Evidence-based guideline: Management of
an unprovoked first seizure in adults
Report of the Guideline Development Subcommittee of the
American Academy of Neurology and the American Epilepsy Society

Allan Krumholz, MD ABSTRACT
Samuel Wiebe, MD Objective: To provide evidence-based recommendations for treatment of adults with an unpro-
Gary S. Gronseth, MD voked first seizure.
David S. Gloss, MD
Methods: We defined relevant questions and systematically reviewed published studies according
Ana M. Sanchez, MD
to the American Academy of Neurology’s classification of evidence criteria; we based recommen-
Arif A. Kabir, MD
dations on evidence level.
Aisha T. Liferidge, MD
Justin P. Martello, MD Results and recommendations: Adults with an unprovoked first seizure should be informed that
Andres M. Kanner, MD their seizure recurrence risk is greatest early within the first 2 years (21%–45%) (Level A), and
Shlomo Shinnar, MD, clinical variables associated with increased risk may include a prior brain insult (Level A), an EEG
PhD with epileptiform abnormalities (Level A), a significant brain-imaging abnormality (Level B), and a
Jennifer L. Hopp, MD nocturnal seizure (Level B). Immediate antiepileptic drug (AED) therapy, as compared with delay of
Jacqueline A. French, MD treatment pending a second seizure, is likely to reduce recurrence risk within the first 2 years
(Level B) but may not improve quality of life (Level C). Over a longer term (.3 years), immediate
AED treatment is unlikely to improve prognosis as measured by sustained seizure remission
Correspondence to (Level B). Patients should be advised that risk of AED adverse events (AEs) may range from
American Academy of Neurology: 7% to 31% (Level B) and that these AEs are likely predominantly mild and reversible. Clinicians’
recommendations whether to initiate immediate AED treatment after a first seizure should be
based on individualized assessments that weigh the risk of recurrence against the AEs of AED
therapy, consider educated patient preferences, and advise that immediate treatment will not
improve the long-term prognosis for seizure remission but will reduce seizure risk over the sub-
sequent 2 years. Neurology® 2015;84:1705–1713

AAN 5 American Academy of Neurology; AE 5 adverse event; AED 5 antiepileptic drug; CI 5 confidence interval; ILAE 5
International League Against Epilepsy; QOL 5 quality of life.

An estimated 150,000 adults present annually with antiepileptic drug (AED) therapy are important. A
an unprovoked first seizure in the United States.1 2007 practice guideline addresses the evaluation of
Even one seizure is a traumatic physical and psycho- an unprovoked first seizure in adults3; the present
logical event that poses difficult diagnostic and treat- practice guideline analyzes evidence regarding prog-
ment questions, and has major social consequences nosis and therapy.
(e.g., loss of driving privileges, limitations for employ- We included studies of adults with an unprovoked
ment).2,3 Recurrent seizures pose even more serious first seizure and excluded those of patients with more
and costly problems.2–4 Therefore, optimal evidence- than one seizure at the time of presentation.3,5,6
based approaches for evaluating and managing adults Unprovoked seizures are classified in 1 of 2 broad
after a first seizure and preventing recurrences with categories: (1) a seizure of unknown etiology, or
Supplemental data
at Neurology.org
From the Department of Neurology, Maryland Epilepsy Center (A.K.), and Department of Neurology (A.M.S., A.A.K., J.P.M., J.L.H.), University
of Maryland School of Medicine, Baltimore; US Department of Veterans Affairs (A.K.), Maryland Healthcare System, Epilepsy Center of
Excellence, Baltimore, MD; Department of Clinical Neuroscience (S.W.), University of Calgary Faculty of Medicine, Canada; Department of
Neurology (G.S.G.), University of Kansas School of Medicine, Kansas City, KS; Department of Neurology (D.S.G.), Geisinger Health System,
Danville, PA; Department of Emergency Medicine (A.T.L.), George Washington University School of Medicine, Washington, DC; Department of
Neurology (A.M.K.), International Center for Epilepsy, University of Miami Miller School of Medicine, FL; Departments of Neurology, Pediatrics,
and Epidemiology & Population Health (S.S.), Albert Einstein College of Medicine, Yeshiva University, Bronx; and New York University
Comprehensive Epilepsy Center (J.A.F.), New York, NY.
Approved by the Guideline Development Subcommittee on November 16, 2013; by the Practice Committee on January 20, 2014; by the AES
Board of Directors on February 13, 2014; and by the AANI Board of Directors on December 1, 2014.
This guideline was endorsed by the World Federation of Neurology on May 20, 2014, and by the American Neurological Association on May 21, 2014.
Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.

