Abstracted data included trial methods, participant characteristics, intervention types, and outcomes. Two review authors independently assessed all included studies for risk of bias and resolved any disagreements by discussion. The quality of the evidence was classified into 4 categories according to the Grading of Recommendations Assessment, Development, and Evaluation approach.Dichotomous outcomes were expressed as risk ratios with 95% confidence intervals. Time-to-event outcomes were expressed as hazard ratios with 95% confidence interval. Clinical heterogeneity was assessed by reviewing the differences in participant characteristics across trials, and statistical heterogeneity was assessed with the χtest. When substantial heterogeneity was identified (I>50%), a random-effects model was used rather than a fixed-effects one. Individual participant data were available for only 2 studies and were used for the time-to-event analysis, whereas both individual participant data and aggregate published data were used for all other analyses.

Randomized controlled trials and quasi–randomized controlled trials that could be blinded or unblinded were independently screened by 2 authors. Studies included people of any age with a first unprovoked seizure of any type (partial, generalized, or unclassified). The included studies compared participants receiving immediate initiation (ie, within one week of seizure) of antiepileptic treatment versus those receiving deferred treatment, those assigned to placebo, and those who were untreated. Any disagreements were resolved by discussion with a third author.

Cochrane Epilepsy Group Specialized Register, Cochrane Central Register of Controlled Trials, PubMed, MEDLINE, EMBASE, clinicaltrials.gov , and the WHO International Clinical Trials Registry Platform were searched without language restrictions through October 13, 2015. Manual searches of the reference lists of the included articles were also performed.

Immediate initiation of antiepileptic drug treatment after an unprovoked first-time seizure may decrease the rate of recurrent seizure, but does not otherwise affect long-term prognosis and is associated with adverse events.

The search identified 568 articles, of which 6 met the inclusion criteria and were included in this systematic review. The 6 studies included 1,634 participants, composed of 676 women (41.4%) and 958 men (58.6%). Two studies recruited only adults, one recruited only children, and the remaining 3 recruited both adults and children. Three studies included only generalized tonic-clonic seizures, whereas the others included both generalized and partial seizures. Among the control groups, 2 studies (n=606) involved delayed treatment, one study (n=113) used a placebo, and 3 studies provided no treatment (n=99). Five studies reported adverse events. Only one study was double blinded; however, the majority of studies were determined to be at low or unclear risk of bias for the remaining components of the Cochrane risk assessment tool. Immediate antiepileptic drug treatment was associated with a reduced risk of seizure recurrence at 1 and 5 years after study enrollment ( Table ). However, another metric for assessing long-term outcome and prognosis is the seizure remission rate,which refers to a period (typically, 2 to 5 years) during which the individual remains seizure free. In this systematic review, there was no significant difference in either the 2- or 5-year remission rate. Therefore, although there was a decrease in the rate of subsequent seizures occurring in the treatment group after enrollment, there was no difference in the subsequent rates of seizure-free periods whether they received initial or delayed treatment. There was also no significant difference in mortality between the treated and untreated groups (risk ratio 1.16; 95% confidence interval 0.69 to 1.95). There was an increased risk of minor adverse events in the treatment groups, commonly reported as drowsiness, gastrointestinal symptoms, depression, anxiety, dizziness, and headaches.

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.

Commentary

3 Hauser W.A.

Beghi E. First seizure definitions and worldwide incidence and mortality. 4 Berg A.T.

Shinnar S. The risk of seizure recurrence following a first unprovoked seizure: a quantitative review. 5 Hauser W.A.

Rich S.S.

Lee J.R.

et al. Risk of recurrent seizures after two unprovoked seizures. 2 Krumholz A.

Wiebe S.

Gronseth G.S.

et al. 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. 2 Krumholz A.

Wiebe S.

Gronseth G.S.

et al. 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. 2 Krumholz A.

Wiebe S.

Gronseth G.S.

et al. 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. , 6 Huff J.S.

Melnick E.R.

Tomaszewski C.A.

et al. American College of Emergency Physicians

Clinical policy: critical issues in the evaluation and management of adult patients presenting to the emergency department with seizures. Seizures are a common presentation to the emergency department (ED), with an estimated 150,000 adults presenting annually with an unprovoked first seizure in the United States.The risk of recurrence after a single episode has been estimated to be approximately 50%and increases to 73% after 2 seizures and 76% after 3 seizures.Abnormal electroencephalographic result with epileptiform activity, previous brain insult, abnormality on brain imaging, and nocturnal seizures are all associated with increased risks of recurrence.There is general agreement that antiepileptic drug treatment should be offered after a second seizure.However, there has been controversy in regard to the initiation of antiepileptic drugs after a first episode.

This systematic review demonstrated a reduction in the rate of recurrent seizures at both 1 and 5 years, with a smaller difference noted over time. However, there was no significant effect on overall prognosis of patients with seizures, as demonstrated by similar recurrence rates at both 2 and 5 years between those receiving immediate and delayed antiepileptic drugs. Additionally, there was a significantly increased rate of adverse effects among patients receiving immediate treatment, which needs to be balanced against the potential benefit. Therefore, it is important to discuss the risks of recurrence and adverse events with patients when considering initiation of an antiepileptic drug after an unprovoked first seizure. The decision to initiate antiepileptic drugs should be based on assessments of the risk of seizure recurrence, potential adverse effects, and patient preference.

7 Marson A.

Jacoby A.

Johnson A.

et al. Medical Research Council MESS Study Group

Immediate versus deferred antiepileptic drug treatment for early epilepsy and single seizures: a randomised controlled trial. The primary studies included in the meta-analysis had several limitations. Only one of the included studies was double blinded, whereas the remainder (including the 2 largest) were open, randomized, controlled trials. The control groups of these 2 larger contributors of data consisted of delayed treatment. The 4 other studies using either placebo or no treatment had small sample sizes and short follow-up periods, so it is still unclear how immediate treatment would compare with no treatment. There was also substantial statistical and clinical heterogeneity, with differences in control groups (ie, delayed treatment, placebo, or no treatment), populations (ie, adults, children, or both), and exclusion criteria. Additionally, despite referring to the treatment as “immediate,” none of these studies prescribed the antiepileptic drug or comparison in the ED setting; most initiated the intervention in an epilepsy clinic, and some did not clearly define the time to initiation in the immediate group. Moreover, in the largest trial,nearly half of all included patients presented with a history of more than one seizure, which many would consider to warrant antiepileptic drug initiation. The included articles studied only first-generation antiepileptic drugs (eg, carbamazepine, lamotrigine, phenobarbital, phenytoin, valproate), so it is unclear whether results would differ with newer-generation antiepileptic drugs. There was not a standardized checklist for adverse events, so it is possible that some were missed. Additionally, rare adverse events with high morbidity and mortality (eg, drug rash with eosinophilia and systemic symptoms syndrome, Stevens-Johnson’s syndrome) may have been missed, given their low incidence. Finally, it is important to consider the potential for drug-drug interactions, especially among the elderly, and also consider issues such as potential fetal risks among patients who become pregnant.

Future studies should determine which patient subgroups may be most likely to benefit from immediate antiepileptic drug treatment after an unprovoked first seizure, provide more precise definitions with respect to the timing of “immediate” initiation of antiepileptic drug, and determine whether newer antiepileptic drugs provide similar reductions in recurrence with decreased incidence of adverse effects.