The majority of the published literature 14 - 16 does not clearly indicate whether relapse occurred during tapering or after complete discontinuation of AEDs. As such, it has been difficult to dissect how the timing of relapse (early compared with late) is related to the completeness of AED withdrawal. In the present work, we performed a longitudinal, retrospective cohort study of relapse in patients with epilepsy according to time of relapse after withdrawal of AEDs with the aim of identifying new prognostic factors.

No consensus has been reached regarding the minimum seizure‐free period that should be achieved prior to AED withdrawal, and there is also no current standard regarding the mode of AED tapering, such as rapid versus slow withdrawal. Cochrane Reviews 11 , 12 of these critical issues presented no robust conclusions. In addition, contradictory results were obtained in a meta‐analysis 13 of recurrence after AED withdrawal, mainly because of the difficulties associated with performing a double‐blind randomized controlled trial due to the above‐mentioned disease‐related environments.

Complete withdrawal of an AED (antiepileptic drug) without relapse is the final goal of epilepsy treatment. Understanding of when to submit seizure‐free patients to AED withdrawal has long been an important issue. Approximately 70% of all newly diagnosed patients with epilepsy become seizure‐free with the use of an AED, 1 and 67% of patients go into terminal remission. 2 However, there have been broad differences among studies 3 - 6 regarding relapse rates following AED withdrawal, which might be due to confounding social factors associated with each patient. Risk–benefit assessments of AED withdrawal are highly dependent on the individual characteristics of each patient, which poses a substantial limitation for trials, and the risk–benefit margin for seizure‐free patients 5 , 7 - 10 is still under debate. A critical review 5 of 28 studies including both adults and children and another literature review 6 reported that the proportion of patients experiencing relapse during or after AED withdrawal ranges from 12 to 66%.

Continuous variables, such as age at epilepsy onset and symptom duration, were dichotomized with thresholds of 20 years for age at onset and 120 months for symptom duration through the method developed by Contal and O'Quigley. 19 Covariates of prognostic significance were identified through simple logistic univariate analysis. Covariates identified as statistically significant were subjected to multivariate logistic regression analysis to compare the prognostic risk between each pair of groups in the set of three groups. The SAS software package (version 9.2; SAS Institute, Cary, NC, U.S.A.) was used for all statistical analyses. Following exclusion of the SF group, the negative prognostic factors identified through multivariate logistic regression were dichotomized into subgroups according to attributes such as age at onset, symptom duration, and epilepsy type. The relapse patterns are presented as K‐M survival curves analyzed via log‐rank tests. Comparisons between subgroups were conducted through post hoc analysis with Bonferroni correction (R version 3.01, The R Foundation for Statistical Computing, Vienna, Austria).

The total symptom duration was defined as the sum of the duration from seizure onset to registration at the epilepsy clinic and the duration from registration to the most recent seizure attack. The total duration of the seizure‐free period was divided into the duration from the most recent seizure attack to the initiation of AED withdrawal and the duration of the AED withdrawal process.

Sex, age at epilepsy onset, symptom duration, presence of antecedents of epilepsy, epilepsy type (localization‐related, idiopathic generalized, or undifferentiated epilepsy), nocturnal preponderance, and relevant lesions on brain magnetic resonance imaging (MRI) scans were compared among the three groups. Perinatal insults, febrile convulsions, family history of epilepsy, head trauma combined with loss of consciousness for >1 h, and history of infections of the central nervous system were regarded as antecedents related to epilepsy. The presence of at least one of these antecedents was regarded as the presence of antecedents. Nocturnal preponderance was defined as the occurrence of >90% of habitual seizures during sleep. Localization‐related epilepsy, including remote symptomatic epilepsy, was defined according to the criteria for epilepsy and epileptic syndrome proposed by the International League Against Epilepsy (ILAE). 17 , 18 The patients in the ER and LR groups underwent an EEG examination as soon as possible after relapse.

The patients were grouped according to the time of relapse: the patients who experienced relapse during AED withdrawal formed the early relapse (ER) group, the patients who experienced relapse after completion of the AED withdrawal process formed the late relapse (LR) group, and the patients who exhibited remission after AED discontinuation formed the seizure‐free (SF) group. Patients on monotherapy were also analyzed using the same grouping criteria.

