Vigabatrin for tuberous sclerosis complex

Department of Neurosciences, Pediatric Neurology, Tor Vergata University, Via di Tor Vergata 135, 00133 Rome, Italy.
Brain and Development (Impact Factor: 1.88). 12/2001; 23(7):649-53. DOI: 10.1016/S0387-7604(01)00290-X
Source: PubMed


Vigabatrin (VGB) was found to be an effective anti-epileptic drug to reduce infantile spasms in about 50% of patients and it has been found most effective in infantile spasms due to tuberous sclerosis (TSC) in which up to 95% of infants had complete cessation of their spasms. VGB was synthesized to enhance inhibitory gamma-aminobutyric acidergic (GABAergic) transmission by elevating GABA levels via irreversible inhibition of GABA transaminase. The mechanism underlying the particular efficacy of VGB in TSC is still unknown. However, its efficacy suggests that epileptogenesis in TSC may be related to an impairment of GABAergic transmission. VGB should be considered as the first line monotheraphy for the treatment of infantile spasms in infants with confirmed diagnosis of TSC. The efficacy of VGB treatment can be assessed in less than 10 days, but usually a few days treatment with a dose of about 100 mg/kg/day stops infantile spasms. The cessation of the spasms is associated with a marked improvement of behaviour and mental development. Unfortunately, it has become clear that the use of VGB is associated with a late appearance of visual-field defects in up to 50% of patients. Currently the minimum duration and doses of VGB treatment that can produce side effects are unknown. The feasibility of using short treatment periods (2-3 months) should be investigated.

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    • "However, in contrast to most other antiseizure medications, VGB is particularly effective for seizures in TSC, especially infantile spasms, a typically devastating type of childhood seizure. VGB has been reported to eliminate spasms in about 95% of cases, which is much higher than all other treatments for spasms due to TSC or any other cause [8], [9]. In fact, this special relationship between VGB and TSC is one of the few documented examples of a medication having individualized efficacy for a specific epilepsy syndrome or cause of epilepsy. "
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    ABSTRACT: Epilepsy is a common neurological disorder and cause of significant morbidity and mortality. Although antiseizure medication is the first-line treatment for epilepsy, currently available medications are ineffective in a significant percentage of patients and have not clearly been demonstrated to have disease-specific effects for epilepsy. While seizures are usually intractable to medication in tuberous sclerosis complex (TSC), a common genetic cause of epilepsy, vigabatrin appears to have unique efficacy for epilepsy in TSC. While vigabatrin increases gamma-aminobutyric acid (GABA) levels, the precise mechanism of action of vigabatrin in TSC is not known. In this study, we investigated the effects of vigabatrin on epilepsy in a knock-out mouse model of TSC and tested the novel hypothesis that vigabatrin inhibits the mammalian target of rapamycin (mTOR) pathway, a key signaling pathway that is dysregulated in TSC. We found that vigabatrin caused a modest increase in brain GABA levels and inhibited seizures in the mouse model of TSC. Furthermore, vigabatrin partially inhibited mTOR pathway activity and glial proliferation in the knock-out mice in vivo, as well as reduced mTOR pathway activation in cultured astrocytes from both knock-out and control mice. This study identifies a potential novel mechanism of action of an antiseizure medication involving the mTOR pathway, which may account for the unique efficacy of this drug for a genetic epilepsy.
    PLoS ONE 02/2013; 8(2):e57445. DOI:10.1371/journal.pone.0057445 · 3.23 Impact Factor
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    • "Infantile spasms affect up to 75% of children with TSC (Thiele 2004) and also occur in the general population as a result of brain dysfunction from a variety of intrinsic or extrinsic causes during prenatal, perinatal, or postnatal brain development (Wong and Trevathan 2001). In contrast to infantile spasms from other causes, TSC-related infantile spasms have a very rapid and sustained response to the seizure medication vigabatrin (Curatolo et al. 2001), an irreversible inhibitor of the c-aminobutyric acid (GABA) degrading enzyme GABA transaminase. This response suggests that the mechanisms leading to infantile spasms in TSC include abnormalities of GABAergic neurotransmission. "
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    ABSTRACT: Tuberous sclerosis complex (TSC) is a genetic disease with severe neurologic and psychiatric manifestations including epilepsy, developmental delay, and autism. Despite much progress in defining abnormal signaling pathways including the contribution of increased mTORC1 signaling, specific abnormalities that underlie the severe neurologic features in TSC remain poorly understood. We hypothesized that epilepsy and autism in TSC result from abnormalities of γ-aminobutyric acidergic (GABAergic) interneurons. To test this hypothesis, we generated conditional knockout mice with selective deletion of the Tsc1 gene in GABAergic interneuron progenitor cells. These interneuron-specific Tsc1 conditional knockout (CKO) mice have impaired growth and decreased survival. Cortical and hippocampal GABAergic interneurons of CKO mice are enlarged and show increased mTORC1 signaling. Total numbers of GABAergic cells are reduced in the cortex with differential reduction of specific GABAergic subtypes. Ectopic clusters of cells with increased mTORC1 signaling are also seen suggesting impaired interneuron migration. The functional consequences of these cellular changes are evident in the decreased seizure threshold on exposure to the proconvulsant flurothyl. These findings support an important role for the Tsc1 gene during GABAergic interneuron development, function, and possibly migration.
    Cerebral Cortex 10/2011; 22(9):2111-9. DOI:10.1093/cercor/bhr300 · 8.67 Impact Factor
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    • "Vigabatrin is used with advantage in treatment of IS especially in cases associated to tuberous sclerosis complex [108-110]. Doses are usually around 100 mg/Kg/day with a gradual increase but maintained at the lowest effective dosage. Superior doses seem not to be of benefit. "
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    ABSTRACT: This epileptic disorder has become a classic topic for neuropediatricians and the interest is documented by the large number of publications on this subject. The relative frequency among the epileptic syndromes is an another reason why not only neuropediatricians but also general pediatricians must be fully informed about diagnostic, clinical, imaging and genetic aspects. Early diagnosis is of paramount importance in order to obtain even complete results in patients with so called idiopathic situations. A number of problems are still to be solved. There is no agreement on the type and the schedule of treatment. A common denominator about this problem is not jet available even if some advances in this regard have been accomplished. Of paramount importance is an accurate clinical and laboratory examination as a prerequisite regarding prognosis and results of therapy in every single case. However, even if more than 170 years have elapsed since the first communication of dr. West on the peculiar syndrome that his child was suffering of, the interest of scientists on this subject has now been enriched and rewarded.
    Italian Journal of Pediatrics 02/2010; 36(1):15. DOI:10.1186/1824-7288-36-15 · 1.52 Impact Factor
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