Original article
Levetiracetam: Safety and efficacy in neonatal seizures

https://doi.org/10.1016/j.ejpn.2010.10.003Get rights and content

Abstract

Purpose

Neonatal seizures are common, especially in prematurity. Phenobarbital (PB) currently represents the antiepileptic drug (AED) of choice, despite being related to increased neuronal apoptosis in animal models and cognitive impairment in human subjects. Levetiracetam (LEV) may have a more favorable profile since it does not cause neuronal apoptosis in infant rodents.

Methods

In a prospective feasibility study, LEV was applied as first-line treatment in 38 newborns with EEG-confirmed seizures, after ruling out hypoglycemia, hypocalcaemia, hypomagnesaemia and pyridoxin dependency. Initial intravenous doses of 10 mg/kg LEV were gradually increased to 30 mg/kg over 3 days with a further titration to 45–60 mg/kg at the end of the week. Acute intervention with up to 2 intravenous doses of PB 20 mg/kg was tolerated during LEV titration. LEV was switched to oral as soon as the infants’ condition allowed. Based on clinical observation, EEG tracings (aEEG/routine EEGs), and lab data, drug safety and anticonvulsant efficacy were assessed over 12 months.

Results

In 19 newborns a single PB dose of 20 mg/kg was administered, while 3 newborns received 2 PB doses. 30 infants were seizure free under LEV at the end of the first week and 27 remained seizure free at four weeks, while EEGs markedly improved in 24 patients at 4 weeks. In 19 cases, LEV was discontinued after 2–4 weeks, while 7 infants received LEV up to 3 months. No severe adverse effects were observed.

Conclusions

These results illustrate the safety of LEV treatment in neonatal seizures, including prematurity and suggest LEV anticonvulsant efficacy. Additional PB treatment admittedly constitutes a methodological shortcoming due to the prolonged anticonvulsive efficacy of PB. Double blind prospective controlled studies and long-term evaluation of cognitive outcome are called for.

Introduction

Neonatal seizures are the most frequent clinical manifestation of central nervous system dysfunction in the newborn, with an incidence of 1.5–3.5/1000 in term newborns and 10-130/1000 in preterm newborns.1 Seizures in the newborn frequently signal significant brain pathology, such as hypoxic-ischemic injury, stroke, intracranial infection, hypoglycemia, inborn errors of metabolism, or brain malformations. Etiology significantly influences outcome. Newborn seizures correlate with higher mortality as well as motor or cognitive disability in survivors.2, 3 Furthermore, an association could be established between the amount of EEG seizure activity and subsequent mortality and morbidity in infants.4 In this light, effective therapeutic interventions addressing both clinical seizures and EEG seizure activity might significantly improve neurocognitive development as well as reduce morbidity and mortality.

There are currently no evidence-based guidelines for evaluation and management of neonatal seizures. Available data indicate that phenobarbital (PB) remains the first-line treatment for neonatal seizures.5 Yet, a recent Cochrane Review concluded that “there is little evidence to support the use of any of the anticonvulsants currently used in the neonatal period”.6 Conventional treatment (phenobarbital and phenytoin) only achieves clinical control in 50%–80% of cases and is even less effective in controlling most neonatal electroencephalographic seizures.7 On the other hand, there is increasing concern over the long time adverse effects of phenobarbital, since it was shown to increase neuronal apoptosis in animal models8 and induce cognitive impairment in infants and toddlers.9

Levetiracetam (LEV) is an effective and well-tolerated antiepileptic drug currently licensed as adjunctive therapy in the treatment of partial onset seizures with and without secondary generalization in adults, children and infants with epilepsy starting from 1 month of age (in oral application) and already licensed in children aged ≥4 years at study initiation.10 Retrospective series in children including patients younger than 4 years showed comparable responder rates and side-effect profiles of add-on LEV treatment.11, 12 Prospective studies with small patient groups in infants and very young children reported similar results.13, 14 There are hardly any reports of severe, life threatening side effects, while most frequently observed adverse effects included somnolence and behavioral problems.15 Furthermore, LEV presents a favorable profile regarding neuronal apoptosis: in contrast to most other established antiepileptic drugs it was not found to increase apoptosis in the developing rodent brain16 or interfere with neuroprotective up-regulation of hypoxia inducible transcription factor 1 (HIF-1α)17 and it was shown to decrease neurodegeneration in rodent models of hypoxia/ischemia18 or epilepsy.19, 20

To date, ten patients with neonatal seizures who were successfully treated with LEV in the neonatal period have been reported in detail,21, 22, 23 while one of these patients received LEV intravenously.21 The preliminary data on safety and anticonvulsive efficacy in the pilot study carried through at the University Hospital of Heidelberg in the years 2004–200623encouraged us to further develop this protocol and initiate a prospective feasibility study in our institution.

