eonatal seizures are one of the most commonly
encountered emergencies in Pediatrics. About two-thirds of cases of
neonatal seizures are due to Hypoxic ischemic encephalopathy (HIE),
which affects approximately 1-2/1000 live births [1]. Phenobarbitone and
phenytoin are the commonly used anticonvulsants for neonatal seizures
after correction of hypoglycemia and hypocalcemia. Good central nervous
system (CNS) penetration, low protein binding, and optimal efficacy make
phenobarbitone the drug of choice for the management of neonatal
seizures [2]. However, long-term use of phenobarbitone is associated
with an impairment of maturation of synapses and enhanced neuronal
apoptosis.
Levetiracetam is a pyrrolidine derivative that binds
to the synaptic vesicle protein SV2a. Some of the favorable
pharmacokinetics of Levetiracetam include minimal protein binding,
safety in liver failure, minimal adverse effect profile, and nearly no
drug interactions. Levetiracetam is approved for use by the Central Drug
Standard Control Organization (CDSCO) and Food and Drug Administration
(FDA) as an adjunctive therapy for partial onset seizure in infants
beyond one month of age. However, the drug has been used off-label in
the management of neonatal seizures [3].
In this issue of Indian Pediatrics, Gowda,
et al. [4] provide robust evidence to support the use of
levetiracetam in neonatal seizures. In their study, 43 out of 50
neonates who received 20 mg/kg of levetiracetam achieved cessation of
seizure with no recurrence in the subsequent 24 hours. Moreover, 16 of
the 19 babies who failed to respond to two doses of phenobarbitone
(cumulative dose of 30 mg/kg) also responded to single dose of 20 mg/kg
of levetiracetam. This raises curiosity to know the baseline
characteristics of babies who responded remarkably to levetiracetam. The
majority of the neonates in this study included term neonates with a
birth weight of 2.5-2.7 kg, enrolled at a mean age of 8-9 days. Neonatal
seizures secondary to HIE mostly present within first 24 hours, and
those secondary to neonatal cerebrovascular stroke occur within the
first 72 hours of birth. Hence, the study results of superior efficacy
of levetiracetam over phenobarbitone in neonatal seizures need to be
interpreted with caution keeping in mind these baseline characteristics.
There is a considerable variation in dosing of
levetiracetam for neonatal seizures with dose as high as 50-60 mg/kg
[5,6]. Gowda, et al. [4] have demonstrated superior efficacy with
a dose of 20 mg/kg of levetiracetam. There are limited studies on the
pharmacokinetics of levetiracetam in the neonatal age group. One such
research has demonstrated that levetiracetam has a longer half-life and
more extensive volume of distribution in neonates when compared to older
children and adults [7]. We eagerly look forward to the results of a
phase II trial planned to determine the optimal dosing of levetiracetam
as the first-line drug for the management of neonatal seizures in HIE
[8].
Levetiracetam in the rat model has demonstrated to
lack any neurotoxic effects at all therapeutic doses [9]. Moreover, it
is also known to decrease the number of apoptotic cells in the
hippocampus and cerebral cortex when administered to babies with hypoxia
[10]. Although the study by Gowda, et al. [4] supports the use of
levetiracetam in neonatal seizures, future trials could be planned to
target a more focused homogenous population like term neonates with HIE.
Also, the proposed research must ideally match standard recommendations
for designing a clinical trial on neonatal seizures to allow
replicability and comparability of study findings [11]. There is a
significant emphasis on the quantification of seizure occurrence with
continuous EEG monitoring being mandatory to assess the treatment
outcome in trials on neonatal seizures.
At the outset, everything looks good about
levetiracetam: favorable pharmacokinetics, good efficacy, and lack of
any significant adverse events. However, currently the evidence is
insufficient to recommend its routine use in neonatal seizures,
especially those due to HIE. In coming years, levetiracetam will be a
promising alternative to phenobarbitone in the management of neonatal
seizures.
1. Saliba RM, Annegers JF, Walker DK, Tyson JE,
Mizrahi EM. Incidence of neonatal seizures in Harris County, Texas,
1992-1994. Am J Epidemiol. 1999;150:763.
2. El-dib M, Soul JS. The use of Phenobarbital and
other anti-seizure drugs in the newborn. Semin Fetal Neonatal Med.
2017;22:321-7.
3. Silverstein FS, Ferriero DM. Off-label use of
antiepileptic drugs for the treatment of neonatal seizures. Pediatr
Neurol. 2008;39:77-9.
4. Gowda VK, Romana A, Shivanna NH, Benakappa N,
Benakappa A. Levetiracetam versus phenobarbitone in neonatal
seizures – A randomized controlled trial. Indian Pediatr. 2019;56:643-6.
5. Khan O, Chang E, Cipriani C, Wright C, Crisp E,
Kirmani B. Use of intravenous levetiracetam for management of acute
seizures in neonates. Pediatr Neurol. 2011;44:265-9.
6. Shoemaker MT, Rotenberg JS. Levetiracetam for the
treatment of neonatal seizures. J Child Neurol. 2007;22: 95-8.
7. Merhar SL, Schibler KR, Sherwin CM, Meinzen-Derr
J, Shi J, Balmakund T, et al. Pharmacokinetics of levetiracetam
in neonates with seizures. J Pediatr. 2011;159:152-4.e3.
8. Favrais G, Ursino M, Mouchel C, Boivin E, Jullien
V, Zohar S, et al. Levetiracetam optimal dose-finding as
first-line treatment for neonatal seizures occurring in the context of
hypoxic-ischaemic encephalopathy (LEVNEONAT-1): study protocol of a
phase II trial. BMJ Open. 2019;9:e022739.
9. Manthey D, Asimiadou S, Stefovska V, Kaindl AM,
Fassbender J, Ikonomidou C, et al. Sulthiame but not
levetiracetam exerts neurotoxic effect in the developing rat brain. Exp
Neurol. 2005;193:497-503.
10. Kilicdag H, Daglioglu K, Erdogan S, Guzel A,
Sencar L, Polat S, et al. The effect of levetiracetam on neuronal
apoptosis in neonatal rat model of hypoxic ischemic brain injury. Early
Hum Dev. 2013;89:355-60.
11. Stevenson NJ, Vanhatalo S. Designing a trial for neonatal seizure
treatment. Semin Fetal Neonatal Med. 2018;23:213-7.
