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 Cochrane Review previously published in 2020.

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 Methods: 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.

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

Data Collection And Analysis: 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).

Main Results: 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). AUTHORS'

Conclusions: 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.

Up to 10% of people living to 80 years of age have one or more seizures; and many will not require anti-seizure medication (ASMs). In 85% of patients, the diagnosis comes from the history of the index event. One-third of patients with an apparent "first seizure" have previous events, changing their diagnosis to epilepsy. Targeted investigations are important for classification and risk prediction. Patients with a low risk of seizure recurrence are not usually offered ASM treatment. High-risk patients have multiple seizures, neurological deficits, intellectual disability and/or relevant abnormal investigations; and are offered ASMs. Individual factors modulate this decision-making. Future integrated technologies offer the game-changing potential for seizure monitoring and prediction, but are not yet robust, convenient or affordable. Therapeutic drug monitoring in patients taking ASMs may confirm ASM toxicity, or when non-adherence, malabsorption, or rapid metabolism are suspected causes of breakthrough seizures. They are less useful when these factors are intermittent or irregular. Current evidence does not favour routine monitoring of serum levels, as it neither reliably predicts control, relapse, or adverse effects. The decision to discontinue ASM should follow a full discussion with the patient of risks and benefits. Along with population risk factors for seizure recurrence, the patient's lifestyle and preferences must be considered. ASM are usually discontinued in a slow step-wise fashion, one at a time, after at least two years of remission. Seizure recurrence risk plateaus only after 2 years following ASM discontinuation, and patients need access to specialist follow-up over that period.

Unlike several epilepsies with onset in pediatric age, adult-onset epilepsies do not typically have a time course that is predictably self-remitting in the large majority of people. Still, about one-half of individuals with adult-onset epilepsy who have been seizure-free for an extended period (two years or longer) on antiseizure medications (ASMs) will remain in remission when their drug therapy is discontinued. Although a number of predictors of outcome have been identified (including specific adult-onset syndromes associated with a low probability of spontaneous remission), in most cases, the only way to establish whether the epilepsy has remitted in a given individual is to gradually withdraw ASMs. ASM withdrawal can be beneficial, particularly when the currently used treatment is not well tolerated, or could lead to adverse outcomes in the future (i.e., teratogenic effects should pregnancy occur in a female of childbearing potential). However, the risks associated with ASM withdrawal are significant. Relapse of seizures can have major adverse psychosocial consequences and also may carry a risk of morbidity and mortality. Most importantly, evidence suggests that in about 20% of individuals whose seizure relapsed following ASM withdrawal, re-institution of pharmacological therapy may not readily restore seizure control. Ultimately, management decisions should prioritize the preference of the well-informed person with epilepsy. Particularly, when adverse drug effects are a concern, options to be discussed should include not only withdrawal or continuation of the current treatment but also dose reduction or substitution with a different ASM.

In adults who have been seizure-free for 2 years, there is not evidence to support or refute a difference in the rate of seizure recurrence in those who taper ASMs vs those who do not. The point estimate is 2 times greater seizure recurrence in those who taper vs those who do not (15% vs 7%), although this difference is not significantly different. The strength of evidence was downgraded due to imprecision. There were discussions about how to handle the fact that the study had lower risk of seizure recurrence than all other studies, and it was downgraded again for a lack of generalizability because the authors believed that this study represented a different population than is typical (very low confidence, 1 Class I study downgraded for imprecision and generalizability). In the long term (24–60 months), the risk of seizure recurrence is possibly higher among those who taper ASMs (low confidence, 2 Class III studies).