Seizures in the Preterm Neonate

Lekha M. Rao, MD,* Charles J. Marcuccilli, PhD, MD

*Department of Pediatrics, Division of Neurology, University of California-Los Angeles, Los Angeles, CA

Department of Pediatrics, University of Chicago, Chicago, IL

Objectives After completing this article, readers should be able to:

1. Recognize the types of seizures most commonly seen in the neonatal

population.
2. Be familiar with the most common etiologies underlying seizures in the
premature population.
3. Understand the importance and challenges of diagnostic testing in
evaluation of the neonate with seizures.
4. Develop recommendations for management and follow-up for a neonate
diagnosed with seizures.

Abstract
Preterm infants are at high risk for central nervous system injury, with seizures
occurring in 6% to 48% of this population. Seizures are more likely to
contribute to adverse neurodevelopmental outcomes in preterm infants.
Preterm infants are also more likely to have subclinical seizures;
therefore, electrographic detection is essential for their diagnosis. Once
identied, seizures are traditionally treated with phenobarbital, but newer-
generation antiepileptic medications have growing evidence for safety and
efcacy. The treatment of seizures may also affect neurodevelopmental AUTHOR DISCLOSURE Drs Rao and
Marcuccilli have disclosed no nancial
outcome. relationships relevant to this article. This
commentary does not contain a discussion of
an unapproved/investigative use of a
commercial product/device.
INTRODUCTION
ABBREVIATIONS
Preterm infants are at high risk for neurologic morbidity and central nervous aiEEG amplitude-integrated
system (CNS) injury, with seizures occurring in up to 6% to 48% of this electroencephalography
CNS central nervous system
population. (1)(2) Seizures in preterm neonates are more likely to be associated
EEG electroencephalography
with adverse neurodevelopmental outcomes. (3) Specically, seizures are asso- HIE hypoxic-ischemic
ciated with increased risk for mortality and postnatal morbidities, such as encephalopathy
neurodevelopmental impairment and epilepsy. (4)(5)(6)(7) Extremely low birth- HUS head ultrasonography
weight infants and those with hypoxic-ischemic encephalopathy (HIE) appear to IVH intraventricular hemorrhage
MRI magnetic resonance imaging
be at greatest risk. (1)(8) There are multiple challenges in detecting seizures in
PVL periventricular leukomalacia
preterm infants. For example, many movements in the preterm neonate can vEEG video electroencephalography
appear abnormal and concerning for seizure activity. Therefore, electroenceph- VLBW very low birthweight
alography (EEG) is essential for diagnosis in this population. WHO World Health Organization

