Published online: 2020-12-08

Review Article

Recent Advances in the Diagnosis and Treatment

of Neonatal Seizures
Debopam Samanta1

1 Child Neurology Section, Department of Pediatrics, University of Address for correspondence Debopam Samanta, MD, Child
Arkansas for Medical Sciences, Little Rock, Arkansas, United States Neurology Section, Department of Pediatrics, University of Arkansas
for Medical Sciences, 1 Children’s Way, Little Rock, AR 72202, United
Neuropediatrics States (e-mail: dsamanta@uams.edu).

Abstract Seizures are the most common neurological emergency in the neonates, and this age
group has the highest incidence of seizures compared with any other period of life. The
author provides a narrative review of recent advances in the genetics of neonatal
epilepsies, new neonatal seizure classification system, diagnostics, and treatment of
neonatal seizures based on a comprehensive literature review (MEDLINE using PubMED
and OvidSP vendors with appropriate keywords to incorporate recent evidence),

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personal practice, and experience. Knowledge regarding various systemic and post-
zygotic genetic mutations responsible for neonatal epilepsy has been exploded in
recent times, as well as better delineation of clinical phenotypes associated with rare
neonatal epilepsies. An International League Against Epilepsy task force on neonatal
seizure has proposed a new neonatal seizure classification system and also evaluated
the specificity of semiological features related to particular etiology. Although
continuous video electroencephalogram (EEG) is the gold standard for monitoring
neonatal seizures, amplitude-integrated EEGs have gained significant popularity in
resource-limited settings. There is tremendous progress in the automated seizure
detection algorithm, including the availability of a fully convolutional neural network
using artificial machine learning (deep learning). There is a substantial need for
ongoing research and clinical trials to understand optimal medication selection (first
line, second line, and third line) for neonatal seizures, treatment duration of antiepi-
leptic drugs after cessation of seizures, and strategies to improve neuromorbidities
Keywords such as cerebral palsy, epilepsy, and developmental impairments. Although in recent
► neonatal seizures times, levetiracetam use has been significantly increased for neonatal seizures, a
► epilepsy multicenter, randomized, blinded, controlled phase IIb trial confirmed the superiority
► amplitude-integrated of phenobarbital over levetiracetam in the acute suppression of neonatal seizures.
EEG While there is no single best choice available for the management of neonatal seizures,
► treatment institutional guidelines should be formed based on a consensus of local experts to
► phenobarbital mitigate wide variability in the treatment and to facilitate early diagnosis and
► levetiracetam treatment.

received © Georg Thieme Verlag KG DOI https://doi.org/

June 12, 2020 Rüdigerstraße 14, 70469 Stuttgart, 10.1055/s-0040-1721702.
accepted after revision Germany ISSN 0174-304X.
September 16, 2020
Recent Advances in the Diagnosis and Treatment of Neonatal Seizures Samanta

Introduction encephalitis (►Table 1). Seizure etiology is different in

Seizures are the most common neurological emergency in the
neonates, and this age group has the highest incidence of
seizures compared with any other period of life.1 Neonatal
seizures are associated with at least 10 seconds (can be shorter
if associated with clinical changes) of paroxysmal, abnormal,
and sustained ictal rhythm (a repetitive and evolving pattern
with a minimum of 2 microvolts amplitude) in the electroen-
cephalogram (EEG).2 Neonatal seizures affect 1 to 3 per 1,000
term life births with high mortality and neuromorbidity.3,4
Due to underreporting, the value of using national birth
certificate data are limited in the understanding of the epide-
miology of neonatal seizures in most countries.5 In the last
5 years, tremendous progress has been made in the genetic
diagnosis of neonatal epilepsy and the development of an
automated seizure detection system. A new classification
system has been proposed for neonatal seizures, and some
preliminary work to link seizure semiology to a particular
etiology has been initiated. Higher overall seizure burden has
extreme and very preterm compared with the term and
near-term neonates. Intracranial/intraventricular hemorrhage
is the most common cause of seizures in neonates born at less
than 32 weeks of gestation, but in moderate and late prema-
ture infants, the most common etiology is HIE. A small number
of neonates can have seizures secondary to easily correctable
causes such as hypoglycemia and electrolyte abnormalities.
However, 15 to 25% of neonatal seizures can be an initial
manifestation of neonatal epilepsy.6,7 Knowledge regarding
various systemic and postzygotic mutations responsible for
neonatal epilepsy has been exploded in recent times. The
genetic underpinning of many neonatal epilepsies have
been discovered secondary to structural (lissencephaly, hemi-
megalencephaly), metabolic (pyridoxine-dependent seizures,
glycine encephalopathy, molybdenum cofactor deficiency,
sulfite oxidase deficiency, etc.), or nonstructural functional
impairment in the cortex (KCNQ2, KCNT1, CDKL5, STXBP1, etc.).
Although most neonatal seizures are due to acute symp-
tomatic causes, there is increasing recognition of neonatal

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been associated with higher neuromorbidity, but the indepen-
dent negative effect of seizure over and above the underlying
etiology has not been definitively proven. Similarly, it is
currently unknown if prompt and effective treatment of
neonatal seizures can definitively improve developmental
outcomes. Additionally, substantial controversy exists in the
therapeutic choice in the management of neonatal seizures
and the use of the appropriate sequence of antiseizure med-
icines for acute control of seizures. Unfortunately, the preva-
lence of neuromorbidity remains high in spite of a significant
reduction in the early mortality from neonatal seizures in the
last few decades. In this review, the author highlights pivotal
studies of recent times to delineate recent progress in the
diagnosis and management of neonatal seizures.
