Turkish

REVIEW
Archives of DOI: 10.5152/TurkArchPediatr.2024.23250
Pediatrics

Neonatal Seizures in Low- and Middle-Income Countries: A Review of

the Literature and Recommendations for the Management
Sarah Spenard , Carlos Ivan Salazar Cerda
1 2
, Mehmet N. Cizmeci 1 T.ME/NEONATOLOGY

Division of Neonatology, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, Canada
1

Division of Neurology, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, Canada
2

ABSTRACT

Neonatal seizures are a common cause of neonatal intensive care unit (NICU) admission and a
significant source of morbidity and mortality worldwide. Over the recent decades, there have
been significant improvements in perinatal and neonatal medicine and elect​roenc​ephal​ograp​
hic monitoring that have enhanced the diagnosis and treatment of neonatal seizures in high-
income countries. However, the management of neonatal seizures remains a major challenge
in low- to middle-income countries, where the availabilityof resources is limited. The purpose of
this article is to present a comprehensive review of the current evidence on the etiology, patho-
physiology, diagnosis, and treatment of neonatal seizures and to offer practical management

t.me/neonatology
recommendations that could be implemented in resource-limited settings.

Keywords: Low- and middle-income countries, neonate, seizure

INTRODUCTION
Neonatal seizures (NS) are defined as seizures presenting in the first 4 weeks after birth in
term neonates or within 44 weeks of corrected gestational age in preterm infants.1 A sei-
zure is the manifestation of excessive synchronous electrical discharge within the neurons
of the central nervous system.2-4 This imbalance is thought to be secondary to an excessive
excitation over an insufficient inhibition and impaired influx–efflux balance of major ions
(i.e., sodium, potassium, and chloride) in the developing brain. Many pathophysiological
mechanisms may explain the occurrence of seizures in newborns, including a failure in the
adenosine triphosphate-dependent sodium–potassium pump to maintain stable neuro-
nal membrane potential and a membrane alteration with increased sodium permeability.
Specific neonatal conditions, such as hypoxic–ischemic injury and hypoglycemia, can also
decrease cellular energy production and lead to the release of excessive extracellular gluta-
mate, an excitatory neurotransmitter.4

Corresponding author:
Mehmet N. Cizmeci
 mehme​t.ciz​meci@​sickk​ids.c​a
Received: October 15, 2023
Accepted: October 24, 2023
Publication Date: January 2, 2024
Content of this journal is licensed
under a Creative Commons
Attribution-NonCommercial 4.0
International License.
Neonatal seizures can be provoked or unprovoked.5 A provoked seizure results from an acute
illness or brain insult caused by a suspected or documented etiology, such as hypoxic–isch-
emic encephalopathy or central nervous system infection. On the other hand, an unprovoked
seizure is not associated with a specific etiology and can meet the diagnosis of epilepsy in
the presence of specific criteria. By definition, epilepsy is diagnosed if any of these condi-
tions are met: (1) at least 2 unprovoked seizures separated by >24 hours, (2) one unprovoked
seizure and a probability of additional seizures that is similar to the recurrence risk after 2
unprovoked seizures (at least 60%), and (3) a diagnosis of an epilepsy syndrome.5,6
Status epilepticus is defined as any continuous clinical seizure lasting more than 5 minutes or 2
or more discrete seizures without recovery of consciousness between seizures.7 Traditionally,
30 minutes was accepted as the cutoff, but it was later understood that seizures that last for
more than 5 minutes have a high potential to turn into status and are operationally defined
Cite this article as: Spenard S, Ivan Salazar Cerda C, Cizmeci MN. Neonatal seizures in low and middle-
income countries: Review of the literature and recommendations for the management. Turk Arch Pediatr.
2024;59(1):13-22.

13

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Neonatal Seizures in Resource-Limited Settings Turk Arch Pediatr 2024; 59(1): 13-22

