Review
Current role of vigabatrin in infantile spasms

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Abstract

Vigabatrin (VGB), a selective irreversible inhibitor of γ-aminobutyric acid transaminase, has proved to be effective against cryptogenic and symptomatic infantile spasms (IS). Unfortunately, reports of serious visual field defects have led to a drastic reduction in the use of the drug. This review is based on a systematic search in the literature for evidence regarding efficacy and safety of VGB in IS. Based on a specific mechanism of action, there is a solid evidence of clinical efficacy of VGB in children with Tuberous Sclerosis. Similarly, VGB could represent a potential effective therapy also for spasms due to focal cortical dysplasia. In infants with spasms due to other causes, the risk of ophthalmologic toxicity should be carefully weighted against the benefit of controlling spasms.

Introduction

Infantile spasms (IS) are a severe epileptic encephalopathy with heterogeneous aetiology that occurs in infancy and early childhood.1 IS are associated with a great variety of neuropathological conditions; about 70% of IS are symptomatic, brain malformations and Tuberous Sclerosis (TSC) accounting for up to 35% of patients, and up to 45% of neuropathologic cases.2 Heterogeneous pathophysiologic mechanisms, including dysfunction of the brainstem, abnormal cortical–subcortical interaction, disturbances of cortical synaptogenesis and abnormal brain-adrenal axis, may be responsible of the genesis of IS.3

Adrenocorticotropic hormone (ACTH) or corticosteroids have been the gold standard treatment for the last 40 years. Corticotropin or corticosteroids are both effective in controlling spasms; in a prospective study of 107 patients the response rates were 76% and 70% respectively.4 In 1990 vigabatrin (VGB), an irreversible and highly selective inhibitor of γ-aminobutyric acid (GABA) transaminase, has been found to be effective in IS, particularly in individuals affected by TSC.5 GABA concentrations increase after 2 h of VGB administration and continue to increase until 6–8 h in the frontal lobe. VGB levels are dose-related, but animal studies show that are significantly higher in the retina than in any other brain tissues.6 Unfortunately, the use of VGB has been significantly restricted by the emergence of apparently irreversible retinal changes and altered peripheral vision.7 The current challenge for neuropediatricians is determining the risk-benefit ratio of VGB and corticosteroids/corticotrophin in children with IS and to specify the aetiological groups where their use could be optimal.8 Recently, further progress has been made in understanding the mechanisms of action of VGB9, 10 and its side effects in early childhood.11, 12

This review is based upon a systematic search in the literature for evidence regarding the efficacy and safety of VGB in IS, in order to reassess its current role in the clinical practice.

Section snippets

Search strategy and selection criteria

Data for this review were identified by search of the medical literature Medline and Pub Med databases with the terms “vigabatrin” combined with the keywords “infantile spasms, West syndrome, focal cortical dysplasia, refractory epilepsy”. A second independent research for reported efficacy and adverse reactions during VGB treatment was done, using the same database, with the keywords: “vigabatrin, side effects, toxicity, retinal damage”. Only reports published in English and conducted on

Efficacy and type of the study

Overall, we included 12 studies (Table 1). Of them, 4 (33%) were randomized controlled trial (RCT), 1 had a cross-over design, 5 were uncontrolled trials, whereas 2 were observational studies. With regard to the outcome, the percentage of spasms cessation during VGB treatment ranged from 11% to 78%. The large variation may be related to several factors, such as the study design, control regimen, different dose, aetiology, and stage and severity of disease. The study from Elterman22 compared the

Efficacy in Tuberous Sclerosis

In 1999, Hancock and Osborne23 reviewed all studies published in the English Language literature investigating the use of VGB in the treatment of spasms in infants suffering from TSC. Overall there were 390 patients treated, with complete cessation of seizures occurring in 242 (62%). Of these 77 had a known underlying diagnosis of TSC; the remaining 313 had IS due to other aetiologies or no-cause found at the time of the study. Of the patients affected by TSC, 73 (95%) had complete cessation of

Safety

VGB is generally well tolerated. Side effects were transitory, and no one was reported to continue after the cessation of the VGB treatment. Headache, drowsiness, psychiatric reactions, and hyperactivity were the most common adverse effects observed in controlled clinical trials, mainly reported in adolescents and young adults.23, 37 Only 7 infants of 390 (0.1%) were reported as having the VGB dropped-out because of hyperactivity, irritability, hypotonia and myoclonus.23 Since 1997 concentric

Conclusions

Since 1958 when ACTH was introduced, VGB represents the only real achievement in the effective treatment of IS. Recent progresses in understanding mechanisms show that response to VGB may be etiologically related in infants with IS, VGB being the first-choice drug in infants with TSC. In our personal experience, low dosages can be rapidly effective in TSC infants, if the treatment is started at the very early onset of spasms. Since early diagnosis of the disease is possible, due to the presence

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