18  Neonatal Seizures
Renée A. Shellhaas, Hannah C. Glass, and Taeun Chang
INTRODUCTION
Children are at highest risk for seizures during the first
month of life.1 Seizures in newborns are usually symptomatic
of an underlying acute injury (such as hypoxic-ischemic injury
or stroke) and are only rarely manifestations of epilepsy syn-
dromes. Similar to other critically ill patient populations,
most neonatal seizures are subclinical—they have no outward
manifestation and are most accurately diagnosed by electro-
encephalography (EEG). Herein, we review the pathophys­
iology, epidemiology, diagnosis, treatment, and long-term
implications of seizures in neonates.
PATHOPHYSIOLOGY
The neonatal period presents the highest lifetime risk for sei-
zures.1 Acute symptomatic seizures caused by birth trauma
and hemorrhage, hypoxic-ischemic injury, perinatal infec-
tions, and metabolic disturbances account for more than 80%
of seizures. In addition, but much less commonly, congenital
brain malformations, inborn errors of metabolism, and epi-
leptic encephalopathies can present in the neonatal period
with seizures as the first sign of neonatal onset epilepsy.
The immature brain is highly susceptible to acute symp-
tomatic seizures because of age-dependent mechanisms that
lead to excess excitation and reduced inhibition.2,3 Results
from animal models suggest that acute symptomatic seizures
are deleterious to the developing brain.4 In humans, seizures
in the newborn period are associated with brain injury and
adverse neurodevelopment.5,6 In addition, among neonates
with hypoxic-ischemic encephalopathy (HIE), seizures are
associated with higher lactate on magnetic resonance (MR)
spectroscopy (indicating injury) and higher rates of adverse
neurodevelopmental outcome that are independent of the
severity of brain injury. These data suggest that seizures may
also be harmful to human newborns with underlying brain
injury.7,8
Mechanisms of Excitability in the   rogenesis, (3) delayed neuronal loss, and (4) changes in hip-
Developing Brain
The developing brain’s propensity to generate seizures is mul-
tifactorial.2,3,9 The primary mechanisms of inhibition (through
gamma-amino-butyric acid [GABA]) and excitation (through
the glutamatergic system) favor excitability during the neona-
tal period.
GABA is the primary inhibitory mechanism of the adult
brain. In mature neurons, GABAA receptor activation leads to
chloride influx to produce membrane hyperpolarization and
inhibits the neuron’s ability to fire action potentials. In imma-
ture neurons, however, there is a net chloride efflux with
GABAA receptor activation, which leads to membrane depolar-
ization that increases the likelihood of the neuron to fire an
action potential. The developmental changes in neuronal
chloride gradients are mediated largely by the membrane ion
transporters NKCC1 and KCC2.
In early life, a relatively higher expression of NKCC1
leads to a high intracellular chloride concentration, and sub-
sequent depolarization upon activation of the GABAA receptor.
With increasing age, the expression of the KCC2 chloride
e318
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co-transporter becomes dominant, which leads neurons to
display the mature pattern of low intracellular chloride and
hyperpolarization with activation of the GABAA receptor.10–12
Thus GABAergic medications (such as benzodiazapines and
barbiturates), which are commonly used to treat seizures in
neonates, could, in theory, cause a paradoxical excitatory
response. Nonetheless, the response to phenobarbital as a
first-line agent is approximately 50%,13 which is similar to the
effect of first-line agents in the pediatric intensive care unit14
and suggests that GABA agents are inhibitory in some popula-
tions of neurons in the neonatal period. Bumetanide, a potent
diuretic that acts to alter the intracellular chloride concentra-
tion in favor of hyperpolarization, has been proposed as an
adjunct to improve the efficacy of phenobarbital, but safety
and efficacy data are not yet available.15
Glutamate is the primary excitatory neurotransmitter.
The glutamate receptors are developmentally regulated, and
lead to enhanced excitability of the immature brain. N-methyl-
d-aspartate (NMDA) receptors are relatively abundant in new-
borns, and their subunits are configured with a high level
of the NR2B subunit, which leads to greater excitability
through prolonged current delay and excitatory postsynaptic
potentials, as well as a relative insensitivity to magnesium
ions.16–18
Finally, excitability is enhanced during the neonatal period
as a result of physiologic, use-dependent synaptogenesis,
when both synapse and dendritic spine density are at their
peak.19,20
The Effect of Seizures on Early  
Brain Development
Seizures during early development can lead to developmental
changes that alter neuronal circuitry and may impair learning
and memory in animal models. Developmental alterations
that have been observed in neonatal animal models after
induced seizures include (1) reduced density of dendritic
spines in hippocampal pyramidal neurons, (2) decreased neu-
pocampal plasticity (e.g., decreased capacity for long-term
potentiation, reduced susceptibility to kindling, and enhanced
paired-pulse inhibition).21–24 Furthermore, in the setting of
brain injury and hyperthermia, seizures can lead to hippocam-
pal necrosis in animal models.25 In addition, in rodent models,
neonatal seizures increase the susceptibility to unprovoked
recurrent seizures (epilepsy) later in the animal’s life.4
EPIDEMIOLOGY
Incidence of Neonatal Seizures
Current estimates of the incidence of seizures in newborns
range from 1 to 3.5 per 1000 live births, or approximately
14,000 newborns annually in the United States.26–29 Estimates
as high as 1 per 20 have been reported for preterm or very low-
birth-weight newborns, with the incidence inversely related to
birth weight and gestational age26,29–31 (Table 18-1). Males are
more often affected than females, and infants of African Amer-
ican origin have a higher incidence of seizures than those of
other races and ethnicities.27,32
 Neonatal Seizures e319

TABLE 18-1  Estimates of Neonatal Seizure Incidence

18
Overall NBW/
Author Year Type Source Method Incidence* Term <36 wk* <2500 g* VLBW*
Holden et al.34 1959–1966 Prospective National Collaborative — 5.0 — 29.5 31 —
Perinatal Project
Lanska and 1980–1991 Retrospective National Hospital Discharge 2.84 2.4 — 9.4 —
Lanska30 Discharge Survey records
Lanska et al.31 1985–1989 Retrospective Fayette County, Birth certificates 3.5 3.6 — 18.6 57.5
Kentucky Hospital records
Ronen et al.29 1990–1994 Prospective Newfoundland, Training 2.6 2.0 11.1 13.5 —
Canada
Saliba et al.32 1992–1994 Retrospective Harris County, Texas Birth and death 1.8 1.4 4.85 5.6 19
and certificates
prospective
Glass et al.27 1998–2002 Retrospective California Birth certificates 0.95 — — — —
Hospital records
NBW, normal birth weight; VLBW, very low birth weight.
*Per 1000 live births.