© 2015 American Academy of Neurology 1705

ª 2015 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

16. rated articles. 1706 Neurology 84 April 21. If recruitment into trials is delayed by criteria. n (%) Ref. We identified 2 prognostic Class I10–14 for seizure recurrence after a first seizure? (2) Does and 8 prognostic Class II studies15–22 addressing the immediate treatment with an AED reduce or change probability that an adult with an unprovoked first (a) short-term risks for a seizure recurrence or (b) long. 32% at 1 year. 47 were judged relevant and in most of these studies. seizure abstract form.11. of the literature published in English and based on including both AED-treated and untreated subjects.19. what are the risks for seizure first seizure.12. Treated 1 mo 3 mo 6 mo 1y 2y 3y 5y . Appendix e-7 presents all due to an acute symptomatic condition (e. 11 I 70% . recurrence? dren. Tables e-1 through e-4 show the data. which are defined as seizures Class I or II (appendix e-6).org).17.3. and estimated term prognosis for seizure freedom or remission? (3) the recurrence risk from these pooled data.5 We excluded studies to evidence strength based primarily on studies rated of provoked seizures. y No. .19 238 164 (69) — — — 38 (16) 50 (21) 60 (29) 70 (34) 81 (39) 12. abolic or toxic disturbance. stroke) and differ in prognosis from unprovoked seizures.9 weeks or months. Unauthorized reproduction of this article is prohibited. Table 1 Risk of seizure recurrence after an unprovoked first seizure in adults (Class I and II studies) Seizure recurrences at various times. cerebral trauma.17. This practice guideline considers the evidence for Question. We linked recommendations “remote symptomatic” seizure). Generalized tonic–clonic convulsive seizures comprise the major DESCRIPTION OF THE ANALYTIC PROCESS This seizure type. 5 years) (table 1.20 812 404 (50) — 179 (22) — 288 (35) — 378 (46) 398 (49) 21 II $16 228 113 (50) — — — 68 (30) — — — — 22 II 18–50 87 45 (52) — — 30 (34) 37 (43) 39 (45) — — Total 3.196 (43) 64 (7) 220 (18) 519 (24) 761 (32) 873 (36) 508 (42) 685 (46) 723 (49) Abbreviation: Ref. and Cochrane Central Register year (i. obtained all in rence and become ineligible. (2) a seizure in relation to a demonstrated preexisting of evidence scheme for prognostic or therapeutic ar- brain lesion or progressive CNS disorder (so-called ticles (appendix e-5).10. figures 1 and 2). Class Age. which For those patients prescribed AEDs immediately. 13 I 72% . figure 1).5 y 10.11. recurrence was lower for patients treated with AEDs Of the selected articles. We searched after the initial seizure and the greatest risk in the first MEDLINE. compared with just 46% by of Controlled Trials databases (1966 to March 2013). a 2003 guideline addresses this for chil. Embase.22 These studies. 5 reference.e. established 2004 process standards from the American demonstrate that the cumulative incidence of seizure Academy of Neurology (AAN) Guideline Development recurrence increases over time. Patient ascertain- and reviewed the literature for relevant publications using ment and treatment differences among studies may established criteria. See appendix e-3 for complete search account for some of the wide variation in recurrence strategy and appendix e-4 for inclusion and exclusion rates observed.20 76 36 (47) 2 (3) 18 (24) 20 (26) 22 (29) — — — — 16 II $16 306 41 (13) 55 (18) 79 (26) 111 (36) 136 (44) 144 (47) — — 19 II 75% .15. a met. with some studies including only pa- is an evidence-based appraisal from a systematic review tients with such seizures. We systematically reviewed and rated randomized.613 articles.212 1. 2015 ª 2015 American Academy of Neurology.12. and selected 281 for full-text review. with the great majority Subcommittee9 (see appendices e-1 and e-2 on the of recurrences occurring within the first 1 to 2 years Neurology® Web site at Neurology. seizure would have recurrent seizures.15 424 ? 38 (9) 89 (21) 127 (30) 153 (36) 191 (45) 204 (48) 237 (56) 244 (58) 20 II 14–91 497 127 (26) — — 191 (38) — — — — 15 II 60% . For the adult who presents with an unpro- prognosis and treatment of adults with an unprovoked voked first seizure.8 We posed 3 questions: (1) What are the risks Evidence. patients may experience a recur- We identified 2.13.16 Also. but treatment often was not acceptable..g. what included studies wherein AED treatment was not ran- are the risks for adverse events (AEs)? domized or controlled (table 1.20 These 2 factors would lead the 47 articles according to the AAN classification to variability and underestimation of recurrence risk..16 397 204 (51) 24 (6) 58 (15) 75 (19) 98 (25) 111 (28) — — — 17 II $16 147 62 (42) — — 39 (27) 50 (34) 60 (41) 61 (41) — — 18 II Mean .5–7 ANALYSIS OF EVIDENCE Risk of seizure recurrence.

