Second Best: The EcLiPSE and ConSEPT trials

Did either prove effective in confronting the most common pediatric neurological emergency?

Every EM physician who has cared for a sick child in status epilepticus can relate to the anxiety provoking feeling that you get when first-line benzodiazepines are not working. As the child continues to seize before you, and you concomitantly are managing their airway…the decision of which second line-agent you choose is a critical next step.

Background

Convulsive status epilepticus (SE) is the most common pediatric neurological emergency worldwide, with significant morbidity and mortality associated with it. Annual incidence of status epilepticus in the pediatric population ranges from 10 to 73 per 100,000.[^1] Status epilepticus is defined as single seizure lasting >20-30 minutes or recurrent shorter seizures without recovery of baseline consciousness in between.[^1] It is well known that the longer the duration of convulsive SE, the more difficult it is to terminate the seizure and the greater the risk of neurodisability and complications. Thus, early amelioration of status epilepticus is prudent.

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The goal in early management of SE is to avoid refractory status epilepticus (RSE). RSE is defined as patients who do not respond to standard treatment and continue to experience either clinical or electrographic seizures despite receiving adequate doses of first and second-line antiepileptic drugs.[²,^3] As you can imagine, a patient in RSE has much higher morbidity and mortality due to a combination of factors.

Patients in RSE already have decreased respirations at baseline due to their suppressed neurologic state. Add to that, respiratory suppression from drug-induced sedation, and it is not surprising that the majority of these patients invariably require advanced airway management and intubation.

Once paralyzed and intubated, the inability to monitor seizure cessation without an EEG increases their risk of neurodisability further. In addition to respiratory compromise, patients also have an increased risk of cardiac instability due to increasing metabolic acidosis, medication side effects and drug-drug interactions.[^3] Collectively there are multiple reasons to treating status epilepticus early and aggressively in hopes to avoid RSE and these downstream complications.

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Both the American Academy of Pediatrics and Advanced Pediatric Life Support (APLS) recommend two doses of benzodiazepines as first-line agents given five minutes apart for the initial treatment of SE.[^4] Second-line agent recommendations vary and can include fosphenytoin (USA), phenytoin (UK and Europe) or phenobarbital. However there has been some recent suggestion that levetiracetam could be an effective and safer alternative.[^4]

New Contenders

Recently two randomized control trials (EcLiPSE and ConSEPT) were published in THE LANCET, April 2019 [⁵,^6] comparing levetiracetam to phenytoin as second-line agents in pediatric status epilepticus.

EcLiPSE was a multicenter, open-label randomized clinical trial performed in the UK from 2015-2018.[^5] This was the largest randomized control trial to-date, comparing levetiracetam (40mg/kg over 5 minutes – Max Dose 2.5g) with phenytoin (20mg/kg over 20 min – Max Dose 2g) for treatment of pediatric convulsive status epilepticus unresponsive to first-line treatment. They enrolled 404 patients (six months to < 18 years), and of these, 286 patients were randomized and treated with one of the second-line agents.

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The primary outcome was time from randomization to cessation of convulsive status epilepticus. Status epilepticus was terminated in 106 (70%) in Levetiracetam group in 35 minutes vs. 86 (64%) phenytoin group in 45 minutes.[^5]

Though at first glance it may appear that levetiracetam was more effective, the results were not statistically significant, demonstrating no superiority of either agent. The EcLiPSE authors ultimately concluded that “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.”[⁵]

ConSEPT was a very similar study comparing levetiracetam versus phenytoin again. This was also a multi-center, open-label randomized controlled trial performed in Australia and New Zealand from 2015-2017.[^6] They randomized 233 children (114 randomized to phenytoin, 119 randomized to levetiracetam) with the same dosages/infusion rates as EcLiPSE. The primary outcome in this study was clinical cessation of seizure activity, five minutes after completion of infusion of the study drug. The authors of this study concluded, “Levetiracetam is not superior to phenytoin for second-line management of pediatric convulsive status epilepticus.”[^6]

Findings

It is important to note that both of these studies excluded focal, non-myoclonic and non-convulsive status epilepticus. Thus, results of either study can only be applied to convulsive tonic-clonic status epilepticus.

