Immediate antiepileptic drug treatment, versus placebo, deferred, or no treatment for first unprovoked seizure

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 on seizure recurrence, seizure remission, side effects and mortality (death). The evidence is current to 13 October 2015.

Methods

Our literature search found six studies (nine reports) that included children, adults, or both, with a first unprovoked seizure of any type (partial, generalised or unclassified). They compared antiepileptic treatment given immediately after the first seizure versus deferred (delayed) treatment, placebo or no treatment.

Results

Compared to controls, participants randomised to immediate treatment had a lower probability of seizure recurrence at one year and at five years (high quality evidence) and a higher probability of five-year remission of seizures (high quality evidence).

Immediate treatment did not contribute to the overall mortality of epilepsy after the first seizure (high quality evidence), but treatment of the first seizure was associated with a significantly higher risk of adverse events. The quality of the evidence for side effects was moderate to low with variable reporting of the outcome in the included studies; there is moderate quality evidence that immediate treatment may result in more side effects than delayed treatment, but it is 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 individualized and based on clinical, legal, and socio-cultural factors.

Authors' conclusions: 

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 individualized and based on patient preference, clinical, legal, and socio-cultural factors.

Read the full abstract...
Background: 

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.

Objectives: 

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, in children and adults.

Search strategy: 

We searched the following databases: Cochrane Epilepsy Group Specialized Register (accessed 13 October 2015), Cochrane Central Register of Controlled Trials (The Cochrane Library September 2015, issue 9, accessed 13 October 2015), PUBMED (accessed 22 April 2015), MEDLINE (Ovid, 1946 to 13 October 2015), EMBASE (accessed 22 April 2015), ClinicalTrials.gov (accessed 15 October 2015), and the WHO International Clinical Trials Registry Platform (ICTRP, accessed 13 October 2015). There were no language restrictions.

Selection criteria: 

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.

Data collection and analysis: 

Two review authors independently assessed the studies identified by the search strategy for inclusion in the review and extracted data. The quality of the evidence 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 generalized tonic-clonic seizures, a major type of seizures that is easily recognised, which should reduce the risk of outcome reporting bias.

Main results: 

After exclusion of uninformative papers, only six studies (nine reports) were selected for inclusion. For the two largest studies data were available for individual participant meta-analysis. 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, high quality evidence), at five years (RR 0.78; 95% CI 0.68 to 0.89; high quality evidence) and a higher probability of an immediate five-year remission (RR 1.25; 95% CI 1.02 to 1.54, high quality 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, high quality evidence). Antiepileptic drugs did not affect overall mortality after a first seizure (RR 1.16; 95% CI 0.69 to 1.95, high quality evidence). Compared to deferred treatment (RR 1.49, 95% CI 1.23 to 1.79, moderate quality evidence), treatment of the first seizure was associated with a significantly higher risk of adverse events. Moderate to low quality imprecise evidence was available for the association of treatment of the first seizure compared to no treatment or placebo (RR 14.50, 95% CI 1.93 to 108.76) and(RR 4.91, 95% CI 1.10 to 21.93) respectively)