Epileptology 1 (2013) 17–20

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Epileptology

2212-82

http://d

n Corr

Milano,

E-m

journal homepage: www.elsevier.com/locate/epilep

When and how to stop antiepileptic drugs

Ettore Beghi a,n, Dieter Schmidt b

a Laboratory of Neurological Disorders, Istituto ‘‘Mario Negri’’, Milano, Italyb Epilepsy Research Group, Berlin, Germany

a r t i c l e i n f o

Available online 2 October 2012

Keywords:

Drug discontinuation

Risk factors

Outcome

Epilepsy

20/$ - see front matter & 2012 Elsevier Gmb

x.doi.org/10.1016/j.epilep.2012.07.001

espondence to: Istituto di Ricerche Famacolo

Italy. Tel.: þ39 0239014542; fax: þ39 02390

ail address: ettore.beghi@marionegri.it (E. Beg

a b s t r a c t

The informed decision to stop anticonvulsant treatment in patients with prolonged seizure remission

requires assessing the risk of seizure relapse and predisposing factors. Although the probability of

remaining seizure-free after treatment discontinuation is about 70%, patients at greater risk for relapse

include those still presenting abnormal EEG and/or a documented etiology of epilepsy. In addition,

seizure outcome depends on the syndromic pattern. Even though these indicators may be strongly

influential, the decision to withdraw or withhold treatment must be still individualized. In any patient,

the decision to discontinue treatment should also take into account social aspects like driving license,

job and leisure activities, emotional and personal factors, and adverse effects or drug interactions.

Patients and caregivers should be informed of the benefits and the risks associated with treatment

discontinuation and should be actively involved in the decision process.

& 2012 Elsevier GmbH. All rights reserved.

1. Introduction

Epilepsy is a treatable clinical condition. Pharmacologicalcontrol of seizures can be attained in up to 80% of cases duringthe course of the disease and seizures remain in remission aftertreatment discontinuation in about 50%. A long-term population-based study has shown that 5-year terminal remission (i.e. off-drugs at the end of follow-up) of epilepsy is 70% at 20 years afterdiagnosis (Annegers et al., 1979). These findings have been laterconfirmed by several other studies (Beghi and Sander, 2008).Studies in untreated patients showed that almost half of theindividuals with chronic epilepsy are seizure-free for more thanfive years (Nicoletti et al., 2009) and the number of individualswith continuing seizures tends to decrease over time (Watts,1992). In contrast, the continued use of AEDs in both children andadults may be associated with adverse effects in a substantialfraction of the exposed population (Shorvon, 2009). Behavioraland cognitive side effects are among the commonest adverseevents in patients on AEDs (Mula and Monaco, 2009; Ortinski andMeador, 2004) and are shown to improve after drug withdrawal(Lossius et al., 2009). Additional disadvantages of continuingtreatment indefinitely include the risk of teratogenicity (Hardenet al., 2009), drug interaction with concurrent medications(Patsalos and Perucca, 2003), and, finally, the concern thattreatment may be unnecessary.

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In spite of these encouraging findings, the withdrawal ofantiepileptic drugs is a complex medical act requiring an accurateevaluation of the medical, psychological, social and personalaspects of seizure relapse. In this context, a correct estimate ofthe risk of seizure relapse and the identification of the factorsmost likely to affect that risk is a key component of the informedmedical decision.

2. Overall risk of seizure relapse after treatmentdiscontinuation

The proportion of patients with relapses during or after treat-ment withdrawal ranges from 12% to 66% (Schmidt and Loscher,2005; Specchio and Beghi, 2004). Using life-table analysis, thecumulative probability of remaining seizure-free in children was66–96% at one year and 61–91% at two years (adults 39–74% and35–57% respectively). The relapse rate was highest in the first 12months (especially in the first six months) and tended to decreasethereafter. In a meta-analysis of 25 studies, the pooled relapse riskwas 25% (95% CI, 21–30%) at one year and 29% (95% CI, 24–34%) attwo years (Berg and Shinnar, 1994). However, the majority of thestudies assessed by this meta-analysis had limited follow-upperiods. Different patterns are documented after prolonged obser-vation of representative patients’ cohorts. In a prospective, long-term population-based study of 144 patients followed on averagefor 37.0 years, 67% were in terminal remission, with or withouttreatment (Sillanpaa and Schmidt, 2006). However, 28 patients(19%) achieved terminal remission following a relapse after early orlate remission, suggesting a remitting–relapsing pattern, and 20

E. Beghi, D. Schmidt / Epileptology 1 (2013) 17–2018

patients (14%) had a relapse after prolonged remission and did notre-enter remission, indicating a worsening course of the disease.

