Original articleLevetiracetam: Safety and efficacy in neonatal seizures
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
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