Seizure: European Journal of Epilepsy 80 (2020) 71–74

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Seizure: European Journal of Epilepsy

journal homepage: www.elsevier.com/locate/seizure

Comparison of the neurocognitive outcomes in term infants treated with T

levetiracetam and phenobarbital monotherapy for neonatal clinical seizures
Pinar Aricana, Nihal Olgac Dundarb,*, Neslihan Mete Ataseverc, Mine Akkaya Inalc,
Pinar Gencpinarb, Dilek Cavusoglud, Sinem Akbaye, Hasan Tekgulf
a
Department of Pediatric Neurology, Kahramanmaraş Necip Fazil Hospital, Kahramanmaraş, Turkey
b
Department of Pediatric Neurology, Izmir Katip Celebi University, Izmir, Turkey
c
Department of Pediatric Neurology, Izmir Tepecik Education and Research Hospital, Izmir, Turkey
d
Department of Pediatric Neurology, Afyon Kocatepe University, Afyon, Turkey
e
Neonatology Department, Manisa City Hospital, Izmir, Turkey
f
Department of Pediatric Neurology, Ege University, Izmır, Turkey

A R T I C LE I N FO A B S T R A C T

Keywords: Purpose: This study aims to compare the neurocognitive outcome in term infants who were treated using phe-
Infant nobarbital (PB) and levetiracetam (LEV) monotherapy for neonatal clinical seizures.
Monotherapy Methods: Term infants who were treated using PB or LEV monotherapy as the first-line anti-epileptic treatment
Neonatal for neonatal clinical seizures and followed-up in a pediatric neurology outpatient clinic were enrolled in this
Neurodevelopment
study. Neurodevelopmental outcome assessments were carried out using the Bayley Scales of Infant
Seizure
Development, third edition (BSID-III), including cognitive, receptive language, expressive language, fine motor
and gross motor subscales.
Results: The study group consisted of 62 infants who received monotherapy with PB monotherapy (n = 22) and
LEV (n = 40). The mean duration of monotherapy treatment was 8 ± 6 months. There was no statistically
significant difference between PB and LEV monotherapy groups concerning each outcome parameter on the
BSID-III. There was also no statistically significant difference between PB and LEV monotherapy subgroups
excluding the infants with neurodevelopmental impairment with a BSID-III scale score < 7 or a composite
score < 85.
Conclusion: Our findings suggest that both LEV and PB therapy can be equally safe as monotherapy for neonatal
clinical seizures for the neurodevelopmental outcome assessment with BSID-III.

1. Introduction known for decades [21,22]. Intrauterine exposure to PB and phenytoin

Treatment of neonatal seizures with a proper antiepileptic drug
remains a significant clinical problem in medicine [1–3]. There are few
evidence-based guidelines for the evaluation and management of neo-
natal seizures. Available guidelines indicate that phenobarbital (PB)
remains the first-line treatment for neonatal seizures [4,5]. Currently,
there is no consensus regarding the second-line antiepileptic drugs,
such as levetiracetam (LEV), benzodiazepine, fosphenytoin, or lido-
caine [6–8]. In the last decade, case series and clinical studies have
suggested LEV as a first-line antiepileptic drug in neonatal seizures
because of its good pharmacokinetics and having an acceptable side
effect profile [9–20].
The potential neurotoxic effects of antiepileptic drugs have been
is a risk factor for developmental defects, microcephaly, mental re-
tardation, and learning deficits or lower IQ scores [23,24]. Studies on
animal models have proposed that phenobarbital and phenytoin seem
to have an effect of accelerating the neuronal apoptosis when ad-
ministered to the immature brain [25]. Contrary to recent few studies,
animal models have shown that LEV does not lead to neuronal apop-
tosis in the immature brain or disrupt synaptic development [26,27].
Differential cognitive effects of antiepileptic drugs have been a concern
for therapeutic decisions. However, the effects of the therapeutic doses
of these agents on neurodevelopmental outcomes in newborns with
seizures are not known.
In this cross-sectional study, we aimed to evaluate the neurodeve-
lopmental outcome of the term infants with neonatal clinical seizures

⁎
Corresponding author at: Department of Pediatric Neurology, Izmir Katip Celebi University, Cıglı, 35620, Izmir, Turkey.
E-mail address: nodundar@gmail.com (N. Olgac Dundar).

