special issue article

Evaluation of the Neonate with

Seizures
Monika Martin, MD; Jyes Querubin, MD; Eunice Hagen, DO; and Jina Lim, MD

the first 10 days of postnatal life.3 Al-

Abstract though neonatal seizures share some
Neonatal seizures are common, occurring in 2 to 5 of 1,000 live births in the United common etiologies with seizures occur-
States. The neonatal brain is thought to be predisposed toward seizures due to a combi- ring later in childhood, the majority are
nation of excessive excitatory and deficient inhibitory neuronal activity. The seizures tend caused by conditions unique to the neo-
to be focal or multifocal without secondary generalization, resulting in subtle seizure ap- natal period.
pearance. There are five main categories of neonatal seizures: focal clonic, focal tonic,
myoclonic, subtle, and generalized tonic. An electroencephalogram is recommended to Pathophysiology
diagnose and treat neonatal seizures due to poor reliability of the clinical examination. Seizures are caused by excessive syn-
Causes of neonatal seizures are broad, including trauma, structural brain anomalies, in- chronous neuronal depolarization. Neu-
fections, metabolic disorders, drug withdrawal or intoxication, and neonatal epilepsy syn- ronal depolarization occurs via influx of
dromes. Treatment of neonatal seizures involves management of cardiorespiratory status, sodium (Na+), and repolarization occurs
correction of metabolic derangements, and antiepileptics as needed. The most common via efflux of potassium (K+). This repo-
antiepileptics used in neonates are phenobarbital, levetiracetam, and fosphenytoin. The larization is driven by an adenosine tri-
long-term risk of neurodevelopmental disability varies depending upon the etiology of phosphate (ATP)-dependent pump that
neonatal seizures. Close attention to developmental milestones and neurology follow-up exchanges Na+ for K+. Certain common
is recommended for all neonates with seizures. [Pediatr Ann. 2020;49(7):e292-e298.] pathologic conditions in the neonatal
period, such as hypoglycemia and hy-

L
ifetime risk of seizures is highest able and may be life threatening, prompt poxic ischemic encephalopathy, result
in the neonatal period, and sei- identification and treatment are critical. in failure of this Na+/K+ ATPase pump
zures are one of the most com- and destabilization of the membrane
mon neurologic complications encoun- Epidemiology potential, resulting in seizures. The
tered by the pediatric practitioner. In Neonatal seizures are relatively com- increased incidence of seizures in the
addition, seizure burden in the neonatal mon and are estimated to occur in ap- neonatal period is thought to be due to a
period can be associated with significant proximately 2 to 5 per 1,000 live births combination of excessive excitatory and
morbidity and mortality. Because many in the United States.1,2 In this population, deficient inhibitory neuronal activity.
of the etiologies of seizures are treat- seizures are most likely to occur within The neonatal brain contains elevated
levels of excitatory neurotransmitters,
Monika Martin, MD, is a Neonatology Fellow, Division of Neonatology, Harbor-University of Califor- particularly glutamate, which are im-
nia, Los Angeles Medical Center. Jyes Querubin, MD, is a Pediatric Neurologist, Department of Pediat- portant for activity-dependent synap-
rics, Huntington Hospital. Eunice Hagen, DO, is a Neonatologist, Department of Pediatrics, Hunting- togenesis but also increase likelihood
ton Hospital. Jina Lim, MD, is a Neonatologist, Division of Neonatology, Children’s Hospital of Orange of seizures.4,5 Additionally, the primary
County. inhibitory neurotransmitter, gamma-
Address correspondence to Jina Lim, MD, Division of Neonatology, Children’s Hospital of Orange aminobutyric acid, is relatively less
County, 1201 West La Veta Avenue, Orange, CA 92868; email: jlim@choc.org. prevalent and exhibits an excitatory
Disclosure: The authors have no relevant financial relationships to disclose. rather than inhibitory effect on the de-
doi:10.3928/19382359-20200623-01 veloping brain.5

