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Levetiracetam for the Treatment of Neonatal Seizures

Michael T. Shoemaker and Joshua S. Rotenberg J Child Neurol 2007 22: 95 DOI: 10.1177/0883073807299973 The online version of this article can be found at: http://jcn.sagepub.com/content/22/1/95 Published by:
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Brief Communication

Levetiracetam for the Treatment of Neonatal Seizures

Michael T. Shoemaker, MD, PhD, and Joshua S. Rotenberg, MD
Seizures are a common occurrence in the neonatal intensive care unit, especially among low-birth-weight infants. The efficacy and safety of standard anticonvulsants have not been evaluated extensively in the neonate. In addition, there is concern for the adverse effects of phenobarbital on longterm development. Levetiracetam has been a commonly prescribed oral anticonvulsant for the use of adjunctive therapy for partial seizures in adults with favorable tolerability, and it has been recently approved for children older than age

Journal of Child Neurology Volume 22 Number 1 January 2007 95-98 2007 Sage Publications 10.1177/0883073807299973 http://jcn.sagepub.com hosted at http://online.sagepub.com

4 years. There are no published studies regarding the safety and efficacy of this medication in the infant population. This report describes the initiation of levetiracetam in 3 infants, aged 2 days to 3 months, for refractory seizures or intolerance to other anticonvulsants. Each patient was without seizure on levetiracetam monotherapy, and there were no adverse effects. Keywords: levitiracetam; neonate; seizure

eonatal seizures occur in 2 to 4 per 1000 births, with most occurring in the first days of life. There are limited data regarding the efficacy and longterm effects of the standard antiseizure medications in the neonatal period. There is even concern for the long-term adverse effects of phenobarbital on development and epileptogenesis. Other standard medications such as fosphenytoin, benzodiazepines, paraldehyde, carbamazepine, primidone, lidocaine, and valproate have not been evaluated extensively for the neonate. Levetiracetam is a commonly prescribed oral medication used as an adjunctive therapy for partial seizures in adults and has been recently approved for use in children older than 4 years. There are no published studies regarding the safety and efficacy of this medication in the infant population. We conducted a retrospective chart review of 3 infants aged 2 days to 3 months with seizures of varying etiology who received levetiracetam in our neonatal intensive care unit. All infants had clinical and electrographic seizures and were initially treated with other antiepileptic drugs prior to the initiation of levetiracetam, which was initiated because
From the Department of Neonatology (MTS) and the Department of Pediatric Neurology (JSR), Wilford Hall Medical Center, Lackland AFB, Texas. The opinions expressed are those of the authors and do not represent those of the Department of the Air Force or the Department of Defense. Dr Rotenberg has received honoraria from UCB Pharma and Solistice Pharmaceuticals. Address correspondence to: Joshua S. Rotenberg, MD, Department of Pediatrics, 2200 Bergquist Drive, Wilford Hall Medical Center, Lackland AFB, TX 78236; e-mail: joshua.rotenberg@lackland.af.mil. Shoemaker MT, Rotenberg JS. Levetiracetam for the treatment of neonatal seizures. J Child Neurol. 2007;22:95-98.

of refractory seizures in 2 cases or an adverse effect from another antiepileptic drug in 1 case. In each case, the parents were informed of the off-label usage of levetiracetam prior to the infants receiving the medication. The dosing regimen was based on prior studies of levetiracetam involving pediatric patients,1-3 which is 20 to 60 mg/kg/d divided 2 or 3 times a day. Levetiracetam trough levels were drawn in all 3 infants and fell within published therapeutic ranges. All infants were observed for adverse effects and frequency of clinical seizures during their hospitalization. Long-term outpatient follow-up by the pediatric neurologist and Special Baby Clinic ranged from 4 to 18 months. This study obtained approval from the Institutional Review Board of our institution in September 2005.

Case 1
A 41 6/7week gestation female infant was born at another hospital by emergent caesarean section for fetal distress. The infant had no respiratory effort or heart rate, resulting in 2 minutes of positive pressure ventilation, chest compressions, and 1 dose of epinephrine. Apgar scores were 0, 5, and 7 at 1, 5, and 10 minutes of life, respectively. At 4 hours of life, she developed right-sided tonic-clonic seizures, which were treated with intravenous phenobarbital (20 mg/kg) and midazolam (0.1 mg/kg). The patient was transferred to our neonatal intensive care unit at 24 hours of life. Upon arrival, right-sided seizure activity was again noted, and fosphenytoin (12.5 PE/kg/d) was added. A lumbar puncture finding was unremarkable including a negative herpes simplex polymerase chain reaction. Computed tomography and magnetic resonance imaging showed a large left hemispheric infarct, presumed to have occurred in
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Figure 1. Electroencephalogram (EEG) response to levetiracetam. (A) An ongoing seizure from the left centrotemporal region of patient 1 on day 1 of life after receiving phenobarbital, fosphenytoin, and midazolam. (B) EEG result of the same patient 17 minutes after receiving an oral loading dose of levetiracetam of 60 mg/kg. Persistent interictal discharges remained, but the seizure activity resolved.

