SGEM#265: Total EcLiPSE of the Seizure – What a ConSEPT - The Skeptics Guide to Emergency Medicine

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Date: September 5th, 2019

Reference: Dalziel et al. Levetiracetam versus phenytoin for second-line treatment of convulsive status epilepticus in children (ConSEPT): an open-label, multicentre, randomised controlled trial. The Lancet May 2019

Guest Skeptic: Dr. Tessa Davis is a Paediatrician specializing in Paediatric Emergency Medicine and currently practicing at the Royal London Hospitals. She is also the co-founder of Don’t Forget the Bubbles and on the FeminEM Speaker Bureau.

Case: Julia is a 4-year-old girl with a history of seizures and developmental delay. She presents the emergency department with another seizure for more than five minutes and has not been aborted with two doses of midazolam intramuscularly.You know the guidelines recommend phenytoin as a second line agent, but the junior doctor asks you if levetiracetam would work faster with less side effects.

Background: Convulsive status epilepticus can be defined as a single seizure lasting greater than 20 to 30 minutes, or recurrent shorter seizures without recovery of consciousness between seizures.

Status epilepticus is a common paediatric emergency with significant consequences for the patients. Our focus on management of status is to stop the seizures quickly to avoid any complications.

Guidelines recommend benzodiazepines as the first line treatment, and we have plenty of evidence to back this up. Most guidelines recommend phenytoin or fosphenytoin as a second-line treatment, but the evidence base for its use is much weaker.

CPS – Emergency management of the paediatric patient with generalized convulsive status epilepticus
APLS – Advanced Life Support Group. Advanced paediatric life support: a practical approach to emergencies, 6th edn. Hoboken: Wiley-Blackwell, 2016.
NICE – Epilepsies: diagnosis and management. London: National Institute for Health and Care Excellence, 2012.
AES – Glauser T, Shinnar S, Gloss D, 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

Phenytoin is linked to many adverse events including liver damage, Steven-Johnson syndrome, extravastion, pancytopenia, hypotension, arrhythmias, and death due to dosing errors.

Levetiracetam is an alternative to phenytoin for second line treatment of convulsive status epilepticus. It can be given more quickly, is more compatible with intravenous fluids, has less drug interactions, and has a lower risk of adverse events.

Although small studies suggest that levetiracetam is effective, there have been no comparison studies until now.

Clinical Question: Is levetiracetam superior to phenytoin as a second-line treatment for convulsive status epilepticus in children?

Reference: Dalziel et al. Levetiracetam versus phenytoin for second-line treatment of convulsive status epilepticus in children (ConSEPT): an open-label, multicentre, randomised controlled trial. The Lancet May 2019

Population: Children aged three months to 16 years of age presenting to 13 emergency departments in Australia and New Zealand in status epilepticus. Convulsive status epilepticus was defined as having a seizure for more than five minutes or two or more recurrent seizures without recovery of consciousness between seizures. Or three or more seizures within the preceding hour and a current seizure. They also had to have received two doses of benzodiazepines.
- Exclusions: Being on regular phenytoin or levetiracetam; having already had a second-line treatment; known to be refractory to the medication; allergy; seizures secondary to a head injury; or seizure due to eclampsia in late pregnancy.
Intervention: Levetiracetam 40mg/kg (max 3g) IV or IO over five minutes.
- Five minutes after the infusion finished, patients were assessed to see if the seizures had stopped. If the patient was still convulsing, then the other drug was given.
Comparison: Phenytoin 20mg/kg (max 1g) IV or IO over 20 minutes.
Outcome:
- Primary Outcome: Seizure cessation five minutes after the drug infusion
- Secondary Outcomes: Time to cessation of seizures; the need for other medications/interventions; adverse events; ICU admissions; airways complications; arrhythmias; length of hospital stay; or seizure status up to two months later.
- Adverse Reactions: Death, Stevens-Johnson syndrome, rash, airway complications, cardiovascular instability, extravasation injury, and extreme agitation, as well as those listed in the summary product characteristic of each treatment.

Authors’ Conclusions: “Levetiracetam is not superior to phenytoin as a second line agent for convulsive status epilepticus.”

Quality Checklist for Randomized Clinical Trials:

The study population included or focused on those in the emergency department. Yes
The patients were adequately randomized. Yes
The randomization process was concealed. Yes
The patients were analyzed in the groups to which they were randomized (ITT). Yes
The study patients were recruited consecutively (i.e. no selection bias). Unsure
The patients in both groups were similar with respect to prognostic factors. Yes
All participants (patients, clinicians, outcome assessors) were unaware of group allocation. No
All groups were treated equally except for the intervention. Yes
Follow-up was complete (i.e. at least 80% for both groups). Yes
All patient-important outcomes were considered. Unsure
The treatment effect was large enough and precise enough to be clinically significant. No

Key Results: There were 233 children identified, who met eligibility criteria and consented for this trial out of 639 and who presented to participating EDs with convulsive status epilepticus. Of those enrolled, 114 assigned to phenytoin and 119 assigned to levetiracetam. The mean age was four years of age with close to ¾ presenting febrile.