e292 Copyright © SLACK Incorporated


Clinical Manifestations
Neonatal seizures have unique clini-
cal characteristics compared to older in-
fants, children, and adults. This is due to
neuroanatomical differences. The neo-
natal brain is incompletely myelinated,
which impairs seizure propagation. As
a result, neonatal seizures tend to have
a focal or multifocal onset without sec-
ondary generalization, especially across
hemispheres. As such, they tend to be
brief, often subtle, and nonspecific in ap-
pearance, and can be misinterpreted as
normal neonatal movements. Thus, an
electroencephalogram (EEG) is always
recommended in cases where seizure
activity is suspected due to poor reli-
ability of the clinical examination alone.
Neonatal seizures are classified into
five categories: focal clonic, focal tonic,
myoclonic, subtle (motor or autonomic),
and generalized tonic (Table 1).3,4
Focal clonic seizures are character-
ized by slow, rhythmic jerking of one or
more extremities or rhythmic twitching
of the face. Movements in different ex-
tremities or sides of the body may oc-
cur simultaneously. These movements
are nonsuppressible, which may help
distinguish them from nonepileptic eti-
ologies such as jittery movements, limb
clonus, or benign sleep myoclonus. Jit-
tery movements generally involve all ex-
tremities and are characterized by short,
rapid tremors that resolve with restraint
or repositioning of the infant. Benign jit-
tery movements occur when the infant is
awake and in an alert state. Limb clonus
is generally restricted to a single joint,
characteristically the ankle, and is char-
acterized by short bursts of jerking that
can be elicited by stretching the affected
tendon and suppressed by releasing the
stretch on the tendon.
Focal tonic seizures are characterized
by slow, sustained stiffening of a limb or
limbs, often with associated posturing
of the limb and asymmetric posturing of
PEDIATRIC ANNALS • Vol. 49, No. 7, 2020
special issue article
the trunk. Seizures do not terminate with
tactile stimulation or repositioning of the
limb and cannot be induced by stimula-
tion. They may also be associated with
sustained eye and head deviation.
Myoclonic seizures are character-
ized by rapid, single jerks of one or
more extremities or the extremities and
trunk. They may be repetitive but do not
necessarily occur in a rhythmic manner.
Unlike benign sleep myoclonus, which
occurs exclusively during sleep, myo-
clonic seizures generally occur while
neonates are awake.
Subtle seizures can be divided into
motor and autonomic subsets. Subtle
motor seizures are brief, stereotyped
movements of the face or extremities
such as eye deviation, blinking, nystag-
mus, tongue thrusting, chewing move-
ments, “swimming” movements of the
arms, or bicycling of the legs. Subtle
autonomic seizures involve rapid, brief
changes in heart rate (generally tachy-
cardia), hypertension, and/or apnea.
Subtle seizures occur more frequently
in preterm infants, although apnea in the
full-term infant is more commonly as-
sociated with subtle seizures than in the
preterm infant.4
Epileptic spasms are a rare type of
neonatal seizure. Spasms in the neonatal
period have similar electroclinical char-
acteristics as infantile spasms.6 Clinical-
ly, spasms are observed as brief flexion
and/or extension of extremities lasting
seconds and frequently occurring in
clusters. The duration of extension and/
or flexion is longer than myoclonus and
shorter than tonic seizures.7
Generalized tonic seizures are associ-
ated with trunk and limb posturing, ei-
ther in flexion or extension. They may
be provoked or intensified with tactile
stimulation and will generally terminate
with restraint or containment. These
sustained episodes do not generally cor-
relate with epileptiform discharges on
EEG and are thus felt to be a “brainstem
release phenomenon” rather than true
seizures.8
Etiology
The differential diagnosis for neona-
tal seizures is broad and includes trau-
matic or structural causes, infectious and
metabolic etiologies, drug withdrawal or
intoxication, and neonatal epilepsy syn-
dromes (Table 2).
Hypoxic Ischemic Encephalopathy
The most common cause of neonatal
seizures is hypoxic ischemic encepha-
lopathy (HIE), accounting for up to
50% to 60% of cases. HIE results in de-
creased blood flow and oxygen delivery
to the brain and generally occurs imme-
diately prior to, during, or immediately
after birth. Seizures caused by HIE gen-
erally present before 24 hours of postna-
tal life with highest frequency occurring
between age 12 and 24 hours,1,4 as well
as during the rewarming period. Due
to the high risk of acute seizures, long-
term EEG monitoring is recommended
for all neonates undergoing therapeutic
hypothermia.
Vascular Lesions
Vascular lesions are the second most
common etiology for seizures. This cat-
egory includes ischemic stroke, hemor-
rhage, thrombosis, and congenital vas-
cular anomalies of the brain (ie, vein of
Galen malformation). Ischemic stroke
can occur in arterial, venous, or water-
shed distributions, and they account for
10% to 20% of seizures in the neona-
tal period. Most of these strokes occur
prenatally, and seizures tend to present
after age 12 hours in an otherwise alert
and well-appearing infant. Seizures are
the presenting feature in up to 97% of
cases and are often the only symptom.4
e293