Although seizure incidence reported in more recent studies
is lower than that reported in older studies,27,32 differences in
case ascertainment or study site(s) may be responsible for this
variation. The true incidence of seizures in the newborn is
difficult to determine as population studies have been based
on clinically observed or reported seizure-like activity, without
EEG confirmation. More recent data suggest that such case
ascertainment may include infants whose events were not, in
fact, seizures, while excluding those with exclusively subclini-
cal seizures. Most studies use a case definition of seizures in
infants up to 44 weeks’ postmenstrual age (PMA).
Published epidemiologic studies have mainly been retro-
spective and based on clinical observation of neonatal sei-
zures, as documented in birth certificates, death certificates,
medical records, discharge records, and/or diagnostic codes.
Glass et al.27 included discharge codes from birth admissions
only. Newborns diagnosed with neonatal seizures after trans-
fer from birth hospital to a tertiary hospital or after discharge
would not have been captured. Saliba et al.32 observed that
infants treated in more tertiary Neonatal Intensive Care Units
(NICUs) were at higher risk of seizures, reflecting a higher risk
population. A prospective study at a single tertiary children’s
hospital serving a rural region observed a seizure incidence of
8.6% of NICU admissions.33
Seizures are up to 10 times more common in preterm than in
term infants with incidence inversely related to birth weight30,31
and gestational age.29 The risk for seizures in very low-birth-
weight (<1500 g) infants is 57.5 per 1000 live births, 4.4 in
1500- to 2499-g infants, 2.8 in 2500- to 3999-g infants, and 2.0
in infants greater than 4000 g.31 No gender or racial variation
was found.30,31 These reported rates are higher than in a study by
two of the same authors in a nationwide survey of short-stay
hospitals examining neonatal seizures in infants with less than
30 days of hospitalization. Diagnoses made after transfer or
infants discharged beyond 30 days were not captured.
Sheth et al.33 observed a parabolic relationship between
seizure incidence and gestational age, with 30 to 36 weeks’
gestational age infants at lowest risk. This observation may be
related to the two most common causes of seizures, intraven-
tricular hemorrhage and hypoxic ischemic injury, being more
common in the younger and older age groups, respectively. Of
note, this study involved a single tertiary center with a clinical
neonatal seizure case definition of only infants that required
anticonvulsant medications for their seizures.
Seizures in the newborn usually occur in the first week of
life (~70–85%), particularly in the first 2 days.29,32 In the
National Collaborative Perinatal Project of 1959 through
1966,34 23% of seizures were diagnosed in the first 12 hours
of life, 42% in the first 24 hours, and 65% in the first 2 days.
In a more recent study in Newfoundland, Canada,29 36% of
affected infants had seizure onset in the first 24 hours and
64% within the first 48 hours. Similar findings were noted in
the more diverse population of Harris County, Texas.32
Seizure duration in newborns has not commonly been
examined in these population-based studies as seizures were
defined clinically and often retrospectively. Ronen et al.29 did
capture seizure duration in their questionnaires to the witness-
ing provider. Similar to EEG-based case cohort studies of new-
borns with seizures, 85% of seizures lasted less than 5 minutes.
Although rare, 5% of newborns were clinically observed to
have seizures lasting more than 30 minutes. Emergence of
continuous prolonged video-EEG recordings with the conver-
sion from pen-and-paper to digital EEG technology has
improved our ability to capture and characterize neonatal sei-
zures. Seizures and status epilepticus may be more common
than previously realized,35–37 but most neonatal seizures
remain brief, with 60% lasting less than 90 seconds.38
Risk Factors for Neonatal Seizures
Risk factors for neonatal seizures are related to their long list
of underlying etiologies (Table 18-2). In addition to low birth
weight and gestational age, risks for seizures in a newborn
include preexisting maternal diabetes, maternal fever or infec-
tion, perinatal or postnatal infection, major morbidities
or surgical interventions in the infant, evidence of fetal dis-
tress, and postterm delivery.27,28,39,40 Possible risk factors also
include advanced maternal age, maternal nulliparity, and male
gender.27,39
ETIOLOGY
The causes of seizures in newborns are numerous and diverse
(see Table 18-2); a single newborn can have more than one
cause of seizures. Most neonatal seizure etiologies reflect
underlying acute brain injury rather than epilepsy. Our ability
to determine etiology has improved with enhanced access to
EEG monitoring and brain magnetic resonance imaging

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e320 PART IV  Perinatal Acquired and Congenital Neurologic Disorders

TABLE 18-2  Distribution of Neonatal Seizure Etiologies

Mastrangelo
Loman et al.56 Pisani et al.41 Tekgul et al.43 et al.44 Ronen et al.29
(2002–2009), (1999–2004), (1997–2000), (1990–1998), (1990–1994),
N = 221 N = 106 N = 89 N = 94 N = 89
Hypoxic-ischemic encephalopathy, % 57.5 43.4 40 44.7 40
Metabolic or electrolyte disturbances, % 10.9 6.6 3 3.2 19
Intracranial hemorrhage, % 9.0 23.6 17 4.3 11
Cerebrovascular disorders, % 7.7 — 18 7.4 7
Infections, % 6.3 7.5 3 10.6 20
Congenital central nervous system 3.2 5.7 5 9.6 10
abnormalities, %
Inborn errors of metabolism, % 2.3 6.6 1 7.4 —
Epilepsy syndromes, % 2.3 — — 5.3 6
Intoxications, % 0.5 — — — —
Unknown, % 0.5 6.6 12 1.1 14

