Rebecca Bresnahan1, Myrsini Gianatsi2, Melissa J Maguire3, Catrin Tudur Smith2, Anthony G Marson1,4,5. 1. Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Liverpool, UK. 2. Department of Biostatistics, University of Liverpool, Liverpool, UK. 3. Department of Neurology, Leeds General Infirmary, Leeds, UK. 4. The Walton Centre NHS Foundation Trust, Liverpool, UK. 5. Liverpool Health Partners, Liverpool, UK.
Abstract
BACKGROUND: This is an updated version of the original Cochrane Review published in 2008 and updated in 2013. Epilepsy is a common neurological condition which affects up to 1% of the population. Approximately 30% of people with epilepsy do not respond to treatment with currently available drugs. The majority of these people have focal epilepsy. Vigabatrin is an antiepileptic drug licensed for use in drug-resistant epilepsy. OBJECTIVES: To assess the efficacy and tolerability of vigabatrin as an add-on therapy for people with drug-resistant focal epilepsy. SEARCH METHODS: For the latest update of this review, we searched the following databases on 1 November 2018: Cochrane Register of Studies (CRS Web), MEDLINE (Ovid 1946 to 31 October 2018), ClinicalTrials.gov and the World Health Organization International Clinical Trials Registry Platform. The Cochrane Epilepsy Group Specialized Register and the Cochrane Central Register of Controlled Trials (CENTRAL) are both included in the Cochrane Register of Studies (CRS Web). We checked reference lists of retrieved studies for additional reports of relevant studies and contacted Hoechst Marion Roussel (manufacturers of vigabatrin) in 2000. SELECTION CRITERIA: We included randomised, double-blind, placebo-controlled, fully published trials of vigabatrin in people of any age with drug-resistant focal epilepsy. DATA COLLECTION AND ANALYSIS: Two review authors assessed trials for inclusion and extracted data using the standard methodological procedures expected by Cochrane. Primary analysis was by intention-to-treat (ITT). We evaluated: 50% or greater reduction in seizure frequency, treatment withdrawal, adverse effects, dose-response analysis, cognitive outcomes and quality of life. We presented results as risk ratios (RR) with 95% or 99% confidence intervals (CI). MAIN RESULTS: We identified 11 trials that included 756 participants (age range: 10 to 64 years). The trials tested vigabatrin doses between 1 g/day and 6 g/day. All 11 trials displayed a risk of bias across at least three risk of bias domains. Predominantly, the risk of bias was associated with: allocation concealment (selection bias), blinding of outcome assessment (detection bias) and incomplete outcome data (attrition bias). Participants treated with vigabatrin may be two to three times more likely to obtain a 50% or greater reduction in seizure frequency compared with those treated with placebo (RR 2.60, 95% CI 1.87 to 3.63; 4 studies; low-certainty evidence). Those treated with vigabatrin may also be three times more likely to have treatment withdrawn although we are uncertain (RR 2.86, 95% CI 1.25 to 6.55; 4 studies; very low-certainty evidence). Compared to placebo, participants given vigabatrin were more likely to experience adverse effects: dizziness/light-headedness (RR 1.74, 95% CI 1.05 to 2.87; 9 studies; low-certainty evidence), fatigue (RR 1.65, 95% CI 1.08 to 2.51; 9 studies; low-certainty evidence), drowsiness (RR 1.70, 95% CI 1.18 to 2.44; 8 studies) and depression (RR 3.28, 95% CI 1.30 to 8.27; 6 studies). Although the incidence rates were higher among participants receiving vigabatrin compared to those receiving placebo, the effect was not significant for the following adverse effects: ataxia (RR 2.76, 95% CI 0.96 to 7.94; 7 studies; very low-certainty evidence), nausea (RR 3.57, 95% CI 0.63 to 20.30; 4 studies), abnormal vision (RR 1.64, 95% CI 0.67 to 4.02; 5 studies; very low-certainty evidence), headache (RR 1.23, 95% CI 0.79 to 1.92; 9 studies), diplopia (RR 1.76, 99% CI 0.94 to 3.30) and nystagmus (RR 1.53, 99% CI 0.62 to 3.76; 2 studies; low-certainty evidence). Vigabatrin had little to no effect on cognitive outcomes or quality of life. AUTHORS' CONCLUSIONS: Vigabatrin may significantly reduce seizure frequency in people with drug-resistant focal epilepsy. The results largely apply to adults and should not be extrapolated to children under 10 years old. Short-term follow-up of participants showed that some adverse effects were associated with its use. Analysis of longer-term observational studies elsewhere, however, has demonstrated that vigabatrin use can lead to the development of visual field defects.