A total of 378 patients with epilepsy who experienced complete seizure control for at least 4 years were consecutively recruited between March 1999 and July 2014 from Severance Hospital, a tertiary hospital in Korea. All of the patients were regularly treated and followed from registration through withdrawal by a corresponding author. Patients who had undergone epilepsy surgery, patients with juvenile myoclonic epilepsy (these patients exhibit a greater tendency towards relapse), and patients with benign childhood epilepsy with centrotemporal spikes were excluded. All of the patients underwent electroencephalography (EEG) examination immediately before the initiation of AED withdrawal, and only those patients without epileptiform discharges continued the withdrawal process.

Relapse patterns among subgroups categorized by negative prognostic factor and outcomes presented as K‐M survival curves. The relapse patterns based on the K‐M survival curves show that the peak relapse period for the patients in the ER and LR groups was 13–18 months after four seizure‐free years ( A ). Comparisons of K‐M survival curves and post hoc results found that a symptom duration >120 months ( B ), an age at epilepsy onset of ≤20 years ( C ), and the presence of localization‐related epilepsy ( D ) were negative prognostic factors for relapse in the LR group compared with the ER group.

Figure 4 A shows the K‐M survival curves for the patients in the LR and ER groups. In the analyses of the dichotomized subgroups following exclusion of the SF group, comparisons of opposing attributes within the same group (e.g., age of onset ≤20 in the LR group vs. age of onset >20 in the LR group) did not reveal any differences in prognosis. Subgroup comparisons assessing the same attribute between different groups (e.g., age of onset ≤20 in the LR group vs. age of onset ≤20 in the ER group) revealed significant differences for age of onset >20 years, symptom duration >120 months, and no localized‐related epilepsy. Subgroup comparisons of opposing attributes between different groups (e.g., age of onset ≤20 in the ER group vs. age of onset >20 in the LR group) confirmed that an age at epilepsy onset of ≤20 years, a symptom duration >120 months, and the presence of localized‐related epilepsy were statistically poor prognostic factors (Fig. 4 B–D).

According to univariate logistic analysis, age at epilepsy onset (with a threshold of 20 years), symptom duration (with a threshold of 120 months), seizure type, and lesions on brain MRIs were covariates of prognostic significance for all groups (Table 1 ). Multivariate logistic regression analysis performed using the above‐determined prognostic covariates, including nocturnal preponderance, revealed that a symptom duration >120 months, an age at epilepsy onset of ≤20 years, and the presence of localization‐related epilepsy were negative prognostic factors. These negative prognostic factors were associated with 4.7‐fold (OR; 95% confidence interval [CI] 2.409–9.326; p < 0.00), 2.9‐fold (95% CI 1.425–5.837; p < 0.01), and 2.5‐fold (95% CI 1.043–5.774; p = 0.04) higher risks of recurrence in the ER group compared with the SF group. In addition, a symptom duration >120 months and an age at epilepsy onset of ≤20 years were associated with 3.1‐fold (95% CI 1.619–5.881; p = 0.00) and 2.3‐fold (95% CI, 1.152–4.487; p < 0.02) higher risks of recurrence, respectively, in the ER group compared with the LR group (Table 2 ). No prognostic factors were identified when comparing the SF and LR groups. For patients on monotherapy, the same covariates of negative prognostic significance were identified; however, statistically significant differences were observed only between the ER and SF groups (the detailed results of this analysis are presented in the supplementary data).

Five (4.2%) and 12 (8.6%) patients in the SF and LR groups, respectively, experienced epileptiform discharges just prior to or within several months after the discontinuation of AEDs, and 13 (16.7%) patients in the ER group experienced epileptiform discharges immediately after relapse; these differences are significant (p < 0.01). However, the corresponding analysis of patients on monotherapy did not reveal a significant difference among the three groups (Table 1 ). Details regarding the number of patients in each group with the presence of antecedents (epilepsy, epilepsy type, nocturnal preponderance, and relevant lesions in brain MRIs) are presented in Table 1 .

