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A male infant was born at 39 weeks’ gestation by spontaneous vaginal delivery. The mother was a 32-year-old primigravida. Antenatal course was uneventful. Apgar score was 9 at 1 min and 10 and 5 min. He did not require resuscitation and was transferred to the postnatal ward with the mother. At 30 hours of age, he developed right arm and leg jerking. A bedside cranial ultrasound suggested a left middle-cerebral artery territory infarct.
Given the frequent use of levetiracetam in paediatric seizures with a good effect, should this drug be used as first-line in the treatment of neonatal seizures?
Structured clinical question
In neonates diagnosed with seizures, is there evidence to support levetiracetam rather than phenobarbitone as the first-line treatment of neonatal seizures?
MEDLINE, PubMed, Embase and TRIP were searched using the following search terms:
(Neonat* [neonate, neonates, neonatal] OR newborn) AND (Levetiracetam OR Keppra) AND (Seizure OR epilepsy OR convulsion)
(Neonat* [neonate, neonates, neonatal] OR newborn AND (Phenobarb [phenobarbitone, phenobarbital]) AND (Seizure OR epilepsy OR convulsion)
The Cochrane Library was searched using a combination of the terms as outlined for primary sources.
Inclusion and exclusion criteria
To further refine the search criteria and retrieve the most relevant publications, we applied strict inclusion and exclusion criteria. All neonates diagnosed and treated for seizures were included regardless of their gestational age and method of seizure diagnosis (clinically, electrographically or both). Seizures had to be treated with either levetiracetam or phenobarbitone as first-line treatment, and only studies where both drugs were used as comparison were included. Only studies published in English were included.
A total of 347 abstracts with keywords as described in the search criteria were reviewed. Five studies were identified as relevant to the clinical question and fulfilled inclusion criteria. Critical appraisal of these papers is summarised in table 1.
Neonatal seizures are the most common neurological manifestation in the neonatal period, estimated to occur in 1 to 3.5 per 1000 term infants and 10–130 per 1000 preterm infants.1–4 The main causes of seizures in the neonatal period are hypoxic–ischaemic encephalopathy, intracranial haemorrhage, ischaemic stroke or infection. Seizures in this age group are usually focal, subtle and often difficult to detect clinically; a large percentage are subclinical or electrographic only.5 Increasing evidence suggests that neonatal seizures are associated with poorer neurodevelopmental outcomes, though unclear if neonatal seizures themselves propagate injury or are a marker of severity of the underlying injury.6 Therefore, quicker cessation of neonatal seizures may confer long-term, neurodevelopmental benefits.
To date, there are no US Food and Drug Administration approved drugs for use in neonates, and most of the data obtained about the efficacy of different drugs is extrapolated from studies performed in infants and children.3 4 Practices are largely based on data from small retrospective studies and driven by clinician’s personal experience and preference. Levetiracetam is increasingly used in clinical practice as first and second-line treatment for neonatal seizures. The mechanism of action is not fully understood; LEV likely impedes the release of neurotransmitters.1 3 It appears to have ideal characteristics for use in neonates: it does not require hepatic cytochrome P450 for its metabolism (and is therefore less likely to be affected during therapeutic hypothermia and hepatic dysfunction) and is largely excreted unchanged in the urine.1 3 7
All papers differ significantly in their methodology, loading doses administered, outcomes and results. Majority of the studies reviewed favoured the use of LEV as first-line treatment for neonatal seizures; however, these studies have multiple limitations: seizures diagnosed clinically, lack of consistency between the doses and escalation protocols for each drug. Gowda et al was a randomised control trial (RCT) and therefore ranks high in the hierarchy of evidence. However, its methodology of seizure diagnosis is flawed; neonatal seizures are predominantly subclinical; and as previously demonstrated, clinicians have very poor ability to detect clinical seizures.5 Sharpe et al is a well-designed RCT with consistent dosages administered for each drug and well-defined escalation protocols; it demonstrated strong evidence that PB remains superior to LEV as first-line treatment for neonatal seizures (80% vs 28% seizure freedom with the first dose of PB, p value<0.001).8 In this study, all neonates had seizures confirmed by continuous electroencephalography and validated by two independent neurophysiologists. Seizure cessation was defined clinically and electrographically and thus captured and monitored the full burden of seizures.
From our review, the evidence does not support the use of LEV as first-line antiepileptic medication. A majority of the studies supporting the use of LEV are retrospective, use variable dosing regimens and diagnosis seizures clinically rather than electrographically. Therefore, a change in current practice is not recommended. Phenobarbitone should remain the first-line treatment for neonatal seizures, PB has been demonstrated to be more effective than LEV in achieving seizure cessation.
Clinical bottom line
Phenobarbitone should continue as the first-line treatment for neonatal seizures (Grade A).
Twitter @mijkboyle, @lilkatg
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests None declared.
Patient consent for publication Not required.
Provenance and peer review Not commissioned; internally peer reviewed.