(MRI), as well as advances in genetic testing. Determination
of seizure etiology is critical, as treatment of the underlying
cause may be life-saving (e.g., antibiotics for a newborn with
bacterial meningitis), and combining seizure burden with eti-
ology41,42 can assist in assessing prognosis.
Etiologies of neonatal seizures can be divided into three
broad categories: (1) acute symptomatic seizures (by far the
most common); (2) developmental brain abnormalities; and
(3) genetic or neonatal epilepsy syndromes. The following
sections highlight the more common causes.
Acute Symptomatic Seizures
Hypoxic ischemic encephalopathy (HIE) is the most frequent
cause and accounts for up to 40% to 45% of neonatal sei-
zures.41,43,44 Therapeutic hypothermia is now standard care for
HIE in newborns 36 weeks’ gestation or greater, and EEG
monitoring is recommended for cooled newborns. Prolonged
continuous video EEG throughout cooling and rewarming is
preferred. If continuous EEG is not available, then continuous
amplitude-integrated EEG (aEEG), or daily serial routine EEGs
for the first 4 days of life are suggested. Even though cooling
may decrease seizure burden, about half of treated newborns
still have seizures during therapeutic hypothermia.45–49 Seizure
onset continues to be within the first 24 hours of life.43,45,48
See Chapter 19 for more details.
Cerebrovascular events, including arterial and venous infarc-
tions and intracranial hemorrhages, are the second most common
cause of neonatal seizures (7%–18%) (Chapter 20). Recogni-
tion and characterization of cerebrovascular events in new-
borns has improved with increased access to brain MRI.
Arterial ischemic perinatal strokes (AIS) occur in 1 in 2300 to
5000 live births50 and are typically the result of embolism
from the placenta or umbilical cord, carotid artery, or heart.
Seizures are the most frequent presenting symptom of AIS.51
Almost two thirds involve the left middle cerebral artery terri-
tory. Maternal risk factors for perinatal arterial ischemic strokes
include oligohydramnios, clinical or histologic chorioamnio-
nitis, premature rupture of membranes, preeclampsia, diabe-
tes, and smoking. Risk factors in the neonate include congenital
cardiac abnormalities, systemic infections, coagulation disor-
ders in the neonate, placental abnormalities, and male
gender.51–53
Cerebral sinovenous thrombosis (CSVT) usually involves
the superior sagittal sinus and/or transverse sinus in term
neonates and medullary vein thrombosis in preterm neonates.
The incidence is rare, between 1 and 2.69 per 100,000 new-
borns.54 Venous infarction occurs in approximately 60% of
reported cases. Two thirds of affected neonates present during
the first week of life and with seizures.55 Maternal, fetal, and
neonatal risk factors for CSVT are similar to those outlined
earlier for arterial strokes, and many infants have a combina-
tion of predisposing factors that include neonatal sepsis and
dehydration.
Intracranial hemorrhages can result in neonatal seizures.
Diagnosis typically requires neuroimaging, and head ultraso-
nography and brain MRI are the preferred modalities. Com-
puted tomography is not preferred for newborns, given the
risk of radiation and lack of benefit relative to ultrasonography
for identification of conditions for which neurosurgical inter-
ventions are required. Hemorrhages in term neonates may be
caused by trauma, coagulopathy, or vascular malformations.
Subarachnoid hemorrhage (SAH) and subdural hemorrhage
(SDH) are common in healthy term infants, related to labor
and delivery, and are usually not significant (i.e., they are not
necessarily the primary etiology for a newborn who develops
seizures) (Chapter 21). Intraventricular hemorrhage (IVH) is
common in preterm infants less than 30 weeks’ gestation but
on occasion can present in term infants (Chapter 22) usually,
in this case, because of sinovenous thrombosis. IVH is the
primary seizure etiology in preterm infants.33 Seizures are
associated with IVH grade 3 or periventricular hemorrhagic
infarct (IVH grade 4) and typically occur in the first 3 days
of life.
Systemic or central nervous system (CNS) infections are
the third most common cause of seizures in newborns
(3–10%).41,43,44,56 This category includes in utero or post­
natal infections, meningitis, and meningoencephalitis. Viral
etiologies include herpes simplex virus (HSV), cytomegalovi-
rus (CMV), parechovirus, lymphocytic choriomeningitis virus
(LCMV), disseminated enterovirus, and parvovirus (Chapter
115). Bacterial sources include group B streptococcus (early
and late), Escherichia coli, and toxoplasmosis (Chapter 114).
Lumbar puncture is recommended in all neonates with sus-
pected infection. Infants too unstable to undergo lumbar
puncture should be treated empirically for CNS infection.
Seizures caused by primary metabolic disturbances, or meta-
bolic abnormalities associated with acute medical illness,
account for 3% to 7% of EEG-confirmed seizures.41,43,44 Such
disturbances most often include abnormal glucose, calcium,