3. Factors affecting the risk of relapse

In a systematic review of the literature, the relapse rate at twoyears was found to range from 43% to 65% in adults and from 9% to39% in children (Specchio and Beghi, 2004). Factors consistentlyfound by Berg and Shinnar (1994), to indicate a higher-than-averagerisk of seizure relapse included adolescent-onset epilepsy, partialseizures, presence of an underlying neurological condition, andabnormal EEG findings (children). Adolescent age at onset ofseizures had a 1.34 risk of relapse (95% CI 1.00–1.81) compared toadult age at onset. Those with remote symptomatic seizures had a1.55 risk of relapse (95% CI 1.21–1.98). An abnormal EEG prior todrug discontinuation was associated with a 1.45 risk of relapse (95%CI 1.18–1.79). Factors associated with a lower-than-average riskwere childhood epilepsy, idiopathic generalized epilepsy, and — forchildren — normal EEG. Selected epilepsy syndromes may carry ahigher than average risk of relapse (e.g., juvenile myoclonic epilepsy)or a lower risk (e.g, benign epilepsy with centrotemporal spikes)after treatment withdrawal.

The duration of seizure freedom and the mode of withdrawalare further critical issues. In the systematic review by Specchioand Beghi (2004), prognosis following drug withdrawal wassimilar in those with a prior 2-year or a 4-year seizure-freeinterval. In contrast, in a long-term population-based study,treatment duration was shorter in patients who relapsed(6.176.2 years, median¼4.0, range¼1–23) than in those whodid not relapse (10.279.0 years, median¼8.0, range¼1–36)(Sillanpaa and Schmidt, 2006). This finding has been consistentlyconfirmed by other reports. Sillanpaa and Schmidt, (2006) alsofound that most patients who did not relapse had idiopathicepilepsy (20% vs. 16%), or epilepsy with generalized tonic–clonicseizures randomly distributed during the sleep–wake cycle (22%vs. 9%). However, there were no significant differences withrespect to gender, age at onset of epilepsy, generalized epilepsy,or extratemporal localization-related epilepsy (Sillanpaa andSchmidt, 2006).

4. The role of treatment

Treatment may modify the risk of relapse after discontinua-tion. However, despite experimental evidence of a neuroprotec-tive effect on the pathology of recurring seizures (Pitkanen, 2002),AEDs fail to prevent epilepsy from starting (Temkin, 2001). Thus,AEDs seem to act as symptomatic agents by suppressing seizuresbut they do not seem to be able to affect the course of theunderlying disease. Whether remaining seizure free after AEDdiscontinuation reflects spontaneous remission (i.e., regardless ofprior drug treatment) or is influenced by prior AED exposure(which would possibly indicate an effect on disease modification)is a topic of ongoing research. In this regard, the current view isthat permanent remission (i.e., no relapse after treatment dis-continuation) is a reflection of a spontaneous extinction of thedisease rather than a curative effect of drugs, may need to berevised once we discover anti-epilepsy effects of past or futuredrugs. In this perspective, careful consideration of the risk ofrelapse must be taken into account, even in patients presentingprolonged seizure remission during treatment.

In the MRC trial (MRC Antiepileptic Drug Withdrawal Group,1991), patients randomized to continued treatment showed a 22%relapse at two years, while patients randomized to slow drugwithdrawal had 41% relapse. This differential risk of relapse was

maximal between one and two years and declined thereafter.After 2 years, the risk of subsequent relapse was the same for bothtreatment groups. In this trial, the most important predictor ofseizure recurrence was continued therapy, which was the case forbarbiturates, phenytoin and valproate. In contrast, there was nodifference for patients taking carbamazepine because the rate ofrecurrence was low in those discontinuing the drug (Chadwick,1999).

In the second trial that included only patients with a low riskof relapse (Lossius et al., 2008), 15% patients randomized totreatment withdrawal and 7% of those randomized to remain ontreatment had a relapse at 12 months, a non-significant differ-ence. However, compared to the latter, the former improvedsignificantly in their neuropsychological performance. Theauthors also found that drug withdrawal led to a significantincrease in serum testosterone levels and free androgen index(Lossius et al., 2007) and free thyroxin levels (Lossius et al., 2009)in both sexes.