and cognitive develop. as compared with 10%. The follow- Figure 1 Percentages of patients with first seizure experiencing a recurrent seizure over time ing are representative examples of increased seizure recurrence risks or hazard ratios from studies of mixed cohorts of AED-treated and untreated subjects: • A prior brain insult as a seizure cause was associ- ated with an increased relative rate for seizure recurrence at 1 to 5 years of 2. and 48% at 1. with recovery between them.3.24 and a nocturnal seizure.17 We also identified clinical variables found in stud. majority of 2 Class I11.23. family history of seizures. Comparably increased recur. and and 1 Class III study.17 Of 2 subjects.44) as compared with that in patients without imaging abnormalities.20.11. 3.20 (1) the short-term risk for a seizure recurrence. and this risk appears to be lower for patients treated mental disability).19.20 most confirm is at greatest risk of a recurrence relatively early.1 (95% CI 1. Unauthorized reproduction of this article is prohibited. trauma. a so-called “remote symptomatic” with AEDs. clinical variables that were not consis- ies to be associated with an increased risk of seizure tently associated with an increased seizure recurrence recurrence.11 Regarding EEG findings. sei- lowing an unprovoked first seizure include a prior zure type. and a nocturnal seizure (2 Class II studies). 2015 1707 ª 2015 American Academy of Neurology.11 • Abnormal brain imaging was associated with a hazard ratio increase for seizure recurrence at 1 to 4 years of 2.11.24 a signif. seizure occurred while they were awake.5. subjects manifesting clinically relevant structural Question.16. 1 Class of unknown cause. that individuals with a seizure related to a prior brain within the first 2 years (21%–45%).3.20 Likewise. such as MRI or CT in 2 Class II studies16.19.13. and 5 2 Class II studies).09–5.24 multiple (2 or more) discrete seizures within 24 hours an EEG with epileptiform abnormalities (character.0–4. in the first year (2 Class I studies.12 and 4 Class II studies16–19 confirm a similar increased recurrence risk for an epi. we considered imaging.3) as compared with than 5 years. In contrast.11.55 (95% confi- dence interval [CI] 1.38) as compared with that in patients without such EEG abnormalities. and presentation with status epilepticus or brain lesion or insult causing the seizure. a III study). respectively. does immediate treatment with similarly increased risk for patients experiencing a an AED change the short-term (2-year) prognosis nocturnal seizure as compared with those whose first for seizure recurrence? Neurology 84 April 21.13 and 2 Class II studies. seizure.23.16 (95% CI 1.44–4.25 with approximately 10% of (2) the longer-term potential for seizure remission.3.23. sex.11–13. a significant 29% at these same intervals for patients with a seizure brain-imaging abnormality (2 Class II studies. 41%. a seizure while the patient was awake. immediate AED treatment of an unprovoked first rence risk is noted with respect to abnormal brain seizure in adults changes prognosis. lesion or insult causing the seizure (2 Class I studies.10. For the adult presenting with an unpro- lesions.24 ized by spikes or sharp waves).25 • A nocturnal seizure was associated with an This graph is based on a fixed-effect pooled percentage model from data in table 1 and increased recurrence risk odds ratio at 1 to 4 shows the cumulative average and the range for each time period from 1 month to more years of 2. the patient’s age.13. risk after an unprovoked first seizure in adults include ciated with an increased risk of seizure recurrence fol. CNS infection. rence rates of 26%. and especially lesion11.20 (including those due to stroke. These include a prior brain illustrated in a representative study with seizure recur.23. 4 Class II studies).44 (95% CI 1. 24%. Management. To evaluate evidence as to whether leptiform abnormality. and ities (2 Class I studies.3.20.51) as compared with that in patients with seizures of unknown cause. . The most consistently noted factors asso.07–4.16.19. 8 Class II studies). 2 Class II studies16. Based on data from studies including icant brain-imaging abnormality (judged the cause of mixed cohorts of both AED-treated and untreated the seizure).16–19. an adult with an unprovoked first seizure Class I11.6.24 demonstrate an approximately 2-fold.3.17 report a voked first seizure. an EEG with epileptiform abnormal- years. cerebral palsy. The risk of seizure recurrence increases in certain higher risk of seizure recurrence.11 • An EEG with epileptiform abnormalities was associated with a relative rate increase for seizure recurrence at 1 to 5 years of 2. That increased risk is clinical circumstances. Conclusion.9.

most recurrences happen presents with an unprovoked first seizure. and 1 Class III study28 addressing the nature and strating significantly fewer seizure recurrences (table 2). Risks of AED treatment. notes that specific study.22 only Class I study and 3 of 4 Class II studies demon. and by 3 months in 81%. We identified 4 Class II studies12. by 1 month in 55%. it was within 1 week in 30% of subjects.18. and in this which. figures 1 and 2). For the adult presenting with an unpro- voked first seizure. The generally accepted metric for assessing long-term outcome and prognosis is the seizure remission rate.15. These studies focused 1708 Neurology 84 April 21. does immediate treatment with an AED as compared with delay pending a seizure recurrence influence prognosis.22.22 Despite this reduced risk of early seizure recur- rence. typically 2 to 5 years. which is from a Class II study. Immediate treatment in the only Class I study meant AED therapy started within 1 week of the index seizure.365:2007–2013). immediate AED therapy as com- pared with no treatment is likely to reduce absolute risk by about 35% for a seizure recurrence within the subsequent 2 years (1 Class I study. the nature and frequency of AEs with AED diate AED treatment convincingly reduces that risk treatment? within the first 2 years of the initial seizure. immediate AED treatment as Evidence. controlled trial.12–15 Studies demonstrate that immediate AED treatment after an unprovoked first seizure as compared with treatment delayed pending another seizure does not increase the inci- Cumulative proportion of patients with an unprovoked first seizure experiencing a seizure dence of sustained seizure remission (table 3). Immediate versus immediate treatment does not affect mortality over deferred antiepileptic drug treatment for early epilepsy and single seizures: a randomised a 20-year period. A random-effects meta-analysis of data from the stud- Figure 2 Cumulative proportion of patients experiencing a seizure recurrence after randomization. such as the potential for seizure remission over the longer term (.26 Conclusion. Although cumulative risk of seizure recur. comparing those individuals with patients who had multiple seizures before randomization to treatment (B). validated 2-year QOL measures.21. comparing immediate vs deferred treatment ies in table 2 indicates an absolute risk reduction in seizure recurrence of 35% (95% CI 23%–46%) in a comparison of immediate and delayed AED treatment for pooled 2-year data. Long- recurrence after randomization and comparing patients with immediate antiepileptic drug term survival is addressed only in 1 Class III study.15 Conclusion. For the adult who rence increases over time. the only quality of life (QOL) analysis. 1 Class II study).12. with the Evidence. For adults presenting with an unpro- voked first seizure.3 years)? Evidence. Question.15. Unauthorized reproduction of this article is prohibited. Question. 4 Class II studies) but might not affect QOL (1 Class II study). 2015 ª 2015 American Academy of Neurology.15 Details regarding what constituted immediate AED treatment were not provided in the other Class II studies.21. in the short term. although limited by sample size. Reprinted from The Lancet (Marson et al. We identified 1 Class I study12–14 and 1 Class II study15 addressing this issue and longer- term prognosis (table 3). which is a measure of maintaining seizure freedom for a specified time dura- tion. which we define as within 2 years (figure 1).3 years) (1 Class I study.26 addressing this issue (table 2). Imme.27 treatment vs patients with treatment deferred pending a seizure recurrence (A). For adults presenting with an unpro- voked first seizure. frequency of AEs (table e-5). © 2005. We identified 1 Class I study12–14 and 4 compared with treatment delayed until a second Class II studies15. . Lancet 2005. seizure occurs is unlikely to improve the chance of Immediate therapy with an AED after an unprovoked attaining sustained seizure remission over the longer first seizure in adults significantly reduces seizure risk term (.18. what are within the first year (table 1.13 whereas in 1 Class II study.21. with permission from Elsevier. demonstrates no significant differences in standard.