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TYPES OF SEIZURES agents in the neonatal population. In rodent models of the
immature brain, activation of g-aminobutyric acid receptors
The most frequent types of seizures seen in the preterm
results in depolarization rather than hyperpolarization. This is
neonate are clonic, tonic, and myoclonic (Table 1). Myeli-
due to relative underexpression of the chloride exporter KCC2,
nation in neonates is incomplete, therefore, generalized
resulting in reversal of the chloride current. In addition, the a4
tonic-clonic seizures do not occur (9); most seizures involv-
subunit of the GABA receptor is relatively overexpressed,
ing multiple extremities more likely represent multifocal
making it less sensitive to benzodiazepines. Glutamate recep-
clonic seizures. Whole body extensor posturing has been
tors are also transiently overexpressed in the developing brain,
characteristically associated with silent seizures or clin-
leading to a tendency toward neuronal excitation. (12)
ical only seizures, a term that is now being largely aban-
Structural lesions are also common causes of seizures in
doned because these motor movements are usually seen in
the preterm neonate, (1)(4)(8)(13) with intraventricular hem-
extremely encephalopathic infants and portend a poor prog-
orrhage (IVH) being the most common cause. Scher et al (4)
nosis. (10) Clonic activity is usually characterized by focal
followed a cohort of 90 infants over 4 years, 62 of whom were
rhythmic jerking of 1 or more extremities, which is not
preterm. Ninety percent of the preterm infants with seizures
suppressible. Exquisitely unilateral clonic activity may be
exhibited brain lesions, 45% secondary to intraventricular
suggestive of an underlying focal structural lesion such as
hemorrhage, and 39%, cerebral infarction. (4) There is also a
acute ischemic stroke or focal cortical malformation. Tonic
potential twofold increased risk of seizures in very low birth-
seizures involve sustained extension of an extremity, which
weight (VLBW) infants with periventricular leukomalacia
cannot be overcome by an examiner. Myoclonic seizures
(PVL). (14) Kohelet et al found that in these infants with
characteristically involve a rapid jerk of an extremity. Finally,
VLBW and PVL, decreasing gestational age, IVH, posthem-
subtle clinical seizures can be associated with movements
orrhagic hydrocephalus, sepsis, and necrotizing enterocolitis
such as nystagmus, tongue thrusting, and bicycling. Seizures
were additional independent risk factors for seizures. (13) In
accompanied solely by autonomic changes (such as change in
all these studies, however, there were still a few patients with
heart rate, oxygenation, and respiration) are rare, but are more
no abnormalities on imaging who demonstrated electro-
common in preterm than term neonates. (1)(11) Seizures in
graphic seizures. Shah et al found that in their cohort of 8
this population are also frequently subclinical, and therefore
patients with IVH, 5 had seizures, 4 of which preceded
electrographic monitoring is essential to their detection.
imaging ndings. (1) Hence, seizures in this group of patients
may reect an underlying systemic process, potentially one in
an early stage before reliable detection with neuroimaging.
ETIOLOGY
Other potential causes for seizures in the premature
Seizures occur more readily in the neonatal brain because of neonatal population include HIE, electrolyte abnormalities,
differences in ion channel gradients, as compared to the adult CNS infections, and genetic causes including cortical mal-
brain. Understanding these differences is also helpful in under- formations. Although HIE is the most common cause of
standing management strategies and preferred therapeutic seizures in the term neonate, it is difcult to determine its

TABLE 1. Neonatal Seizure Types

MOVEMENT TYPE LOCALIZATION/CLINICAL SIGNS ELECTROGRAPHIC CORRELATE

Clonic Focal rhythmic jerking of an extremity Yes

Nonsuppressible
Tonic Focal sustained extension or exion of an extremity Yes
Not able to overcome with external manipulation
Sustained extension of the whole body Not usually
Myoclonic Single jerk or multiple nonrhythmic jerks of an extremity Usually
Spasms Focal or generalized Yes
Flexor, extensor, or mixed exor/extensor

Adapted from Rao LM, Matsumoto JH, Lerner JT, and Nuwer MR. EEG Monitoring in Neonatal Epilepsies. In: Galloway G, ed. Clinical Neurophysiology in
Pediatrics. New York, NY: Demos Medical Publishing; 2015: 6.

