Early versus late antiepileptic drug withdrawal for people with epilepsy in remission

Epilepsy is a disorder where recurrent seizures are caused by abnormal electrical discharges in the brain. Antiepileptic drugs (AEDs) are commonly used to prevent these seizures but have long-term side effects. When in remission (seizure free), it may be best to stop using the drugs but the right time to withdraw them is still unclear.

We searched electronic databases in June 2014, adding to the research done in a previous version of this review. The same five trials were included in our analysis, comprising 924 epileptic children (all below 16 years old) who were randomly assigned to either early removal of AEDs (before completing two years without seizures); or late withdrawal of AEDs (after completing two years without seizures). Considering all evidence, we found that stopping AED intake before completing two years without seizures increases the risk of seizure relapse by around 34%. This percentage is increased if the child has partial seizures (if the electrical burst only involves a part of the brain, resulting mainly in localized symptoms); or an abnormal electroencephalogram (EEG) record (unusual patterns of electrical activity in the brain). Other factors that might be related to a higher relapse rate are: age below two years or above 10 years when epilepsy started; history of status epilepticus (convulsions longer than 30 minutes); an IQ lower than 70; and high frequency of seizures before and during treatment. Overall, the included trials provided a moderate quality of evidence.

The review of trials found that there is evidence to support waiting at least two years or more seizure free before discontinuing AEDs in children, especially if they had partial seizures or abnormal EEG.

There is not enough evidence to show the best time to withdraw antiepileptic drugs in adults with epilepsy who are free of seizures.

There is not enough evidence that demonstrates the optimal time to remove antiepileptic drugs in people (children or adults) with generalised seizures (if the electrical discharges affect the whole brain, causing global symptoms).

More research is needed, particularly involving adults and those with generalised seizure types.

Authors' conclusions: 

There is evidence to support waiting for at least two seizure-free years before discontinuing AEDs in children, particularly if individuals have an abnormal EEG or partial seizures, or both. There is insufficient evidence to establish when to withdraw AEDs in children with generalised seizures. There is no evidence to guide the timing of withdrawal of AEDs in seizure-free adults. Further high-quality randomised controlled trials are needed, particularly recruiting adults and recruiting those with generalised seizure types, to identify the optimal timing of AED withdrawal and risk factors predictive of relapse.

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Background: 

Epilepsy is a chronic neurological disorder which affects millions of people around the world. Antiepileptic drugs (AED) are the main interventions used to prevent seizures and control epilepsy. Although effective in most cases, AEDs are related to long-term adverse effects, such as cognitive and behavioural alterations. Thus when epilepsy is in remission, it may be in the individual’s best interest to discontinue medication. However, the optimal timing of AED discontinuation is still unknown.

This is an updated version of the original Cochrane review published in Issue 3, 2001.

Objectives: 

(1) To quantify and compare risk of seizure recurrence, status epilepticus and mortality after early and late AED discontinuation in adult and pediatric epilepsy patients.

(2) To assess which variables modify the risk of seizure recurrence.

(3) To define a subpopulation in which early AED discontinuation is safe.

Search strategy: 

We searched the Cochrane Epilepsy Group Specialised Register (June 2014); CENTRAL (Issue 5, The Cochrane Library, May 2014); MEDLINE (1946 to June 2014); CINAHL (23 June 2014); Scopus (1823 to June 2014); ClinicalTrials.gov (23 June 2014); and WHO International Clinical Trials Registry Platform (23 June 2014). We also checked the reference lists of studies found through the electronic searches.

Selection criteria: 

Randomised controlled trials that evaluate withdrawal of AEDs after varying periods of seizure remission in adults and children with epilepsy. Included studies compared an early AED discontinuation time (defined as a period of remission of seizures of less than two years) versus a late AED discontinuation time (defined as a period of remission of seizures of more than two years).

Data collection and analysis: 

Two authors independently extracted data and assessed trial quality. Risk ratio (RR) with 95% confidence interval (CI) was calculated for each trial. Summary RRs and 95% CIs for dichotomous data were calculated using a fixed-effect model. A test of statistical heterogeneity was conducted for each pooled risk ratio calculation. Each included study underwent a 'Risk of bias' assessment, based on the Cochrane Handbook recommendations, and we examined the overall quality of information through the GRADE system, presented in two 'Summary of Findings' tables.

Main results: 

Five trials were included in this review, representing 924 randomised children with epilepsy, all under 16 years of age at randomisation, with a median follow-up of 5.6 years. No eligible trial evaluated adults or assessed mortality or status epilepticus as outcomes. The pooled risk ratio for seizure relapse after AED withdrawal was 1.34 (95% CI 1.13 to 1.59, P = 0.0007). Conforming to this estimate, the number needed to harm, that is expose an individual to a higher risk of seizure relapse because of early withdrawal of AED, is 8 (95% CI 5 to 20). Early discontinuation was associated with greater relapse rates in people with partial seizures with a pooled risk ratio of 1.51 (95% CI 0.97 to 2.35, P = 0.07). Absence type epilepsy showed a lower risk of relapse. Variables associated with higher risk of seizure relapse were abnormal EEG findings (pooled RR 1.44, 95% CI 1.13 to 1.83, P = 0.003), especially epileptiform activity (RR 2.58, 95% CI 2.03 to 3.28, P < 0.0001); epilepsy onset before 2 years or after 10 years of age; history of status epilepticus; intellectual disability (IQ < 70); and high seizure frequency before and during treatment. Gender and family history did not show any significant influence over seizure relapse. Overall, the included trials were classified as low or unclear risk of bias where methodological information was not reported and could not be provided by original study authors.

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