as status epilepticus.8 This definition is difficult to apply to neo- Table 1. Common Etiologies of Neonatal Seizures
nates because NS require elect​roenc​ephal​ograp​hic (EEG) con-
Hypoxia–ischemia Global: Hypoxic–ischemic encephalopathy
firmation, and it is difficult to evaluate for interictal return to Focal: Arterial ischemic stroke, cerebral
baseline mental status in infants. Therefore, the term “status sinus venous thrombosis
epilepticus” should be used with caution in neonates.9
Infection Meningitis (bacterial, viral, fungal)
Encephalitis
INCIDENCE
Intracranial Germinal matrix hemor​rhage​–intr​avent​
The immature neonatal brain exists in a state of excitation/inhi- hemorrhage ricul​ar hemorrhage
bition imbalance; its increased excitation facilitates a number Other parenchymal hemorrhages
of activity-dependent developmental processes, such as neuro- Metabolic/genetic Hypoglycemia
genesis and neural circuit development.10 This increased excit- Hypocalcemia, hypomagnesemia,
ability makes the neonatal brain more susceptible to seizures. hyponatremia
Hence, seizures happen more commonly in the neonatal period Disorders causing hyperammonemia
than at any other time over the human lifespan. The incidence Acute bilirubin encephalopathy
Nonketotic hyperglycinemia
rate of seizures in term neonates is estimated to be 1-5 per 1000
Pyridoxine-dependent conditions
live births.6,9,11,12 Preterm infants and small​-for-​gesta​tiona​l-age​
Peroxisomal disorders
infants are at increased risk of seizures, with an incidence of
Drug withdrawal Maternal subst​ance/​polys​ubsta​nce abuse
11.1 per 1000 and 13.5 per 1000, respectively.11,13 It is important
during pregnancy
to note that these incidence rates are based on studies done
Brain Focal cortical dysplasia,
in high-income countries (HIC). The incidence of reported NS
malformations hemimegalencephaly, lissencephaly,
in low- and middle-income countries (LMIC) is higher, ranging
schizencephaly, polymicrogyria
from 4 per 1000 live births (in Iran)14 to 40 per 1000 live births
Heterotopia
(in Kenya and Nigeria).15,16 The high variability in the reported
Tuberous sclerosis
incidence of NS in LMIC can be explained by limited access to

neurocritical monitoring and care resources. Most seizures are
diagnosed clinically and are not based on EEG studies. Some
seizure-like events may be misdiagnosed as seizures, while
subclinical seizures may be missed.17 Furthermore, a higher
rate of home deliveries in LMIC may lead to an underestima-
tion of NS, as some seizures may go undiagnosed in the early
neonatal course. Some neonates may also die in the commu-
nity from complications of seizures before reaching the hospi-
tal.15 Hence, the incidence of NS in LMIC remains unknown but
is likely superior to HIC due to resource limitations and the high
prevalence of risk factors for neonatal brain insult.
Key Points
• Neonatal seizures are more frequent in preterm infants.
• The true incidence of NS is unknown in LMIC but likely supe-
rior to HIC due to relatively limited access to healthcare
resources and high prevalence of risk factors for perinatal
brain insult.
ETIOLOGY
Various etiologies can increase the excitability of the neona-
tal brain or cause injury to neurons, which can both increase
the risk for seizures. Table 1 contains the most common causes
of seizures in newborns.4,18-20 The most common etiologies of
seizures in late preterm and term infants are hypoxic–isch-
emic encephalopathy, followed by perinatal arterial ischemic
stroke.1,21,22 On the other hand, intracranial hemorrhage is the
most common seizure etiology in preterm infants, followed by
central nervous system infections.10,22 The proportion of uniden-
tified etiologies is similar throughout all gestational groups.22
Birth asphyxia, perinatal infection, and hypoglycemia are the
most frequently identifiable etiologies of NS in LMIC, based
on studies from Pakistan, Kenya, Nigeria, and Iran.15,16,23,24
Undiagnosed acute bilirubin encephalopathy may add to the
problem in LMIC. The underrepresentation of intracranial
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Neonatal-onset Channelopathies
epilepsy Other genetic conditions causing epilepsy
hemorrhage in neonates living in LMIC could be explained
by limited access to neuroimaging, especially brain magnetic
resonance imaging (MRI). The burden of preventable neonatal
morbidities remains high in LMIC. Perinatal asphyxia is a fre-
quent reason for hospital admission, encompassing 1 out of 6
NICU admissions in resource-limited settings.25 The case fatal-
ity rate of early-onset group B Streptococcus (GBS) neonatal
meningoencephalitis is around 10%, ranging from 5% in devel-
oped countries to up to 27% in sub-Saharan Africa.26 Higher
rate of NS may also be partly due to the higher rate of consan-
guinity in LMIC countries, which can increase the risk of brain
malformations and neurometabolic disorders that can cause
NS. Improving antenatal and perinatal care in LMIC could
likely prevent the occurrence of these neonatal morbidities and
decrease the associated risk of seizures. Interventions, includ-
ing neonatal resuscitation training of local birth attendants and
the provision of basic resuscitation equipment to local health-
care centers, could potentially decrease the burden of peri-
natal asphyxia.25 Furthermore, improving antenatal maternal
serology screening, routine maternal immunization, neonatal
skin care, and most importantly improved breastfeeding rates
are other strategies that could be used to decrease the burden
of neonatal bacterial infection in LMIC.27
Key Points
• Perinatal asphyxia, perinatal infections, hypoglycemia, and
acute bilirubin encephalopathy are potential causes of NS in
LMIC.
• Parental consanguinity, by increasing the likelihood of cere-
bral malformations and neurometabolic conditions, may
potentially add to the problem.
• Improving antenatal and perinatal care with standard-
ized, cost-effective strategies, such as community-based