Main Types of Neonatal Seizures
Seizure classification
Focal clonic seizures
Focal tonic seizures
Myoclonic seizures
Subtle motor seizures
Subtle autonomic seizures
Epileptic spasms
Generalized tonic seizures
Adapted from Natarajan and Gospe,1 Abend et al.,2 and Martin et al.4
Cerebral sinus venous thrombosis is as-
sociated with venous infarct and has a
high risk of hemorrhagic conversion.1
Although less common than ischemic
stroke, it affects up to 1 in 8,000 infants.4
Intracranial Hemorrhage
Intracranial hemorrhage is the most
frequent hemorrhagic cause of seizures
in infants. High-grade intraventricu-
lar hemorrhage in the preterm neonate
may result in seizures in about 15% of
cases.1,2 Less common causes include
subarachnoid and subdural hemorrhage,
and in these cases, seizures are often the
result of underlying cerebral contusion
rather than the bleed itself. These bleeds
may result due to normal birth trauma,
but neonates presenting after the first
days of postnatal life should be evaluated
for non-accidental trauma.
Congenital Brain Malformations
Congenital brain malformations can
result in seizures that present at any point
e294
special issue article
Table 1
Typical presentation Other characteristics
Slow, rhythmic jerking Occurs while awake; not
suppressible; common mani-
festation in term neonates
Slow, sustained limb or trunk Not suppressible; com-
posturing mon manifestation in term
neonates
Rapid, single jerks, may be Occurs while awake; may be
repetitive but generally not provoked by stimulation
rhythmic
Blinking, sucking, chewing, May be provoked or intensi-
tongue protrusions fied by stimulation
Tachycardia, apnea, hyper- Occurs more frequently in
tension preterm infants
Brief flexion, extension, or May occur in clusters; not
mixed flexor/extension suppressible; rare
Slow, sustained posturing of May be provoked by stimula-
limbs and trunk tion; suppressible
in the neonatal or infantile period due to
inherent alterations in the cortical struc-
ture. These include focal (focal cortical
dysplasia and schizencephaly) and diffuse
(polymicrogyria, lissencephaly) lesions.
Infections
Bacterial, fungal, and viral infections
of the central nervous system are a serious
cause of seizures that require urgent treat-
ment to prevent death and long-term neu-
rodevelopmental impairment. The most
common bacterial etiologies of seizure are
meningitis caused by Group B streptococ-
ci and Escherichia coli. Seizures related to
these pathogens generally occur around or
after the later part of the first week after
birth. Seizures related to herpes simplex
virus generally occur within 7 days of birth
in a previously healthy newborn. Seizures
may also be a sequela of other congenital
infections. Congenital infections that are
associated with seizures include toxoplas-
mosis, rubella, syphilis, cytomegalovirus,
coxsackie virus, and others viral causes.
Seizures associated with congenital infec-
tions typically occur in the first days of
postnatal life and are generally accompa-
nied by findings such as hydrocephalus or
calcifications on head imaging.
Metabolic Derangements
Metabolic derangements represent a
treatable and reversible cause of seizures;
thus, prompt recognition is critical. These
include hypoglycemia, hypocalcemia, hy-
pomagnesemia, hypophosphatemia, hypo-
or hypernatremia, as well as certain inborn
errors of metabolism.
Hypoglycemia is most common in in-
fants who are growth restricted or small
for gestational age, as well as infants of
mothers with diabetes. Hypoglycemia
may cause jitteriness, lethargy, apnea,
and seizures. Duration of hypoglycemia
is most closely correlated with neurologic
manifestations, and hypoglycemia severe
enough to cause seizures is generally as-
sociated with persistent deficits.1
Hypocalcemia has two peak incidences
in the neonatal period. The first occurs in
the 2 to 3 days after birth and is most com-
mon in infants who are preterm, growth re-
stricted, and small for gestational age, and
in infants whose mothers have diabetes.
The hypocalcemia is generally transient
and responds well to calcium replacement.
The second peak occurs between ages 4
and 28 days and has a wider differential
diagnosis, including hypoparathyroidism
(transient or congenital), congenital heart
disease, DiGeorge syndrome, or nutrition-
al deficits (vitamin D deficiency or high
consumption of formula low in calcium).
Symptomatic hypocalcemia presents with
hyperreflexia, ankle, knee and jaw clonus,
jitteriness, and focal seizures.
Cofactor and vitamin deficiencies, al-
though rare, represent another potentially
treatable metabolic cause of refractory
neonatal seizures. These include pyridox-
amine 5’-phosphate oxidase (PNPO) de-
ficiency, pyridoxine-dependent epilepsy
Copyright © SLACK Incorporated