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 incidence in the preterm population, because the examina-
tion and antepartum events are not reliable indicators of its
diagnosis. (15) In a recent set of guidelines published by the
World Health Organization (WHO), apparent differences in
the prevalence of HIE between term and preterm neonates
could not be determined. (16) In this population, it is also
extremely important to rule out electrolyte abnormalities
and infectious etiologies, especially meningitis, because
these critically ill infants are often at risk for sepsis and
their blood-brain barrier is immature. Bacterial and viral
meningitis, as well as congenital toxoplasmosis, other (syph-
ilis, varicella-zoster, parvovirus B19), rubella, cytomegalovi-
rus, and herpes (TORCH) infections are also possible in this
population. Hypoglycemia, hypocalcemia, hypomagnese-
mia, and hypo/hypernatremia are readily identiable and
treatable causes of neonatal seizures. Inborn errors of
metabolism can also present with seizures and acid-base
disturbances in the neonatal period. Finally, cortical mal-
formations such as cortical dysplasia, hemimegalencephaly,
and schizencephaly are rare but potential causes of focal
seizures in neonates, though some may present later in
infancy and childhood.
DIAGNOSTIC EVALUATION: ELECTROGRAPHIC
DETECTION
Critically ill neonates are at high risk for seizures, the
majority of which are subclinical. (1)(4)(8)(12) Therefore,
it is important to have a low threshold for obtaining an EEG
in an infant with suspected seizures or at high risk for
seizures. The neonatal EEG is rst evaluated for background
TABLE 2. Electroencephalography (EEG) Background in Prematurity
CONCEPTIONAL AGE (WEEKS) MAXIMUM INTERBURST DURATION (S)
2425 60
2730 35
3133 20
3436 10
3740 6 Wake and active sleep: Mixed frequency continuous (activit
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ndings, which vary depending on gestational age (Table 2).
Knowing the conceptional age at the time of acquisition,
therefore, is important to the interpreting encephalogra-
pher. Seizures are dened as rhythmic discharges with a
minimum duration of 10 seconds, and evolving in fre-
quency, morphology, and amplitude. (17) Although video-
EEG (vEEG) monitoring is considered in the neurology
community to be the gold standard in diagnosis of sei-
zures, especially given that the majority of electrographic
seizures are subclinical, (18) this technology is not yet
available in all centers, and interpretation is limited to a
trained encephalographer. Amplitude-integrated EEG (aiEEG),
therefore, has become more frequently used at the
bedside in the NICU. (19)
aiEEG has been used to detect electrographic seizures,
and has the added benet of being interpretable by the
bedside clinician. Single-channel recordings, as historically
used in cerebral function monitors, involve biparietal elec-
trodes (P3-P4), and were originally chosen to avoid muscle
and movement artifact; these channels lie over the vertex,
which is a watershed zone for the neonatal cortex. The use of
2-channel recording over central and parietal regions (C3-P3
and C4-P4) has now been advocated, because it allows for
better comparison of interhemispheric asymmetries and
possibly increases sensitivity. (19) Interpretation is largely
visual, with evaluation of amplitude and frequency. Seizures
are detected by a sustained spike in amplitude (Fig 1).
Concern has been raised, however, at the inability of
aiEEG to detect short seizures, given that 12-hour-long
epochs of recording are compressed into 1 page and neo-
natal seizures are typically short in duration, ranging on
EEG BACKGROUND FEATURES
No sleep organization or reactivity
Discontinuous in both wake and sleep, some reactivity
Differentiation between active and quiet sleep patterns
Wake and active sleep: Mixed frequency continuous (activit
moyenne)
Quiet sleep: Interburst intervals amplitude nearly isoelectric,
<25 mV (trace discontinue pattern)
Wake and active sleep: Mixed frequency continuous (activit
moyenne)
Quiet sleep: Interburst intervals increase in amplitude,
eventually exceeding 25 mV (trace alternant pattern)
moyenne)
Quiet sleep: Interburst intervals continue to increase in
amplitude, increasing continuity (trace alternant
transitioning to continuous slow wave sleep pattern)
Figure 1. Representative amplitude-integrated electroencephalographic (aiEEG) recording. aiEEG here has been derived from a conventional neonatal set of
electrodes using central and occipital channels in each hemisphere. Seizures in the right hemisphere are seen here as slight overall increases in amplitude.