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utero, as well as small areas of right-sided infarcts. There were also injuries to the right internal capsule and hippocampus. Despite therapeutic levels of phenytoin (16 g/mL) and phenobarbital (38 g/mL) on day 1 of life, she continued to frequently experience abnormal tongue thrusting, lip smacking, and yawning lasting 1 to 2 minutes as well as right-sided tonic-clonic activity. Refractory status epilepticus was confirmed by continuous electroencephalogram (EEG) monitoring. Levetiracetam was administered as a 60mg/kg orogastric bolus and maintained at 30 mg/kg/d through an orogastric tube. Her refractory status epilepticus was controlled within 17 minutes of the bolus (Figure 1). Phenobarbital, fosphenytoin, and midazolam were discontinued by day 10 of life. Her levetiracetam blood trough was 31 g/mL (therapeutic range, 10-40 g/mL) at discharge. She is now 18 months old and has been seizure free since discharge from the hospital. She continues on levetiracetam monotherapy with normal EEG results, and she is developing normally. No untoward events have been reported.

Case 2
A 25 6/7week gestation infant male was delivered emergently by caesarean section for fetal decelerations and a prolapsed umbilical cord. Congenital hydrocephalus with an enlarged cerebellum was noted on a prenatal ultrasound earlier in that day. He was delivered and intubated in the delivery room for birth depression. On his first day of life, tonic-clonic activity was noted in all extremities. The seizures were controlled with a midazolam bolus and phenobarbital (20 mg/kg). Seizure activity was again noted on day 3 of life, which prompted another midazolam bolus and the addition of fosphenytoin (10 PE/kg/d). The infant was continued on fosphenytoin, and the phenobarbital was discontinued. A standard EEG finding was remarkable for excessive discontinuity for age, but no epileptiform elements were noted. He was seizure free for 2 months until tonic-clonic activity was noted again despite therapeutic levels of phenytoin, although no EEG was obtained at that time. He was also found to have increasing ventricular size, requiring the placement of a ventriculoperitoneal shunt. Levetiracetam (30 mg/kg/d) was initiated at this time through an orogastric tube, and the fosphenytoin was discontinued. Six weeks passed, and he remained seizure free at discharge. A trough levetiracetam level was 13 g/mL. He was seizure free on levetiracetam monotherapy with developmental delay at 4 months of life when the family moved to another city. The parents reported no adverse effects at the infants last follow-up visit.

another hospital and had grade 3 and grade 4 intraventricular hemorrhages with hydrocephalus requiring a ventriculoperitoneal shunt. His course was further complicated by necrotizing enterocolitis with perforation and sepsis, after which he was transferred to our neonatal intensive care unit. On day 2 in our care, he was diagnosed with group B streptococcal meningitis. Three days later, he was noted to be having partial seizures of 2 apparent types. These involved right-eye nystagmus and downward deviation. Seizure activity was confirmed by video EEG monitoring. Fosphenytoin was administered initially for seizure control. A few days later, oxcarbazepine was initiated, and the fosphenytoin was weaned. The patient was without clinical or electrographic seizures on oxcarbazepine, but he was increasingly hypophosphatemic despite adequate phosphate intake. Because of this, the oxcarbazepine was discontinued, and levetiracetam was initiated, per orogastric tube at a dosage of 30 mg/kg/d. The patients phosphate normalized, and he continued to be seizure free despite continued hydrocephalus and a ventriculoperitoneal shunt malfunction 3 weeks later. The trough level of levetiracetam after 1 week of therapy was 11 g/mL. At 1 year of life, he remained seizure free with a normal EEG result on levetiracetam monotherapy despite several shunt malfunctions. He is moderately developmentally delayed but progressing, and the parents report no adverse events.

Discussion
The causes of neonatal seizures vary as do the duration and frequency,4 and the distinction between an epileptic and nonepileptic event in neonates is often difficult to demonstrate. More recent literature has indicated that neonatal seizures affect the developing brain with longterm adverse effects on cognition, learning, and seizure threshold, and when a suspicious event is confirmed electrographically, treatment seems warranted.5-7 The most common anticonvulsant used initially in the newborn period for seizure treatment is intravenous phenobarbital. There are many concerns for the short-term adverse effects of phenobarbital as well as long-term effect on infant neurocognitive development. Intravenous phenytoin, fosphenytoin, and benzodiazepines are commonly employed as second-line intravenous medications in the treatment of neonatal seizures. The adverse effects of phenytoin are well known and include cardiac arrhythmias and hypotension. Fosphenytoin may be a safer alternative but is less studied. Benzodiazepines have been successfully used to stop status epilepticus, but the longterm use of these medications concerns many clinicians. Paraldehyde, carbamazepine, primidone, lidocaine, and valproate are other medications that have been used with limited data on success and safety. Levetiracetam, a novel oral anticonvulsant drug with a nonconventional mechanism of action,8 is well studied as