https://doi.org/10.1016/j.seizure.2020.06.006
Received 1 January 2020; Received in revised form 1 June 2020; Accepted 2 June 2020
1059-1311/ © 2020 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.
P. Arican, et al. Seizure: European Journal of Epilepsy 80 (2020) 71–74

who were treated with PB and LEV monotherapy using the Bayley Table 1
Scales of Infant Development, third edition (BSID-III). Demographic characteristics and clinical features of infants with clinical neo-
natal seizures.
2. Methods Levetiracetam Phenobarbital p value
monotherapy (n = monotherapy (n =
2.1. The study group and data collection 40) 22)

Gender, n (%) .790

Term infants who were treated using PB or LEV monotherapy as the Female 21 (53 %) 13 (59 %)
first-line treatment for neonatal seizures and followed-up in a pediatric Male 19 (47 %) 9 (41 %)
neurology outpatient clinic were enrolled in this study. Infants were Age (months)(means ± 18 ± 7 20 ± 8 .339
SD)
excluded from the study group if they had received a second anti-
Seizure etiology, n (%) .184
epileptic drug in the neonatal intensive care unit or during the out- Specific underlying 23 (58 %) 8 (36 %)
patient follow-up. etiologies
Demographic data, clinical reports, cranial magnetic resonance Unknown etiologies 17 (42 %) 14 (64 %)
imaging (MRI) and electroencephalography (EEG) results of the in- Cranial MRI, n (%) .595
Normal 16 (40 %) 11 (50 %)
cluded infants were collected from the medical records and reviewed.
Abnormal 23 (60 %) 11 (50 %)
According to the International League against Epilepsy 2017 classifi- EEG findings, n (%) .584
cation of seizure, seizure etiology was classified as structural, meta- Normal 27 (68 %) 13 (59 %)
bolic, genetic, infectious, and unknown [28]. Laboratory and safety Abnormal 13 (32 %) 9 (41 %)
EEG improvement, n (%) .36
measures were evaluated with complete peripheral blood counts, ala-
Yes 9 (69 %) 8 (89 %)
nine aminotransferase levels, and vital sign parameters at routine No 4 (31 %) 1 (11 %)
follow-up visit records. EEG improvement was defined by a pre-treat- Treatment duration 8±6 8±7 .917
ment EEG that was abnormal and a second EEG that was normal (no (months) (mean ±
spikes or abnormalities). SD)
The study protocol was approved by the local ethics committee.
EEG: electroencephalography; MRI: magnetic resonance imaging; SD:standard
Informed consent was obtained from the parents.
deviation.

