Lamotrigine as add-on therapy for drug-resistant generalised tonic-clonic seizures

This is an update of a review first published in 2010.

Background

Epilepsy is a common neurological (brain) condition that is characterised by repeated seizures. Most people can control their seizures with a single antiepileptic medicine, however, about 30% continue to have seizures. These people are said to have drug-resistant epilepsy. Lamotrigine is an antiepileptic medicine, which can be used as add-on treatment with other antiepileptic medication to try to manage drug-resistant epilepsy.

Aim of review

This review studied whether lamotrigine was effective and tolerable when used as add-on treatment, alongside other antiepileptic medicines, for people with drug-resistant generalised epilepsy (affecting the entire brain from onset) with tonic clonic-seizures (seizures where people lose consciousness and jerk quickly and rhythmically).

Results

We found three trials, involving 300 people, that investigated lamotrigine for people with drug-resistant generalised tonic-clonic seizures. People who received add-on lamotrigine were almost twice as likely to have a 50% or greater reduction in the number of generalised tonic-clonic seizures than people who received add-on placebo (an inactive, dummy drug). Lamotrigine did not significantly affect: the number of people who were completely free of seizures, the number of people who withdrew from treatment, or the number of people who experienced common adverse effects.

However, we are very uncertain whether these findings are accurate. This is because there were not many people involved in the studies, and we are unclear about the methods some of the studies used. For this reason, we cannot comment on the use of lamotrigine.

More trials, which include more people, and are carried out over longer time periods are needed to properly guide the use of lamotrigine for people with drug-resistant generalised tonic-clonic seizures.

The evidence is current to March 2019.

Authors' conclusions: 

This review provides insufficient information to inform clinical practice.

Low-certainty evidence suggests that lamotrigine reduces the rate of generalised tonic-clonic seizures by 50% or more. Very low-certainty evidence found inconclusive results between groups for all other outcomes. Therefore, we are uncertain to very uncertain that the results reported are accurate, and suggest that the true effect could be grossly different.

More trials, recruiting larger populations, over longer periods, are necessary to determine lamotrigine's clinical use.

Read the full abstract...
Background: 

This is an update of the Cochrane Review first published in 2010; it includes one additional study.

Primary generalised tonic-clonic seizures are a type of generalised seizure. Other types of seizures include: absence, myoclonic, and atonic seizures. Effective control of tonic-clonic seizures reduces the risk of injury and death, and improves quality of life. While most people achieve seizure control with one antiepileptic drug, around 30% do not, and require a combination of antiepileptic drugs.

Objectives: 

To assess the effectiveness and tolerability of add-on lamotrigine for drug-resistant primary generalised tonic-clonic seizures.

Search strategy: 

For the latest update, we searched these databases on 19 March 2019: Cochrane Register of Studies (CRS) Web, MEDLINE Ovid, and the WHO International Clinical Trials Registry Platform (ICTRP). The CRS includes records from the Cochrane Epilepsy Group Specialized Register, CENTRAL, Embase, and ClinicalTrials.gov. We imposed no language restrictions. We also contacted GlaxoSmithKline, manufacturers of lamotrigine.

Selection criteria: 

Randomised controlled parallel or cross-over trials of add-on lamotrigine for people of any age with drug-resistant primary generalised tonic-clonic seizures.

Data collection and analysis: 

We followed standard Cochrane methodology; two review authors independently assessed trials for inclusion, evaluated risk of bias, extracted relevant data, and GRADE-assessed evidence. We investigated these outcomes: (1) 50% or greater reduction in primary generalised tonic-clonic seizure frequency; (2) seizure freedom; (3) treatment withdrawal; (4) adverse effects; (5) cognitive effects; and (6) quality of life. We used an intention-to-treat (ITT) population for all analyses, and presented results as risk ratios (RRs) with 95% confidence intervals (CIs); for adverse effects, we used 99% CIs to compensate for multiple hypothesis testing.

Main results: 

We included three studies (total 300 participants): two parallel-group studies and one cross-over study. We assessed varied risks of bias across studies; most limitations arose from the poor reporting of methodological details. We meta-analysed data extracted from the two parallel-group studies, and conducted a narrative synthesis for data from the cross-over study.

Both parallel-group studies (270 participants) reported all dichotomous outcomes. Participants taking lamotrigine were almost twice as likely to attain a 50% or greater reduction in primary generalised tonic-clonic seizure frequency than those taking a placebo (RR 1.88, 95% CI 1.43 to 2.45; low-certainty evidence). The results between groups were inconclusive for the likelihood of seizure freedom (RR 1.55, 95% CI 0.89 to 2.72; very low-certainty evidence); treatment withdrawal (RR 1.20, 95% CI 0.72 to 1.99; very low-certainty evidence); and individual adverse effects: ataxia (RR 3.05, 99% CI 0.05 to 199.36); dizziness (RR 0.91, 99% CI 0.29 to 2.86; very low-certainty evidence); fatigue (RR 1.02, 99% CI 0.13 to 8.14; very low-certainty evidence); nausea (RR 1.60, 99% CI 0.48 to 5.32; very low-certainty evidence); and somnolence (RR 3.73, 99% CI 0.36 to 38.90; low-certainty evidence).

The cross-over trial (26 participants) reported that 7/14 participants with generalised tonic-clonic seizures experienced a 50% or greater reduction in seizure frequency with add-on lamotrigine compared to placebo. The authors reported four treatment withdrawals, but did not specify during which treatment allocation they occurred. Rash (seven lamotrigine participants; zero placebo participants) and fatigue (five lamotrigine participants; zero placebo participants) were the most frequently reported adverse effects.

None of the included studies measured cognition. One parallel-group study (N = 153) evaluated quality of life. They reported inconclusive results for the overall quality of life score between groups (P = 0.74).

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