In a Cochrane review of trials done in children and adults(Sirven et al., 2001), the pooled relative risk for seizure relapse inearly (less than two seizure free years) versus late (more than twoseizure free years) AED withdrawal was 1.32 (95% confidenceinterval 1.02–1.70), a statistically significant but clinically unim-portant difference. In another Cochrane review, however, after a4-year follow-up, children randomized to early withdrawal (sixmonths) had more relapses than children randomized to latewithdrawal (12 months) (Geerts et al., 2005).

Ranganathan and Ramaratnam (2006), assessed the compara-tive effects of slow versus rapid AED withdrawal. Only one trialdone in children satisfied the selection criteria. In this study, nodifferences were found in the risk of relapse comparing rapid (sixweeks) to slow (nine months) taper group. However, in view ofthe methodological deficiencies and small sample size in thesolitary study identified, the authors could not derive any reliableconclusions regarding the optimal rate of tapering of AEDs.

5. Seizure control after relapse

In a systematic review of 13 studies, seizure recurrence rateafter AED discontinuation ranged between 12% and 66% (mean34%, 95% CI: 27–43) (Schmidt and Loscher, 2005). In these cases,reinstitution of AEDs brought to seizure remission in 64–91%(mean of 14 studies, 80%, 95% CI: 75–85%) after a mean follow-upranging from 1 to 9 years, with no differences between childrenand adolescents (84%, 95% CI: 75–93) and adults (80%, 95% CI: 74–86). Although seizure control was regained within approximatelyone year in half of the cases becoming seizure free, some patientsregained seizure control in as many as 5–12 years. In addition, in19% (95% CI: 15–24%), seizure control was incomplete and chronicdrug-resistant epilepsy was seen in up to 23% of patients. Factorsassociated with poor outcome after treating recurrences weresymptomatic etiology, partial epilepsy and cognitive deficits.Interestingly, treatment of a recurrence was not confirmed apredictive factor for a better seizure outcome (Matricardi et al.,1995). In the MRC Antiepileptic Drug Withdrawal trial the risk ofrecurrence was also similar in patients who relapsed after with-drawal of AEDs and in those who relapsed while remaining ontreatment (Chadwick et al., 1996).

5.1. Treatment discontinuation after epilepsy surgery

In a meta-analysis of 10 studies of temporal lobe surgery(Tellez-Zenteno et al., 2007), 14% of patients achieved long-termAED discontinuation, 50% achieved monotherapy, and 33%remained on polytherapy. The risk of recurrence ranges from

E. Beghi, D. Schmidt / Epileptology 1 (2013) 17–20 19

25% to 50% over 10 years and the chance of remaining seizure-free is unaffected by treatment stop (Cole and Wiebe, 2008). Therisk of seizure recurrence is, however, unpredictable, and with theexception of patients with foreign tissue lesions or hippocampalsclerosis (who are most likely to remain seizure-free) (McIntoshet al., 2004), there are no evidence-based findings in support ofrisk stratification. In addition, although medication withdrawalmay induce anxiety and depression in some cases, there is noevidence of major physical harm or of increasing risk of recurrentactive epilepsy. There are no studies done in surgical patientsshowing that the risk of recurrence could be affected by treatmentchange. In contrast, the continued use of AEDs carries the risk ofpersisting adverse events, increases the costs of epilepsy manage-ment, and preserves the idea that epilepsy is a lifelong clinicalcondition.

5.2. Guidelines for stopping antiepileptic drugs

The greater is the number of risk factors for seizure recurrence,the greater is the likelihood of recurrence (Berg and Shinnar,1994; Gherpelli et al., 1992), For this reason, prognostic indexeshave been developed to help quantify the risk for an individualpatient given the number and type of risk factors for recurrence.One such index was developed by the MRC Antiepileptic DrugWithdrawal Study Group based on the results of the Cox’sproportional hazard model (MRC Antiepileptic Drug WithdrawalStudy Group, 1993). The index included age 16 or older, use ofmore than one antiepileptic drug, experiencing seizures after startof drug treatment, history of primarily or secondarily generalizedtonic–clonic seizures, history of myoclonic seizures, and havingan abnormal EEG. Other models have been developed, based ondifferent combinations of the above prognostic factors, to predictthe outcome of epilepsy in seizure-free children who discontin-ued treatment (Berg and Shinnar, 1994; Braathen and Melander,1997; Gherpelli et al., 1992).