Case 3
A 26-week gestation infant male twin was born via caesarean section for preterm labor and breech presentation at

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an adjunctive therapy for partial epilepsy. Given the safety profile9 of this medication as well as its linear pharmacokinetics (half-life of 7 hours), rapid absorption (30 minutes), nonhepatic elimination, lack of protein binding (<10%), no known interactions with other antiepileptic drugs,10 and favorable efficacy in children, we used levetiracetam in infants. Levetiracetam has been recently approved for use in children older than 4 years. Several pediatric studies have reported marked seizure frequency reduction in seizures with the use of levetiracetam, with the youngest patient being an 11-month-old.1-3,11-16 Some mild adverse side effects were reported, with the most common being drowsiness. Long-term follow-up in 1 study was associated with no adverse effects in 99 patients aged 12 months to 32 years.17 Finally, a recent study of breastfeeding women treated with levetiracetam showed extensive transfer of the medication to breast milk as well as to the fetus prenatally. No adverse effects were noted in the infants.18 While levetiracetam appears to be safe and efficacious in the pediatric population, there have been no reports of its use in the 0- to 3-month-old population. The 3 infants in this series had seizures of different etiologies, which were either refractory to standard medications or associated with untoward effects. No adverse events have been found to be caused by levetiracetam in these infants, and they remain seizure free. Currently, the medication is available only orally, which could limit its use in certain critically ill infants, including those with necrotizing enterocolitis; however, an intravenous formulation is scheduled to be available soon. While further controlled trials need to be completed to better evaluate the safety and efficacy of levetiracetam in infants, the results of these 3 cases suggest that levetiracetam may be a valuable adjunct to the treatment of neonatal seizures.

References
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3. Glauser TA, Pellock JM, Bebin EM, et al. Efficacy and safety of levetiracetam in children with partial seizures: an open-label trial. Epilepsia. 2002;43:518-524. 4. Mizrahi E. Neonatal seizures and neonatal epileptic syndromes. Neurol Clin. 2001;19:427-463. 5. Zupanc ML. Neonatal seizures. Pediatr Clin North Am. 2004; 51:961-978. 6. Volpe JJ. Neurology of the Newborn. 4th ed. Philadelphia, Pa: WB Saunders; 2001. 7. Hahn CD, Riviello JJ. Neonatal seizures and EEG: electroclinical dissociation and uncoupling. Neoreviews. 2004;5:e350-e355. 8. Sankar R, Holmes GL. Mechanisms of action for the commonly used antiepileptic drugs: relevance to antiepileptic drugassociated neurobehavior adverse effects. J Child Neurol. 2004; 19(suppl 1):S6-S14. 9. Klitgaard H. Levetiracetam: the preclinical profile of a new class of antiepileptic drugs? Epilepsia. 2001;42(suppl 4):13-18. 10. French JA, Kanner AM, Bautista J, et al. Efficacy and tolerability of the new antiepileptic drugs, II: treatment of refactory epilepsy: report of the TTA and Qss Subcommittees of the American Academy of Neurology and the American Epilepsy Society. Epilepsia. 2004;45:410-423. 11. Koukkari MW, Guarino EJ. Retrospective study of the use of levetiracetam in childhood seizure disorders. J Child Neurol. 2004;19:944-947. 12. Lagae L, Buyse G, Deconinck A, et al. Effect of levetiracetam in refractory childhood epilepsy syndromes. Eur J Paediatr Neurol. 2003;7:123-128. 13. Lagae L, Buyse G, Ceulemans B. Clinical experience with levetiracetam in childhood epilepsy: an add-on and mono-therapy trial. Seizure. 2005;14:66-71. 14. Wheless JW, Ng Y. Levetiracetam in refractory pediatric epilepsy. J Child Neurol. 2002;17:413-415. 15. Herranz JL, Rufo-Campos M, Arteaga R. Effectiveness and tolerability of levetiracetam in 43 children and adolescents with epilepsy. Rev Neurol. 2003;37:1005-1008. 16. Grosso S, Franzoni E, Coppola G, et al. Efficacy and safety of levetiracetam: an add-on trial in children with refractory epilepsy. Seizure. 2005;14:248-253. 17. Coppola G, Mangano S, Tortorella G, et al. Levetiracetam during 1-year follow-up in children, adolescents, and young adults with refractory epilepsy. Epilepsy Res. 2004;59:35-42. 18. Johannessen SI, Helde G, Brodtkorb E. Levetiracetam concentrations in serum and in breast milk at birth and during lactation. Epilepsia. 2005;46:775-777.

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