The proportion of male patients was higher than that of females in each group, although the difference was not significant. The mean age at epilepsy onset for all of the patients was 23.2 ± 15.2 years, and the peak range was 11–15 years. Of the 336 patients, 192 (57.1%) reported an age at epilepsy onset of ≤20 years. For the patients on monotherapy, the mean age at epilepsy onset was 23.3 ± 14.2 years. The mean symptom duration for all of the patients was 126.4 ± 112.2 months. Specifically, the mean symptom durations for the SF, LR, and ER groups were 92.8 ± 97.7, 116.6 ± 105.7, and 195.1 ± 115.9 months, respectively, and these durations are significantly different (p < 0.00). In addition, the mean duration from seizure onset to registration and from registration to the most recent seizure were significantly different among the groups (Table 1 ). For patients on monotherapy, the age at epilepsy onset and the symptom duration presented similar trends among the three groups; the results are presented in Table 1 . The mean duration from the most recent seizure to the initiation of AED withdrawal and the mean duration of AED withdrawal did not differ significantly among the three groups, and the corresponding analyses for the patients on monotherapy also revealed no differences (Table 1 ).

Overall relapse patterns after the initiation of AED withdrawal based on the follow‐up time. Two hundred patients among the 217 patients (92.2%) who belonged to the LR and ER groups exhibited relapse within 36 months after the initiation of AED withdrawal. The numbers on the K‐M curve represent the patients omitted at each 6‐month interval based on the follow‐up time.

The peak relapse period ranged from 13 to 18 months after initiation of AED withdrawal (Fig. 2 ). Of the 217 patients in the LR and ER groups, 80 (36.9%) and 167 (77.0%) experienced relapse within 12 and 24 months, respectively. The median follow‐up durations in the LR and ER groups were 11 months (range, 1–55) and 17 months (range, 4–102), respectively, after the initiation of AED withdrawal; patients were separated according to 12‐month intervals as presented in Table 1 . Figure 3 shows a K‐M curve depicting the overall relapse patterns after the initiation of AED withdrawal; the number of patients excluded is presented in 6‐month intervals based on the follow‐up times.

After the consecutive recruitment of patients who had been seizure‐free for 4 years, 42 patients were excluded due to violation of the study protocol for diverse causes, including refusal to continue the withdrawal process and loss to follow‐up (Fig. 1 ). Of the remaining 336 patients, 119 patients (35.4%) were included in the SF group. The overall relapse rate was 64.6%. One hundred thirty‐nine patients (41.4%) and 78 patients (23.2%) were included in the LR and ER groups, respectively. Among the 336 patients, 259 (77.1%) received monotherapy, and 85.4% of these patients received first‐generation AEDs as described earlier for the AED withdrawal protocol.

Discussion

The relapse rate (64.6%) measured in the present study is close to the upper range of the relapse rates reported in previous investigations.6 The cumulative relapse rates in the present study were 36.9% for the first 12 months and 77.9% for the next 12 months; these rates were markedly higher than the corresponding rates of 25 and 29% obtained in a meta‐analysis of 25 studies.13 The fact that 92.2% of patients exhibited relapse within 36 months after the initiation of AED withdrawal in this study (Fig. 3) suggested that a follow‐up duration of 3 years is adequate to determine overall prognosis. The peak period of relapse detected in this study was 13–18 months, which was later than the period obtained in the above‐referenced meta‐analysis (within the first 12 months).13 Thus, the prolonged follow‐up duration used in the present study might explain the high relapse rate and late peak period of relapse observed. In terms of seizure‐free duration before AED withdrawal, randomized controlled trials12, 20 have suggested a range of two to five seizure‐free years, and one report7 recommends at least four seizure‐free years. A review by the Medical Research Council (MRC)21 indicated that a longer seizure‐free period is one of the most important factors in determining patient outcome. A small prospective study15 of patients with at least four seizure‐free years reported a 57% relapse rate, which is consistent with the present results. Although similar prognoses following AED withdrawal were observed between patients who had been seizure‐free for 2 years and those who had been seizure‐free for 4 years,5 the lack of eligible trial results has created insufficient evidence to guide the timing of AED withdrawal in seizure‐free adults.11 Recently, a practical definition for the resolution of epilepsy14 consisting of seizure remission for 10 years, including at least 5 years without seizure medication, was suggested by the International League Against Epilepsy (ILAE). In the present study, considering the duration of the AED withdrawal process, the actual seizure‐free duration was >5 years, and an additional 3 years of follow‐up nearly satisfied the recommendations of the ILAE even though randomization was not executed. In addition, this study was designed according to the timing of relapse, which might offer a method of overcoming the difficulties associated with conducting a double‐blind randomized trial. To date, the only data available from a double‐blind randomized trial were generated in the Akershus study,22 which reported a 27% recurrence rate in adult patients on monotherapy who had been seizure‐free for >2 years.