(PDE), and biotinidase deficiency.4 Sei-
zures generally present in the first hours
after birth, although intrauterine seizures
have been described. These disorders pres-
ent with a variety of seizure types, includ-
ing infantile spasms, that are refractory
to antiepileptic medications. These con-
ditions should be suspected in a neonate
that presents with intractable seizures soon
after birth that fail to respond to multiple
antiepileptic medications. In these condi-
tions, the associated encephalopathy is
typically progressive and results in death
if not recognized and treated. Seizure con-
trol is achieved with cofactor or vitamin
replacement, but neurodevelopmental out-
comes are generally poor.
Inborn Errors of Metabolism
Many inborn errors of metabolism
may present with seizures in the neonatal
or infantile period. Inborn errors should
be suspected in an infant with encepha-
lopathy who presents within a few days
of birth after an uncomplicated pregnancy
and delivery. Affected neonates will be as-
ymptomatic at birth and then experience a
clinical deterioration within the first days
to weeks after delivery. Excessive irrita-
bility or crying, recurrent apnea, lethargy,
poor feeding, and hiccups may precede
seizure activity. Unlike other causes of sei-
zures, neonates will generally not return to
a normal neurologic baseline but instead
remain encephalopathic between seizures.
Family history may reveal consanguin-
ity or a history of neonatal deaths. Infants
may have elevated ammonia levels and
may have profound metabolic acidosis.
The most common inborn errors present-
ing with seizures in the neonatal period
include the organic acidemias, urea cycle
defects, nonketotic hyperglycinemia, and
aminoacidopathies.3
Neonatal Drug Withdrawal
Neonatal drug withdrawal, particularly
from opiates/opioids, is a rare cause of
PEDIATRIC ANNALS • Vol. 49, No. 7, 2020
special issue article
Table 2
Etiology of Neonatal Seizures
Cause of seizure Description
Hypoxic ischemic encephalopathy (50%-60%) Generally occur within 12 to 24 hours of birth
Vascular lesions (10%-20%)
Hemorrhage
Intracranial
Subdural Includes venous sinus thrombosis, arteriove-
Subarachnoid nous malformation, venous malformations
Germinal matrix
Ischemic stroke
Congenital vascular anomaly
Congenital brain malformations (5%-10%) Focal: agenesis of the corpus callosum,
Dandy-Walker malformation
Focal
Diffuse: holoprosencephaly, lissencephaly,
Diffuse
polymicrogyria
Infection (5%-10%)
Bacterial
Can present early (first 72 hours of life) or late
(after 7 days of life)
Viral
Seizures often prolonged and difficult to
Congenital Infections (ie, TORCH)
treat
Fungal
Metabolic (~5%)
Hypoglycemia
Hyponatremia Reversible causes of neonatal seizures
Hypomagnesemia include electrolyte abnormalities as well as
Hypocalcemia cofactor and vitamin deficiencies
Cofactor/vitamin deficiency
Inborn errors
Drug intoxication or withdrawal (~1%) Most common drugs include narcotics,
benzodiazepines/barbiturates, tricyclic anti-
depressants, cocaine, and alcohol
Neonatal epilepsy syndromes (~1%)
Benign familial neonatal epilepsy
Very rare, family history may reveal this etiol-
Benign nonfamilial neonatal convulsions
ogy although many mutations are de novo
Early myoclonic encephalopathy/Otahara
syndrome
Abbreviation: TORCH, Toxoplasmosis, Other agents, Rubella (also known as German measles), Cytomegalovirus, and Herpes simplex.
Adapted from Natarajan and Gospe,1 Abend et al.,2 and Martin et al.4
neonatal seizures, although its incidence posure to cocaine, alcohol, and tricyclic
is increasing due to the rise in maternal antidepressants has also been implicated
drug use and postnatal opiate exposure. in neonatal seizures. Infants with neonatal
The substances most frequently associ- abstinence syndrome may manifest a va-
ated with seizures are narcotics, benzodi- riety of abnormal movements such as ex-
azepines, barbiturates, selective serotonin aggerated Moro reflex, myoclonic jerks,
reuptake inhibitors, and serotonin-nor- and tremors, so EEG is recommended
epinephrine reuptake inhibitors. Fetal ex- to identify true seizure activity. Seizures
e295

