Rapid versus slow withdrawal of antiepileptic drugs.

Abstract

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 Cochrane Review previously published in 2020. 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. For the latest update, on 8 November 2021, we searched: Cochrane Register of Studies (CRS Web), MEDLINE (Ovid), and SCOPUS. There were no language restrictions. CRS Web includes randomized or quasi-randomized, controlled trials from PubMed, Embase, ClinicalTrials.gov, the World Health Organization International Clinical Trials Registry Platform (ICTRP), CENTRAL, and the Specialized Registers of Cochrane Review Groups including Epilepsy. Randomized controlled trials that evaluated withdrawal of AEDs in a rapid or slow tapering after varying periods of seizure control in people with epilepsy. Two 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). There are two included studies in this review. One study randomized 57 children with epilepsy with seizure freedom for at least two years to taper down the AED 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. The other study involved 149 children. There was a non-significant trend towards 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. Currently, one Italian trial is ongoing that is investigating if a slow or a rapid withdrawal schedule of AEDs 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). 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 an overall 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, aetiology, intellectual disability, electroencephalography abnormalities, presence of neurological deficits, and other comorbidities on the rate of tapering.