immediate AED treatment AEDs at the time of the studies.12.05. a study of patients with new-onset epilepsy found that Table 2 Rates for short-term (1 and 2 years) seizure recurrence after an unprovoked first seizure in adults as related to immediate antiepileptic initial AED monotherapy with either phenytoin or drug treatment (Class I and II studies) topiramate was associated with AEs leading to AED discontinuation in only 7% to 13% of patients. supports low AED risks. untreated. the risk of a recurrence poses major concerns and raises the question of whether immediate AED Table 3 Rates of 2-year seizure remission over the longer term (.28 some of which may now be consid. rate Recur. phenobarbital. CLINICAL CONTEXT For an adult with a first sei- zure.34. chance for a recurrent seizure is greatest within the first voked first seizures. Reported immediate AED therapy.31 a Conclusion. valproic acid. seizure recurrence include a prior brain insult such as tially treated with a single AED for an unprovoked a stroke or trauma (Level A). some treated with newer drugs. in approximately 7% to 31% of patients (4 Class II a Significant difference. most events are known to be seizure remission (Level B).35 a Rates of 5-year seizure remission in patients followed longer were also not significantly For a patient with a first unprovoked seizure. QOL (Level C). Ref.33 In contrast. Remission. n (%) follow-up tional seizures is very high (57% by 1 year and 73% 12–14 I 419 215 (51) 174 (81). Class No. stratified on the basis of clinical factors. seizure is not well accepted and is debated. Unauthorized reproduction of this article is prohibited.33. and lamotri. immediate Total 1. an Immediate Remission.32 Recur. on the effects of AEDs on seizure recurrence risk and RECOMMENDATIONS Adults presenting with an included data on medication AEs.3 years). as compared with delay of AEs in these studies appear to be mild and reversible treatment pending a second seizure. For adults with an unprovoked first sei- 21 II 228 113 (50) 5 (4) 63 (55) 1 zure immediately treated with AEDs. by studies in patients with new-onset epilepsy initially Clinicians should also advise such patients that treated similarly with AEDs. gine. 0.15 AEDs included phenytoin. rate Treated. dose-related and reversible through dose reduction or Patients should be advised that their risk for AED discontinuation of the responsible drug. the different. Recur. n (%) treatment.3 years). n (%) n (%) n (%) follow-up. Class No. No AED-related abnormality (Level B). but population size was limited. y lepsy initially treated with AEDs found that AEs were 12–14 I 397 204 (51) 36 (18)a 75 (39) 2 no more likely to occur than in untreated controls 18 II 76 36 (47) 4 (11)a 18 (45) 1 and proposed that this was because the drugs were 15 II 812 404 (50) 129 (32) 159 (39) 2 typically started as monotherapy and at low doses.2.231 619 (50) 546 (88) 534 (87) AED treatment at the time of the first unprovoked Abbreviations: NS 5 not a significant difference. Clinicians should advise patients that over the ered older AEDs but were standard.29–32 clinical factors associated with an increased risk of The incidence of AEs from AEDs in adults ini. with greater Neurology 84 April 21. 2015 1709 ª 2015 American Academy of Neurology. treated.15. comparable findings are reported 2 years after a first seizure (21%–45%) (Level A). quent to a first seizure (Level B). with risk increasing proportionally after 15 II 812 404 (50) 372 (92). b Rates of longer seizure remission in patients with greater follow-up were also not chance for a seizure recurrence can be estimated and significantly different. patient populations with epilepsy. although described. NS 375 (92) 5 yb each subsequent recurrence as the time interval between seizures decreases. commonly used longer term (.34 It is a proposed and now comparing immediate with deferred antiepileptic drug treatment of an unprovoked first seizure in adults (Class I and II studies) generally accepted principle that when a patient with a first seizure has one or more ensuing seizures. p .30. AED should be initiated because the risk of yet addi- treatment.22. immediate deferred Length of Ref.21.13. n (%) treatment. it may not improve carbamazepine. is likely to reduce when an affected patient is switched to another the risk of a seizure recurrence in the 2 years subse- AED. 1 Class III study). treatment is advisable. 5 recurrence.31 AEs ranges from 7% to 31% (Level B) and that these Evidence from reports of AED AEs in comparable AEs are predominantly mild and reversible. 5 reference.30 For example.30 Although AEDs is unlikely to improve the prognosis for sustained may cause different AEs. an EEG with epileptiform first seizure is reported to range from 7% to 31% abnormalities (Level A). studies of the 22 II 87 45 (52) 9 (20)a 28 (66) 2 nature and incidence of AEs indicate a wide range Total 1. studies. NS 159 (78) More than 3 ya by 4 years). deaths or life-threatening allergic reactions were Clinicians should advise patients that. . or a nocturnal seizure (Level B). Although those unprovoked first seizure should be informed that the articles specifically addressed populations with unpro. Length of Another study in a mixed group of patients with epi- Ref.600 804 (50) 183 (23) 343 (43) 1 or 2 of predominantly mild and reversible AEs that occur Abbreviations: Ref. a significant brain-imaging for a variety of AEDs (table e-5). 5 reference.

