Article In Brief
Results of a new study suggest that levetiracetam could be considered as an alternative therapy to phenytoin for second-line management of pediatric convulsive status epilepticus.
Two new randomized studies have answered a longstanding clinical question: Is levetiracetam (Keppra) superior to phenytoin (Dilantin) for second-line management of convulsive status epilepticus (CSE)? The results indicate that either drug can stop prolonged seizures in at least 50 percent of children.
These are the first robust randomized clinical trials to compare the efficacy and safety of two anti-convulsant medications in the second-line management of CSE, both published in the April 17 online edition of TheLancet.
“This provides new and unique scientifically-robust data to better inform pediatricians on how to improve their management of CSE in children. Specifically, it shows that both levetiracetam and phenytoin could be used as a first-choice anticonvulsant in the second-stage of pediatric CSE,” lead investigator Richard Appleton, MD, professor of pediatric neurology at Alder Hey Children's Health Park in Liverpool, England, told Neurology Today in an email.
Dr. Appleton led the Emergency treatment with Levetiracetam or Phenytoin in convulsive Status Epilepticus in children (EcLiPSE) trial in the United Kingdom.
In addition, administering each drug sequentially rather than alone reduced the failure rate by more than 50 percent in the second randomized trial—Convulsive Status Epilepticus Paediatric Trial (ConSEPT)—adding only an additional 10 minutes to the treatment time, according to ConSEPT lead investigator Stuart R. Dalziel, MBChB, FRACP, PhD, a pediatric emergency medicine specialist at Starship Children's Hospital in Auckland, New Zealand, who led the ConSEPT in Australia and New Zealand.
Researchers conducted open-label randomized clinical trials involving 13 emergency departments in Australia and New Zealand and 30 emergency departments in the United Kingdom. Children who had failed benzodiazepine treatment were randomly assigned to receive either phenytoin or levetiracetam.
The ConSEPT trial enrolled 239 children with a mean age of 4 years old between March 2015 and November 2017 and the EcLiPSE trial enrolled 404 children with a mean age of 2.7 years between July 2015 and April 2018, with 286 final participants. The number of girls and boys in both trials were nearly equal.
The children were treated intravenously with either levetiracetam over five minutes with 40 mg/kg or phenytoin at 20mg/kg for at least 20 minutes.
The primary outcome measures for EcLIPSE were the time from randomization to seizure cessation and the proportion of children whose seizures stopped five minutes after the first trial drug infusion was completed (for ConSEPT), which was 10 minutes after starting levetiracetam and 25 minutes after starting phenytoin.
Both trials reported that levetiracetam was not more effective than phenytoin nor safer. In ConSEPT, once the study drug infusion started, seizures stopped in 60 percent of 114 children randomly assigned to phenytoin and 50 percent of 119 children randomly assigned to levetiracetam.
“In more than 70 percent of cases, seizure control was maintained for two hours with use of either drug alone or both drugs sequentially. We found no differences between treatment groups in intubation rates, rate and length of intensive care unit admission, hospital length of stay, or safety outcomes,” Dr. Dalziel stated in the paper, who was unavailable for comment.
In the EcLiPSE trial, the seizures stopped in 70 percent of 152 children receiving levetiracetam and 64 percent of 134 children receiving phenytoin. The median time from randomization to CSE cessation was 35 minutes in the levetiracetam group and 45 minutes in the phenytoin group (hazard ratio 1.20, 95% CI 0.91-1.60; p=0.20), according to the published paper.
The main limitations of each study were the open-label and unblinded design, which may have introduced bias. “Realistically it would have been very difficult to conduct our study using a blinded design in view of the different anticonvulsant infusion rates,” said Dr. Appleton.
He and his colleagues also discovered that the vast majority of families and patients in emergency pediatric settings were willing to defer informed consent to participate in the trial. “This is very encouraging for future researchers who wish to undertake studies and trials in a pediatric emergency setting.”
To improve CSE outcomes, future research should focus on reducing its frequency and the time it takes to implement effective anticonvulsant use, which would lead to shorter duration and fewer potential complications, suggested Dr. Appleton.
Independent experts told Neurology Today that the two studies were well designed and filled an important gap in CSE comparative effectiveness research.
“These studies provide good evidence from open-label randomized trials to help clinicians decide on the second agent to use for CSE in children,” said Phillip L. Pearl, MD, FAAN, director of epilepsy and clinical neurophysiology at Boston Children's Hospital and professor of neurology at Harvard Medical School.
Most hospitals in the US use fosphenytoin (Cerebyx) instead of phenytoin for second line CSE management, which, despite its higher cost, has several advantages including more rapid administration and a lower potential for local tissue and cardiac toxicity, according to Dr. Pearl.
However, for hospitals in other countries that still use phenytoin, “levetiracetam emerges as a particularly appropriate alternative due to its better safety profile. Also, as the ConSEPT study showed, both drugs can be used sequentially to obtain a 50 percent better outcome in seizure cessation rates. An additional 10 minutes to administer a dose of the alternative second-line agent is worth it for that improvement and to avoid the greater morbidity associated with more aggressive treatment such as rapid sequence induction, intubation or ICU admission,” said Dr. Pearl.
Based on the findings, Dr. Pearl said he would be more inclined to try fosphenytoin or levetiracetam and then switch if the first drug didn't work, before trying a different class of drug such as phenobarbital or valproate, which is the current practice at Boston Children's Hospital before rapid sequence induction.
“Ideally, all these drugs would be given within the 30-minute window of seizure onset used to establish status epilepticus,” said Dr. Pearl.
Many hospital status epilepticus protocols recommend using levetiracetam before fosphenytoin/phenytoin because of its many advantages including ease of preparation, rapid infusion time, limited drug interactions, and possibly fewer side effects such as cardiac arrythmias and extravasation burns associated with fosphenytoin/phenytoin, said Eric T. Payne, MD, MPH, assistant professor of pediatrics and neurology at Mayo Clinic Children's Center in Rochester MN.
In addition, some hospitals including Mayo Clinic, use higher doses than the 40 mg/kg of levetiracetam given in the two studies.
“Following benzodiazepines, our second line status epilepticus treatment starts with a bolus of 50 mg/kg, while some hospitals start with a dose between 60 and 80 mg/kg. This raises the question of whether the two studies had used higher doses of the drug, levetiracetam would have been more effective than phenytoin,” said Dr. Payne.
He said he preferred the primary outcome measurement as time to seizure cessation used in the EcLiPSE study, noting that many children in the phenytoin group were still seizing 20 minutes after the drug was given, and that a delay of even 10 minutes can have neurological implications. “Because of the 15-minute increased duration with phenytoin, even if the drug worked, the patient may continue to seize,” said Dr. Payne.
Another challenge is obtaining rapid EEG monitoring. Dr. Payne referred to data from the Pediatric Status Epilepticus Research Group, of which he is a member, showing that one-third of children with CSE will continue to experience electrographic seizures. “Since many lack any clinical signs, EEG monitoring is needed for their detection, but difficult to obtain.”
Other studies are looking beyond phenytoin and levetiracetam for second-line management of CSE in children and adults. A new recently completed study compared levetiracetam, phenytoin and valproate. “It's possible that valproate or another drug will perform even better,” said Dr. Payne.
Drs. Appleton, Payne, and Pearl reported no disclosures.