Etiology
Most neonatal seizures are symptomatic and secondary to
acute neuronal injuries, such as secondary to hypoxic-ischemic
encephalopathy (HIE), intracranial hemorrhage, or meningo-
onset epilepsy syndromes, both self-limiting, benign variants,
and severe, early epileptic encephalopathies. Two severe forms
of neonatal onset electroclinical syndromes are Ohtahara
syndrome and early neonatal myoclonic epilepsy. The etiolo-
gies of these epileptic encephalopathies are diverse. Although
the neonates with the Ohtahara syndrome present with tonic
seizures and spasms more commonly than the early neonatal
myoclonic epilepsy, now both of these are considered part of
the same early epileptic encephalopathy spectrum. Approxi-
mately 60% of patients in a cohort of 28 patients with early-
onset epileptic encephalopathy without cortical anomaly had
pathogenic genetic mutations involving KCNQ2, STXBP1,
SCN2A, PNPO, PIGA, and SEPSECs.8 The yield of genetic testing
in early life epilepsy of any cause is approximately one-third.9
However, the previous study showed a significantly increasing
yield (nearly double) in a subgroup of neonates with early
burst suppression patterns in EEG in the absence of cortical
malformation. Among all genetic mutations, KCNQ2, STXBP1,
and SCN2A were most frequently detected. Other associated
mutations associated with Ohtahara syndrome are SLC25A22,

Table 1 Important causes of neonatal seizures

Hypoxic-ischemic encephalopathy
Acute metabolic derangements
Inborn errors of metabolism
Cerebrovascular insult
Central nervous system infection
Developmental structural
cerebral malformations
Epilepsy syndromes
Genetic syndromes
The most common cause in term neonates (60% of moderate to late preterm neonates)
Hypoglycemia, hypocalcemia, hypomagnesemia, hypo- or hypernatremia, withdrawal
syndromes with maternal drug use during pregnancy
(metabolic causes may represent 10% of neonatal seizures)
Pyridoxine-dependent seizures, nonketotic hyperglycinemia
Perinatal stroke, intracerebral hemorrhage, intraventricular hemorrhage (most common
cause in premature neonates), subdural hemorrhage, subarachnoid hemorrhage
Intracranial hemorrhage cause seizures in a third of preterm neonates and may be the
most common etiology for neonates < 32 weeks’ gestation.
Bacterial, viral, or fungal meningoencephalitis, intrauterine (TORCH) infections
Cerebral dysgenesis, lissencephaly, hemimegalencephaly
Benign neonatal familial convulsions, Ohtahara syndrome, early myoclonic epilepsy
KCNQ2, KCNT1, CDKL5, STXBP1, etc. (15–25%)

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 Recent Advances in the Diagnosis and Treatment of Neonatal Seizures
Table 2 Comparison between amplitude-integrated and conventional video EEGs
Amplitude-integrated EEG (aEEG)
Bandpass filtered, rectified, and compressed, semilogarithmic
EEG display with a line drawn between upper and lower peaks
of the processed signal
Two to four recording electrodes with a ground electrode
Usually not linked to other physiologic parameters
Easier to set up
Interpretation readily available
Misses short duration seizures, focal seizures with no
involvement of the central-parietal regions, as well as ictal
discharges of lower amplitude
Accuracy of sensitivity and specificity variable and depend on
the experience of the raters, patient population, and the
availability of raw tracing for review
Abbreviation: EEG, electroencephalogram.
ARX, STXBP1, PLCB1, PNKP, CDKL5, PNPO, PIGA, SEPSECS, and
SCN3A.
During recent times, clinical phenotypes associated with
rare neonatal epilepsies have been refined. For example, KCNQ2
encephalopathy has been noted to have asymmetric tonic
seizures in association with apnea and desaturations, with or
without a unilateral or bilateral clonic component afterward.
Besides early and persistent tonic seizures and spasms, early
resolution of the burst suppression pattern and signal abnor-
mality in the deep gray matter may also suggest a diagnosis of
KCNQ2 epileptic encephalopathy.10 Early treatment with oxcar-
bazepine or carbamazepine can be considered in these patients
before confirmation of the KCNQ2 diagnosis.11 Another exam-
ple of precision-based therapy is the use of quinidine in
migrating focal seizure patients secondary to KCNT1 encepha-
lopathy.12 However, for the vast majority of the cases, genetic
confirmation is necessary due to significant phenotypic and
genotypic heterogeneity. New types of epileptic encephalopa-
thies such as SLC13A5 (citrate transporter defect), PNPO, PIGA,
ARX (males), CASK (males), PLCB1, TBC1D24, QARS, and SIK1
have been described with the elucidation of clinical, EEG, and
neuroradiologic phenotypes.13
In appropriate clinical settings, early genetic testing is
necessary to provide education about family planning, to
prevent unnecessary testing, and to consider precision-
based therapy, if applicable. However, there are several
different types of genetic testing, such as chromosomal
microarray, neonatal-infantile epilepsy-specific next-gener-
ation sequencing panel, or whole-exome sequencing, and the
type of genetic testing to be utilized and in what sequence or
in combination has not been standardized.