14
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Turk Arch Pediatr 2024; 59(1): 13-22 Spenard et al.

education of neonatal resuscitation programs and hygiene
control, could prevent neonatal morbidities associated with
seizures.
CLINICAL MANIFESTATIONS
According to the International League Against Epilepsy (ILAE)
Task Force on NS, the presentation of NS can be divided into
motor, nonmotor, sequential, and unclassified categories.5
Motor seizures can further be classified into automatism, clonic,
myoclonic, tonic seizures, and epileptic spasms. Nonmotor sei-
zures can be subdivided into autonomic and behavioral arrest.
It should be remembered that the most common seizure semi-
ology in newborns is EEG-only (electrographic, subclinical)
seizures. Table 2 summarizes the different types of clinical pre-
sentation of seizures.
Nonmotor seizures can be quite subtle. Neonatologists and
pediatric neurologists can find it quite challenging to dis-
tinguish apneas caused by autonomic seizures and apneas
caused by other neurologic and nonneurologic disorders.
Most ictal apneas are associated with the limbic/paralimbic
mesial temporal cortex involvement, and they should be distin-
guished from nonictal apneas.28,29 Continuous video-integrated
EEG monitoring is required for diagnosing ictal apneas since
settings. The evidence behind clinical characteristics specific
to ictal apneas is scarce. However, some clinical clues can be
helpful to distinguish ictal apneas from nonictal events. First,
apneas are more frequently associated with electrical sei-
zure activity in term compared to preterm neonates.4 Second,
in preterm infants with recurrent apneas that persist despite
the introduction of caffeine treatment, an ictal process should
be kept in the differential.30 Of note, while tachycardia was
thought to be the hallmark of apneic seizures, it should be
remembered that bradycardia may also accompany apneic
seizures in the newborn population.30,31 Neonates with 1 or more
of these clinical features should be triaged for transfer to ter-
tiary care facilities to obtain an EEG evaluation.
Various atypical neonatal movements can mimic NS, includ-
ing jitteriness, benign neonatal sleep myoclonus, and trem-
ors. Some bedside maneuvers can be helpful in distinguishing
seizures from nonictal behaviors. If similar behaviors can be
provoked by stimulation of the infant and can be interrupted
by restraining the affected limbs, then they are unlikely to
be seizures.5 Hyperekplexia is another seizure mimicker that
should not be missed by healthcare practitioners because its
diagnosis is clinical and it can lead to developmental delay.32-
34
Hyperekplexia is commonly described as an exaggerated