generally begin within the first few days
after birth and may require antiepileptic
therapy until the withdrawal symptoms
have resolved.
Neonatal Epilepsy Syndromes
Unlike the above etiologies, the neo-
natal epilepsy syndromes represent un-
provoked causes of seizure activity in
the neonate. Three syndromes are rec-
ognized by the International League
Against Epilepsy: benign familial neo-
natal epilepsy (BFNE), early (neonatal)
myoclonic encephalopathy (EME) and
early infantile epileptic encephalopathy
(Otahara syndrome).
BFNE, as its name implies, is a rela-
tively benign condition generally associ-
ated with excellent neurologic outcomes.
This autosomal dominant condition is
classified by seizures that begin within
the first week of life and generally re-
solve by age 1 to 12 months. Seizures
may be tonic, clonic, or associated with
apneic spells. Development is generally
normal although 10% to 15% of infants
may go on to develop epilepsy later in
life.4 Diagnosis is typically made based
on characteristic EEG findings as well as
genetic testing. BFNE is associated with
mutations in potassium channel genes
KCNQ2 and KCNQ3 on chromosome
20q and 8q respectively. These potas-
sium channels control neuronal connec-
tivity, and mutations in the channel re-
sult in hyperexcitability of the neuron.4
Epileptic encephalopathies such as
EME and Otahara syndrome are both
devastating conditions characterized by
severe, intractable seizures with failure
to gain developmental milestones. Both
are characterized by significantly ab-
normal background EEG activity, fre-
quently with suppression-burst activity
on EEG. EME is generally caused by
an underlying metabolic disorder, most
commonly nonketotic hyperglycinemia,
although it can also be due to amino
e296
special issue article
acid or organic acid disorders. Otahara
syndrome is most often due to structural
brain malformations; however, several
genetic causes have been identified for
both conditions.8
Testing
After a thorough history is obtained
and physical examination is completed,
with special focus on the neurologic
component, initial testing should focus
on identification of potentially treat-
able etiologies such as infectious and
metabolic derangements. Early labora-
tory testing should include a rapid point
of care glucose level, serum chemistry
panel, complete blood count, and blood
culture. Clinicians should maintain a
low threshold for obtaining cerebral spi-
nal fluid (CSF) for gram stain and cul-
ture, chemistry, and cell counts to rule
out infectious etiologies. If an infectious
cause is suspected, then HSV testing
should be performed, including HSV
CSF polymerase chain reaction testing.
Based upon the infant’s history, it may
be beneficial to obtain a C-reactive pro-