Levetiracetam was found not to be superior to phenytoin.

Primary Outcome: Cessation of seizures five minutes post the infusion
- 60% in the phenytoin group vs. 50% in the levetiracetam group
- Risk difference –9·2% [95% CI –21·9 to 3·5]; p=0·16)
Secondary Outcomes: There was no statistical difference in number needed to be intubated, other drug used in less than two hours, seizure stopping within two hours, intensive care unit admissions, intensive care unit length of stay or hospital length of stay.

Adverse Events: No statistical differences in adverse events between the two groups was observed. One child died 27 days later but this was not thought to be due to the study drug.

Reference: Lytte et al. Levetiracetam versus phenytoin for second-line treatment of paediatric convulsive status epilepticus (EcLiPSE): A multicentre, open-label, randomised trial. The Lancet May 2019

Population: Children aged six months to 18 years of age presenting to 30 emergency departments in UK with convulsive status epilepticus. This was defined as generalized tonic-clonic, generalized clonic or focal clonic seizure). Participants also had to have received two doses of benzodiazepines.
- Exclusions: “Patients with absence, myoclonic, or non-convulsive status epilepticus, or infantile spasms; were known or suspected to be pregnant; had a contraindication or allergy to levetiracetam or phenytoin; had established renal failure; had received a second-line anticonvulsant during the presenting episode of convulsive status epilepticus, before screening; or were known to have been previously enrolled in the EcLiPSE trial.”
Intervention: Levetiracetam 40mg/kg (max 2.5g) IV or IO over 5 minutes.
Comparison: Phenytoin 20mg/kg (max 2g) IV or IO over 20 minutes.
Outcome:
- Primary Outcome: Time to seizure cessation (all visible signs of convulsive activity, defined as cessation of all continuous rhythmic clonic activity, as judged by the treating clinician)
- Secondary Outcomes: Need for other medications, rapid sequence intubation or ICU admissions.
- Serious Adverse Events: These were defined as death, Stevens-Johnson syndrome, rash, airway complications, cardiovascular instability, extravasation injury, and extreme agitation, as well as those listed in the summary product characteristic of each treatment.

Authors’ Conclusions: “Although levetiracetam was not significantly superior to phenytoin, the results, together with previously reported safety profiles and comparative ease of administration of levetiracetam, suggest it could be an appropriate alternative to phenytoin as the first-choice, second-line anticonvulsant in the treatment of paediatric convulsive status epilepticus.”

Quality Checklist for Randomized Clinical Trials:

The study population included or focused on those in the emergency department. Yes
The patients were adequately randomized. Yes
The randomization process was concealed. Yes
The patients were analyzed in the groups to which they were randomized (ITT). No
The study patients were recruited consecutively (i.e. no selection bias). Unsure
The patients in both groups were similar with respect to prognostic factors. Yes
All participants (patients, clinicians, outcome assessors) were unaware of group allocation. No
All groups were treated equally except for the intervention. Yes
Follow-up was complete (i.e. at least 80% for both groups). Yes
All patient-important outcomes were considered. Unsure
The treatment effect was large enough and precise enough to be clinically significant. No

Key Results: There were 286 patients included in the modified intention-to-treat analysis. The median age was 2.7 years, about ¾ presented with a generalized tonic-clonic seizure and 1/3 had pre-existing epilepsy. Convulsive status epilepticus was terminated in 70% of patients receiving levetiracetam and 64% of patients receiving phenytoin.

Levetiracetam was not superior in seizure cessation compared to phenytoin.

Primary Outcome: Median time from randomization to seizure cessation
- 35 minutes levetiracetam vs. 45 minutes phenytoin (log-rank test p=0.20)
Secondary Outcomes: There was no statistically significant differences were observed between phenytoin and levetiracetam.

There were five serious adverse events recorded in the trial. Three were in two patients receiving phenytoin, one in a patient receiving levetiracetam, and one in a patient who received both medications.

1) Selection Bias: It is possible that there was selection bias in ConSEPT. This is because they missed 127 children who presented to the ED with convulsive status epilepticus. Why were these children missed? In addition, they used opaque sealed envelopes rather than a computer-based system that assigned group allocation. Both of these could have introduced selection bias into the trial.

EcLiPSE could have also had some selection bias. There were 53 patients eligible but not randomly allocated. The reasons for not randomizing these children were included no trial-trained doctor available, loss of or failure to achieve intravenous access, clinical judgment, and treatment given before random assignment.