2.2. Neurodevelopmental outcome measurement

Neurodevelopmental assessments were carried out using the BSID-
III by one of the co-authors of this research, MA. Neurodevelopmental
outcomes were assessed by motor, cognitive, and language performance
on the BSID-III. Neurodevelopmental impairment was defined as a
BSID-III scale score < 7 or a composite score < 85 [29]. Subgroup
analysis was carried out to explore the effects of antiepileptic drugs on
the neurodevelopmental outcomes in infants, excluding the infants with
neurodevelopmental impairment based on the BSID-III scale or com-
posite scores.
2.3. Seizure treatment protocols
Phenobarbital was used as the first-line antiepileptic drug, the in-
itial dosage was intravenously 20 mg/kg, and the dosage was increased
by 10 mg/kg up to 40 mg/kg in the case of persistent seizures. From
2010, following the availability of intravenous LEV in Turkey, term
neonates with clinical seizures has also been treated with the treatment
protocol of our department. Intravenous LEV was used as the first-line
antiepileptic drug, the initial dosage was intravenously 20 mg/kg, and
the dosage was increased by 10 mg/kg up to 40−60 mg/kg in the case
of persistent seizures.
Once seizures have ceased, if the neurological examination and EEG
were both normal, antiepileptic drug monotherapy was discontinued in
the neonatal intensive care unit. During the follow-up, a control EEG
was performed at three months of age, and we stopped the mono-
therapy if the patient was seizure-free, and the EEG was normal. For
infants without a clinical seizure, cessation of treatment protocol was
considered in every three months of the follow-up period in the pre-
sence of normal EEG.
2.4. Statistical analysis
Statistical analysis was performed using Statistical Package for the
Social Sciences software program version 21.0. Categorical variables
were summarized using percentages. Continuous variables were sum-
marized using means and standard deviations (SD). The Chi-square test
and Fisher’s exact test were used for comparison of categorical data
between independent groups. For all statistical analyses, p < 0.05 (two-
tailed) values were considered statistically significant.
3. Results
3.1. Patients characteristics
The study group consisted of 62 infants who received monotherapy
with PB (n = 22) and LEV (n = 40). The mean duration of mono-
therapy was 8 ± 6 months. The mean time of the follow-up period in
the pediatric neurology outpatient clinic was 19 ± 7 months (range
9–42 months).
Of the 62 patients, 34 (55 %) were female, and 28 (45 %) male, the
mean age was 19 ± 7 months. The etiology was structural in 25 (40 %),
metabolic in five (8%), infectious in one (2%) and unknown in 31 (50
%) patients. EEG was obtained in 62 patients and was normal in 40 (65
%) patients. Of 22 patients with initial abnormal EEGs, 17 (77 %) pa-
tients demonstrated improvement. There were no significant intergroup
differences in sex, age, seizure etiology, cranial MRI findings, EEG
findings, EEG improvement rate and duration of the treatment
(p > .05) (Table 1).
There were no clinically relevant hematological, biochemical or
vital sign parameters changes reported in any child. No patient dis-
continued antiepileptic therapy because of treatment-related side ef-
fects.
3.2. Neurodevelopmental outcome
The neurodevelopmental outcome of the infants was assessed using
BSID-III. Eight outcome parameters were scored in the test as follows:
(1) cognitive scale, (2) receptive language, (3) expressive language, (4)
fine motor, (5) gross motor (6) cognitive composite, (7) language
composite, and (8) motor composite. There was no statistically sig-
nificant difference between PB and LEV monotherapy groups for each
outcome parameter on the BSID-III (Table 2).
To make a definite conclusion about the comparison of antiepileptic
drug-induced neurodevelopmental impairment for PB versus LEV
monotherapy, we excluded the infants with neurodevelopmental

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P. Arican, et al. Seizure: European Journal of Epilepsy 80 (2020) 71–74

Table 2
Comparison of the BSID-III mean composite and scale scores of term infants with levetiracetam and phenobarbital monotherapy.
Levetiracetam monotherapy (n = 40) Phenobarbital monotherapy (n = 22) p value

Cognitive scale score 7 ± 5.7 8 ± 5.5 .484

Receptive language scale score 7 ± 5.4 8.3 ± 5.2 .34
Expressive language scale score 7.2 ± 5.6 8 ± 5.5 .599
Fine motor scale score 7.2 ± 5.8 8.2 ± 5.7 .535
Gross motor scale score 7.6 ± 6.4 9.9 ± 6.5 .177
Cognitive composite score 84.6 ± 28.1 90 ± 27.6 .492
Language composite score 82.6 ± 31.7 89.1 ± 31.3 .435
Motor composite score 83.6 ± 34.4 94.3 ± 34.8 .249

BSID-III: Bayley Scales of Infant Development, third edition.

Table 3
Comparison of BSID-III mean composite and scale scores in infants without neurodevelopmental impairment* between levetiracetam and phenobarbital mono-
therapy groups.
Levetiracetam Phenobarbital
Monotherapy Group Monotherapy Group

No of patients BSID-III mean score No of patients BSID-III mean score p value

Cognitive scale score 17 12,1 ± 4,4 14 11,5 ± 3,4 .645

Receptive language scale score 18 11,5 ± 4.8 16 10,7 ± 3,8 .621
Expressive language scale score 18 10,8 ± 4.8 16 13 ± 3,6 .223
Fine motor scale score 22 11,1 ± 4.8 14 11,6 ± 4 .745
Gross motor scale score 19 11 ± 4.7 16 13,1 ± 4,1 .904
Cognitive composite score 17 110.5 ± 22.1 14 107.5 ± 17 .672
Language composite score 11 125.3 ± 23.8 10 117.6 ± 19.9 .431
Motor composite score 16 117.3 ± 25.7 14 116.7 ± 18.8 .943

BSID-III: Bayley Scales of Infant Development, third edition.