average from 10 to 90 seconds, and may be shorter in the
preterm neonate. (11)(17) In addition, because the number of
recording channels is limited, seizures may occur spatially
in areas that cannot be detected by electrode placement.
Finally, subtle electrographic seizures, such as rhythmic
alpha waves often associated with apneic seizures in neo-
nates, may not be detected with aiEEG (Fig 2). (20)(21) These
limitations are important to consider, because a negative
aiEEG may not rule out the presence of seizures.
In addition, aiEEG is extremely operator-dependent. In a
study by Rennie et al, (22) 40 recordings were analyzed by
nonexpert users. The sensitivity for detecting seizures on a
tracing was 26% to 52%, with a specicity of 71% to 100%
depending on the speed of aiEEG, but inter-rater agreement
was low. (22) A similar study by Frenkel et al (23) compared
readings by a medical student, neonatology fellow, and
senior neonatologist. Agreement between the student and
fellow was poor, and specicity increased with increas-
ing experience at interpreting aiEEG. The student was also
more likely to overdiagnose seizures. This study shows that
although inexperienced clinicians or bedside nurses could
be trained in reading aiEEG, it becomes a more accurate tool
in the hands of experienced readers. (23)
Shellhaas et al (24) analyzed 851 neonatal seizures from
125 conventional EEGs in patients 34 to 50 weeks of gesta-
tional age. aiEEGs derived from these recordings using the
C3-C4 channel were then interpreted by neonatologists. The
neonatologists identied seizures in 22% to 57% of the 125
records with neonatal seizures, but were only able to detect
12% to 38% of the 851 individual seizures. Seizures that were
repetitive in nature were more readily detectable by visual
inspection, but seizures that were brief, infrequent, or low
amplitude were difcult to detect with aiEEG. (24) Shah et al
(19) compared simultaneous aiEEG and continuous EEG
recordings as assessed by experienced reviewers with access
to raw EEG, and the sensitivity of detecting seizures in-
creased from 25% to 56% to 76%.
Conventional EEG is frequently used in the NICU, either
as 60-minute recordings, or continuous vEEG (Fig 2). Elec-
trodes are placed by a modied 10 to 20 placement as per
minimum standards provided by the American Clinical
Neurophysiology Society. (25) EEG has been used on a

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 Figure 2. Conventional continuous video-electroencephalographic monitoring in a premature neonate who sustained perinatal depression,
demonstrating rhythmic alpha (812 Hz) activity over the left centrotemporal head region (upper 4 lines in black).

periodic basis to evaluate for encephalopathy, follow the
evolution of background abnormalities, and detect seizures.
(10) Routine EEG has been used after the observation of
clinical seizures, and can be useful in evaluating the interictal
background to help guide prognosis, but because of the short
duration, may not capture electrographic seizure activity.
Wietstock et al (18) prospectively followed 595 neonates,
400 of whom received clinically indicated vEEG. A total of
26% of neonates in their cohort had electrographic seizures,
of which 24% were entirely subclinical and were not associ-
ated with any clinical events before monitoring that were
suspicious for seizures. (18) Murray et al (26) studied 51
infants, 9 of whom had electrographic seizures, but only one-
third of whom had clinical manifestations. In addition,
bedside staff were not accurate at detecting clinical seizure
activityof the documented suspected seizures, only 27%
had corresponding electrographic evidence, and only 9%
of electrographic seizures with clinical manifestations were
recognized by staff. (26) Continuous vEEG monitoring is
therefore considered the gold standard in detecting neonatal
seizures. Recent guidelines suggest a minimum duration of
24 hours in high-risk infants to screen for seizures, and
continuing monitoring until 24 hours of freedom from sei-
zures. (25) Preterm infants may also be at risk for seizures later
than term infants, with a median onset greater than 48 hours,
as opposed to 24 hours in the term population, (4)(7) so
extended monitoring may be more useful in this population,
though further studies are needed to establish this.
DIAGNOSTIC EVALUATION: IMAGING
Head ultrasonography (HUS) has historically been the most
common imaging modality used in the NICU, because of its
ready availability and ease of bedside use. HUS is most
commonly used to evaluate for periventricular lesions such
as IVH and PVL, but has limitations in its ability to detect
subcortical white matter injury and posterior fossa lesions.
Leijser et al (27) evaluated 110 preterm infants (<32 weeks)
with serial HUS during their hospital course and again
around term equivalent with magnetic resonance imaging
(MRI). HUS was able to detect severely abnormal white
matter injury but had a lower positive predictive value for
normal, mildly abnormal, and moderately abnormal scans
compared with MRI. Therefore HUS may be negative in