Experts recommend a 2-year period of seizure freedom beforeconsidering AED discontinuation (Practice Parameter, 1996).Treatment stop in children might be considered after shorterperiods of remission as in children the social and the personalimplications of a recurrence may be less important than in adultsand the outcome of seizures can be largely predicted by theepilepsy syndrome. In adults, unlike children, epilepsy syndromesare less well-defined and factors like driving license, employmentand quality of life are important components of the decisionprocess.

A minimum (2-year) period of seizure freedom is recom-mended before considering drug withdrawal. Shorter treatmentperiods might be considered in children, especially when epilepsysyndromes with favorable prognosis are considered. Although thetapering rate has modest effects on the risk of relapse, a sugges-tion is made to complete treatment stop in a 6-month period.The patients and their caregivers should be informed of thebenefits and the risks associated with treatment discontinuationand should be actively involved in the decision process.

6. Conclusions

Fortunately, most seizure-free patients will not suffer a seizurerelapse after AED discontinuation. However, the risks of even asingle seizure relapse can be enormous, particularly for adults.Furthermore, predicting relapse remains difficult. Most patientsin whom recurrence occurs achieve renewed seizure freedom,although this may take several years. A recurrence itself does notseem to have grave medical consequences: most patients do notsuffer complications from a relapse and 80% eventually become

seizure-free again. On the other hand, prolonged AED treatmentafter two years without seizures does not guarantee lifelongseizure freedom in adults and children. In this light, discontinua-tion of drug treatment is not dangerous but exposes patients whowere seizure-free for years to an increased risk of seizures for thefirst two years after stopping AEDs. In addition, as shown above,20% of patients who were seizure-free for years, do not becomeseizure-free immediately after restarting AED treatment afterrelapse. Nevertheless, stopping AEDs is a valuable option thatneeds to be carefully considered in most patients with epilepsywho are seizure-free for two years or longer. The decision towithdraw or withhold treatment in these cases must be, however,individualized. The decision is driven by assessing the individualrisk of relapse after stopping treatment and by patient preferenceafter informed consent. Although moderate, the risk of provokinguncontrollable epilepsy in some patients undoubtedly exists andmust be mentioned when discussing AED discontinuation or taperin seizure-free patients. In any patient, the individualized decisionto discontinue treatment should also take into account socialaspects like driving license, job and leisure activities as well asemotional and personal factors and adverse effects or druginteractions, and patients will ultimately decide whether theywish to discontinue drug treatment.

References

Annegers JF, Hauser WA, Elveback LR. Remission of seizures and relapse inpatients with epilepsy. Epilepsia 1979;20:729–737.

Beghi E, Sander JW. The natural history and prognosis of epilepsy. In: Engel Jr J, PedleyTA, editors. Epilepsy: A comprehensive textbook. Philadelphia, USA: WoltersKluver/Lippincott William & Wilkins; 2008. p. 65–70.

Berg AT, Shinnar S. Relapse following discontinuation of antiepileptic drugs:a meta-analysis. Neurology 1994;44:601–608.

Braathen G, Melander H. Early discontinuation of treatment in children withuncomplicated epilepsy: a prospective study with a model for prediction ofoutcome. Epilepsia 1997;38:561–569.

Chadwick D, Taylor J, Johnson T. Outcomes after seizure recurrence in people withwell-controlled epilepsy and the factors that influence it. Epilepsia1996;37:1043–1050.

Chadwick D. Representing the MRC antiepileptic drug withdrawal study group.Brain 1999;122:441–448.

Cole AJ, Wiebe S. Debate: Should antiepileptic drugs be stopped after successfulepilepsy surgery? Epilepsia 2008;49(Suppl. 9):29–34.

Geerts AT, Niermeijer JM, Peters AC, Arts WF, Brouwer OF, Stroink H, et al. Four-year outcome after early withdrawal of antiepileptic drugs in childhoodepilepsy. Neurology 2005;64:2136–2138.

Gherpelli JL, Kok F, dal Forno S, Elkis LC, Lefevre BH, Diament AJ, et al.Discontinuing medication in epileptic children: a study of risk factors relatedto recurrence. Epilepsia 1992;33:681–686.

Harden CL, Meador KJ, Pennell PB, Hauser WA, Gronseth GS, French JA, et al.Management issues for women with epilepsy—focus on pregnancy (anevidence-based review): II. Teratogenesis and perinatal outcomes. Epilepsia2009;50:1237–1246.

Lossius MI, Tauboll E, Mowinckel P, Morkrid L, Gjerstad L. Reversible effects ofantiepileptic drugs on reproductive endocrine function in men and womenwith epilepsy—a prospective randomized double-blind withdrawal study.Epilepsia 2007;48:1875–1882.