BACKGROUND: This is an updated version of the original Cochrane Review published in 2008 and updated in 2013. Epilepsy is a common neurological condition which affects up to 1% of the population. Approximately 30% of people with epilepsy do not respond to treatment with currently available drugs. The majority of these people have focal epilepsy. Vigabatrin is an antiepileptic drug licensed for use in drug-resistant epilepsy. OBJECTIVES: To assess the efficacy and tolerability of vigabatrin as an add-on therapy for people with drug-resistant focal epilepsy. SEARCH METHODS: For the latest update of this review, we searched the following databases on 1 November 2018: Cochrane Register of Studies (CRS Web), MEDLINE (Ovid 1946 to 31 October 2018), ClinicalTrials.gov and the World Health Organization International Clinical Trials Registry Platform. The Cochrane Epilepsy Group Specialized Register and the Cochrane Central Register of Controlled Trials (CENTRAL) are both included in the Cochrane Register of Studies (CRS Web). We checked reference lists of retrieved studies for additional reports of relevant studies and contacted Hoechst Marion Roussel (manufacturers of vigabatrin) in 2000. SELECTION CRITERIA: We included randomised, double-blind, placebo-controlled, fully published trials of vigabatrin in people of any age with drug-resistant focal epilepsy. DATA COLLECTION AND ANALYSIS: Two review authors assessed trials for inclusion and extracted data using the standard methodological procedures expected by Cochrane. Primary analysis was by intention-to-treat (ITT). We evaluated: 50% or greater reduction in seizure frequency, treatment withdrawal, adverse effects, dose-response analysis, cognitive outcomes and quality of life. We presented results as risk ratios (RR) with 95% or 99% confidence intervals (CI). MAIN RESULTS: We identified 11 trials that included 756 participants (age range: 10 to 64 years). The trials tested vigabatrin doses between 1 g/day and 6 g/day. All 11 trials displayed a risk of bias across at least three risk of bias domains. Predominantly, the risk of bias was associated with: allocation concealment (selection bias), blinding of outcome assessment (detection bias) and incomplete outcome data (attrition bias). Participants treated with vigabatrin may be two to three times more likely to obtain a 50% or greater reduction in seizure frequency compared with those treated with placebo (RR 2.60, 95% CI 1.87 to 3.63; 4 studies; low-certainty evidence). Those treated with vigabatrin may also be three times more likely to have treatment withdrawn although we are uncertain (RR 2.86, 95% CI 1.25 to 6.55; 4 studies; very low-certainty evidence). Compared to placebo, participants given vigabatrin were more likely to experience adverse effects: dizziness/light-headedness (RR 1.74, 95% CI 1.05 to 2.87; 9 studies; low-certainty evidence), fatigue (RR 1.65, 95% CI 1.08 to 2.51; 9 studies; low-certainty evidence), drowsiness (RR 1.70, 95% CI 1.18 to 2.44; 8 studies) and depression (RR 3.28, 95% CI 1.30 to 8.27; 6 studies). Although the incidence rates were higher among participants receiving vigabatrin compared to those receiving placebo, the effect was not significant for the following adverse effects: ataxia (RR 2.76, 95% CI 0.96 to 7.94; 7 studies; very low-certainty evidence), nausea (RR 3.57, 95% CI 0.63 to 20.30; 4 studies), abnormal vision (RR 1.64, 95% CI 0.67 to 4.02; 5 studies; very low-certainty evidence), headache (RR 1.23, 95% CI 0.79 to 1.92; 9 studies), diplopia (RR 1.76, 99% CI 0.94 to 3.30) and nystagmus (RR 1.53, 99% CI 0.62 to 3.76; 2 studies; low-certainty evidence). Vigabatrin had little to no effect on cognitive outcomes or quality of life. AUTHORS' CONCLUSIONS:Vigabatrin may significantly reduce seizure frequency in people with drug-resistant focal epilepsy. The results largely apply to adults and should not be extrapolated to children under 10 years old. Short-term follow-up of participants showed that some adverse effects were associated with its use. Analysis of longer-term observational studies elsewhere, however, has demonstrated that vigabatrin use can lead to the development of visual field defects.