EcLiPSE

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Lyttle MD. "Levetiracetam versus phenytoin for second-line treatment of paediatric convulsive status epilepticus (EcLiPSE): a multicentre, open-label, randomised trial.". Lancet. 2019. 393(10186):2125-2134.
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Clinical Question

In paediatric patients that present with status epilepticus, following first-line benzodiazepines, how does levetiracetam compare to phenytoin for second line therapy?

Bottom Line

There was no difference for second line therapy with levetiracetam compared to phenytoin and levetiracetam may have advantages such as faster infusion time and fewer adverse effects.

Major Points

If a seizure lasts longer than 5 minutes, the chances of spontaneous resolution dramatically decreases without intervention. Abortive therapy ranges from benzodiazepines to barbiturates. Second-line therapy, either as an abortive or to prevent further seizure activity, may include any number of anti-convulsants, including but not limited to phenytoin, fosphenytoin, levetriacetam, or lacosamide. Guideline recommendations have been largely based on generally small and observational trials. Phenytoin, developed in the mid-last century has been the mainstay of second line therapy for decades and thus is a reasonable benchmark for comparison, however, at baseline in this trial none of the participants were receiving phenytoin and 20% levetriacetam.

The British Emergency treatment with Levetiracetam or Phenytoin in convulsive Status Epilepticus in children (EcLiPSE) trial conducted between July 2015 and April 2018 in 30 Emergency Departments across the United Kingdom, enrolled 296 children between 3 months and 18 years old. They compared levetiracetam 40 mg/kg over 5 minutes to phenytoin 20 mg/kg over 20 minutes as second line treatment for convulsive status epilepticus. Having equal representation of sex, 45% we first presentation of seizure and the majority were generalized tonic-clonic in nature. With a primary outcome of time from randomization to cessation of seizure, there was no difference found between either treatment; a slight trend towards levetriacetam with 35 min vs. 45 min for phenytoin, P = 0.20. Secondarily there was no appreciable difference for rate of termination of status, receiving additional anticonvulsants, or intubation due to ongoing seizure activity. They also reported similar rates of adverse effects from both arms.

This trial demonstrated that intravenous levetriacetam is non-inferior to phenytoin for emergency management of status epilepticus. The trend towards faster resolution may owe to the more rapid infusion of levetriacetam as compared to phenytoin. There are several challenges with the trial, including that the trial was not powered for safety outcomes so any adverse effects would be found by chance, this was conducted as an open-label / unblinded study due to logistical challenges, and the primary outcome was determined by the treating physician, not by EEG or video-taped assessment, which may have introduced some bias.

Guidelines

Guidelines for Treating Convulsive Status Epilepticus by the American Epilepsy Society, 2016[1], adapted

Second line options, none preferred over another:

  • IV fosphenytoin 20 mg PE/kg, MAX 1500mg PE/dose
  • IV valproic acid 40 mg/kg, MAX 3000mg/dose
  • IV levetriacetam 60mg/kg, MAX 4500mg/dose

Design

  • Multicenter, open-lable, randomized, controlled trial
  • N=296
    • Levetiracetam (n=152)
    • Phenytoin (n=134)
  • Setting: 30 Emergency Departments in the UK
  • Enrollment: 17 July 2015 to 7 April 2018
  • Analysis: modified Intention-to-Treat
  • Primary Outcome: time from randomization to cessation of seizure

Population

Inclusion Criteria

  • age 6 months to 18 years
  • presenting with convulsive status epilepticus (generalised tonic-clonic, generalized clonic, or focal clonic seizure) requiring second line therapy

Exclusion Criteria

  • presented with absence, myoclonic, or non-convulsive status epilepticus, or infantile spasms
  • known or suspected to be pregnant
  • Contraindication or allergy to study drugs
  • established renal failure
  • received a second-line anticonvulsant during the presenting episode of convulsive status epilepticus before screening
  • previously enrolled in the trial

Baseline Characteristics

Levetiracetam Group displayed

  • Demographics: 51% female, 45% first seizure at presentation
  • Age: 43% 6months-2years, 53% 2-11years, 4% 12-17years
  • Weight: 34% <12 kg, 57% 12-36 kg,
  • Seizure type: 70% generalized tonic-clonic, 8% generalized clonic, 22% focal clonic
  • Seizure cause: 41% febrile, 30% pre-existing seizure disorder, 4% CNS infection, 7% indeterminate, 18% other
  • Maintenance medications at presentation: levetiracetam 19%, valproate 11%, carbamazepine 8%, clobazam 6%, topiramate 3%, phenytoin 0%, other 7%

Interventions

  • Levetiracetam 40 mg/kg over 5 minutes (maximum 2500mg)
  • Phenytoin 20 mg/kg over 20 minutes (maximum 2000mg)

Outcomes

Comparisons are levetiracetam vs. phenytoin.

Primary Outcomes

Time from randomization to seizure cessation, median
35 min vs. 45 min (HR 1.2, 95% CI 0.91-1.60) P = 0.20

Secondary Outcomes

Termination of status-epilepticus
70% vs. 64%
Time to initiation of study drug infusion
11 min vs. 12 min
Receipt of additional anticonvulsants
38% vs. 37% (RR 1.01, 95% CI 0.74-1.36) P = 0.97
Patients receiving Rapid Sequence Intubation (RSI) due to ongoing seizure activity
29% vs. 35% (RR 0.83, 95% CI 0.59–1.16) P = 0.27

Adverse Events

Any adverse event
11% vs. 13%

Criticisms

  • unblinded, open-label
  • Primary outcome determined by treating physician
  • Trial was not powered for safety outcomes, rates were varied in both arms

Funding

  • National Institute for Health Research Health Technology Assessment programme, project grant 12/127/134

Further Reading

  1. Glauser T et al. Evidence-Based Guideline: Treatment of Convulsive Status Epilepticus in Children and Adults: Report of the Guideline Committee of the American Epilepsy Society. Epilepsy Curr 2016. 16:48-61.