2) Lack of Blinding: ConSEPT and EcLiPSE physicians, research nurses and investigators were not masked to treatment assignment. This could have introduced bias into the study.

3) Outcome Assessment ConSEPT: The primary outcome was 5 minutes after the infusion. This would have been 25 minutes for phenytoin and 10 minutes in the levetiracetam group. Would this 15 minute difference in time have an impact on the results? Seizures tend to stop over time. Both groups already had two doses of benzodiazepines prior to enrolment. This bias should have favoured the control (phenytoin group). This makes me wonder if there would have been a difference or superiority to levetiracetam? However, there was no statistical difference in the number of patients whose seizure stopped in under two hours.

4) DOO vs. POO: Does any difference in time to termination of seizure activity have a clinically important impact? In ConSEPT, the median time to termination of seizure activity was 22 minutes for phenytoin vs. 17 minutes for levetiracetam. In EcLiPSE the difference was 10 minutes (35 minutes vs. 45 minutes). None of these time differences were statistically different, but would this disease-oriented outcome translate into a patient-oriented outcome?

5) Subjective Outcome: Clinicians decided in both trials if the seizure activity had stopped. While this is pragmatic it is also subjective. It would have been more objective to have EEGs to confirm termination of seizure activity.

6) Observer Bias: This can be defined as the tendency for the researcher to see what they expect to see or what they want to see. It is also called experimental bias or research bias. In this case, the researchers may have had a conscious or unconscious bias towards the efficacy of the intervention (levetiracetam). They attempted to minimize this by recording, if possible, the primary outcome assessment. This was reviewed by two emergency physicians and one neurologist who were blinded to group allocation. While this is an interesting way to address observer bias, only 2/3 of the cases were recorded.

7) Seizure Cessation Rates: Previous retrospective data had suggested a seizure cessation rate of 60% with phenytoin and both ConSEPT and EcLiPSE confirmed this number. In contrast, seizure cessation rate was expected to be 80% with levetiracetam based on previous retrospective studies. The rate observed in ConSEPT was only 50% and 70% in EcLiPSE. Why was the efficacy of levetiracetam less than expected? Is this because of the bias in the literature that new drugs seem more efficacious, but the magnitude of effect seems to decrease over time?

8) ITT Analysis vs. PP Analysis: Intention-to-treat (ITT) is preferred method of analysis in superiority trials because it is more conservative. Per-protocol (PP) analysis can bias the results towards the intervention group. In ConSEPT both the ITT and PP analysis failed to demonstrate superiority of levetiracetam. EcLiPSE used a modified ITT analysis. This too would have tended to bias the results toward levetiracetam. Because both trials failed to demonstrate superiority compared to phenytoin using these statistical methods it strengthens our confidence in the results.

9) Adverse Event Rates: The adverse event rates in ConSEPT and EcLiPSE due to phenytoin was not as pronounced as previous reported. This is interesting and it makes me wonder if the concerns have been highlighted more for the older drug (phenytoin) in order to promote the newer drug (levetiracetam)?

10) Superiority and Equivalent Trials: Both of these trials were designed as superiority trials and failed to demonstrate superiority of levetiracetam to phenytoin. That does not mean equivalence can be claimed but rather we have to accept the null hypothesis that levetiracetam is not superior to phenytoin in these patients. To make the claim of equivalence the 95% confidence intervals of the point estimate of the intervention must fit between a pre-defined delta of the comparator.

Comment on Authors’ Conclusion Compared to SGEM Conclusion: We generally agree with the authors’ conclusions.

SGEM Bottom Line: Levetiracetam is not statistical superior to phenytoin for the management of status epilepticus but it’s clinical suitability as a replacement or additional agent may still need further investigation.

Case Resolution: You give the patient phenytoin 20mg/kg IV over 20 minutes. The seizure activity does not seem to stop after five minutes. You then start levetiracetam 40mg/kg over five minutes and at the end of the infusion the seizure activity seems to cease.

Clinical Application: Although not a direct safety analysis the results suggest that levetiracetam is unlikely to cause harm in children with status and therefore can be considered as treatment agent. How units amend their current protocols will depend on their current experience with levetiracetam, the local anasethetic and intensive care support and whether they feel amendment to national seizure guidance is necessary first.

What Do I Tell the Parents? In a recent study another anti-seizure medication was demonstrated to have similar outcomes to phenytoin in children who have very prolonged seizures. We feel comfortable using the new drug if the phenytoin does not stop your child’s seizure.

Keener Kontest: Last weeks’ winner was Harrision Pidgeon. He knew the Cochrane Logo is the Forest Plot from a SRMA by Patricia Crowley et al in the American Journal of Obstetrics and Gynecology called: Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth.

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