Lamotrigine add-on therapy for drug-resistant focal epilepsy

Background

Epilepsy is a disorder in which unexpected electrical discharges from the brain cause seizures. Approximately one-third of patients with epilepsy continue to have seizures, despite treatment with presently used (older) antiepileptic drugs (AEDs). In addition, the older AEDs have a lot of adverse effects. Therefore, the development of effective new therapies for the treatment of drug-resistant seizures is of considerable importance. As a result, a range of new AEDs has been developed as 'add-on' treatments. Lamotrigine is one of these drugs.

Aims of the review

This review aimed to determine the effects of lamotrigine on seizures, adverse effects, cognition (ability to learn and understand) and quality of life compared to placebo controls, when used as an add-on treatment for people with focal epilepsy that would not respond to existing AEDs. For this update, we did not identify any new studies to add, and thus, the conclusions remain unchanged. The review included 14 randomised controlled trials with a total number of 1806 participants.

Results

Lamotrigine, used in combination with other AEDs in patients who have drug-resistant focal epilepsy can decrease the frequency of seizures further. However, adding lamotrigine to the usual treatment is more often associated with an increase in adverse effects such as unsteadiness (ataxia), dizziness, double vision (diplopia), and nausea.

Certainty of the evidence

We assessed the trials with regards to risk of bias and overall we judged them as low to unclear. We rated the certainty of the evidence as high to moderate.

Conclusions

Further high-quality research is needed to fully evaluate the efficacy and tolerability of lamotrigine and compare it with other newer AEDs.

The evidence is current to 9 March 2020.

Authors' conclusions: 

Lamotrigine as an add-on treatment for drug-resistant focal seizures appears to be effective in reducing seizure frequency, and seems to be fairly well-tolerated. However, the trials were of relatively short duration and provided no evidence for the long term. Further trials are needed to assess the long-term effects of lamotrigine, and to compare lamotrigine with other add-on drugs.

Read the full abstract...
Background: 

This is an updated version of the Cochrane Review previously published in 2016.

Epilepsy is a common neurological disorder, affecting 0.5% to 1% of the population. For nearly 30% of these people, their epilepsy is resistant to currently available drugs. Pharmacological treatment remains the first choice to control epilepsy. Lamotrigine is one of the newer antiepileptic drugs. Lamotrigine, in combination with other antiepileptic drugs (add-on), can reduce seizures, but with some adverse effects.

Objectives: 

To determine the effects of lamotrigine on (1) seizures, (2) adverse-effect profile, and (3) cognition and quality of life, compared to placebo, when used as an add-on treatment for people with drug-resistant focal epilepsy.

Search strategy: 

For the latest update of the review, we searched the following databases on 9 March 2020: Cochrane Register of Studies (CRS Web), MEDLINE (Ovid, 1946 to March 06, 2020). CRS Web includes randomized or quasi-randomized, controlled trials from PubMed, EMBASE, ClinicalTrials.gov, the World Health Organization International Clinical Trials Registry Platform (ICTRP), the Cochrane Central Register of Controlled Trials (CENTRAL), and the Specialized Registers of Cochrane Review Groups including Epilepsy. No language restrictions were imposed.

Selection criteria: 

Randomised placebo-controlled trials of people with drug-resistant focal epilepsy of any age, in which an adequate method of concealment of randomisation was used. The studies were double-, single- or unblinded, placebo-controlled. For cross-over studies, the first treatment period was treated as a parallel trial. Eligible participants were adults or children with drug-resistant focal epilepsy.

Data collection and analysis: 

For this update, two review authors independently assessed the trials for inclusion, and extracted data. Outcomes included 50% or greater reduction in seizure frequency, treatment withdrawal (any reason), adverse effects, effects on cognition and quality of life. Primary analyses were by intention-to-treat. Sensitivity best- and worse-case analyses were undertaken to account for missing outcome data. Pooled risk ratios (RRs) with 95% confidence intervals (95% Cls) were estimated for the primary outcomes of seizure frequency and treatment withdrawal. For adverse effects, we calculated pooled RRs and 99% Cls.

Main results: 

We did not identify any new studies for this update, therefore, the results and conclusions are unchanged.

In previous updates of this review, the authors found five parallel add-on studies, eight cross-over studies in adults or children with drug-resistant focal epilepsy, and one parallel add-on study with a responder-enriched design in infants. In total, these 14 studies included 1806 eligible participants (38 infants, 199 children, 1569 adults). Baseline phases ranged from four to 12 weeks; treatment phases from eight to 36 weeks. Overall, 11 studies (1243 participants) were rated as having low risk of bias, and three (697 participants) had unclear risk of bias due to lack of reported information around study design. Effective blinding of studies was reported in four studies (563 participants).

The overall risk ratio (RR) for 50% or greater reduction in seizure frequency was 1.80 (95% CI 1.45 to 2.23; 12 trials, 1322 participants (adults and children); moderate-certainty evidence) indicating that lamotrigine was significantly more effective than placebo in reducing seizure frequency. The overall RR for treatment withdrawal (for any reason) was 1.11 (95% CI 0.91 to 1.37; 14 trials; 1806 participants; moderate-certainty evidence). The adverse events significantly associated with lamotrigine were: ataxia, dizziness, diplopia (double vision), and nausea. The RR of these adverse effects were as follows: ataxia 3.34 (99% Cl 2.01 to 5.55; 12 trials; 1525 participants; high-certainty evidence); dizziness 2.00 (99% Cl 1.52 to 2.64;13 trials; 1768 participants; moderate-certainty evidence); diplopia 3.79 (99% Cl 2.15 to 6.68; 3 trials, 944 participants; high-certainty evidence); nausea 1.81 (99% Cl 1.22 to 2.68; 12 studies,1486 participants; moderate-certainty evidence). The limited data available precluded any conclusions about effects on cognition and quality of life. No important heterogeneity between studies was found for any of the outcomes. Overall, we assessed the evidence as high to moderate certainty, due to incomplete data for some outcomes.

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