Rapid versus slow withdrawal of antiepileptic medicines

Background

Epilepsy is a disorder where recurrent seizures (fits) are caused by abnormal electrical discharges of the brain. Antiepileptic medicines are used to prevent these seizures. Regular intake of antiepileptic medicines may have long-term side effects. When in remission (free of seizures for some time), it is logical to attempt to stop the medicines. Two important issues are how and when to stop them.

Aim of the review

This review analyzed the various studies for evidence regarding rapidity of withdrawal of antiepileptic medicines. We included randomized controlled trials evaluating the rapid or slow withdrawal (tapering down) of these medicines after varying periods of seizure control in people with epilepsy.

Results

We included only two small studies conducted in 206 children with epilepsy. The included studies found no difference in the proportion of participants remaining seizure-free between the rapid and the slow-tapering groups at different time points. There were no data for other measures such as status epilepticus (a long seizure), death, illness relating to seizures, and quality of life. We found no completed trials investigating antiepileptic medicine withdrawal in adults.

Currently, one Italian trial is ongoing that is investigating if a slow or a rapid withdrawal schedule of antiepileptic medicine influences return of seizures (relapse) in adults with focal or generalized epilepsy who have been seizure free for at least two years (no preliminary results available).

Reliability of the evidence

Evidence from the two included studies was of very low reliability. Both studies were conducted in a small number of participants and there were not enough data to detect a difference between the groups. Furthermore, they included only children, hence the results cannot be generalized to adults. Therefore, no reliable evidence is currently available on the optimal rate of tapering of antiepileptic medicines.

The evidence is current to April 2019.

Authors' conclusions: 

Since the last version of this review was published, we found one new pediatric study. In view of methodological deficiencies, and small sample size of the two included studies, we cannot draw any reliable conclusions regarding the optimal rate of tapering of AEDs. Using GRADE, we assessed the certainty of the evidence as very low for outcomes for which data were available. We judged both studies to be at high risk of bias.

Further studies are needed in adults and children to investigate the optimal rate of withdrawal of AEDs and to study the effects of variables such as seizure types, etiology, mental retardation, electroencephalography abnormalities, presence of neurologic deficits, and other comorbidities on the rate of tapering.

Read the full abstract...
Background: 

The ideal objective of treating a person with epilepsy is to induce remission (free of seizures for some time) using antiepileptic drugs (AEDs) and withdraw the AEDs without causing seizure recurrence. Prolonged usage of AEDs may have long-term adverse effects. Hence, when a person with epilepsy is in remission, it is logical to attempt to discontinue the medication. The timing of withdrawal and the mode of withdrawal arise while contemplating withdrawal of AEDs. This review examines the evidence for the rate of withdrawal of AEDs (whether rapid or slow tapering) and its effect on seizure recurrence.

This is an updated version of the original Cochrane Review published in 2006, Issue 2.

Objectives: 

To quantify risk of seizure recurrence after rapid (tapering period of three months or less) or slow (tapering period of more than three months) discontinuation of antiepileptic drugs in adults and children with epilepsy who are in remission, and to assess which variables modify the risk of seizure recurrence.

Search strategy: 

For the latest update, on 9 April 2019, we searched: Cochrane Register of Studies (CRS Web, which includes the Cochrane Epilepsy Group Specialized Register, CENTRAL, and ClinicalTrials.gov), MEDLINE (Ovid; 8 April 2019), the WHO International Clinical Trials Registry Platform, and SCOPUS. There were no language restrictions.

Selection criteria: 

Randomized controlled trials that evaluate withdrawal of AEDs in a rapid or slow tapering after varying periods of seizure control in people with epilepsy.

Data collection and analysis: 

Review authors independently assessed the trials for inclusion and extracted the data. The outcomes assessed included seizure freedom after one, two, or five years of AED withdrawal; time to recurrence of seizure following withdrawal; occurrence of status epilepticus; mortality; morbidity due to seizure, such as injuries, fractures, and aspiration pneumonia; and quality of life (assessed by validated scale).

Main results: 

In this review update, we have included one new study. The new study randomized 57 children with epilepsy with seizure freedom for at least two years to taper the AED during over one or six months. The study was not blinded and there were no details of randomization. Over the period of 54 months of follow-up, 20/30 participants in the one-month group remained seizure-free compared to 15/27 participants in the six-month group (no evidence of a difference). There was no information on time of seizure recurrence for each group to allow a comparison.

One trial had already been included in the previous version of the review; it involved 149 children. There was a non-significant trend toward a lower risk of seizure recurrence after one year of AED withdrawal in participants allocated to slow tapering (risk ratio (RR) 0.76, 95% confidence interval (CI) 0.58 to 1.01; P= 0.06; very low-certainty evidence). At the end of two years, 30 participants were seizure free in the rapid-tapering group and 29 participants in the slow-tapering group (RR 0.87, 95% CI 0.58 to 1.29; P = 0.48; very low-certainty evidence). At the end of five years, 10 participants were seizure free in the rapid-tapering group and six participants in the slow-tapering group (RR 1.40, 95% CI 0.54 to 3.65; P = 0.49; very low-certainty evidence). There were no data for the other outcomes.

Due to the methodological heterogeneity and the difference in the duration of tapering we did not perform a quantitative synthesis of these studies.

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