When the age at epilepsy onset was dichotomized using a threshold of 20 years, the mean ages at onset for the subgroups of patients with ages at onset < and >20 years were 12.7 ± 4.5 and 37.2 ± 13.0 years, respectively; as a result, these patients were considered to have young‐onset and adult‐onset epilepsy, respectively. The percentage of seizure‐free patients with adult‐onset epilepsy (43.7%) was higher than the percentage of patients with young‐onset epilepsy (29.2%). These findings are inconsistent with those detailed in a previous report13 that showed a higher risk of relapse in adult‐onset epilepsy compared with childhood‐onset and adolescent‐onset epilepsy. A recent report16 detailing the guidelines of the Italian League Against Epilepsy suggested that an older age at onset enhanced the risk of relapse. However, the guidelines also stated that the age at epilepsy onset should not affect the decision to stop treatment in the absence of other negative prognostic predictors.

Previous reports have failed to provide clear information on whether relapse occurred during tapering or after complete discontinuation of AEDs,5, 6, 14-16 which would have allowed for a comparison of LR and ER groups. Of interest, in the present study, no differences were found among the three groups in the mean duration from the most recent seizure to the initiation of AED withdrawal, the mean duration of AED withdrawal, and the number of AEDs, indicating that an effect of seizure‐free duration or mode of AED tapering on prognosis could be excluded in this study. In contrast, the mean duration from seizure onset to registration in our hospital and the mean duration from registration to the time of the most recent seizure were significantly longer in the ER group compared with the other two groups. Although the treatment might not have been sufficient for seizure control or remission during the duration from seizure onset to registration at the epilepsy clinic and, as such, could have affected the duration needed to achieve complete seizure control, combined with the above‐presented results, the finding that the SF group exhibited the shortest total symptom duration supports the hypothesis that symptom duration has a strong prognostic impact on seizure relapse despite the limitation described above. Therefore, a longer symptom duration could affect the intrinsic reactivation of the disease. This hypothesis is also consistent with the results of a previous study,23 which showed that patients with long AED response times exhibit a higher risk of seizure recurrence. In contrast, the results of a long‐term population‐based study of childhood‐onset epilepsy24 are inconsistent with the results of the present study. However, direct comparisons with either of the previous reports are not possible because the previous reports did not clearly state whether the duration of the AED withdrawal process was included in the treatment duration.23, 24

Another interesting point in this study is that no predictor was consistently reliable between the SF and LR groups. Although there might be unknown risk factors in the LR group, such as an idiosyncratic or genetic causes, the data in this study suggest that the clinical characteristics of the LR group did not differ from those of the SF group. Thus, relapse after AED withdrawal is thought to result from the prolonged follow‐up of seizure‐free patients. Indeed, 76.8% of patients successfully discontinued AED in this study; however, depending on the length of time that elapsed, 41.4% of patients (LR group) who experienced relapse should have resumed AED, while the remaining 35.4% patients (SF group) maintained a seizure‐free status without AED intake, which indicates one aspect of the natural history of the medical treatment of epilepsy.3, 4, 25

In terms of EEG, abnormal EEG findings have been reported to have a modest impact on recurrence.16, 26, 27 However, the EEG variable was not identified as a prognostic covariate in this study.

Among the three factors with negative prognostic impacts, a symptom duration of >120 months showed the strongest prognostic impact. Moreover, the impact of symptom duration on recurrence in the ER group compared with the SF group was stronger than the impact found for the ER group compared with the LR group. After exclusion of the SF group, comparisons of the K‐M survival curves clearly supported the results of the analyses of the three groups.

Although the fact that this study was performed in only one tertiary referral center might limit interpretations of the meaning of the results, the patients included were distributed nationwide, lending strength to our findings. In summary, the present longitudinal, retrospective cohort study was designed to address issues associated with epilepsy treatment that are currently under debate. Patient grouping according to time of relapse could be an alternative approach to studying these issues that overcomes the difficulties associated with performing controlled trials of epilepsy and may provide new evidence for the identification of prognostic factors related to relapse after AED withdrawal. Additional studies are needed to support the conclusions drawn here.