14. psychosocial symptomatic seizure etiology as the only independent factors. caution should be incorporated into decision-making and is urged regarding the calculation of additive risk of guideline development.36 seizure recurrence after a first unprovoked seizure. and by whom a patient would be best advised cally regarding additive effects or covariance of the regarding driving laws and other social issues such as risk factors for seizure recurrence after a first seizure.34 Physicians on the extent. such as seizure etiology. and AE profiles on an individualized basis. such as QOL.15 Moreover.12 and the other reported a remote further studies of patient preferences. the lack of evidence regarding specific risk with immediate AED therapy. For example.20 Because of this lack of evidence.2 Still.24 interventions. it would be helpful to know when. and timing of planning to prescribe an AED for treatment should seizure recurrence risks associated with specific clini- also carefully consider the drug’s specific therapeutic cal variables. as our analysis indicates and the ILAE unprovoked first seizure demonstrates no advantage cautions.25. One study noted that study noted that the only independent risk factor only 21% of all patients with first seizures received for seizure recurrence was an EEG with epileptiform correct advice about driving limitations. well-designed (e.2.2.15 factors and their interactions poses limitations.3.17.34 Predictive statistical mod- decided by individualized considerations. Such seizure recurrence prevention. have been demonstrated to be feasible and Indications for immediate AED treatment are potentially useful.15. are limited and needed. employment.35 Also.34 The ILAE expanded the diagnosis of ual seizure recurrences pose some risk for physical epilepsy beyond the prior standard requiring at least harm and even death.12. with potentially research on the nature and risks of AEs with AED 1710 Neurology 84 April 21. Unauthorized reproduction of this article is prohibited.24 Such risk stratification ing privileges and limitations on employment. although complex and diffi- caution also applies to decisions in AED treatment. may help guide physicians counseling patients about one controlled Class II study comparing immediate their risks for seizure recurrence and options for man. rigorous. risk associated with a prior brain insult or lesion as the greater implications for adults than for children. even There also is a need for better and more focused in the short term. dence. and counseling that focus on objective The relatively small numbers of subjects in studies outcomes.3.26 International League Against Epilepsy (ILAE) pro.30 Evidence and brain imaging. The issue of exactly how to use complicated risk The ILAE report states as much: “No formula can data of recurrences and seizure remission to guide be applied for additive risks since data are lacking on management is a question that warrants further how such risks combine.2 addressing this issue limit the strength of evi.34 Only 2 studies analyzed evidence specifi.8. brain-imaging abnormality) likely are related. such risks will have to be research and clarification. a prior brain lesion as a seizure cause. and QOL measures are encouraged and risk factor. One personal preference for AEDs.13. els and analyses would benefit from additional data vidual’s risk of a seizure recurrence. a significant brain-imaging abnormality. Such matters also may guide a patient’s and reached somewhat different conclusions. how.g.12. .23..2. In some instances. It would also be important to indicates that immediate AED therapy is likely to determine the degree to which AED treatment may reduce seizure recurrence risk for individuals with influence the risk of seizure recurrence for each of an unprovoked first seizure.13. potential additive effects. Some of these risk factors may be independent FUTURE RESEARCH RECOMMENDATIONS For predictors for risk of recurrence. AED treatment with treatment deferred until after a agement.3. However. whereas others patients with a first seizure. an EEG with epileptiform abnor. first 2 years. or a studies analyzing patient management techniques.15 A recent report from the from driving. the only study appraising seizure recurrence over the subsequent 10 years. such as those who have already experienced treated with AEDs were more likely to be restricted multiple seizures. or a psychological and social consequences as loss of driv- nocturnal seizure.34 cult.16. seizure freedom demonstrates no benefit for immedi- rence risk for individuals with a first unprovoked ate AED treatment. 2015 ª 2015 American Academy of Neurology. adults.37 These types of predictive mod- based largely but not only on estimations of an indi. seizure recurrences may cause such serious malities. may be important. the incidence of sudden unexplained death after an However. The longer-term prognosis for patients with a first motes a new practical clinical definition of epilepsy seizure as measured by whether patients maintain that emphasizes the importance of estimating recur. particularly within the those clinical factors taken individually or together.”34 Such els to analyze such risks. EEG findings. a patient’s statistical risk seizure recurrence found no significant difference in for a seizure recurrence may approach that of patients standard 2-year QOL measures.26 Also.34. although individ- seizure.12.33.15 there is no evidence that 2 unprovoked seizures to encompass people with an immediate AED treatment reduces that risk or im- unprovoked seizure and a high (at least 60%) risk of proves QOL. For cause of the seizure.23. abnormalities. that study for whom immediate AED treatment is generally also noted that patients who were not immediately accepted.