tein level, urinalysis, urine culture, and
urine toxicology. If a congenital infec-
tion (ie, TORCH [Toxoplasmosis, Other
agents, Rubella, Cytomegalovirus, and
Herpes simplex] infection) needs to be
ruled out, then the appropriate diagnos-
tic tests should be ordered. Additional
testing should include blood gas, lactate,
pyruvate, and ammonia levels. New-
born screen results should be obtained if
available. In regard to radiologic studies,
cranial ultrasound can be a useful rapid
bedside tool, but brain magnetic reso-
nance imaging is the gold standard for
head imaging. If the above fails to yield a
diagnosis, more extensive metabolic and
genetic testing may be indicated, such as
urine organic acids, plasma amino acids,
vitamin levels, CSF neurotransmitters,
and a comprehensive epilepsy genetic
panel.
Diagnosis
Seizures in the neonatal period are
frequently brief, subtle, and clinically
nonspecific. It can be difficult for the
bedside provider to distinguish clinical
seizure from normal movements. In ad-
dition, up to 80% to 90% of neonatal sei-
zures are electrographic without clinical
correlate.9 Thus, an EEG is recommend-
ed in the detection of seizure activity.
Electrographic seizure is defined as
repetitive and rhythmic pattern of at least
10 seconds in duration (Figure 1). EEG
with video is important in helping distin-
guish seizures from nonepileptic move-
ments.9 Moreover, in neonatal seizures,
treatment of clinical seizures with anti-
convulsants often results in subsequent
persistent electrographic seizures with-
out clinical correlate (called “electro-
clinical dissociation”). Therefore, con-
tinuous video EEG monitoring (cEEG)
is recommended to characterize seizures,
quantify seizure burden, and assess re-
sponse to treatment.6,9 In addition, it is
recommended to continue video EEG
until the patient is seizure free for 24
hours.
Although cEEG is the diagnostic test
of choice, there are many barriers to ac-
cessing EEG in institutions. As a result,
amplitude-integrated EEG (aEEG) is a
bedside tool that is increasingly imple-
mented in the neonatal intensive care
unit due to ease of application and in-
terpretation by a neonatologist.10 aEEG
uses limited EEG signals that are fil-
tered, processed, and displayed in time-
compressed scale, often in conjunction
with raw EEG signal to provide assess-
ment of background as well as to assist in
detecting neonatal seizures. Importantly,
it allows neonatologists a timely and
convenient instrument for neuromonitor-
ing. However, it is important to note that
aEEG has limitations. There is potential
of overdiagnosis of seizures attributed to
mistaking artifact for seizure activity.10 It
Copyright © SLACK Incorporated
 special issue article