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infants with mild injury. (27) Glass et al (8) evaluated 236
infants of less than 34 weeks gestation, 9 of whom had
clinical suspicion for seizures, all of whom had abnormal
MRI ndings. Infants with seizures were more likely to have
white matter injury, and most commonly had periventric-
ular hemorrhagic infarcts. HUS was unable to detect the
extent of injury in 8 (89%) of the 9 infants with seizures. (8)
Therefore MRI may be better for evaluating for structural
abnormalities in preterm infants with seizures. Another use
for MRI brain studies may be in predicting neurodevelop-
mental outcomes. A recent study by vant Hooft and col-
leagues (28) sought to determine the prognostic accuracy of
an MRI performed at term equivalent in very preterm (32
weeks) or low birthweight (1,500 g) infants on neurodevel-
opmental outcomes. The study demonstrates that moderate
to severe white matter abnormalities seen on brain MRI per-
formed at term equivalent are predictive of motor function
and cerebral palsy. However, brain MRI was poor at prognos-
ticating visual/hearing decits or neurocognitive/behavioral
problems. (28)
DIAGNOSTIC EVALUATION FOR OTHER CAUSES
Hypoglycemia, hypocalcemia, hypomagnesemia, and hypo-
or hypernatremia are all easily identiable and treatable
causes of neonatal seizures. Evaluation for electrolyte and
serum glucose derangements should be routine for new-
onset seizures. Preterm infants are also at higher risk for
CNS infections, and evaluation with lumbar puncture
should be considered. Genetic syndromes, such as pyridox-
ine-dependent seizures, benign neonatal convulsions, and
early myoclonic epilepsy of infancy, should also be consid-
ered in highly refractory cases. (12)
TREATMENT
The treatment of neonatal seizures has also been contro-
versial, and methods are not standardized across institu-
tions. Phenobarbital has been associated with less than 50%
efcacy in the treatment of neonatal seizures, (29) yet a
survey of neurologists and neonatologists by Glass et al
showed that phenobarbital is still the most commonly used
rst-line agent in preterm infants. (30) Other seizure med-
ications such as phenytoin and benzodiazepines are equally
inefcacious, yet little evidence exists to support the use of newer-
generation antiseizure medications. Although phenobarbital
is commonly used in the neonatal population, animal studies
have raised concern about its effects on the developing brain.
(31) Nevertheless, with lack of a better alternative, the WHO
has recommended that phenobarbital be used as a rst-line
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agent with either a benzodiazepine or phenytoin as second-
line treatment. (16) Commonly, an initial loading dose of 10 to
20 mg/kg phenobarbital is used on initial detection of clinical
and/or electrographic seizures, and continued at a mainte-
nance dose of 2.5 to 10 mg/kg per day. Goal therapeutic levels
may range from 20 to 40 g/mL, though higher levels have
been used in infants receiving mechanical ventilation to
achieve freedom from seizures. Given the tendency toward
electroclinical dissociation, wherein seizures appear to cease
clinically after the administration of phenobarbital but con-
tinue to be present electrographically, (32)(33) EEG monitor-
ing is essential in acute refractory seizures.
Recent studies have suggested that levetiracetam may
exhibit modest efcacy in the treatment of neonatal seizures
(34)(35)(36) without evidence for apoptosis in animals. (37)
(38) These studies, however, were observational with con-
current use of other antiseizure medications. The optimal
loading dose has also not been studied or standardized, but
doses of 20 to 30 mg/kg are usually considered acceptable,
with a maintenance dose of 20 to 60 mg/kg per day.
Therefore, further randomized controlled trials are needed
to establish safety, dosing, and efcacy in this population.
Studies have also shown that treatment and control of
seizures in the neonatal period do not necessarily preclude
development of epilepsy later in life. Seizures are also
commonly acute reactions to brain injury, and the temporal