critical. Marinus.aan. Arif Kabir: acquisi- does not account for individual variation among patients. and of the manuscript for important intellectual content. guide a patient’s decision-making about AED initia. Jacqueline French: study to minimize the potential for conflicts of interest to influence the concept and design. critical its affiliates are assessments of current scientific and clinical information pro- revision of the manuscript for important intellectual content. further studies are war. analysis or interpretation of data. Kanner serves as a journal editor for Epilepsy Currents and as a Therefore. critical revision pendent professional judgment of the treating provider. and Upsher-Smith. Go to Neurology. D. and has given expert testimony. analysis or interpretation of data. tion is developed and when it is published or read). Aisha Liferidge: acquisition of data. . and (5) is not intended to substitute for the inde- or interpretation of data. critical revision of the manu- warranty. Foundation of Alberta. Kabir. A.30 uscript. UCB. Sanchez. Johnson groups of patients with various epilepsy or seizure & Johnson. Wiebe has viewed at www. Society (AES) are committed to producing independent. AAN assumes no responsibility for any injury or damage to per- critical revision of the manuscript for important intellectual content. and fees are paid to the Consortium. A. drafting/revising the manuscript. and J. S. critical revision of the manuscript for important intellectual the context of treating the individual patient. and the Hotchkiss Brain Institute of the Received March 10. Significant efforts are made manuscript for important intellectual content. The AAN Guideline Author Conflict of Interest Policy can be Neuroscience. lepsy Study Consortium.2. other guidance published by the American Academy of Neurology and Sam Wiebe: acquisition of data. Accepted in final form October 30. Epilepsy Research Foundation. All consulting is done on behalf of the Consortium.30 Treatment. the tion of data. S. updated studies utilizing newer AEDs regional editor for Epileptology. acquisition of data. the AAN and drafting/revising the manuscript. Krumholz serves on the editorial board for Clinical EEG and fields. has AEDs is also lacking. analysis or interpretation of data. SK Life Science. French has served as a consultant for tion. AAN specifically script for important intellectual content. and ranted because these data may not apply to individ. analysis or interpretation of data. practice advisories. but A. A. recommendations of this CPG. Psychiatric Controversies in Epilepsy. Ana Sanchez: acquisition of data. regarding the information. AUTHOR CONTRIBUTIONS Allan Krumholz: study concept and design.38 New York University receives salary support from the Consortium. There are some data on such matters in mixed Acorda. analysis or interpretation of data. In all cases. The AAN and AES forbid commercial participation in. (3) addresses only the drafting/revising the manuscript. critical revision of the manuscript for important The American Academy of Neurology (AAN) and the American Epilepsy intellectual content. Conflict of interest forms were obtained from all authors and reviewed by an oversight committee before project initiation. results using mostly older AEDs (table e-5).org for full disclosures. and Vertex. analysis or interpre- ered inclusive of all proper treatments. study supervision. David Gloss: study con- most recent evidence (new evidence may emerge between the time informa- cept and design. Liferidge. The information: (1) should not be consid- seth: study concept and design. J. Novartis. Drafts of the guideline have been reviewed by at least 3 AAN committees. treatment for patients with an initial seizure. discontinuation. acquisition of data. received research funding from the Alberta Heritage Medical Research access the 2004 AAN process manual. however.I. Neurology peer reviewers.9 Foundation. drafting/revising the man- selected course of action should be considered by the treating provider in uscript. and has given expert testimony. To the extent possible. Unauthorized reproduction of this article is prohibited. Epilepsy Therapy Project. ing/revising the manuscript. and Depression in Research on AED discontinuation in patients with Neurologic Disorders. Eisai Medical Research. Supernus Pharmaceuticals. Jennifer Hopp: acquisition of data. For complete information on this process. G. as the information of the manuscript for important intellectual content. critical revision of the manuscript for AES keep separate those who have a financial stake in the success or fail- important intellectual content. Epi- discontinued AEDs. Neurology 84 April 21. draft- for any errors or omissions. AAN STUDY FUNDING and AES limit the participation of authors with substantial conflicts of This guideline was developed with financial support from the American interest. systematic reviews. acquisition of data. AAN provides this information on an “as is” basis. Gronseth reports no disclosures relevant to the manuscript. critical revision of the truthful clinical practice guidelines (CPGs). and pretation of data. Shlomo Shinnar: study concept and design. study supervision. purpose. Hopp has received royalties from publishing from UpToDate and honoraria from lectures for UCB Pharma. The University of Calgary. Upsher-Smith. uals who experience only an initial seizure. Use of the information is vol- content. UCB.com. ure of the products appraised in the CPGs and the developers of the guidelines. Pfizer. Gary Gron- vided as an educational service. and has received royalties from UpToDate. has received royalties for Febrile a first unprovoked seizure or recurrence who receive Seizures and honoraria from Questcor. drafting/revising the manuscript. (2) is not continually updated and may not reflect the manuscript for important intellectual content. and representatives from related A. expressed or implied. Pfizer. drafting/revising the manuscript. critical revision of the the standard of care. drafting/ CONFLICT OF INTEREST revising the manuscript. analysis DISCLAIMER or interpretation of data. Shinnar has served on scientific advisory boards for Acorda. a network of DISCLOSURE neurologists. critical revision Clinical practice guidelines. GlaxoSmithKline. 2015 1711 ª 2015 American Academy of Neurology. critical revision of the manuscript for important intellectual content. has received types who have become seizure-free and who have grants from Eisai Medical Research. An- sons or property arising out of or related to any use of this information or dres Kanner: acquisition of data. drafting/revising the manuscript. Second Edition: A Practical Guide to Diagnosis and this and comparable patient populations. Gloss is a paid evidence-based medicine consultant existing studies of AED AEs for such patients report for the American Academy of Neurology. Sunovion. analysis course of medical care. acquisition of data. Impax. 2014. drafting/revising the manuscript. guideline projects. analysis or interpretation of data. 2014. or fund- Academy of Neurology.S. (4) does not mandate any particular important intellectual content. Biotie. acquisition of data. drafting/revising the manuscript. analysis or interpretation of data. serves on the editorial boards of Epilepsy & Behavior and CNS Spectrums. analysis or interpretation untary. analysis or inter. and makes no of data. Questcor. ing of. UCB. critical revision of the manuscript for question(s) specifically identified. or as a statement of tation of data. the Canadian Institutes for Health Research. and is president of the Epilepsy Study Consortium. as this type of information may help has served on speakers bureaus for UCB Pharma and GlaxoSmithKline. methods of care. LCGH. the M. and Upsher-Smith. It is important for patients to received research funding from the National Institute of Neurological Dis- appreciate how long they may need to be on an orders and Stroke and the Citizens United for Research in Epilepsy Foun- AED once it has been started and the risks of AED dation. at least one AES committee. J. Justin Martello: acquisition of disclaims any warranties of merchantability or fitness for a particular use or data. Martello report no disclosures relevant to the man- newer AEDs may have fewer and different AEs. Lundbeck. and has received royalties for Psychiatric for initial therapy are warranted and encouraged for Issues in Epilepsy.