is also less accurate compared to cEEG

in detecting seizures that are brief (<90
seconds in duration) and low voltage,9,10
which are common features in neonatal
seizures. As a result, there is also a po-
tential for underdiagnosing seizure fre-
quency. Finally, aEEG interpretation is
largely dependent on user experience.
Nonetheless, the specificity and sen-
sitivity for seizure detection can be up
to 85% in an experienced user.10,11 De-
spite its limitations, studies have shown
that aEEG has resulted in improved
decision-making and better neurological Figure 1. Neonatal electroencephalogram (EEG) findings. (A) Normal awake neonatal EEG from a 3-day-
outcomes.9 Therefore, although cEEG is old infant born at 38 weeks gestational age with episodes of apnea and desaturations. Note the con-
tinuous background with variable frequency. Occasional frontal sharp transients (asterisk symbol) are
the gold standard for seizure detection, normal. (B) Multifocal sharp discharges and discontinuity. This is from a 1-month-old infant with con-
aEEG is a useful screening tool until genital heart disease on extra-corporeal membrane oxygenation (ECMO). Background is discontinuous
with diffuse voltage attenuation (down arrow symbol) and excessive sharp discharges (double dagger
conventional EEG can be obtained. symbol). (C, D) Electrographic seizures with multifocal onset from a 4-day-old infant with hypoglyce-
mia, hyperammonemia, and body jerking concerning for seizure. (C) EEG demonstrates focal low volt-
age monomorphic rhythmic activity (right arrow symbol) localized in right central region. (D) This same
Treatment patient had focal seizure arising from left central region (left arrow symbol) then another seizure arising
The first priority in treating neonatal independently from right central region. Both seizures were electrographic without clinical correlation.
seizures is to manage airway, breathing,
and circulation. This is followed by cor-
rection of any metabolic derangements
that may be the underlying cause of the
seizures. In the case of ongoing seizure
activity, antiepileptics are used to con-
trol persistent seizures (Figure 2). Phe-
nobarbital is the most frequently used
first-line antiepileptic agent. Seizures
are controlled in approximately 50% to
70% of neonates once a therapeutic level
of phenobarbital, about 40 mcg/mL, is
reached.2,4,12 Phenobarbital is generally
administered in sequential loading dos-
es until seizure control is reached, then
maintenance dosing is started. Levels
are generally checked 1 to 2 hours after
each load, and periodically during main-
tenance therapy. There is concern in the
animal model for neuronal apoptosis with
phenobarbital, although human studies Figure 2. Treatment algorithm for neonatal seizures. BID, two times daily; IV, intravenous; TID, three times
daily.
have failed to consistently demonstrate
this.11,13,14 Choice of second-line agents
is variable among providers but is gen- in a randomized controlled trial,15 but may be a safer and equally efficacious
erally split between levetiracetam or fos- also has been shown to cause neuronal treatment option.16,17 although optimal
phenytoin. Fosphenytoin demonstrated apoptosis in an animal model.14 There dosing regimens and randomized con-
equivalent efficacy to phenobarbital is emerging evidence that levetiracetam trolled efficacy data are lacking. Sei-

PEDIATRIC ANNALS • Vol. 49, No. 7, 2020 e297


zures refractory to multiple loading
doses of the above medications may re-
spond to continuous infusion of a ben-
zodiazepine,18,19 which can be titrated
based on cEEG monitoring. Lidocaine
is used in some centers, although its use
carries risk of arrhythmia so duration of
treatment is limited.
Long-Term Outcomes
Neonatal seizures carry an increased
risk of mortality and neurodevelopmen-
tal disability that vary greatly depending
upon etiology and prompt recognition/
management. Overall, mortality rates
are about 15% to 20%.20,21 In survivors,
there is an increased risk of cerebral pal-
sy, developmental delay, and epilepsy.
Risk of cerebral palsy is 25% to 45%,
risk of global developmental delay is
about 50%, and risk of epilepsy is about
20% to 30%.21-24 Risk of cerebral palsy
and epilepsy is increased in preterm in-
fants, infants with low Apgar scores, se-
vere encephalopathy, severe parenchy-
mal injury, cerebral dysgenesis, status
epilepticus, and abnormal background
EEG activity.20-24
Close follow-up of the neonate with
seizures is important, as well as prompt
and aggressive early intervention thera-
pies as indicated to address specific
neurologic deficits. Infants should, at
minimum, be observed by neurology
as an outpatient, as well as physical,
occupational, and speech therapies as
indicated. Infants with concern for an
underlying genetic etiology may need
outpatient follow-up with a geneticist at
discharge.
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