure.
All vigabatrin-treated patients in the United States are required to enroll in the vigabatrin patient registry, which was started in 2009 following approval of vigabatrin by the FDA. Vision assessments are now required at baseline after therapy initiation, every three months during therapy, and three to six months after discontinuation of treatment (18).
Ophthalmological assessments, including electroretinograms, are recommended for monitoring retinal health during vigabatrin treatment. A prospective study has shown the reliability of RETeval, a hand-held, dilation-free device for electroretinography in children under three years of age treated with vigabatrin (13).