it measures cortical electrical activity and vital sign variabil-
ity simultaneously, but access to continuous video-integrated
EEG monitoring can be a major challenge in resource-limited
Table 2. Semiology of Neonatal Seizures5
Type Description
1) Motor
Automatism Semi-coordinated, repetitive
movements (e.g., mouthing,
bicycling)
Clonic Slow rhythmic jerking of a muscle
group
Epileptic spasm Prominent flexion, extension, or
extension–flexion of proximal and
truncal muscles that lasts longer
than myoclonus
Myoclonic Sudden, quick contraction of
muscles
Tonic Prolonged contraction of a group
of muscle
2) Nonmotor
Autonomic Altered autonomic function of the
cardiovascular, pupillary,
gastrointestinal, vasomotor, or
thermoregulatory system
Behavior arrest Sudden immobilization during
activity
3) Sequential Variety of clinical signs happening
in a sequence within or between
seizure episodes
4) Elect​roenc​ephal​ograp​hic Subclinical seizure with
only electrographic-only activity
5) Unclassified Inability to categorize a seizure
due to insufficient information or
atypical features
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startle response to external stimuli. Its hereditary form involves
genes that affect glycine neurotransmission and presents in
the newborn period.34 Neonates with hereditary hyperekplexia
exhibit an exaggerated startle response, usually followed by
prolonged stiffening. A useful bedside clinical examination is
to elicit a nonfatigable glabella reflex by tapping on the gla-
bella region or head retraction by tapping repeatedly on the
trigeminal area of the face.33 Hyperekplexia movements can be
aborted by the Vigevano maneuver, which consists of a forced
flexion of the head and legs on the trunk.32
Key Points
• The clinical presentation of NS can be divided into EEG only,
motor, nonmotor, sequential, and unclassified.
• Ictal apneas should be kept in the differential when apneas
are seen in term infants. In preterm infants, ictal apneas
should be considered if they are refractory to caffeine
treatment.
• Seizure mimickers should be high in the differential if they
are provoked by stimulation of the infant and can be inter-
rupted by restraining the affected limbs.
ELECT​ROENC​EPHAL​OGRAP​HIC STUDY MODALITIES
Neonatal seizures have a wide range of presentations, mak-
ing it challenging for medical providers to diagnose a seizure
solely based on the clinical assessment. An observational study
published by Malone et al35 evaluated the accuracy of medical
providers in distinguishing true seizures from seizure mimickers
caught on video recordings. Only around half of the record-
ings were identified correctly, and the interobserver agree-
ment was suboptimal. Furthermore, the majority of NS are
subclinical, meaning that they are electrographic only and are
not associated with clinical manifestations.36-38 This holds espe-
cially true for neonates at risk for seizures, such as neonates
with hypoxic–ischemic encephalopathy, perinatal stroke, or
central nervous system infections. Murray et al37 showed that