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or sodium levels. Typically, reversal of these abnormalities
results in resolution of the neonatal seizures.
Hypoglycemia occurs in 1 to 3 out of 1000 live births. The
definition is based on gestational age and day of life. In
general, hypoglycemia is defined as less than 45 mg/dL in
term infants and less than 30 mg/dL in preterm infants. Risk
factors include maternal diabetes, small for gestational age, in
conjunction with illness, feeding issues, and/or pancreatic
insulinoma. Overall the incidence has declined with improved
neonatal care. Initial treatment is to provide supplemental
glucose. Antiseizure drug administration is necessary only if
seizures persist despite glucose boluses. Severe hypoglycemia
may result in brain parenchymal injury, which is most often
localized to the posterior brain quadrants.57
Hypocalcemia is the cause of 1% of all neonatal seizures.43
It is defined based on free ionized calcium levels rather than
total serum calcium. Early onset hypocalcemia, within 3 days
of life, is associated with low-birth-weight infants, maternal
diabetes, HIE, and endocrinopathies. Late onset, after 1 week
of life, is now rare but is associated with maternal hyperpara-
thyroidism or maternal vitamin D deficiency, or may be a
manifestation of DiGeorge syndrome. Hypocalcemia caused
by high-phosphorus–containing formulas or use of cow’s milk
is uncommon in the United States.
Hyponatremia or hypernatremia is seen most commonly
in extremely premature infants. Among term infants, sodium
imbalance can be caused by incorrect mixing, because of
incorrect mixing of formula or severe dehydration, or can
be a complication of intracranial injury. Severe dehydration
with hypernatremia and seizures may be associated with
CSVT.
Inborn errors of metabolism (IEM) cause 1% to 7% of neo-
natal seizures.41,43,44 Prompt diagnosis is necessary to correct
the underlying metabolic disorder and minimize irreversible
brain injury. The presence of seizures is related to the degree
of metabolic derangement and resultant brain injury. Seizures
can be associated with urea cycle defects (hyperammonemia),
organic acidurias, and aminoacidopathies (metabolic acido-
sis). These are discussed further in Chapter 23.
Metabolic epileptic encephalopathies are uncommon, but
sometimes treatable causes of seizures in newborns. These
disorders can be divided into three broad categories: (1) dis-
orders of neurotransmitter metabolism; (2) disorders of
energy metabolism; and (3) biosynthetic defects causing brain
malformation, dysfunction, and degeneration.58
Disorders of neurotransmitter metabolism (Chapter 44)
include nonketotic hyperglycinemia, pyridoxal-5′-phosphate–
responsive encephalopathy (Chapter 76), pyridoxine-
dependent epilepsy (PDE) (Chapter 76), folinic acid–responsive
seizures, mitochondrial glutamate transporter, aromatic
amino acid decarboxylase deficiency (AADC), D-2-
hydroxyglutaric aciduria, and GABA disorders (Chapter 76).
Nonketotic hyperglycinemia (NKH) is a defect in the glycine
cleavage system. Newborns often present with apnea, hypoto-
nia, encephalopathy, and refractory seizures. Seizures are
believed to be the result of overactivation of NMDA excitatory
amino acid receptors. Diagnosis is by detecting an elevated
cerebrospinal fluid (CSF)–to–serum glycine ratio.
PDE is caused by a rare autosomal recessive antiquitin
deficiency (ALDH7A1 gene). The seizures rapidly respond to
intravenous (IV) pyridoxine, and so a pyridoxine administra-
tion trial is warranted for newborns with unexplained
treatment-resistant seizures (see Treatment section later).
Folinic acid–dependent seizures are an allelic phenotype.
Diagnosis is by examining alpha-aminoadipic semialdehyde
levels in urine, and by observation of seizure remittance with
pyridoxine treatment. Pyridoxine-5′-phosphate deficiency is
related to PDE, but often presents with severe epileptic
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Neonatal Seizures e321
encephalopathy and is responsive to oral pyridoxal phosphate
and not to pyridoxine. 18
Disorders of energy metabolism include glucose transporter
deficiency (Chapter 76), pyruvate dehydrogenase deficiency
(PDH), pyruvate carboxylase deficiency (PCD), biotinidase
deficiency, respiratory chain disorders (Leigh disease and
Alpers disease), Menkes disease, fumarase deficiency, sulfite
oxidase deficiency, purine disorders, and creatine synthesis
and transporter defects. Glucose transporter type 1 deficiency
(GLUT-1) results in decreased transport of glucose at the
blood–brain barrier and across glial cell membranes causing
hypoglycorrhachia (CSF glucose less than 40 mg/dL). Seizure
onset is usually between 6 and 12 weeks of life and is associ-
ated with developmental delay. Treatment is with the keto-
genic diet. Molybdenum cofactor deficiency and isolated sulfite
oxidase deficiency are rare but can mimic HIE in clinical presen-
tation. Affected infants have cystic white matter changes seen
on neuroimaging.
Biosynthetic defects causing brain malformation and cerebral
dysfunction include peroxisomal disorders (Chapter 43),
congenital disorders of glycosylation (CDG) (Chapter 40),
glycolipid synthesis (GM3 synthase deficiency), cholesterol
synthesis (Smith–Lemli–Opitz syndrome) (Chapter 39),
serine and glutamine deficiency syndromes (rare), methyla-
tion disorders (homocysteine and folate disorders), neuronal
ceroid lipofuscinosis, and lysosomal disorders (Chapter 41).
Peroxisomal biogenesis disorders include Zellweger syndrome,
neonatal adrenoleukodystrophy, and infantile Refsum disease.
Presentation includes severe encephalopathy, refractory neo-
natal seizures, and subtle dysmorphic features. The diagnosis
is made by measurement of very long-chain fatty acids and
phytanic acid.
Developmental Brain Abnormalities
Congenital CNS abnormalities are relatively common causes
of neonatal seizures (5–10%). Diagnosis requires neuroimag-
ing, with MRI the preferred imaging modality. Recognition
and precise classification have increased with brain MR
imaging. Affected newborns may have comorbid HIE as they
may not tolerate labor and delivery. Common developmental
brain abnormalities include focal cortical dysplasia, hemi-
megalencephaly, lissencephaly, heterotopias, schizencephaly,
and polymicrogyria (see Chapters 24–32 for details). Neona-
tal seizures in the context of developmental brain abnormali-
ties are associated with intractable seizures, chronic epilepsy,
and poor neurodevelopmental outcome. Some neurocutane-
ous disorders, in particular tuberous sclerosis complex, can
present with seizures in the newborn period.
Epilepsy Syndromes
Recognition of monogenic causes of neonatal or early infan-
tile epilepsy has increased dramatically with recent advances
in genetic testing. Identification of a specific genetic etiology
provides insight into the pathophysiology of seizures, may
direct treatment options, and can allow for specific discussions
regarding prognosis. Neonatal epilepsy syndromes can range
from benign (seizures expected to resolve quickly and long-
term neurodevelopment likely to be normal) to severe early
onset epileptic encephalopathies (seizures expected to be
treatment-resistant and long-term neurodevelopment likely to
be abnormal).
Severe epilepsy syndromes should be suspected for neo-
nates with no obvious acute symptomatic cause of seizures,
especially if the EEG background shows burst suppression.
Initial diagnostic testing should include brain MRI, often with
MR spectroscopy.58 MRI findings may help narrow the
e322 PART IV  Perinatal Acquired and Congenital Neurologic Disorders
differential diagnosis and tailor the subsequent workup. An