Krumholz A. Risk of recurrence after a first unprovoked sei- mission on Epidemiology and Prognosis. and clinical definition of epilepsy.27:43–50. Efficacy.T. Jallon P. Risk of recurrence after first unprovoked tonic- wide incidence and mortality. Marson A. Jacoby A.55:475–482.S. Management of Newly Diagnosed Patients with Epilepsy: Seizure recurrence after a first unprovoked seizure. England MJ. Seizure Research Quality. mortality: long-term follow-up of a randomised clinical emy of Neurology and the Practice Committee of the Child trial. Benn EK. Epilepsia 2010. Lampl Y.1:721–726. Hauser WA. Epilepsia standing. Neurology 2007. Hauser WA. Johnson A. Risk of recur- 2. Berg AT. Bettis D. Epilepsia ing a first unprovoked seizure: a quantitative review. Neurology and the American Epilepsy Society. Arzimanoglou A. Bautista J. DC: The National Academies 1986. 30. Annegers JF.76:273–279. The risk of seizure recurrence follow- population-based clinical and survey data. 14. Medical Research Council MESS Study Group. Hesdorffer DC. Wiebe S. MN: American Study Area (MESA). et al. Krumholz A. Edmondstone WM. 2004. Leone MA. Kim L. Arch Neurol 1996. Musicco M. 2004 ed. Kurland LT. et al. FIRST Group. Rockville. Practice parameter: treat. Randomized ability of the new antiepileptic drugs I: treatment of new clinical trial on the efficacy of antiepileptic drugs in reduc. and safety of rapid remission of epilepsy. League Against Epilepsy. Newly diagnosed unprovoked after a first untreated seizure in the Hong Kong Chinese epileptic seizures: presentation at diagnosis in CORALE population. Ruggles KH. Standards Subcommittee of the American Academy of Clin Neurol Neurosurg 1992. Kho LK. Lancet 2005. Institute of Medicine (US) Committee on the Public rence of seizures following a single unprovoked idiopathic Health Dimensions of the Epilepsies. et al. First Seizure Trial American Epilepsy Society. Solari A. Berg RL. Solari A. Neu. Lal V. Clinical Practice Guide. 19. St. Engl J Med 1998.242:157–163.68: for recurrent seizure. Strawbridge LM.50:1102–1108. Recurrence 6.82:924–927. 8. Clarke C. Viani F. rology 1991.51:1970–1977. et al. Berg AT. Famulari M. First Seizure Trial Group (FIR. No. McRoberts SM. onset epilepsy: report of the Therapeutics and Technology ing the risk of relapse after a first unprovoked tonic-clonic Assessment Subcommittee and Quality Standards Subcom- seizure. Faught E. Perruca P. American Academy of Neurology. Neurology 2004. Linto J. Coordination Active du Réseau Observatoire Longi. J Neurol 1995. Efficacy and toler- 12. Early treatment of a single generalized tonic-clonic seizure 4. Cascino GD. Ramsay E. 18. Unauthorized reproduction of this article is prohibited. seizure.67:1047–1049.62:1252–1260. seizures in the elderly in the Marshfield Epidemiologic line Process Manual. How do we manage the first seizure zure recurrence. Practice param. adults (an evidence-based review): report of the Quality 21. Annegers JF. Beghi E. Hui AC. new-onset epilepsy: a randomized double-blind clinical Chadwick D. Seckin B. mittee of the American Academy of Neurology and the 13.365:2007–2013.49(suppl 1):13–18. Haessly SM. Leone MA. Shinnar S. Marson A. Prabhakar S. tolerability. et al. Kay R. Anderson VE.49(suppl 1): clonic seizure in adults. Garman A.94(suppl):S61–S63.69:1996–2007.42:1594–1599. Sarova-Pinchas I. Neurology 22. 5. Quality 7. study. Rich SS. International zure. Epilepsia 2008.67:2227–2229. Gabbay U. MD: Agency for Health 11. Epilepsia 2008. Medical Research Council MESS Study trial. initiation of topiramate versus phenytoin in patients with 15. French JA. 28. J Neurol Neurosurg Psychiatry 2011.41:342–351. Shirts SB. 1188–1196. Jacoby A. Neurology 1993. Rich SS. Mok V. Group. Epilepsia 2001. 1712 Neurology 84 April 21.307:522–528. Behgi E. Das CP.53:1149–1152. Eshel Y. Gilad R. Solari A. follow-up. FIRST Group. electroencephalography. leptic drug effects in new-onset seizures: a case control rology 1997.S. Annegers JF. Hirtz D.43:478–483. 2015 ª 2015 American Academy of Neurology. A practical life: value of clinical features. Gronseth G. Lee JR. Sadikoglu S. Epilepsia 2009. 25. 1. . Gamble C. Epilepsia 2001. Begley CE. Turan F. REFERENCES 17. Neu- 2000.41:965–972. Epilepsia 2014.42:94–97. Epilepsia 2001. Paul. 29. 2001. Academy of Neurology. First seizure 3. ment for early epilepsy and single seizures: a randomised Risk of recurrent seizures after two unprovoked seizures. Loewenson RB. Treatment of 32. Marson AG. of epilepsy in the United States: an estimate from 23. study.40:1163–1170. Sawhney IM. Loiseau J. Neurology 2006. Epilepsia 1993. Department of Health and Human recurrence after a 1st unprovoked seizure: an extended Services. U.34:592–596. 