Classification and Seizure Semiology
An International League Against Epilepsy (ILAE) task force on
neonatal seizure has been established to formulate a new
neonatal seizure classification system to facilitate etiologic
Samanta
Conventional video EEG (cEEG)
Display of ongoing waveforms across multiple channels
Minimum of 9–11 recording electrodes
Frequently linked to ECG, EMG, SpO2, and video for com-
prehensive assessments any event
Needs expert technician with knowledge of 10/20 EEG
measuring system
Needs expert neurophysiologist
Better sensitivity and specificity for detection of neonatal
seizures
The current gold standard for diagnosis of neonatal seizures
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diagnosis and outcome prediction.14 This group emphasized
two particular points: electrographic-only seizures as one of
the prevalent seizure types in the neonate and clinical events
should have accompanying ictal changes in the EEG for confir-
mation as seizures. This task force also proposed to exclude
generalized seizures from the classification scheme as all
seizures in the neonatal age group are focal in onset. After
differentiating seizures as electroclinical versus electrographic
only, electroclinical seizures have been distinguished based on
the most prominent clinical sign rather than entirely following
the ILAE seizure classification system of 2017, which classifies
seizures based on the appearance of the first symptom or sign.
Additionally, sensory seizures or classification based on
awareness were advised to be not included in the classification
system as these are difficult to confirm in neonates.
ILAE neonatal seizure task force reviewed 147 different
seizures to come up with some semiological clues for etiologic
diagnosis.15 The group noted that clonic seizures were partic-
ularly associated with vascular etiologies, such as ischemic
stroke and hemorrhage, while tonic seizures and sequential
seizures (evolving features of various clinical signs) were
associated with genetic etiologies. Myoclonic seizures were
most commonly related to inborn errors of metabolism, and
these were difficult to distinguish from nonepileptic myoclo-
nus without confirmation by EEGs. Electrographic seizures
were prevalent in neonates with HIE or infections. Premature
neonates also had more electrographic-only seizures. During
the review of these EEGs, it was also noted that autonomic and
automatic seizures, as well as seizures associated with behav-
ioral arrest, were difficult to diagnose without EEGs, and these
seizures were very rarely present in isolation. Previously,
several of these seizures with alteration in the heart rate,
breathing, blood pressure, and pupillary dilatation were
labeled as “subtle seizures.”
With the widespread use of video EEG, it has been noted
that the vast majority of seizures are electrographic-only
with no or only subtle clinical signs. Electrographic-only
Neuropediatrics
Recent Advances in the Diagnosis and Treatment of Neonatal Seizures
seizures can be secondary to electromechanical dissociation,
particularly after administration of antiepileptic drugs
(AEDs) or in association with severe neuronal injury. Prema-
ture infants were noted to have a higher burden of exclusive
subclinical seizures. Glass et al retrospectively evaluated
seizure patterns in 92 premature neonates and confirmed
this finding.16
Neonates also cannot communicate about aura, and clinical
manifestation mostly becomes evident if the ictal discharge
involves the motor cortex. Moreover, various equipment and
personnel surrounding the critically sick neonate prevent the
unobstructed view to confirm clinically subtle seizures. Addi-
tionally, clinical symptoms such as apnea or myoclonus can be
present in neonates as a nonepileptic phenomenon.
Electroencephalography
As it becomes more apparent that neonatal seizures can be
vastly subclinical or with subtle signs (especially after the
administration of AEDs), confirmation of neonatal seizures
and responsiveness to AEDs have been performed using
video EEGs, which can reduce high false positive and nega-
tive rates of seizure diagnosis compared with diagnosis by
only clinical observation. Wietstock et al showed that video
EEG could help to confirm or to rule out seizures in approxi-
mately one-third of neonates with seizure-like activities.17
Ideally, the seizure burden should be quantified to reduce
inter- and intrarater differences originating for qualitative
visual inspection of the EEG. The total seizure burden can be
measured objectively by calculating the duration of recorded
seizures in minutes, mean seizure duration, and the total
number of seizures over a particular time. The use of an
automated seizure detection algorithm (SDA) may be neces-
sary for the measurement of the quantitative seizure burden
in routine clinical practice.
There are some characteristic ictal and interictal patterns
noted in EEG that can facilitate etiologic diagnosis: Zip-like
electrical discharges in HIE, suppression–burst pattern in
neonatal epileptic encephalopathies, theta pointu alternant
of benign neonatal convulsions, persistent focal sharp or
slow waves in localized lesions, and quasi-periodic focal or
multifocal pattern in neonatal herpes simplex encephalitis.