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Though both EcLiPSE and ConSEPT hoped to demonstrate that levetiracetam was superior as a second-line agent, neither study demonstrated superiority in efficacy nor safety. Given these studies showed equivocal efficacy for seizure cessation, the decision of which drug to use as a second-line agent remains multifactorial.

When considering your options for a second-line agent, it is important to note that both phenytoin and levetiracetam have a wide-spectrum of adverse effects. The most serious adverse reactions for levetiracetam can include: anaphylaxis, Stevens Johnson Syndrome (SJS)/Toxic Epidermal Necrolysis (TEN). More commonly levetiracetam can cause a range of psychiatric manifestations: psychosis, suicidality, hostility/aggression, depression and agitation, which is why this drug should be avoided in children with known underlying psychiatric disorders.

The side effect profile for phenytoin however is far more severe and can include: cardiovascular collapse, arrhythmias (AV-conduction disturbances, V-fibrillation, bradycardia), hepatotoxicity, SJS/TEN.

More commonly, tissue necrosis due to local extravasation has been noted with phenytoin and is one of the primary reasons that the United States switched from phenytoin to fosphenytoin approximately 15 years ago despite the higher cost of the drug. Admittedly both fosphenytoin and phenytoin can cause hemodynamic instability. Arrhythmias, (namely V-Fib and AV conduction delays) as well as local tissue necrosis, is seen less often with fosphenytoin, still making it the preferred drug in the US.

Safety is not the only factor that one needs to consider. Knowing which home medications, a patient is on is important to note prior to initiating a second-line agent. For patients who are already on phenytoin/fosphenytoin at home, giving a second dose of the same drug could potentially increase their drug levels to toxic states, and thus should be avoided. On the contrary, levetiracetam doesn’t appear to have this additive toxic effect. Unlike phenytoin, if a child takes levetiracetam at home, most providers are apt to use this again as a second-line agent.

In addition to safety, there are pragmatic considerations when deciding which second-line drug is best. The practical aspects of drug preparation and administration as well as familiarity and comfort in its use with our nursing colleagues should be considered.

In the EcLiPSE trial, clinical teams reported that it was easier to prepare and administer levetiracetam than phenytoin because of calculations that needed to be performed in reconstituting phenytoin, the number of vials required with phenytoin, and the procedures needed for its administration.[^5]

Conclusion

Though neither EcLiPSE  nor ConSEPT demonstrated levetiracetam as a superior agent to phenytoin, we should appreciate that levetiracetam has undergone a notable shift in gears. Having previously been considered strictly a “prophylactic agent,” it now appears to be considered a therapeutic agent in the acute care setting, which is rather remarkable. Though it has yet to prove superiority to phenytoin, the fact that we have another equivocal option for second line seizure-cessation is a significant one.

Bringing it back to the bedside, both of these studies have elucidated that levetiracetam is now an added option in our armamentarium of second-line agents. Given our current evidence, and the above considerations, the decision of which drug to use as a second-line agent needs to be individualized to both the patient and institution.

Ultimately the goal is to treat status epilepticus aggressively and early, in hopes to prevent refractory status epilepticus, and all other downstream complications.

References:

1. Joshi S.  Seizure Emergencies: Status Epilepticus. American Academy of Pediatricshttps://www.aap.org/en-us/Documents/echo_session_10_seizure_emergencies.pdf
2. Hartman AL, Devore CDL, AAP and the SECTION ON NEUROLOGY, et al. Rescue Medicine for Epilepsy in Education Settings. Pediatrics. 2016;137(1):e20153876
3. Brophy B et al. Guidelines for the evaluation and management of status epilepticus. Neurocritical Care 2012, Aug; 17 (1):3-23. PMID: 22528274
4. APLS Status Epilepticus Algorithm https://www.apls.org.au/sites/default/files/uploadedfiles/Status%20epilepticus%20management.pdf
5. Lyttle MD et al. Levetiracetam Versus Phenytoin for Second-Line Treatment of Paediatric Convulsive Status epilepticus (EcLiPSE): A Multicentre, Open-Label, Randomised Trial. LANCET 2019. PMID: 31005385
6. Dalziel SR et al. Levetiracetam Versus Phenytoin for Second-Line Treatment of convulsive Status Epilepticus in Children (ConSEPT): An Open-Label, Multicentre, Randomised Controlled Trial. LANCET 2019. PMID: 31005386