* Neurodevelopmental impairment was defined as BSID-III scale scores < 7 or composite scores < 85.

impairment defined as a BSID-III scale score < 7 or a composite
score < 85 for a subgroup comparison. The BSID-III cognitive, lan-
guage, the motor composite performance had better scores in the le-
vetiracetam monotherapy subgroup; however, there was no statistically
significant difference between levetiracetam and phenobarbital mono-
therapy subgroups (Table 3).
4. Discussion
There has been a general concern about the neurodevelopmental
adverse effects of antiepileptic drugs in the developing brain [22–25].
In this study, we identified that exposure to a PB and LEV monotherapy
in term infants with neonatal clinical seizures was associated with si-
milar neurodevelopmental outcomes at 18–24 months of age.
Risk factors for the adverse neurodevelopmental outcomes are un-
derlying etiology, younger age at seizure onset, receiving polytherapy
and side effects of antiepileptic drugs [30,31]. In the present study,
each infant received PB or LEV monotherapy. There were no significant
differences in sex, age, seizure etiology (specific etiology versus un-
known etiology), cranial MRI findings, EEG findings, EEG improvement
rate, and duration of treatment between LEV and PB monotherapy
groups. Because of the relatively homogenous structure of our study
cohort, including the term infants with only neonatal clinical seizures
with an equal rate of specific etiologies (50 %) and of unknown etiol-
ogies (50 %), we compared only monotherapy with LEV or PB for sei-
zures. No adverse hematological, biochemical, or vital sign parameters
changes were reported in any child, and no patient discontinued anti-
epileptic therapy because of treatment-related side effects.
Phenobarbital is the most frequently used antiepileptic drug for
neonatal seizures; however, LEV is currently proposed as an alternative
to PB in recent clinical studies [9–20]. In a recent study, Rao et al.
suggested that LEV is a viable alternative to PB in the treatment of
neonatal seizures [32]. At the time of our study, there was a rando-
mized, blinded controlled phase 1/2 trial of intravenous LEV versus
intravenous PB (clinicaltrials.gov identifier: NCT01720667). This study
aimed to investigate the efficacy of intravenous LEV in terminating
neonatal seizures when administered as first-line therapy compared to
phenobarbital. There was also an open-label phase II study to evaluate
the LEV efficacy and safety as the first-line treatment of neonatal sei-
zures in hypoxic-ischemic encephalopathy [33].
There were limited data in the literature about the effects of anti-
epileptic drugs on neurocognitive outcome measures, and most studies
have focused on the efficacy of the drugs. Maitre et al. reported adverse
neurodevelopmental outcomes after PB and LEV treatment for neonatal
seizures [24]. They assessed neurodevelopmental outcomes with BSID-
III and reported that PB was associated with worse neurodevelopmental
outcomes than LEV. However, in their study, most of the infants were
also included in both groups and received both PB and LEV. Only a few
neonates received monotherapy; thus, it is difficult to make conclusions
about the comparison of neurodevelopmental outcomes in infants with
neonatal seizures receiving PB and LEV monotherapy. In our study, we
identified that exposure to a six to nine months PB and LEV mono-
therapy in term infants was associated with similar neurodevelop-
mental outcomes at 18–24 months of age.
Our study has some limitations. First, this study was a non- rando-
mized study with relatively small sample size and no control group.
Phenobarbital was used as the first-line antiepileptic drug; however,
after the availability of intravenous LEV, we started to use LEV as the
first-line antiepileptic drug. Thus, some neonates were administered PB,
and the others were administered LEV, if available. We retrospectively
enrolled infants who were exposed to PB and LEV monotherapy.
However, there were no significant differences between the two groups
concerning gender, age, seizure etiology, cranial MRI findings, EEG
findings, EEG improvement rate, and duration of treatment. We in-
cluded neonates who received only monotherapy to avoid the neuro-
cognitive effects bias of polytherapy. Also, using the BSID-III test, we
were able to include infants only younger than 42 months old for
neurodevelopmental assessments given that BSID-III test is used for
infants who are 1–42 months. Second, only clinical seizures were in-
cluded in the study population with routine EEG. Electrographic