Though continuous video EEG (cEEG) is the gold standard for
monitoring neurological function in newborns, it is, unfortu-
nately, difficult to obtain in most parts of the world due to the
need for 24
7 availability of technicians to apply electrodes, to
maintain the integrity, and to provide continuous monitoring
of the neurophysiologic data. Additionally, the availability of
the clinical neurophysiologists is limited throughout the day—
particularly times other than the office hours—for live inter-
pretation and confirmation of neonatal seizures. Due to these
resource-intensive requirements, amplitude-integrated EEGs
(aEEGs) that utilize reduced montage EEGs with limited cover-
age have gained widespread popularity in neonatal intensive
care units (NICUs) all over the world. In aEEGs, brain waves are
compressed, heavily filtered, and displayed in a semilogarith-
mic fashion, with several hours of EEG data visible on a single
bedside screen. Studies demonstrated (►Table 2) that aEEGs
Neuropediatrics
Samanta
could detect neonatal seizures in up to 80% sensitivity, espe-
cially if seizures involve the central part of the brain. Confirma-
tion by expert reviewers and availability of raw data for analysis
—both difficult to obtain in day-to-day operation—significantly
increase the sensitivity and specificity of seizure detection by
aEEGs. Without these, the presence of biological and environ-
mental artifacts remarkably decreases specificity. Moreover,
neonatal seizures in the era of therapeutic hypothermia—with
lower amplitude and shorter duration seizures—can be more
frequently missed in aEEG evaluations. Besides, seizures in
premature neonates may disproportionately involve occipital
regions and may remain undetected in aEEGs. Rakshasbhu-
vankar et al reviewed five studies of aEEGs and detected
sensitivity of 76% and a median specificity of 85%, with the
availability of raw EEG channels to review.18 However, in a
prospectively conducted study, the sensitivity was noted to be
much lower at 33.7% for individual seizures.19 Although sensi-
tivity was 86% for identifying any seizures, specificity was low
at 50% due to a high rate of false positivity. Besides, in this last
study, a significant proportion of the neonates had HIE and
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received hypothermia and AED treatment, which might alter
amplitude and propagation of seizures to decrease sensitivity;
however, both hypothermia and use of AEDs are standard of
treatment, and aEEG needs to overcome these constraints in
the real-world application.
Due to logistical difficulties associated with monitoring and
reporting of seizures, more attention has been directed to the
automated detection of seizures from both cEEGs and aEEGs.
Feature extraction from preprocessed EEGs followed by the use
of classifiers and decision-making about seizure versus not
seizure (both as a binary and a probabilistic trace) is the basic
framework of automated seizure detection.20 Mathieson et al
used a large data set to validate their SDA with reasonable
seizure detection rates.21 False-positive detections were mostly
due to artifacts from pulse, respiration, and sweating. False-
negative detections were noted in brief seizures, as well as ictal
discharges with dysrhythmic with complex morphology, and of
lower amplitude. This type of sophisticated SDA can minimize
missed seizure diagnosis stemmed from delayed review by
human experts and prevent under- and overtreatment. How-
ever, which thresholds to use to have an appropriate detection
rate without excessive false alarms are still unknown. More-
over, the performance of these algorithms needs to be evaluated
in multicenter, randomized controlled trials (RCTs).
In addition, the machine needs to learn different features as
epileptic versus artifactual, primarily by inputs from human
experts. Unfortunately, experts may have only modest agree-
ment to classify individual seizure as a true ictal event versus
changes due to artifact, and the machine’s ability to differenti-
ate these will be dependent on that. Moreover, the availability
of the experts to help with feature extraction and provision of
input may again make the system labor-intensive. Besides the
use of multiple classifiers, novel mechanisms to avert the need
for expert input haven been explored. Fully convolutional deep
neuronal networks have been developed that can outclass the
current state-of-the-art support vector machine-based algo-
rithm, which is dependent on hand-crafted data extraction.
O’Shea et al showed that the fully convolutional neural network
 Recent Advances in the Diagnosis and Treatment of Neonatal Seizures
could classify raw EEG features as seizures versus non-seizures
comparable to a previously developed algorithm that had used
heavily engineered features.22
Although complete replacement of the expert human
reviewer is not possible at this time, user-friendly alarm to
notify bedside providers about the probability of seizures
can be particularly helpful in the early diagnosis and treat-
ment of neonatal seizures.
Neuroimaging
Recent evidence suggested that approximately one-quarter
neonates with encephalopathy continue to receive computed
tomography (CT) head during the evaluation process, despite
concern related to the negative consequence of radiation expo-
sure in the immature brain, including cognitive impairment and
late development of malignancy.23 Moreover, CT is inferior to
magnetic resonance imaging (MRI) for the detection of lesions
in the deep gray matter, brain stem, cerebellum, and white
matter. Except in cases of traumatic birth with low hemoglobin
or associated coagulopathy, ultrasound head followed by MRI is
a better way to evaluate structural brain injuries. It is well
established that MRI is superior in the diagnosis of cerebral
venous sinus thrombosis, cerebral dysgenesis, as well as delin-
eation of the full spectrum of the injury.24 Recently, the use of
magnetic resonance spectroscopy has been investigated to
determine its role in the provision of additional information
over routine MRI.25 It was noted to be particularly useful for the
evaluation of inborn error of metabolism and for prognostica-
tion of HIE (deep gray matter high lactate-to-N-acetyl aspartate
ratio has been associated with poor prognosis). The usefulness
of comprehensive MRI injury scores—including diffusion-
weighted and spectroscopic images—have been investigated
to provide long-term prognosis.26 Though long accusation time
of MRI is a concern, research related to rapid MRI sequences is
currently ongoing. Czech and Pardo showed that the use of rapid
MRI sequencing caused lower utilization of CTscan in a neonatal
cohort with faster identification of stroke or hemorrhage;
however, this ultimately did not decrease the length of the
hospital stay of this cohort.27
Treatment
Challenges in the Treatment of Neonatal Seizures and
Diagnosis/Treatment Algorithms
The basic treatment paradigm of neonatal seizures has
remained constant: confirmation of the clinical event as
seizure; the stability of airway, breathing, and circulation;
examination of glucose and electrolytes; and evaluation for
sepsis and structural injury in the brain (primarily by head
ultrasound). Clinical seizures with focal tonic or clonic semiol-
ogy in the high-risk population can be treated with AEDs prior
to video EEG confirmation. However, seizure-like activities in
neonates with ambiguous or subtle clinical presentation,
particularly in stable patients, should be confirmed with video
EEG before initiation of treatment. Although there is no single
best choice available for the management of neonatal seizures
(except relatively recent NEOLEV-2 study suggesting the
Samanta
efficacy of phenobarbital [PHB] for acute suppression of seiz-
ures), an institutional guideline should be created based on a
consensus of local experts to mitigate wide variability in the
management and to facilitate early diagnosis and treatment.