IV pyridoxine challenge (as outlined in the Treatment section)
should be performed while serum, urine, CSF, and genetic
studies are collected and processed.
Familial epilepsies include benign familial neonatal epi-
lepsy (BFNE) and benign idiopathic neonatal seizures (BINS,
previously known as fifth-day fits) (Chapters 64 or 70). BFNE
is an autosomal dominant epilepsy syndrome with 85% pen-
etrance that is related to KCNQ2 or KCNQ3 voltage-gated
potassium channel mutations. Repolarization of the cell
membrane is impaired, and this leads to neuronal hyperexcit-
ability. Seizure onset is usually in the first week of life and the
semiology is commonly focal tonic seizures. Seizures resolve
spontaneously in early infancy. Infants have a normal neuro-
logic examination, normal interictal EEG, and a family history
of neonatal seizures. BINS usually occur between 4 and 6 days
of life and resolve within 2 weeks, and the infant has no family
history of neonatal seizures. Seizures can be focal clonic,
apneic, and sometimes status epilepticus, but the evaluation
for etiology is unrevealing. Some affected individuals have
been reported to have KCNQ2 mutations.
A more severe phenotype is also associated with KCNQ2
mutations. KCNQ2 encephalopathy presents with frequent
pharmacoresistant seizures in the first week of life. Seizures
often have a tonic semiology. The interictal EEG is markedly
abnormal and often meets criteria for burst suppression. Brain
MRI reveals subtle T1 and T2 hyperintensities in the basal
ganglia and thalami—findings that may resolve after the neo-
natal period. Affected children typically have severe global
neurodevelopmental disabilities.59
There are two classic neonatal epileptic encephalopathy
syndromes.60 Early myoclonic encephalopathy (EME) has neona-
tal onset with erratic focal myoclonic jerks, often accompanied
by focal seizures and occasionally by tonic seizures. The typical
interictal EEG shows a burst–suppression pattern during
sleep. Later, the EEG evolves into atypical hypsarrhythmia or
multifocal sharp waves or spikes. EME is typically caused by
metabolic disorders, such as nonketotic hyperglycinemia,
pyridoxine dependency, and propionic aciduria; molybdenum
cofactor deficiency; sulfite oxidase deficiency; Menkes disease;
and Zellweger syndrome. Ohtahara syndrome presents with fre-
quent tonic spasms in newborns or young infants. It is associ-
ated with a burst–suppression EEG pattern during both the
awake and sleep states, along with severe encephalopathy and
treatment-resistant epilepsy. Causes typically include struc-
tural brain abnormalities (cerebral dysgenesis, lissencephaly,
porencephaly, hemimegalencephaly, and Aicardi syndrome)
and monogenic mutations (e.g., ARX, SLC25A22, PLCβ1, and
PNKP).
DIAGNOSIS
Traditionally, neonatal seizures were diagnosed by clinical
observation, with the semiology categorized according to a
system developed by Volpe.61 This schema classifies seizures
according to their motor manifestations—focal clonic, multi-
focal clonic, generalized tonic, myoclonic, and subtle. The
“subtle” semiology refers to seizures with signs such as abnor-
mal eye movements, lip smacking, swimming or pedaling
movements, or apnea.
Although classic research relied on recognition of clinical
signs for the diagnosis of neonatal seizures, modern EEG
data have demonstrated that not all clinically suspicious
events are epileptic seizures—indeed, most are not. For
example, in one seminal study of 349 neonates, clinical signs
seen on video were correlated with simultaneously recorded
EEG.62 Of 415 clinical events characterized as seizures on the
basis of the video recording, 296 (71%) had an inconsistent
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relationship, or no relationship at all, to seizures on EEG.
Motor automatisms (abnormal mouth or eye movements)
and myoclonus were often found to lack clear EEG correlate.
These data highlight the difficulty in relying on clinical obser-
vation for the diagnosis of epileptic neonatal seizures.
Although it is possible that the events that lacked EEG corre-
lates truly were epileptic seizures, but with foci too deep to
record on scalp EEG, it is more likely that many of the abnor-
mal events diagnosed clinically as seizures were, in fact, not
epileptic seizures.
Additional studies have clearly demonstrated that bedside
clinical observation is inaccurate for neonatal seizure detec-
tion. In one study, bedside clinicians (nurses and physicians)
were trained to record any events that were suspicious for
seizures for a sample of high-risk neonates who were undergo-
ing conventional EEG recording. Only 9% (48 of 526) of all
EEG-confirmed seizures had clinical signs that were noted in
the bedside logs, whereas 78% (129 of 177) of the abnormal
paroxysmal events documented by NICU staff had no EEG
correlate (i.e., the events were not seizures).63 In another study,
137 physicians and nurses viewed video recordings of electro-
clinical seizures (EEG-confirmed seizures that had clinical
signs) and nonseizure events (events that had no correspond-
ing EEG change).64 Interobserver agreement was poor (multi-
rater kappa 0.21–0.29) and although 66% of clonic seizures
were correctly diagnosed, only 32% of seizures with other
semiologies were accurately identified. Conversely, only 29%
to 55% of nonseizure events (such as nonseizure clonus,
benign sleep myoclonus, or other nonspecific movements)
were classified correctly.
Imprecise seizure diagnosis has significant consequences:
newborns with primarily subclinical seizures may be under-
treated, whereas many infants whose paroxysmal events are,
in fact, not because of seizures, may be exposed unnecessarily
to potentially detrimental anticonvulsant medications.
Although some neonatal seizures have associated clinical
signs, multiple studies of critically ill newborns have high-
lighted the fact that most neonatal seizures are subclini-
cal.48,65–67 Subclinical seizures have no outward manifestation,
and are therefore only detectable with EEG. That most neona-
tal seizures are subclinical should not be surprising. Preverbal
children cannot communicate their experiences of sensory
phenomena caused by seizures (e.g., visual changes associated
with occipital seizures, or déjà vu because of temporal lobe
seizures), and unless the seizure originates from, or propa-
gates to, the motor cortex, there will be no abnormal move-
ments. Isolated paroxysmal changes in blood pressure or heart
rate, without other associated clinical signs, often raise concern
for seizures in high-risk newborns, but these events are rarely
because of seizures.66,68 Even neonates who present with clini-
cally apparent seizure semiologies often experience electro-
clinical dissociation when medication is administered (e.g.,
EEG seizures persist even after resolution of the clinical
signs).67
Because clinical signs of neonatal seizures are uncommon
and difficult to identify, EEG monitoring is required for precise
diagnosis of paroxysmal events and for quantification of
seizure burden. Neonatal seizures are most properly defined
by their EEG patterns and they need not have a clinical semiol-
ogy. A seizure is an abnormal EEG pattern that evolves, is of
greater than 2-µV amplitude, and has a duration of 10 seconds
or greater (Figure 18-1).69 Distinct seizures are separated by a
10-second or greater seizure-free interval. It is very uncommon
for individual neonatal seizures to be more than a few minutes
in duration, but the seizures are often very frequent. Therefore
neonatal status epilepticus is defined as seizures that occupy
more than 50% of any 1-hour EEG epoch (e.g., a newborn
with 30 1-minute seizures in an hour would meet criteria for
 Neonatal Seizures e323