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Neonatal Seizures in Resource-Limited Settings
only around a third of electrographic seizures in term infants at
risk of seizures had associated clinical manifestations caught
on simultaneous video recording, and that only 9% of elec-
trographic seizures had clinical features that were identified
by physicians. A more recent study published by Chen et al38
showed that 80% of electrographic seizures captured on con-
tinuous video EEG monitoring in neonates with encephalopathy
did not have a clinical correlate. Therefore, in order to avoid
the risk of over- or undertreating seizures, EEG monitoring has
now become the standard of care for diagnosing seizures in
newborns.
The ILAE Task Force on NS defines a seizure as “an electro-
graphic event with a pattern characterized by sudden, repeti-
tive, evolving stereotyped waveforms with a beginning and
end.” The group does not specify a duration in their most
recent definition. They rather explain that the event “has to be
sufficient to demonstrate evolution in frequency and morphol-
ogy of the discharges and needs to be long enough to allow
recognition of onset, evolution, and resolution of an abnor-
mal discharge.”5 The omission of a specific duration contrasts
with the previous definition published in 2013 by the American
Clinical Neurophysiology Society critical care monitoring com-
mittee,39 which included that a seizure needs to be at least
10 seconds long.
Premature neonates are at higher risk of developing seizures
than their term counterparts. Although the definition of sei-
zures does not vary based on the degree of prematurity, ges-
tational age does affect the electrographic background of
EEG.40 A multichannel, continuous EEG (cEEG) is the method of
choice to monitor seizures in premature infants because pre-
term infants have shorter seizures and can have a background
that is challenging to differentiate from true ictal activity.41
Given that access to a cEEG is challenging in resource-limited
settings, certain risk factors that can increase the likelihood of
seizures in preterm infants can be used to prioritize the infants
for further EEG assessments. These risk factors include a lower
gestational age with low Apgar scores at birth, higher Clinical
Risk Index for Babies Score II, evidence of hemorrhagic or
ischemic brain injury, or major cerebral malformations on cra-
nial ultrasound scans.41,42 Monitoring preterm infants at high
risk for seizures for a maximum of 24 hours is sufficient and
cost-effective.40,42,43
While cEEG remains the gold standard for seizure detection in
neonates, it remains a resource-intensive and costly investiga-
tion tool with limited accessibility across the globe, especially
in LMIC.44-46 Amplitude-integrated EEG (aEEG) is a reliable
alternative to screen for seizures. Amplitude-integrated EEG is
a simplified EEG that uses a montage of 2-4 electrodes, which
captures the activity of the cortex close to each electrode,
resulting in a raw EEG recording. It also compresses and rec-
tifies the EEG tracing over time to provide a rough overview
of the brain background activity and its evolution over time.
Amplitude-integrated EEG can also give prognostic informa-
tion based on the evolution of the background findings and
the emergence of sleep–wake cycling. However, it should be
remembered that aEEG has major limitations compared to
cEEG. Seizures with low amplitude or brief duration or seizures
occurring remotely from the aEEG leads can be easily missed
16
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Turk Arch Pediatr 2024; 59(1): 13-22
with the use of aEEG.47 Although aEEG does not replace cEEG,
they both can be used complementarily, as aEEG can help cli-
nicians at the bedside identify neonates who need cEEG.48
Different strategies can be used to increase the accessibility of
EEG studies in LMIC.
1. Improving pediatric EEG training curriculum: As access to
electrophysiology equipment is becoming more readily
available in LMIC, access to neurologists and neurophysi-
ologists skilled in reading pediatric EEG remains scarce.
More training needs to be provided to nonspecialist clini-
cians in order to improve access to safe and accurate EEG
interpretation in LMIC.49 Some learning initiatives have
already been launched in LMIC to improve pediatric EEG
training. For instance, the Global Organization of Health
Education50 offers face-to-face teaching and online teach-
ing resources in sub-Saharan African countries, such as
Ethiopia and Nigeria. Although more research is needed
to evaluate existing curricula, pioneering initiatives have
already set the foundations for dual online and in-person
learning programs in pediatric EEG for nonspecialist clini-
cians. Access to training modules, in addition to individual
tutoring and ongoing support to maintain skills, seems to
be the best approach to enable basic EEG interpretation
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skills in LMIC.51
2. Increasing use of digital technologies: The rapid growth of
digital technology in medicine can also facilitate remote EEG
specialist review and reporting. The ongoing Prevention
of Epilepsy by Reducing Neonatal Encephalopathy52 trial
aims to implement a care bundle to reduce birth injury-
related epilepsy at 18 months of age in India. To improve
the accessibility to EEG interpretation, video EEG will be
uploaded onto a secure cloud-based server for central
reporting, while aEEG will be locally read in real time to
assist clinical decision-making.53 Smartphones can also
be used to facilitate remote EEG reading. Williams et al54
evaluated the use of a smartphone EEG and remote online
interpretation for children with epilepsy in the Republic of
Guinea. The Smartphone Brain Scanner-2 allowed for EEG
data acquisition, filtering, artifact removal, and recording.
Data obtained from the application was then converted on