A suggested diagnostic and treatment algorithms are pre-
sented in ►Figs. 1 and 2. Although the implementation of
EEG monitoring significantly increases the diagnostic sensi-
tivity and specificity of seizures, suboptimum care with both
over- and undertreatment may persist. Rennie et al noted that
in a cohort of 214 neonates—monitored with cEEG—that 19%
with electrographic seizures did not receive AEDs and also 19%
of the neonate without electrographic seizures received
AEDs.28 Harris et al showed that implementation of a stan-
dardized institutional protocol could significantly increase not
only an adherence to the treatment guideline but also
decreased progression to status epilepticus and length of the
hospital stay in the survivors.29
First- and Second-Line Therapy and Relevant Studies
Since two RCTs by Painter et al and Boylan et al, no other
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significant RCTs related to neonatal seizures have been per-
formed until recently, when two studies—NEMO and NEOLEV2
—were completed.30–33Painter et al performed the first RCT to
compare PHB and phenytoin (PHT) as first-line therapy for
neonatal seizures. This study was conducted before therapeu-
tic hypothermia became the standard of care for the manage-
ment of HIE. Both PHB and PHT were noted to be ineffective in
controlling seizures in approximately half of the neonates with
an additional benefit when switched to the other agent. Out of
59 neonates who had received randomly either of these AEDs
to achieve targeted plasma concentration, 43% had complete
control of seizures in the PHB group (13 out of 30), while 45%
had seizure control in the PHT group (13 of 29 neonates).
Neonates with inadequate control of seizures (any seizure
lasting longer than 2.5 minutes or cumulative seizure activity
more than 2.5 minutes over a 5-minute period) were treated
with a combination of both PHT and PHB; 57% patients in the
initial PHB group became seizure-free and 62% patients of the
initial PHT group. There was no difference in responsiveness
between these two groups, and neonates with mild seizures or
with seizures with decreasing in severity prior to the treat-
ment responded better irrespective of the treatment assign-
ment. However, the use of PHT as first-line therapy for
neonatal seizures remained less popular as reliable serum
concentration (particularly with oral administration) is chal-
lenging to maintain due to its variable absorption and complex
pharmacokinetics. In recent times, fosphenytoin has been
used more frequently than PHT due to less cardiotoxic and
extravasation-related side effects.
PHB remained the most commonly used AED in the neonatal
age group; however, several recent studies highlighted the
ineffectiveness of PHB therapy. Glass et al retrospectively
evaluated seizure patterns in 92 premature neonates and
approximately two-thirds of preterm neonates did not respond
to the first dose of PHB.16 Dwivedi et al retrospectively
reviewed 50 term neonates (> 35 weeks’ gestation) with HIE
and seizures treated with PHB.34 They noted that higher MRI
injury scores in the white matter, cortex, and watershed
Neuropediatrics
Recent Advances in the Diagnosis and Treatment of Neonatal Seizures
Fig. 1 Diagnostic algorithm for neonatal seizures.
regions were associated with the ineffectiveness of PHB as first-
line therapy. Moreover, moderate-severe background
abnormality was also associated with poor response to PHB.
Rao et al retrospectively evaluated the effectiveness of PHB and
levetiracetam (LEV) as a first-line AED in a cohort of neonates
with HIE and seizures.35 LEV was noted to be associated with
faster seizure freedom, even after adjustment of initial seizure
frequency and HIE severity. However, as with previous other
studies, the major limitation of this particular study was the
retrospective design and nonrandom treatment allocation.
In recent times, LEV use has been significantly increased
due to its relatively benign side effect profile and already
approved use up to 1 month of age. More than 10 published
reports (mostly retrospective but at least three prospective)
suggested that LEV has modest efficacy against neonatal
seizures.36–48 Additionally, LEV was noted to spare neuronal
apoptosis in animal studies contrary to PHB. The efficacy of
LEV was reported to be 30 to 84% from uncontrolled case
series, primarily in retrospective studies. Besides, in many
studies, LEV was used as a second-line therapy, and video
EEG was not utilized for confirmation of seizures. Most
importantly, these studies did not have an adequate control
group to compare LEV to another first-line agent. McHugh
et al performed a systematic review of the efficacy of LEV in
neonatal seizures.49 The authors pooled five previously done
studies (total 102 neonates) and compared the efficacy with
Neuropediatrics
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historical cohorts of neonatal seizures treated with PHB.