18

Figure 18-1.  This electroencephalography was recorded from a 3-day-old male, born at 38 weeks’ gestation, who presented with apnea
associated with focal tonic stiffening. The arrow indicates an electrographic seizure, which arose from the right temporal region. The star
indicates the respiratory channel, which demonstrated apnea associated with the seizure.

status epilepticus, as would an infant with a single seizure that

lasts 30 minutes or greater).69

Neonatal Electroencephalogram Monitoring Fp1 Fp2

Conventional Video Electroencephalogram
Video EEG monitoring remains the gold standard for neonatal
seizure detection and is indispensible for research studies that Fz
attempt to quantify seizure burden and/or treatment responses.
Standard electrode positions, using the international 10–20
system, modified for neonates are recommended70 (Figure
18-2). In addition to the scalp electrodes, extracerebral leads T3 C3 Cz C4 T4
for respiratory and electrocardiogram recording are required
for accurate evaluation of behavioral state and exclusion of
extracerebral artifacts. Time-locked video monitoring is highly
recommended during the EEG recording to assist in the dif- Pz
ferential diagnosis of abnormal paroxysmal events. Video is
critical to distinguish sources of artifact, such as handling or
patting the infant, or electronic interference from intensive care O1 O2
unit (ICU) equipment. Surface electromyography and extra-
oculogramy leads are often utilized, but these are not manda-
tory. A bedside observer (typically the bedside nurse) is also
important, as this person can press a patient event marker, or Figure 18-2.  The international 10–20 system for electroencepha-
enter information directly onto the digital file through a lography electrode placement, modified for neonates, includes
bedside computer, to alert the neurophysiologist to clinically the electrode positions indicated by the boxes. By convention, the
important events, such as the occurrence of target paroxysmal odd and even numbers designate the left and right sides of the head,
events or administration of neuroactive medications. The respectively, and “z” labels the midline positions. Additional extracere-
minimum standards for neonatal EEG recording have been bral channels, including respiratory and electrocardiogram tracings,
defined by the American Clinical Neurophysiology Society.71 are also necessary to exclude artifact and determine behavioral state.
Extraocular and surface electromyography leads are often useful, but
not always required.
Indications for Electroencephalogram Monitoring
Not every sick newborn requires EEG monitoring. Rather, this Society also provides guidelines on selection of newborns for
resource-intensive monitoring should be targeted at those at EEG monitoring.70
highest risk for seizures. In general, consideration for EEG
monitoring is recommended for neonates with paroxysmal
clinical events that are suspicious for seizures, as well as those
Duration of Electroencephalogram Recording
with proven or suspected acute brain injury and clinical A routine-length, 60-minute, neonatal EEG is inadequate to
encephalopathy. The American Clinical Neurophysiology screen for neonatal seizures.70 High-risk newborns should

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e324 PART IV  Perinatal Acquired and Congenital Neurologic Disorders
ideally be monitored with at least 24 hours of conventional
EEG if seizures are suspected, because nearly all neonates with
seizures will be identified within 24 hours of monitoring.66,72,73
If seizures are identified, experts suggest that they be moni-
tored with EEG until the infant is seizure-free electrographi-
cally for at least 24 hours, although there are no published
data to support this recommendation.70 In some circum-
stances this duration of monitoring is not feasible, or is not
in the infant’s best interests (e.g., an infant with a severe neo-
natal epilepsy syndrome might not be expected to remain
seizure-free, or monitoring might be appropriately suspended
to allow for neuroimaging).
A 60-minute routine-length neonatal EEG is typically suf-
ficient to assess the EEG background, which might be of inter-
est as a marker of prognosis or as an adjunctive tool for
estimating gestational age. The suggested 60-minute duration
is longer than routine-length EEGs for older infants or chil-
dren, because it is imperative that all behavioral states be
recorded. It is not unusual for a newborn to have a relatively
normal awake EEG background but have clinically significant
abnormalities detected during quiet sleep.
If EEG monitoring is initiated in order to clarify whether a
newborn’s paroxysmal clinical events are caused by seizures,
then the EEG should be recorded until several typical episodes
are captured. If the EEG background is stable and the target
events are not seizures, then monitoring for this purpose can
be terminated.
As discussed under the Acute Symptomatic Seizures sub-
heading, HIE is the most common etiology of neonatal sei-
zures. These newborns are now treated with therapeutic
hypothermia for neuroprotection. Because at least half of
neonates treated with therapeutic hypothermia for HIE have
EEG-confirmed seizures,45,49 many neonatal neurointensive
care programs recommend that EEG monitoring continue
throughout cooling and rewarming. EEG background patterns
and their prognostic significance are altered by therapeutic
hypothermia. Sleep–wake cycling, for example, emerges later
in infants who are cooled than those who do not receive
therapeutic hypothermia, and not all neonates with a sup-
pressed EEG background in the first day of life will have a poor
prognosis, especially in the setting of sedative anticonvulsant
medication.74,75 Despite therapeutic hypothermia, severe inter-
ictal EEG abnormalities, especially burst suppression, remain
ominous if they persist beyond 24 to 30 hours of life.73
Suspected clinical seizures
Initiate or review EEG
EEG-confirmed seizures
• Rapid medication titration*** until EEG
seizures controlled  24 hours
• Continued evaluation for etiology
* High-risk scenarios: known or suspected acute brain injury, encephalopathy, previous EEG seizures, first 72 hours of life
** Reverse glucose or electrolyte abnormalities, and/or administer lorazepam 0.1 mg/kg IV, and/or administer
phenobarbital loading dose.
*** Refer to Figure 18.5
Figure 18-3.  Assessment algorithm for newborns with suspected seizures.
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Because conventional EEG monitoring is resource-intensive
and requires specialized equipment, available technologists,
and trained electroencephalographers, a reduced-montage
EEG has gained popularity in many Neonatal Intensive Care
Units (NICUs). aEEG is a simplified trend monitor that dis-
plays one or two channels of time-compressed, processed EEG
signal on a semilogarithmic scale.76,77 Interpretation of the
aEEG signal is enhanced by concurrent display of the raw
single or multichannel EEG. aEEG background patterns have
predictive value for neonates with HIE and other causes of
encephalopathy.74,78,79 The use of aEEG for seizure detection is
controversial, as this tool is specific but not sensitive in this
capacity. There is substantial variability in the reported sensi-
tivity of aEEG for seizure detection (usually 25–35%, but
occasionally reported 85% sensitivity for individual seizure
detection).80
Diagnostic Considerations for Neonates  
with Seizures
If the diagnosis of neonatal seizures is being entertained, a
complete evaluation for the etiology is warranted (Figures
18-3 and 18-4). The great majority of neonatal seizures are
acute symptomatic manifestations of brain injury and many
require urgent, specific treatment. This diagnostic evaluation
should occur in tandem with the treatment of seizures. Glucose
and electrolyte levels should be measured and any abnormal-
ity corrected emergently. A full sepsis evaluation, including
cultures of blood, urine, and CSF, is strongly recommended
(unless the infant is too unstable to undergo a lumbar
puncture or a definite alternative diagnosis is made). Empiric
antibiotics are usually administered until the cultures are
negative.
In most hospitals and emergency departments, it is straight-
forward to obtain a head ultrasound. Despite its low resolu-
tion, cranial ultrasonography can be used to screen for obvious
hydrocephalus or intracranial hemorrhage. Computed tomog-
raphy is usually avoided in neonates, because of the concern
about radiation exposure. Rather, MRI is the standard neuro-
imaging modality for neonates with seizures. If arterial ische-
mic stroke or vascular malformations are suspected, an MR
angiogram is recommended. If a venous sinus thrombosis is
suspected (e.g., in a term neonate with intraventricular or
High risk*
Begin evaluation for acute
symptomatic etiology.
Treat as soon as possible.**
No EEG seizures
Record 3–4 typical events or
24 hours without seizures
Discontinue EEG and seizure medication
 Neonatal Seizures e325

