Survey data suggest that levetiracetam is commonly recommended by pediatric neurologists managing neonatal seizures,26
despite a paucity of data regarding safety, tolerability, and efficacy. Our retrospective cohort study of 23 neonates with electro-graphically confirmed seizures did not identify any serious adverse cardiopulmonary effects, and levetiracetam was not discontinued in any neonates because of serious adverse events. Levetiracetam was associated with greater than 50% seizure reduction within 24 hours of treatment initiation in 35% of neonates. Of those who benefited, 88% were rendered seizure free.
Levetiracetam's pharmacokinetic profile suggests it could be a useful medication in critically ill neonates with seizures. Neonates have lower serum protein values compared to adults, placing them at an increased risk for toxicity secondary to elevated free drug concentrations of highly protein bound antiseizure medications such as phenytoin, and levetiracetam has minimal protein binding. Furthermore, critically ill neonates with seizures are often receiving polypharmacy and, in contrast to other intravenous antiseizure medications, levetiracetam has no cytochrome P450 drug-drug interactions. Clinical seizure types observed in our retrospective study included focal or multifocal clonic or tonic, and subtle seizures. Levetiracetam is approved by the FDA for use in partial onset seizures, juvenile myoclonic epilepsy, myoclonic seizures, and primary generalized tonic clonic seizures, suggesting the potential for benefit in neonates with the types of seizures occurring in our cohort. Finally, in epileptic children, interictal intravenous levetiracetam boluses of up to 60 mg/kg administered over 5 to 6 minutes achieved serum levels of more than 100 mg/ml and resulted in no significant changes in blood pressure, electrocardiographic abnormalities, or local infusion site reactions.27
The observation that intravenous levetiracetam can be delivered quickly and achieve high serum levels suggests a possible role for levetiracetam in the management of acute seizures.
Case series and case reports have described tolerability and possible efficacy of levetiracetam for neonatal seizures, including 2 neonates with seizure administered oral levetiracetam,9
a neonate with intractable malignant migrating partial seizures,10
as a prophylactic antiseizure medication in a neonate with presumed acute symptomatic seizures because of leukemia.12
Slightly more data are available in infants. A case series of 11 children aged 2 days to 9 years with refractory status epilepticus treated with levetiracetam doses of 15 to 70 mg/kg (intravenous in 6, nasogastric in 5) did not result in adverse effects. A total of 5 children, all of whom had received at least 30 mg/kg/ day, had some benefit in a median of 1.5 days.13
Another case series of 28 children under the age of 2 years included some neonates (minimum age 2 weeks) and reported that with a 6.3-month mean duration of treatment, levetiracetam reduced seizures in 54%, including 14% with seizure freedom.11
However, data were not available for the individual neonates. Our data describing a larger consecutive cohort of neonates treated with levetiracetam substantially expands the reported clinical experience with levetiracetam in neonates.
Although there have been no prospective studies comparing levetiracetam to other antiseizure medications, a growing number of retrospective, single-center, open-label case series and case reports have provided additional evidence that levetiracetam may be safe and effective for treating status epilepticus and acute repetitive seizures in nonneonatal children. One series described 32 children treated with intravenous levetiracetam (50 mg/kg over 15 minutes) for acute seizures or status epilepticus and reported that all patients had seizure termination within 25 to 30 minutes of infusion.17
A second series reported that intravenous levetiracetam loading doses of 6.5 to 31 mg/kg terminated nonconvulsive status epilepticus in 2 of 2, acute repetitive seizures in 4 of 4, and resulted in temporary seizure termination in 3 with refractory status epilepticus.14
A third series reported 10 children who received intravenous levetiracetam and described status epilepticus termination in 1, status epilepticus improvement in 1, and acute repetitive seizure termination in 2.16
Finally, 2 infants with migrating partial seizures of infancy in refractory status epilepticus had seizure termination within 12 hours of 60 mg/kg intravenous levetiracetam loads.28
None of these series described any adverse effects.14,16,17,28
Additional case reports have reported that levetiracetam resulted in improvement in nonconvulsive status epilepticus15,19,29
and myoclonic status epilepticus18
Our retrospective cohort study has multiple limitations. First, although no adverse cardiopulmonary events were identified, the retrospective nature of chart review limits firm conclusions about levitiracetam's safety and tolerability. While our safety profile was consistent with other studies of intravenous levetiracetam in critically ill children13,14,16,17
and larger studies of critically ill adults,20-22,24,25,30
there are rare reports of elevations in liver enzymes,25
possible fulminant hepatic failure31
This study is too small to detect rare events and we did not perform extensive laboratory testing in a standardized manner. Second, dosing was not standardized, and it is unknown whether dosing was optimal as neonatal pharmacokinetic data are not available. A retrospective series of children with refractory epilepsy reported no correlation between plasma level and efficacy,33
suggesting it may be difficult to identify an optimal dosing regimen. Third, while levetiracetam was associated with a greater than 50% reduction in seizures in 35% of neonates within 24 hours, this small retrospective uncontrolled study does not provide quality efficacy data and merely suggests future prospective study of levetiracetam effectiveness is warranted. Seizures because of acute encephalopathy are known to spontaneously cease over time. Given that levetiracetam was often used as a second or third line antiseizure medication, some of the association with seizure reduction, especially in the 4 neonates with improvement noted in 2 to 3 days, may have simply related to passage of time and not levetiracetam efficacy. Furthermore, because of variation in management, the duration of the pre-levetiracetam period used to calculate pre-levetiracetam seizure burden varied across subjects. Without a placebo group and standardized timing, it is not possible to determine whether some or all seizure improvement relates to the passage of time or levetiracetam administration.
Despite the limitations of this small retrospective observational study, the findings are in agreement with other smaller reported series and suggest that levetiracetam is safe and well-tolerated when administered to critically ill neonates. There is an association with seizure reduction or termination within 24 hours of administration, primarily when used as a second-line antiseizure medication. Additional, larger prospective studies are warranted to define the role of levetiracetam in the management of neonatal seizures. A dose finding study may be needed initially and must include data regarding serum levels of levetiracetam. In our cohort, dosing of 40 mg/kg/day was not associated with major adverse effects and none of the neonates who benefitted from levetiracetam discontinued the medication because of intolerability, so this may be a reasonable dose to study. Consistent with data regarding phenytoin and phenobarbital,8
levetiracetam administration was associated with seizure improvement in less than half of neonates, and this low but expected response rate has implications for sample size calculations in future prospective comparative studies.