ReviewCurrent role of vigabatrin in infantile 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
References (65)
Histopathology of brain tissue from patients with infantile spasms
Int Rev Neurobiol
(2002)- et al.
United Kingdom Infantile Spasms Study. The United Kingdom Infantile Spasms Study (UKISS) comparing hormone treatment with vigabatrin on developmental and epilepsy outcomes to age 14 months: a multicentre randomised trial
Lancet Neurol
(2005) - et al.
Vigabatrin in infantile spasms
Lancet
(1990) - et al.
Acute regulation of steady-state GABA levels following GABA-transaminase inhibition in rat cerebral cortex
Neurochem Int
(2006) Vigabatrin in the management of generalized seizures in children
Seizure
(1995)- et al.
Vigabatrin for infantile spasms
Pediatr Neurol
(2002) - et al.
The United Kingdom Infantile Spasms Study comparing vigabatrin with prednisone or tetracosactide at 14 days: a multicentre, randomised controlled trial
Lancet
(2004) - et al.
Tuberous sclerosis complex: a review of neurological aspects
Eur J Paediatr Neurol
(2002) - et al.
Characteristics of epilepsy in focal cortical dysplasia in infancy
Epilepsy Res
(2002) Succinic semialdehyde dehydrogenase deficiency (SSADH) (4-hydroxybutyric aciduria, gamma-hydroxybutyric aciduria)
Eur J Paediatr Neurol
(2004)
Reversibility of vigabatrin-induced visual-field defect
Lancet
Reversed visual field constrictions in children after vigabatrin withdrawal-true retinal recovery or improved test performance only?
Seizure
Characteristic retinal atrophy with secondary “inverse” optic atrophy identifies vigabatrin toxicity in children
Ophthalmology
Scotopic threshold response changes after vigabatrin therapy in a child without visual field defects: a new electroretinographic marker of early damage?
Neurobiol Dis
The latest of infantile spasms
Curr Opin Neurol
Phatogenesis of infantile spasms: a model based on developmental desynchronization
J Clin Neurophysiol
Vigabatrin and GABA concentration inter-relationship in rat extracellular fluid (EDF) from frontal cortex and hippocampus
Epilepsia
Severe persistent visual field constriction associated with vigabatrin
BMJ
A risk-benefit assessment of treatments for infantile spasms
Drug Saf
Vigabatrin in low doses selectively suppresses the clonic component of audiogenically kindled seizures in rats
Epilepsia
Is visual field constriction in epilepsy patients treated with vigabatrin reversible?
J Neurol
Are vigabatrin-associated visual field constrictions asymptomatic?
J Neurol
Therapeutic trial of Vigabatrin in refractory infantile spasms
J Child Neurol
Vigabatrin in the treatment of infantile spasms
Neuropediatrics
Vigabatrin in newly diagnosed infantile spasms, letter
Neuropediatrics
Vigabatrin as initial therapy for infantile spasms: a European retrospective survey. Sabril IS Investigator and Peer Review Groups
Epilepsia
Vigabatrin versus ACTH as first-line treatment for infantile spasms: a randomized, prospective study
Epilepsia
Randomised, placebo-controlled study of vigabatrin as first line treatment of infantile spasms
Epilepsia
Efficacy of Vigabatrin in subject with infantile spasms
Epilepsia
Vigabatrin in the treatment of infantile spasm in tuberous sclerosis: literature review
J Child Neurol
Current management for epilepsy in tuberous sclerosis complex
Curr Opin Neurol
Taylor-type focal cortical dysplasia in infants: some MRI lesions almost disappear with maturation of myelination
Epilepsia
Cited by (53)
Phakomatoses
2019, Dermatologic ClinicsCitation Excerpt :The mTOR inhibitors have also shown benefit with seizures290–292 and possibly for TS-associated neuropsychiatric disorder.269 Treatment for symptomatic and asymptomatic epileptic activity is suggested293–295 with no medical therapy showing specific advantage except vigabatrin for infantile spasm296,297 and vagal nerve stimulator for children at risk of regression.269 Cannabidiol is currently being investigated for seizure control298 (NCT02544763).
Mammalian Target of Rapamycin Inhibitors and Life-Threatening Conditions in Tuberous Sclerosis Complex
2015, Seminars in Pediatric NeurologyTuberous Sclerosis Complex
2015, Pediatric Clinics of North AmericaTuberous sclerosis complex surveillance and management: Recommendations of the 2012 international tuberous sclerosis complex consensus conference
2013, Pediatric NeurologyCitation Excerpt :Category 3) Strong evidence demonstrates superior efficacy for the treatment of infantile spasms with vigabatrin in patients with TSC34–37; therefore, vigabatrin should be first-line treatment. However, the prescribing clinician should be aware of possible side effects, particularly possible retinal toxicity, and how to monitor for these.