a secure web-based platform, and EEGs were read by HIC
board-certified neurologists. The use of this platform was
found to have moderate sensitivity and high specificity for
the detection of epileptiform abnormalities in children in
low-income countries.
3. Improving access to telemedicine: Telemedicine could also
be helpful in providing real-time access to neurologists
and neurophysiologists to facilitate the interpretation of
EEG studies. A prospective, multicenter, and observational
study is currently ongoing in Brazil to evaluate the impact
of an advanced telemedicine model of neonatal neurocrit-
ical care on clinical outcomes.55
The use of EEG in the NICU may also be hindered by the lack
of trained personnel who can perform EEG recordings. One
potential solution to this problem is to train NICU nurses to
attach the EEG electrodes to newborns, which can save time
and reduce errors. This can potentially optimize the use of
EEG in the NICU by increasing the availability of EEG data,
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Turk Arch Pediatr 2024; 59(1): 13-22
facilitating timely diagnosis and treatment of NS, and improv-
ing the outcome of affected infants.
Key Points
• The gold standard for seizure detection is electrographic
monitoring with cEEG ideally with video monitoring.
• Amplitude-integrated EEG that uses a reduced number of
electrodes is the second-best alternative to cEEG, which
can be more readily available in resource-limited settings.
However, it should be remembered that the sensitivity of
aEEG in seizure recognition is limited compared to cEEG.
• Amplitude-integrated EEG monitoring can also provide prog-
nostic information in infants with neonatal encephalopathy.
• Different strategies can be used to improve access to EEG
evaluation in LMIC, including developing a pediatric EEG
training curriculum and optimizing the use of digital tech-
nologies and telemedicine in neonatal units.
CLASSIFICATION
The ILAE Task Force on NS published a diagnostic framework
to guide clinicians in the classification of seizures.5 According
to this framework, neonates who present with abnormal move-
ments require electrographic recording to confirm seizures,
and those with an electrographic component can then be clas-
sified as electro-clinical or electrographic only based on the
presence or absence of a clinical component. A recent study
published by Yozawitz et al56 showed that this classification
system can be used by all health-care providers to identify a
predominant seizure type. There was also an average accu-
racy of 85% across the 5 seizure types. Elect​roenc​ephal​ograp​
hic studies are central to this classification system as today the
most common semiology of NS is electrographic only. The ILAE
task force excluded “clinical-only seizures” from their classifi-
cation system, as studies have shown that most clinical-only
events do not truly have an epileptic origin.37,57 Furthermore,
a distinction between focal and generalized seizures was not
included in the neonatal classification because all seizures in
the neonatal period have a focal onset.5
Key Points
• Health-care providers across the globe should use the diag-
nostic framework from the ILAE Task Force on NS to classify
seizures in the neonatal period.
• Transferring neonates from resource-limited settings to
higher-level units where they can be monitored with EEG
modalities is crucial to optimizing the treatment of NS.
MANAGEMENT OF NEONATAL SEIZURES
Initial steps
The first step in NS management is to assess and secure the
airway, breathing, and circulation of the patient and to inter-
vene promptly if necessary. Identifying and managing the
underlying cause of a seizure is crucial for achieving adequate
seizure control.1,17,58 One important point is to remember that
the treatment should not be deferred while waiting for prelimi-
nary and further testing.
Access to neuroimaging, especially brain MRI, is far from
being universal in LMIC.44,59 Cranial ultrasonography can be
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Spenard et al.
used as an initial neuroimaging modality to assess for intra-
ventricular hemorrhage, parenchymal hemorrhage, and
posthemorrhagic ventricular dilatation.60 However, ultraso-
nography is not a substitute for brain MRI and is less sensitive
in detecting ischemic injury. Brain MRI can be particularly
useful in diagnosing hypoxic–ischemic encephalopathy,
neonatal arterial ischemic stroke, central nervous system
infections, cerebral venous sinus thrombosis, some meta-
bolic disorders, and cerebral malformations.21 Hence, every
neonate with seizures of unknown etiology should undergo
a brain MRI if available. Further investigations can be done
when seizures are recurrent and resist first-line treatment or
when their underlying etiology remains unknown. Metabolic
testing for organic acidemias, urea cycle defects and fatty
oxidation defects, screening for intrauterine infections,
genetic testing, and pathological assessment of the placenta
can be considered based on available resources.1 A pediat-
ric neurologist should be involved early in the management
whenever possible.
TREATMENT
Despite earlier recommendations stating that antiepileptic
treatment should be initiated once reaching a cumulative
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electrographic seizure burden of at least 30 seconds/hour,
seizures should ideally be treated as soon as possible to pre-
vent further injury.61 However, in resource-limited settings
without access to EEG monitoring, clinicians may need to rely
on their clinical assessment. The levels of diagnostic certainty
published by the Brighton Collaboration Neonatal Seizures
Working Group can guide clinicians in their decision to start
antiepileptic treatment (Table 3).62 When the suspected event
has a focal clonic or focal tonic presentation, with or with-
out associated ictal EEG corroboration, administration of an