27. Group). Ogul E. Lawn ND. tudinal de l’Epilepsie. Is a of life outcomes of immediate or delayed treatment of first acute symptomatic seizure epilepsy? Mortality and risk early epilepsy and single seizures.42:464–475. Anderson VE. Beghi E.338:429–434. The cost to prevent recurrence. N Engl J A Systematic Review of the Literature (AHRQ Publication Med 1982. computerised tomographic scanning in prediction of sei. Dunne JW. et al. 2007. Group (FIRST Group). First seizure definitions and world.60:166–175. Annegers JF. 35. Anderson VE. 01-E038). 26. Agency for Healthcare Research and Quality (AHRQ). Risk of lepsy Across the Spectrum: Promoting Health and Under. 33. Guidelines for epidemiologic studies on epilepsy. Com. Livermari CT. Treatment of first tonic-clonic 31. 20. Neurology 2011. Loiseau P. Bora I. Washington. First seizure in adults: to treat or not to treat. Berg A. Hopkins A. Neurology 2003. Neurology 1990. presentation: do multiple seizures within 24 hours predict eter: evaluating an apparent unprovoked first seizure in recurrence? Neurology 2006.48:357–360. editors. Wong KS. Acevedo C. Epi. Immediate versus deferred antiepileptic drug treat. Prospective study of 9. Lancet 1988. Jacoby A. Chandra B. 16. CAPSS-272 the first tonic-clonic seizure does not affect the long-term Study Group. Gamble C. Hauser WA. The first seizure in adult 34. Neurol India 2000.49:991–998. Doughty J. Kanner AM. Press. ment of the child with a first unprovoked seizure: report of Treatment of a first tonic-clonic seizure does not affect the Quality Standards Subcommittee of the American Acad. 24. Neurology Society. 10. Fisher RS.29:289–294. recurrence after an initial unprovoked seizure. Vallalta R. Adverse antiepi- seizure does not improve the prognosis of epilepsy. Schultz AM. in adults? J R Coll Physicians Lond 1995. N controlled trial. Beghi E. Hauser WA. Chadwick D. Tang A. 2012. Hauser WA. 8–12. et al. Hauser WA. Zarifoglu M.

JAMA 2008.5:317–322. Naglie G. Neurology 84 April 21. MRC withdrawal and the implications for driving: further results MESS Study Group. Johnson TL. 82:1328–1333. 2015 1713 ª 2015 American Academy of Neurology. The next step in guideline development: 38. Bonnett LJ. Chadwick DW. Marson AG. incorporating patient preferences. Prediction of seizure recurrence after from the MRD Antiepileptic Drug Withdrawal Study and a single seizure and early epilepsy: further results from the a systematic review. Marson AG. Krahn M. Unauthorized reproduction of this article is prohibited. Tudur-Smith C. Lancet Neurol 2006. . MESS trial. Kim LG. Seizure recurrence after antiepileptic drug 37.300:436–438. Williamson PR. Shukralla A. J Neurol Neurosurg Psychiatry 2011. 36.

neurology.1705-1713 DOI 10. Neurology 2015. Published continuously since 1951. All rights reserved.DC2. can be found at: Services http://www. 2015 Updated Information & including high resolution figures.xhtml#permissions Reprints Information about ordering reprints can be found online: http://www.xhtml#reprintsus Neurology ® is the official journal of the American Academy of Neurology.org/content/84/16/1705.html http://www.html##ref-list-1 Citations This article has been cited by 2 HighWire-hosted articles: http://www.neurology.neurology.html References This article cites 35 articles.neurology.org/content/84/16/1705.org/content/suppl/2015/11/02/WNL.html##otherarticles Subspecialty Collections This article.org/misc/about.0000000000001487 This information is current as of April 20. Print ISSN: 0028-3878. et al.DC1.org//cgi/collection/all_epilepsy_seizures Permissions & Licensing Information about reproducing this article in parts (figures.full.org/content/suppl/2015/04/19/WNL. 13 of which you can access for free at: http://www.neurology. Gronseth.1212/WNL. appears in the following collection(s): All Epilepsy/Seizures http://www. . it is now a weekly with 48 issues per year.html Supplementary Material Supplementary material can be found at: http://www.neurology.0000000000 001487. Gary S.0000000000 001487.neurology. Evidence-based guideline: Management of an unprovoked first seizure in adults: Report of the Guideline Development Subcommittee of the American Academy of Neurology and the American Epilepsy Society Allan Krumholz.org/misc/addir.84.full. along with others on similar topics.full.neurology. Copyright © 2015 American Academy of Neurology.tables) or in its entirety can be found online at: http://www.org/content/84/16/1705. Online ISSN: 1526-632X. Samuel Wiebe.