First-line testing*
Glucose 18
Electrolytes
Sepsis evaluation
Consider lumbar puncture
Consider urgent head ultrasound
Birth and family histories
Check placental pathology

Brain MRI

Suspected HIE Stroke Suspected infection Suspected epilepsy,

or cause unknown

Consider evaluation for Echocardiogram if clinical TORCH titers Pyridoxine trial

secondary seizure etiology
(e.g. infection), depending
on clinical scenario.
suspicion for congenital LP with CSF studies: Genetic testing**
cardiac malformation. Glucose/protein PAA, UOA, lactate, pyruvate, NH3
Consider anticoagulation Cell counts Consider CSF testing (AA, neurotransmitters)
for venous thrombosis. HSV PCR Check newborn screen results
Consider thrombophilia Bacterial culture Ophthalmology exam
evaluation in the nonacute
setting.

Neurology and neurodevelopmental follow-up

**Genetic testing can include: karyotype, chromosomal microarray, epilepsy gene panel, or single gene testing.
Figure 18-4.  Assessment algorithm for newborns with seizures. First-line testing should occur simultaneously with initiation of electroen-
cephalography (and empiric seizure treatment in high-risk clinical scenarios). Most infants should receive neuroimaging, and brain magnetic reso-
nance imaging (MRI) is the preferred neuroimaging modality. Second-line testing depends on the clinical scenario and MRI findings. Newborns
with seizures are at high risk for long-term neurodevelopmental disability and epilepsy, and so they require careful follow-up by appropriate
clinicians.

thalamic hemorrhage), an MR venogram may be diagnostic
and concurrent MRI may reveal venous strokes.
Further diagnostic testing depends on the clinical scenario.
If the evaluation for infection is negative and there is no other
immediately obvious cause of seizures after MRI and basic
metabolic workup, then testing for inborn errors of metabo-
lism is reasonable for newborns with abnormal neurologic
examinations and pharmacoresistant seizures. This testing
may include measurement of lactate, pyruvate, ammonia,
plasma amino acids, urine organic acids, and sometime
advanced testing of the CSF. If the infant has congenital anom-
alies and/or dysmorphic features, or if a neonatal epilepsy
syndrome is suspected, genetic testing and consultation
should be considered. Single-gene testing is occasionally
helpful, but clinical availability of early onset epilepsy gene
panels is improving and may be more cost-effective. Chromo-
somal microarray may also reveal clinically significant
abnormalities.
TREATMENT
Acute Treatment
Because new-onset seizures in a neonate often reflect a serious
underlying neurologic condition, they should be treated as a
medical emergency. Once the bedside clinician has estab-
lished that the vital signs are stable and taken note of the
clinical manifestations of a suspected seizure, glucose must be
checked immediately and electrolytes (including calcium)
drawn to rule out rapidly treatable causes of seizures. Video
EEG should be initiated as soon as possible to confirm that
clinical events have an electrographic correlate.70 If infection
is suspected, appropriate cultures should be drawn and treat-
ment initiated, including broad-spectrum antibiotics for a
suspected bacterial infection and acyclovir for herpes simplex
virus in the appropriate clinical scenario.
The maternal and family history must be reviewed. Mater-
nal nutritional deficiency can affect the developing brain (see
Chapter 47). Prescription and nonprescription drug with-
drawal is increasingly common in neonates. Maternal selective
serotonin reuptake inhibitors (SSRI) use in the third trimester
is a common cause of abnormal movements during the first
12 hours of life, but these are usually not seizures.81,82
Serotonin–norepinephrine reuptake inhibitors (SNRI) with-
drawal may be associated with electroclinical seizures starting
in the first 3 days of life.83,84 Even if withdrawal from prescrip-
tion or illicit drugs is suspected, other serious causes of sei-
zures should be ruled out. Convulsions or other abnormal
movements without electrographic correlate need not be
treated with seizure medications. Family history may reveal
BFNE as the likely cause in an otherwise well-appearing
infant.
Treatment of Acute Symptomatic Seizures
Treatment with antiseizure medications should be initiated as
soon as possible once electrographic seizures are confirmed
(or immediately in a patient with a high-risk condition such
as HIE, acute intracranial hemorrhage, or clonic motor hemi-
convulsions indicating a likely stroke; see Figure 18-3).