anti-seizure medication (ASM) is recommended. Treatment
may be considered but is not necessarily indicated when the
suspected abnormal movement is not associated with focal
clonic or focal tonic movements and when EEG evaluation is
unavailable. Further confirmatory testing should also be con-
sidered. The timing of ASM administration may also be criti-
cal, as treating a seizure within the first hour of its onset may
lower the seizure burden over the next 24 hours.63 It is recom-
mended to continue electrographic monitoring for 24 hours
after the last ASM dose to watch for uncoupling. Uncoupling
refers to the conversion of electroclinical seizures into electro-
graphic-only seizures after the administration of ASM.64
The ILAE Task Force on NS recently published treatment
guidelines that include the following consensus-based
recommendations:65
1. Phenobarbital remains the first-line treatment for NS
regardless of the etiology unless seizures occur in the con-
text of a family history of channelopathy, in which case a
sodium channel blocker such as phenytoin or carbamaze-
pine should be administered.
2. Phenytoin, levetiracetam, midazolam, or lidocaine remain
appropriate second-line ASMs among neonates with sei-
zures that are not responding to phenobarbital.
3. Levetiracetam may be the preferred second-line agent in
neonates with cardiac disorders.
17
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Neonatal Seizures in Resource-Limited Settings
Table 3. Levels of Diagnostic Certainty Adapted from the Brighton Collaboration
Level Clinical Findings
1: Definite seizure Present or absent
2a: Probable seizure Present or absent
2b: Probable seizure Focal tonic or focal clonic movements
3: Possible seizure Clinical event suggestive of a seizure, with motor or
nonmotor manifestations other than focal tonic or
clonic movements
4: Suspected seizure Reported event suggestive of seizure, without sufficient evidence to meet criteria
5: Not a seizure Reported event suggestive of seizure
aEEG, amplitude-integrated elect​roenc​ephal​ograp​hy; cEEG, continuous elect​roenc​ephal​ograp​hy; EEG, elect​roenc​ephal​ograp​hy.
4. A trial of pyridoxine should be considered in newborns with
clinical features of vitamin B6-dependent epilepsy or with
seizures refractory to second-line ASMs.
Today, phenobarbital is considered the preferred first-line ASM
to treat NS.66 However, until recently, a growing body of stud-
ies suggested that the use of intravenous levetiracetam may
be a promising first-line treatment option for NS compared to
phenobarbital.67-71 A study from Egypt showed that levetirace-
tam can be an effective and safe option as a first-line ASM
in NS compared to phenobarbital.67 After administering 1 or
2 doses of levetiracetam or phenobarbital to infants, seizure
cessation was achieved in 79% compared to 65%, respectively
(P = .01). Patients exposed to levetiracetam did not develop
adverse effects, compared to patients treated with phenobar-
bital, who developed hypotension, bradycardia, and respira-
tory depression.
However, in a recent phase IIb randomized controlled trial,
80% of patients randomly assigned to phenobarbital remained
seizure-free for 24 hours, compared with 28% of patients ran-
domly assigned to levetiracetam [P < .001; relative risk 0.35
(95% CI, 0.22-0.56)]. Of note, more adverse effects were seen
in subjects randomly assigned to phenobarbital, but this was
not statistically significant.66 With the current evidence, intra-
venous phenobarbital should be the first-line ASM in neonates
presenting with seizures. Administering phenobarbital prepa-
rations enterally via a nasogastric tube should not be preferred
in settings where intravenous phenobarbital is not accessible.
If intravenous phenobarbital is not readily available, then a
trial of benzodiazepine such as lorazepam or midazolam (both
of which have a shorter half-life than phenobarbital) can be
administered to abort seizures.
The question of continuing antiepileptic medications after dis-
charge from the hospital remained a subject of controversy
for decades. However, several animal studies showed that
antiepileptic medications can be neurotoxic to the developing
brain.72-74 A recent study from Glass et al. also showed that the
neurodevelopmental outcomes and epilepsy risk at 24 months
were similar among children whose ASM was discontinued or
maintained at hospital discharge after the resolution of acute
symptomatic NS. Hence, the updated ILAE Task Force on NS
recommends discontinuation of ASM before discharge home in
neonates hospitalized for acute-provoked seizures who do not
have a diagnosis of neonatal epilepsy. This recommendation
holds true regardless of neuroimaging or EEG findings.65
18
t.me/neonatology
Turk Arch Pediatr 2024; 59(1): 13-22
Elect​roenc​ephal​ograp​hic Findings Management
Ictal activity on cEEG Treat
Ictal activity on aEEG Treat
EEG not available Treat
EEG not available Treatment can
be considered
Do not treat
No ictal activity on simultaneous Do not treat
cEEG or aEEG
As noted earlier, access to ASMs can be challenging in LMIC
due to several factors. In Laos, the national production of
phenobarbital does not match the population’s needs. This
mismatch is caused by delays in the overpriced local produc-
tion of phenobarbital and the centralization of delivery sites
in urban centers.75 Traditional beliefs also limit children with
seizures from having access to appropriate medical services.
Children living with epilepsy tend to be isolated from villages
and referred to traditional care or religious sacrifices. These
misconceptions about epilepsy are also prevalent among Lao
t.me/neonatology
health-care providers, as 1/3 of physicians treating children
had never prescribed ASM.76 Similar challenges, including
population misbeliefs regarding epilepsy, financial barriers,
and disparities in health infrastructures in remote districts,
were also present in Madagascar77 and Cambodia.78