They noted LEV is efficacious as first-line therapy in 77% of
cases and 63% as second-line therapy and suggested at least
as or more effective than PHB (46% efficacy as first-line
therapy). Gowda et al performed another RCT in India
comparing PHB with LEV as first-line treatment of neonatal
seizures in 100 neonates with focusing on the primary
outcome of seizure freedom for 24 hours after receiving 1
or 2 doses of these AEDs.37 Neonates treated with LEV
achieved better seizure control (86% vs. 62%, p  0.01) than
PHB with a better side effect profile. However, limitations of
the study were the unavailability of EEG for evaluation and
lack of therapeutic drug level monitoring.50
Sharpe et al compared PHB and LEV as a first-line AED in a
multicenter, randomized, blinded, controlled phase IIb trial
(NEOLEV-2).32 Approximately 80% neonates (< 2 weeks old,
36–46 weeks’ gestation) in the PHB group (24 out of 30) were
responders (achieving and maintaining seizure freedom for
24 hours) compared with only 28% in the LEV group (15 of 53;
p < 0.001). The similar higher efficacy of PHB compared with
LEV was noted when the efficacy was calculated at 1 and
48 hours after the infusion. However, more neonates had
adverse effects in the PHB group. LEV and PHB were given as
40 and 20 mg/kg infusion, respectively, with an additional
bolus of 20 mg/kg of the same agent if any seizures after
15 minutes of completion of the infusion. A much higher
 Recent Advances in the Diagnosis and Treatment of Neonatal Seizures
Fig. 2 Proposed treatment algorithm for neonatal seizures.
response rate of PHB in this study is likely multifactorial:
concurrent use of hypothermia, a lower seizure burden than
other studies, such as the study by Painter et al, and early
treatment initiation due to prompt detection of seizures.
Efficacy in the LEV group improved by 7.5% when 20 mg/kg
bolus dose was added to the first bolus dose of 40 mg/kg. LEV
had improved efficacy in infants with a low seizure burden,
but some of these seizures might have stopped spontane-
ously. In the LEV group, approximately 49% of patients were
seizure-free in the first hour compared with 28% at 24 hours
and 17% at 48 hours to suggest seizure recurrence secondary
to potentially falling LEV level. Further studies with a higher
dose of LEV are needed. Moreover, seizures in extreme
preterm neonates (< 28 weeks) have noted to be poorly
responsive to LEV. Kurtom et al noted that 74% of 61 neonates
did not respond to LEV monotherapy of dose up to 80 mg/kg/
day.51 However, PHB’s better effectiveness compared with
LEV in the acute control of seizures should be interpreted
with two caveats: long-term neurodevelopmental outcome,
not the acute suppression of seizures, is the best measure of
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efficacy and PHB has been associated with more acute and
chronic adverse effects.
In contrast to the accepted role of benzodiazepines as the
first-line therapy for seizures in older children and adults,
the efficacy of benzodiazepine has not been thoroughly
investigated for neonatal seizures. Dao et al studied the
use of midazolam (intravenous or intranasal) as first-line
therapy for neonatal seizures in 72 neonates.52 Though
effectiveness could not be confirmed due to the absence of
EEG monitoring, midazolam was well tolerated in both
routes. GABAergic drugs are speculated to be less effective
inhibitors during the neonatal age group due to a higher
relative expression of chloride transporters NKCC1, which
leads to higher intracellular chloride concentration. It has
been proposed that GABAergic drugs may lead to depolari-
zation and excitation in immature neurons, rather than usual
inhibition, due to high chloride levels inside the cell.
Pressler et al reported an open-label study of bumetanide
(NEMO trial), an NKCC1 blocker, in 14 infants with HIE as an
add-on therapy to PHB.33 This study was designed to
Neuropediatrics
Recent Advances in the Diagnosis and Treatment of Neonatal Seizures
measure the efficacy of this adjunctive treatment to reduce
80% electrographic seizures without the need for the addi-
tion of other AEDs. Although five infants had seizure reduc-
tion, the study was terminated early as three of the surviving
infants developed hearing loss. Other adverse effects, such as
diuresis, hypotension, etc., were also reported. Soul et al
evaluated the effectiveness of adjunctive bumetanide for the
treatment of neonatal seizures in another phase I/IIb study.53
Neonates (33–44 weeks’ gestations) with continuing seiz-
ures after 20 to 35 mg/kg of PHB enrolled in either of these
two groups to receive another dose of PHB and placebo or to
receive PHB with bumetanide. At baseline, total seizure
burden—measured 2 hours before the randomization—was
higher in the bumetanide group than the control. There was a
significantly higher reduction of the seizure burden in the
bumetanide group in a 4-hour period after the study drug
administration compared with the control group. A total of
three infants (two in the bumetanide group and one in the
non-randomized group) developed hearing loss in this study.
Studies explicitly looking into second-line therapy for
neonatal seizures are also lacking. As described before,
intermittent seizure recurrence after the first-line therapy
is usually managed with a further bolus dose of the initial
medicine or another AED available in the intravenous forms.
A particular choice of the AED is dependent on the comor-
bidities (for example, LEV may be preferred over PHT in the
presence of cardiovascular instability or hepatic dysfunc-
tion), preference of the treating physicians, institutional
guidelines, and availability of a particular AED.