evolution peaks around 3 days after birth in the preterm
neonate then naturally abates. No standard guideline exists
regarding treatment, however, it is commonly accepted that
EEG monitoring, if initiated, should be continued until 24
hours of freedom from seizures is achieved. Maintenance
antiseizure medications are usually continued at least until
term equivalent age or on discharge from the NICU, and
should be titrated slowly to prevent withdrawal seizures.
IMPACT ON MORBIDITY AND MORTALITY
The impact of neonatal seizures on outcome has been his-
torically widely debated, but more recent studies suggest
that seizures can be associated with worse outcomes, includ-
ing neurodevelopmental impairment. (39) Some studies
suggest that the seizures themselves cause or worsen under-
lying brain injury, (40)(41) whereas others suggest that the
underlying cause of seizures leads to worse outcome. (42)
Others have proposed that the treatment of seizures, in
particular phenobarbital, due to concern for neuronal apo-
ptosis, (31) may also contribute to worse outcomes, but this
theory has been largely discounted (43); phenobarbital may
even be neuroprotective, especially with therapeutic hypo-
thermia, (44) but larger studies are still needed.
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 Preterm infants may be more susceptible to potential
injury from seizures than term infants. Scher et al showed
that compared with term infants with electrographic sei-
zures, preterm infants are at higher risk of death, and were
more likely to have neurodevelopmental impairment. (4) In
a study of preterm infants with vEEG-conrmed seizures,
34% had died at 30-month follow-up, with a higher risk of
mortality among patients with a birthweight less than 1,500
g. Of these, 20% had a normal outcome, 40% had cerebral
palsy, and 18% had epilepsy, cerebral palsy, and develop-
mental delay. (7) Vesoulis et al (45) monitored 95 very
preterm infants using aiEEG during the rst 3 days after
birth. The incidence of seizures was 48%, and the presence
of seizures was associated with increased risk for IVH, white
matter injury, and death. The presence of seizures was also
associated with worse language scores at age 2 years, even
after adjusting for social risk factors. (45) Seizures in preterm
infants, therefore, likely contribute to worsening brain injury.
Because these infants are at high risk for poor neuro-
developmental outcomes, it is important for these children
to be followed by a pediatric neurologist, as well as a
multidisciplinary NICU follow-up team, who can help fam-
ilies gain access to developmental services, such as physical,
occupational, and developmental therapy, as needed.
CONCLUSIONS
Seizures are common in preterm infants, occurring in 6%
to 48% of this population. Seizures can carry a risk of
worsening brain injury and affect morbidity and mortality.
They are also frequently subclinical, making EEG monitor-
ing essential for detection. Once detected, seizures should
be treated, because early treatment may lessen the severity
of brain injury and potentially affect outcome.
American Board of Pediatrics
NeonatalPerinatal Content
Specications
Know the indications for and limitations of various neuroimaging
studies and be able to recognize normal and abnormal structures
and changes during development and growth.
Understand the spectrum of clinical seizures in the newborn infant.
Understand the differential diagnosis and evaluation of neonatal
seizures.
Understand the management of neonatal seizures, including the
role of neurophysiologic monitoring.
Understand the clinical manifestations of neonatal seizures, and
their prognosis.
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Vol. 18 No. 1 JANUARY 2017 e59
 Seizures in the Preterm Neonate
Lekha M. Rao and Charles J. Marcuccilli
NeoReviews 2017;18;e52
DOI: 10.1542/neo.18-1-e52

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 Seizures in the Preterm Neonate
Lekha M. Rao and Charles J. Marcuccilli
NeoReviews 2017;18;e52
DOI: 10.1542/neo.18-1-e52

The online version of this article, along with updated information and services, is
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