Background
Antiepileptic drug treatment following a first seizure still remains a controversial issue. In this review, we summarised evidence about the effects of immediate treatment with antiepileptic drugs compared to control (placebo [an inactive dummy treatment], deferred or no treatment) on seizure recurrence, seizure remission, side effects and mortality (death).
The evidence is current to May 2019.
Methods
Our literature search found six studies (eleven reports) that included children, adults, or both, with a first unprovoked seizure of any type (focal, generalised or unclassified). They compared antiepileptic treatment given immediately after the first seizure versus deferred (delayed) treatment, placebo or no treatment. Some of the studies did not clearly describe their methods, or how many people dropped out of the study. In five out of the six studies, the participants, clinicians and researchers involved in the studies knew which groups participants were in (immediate or delayed treatment). However, as most seizure recurrences were generalised tonic-clonic seizures, a convulsive type of seizures that is easily recognisable, we do not think that knowing which group the participants were in influenced the results.
Results
Compared to controls, participants randomised to immediate treatment had a lower probability of seizure recurrence at one year and at five years (high-certainty evidence), although there was no difference between immediate treatment and control in terms of five-year remission at any time.
Immediate treatment did not contribute to the overall mortality of epilepsy after the first seizure (high-certainty evidence), but treatment of the first seizure was associated with a significantly higher risk of adverse events. The certainty of the evidence for side effects was moderate to low with variable reporting of the outcome in the included studies; there was moderate-certainty evidence that immediate treatment may result in more side effects than delayed treatment, but it was unclear if immediate treatment results in more side effects than placebo or no treatment.
Conclusions
In conclusion, treatment of the first unprovoked seizure seems to reduce the risk of relapse but does not affect the long-term prognosis of epilepsy. However, treatment seems to carry a higher risk of side effects. The decision to treat a first unprovoked seizure should be individualised and based on clinical, legal, and sociocultural factors.
Treatment of the first unprovoked seizure reduces the risk of a subsequent seizure but does not affect the proportion of patients in remission in the long term. Antiepileptic drugs are associated with adverse events, and there is no evidence that they reduce mortality. In light of this review, the decision to start antiepileptic drug treatment following a first unprovoked seizure should be individualised and based on patient preference, clinical, legal, and sociocultural factors.
This is an updated version of the Cochrane review previously published in 2016.
There is considerable disagreement about the risk of recurrence following a first unprovoked epileptic seizure. A decision about whether to start antiepileptic drug treatment following a first seizure should be informed by information on the size of any reduction in risk of future seizures, the impact on long-term seizure remission, and the risk of adverse effects.
To review the probability of seizure recurrence, seizure remission, mortality, and adverse effects of antiepileptic drug (AED) treatment given immediately after the first seizure compared to controls (placebo, deferred treatment, or no treatment) in children and adults.
For the latest update, we searched the Cochrane Register of Studies (CRS Web) and MEDLINE (Ovid, 1946 to May 24, 2019) on 28 May 2019. There were no language restrictions. The Cochrane Register of Studies includes the Cochrane Epilepsy Group Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), and randomised or quasi-randomised, controlled trials from Embase, ClinicalTrials.gov and the World Health Organisation International Clinical Trials Registry Platform (ICTRP).
Randomised controlled trials (RCTs) and quasi-RCTs that could be blinded or unblinded. People of any age with a first unprovoked seizure of any type. Included studies compared participants receiving immediate antiepileptic treatment versus those receiving deferred treatment, those assigned to placebo, and those untreated.
Two review authors independently assessed the studies identified by the search strategy for inclusion in the review and extracted data. The certainty of the evidence for the outcomes was classified in four categories according to the GRADE approach. Dichotomous outcomes were expressed as Risk Ratios (RR) with 95% confidence intervals (CI). Time-to-event outcomes were expressed as Hazard Ratios (HR) with 95% CI. Only one trial used a double-blind design, and the two largest studies were unblinded. Most of the recurrences were generalised tonic-clonic seizures, a major type of seizures that is easily recognised, which should reduce the risk of outcome reporting bias.
After exclusion of irrelevant papers, six studies (eleven reports) were selected for inclusion. Individual participant data were available from the two largest studies for meta-analysis.
Selection bias and attrition bias could not be excluded within the four smaller studies, but the two largest studies reported attrition rates and adequate methods of randomisation and allocation concealment. Only one small trial used a double-blind design and the other trials were unblinded; however, most of the recurrences were generalised tonic-clonic seizures, a type of seizure that is easily recognisable.
Compared to controls, participants randomised to immediate treatment had a lower probability of relapse at one year (RR 0.49, 95% CI 0.42 to 0.58; 6 studies, 1634 participants; high-certainty evidence), at five years (RR 0.78; 95% CI 0.68 to 0.89; 2 studies, 1212 participants; high-certainty evidence) and a higher probability of an immediate five-year remission (RR 1.25; 95% CI 1.02 to 1.54; 2 studies, 1212 participants; high-certainty evidence). However, there was no difference between immediate treatment and control in terms of five-year remission at any time (RR 1.02, 95% CI 0.87 to 1.21; 2 studies, 1212 participants; high-certainty evidence). Antiepileptic drugs did not affect overall mortality after a first seizure (RR 1.16; 95% CI 0.69 to 1.95; 2 studies, 1212 participants; high-certainty evidence). Compared to deferred treatment, treatment of the first seizure was associated with a significantly higher risk of adverse events (RR 1.49, 95% CI 1.23 to 1.79; 2 studies, 1212 participants; moderate-certainty evidence). We assessed the certainty of the evidence as moderate to low for the association of higher risk of adverse events when treatment of the first seizure was compared to no treatment or placebo, (RR 14.50, 95% CI 1.93 to 108.76; 1 study; 118 participants) and (RR 4.91, 95% CI 1.10 to 21.93; 1 study, 228 participants) respectively.