Treatment of Refractory Seizures
Refractory seizures to first- or second-line therapies are quite
challenging to manage.54 Although neonates usually do not have
continuous 30 minutes seizures, seizure burden > 30 minutes
over an arbitrary 1-hour period has been considered as neonatal
status epilepticus by some experts. Midazolam infusion has
been utilized often—not based on a lot of evidence—in case of
frequent seizures even after the use of second-line therapies,
particularly in status epilepticus. A small prospective random-
ized control study was done to compare lidocaine with mid-
azolam infusion/clonazepam in term and preterm infants with
seizures unresponsive to PHB. There were no responders among
six neonates in the benzodiazepine group.30 Lidocaine use has
remained limited due to the risk of arrhythmia, especially in the
settings of concurrent PHT use or underlying congenital heart
disease.55,56 Huntsman et al recently described the use of
ketamine infusion as a viable therapeutic option for refractory
neonatal seizures.57,58 Only a handful of cases of ketamine use in
neonatal age group has been reported, and efficacy and safety of
ketamine in neonates have not been validated in a large cohort.
The ketogenic diet also has been rarely used in neonatal
encephalopathy associated with refractory epilepsy.59
As there is no consensus regarding the most appropriate
way to treat neonatal seizures and no Food and Drug Admin-
istration-approved AED in this age group, many other AEDs
such as topiramate has been utilized in neonates with refrac-
tory seizures. However, Courchia et al recently published a case
series of four premature neonates who developed clinical and
Neuropediatrics
Samanta
radiographic signs of necrotizing encephalitis after receiving
topiramate for seizure treatment.60 Further research regarding
the safety of topiramate use is needed.
Another peculiar issue in the management of neonatal
seizures is to determine the duration of AED therapy as most
seizures are secondary to acute neuronal insult and do not
require long duration AED treatment. Shellhaas et al demon-
strated that sending a neonate home with an AED after
acute symptomatic seizures is dependent on the practice of
the hospital rather than any other causes.61 PHB was noted to be
most frequently continuing AEDs despite concern about its
negative effect on neurodevelopment in the long term. This
might be secondary to fear of seizure recurrence and not based
on any robust scientific evidence.
Precision Therapy
With the rapid advancement of precision therapy, early and
prompt diagnosis of genetic etiologies may be valuable to offer
a particular treatment. Neonate with evidence of HIE should
not be excluded from genetic evaluation if the clinical/neuro-
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imaging characteristics do not fit a typical case of HIE. As
voltage-gated sodium and potassium channels colocalize at
the neuronal membrane, AEDs acting on the sodium channels
has been proposed to have modulating effects on both chan-
nels. Pisano et al described early and effective treatment with
sodium channel blockers in 15 patients with KCNQ2 encepha-
lopathy; 11 patients had adequate seizure control in 2 weeks.11
However, 12 out of 15 patients still developed moderate-
severe developmental delays. Additionally, ezogabine, a po-
tassium channel opener, can be beneficial for KCNQ2 epileptic
encephalopathy. However, as this particular encephalopathy
can be associated with both dominant negative and gain of
function mutations, a thorough assessment is necessary to
determine the secondary changes related to the mutation.
Sodium channel blockers, particularly PHT, have been noted to
be beneficial in patients with a gain of function SCN2A patho-
genic variants.62 Pharmacogenomic exploration can also be
important in the management of neonatal seizures. More
robust research is needed, with international collaborative
efforts to enroll neonates in gene-specific clinical trials.
There are continuing refinement in the diagnosis and
treatment of rare neonatal epilepsies. It has been recently
discovered that not all patients with pyridoxine-dependent
epilepsy will uniformly respond to pyridoxine supplementa-
tion, and, on the other hand, responsiveness to pyridoxine is
not a confirmation of the diagnosis of pyridoxine-dependent
seizures. In general, genetic testing to detect ALDH7A1
mutations may be necessary for confirmation of pyridox-
ine-dependent epilepsy. Recently, it has been discovered that
other than pyridoxine supplementation, lysine-restricted
diet and arginine supplementation may improve the out-
come of patients with pyridoxine-dependent seizures.63
Special consideration should be given to the diagnosis of
pyridoxine-5-phosphate oxidase deficiency, as these
patients may also respond—mostly partially—to pyridoxine
supplementation. No specific disease-modifying therapy
exists for sulfite oxidase deficiency; however, a narrow
temporal window of intervention by daily infusions of cyclic
 Recent Advances in the Diagnosis and Treatment of Neonatal Seizures
pyranopterin may exist in children with molybdenum cofac-
tor deficiency, prior to the onset of brain injury.64
Outcome
Neonatal seizures are mostly secondary to acute brain
injury and commonly associated with etiology-related mor-
tality and morbidity (epilepsy, cerebral palsy, intellectual
disability). Death secondary to neonatal seizure has
decreased from 40 to 20% due to the advancement of
sophisticated NICU care; however, neuromorbidity
remained static at 40 to 60% over the last decade. Glass
et al recently published a paper regarding the outcome in
neonatal acute symptomatic seizures.65 Out of 144 neo-
nates, 37 (26%) died in infancy. Eighty-five percent of the
remaining survivors were followed, and 8 out of 87 children
developed epilepsy at the mean age of 4.9 years. Cerebral
palsy and cognitive impairments were present in 21 and
13% of children, respectively. Importantly, the continuation
of antiseizure medications did not decrease the risk of
epilepsy. Pisani et al reported 112 neonates with seizures
over a 13-year period from a NICU in Italy.66 Approximately
25% of patients died in this cohort, and 14.3% developed
epilepsy. Cerebral palsy and developmental delays were
present in approximately one-third of the cohort.
