Prediction of seizure recurrence risk following discontinuation of antiepileptic drugs

Abstract

Objective: Discontinuation of antiepileptic drugs (AEDs) in seizure-free patients is an important goal because of possible long-term side effects and the social stigma burden of epilepsy. The purpose of this work was to assess seizure recurrence risk after suspension of AEDs, to evaluate predictors for recurrence, and to investigate the recovery of seizure control after relapse. In addition, the accuracy of a previously published prediction model of seizure recurrence risk was estimated.

Methods: Seizure-free patients with epilepsy who had discontinued AEDs were retrospectively enrolled. The frequency of seizure relapses after AED withdrawal as well as prognosis after recurrence were assessed and the predictive role of baseline clinical-demographic variables was evaluated. The aforementioned prediction model was also validated and its accuracy assessed at different seizure-relapse probability levels.

Results: The enrolled patients (n = 133) had been followed for a median of 3 years (range 0.8-33 years) after AED discontinuation; 60 (45%) of them relapsed. Previous febrile seizures in childhood (hazard ratio [HR] 3.927; 95% confidence interval [CI] 1.403-10.988), a seizure-free period on therapy of less than 2 years (HR 2.313; 95% CI 1.193-4.486), and persistent motor deficits (HR 4.568; 95% CI 1.412-14.772) were the clinical features associated with relapse risk in univariate analysis. Among these variables, only a seizure-free period on therapy of less than 2 years was associated with seizure recurrence in multivariate analysis (HR 2.365; 95% CI 1.178-4.7444). Pharmacological control of epilepsy was restored in 82.4% of the patients who relapsed. In this population, the aforementioned prediction model showed an unsatisfactory accuracy.

Significance: A period of freedom from seizure on therapy of less than 2 years was the main predictor of seizure recurrence. The accuracy of the previously described prediction tool was low in this cohort, thus suggesting its cautious use in real-world clinical practice.

Keywords: AED withdrawal; anti-seizure medications; epilepsy.

FIGURE 1

Patients enrolled in the study. Two hundred five patients discontinued antiepileptic drugs (AEDs) of the 4154 patients diagnosed with epilepsy between January 1, 1983 and November 30, 2018, at Epilepsy Regional Referral Center (ERCC) of the Neurology 2 Department of Careggi University Hospital (Florence, Italy). After applying the inclusion criteria, a final cohort of 133 patients was selected.

FIGURE 2

A, Time to first seizure recurrence from the beginning of antiepileptic drug (AED) tapering is displayed according to the Kaplan‐Meier method. On the x‐axis, time 0 represents the beginning of AED tapering up to the discontinuation. The number of patients at risk at each time is reported under the x‐axis. B, Multivariate analysis with the Cox regression model is presented, stratified according to the duration of the seizure‐free period on therapy. Each curve represents the whole population and it is weighted in the same way for the other two factors implemented in the multivariate analysis (febrile seizures in childhood and persistent motor deficit; both are fixed to their average values). The only element differentiating the curves are the five different values that were assigned to the variable “seizure‐free period on therapy.” A seizure‐free period on therapy shorter than 2 years was significantly associated with recurrence risk (hazard ratio [HR] 2.365; 95% confidence interval [CI] 1.178–4.7444). It is notable that the strata encompassing the longest seizure‐free periods (36–47 months, 48–59 months, and 60 or more months) substantially overlap: Having a seizure‐free period on therapy longer than 3 years does not seem to lead to any further reduction in seizure recurrence risk (not significant). C, Post hoc analysis of the results represented in 2B. The curves displayed are the graphical representation of multivariate analysis with the Cox regression model where the possible values assigned to the variable “duration of the seizure‐free period on therapy” are 0–23 months, 24–35, and 36 or more months. A period shorter than 2 years is still the only significant seizure recurrence risk factor but, as shown in the table below the graph, also a period of 2 years or longer but shorter than 3 years leads to an increased seizure recurrence risk with more observed recurrences than expected (not significant). D, Time to restore seizure pharmacological control after relapse, displayed using the Kaplan‐Meier method. On the x‐axis, 0 represents the time of seizure relapse after AED discontinuation. The patients at risk at each time are reported under the curve.

FIGURE 3

A, Sensitivity and specificity (y‐axis) plotted at different probability threshold values generated by the Lamberink prediction model (LPM) for seizure recurrence risk at year 2. Dashed curves identify the confidence intervals (CIs). At year 2, under these experimental conditions, LPM shows low accuracy. B, Same parameters at year 5. Under these experimental conditions, LPM shows low accuracy also at year 5.