This study analyses the results regarding anticonvulsant efficacy and treatment safety obtained using LEV in neonates with electroclinical and electrographic-only seizures. Our objectives were to evaluate 1) control of seizures, both clinically and electroencephalographically and 2) adverse effects associated with the intravenous or oral administration of LEV.

Section snippets

Methods

In 2006, following availability of intravenous LEV, consecutively admitted newborns with EEG-confirmed seizures, including premature and extremely premature infants treated at the Department of Neonatology and Pediatric Intensive Care of the University Hospital Carl Gustav Carus Dresden, Germany, were considered for this study. Infants presenting with clinical seizures that were confirmed as such through a clear correlation with pathologic EEG findings were subsequently treated with

Results

In the period between 2006 and 2008, following availability of intravenous LEV, a total of 38 newborns with EEG-confirmed seizures, including 19 extremely premature infants at gestational age <28 + 0 weeks, birth weight 410–1330 g, 6 premature infants with gestational age >28 to 36 + 6 weeks, birth weight 1250–1890 g, and 13 term newborns were evaluated in this study. Clinical data of all infants included in the study are summarized in Table 1, while response to treatment is presented in Table 2

Discussion

The causes of neonatal seizures vary as do the duration and frequency, and the distinction between an epileptic and non-epileptic event in neonates is often difficult to demonstrate.25 On the other hand, current data from animal and human studies suggest that neonatal seizures affect the developing brain with long-term adverse effects on cognition, learning, and seizure threshold,26, 27 and when a suspicious event is confirmed electrographically, treatment seems warranted. Repeated seizures may

References (49)

  • A. Fürwentsches et al.

    Levetiracetam in the treatment of neonatal seizures: a pilot study

    Seizure

    (2010)
  • H. Bassan et al.

    Neonatal seizures: dilemmas in workup and management

    Pediatr Neurol

    (2008)
  • Y. Ben-Ari et al.

    Effects of seizures on developmental processes in the immature brain

    Lancet Neurol

    (2006)
  • M.P. Thibeault-Eybalin et al.

    Carmant. Neonatal seizures: do they damage the brain?

    Pediatr Neurol

    (2009)
  • F.S. Silverstein et al.

    Off-label use of antiepileptic drugs for the treatment of neonatal seizures

    Pediatr Neurol

    (2008)
  • E. Biagioni et al.

    Electroclinical correlation in neonatal seizures

    Eur J Paediatr Neurol

    (1998)
  • F. Pisani et al.

    Preterm infants with video-EEG confirmed seizures: outcome at 30 months of age

    Brain Dev

    (2008)
  • M.S. Scher et al.

    Electrographic seizures in preterm and full-term neonates: clinical correlates, associated brain lesions, and risk for neurologic sequelae

    Pediatrics

    (1993)
  • G.M. Ronen et al.

    Long-term prognosis in children with neonatal seizures: a population-based study

    Neurology

    (2007)
  • M.C. McBride et al.

    Electrographic seizures in neonates correlate with poor neurodevelopmental outcome

    Neurology

    (2005)
  • D. Booth et al.

    Anticonvulsants for neonates with seizures

    Cochrane Database Syst Rev

    (2004)
  • G.B. Boylan et al.

    Phenobarbitone, neonatal seizures, and video-EEG

    Arch Dis Child Fetal Neonatal Ed

    (2002)
  • P. Bittigau et al.

    Antiepileptic drugs and apoptosis in the developing brain

    Ann N Y Acad Sci

    (2003)
  • T.A. Glauser et al.

    Double-blind placebo-controlled trial of adjunctive levetiracetam in pediatric partial seizures

    Neurology

    (2006)
  • Cited by (0)

    View full text