HIE is the most common cause of neonatal seizures in term
infants, and therapeutic hypothermia has become a standard
of therapy for HIE. Srinivasakumar et al showed that neonates
with HIE who had received therapeutic hypothermia had
lower seizure burden (p ¼ 0.003) compared with neonates
without the hypothermia therapy, after controlling for the
structural injury evident in the brain MRI.67 Between moder-
ate and severe HIE, reduction of the seizure burden was only
apparent in the moderate HIE group. Weeke et al showed that
all neonates with high seizure burden (total dura-
tion > 18 minutes) and moderate to severe injury detected
in the brain MRI had an abnormal neurodevelopmental out-
come at 2 years of age, even after receiving therapeutic
hypothermia. However, high seizure burden without MRI
abnormalities was not associated with poor outcome. On the
other hand, near-total asphyxic injury can produce isoelectric
recording without clinical seizures, but profound MRI
changes.68 Fitzgerald et al showed high electrographic seizure
burden and moderate to severe abnormal EEG background—in
116 neonates with HIE (treated with therapeutic hypother-
mia)—were independent predictors of abnormal motor devel-
opment with a median follow-up period of 23 months.69 A
high seizure burden was also independently associated with
abnormal language development.
Srinivasakumar et al performed a single-center, prospec-
tive, RCT to assess the difference in the seizure burden in two
groups of neonates by treating one group with clinical seizures
only (no EEG or seizure detection data were available to
bedside caregivers) versus treating both clinical and electro-
graphic seizures (electrographic seizures were captured by
cEEG monitoring and treated with AEDs if lasted more than
30 seconds or two episodes of any duration in a 24-hour
period) in the other group.70 The authors noted that the
Samanta
treatment of all seizures was associated with significantly
less seizure burden and shorter time to treatment. A higher
seizure burden was associated with higher brain MRI injury
scores. Surviving infants underwent a neurodevelopmental
assessment at 18 to 24 months of age, and increased seizure
burden was associated with lower performance scores in all
three domains of the Bayley Scales of Infant and Toddler
Development. However, this study was not powered to reveal
the difference between neurodevelopmental outcomes
between two primary groups.
Sigurdson et al reported a significant and complex racial
and/or ethnic disparities in the quality of NICU care in the
structure, process, and outcome measures in a systematic
review. Targeted studies to identify the difference in the
outcome of the disadvantaged populations should also be
conducted in neonatal seizures.71
Future Directions
There is a substantial need for ongoing research and clinical
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trials to understand optimal medication selection (first-
line, second-line, and third-line) for neonatal seizures, treat-
ment duration of AEDs after cessation of seizures, and strategies
to improve neuromorbidities such as cerebral palsy, epilepsy,
and developmental impairments. Approximately 75 to 85% of
neonatal seizures are symptomatic in onset and secondary to
asphyxia, stroke, infection, and acute metabolic derangements.
Usually, these symptomatic seizures start within the first few
days of life with a gradual resolution with or without treatment.
On the other hand, seizures from neonatal epilepsy can be
intractable. In clinical trials, assessment of treatment response
and outcome in a homogenous population can be more
constructive rather than including neonates with either symp-
tomatic seizures or seizures from neonatal epilepsies. Addition-
ally, rigorous calculation of seizure burden both pre-and
postadministration of the study drug is necessary to prevent
the erroneous assumption of improvement of seizures from an
AED rather than spontaneous resolution of symptomatic seiz-
ures.72 The sample size to effectively assess the desired effect is
gradually increasing due to therapeutic hypothermia’s effect on
the reduction of the seizure frequency. Moreover, the require-
ment of comparison with an active control or trials of
the second-line agents further increases the required sample
size. Though most previous clinical trials focused on the acute
suppression of seizures, optimum AED selection should be
based on long-term developmental outcome. Long-term, mul-
ticenter studies should be conducted to identify various risk
factors and effective strategies to prevent cognitive disabilities.
Research regarding parental preference and experiences related
to neonatal seizures is seriously lacking, and patient-centered
outcome research should focus on the psychological impact on
the families regarding both acute and long-term consequences
of neonatal seizures.73
Conclusion
Over the past decade, there has been remarkable progress in
the understanding of genetic-metabolic etiologies of neonatal
Neuropediatrics
Recent Advances in the Diagnosis and Treatment of Neonatal Seizures
epilepsies as well as limited use of precision-based therapies.
Additionally, increasing use of EEG monitoring for the diagno-
sis of neonatal seizures has become the standard of care in
regions with adequate resources. There is some consensus that
additional neuronal injury can occur secondary to seizures
over and above the primary etiology, and aggressive manage-
ment of seizures can decrease the total seizure burden. How-
ever, it is still undetermined if the reduction of seizure burden
can definitively improve neurodevelopmental outcomes. This
is also more contentious due to the risk of neurotoxicities from
the AEDs themselves. Moreover, PHB remains the best first-
line therapy of neonatal seizures, although concern about
acute and chronic side effects from PHB persists and search
for safer and more efficacious alternatives continues.
Disclosures
The author declares no potential conflicts of interest with
respect to the research, authorship, and publication of this
article.
Funding
The author received no financial support for the research,
authorship, and/or publication of this article.
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