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P. Arican, et al.
neonatal seizures were not included due to the lack of simultaneous
video-EEG monitoring. Thus, the effects of the seizure burden of the
neurodevelopmental outcomes were not analyzed.
In this cross-sectional study, we designed two study groups (LEV
monotherapy versus PHB monotherapy), including the neonates with
frequent or prolonged seizures, excluding the refractory seizures. This
characteristic feature of the study cohort provided a comparison of
neurocognitive outcomes in term infants treated using LEV and PB
monotherapy for neonatal clinical seizures. The uncoupling effect of PB
was not addressed in this study. Intention to treat design can be per-
formed to answer this question in further prospective randomized stu-
dies. The relatively homogenous structure of the study cohort, in-
cluding the term infants with only neonatal clinical seizures with an
equal rate of specific etiologies (50 %) and of unknown etiologies (50
%) treated with LEV or PB monotherapy, may provide a strong aspect to
this study.
Neonates, with their developing nervous systems, are especially
vulnerable to antiepileptic drug-induced neurodevelopmental impair-
ment. It is essential to identify and minimize the adverse effects of
antiepileptic drugs for neonates with seizures. In our study, mean BSID-
III composite and scale scores showed no statistically significant dif-
ferences between PB and LEV monotherapy groups, even if we excluded
the patients with neurodevelopmental impairment as a subgroup ana-
lysis.
5. Conclusion
Our findings suggest that both LEV and PB therapy were equally
safe as monotherapy for neonatal seizures treatment regarding neuro-
developmental outcomes assessment with BSID-III. Double-blind pro-
spective controlled studies, including efficacy and long-term evaluation
of cognitive outcome, are warranted to establish a reasonable alter-
native of LEV to PB as a first-line antiepileptic treatment.
Funding
The authors received no financial support for this research, au-
thorship, and or publication of this article.
Declaration of Competing Interest
The authors declare no potential conflicts of interest regarding this
research, authorship, and/or publication of this article.
References
[1] Clancy RR. Summary proceedings from the neurology group on neonatal seizures.
Pediatrics 2006;117:23–7.
[2] Jensen FE. Neonatal seizures: an update on mechanisms and management. Clin
Perinatol 2009;36:881–900.
[3] Tekgul H, Gauvreau K, Soul J, et al. The current etiologic profile and neurodeve-
lopmental outcome of seizures in term newborn infants. Pediatrics
2006;117:1270–80. https://doi.org/10.1542/peds.2005-1178.
[4] Booth D, Evans DJ. Anticonvulsants for neonates with seizures. Cochranedatabase
Syst Rev. 2004:CD004218https://doi.org/10.1002/14651858.CD004218.pub2.
[5] McHugh D, Lancaster S, Manganas L. A systematic review of the efficacy of
Levetiracetam in neonatal seizures. Neuropediatrics 2018;49:12–7. https://doi.org/
10.1055/s-0037-1608653.
[6] Bartha AI, Shen J, Katz KH, et al. Neonatal seizures: multicenter variability in
74
Seizure: European Journal of Epilepsy 80 (2020) 71–74
current treatment practices. Pediatr Neurol 2007;37:85–90. https://doi.org/10.
1016/j.pediatrneurol.2007.04.00.
[7] van Rooij LG, Hellström-Westas L, de Vries LS. Treatment of neonatal seizures.
Semin Fetal Neonatal Med 2013;18:209–15.
[8] Pisani F, Spagnoli C. Neonatal Seizures: A Review of Outcomes and Outcome
Predictors. Neuropediatrics 2015;47:12–9. https://doi.org/10.1055/s-0035-
1567873.
[9] Mruk AL, Garlitz KL, Leung NR. Levetiracetam in neonatal seizures: a review. J
Pediatr Pharmacol Ther 2015;20(April):76–89.
[10] Cormier J, Chu CJ. Safety and efficacy of levetiracetam for the treatment ofpartial
onset seizures in children from one month of age. Neuropsychiatr DisTreat
2013;9:295–306.