Key Points
• Stabilization of airway and breathing and establishing circu-
latory support should be prioritized over biochemical, neu-
roimaging, and EEG investigations in a neonate presenting
with seizures.
• If the initial bedside testing shows a simple metabolic
derangement such as hypoglycemia, it should be corrected
immediately, as prolonged metabolic derangements can
further cause brain injury.
• Neonates with evidence of seizures on cEEG or aEEG should
be treated. However, in resource-limited settings, neonates
presenting with focal tonic or clonic movements should also
be treated with ASMs.
• Seizures other than focal clonic and focal tonic types can also
be considered for treatment. In these neonates, clinicians use
their best judgment and take into account the underlying risk
factors (such as the presence of birth asphyxia and enceph-
alopathy) and clinical presentation (such as rhythmic move-
ments continuing despite suppression attempts).
• Intravenous phenobarbital should be the first-line ASM to
treat NS. Administering phenobarbital preparations enter-
ally via a nasogastric tube should not be preferred in LMICs
where intravenous phenobarbital is not accessible. In these
cases, a readily available intravenous alternative (such as
lorazepam or midazolam) should be administered.
• Maintenance ASMs should be discontinued in infants pre-
senting with an acute-provoked seizure, regardless of the
neuroimaging findings. These infants require close monitor-
ing by a pediatric neurologist in the outpatient clinics.
T.ME/NEONATOLOGY
Turk Arch Pediatr 2024; 59(1): 13-22
OUTCOMES
Compelling evidence suggests that NS significantly increase
the risk of cognitive and motor delays and neurodevelopmental
impairment in multiple developmental domains.79-82 Neonatal
seizures also increase the risk of childhood epilepsy, especially
in neonates with extensive perinatal brain injury to their deep
gray matter and cortical regions.83,84 The underlying etiology
of NS remains an important modulator of neurodevelopmental
prognosis.
It remains unclear whether seizures are an epiphenomenon
of brain injury versus an independent effect modifier further
contributing to brain damage.85 Different mechanisms have
been raised to explain how seizures can cause brain injury.
Greater seizure burden has been associated with smaller brain
volumes on term-equivalent age MRI in preterm infants less
than 30 weeks’ gestation.86 A rise in cerebral blood velocity may
also lead to increased intracranial pressure and, consequently,
bleeding from the fragile germinal matrix.87 Another theory
suggests that the increased cerebral metabolic demand dur-
ing an ictal episode88 may “steal” glucose and oxygen supply
from other brain regions, especially in neonates with previous
brain insults.89
Longer duration of seizures may also worsen outcomes,
especially in neonates with perinatal brain injury.90-92 Pisani
et al90 found that an ictal fraction (defined as the total dura-
tion of seizure/duration of the EEG recording × hour) longer
than 10 minutes was significantly associated with adverse
neurodevelopmental outcomes, including cerebral palsy,
intellectual disability, and postnatal epilepsy. Different stud-
ies have looked for possible risk factors that may indepen-
dently influence the outcomes of neonates with seizures.93-96
Garfinkle and Shevell96 designed a 5-point scoring system to
help clinicians in the prognostication of neurodevelopmental
outcomes in neonates who experienced seizures.95 Others
also reported that neonates with seizures who were born
prematurely or had very low birth weight, abnormal cranial
ultrasound findings, or suffered from birth asphyxia, men-
ingitis, or septicemia, were at increased risk for death, had
abnormal examination at discharge, and were phenobarbital
nonresponders.
Key Points
• Children who present with seizures during the neonatal
period are at increased risk of neurodevelopmental delays
and impairments in multiple developmental domains, as well
as postneonatal epilepsy.
• Children who present with NS require long-term neurodevel-
opmental follow-up in resource-limited settings by experi-
enced clinicians who are familiar with neurodevelopmental
disorders. These infants should be prioritized for long-term
follow-up.
CONCLUSION
Seizures in the neonatal period remain a serious neurological
emergency that necessitates admission to neonatal intensive
care units across the globe, and NS is associated with increased
risks of neurodevelopmental impairment and mortality.
t.me/neonatology
Spenard et al.
In recent decades, there have been significant improvements in
perinatal and neonatal medicine and EEG monitoring that have
enhanced the diagnosis and treatment of NS in HIC. However,
the management of NS remains a major challenge in LMICs,
where the availability and accessibility of resources are limited.
Several initiatives have been launched to provide optimal neu-
rological investigations and neuroprotective care to neonates
living in LMIC. However, more efforts are needed to close the
gap and ensure that all neonates with seizures receive the best
possible care.53,97,98 We hope that this review article will provide
clinicians with practical and evidence-based considerations
for the diagnosis and treatment of NS and stimulate further
research in this field.
Peer-review: Externally peer-reviewed.
Author Contributions: Concept – M.N.C., S.S.; Design – M.N.C., S.S.;
Supervision – M.N.C.; Resources – S.S., C.I.S.C.; Materials – S.S., M.N.C.;
Literature Search – S.S., C.I.S.C, M.N.C.; Writing – S.S.; Critical Review –
C.I.S.C., M.N.C.
Declaration of Interests: The authors have no conflict of interest to
declare.
t.me/neonatology
Funding: This study received no funding. Mehmet N. Cizmeci received
support from Dr. Karen Pape Program in Neuroplasticity for neonatal
neurodevelopmental research.
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