Lossius MI, Hessen E, Mowinckel P, Stavem K, Erikssen J, Gulbrandsen P, et al.Consequences of antiepileptic drug withdrawal: a double-blind, randomizedstudy (Akershus Study). Epilepsia 2008;49:455–463.

Lossius MI, Tauboll E, Mowinckel P, Gjerstad L. Reversible effects of antiepilepticdrugs on thyroid hormones in men and women with epilepsy: a prospectiverandomized double-blind withdrawal study. Epilepsy and Behavior2009;16:64–68.

Matricardi A, Bertamino F, Risso D. Discontinuation of anti-epileptic therapy: aretrospective study of 86 children and adolescents. Italian Journal of Neuro-logical Sciences 1995;16:613–622.

McIntosh AM, Kalnins RM, Mitchell LA, Fabinyi GC, Briellmann RS, Berkovic SF.Temporal lobectomy: long-term seizure outcome, late recurrence and risks forseizure recurrence. Brain 2004;127(Pt. 9):2018–30.

MRC Antiepileptic Drug Withdrawal Group. Randomised study of antiepileptic drugwithdrawal in patients in remission. Lancet 1991;337:1175–1180.

MRC Antiepileptic Drug Withdrawal Study Group. Prognostic index for recurrenceof seizure after mission of epilepsy. BMJ 1993;306:1374–1378.

Mula M, Monaco F. Antiepileptic drugs and psychopathology: an update. EpilepticDisorders 2009;11:1–9.

E. Beghi, D. Schmidt / Epileptology 1 (2013) 17–2020

Nicoletti A, Sofia V, Vitale G, Bonelli SI, Bejarano V, Bartalesi F, et al. Naturalhistory and mortality of chronic epilepsy in an untreated population of ruralBolivia: a follow-up after 10 years. Epilepsia 2009;50:2199–2206.

Ortinski P, Meador KJ. Cognitive side effects of antiepileptic drugs. Epilepsy andBehavior 2004;5:S60–S65.

Patsalos PN, Perucca E. Clinically important drug interactions in epilepsy: inter-actions between antiepileptic drugs and other drugs. Lancet Neurology

2003;2:473–481.Pitkanen A. Efficacy of current antiepileptics to prevent neurodegeneration in

epilepsy models. Epilepsy Research 2002;50(1–2):141–160.Practice Parameter: A guideline for discontinuing antiepileptic drugs in seizure-

free patients—summary statement report of the Quality Standard Subcom-

mittee of the American Academy of Neurology. Neurology 1996; 47: 500-602.Ranganathan LN, Ramaratnam S. Rapid versus slow withdrawal of antiepileptic

drugs. Cochrane Database of Systematic Reviews 2006(2): Art. no.: CD005003.Schmidt D, Loscher W. Uncontrolled epilepsy following discontinuation of anti-

epileptic drugs in seizure-free patients: a review of current clinical experience.Acta Neurologica Scandinavica 2005;111:291–300.

Shorvon SD. Drug treatment of epilepsy in the century of the ILAE: the second 50years, 1959–2009. Epilepsia 2009;50(Suppl. 3):93–130.

Sillanpaa M, Schmidt D. Natural history of treated childhood-onset epilepsy:prospective, long-term population-based study. Brain 2006;129:617–624.

Sillanpaa M, Schmidt D. Prognosis of seizure recurrence after stopping antiepi-leptic drugs in seizure-free patients: a long-term population-based study ofchildhood-onset epilepsy. Epilepsy and Behavior 2006;8:713–719.

Sirven J, Sperling MR, Wingerchuck DM. Early versus late antiepileptic drugwithdrawal for people with epilepsy in remission. Cochrane Database ofSystematic Reviews 2001(3): Art no. CD001902.

Specchio LM, Beghi E. Should antiepileptic drugs be withdrawn in seizure-freepatients? CNS Drugs 2004;18:201–212.

Tellez-Zenteno J, Dhar R, Hernandez-Ronquillo L, Wiebe S. Long-termoutcomes in epilepsy surgery: antiepileptic drugs, mortality, cognitive andpsychosocial aspects. Brain 2007;130:334–345.

Temkin NR. Antiepileptogenesis and seizure prevention trials with antiepilepticdrugs: meta-analysis of controlled trials. Epilepsia 2001;42:515–524.

Watts AE. The natural history of untreated epilepsy in a rural community in Africa.Epilepsia 1992;33:464–468.