[11] Falsaperla R, Vitaliti G, Mauceri L, et al. Levetiracetam in neonatal seizures as first-
line treatment: a prospective study. J Pediatr Neurosci 2017;12:24–8. https://doi.
org/10.4103/jpn.JPN_172_16.
[12] Han JY, Moon CJ, Youn YA, Sung IK, Lee IG. Efficacy of levetiracetam for neonatal
seizures in preterm infants. BMC Pediatr 2018;18:131. https://doi.org/10.1186/
s12887-018-1103-1.
[13] Venkatesan C, Young S, Schapiro M, Thomas C. Levetiracetam for the treatment of
seizures in neonatal hypoxic ischemic encephalopathy. J Child Neurol
2017;32:210–4. https://doi.org/10.1177/0883073816678102.
[14] 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. https://doi.org/10.1016/j.pediatrneurol.2010.11.005.
[15] Fürwentsches A, Bussmann C, Ramantani G, et al. Levetiracetam in the treatment of
neonatal seizures: a pilot study. Seizure 2010;19:185–9. https://doi.org/10.1016/j.
seizure.2010.01.003.
[16] Ramantani G, Ikonomidou C, Walter B, Rating D, Dinger J. Levetiracetam: Safety
and efficacy in neonatal seizures. Eur J Paediatr Neurol 2011;15:1–7. https://doi.
org/10.1016/j.ejpn.2010.10.003.
[17] Abend NS, Gutierrez-Colina AM, Monk HM, Dlugos DJ, Clancy RR. Levetiracetam
for treatment of neonatal seizures. J Child Neurol 2011;26:465–70. https://doi.org/
10.1177/0883073810384263.
[18] Rakshasbhuvankar A, Rao S, Kohan R, Simmer K, Nagarajan L. Intravenous leve-
tiracetam for treatment of neonatal seizures. J Clin Neurosci 2013;20:1165–7.
https://doi.org/10.1016/j.jocn.2012.08.014.
[19] Neininger M, Ullmann M, Dahse A, et al. Use of levetiracetam in neonates in clinical
practice: a retrospective study at a German university hospital. Neuropediatrics
2015;46:329–34. https://doi.org/10.1055/s-0035-1558969.
[20] Loiacono G, Masci M, Zaccara G, Verrotti A. The treatment of neonatal seizures:
focus on Levetiracetam. J Matern Fetal Neonatal Med 2016;29:69–74. https://doi.
org/10.3109/14767058.2014.986651.
[21] Kim JS, Kondratyev A, Tomita Y, Gale K. Neurodevelopmental impact of anti-
epileptic drugs and seizures in the immature brain. Epilepsia 2007;48:19–26.
[22] Velez-Ruiz NJ, Meador KJ. Neurodevelopmental effects of fetal antiepileptic drug
exposure. Drug Saf 2015;38:271–8.
[23] Meador KJ, Gevins A, Leese PT, Otoul C, Loring DW. Neurocognitive effects of
brivaracetam, levetiracetam, and lorazepam. Epilepsia 2011;52:264–72.
[24] Maitre NL, Smolinsky C, Slaughter JC, Stark AR. Adverse neurodevelopmental
outcomes after exposure to phenobarbital and levetiracetam for the treatment of
neonatal seizures. J Perinatol 2013;33:841.
[25] Forcelli PA, Janssen MJ, Vicini S, Gale K. Neonatal exposure to antiepileptic drugs
disrupts striatal synaptic development. Ann Neurol 2012;72:363–72.
[26] Bittigau P, Sifringer M, Ikonomidou C, et al. Antiepileptic drugs and apoptosis in the
developing brain. Proc Natl Acad Sci U S A 2002;99:15089–94.
[27] Komur M, Okuyaz C, Celik Y, et al. Neuroprotective effect of levetiracetam on
hypoxic ischemic brain injury in neonatal rats. Childs Nerv Syst 2014;30:1001–9.
[28] Falco-Walter JJ, Scheffer IE, Fisher RS. The new definition and classification of
seizures and epilepsy. Epilepsy Res 2018;139:73–9.
[29] Johnson S, Moore T, Marlow N. Using the Bayley-III to assess neurodevelopmental
delay: which cut-off should be used? Pediatr Res 2014;75:670–4.
[30] Mohanraj R, Brodie MJ. Early predictors of outcome in newly diagnosed epilepsy.
Seizure 2013;22:333–44.
[31] Meador KJ, Gevins A, Leese PT, Otoul C, Loring DW. Neurocognitive effects of
brivaracetam, levetiracetam, and lorazepam. Epilepsia 2011;52:264–72.
[32] Rao LM, Hussain SA, Zaki T, et al. A comparison of levetiracetam and phenobarbital
for the treatment of neonatal seizures associated with hypoxic–ischemic en-
cephalopathy. Epilepsy Behav 2018;88:212–7.
[33] Favrais G, Ursino M, Mouchel C, 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:e022739https://doi.org/10.1136/bmjopen-2018-022739.