Tapered antiepileptic drug withdrawal increased the risk for seizure recurrence
ACP J Club. 1991 Sept-Oct;115:39. doi:10.7326/ACPJC-1991-115-2-039
Medical Research Council Antiepileptic Drug Withdrawal Study Group. Randomised study of antiepileptic drug withdrawal in patients in remission. Lancet. 1991 May 18;337:1175-80.
To compare seizure control during slow antiepileptic drug (AED) withdrawal with continuing therapy in stable epileptic patients and to identify prognostic factors for seizure recurrence.
Randomized controlled trial of up to 4.5 years' duration.
45 centers in the United Kingdom and Europe.
Patients had had ≥ 2 definite seizures, had been seizure-free for ≥ 2 years, were taking AEDs, and had no progressive neurologic or other condition likely to reduce follow-up to ≤ 2 years. 1021 of 1797 eligible patients were randomized; 8 were later withdrawn as not eligible and 3 were lost to follow-up. 60% of study patients had had generalized seizures. Patient characteristics included medians of 5.0 and 4.4 years for duration of epilepsy, 3.2 and 3.4 years for seizure-free period, and 26 and 27 years of age for the continuing and withdrawal groups, respectively. Compared with eligible, nonrandomized patients, study patients were younger, had had epilepsy longer, were more disabled, and drove less.
Patients were randomized to maintenance of current treatment (n = 503) or to slow withdrawal of AEDs (n = 510), with dosage decreases every 4 weeks aiming for complete withdrawal in 6 months.
Main outcome measures
Recurrence of seizure, including death involving seizure, judged by clinicians; relative risks for prognostic factors.
327 (65%) patients in the continuing group maintained AED therapy and 373 (73%) patients in the withdrawal group achieved withdrawal during the trial. Actuarial analysis of seizure-free survival showed a difference at 2 years of 19.5% (95% CI 13.8 to 25.2) with 78% and 59% seizure-free in the continuing and withdrawal groups, respectively. The hazard ratio peaked at 9 months and decreased thereafter. In a multivariate model of prognostic factors for seizure recurrence, the following achieved significance: history of partial seizures (relative risk [RR] 2.51, 95% CI 1.00 to 6.30), myoclonic seizures (RR 1.85, CI 1.09 to 3.12), or tonic-clonic seizures (RR 3.40, CI 1.48 to 7.84); seizures after treatment began (RR 1.57, CI 1.10 to 2.24); > 1 AED at randomization (RR 1.79, CI 1.34 to 2.39); period seizure-free at randomization 3 to < 5 years (RR 0.67, CI 0.48 to 0.93), 5 to < 10 years (RR 0.47, CI 0.32 to 0.69), > 10 years (RR 0.27, CI 0.15 to 0.48).
Patients randomized to slow withdrawal of AEDs had a greater risk for seizure recurrence, especially in the first year, than patients who continued AED treatment. The most important factors that determined seizure recurrence were longer periods free of seizure at randomization (lower risk), greater number of AEDs at randomization, and history of tonic-clonic seizures (increased risk).
Source of funding: Medical Research Council.
Address for article reprint: Dr. D. Chadwick, University Department of Neurosciences, Walton Hospital, Rice Lane, Liverpool L9 1AE, England, UK.
Because of increasing concern about the systemic and neurologic toxicity of long-term treatment with antiepileptic drugs (AEDs) (1), the question of if and when to withdraw AEDs in epileptic patients whose seizures are well controlled is a common clinical problem. Until recently, many physicians were reluctant to discontinue AED therapy because of the lack of reliable data on the risk for seizure recurrence. Further, no study to date has compared the risk for seizure recurrence on withdrawing medication with the risk for recurrence associated with continuing therapy.
This randomized study by the Medical Research Council Antiepileptic Drug Withdrawal Study Group, however, provides the clinician with important prognostic data on AED withdrawal. It is clear that remission of seizures is possible in many epileptic patients whose AEDs are withdrawn slowly. In this study, 59% of patients not taking AEDs remained seizure-free at 2 years. This study helps to identify those for whom drug withdrawal is a possibility. Young patients on one AED who have had a long seizure-free period and a non-tonic-clonic type of seizure pattern are at the lowest risk for recurrence. In thesepatients the clinician may consider slow withdrawal of the AED. 1 potential danger to keep in mind is relapse in an automobile driver. Several authors (2, 3) have suggested that patients should not drive for 1 to 2 years after AED withdrawal.
Barbara Scherokman, MD
Uniformed Services University of Health SciencesBethesda, Maryland, USA