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e326 PART IV  Perinatal Acquired and Congenital Neurologic Disorders

Medication should be administered in adequate bolus doses
titrated to abolish electrographic seizures (including electro-
graphic seizures without clinical correlate) as quickly as pos-
sible (Figure 18-5).
Few data from clinical trials are available to guide anticon-
vulsant management decisions. A suggested treatment algo-
rithm is presented in Figure 18-5. According to international
surveys, phenobarbital remains the most commonly used
agent for first-line treatment of seizures in newborn infants.85,86
Seizures are controlled in roughly half of patients after a single
phenobarbital loading dose of 20 mg/kg.13 Phenytoin (or,
preferably, IV fosphenytoin in the acute setting) has similar
efficacy to phenobarbital when used at a loading dose of
20 mg/kg,13 but maintenance dosing—particularly with oral
administration—is challenging in neonates because of less
predictable absorption and pharmacokinetics than phenobar-
bital. Levetiracetam is increasingly used in spite of limited
safety and efficacy data. Two studies provide pharmacokinetic
data, which suggest use of a levetiracetam loading dose of at
least 40 mg/kg and maintenance dosing of at least 10 mg/kg/
dose administered every 8 hours can be considered.87,88
If seizures are not controlled after repeated loading doses
of standard medications, infusions are sometimes indicated.
Midazolam infusion is an alternative or add-on agent in
refractory cases in the setting of acute brain injury and status
epilepticus.89–91 Lidocaine infusions can be used for refractory
acute symptomatic neonatal seizures.92–94 Note that lidocaine
is contraindicated for neonates with congenital heart disease
and for those who have previously been treated with
phenytoin/fosphenytoin, because of the risk of arrhythmia.
Additionally, lidocaine dosing must be adjusted for neonates
treated with therapeutic hypothermia (phenobarbital dosing
does not need to be adjusted).93,95 Several excellent reviews
provide detailed data about seizure treatment options.45,96,97
To date, data suggest that the available seizure medications
have similar efficacy for acute symptomatic neonatal seizures.
Therefore multiple potential treatment algorithms may be jus-
tifiable. However, establishing a consensus between the neo-
natology and neurology services regarding medication choice,
dose and timing, can help to facilitate rapid administration
of medication, which probably does affect seizure burden,
because infants with fewer seizures are more easily treated.13
Maintenance anticonvulsant medication dosing should be
initiated for neonates who have confirmed electrographic sei-
zures. For newborns with clinical events without proven elec-
trographic seizures, maintenance dosing may be discontinued

Phenobarbital loading dose

20–30 mg/kg

Seizures stop?

Yes No

• Continue electroencephalogram • Continue EEG monitoring

(EEG) monitoring until  24 hours • Repeat 10–20 mg/kg
seizure-free phenobarbital boluses until seizures
• Begin maintenance stop, cumulative dose 40–60 mg/kg,
phenobarbital 4–6 mg/kg or level  40 g/mL
per day in 2 divided doses

No Seizures stop?

Select second-line agent, depending on clinical scenario*

Infrequent seizures, Cardiac abnormality Status epilepticus and Status epilepticus,

no cardiac or hepatic and/or hepatic disorder, no cardiac abnormalities airway secure, and no
abnormalities, and no or and/or cardiovascular and never received hypotension
minimal cardiovascular instability. phenytoin or
instability. fosphenytoin.

Fosphenytoin 20 mg/kg bolus
(may repeat 10 mg/kg bolus),
then 8–10 mg/kg per day in IV
in 2 or 3 divided doses; check
free and total blood levels
Levetiracetam 40 mg/kg bolus
(may repeat 20 mg/kg) then
40–60 mg/kg per day in
2 or 3 divided doses.
Lidocaine infusion
(2 mg/kg bolus, then
6 mg/kg/hour and decrease
by 2 mg/kg/hour every
12 hours). Maximum
infusion time is 48 hours
due to arrhythmia risk.
Midazolam (if bolus,
0.15 mg/kg IV, then 1 g/kg/
min infusion, titrating upward
to effect). Wean gradually,
usually after 24 hours of
seizure freedom.

*If the infant has acute symptomatic seizures, select from these options, based on co-morbidities and seizure severity.
If the newborn has epilepsy (e.g. lissencephaly, tuberous sclerosis), consider levetiracetam, topiramate,
or oxcarbazepine as second- or third-line treatments.
Figure 18-5.  Suggested treatment algorithm for neonatal seizures. The rapidity of medication administration will depend on local guidelines
and resources. Frequent assessment of treatment response is recommended.

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and the EEG reviewed frequently to ensure that the neonate
does not subsequently develop electrographic seizures.
Discontinuation of Medication for Acute
Symptomatic Seizures
Acute symptomatic seizures typically arise within the first 24
to 48 hours of life, after which there is a short period of high
seizure burden, followed by a longer period of lower seizure
burden.98,99 Overall duration of acute symptomatic seizures is
typically 48 to 96 hours. Knowing the seizure tempo and
careful use of video-EEG monitoring to determine when sei-
zures arise and resolve can help guide duration of treatment
with seizure medications. Because the recurrence risk in the
neonatal period is low, many neonates can be safely discon-
tinued from medications after resolution of acute symptom-
atic seizures.100 There is no need to wean medications that have
been used for only a short duration (less than 1 week). If the
child is to be maintained on medications, the regimen should
be simplified and a plan put in place to reassess the infant
after discharge from hospital so that anticonvulsants may be
discontinued during the first few months of life. EEG monitor-
ing after the resolution of seizures has a low yield for seizure
detection and rarely adds to the prognostic impression; centers
with limited resources should consider prolonged, continuous
video EEG during the acute phase of the admission rather than
weekly brief intermittent monitoring.
Treatment of Early Onset Epilepsy Syndromes
If the diagnostic evaluation rules out an acute symptomatic
cause for neonatal seizures, early onset epilepsy should be
suspected. The treatment of epilepsy in the neonatal period is
different from the approach for acute symptomatic seizures.
First, rapid treatment of seizures probably does not affect
seizure burden or long-term outcome, and so medications
should be carefully titrated to maximally tolerated doses to
ensure efficacy or failure. Second, neonates with epilepsy must
continue medications after discharge home, even if seizures
have been controlled with medical management.
Vitamin-responsive inborn errors of metabolism may
present with neonatal encephalopathy and refractory seizures,
and so pharmacologic doses of pyridoxine, folinic acid, and
pyridoxal 5′-phosphate are indicated in this setting.101,102 Neo-
nates with suspected PDE should be administered a trial of IV
pyridoxine (100 mg IV while EEG is recording). The infant
must be monitored during this trial, as apnea and bradycardia
can be provoked. If there is a clear response, test urine alpha-
AASA and/or plasma pipecolic acid levels and consider con-
firmation with ALDH7A1 mutation analysis. If there is no
response to pyridoxine, a trial of pyridoxal 5′-phostphate
(60 mg/kg/day divided 3 times/day for 2–3 days) and then
folinic acid (2.5 mg IV) may be attempted.
Carbamazepine and oxcarbazepine are effective and well
tolerated for neonates with seizures caused by KCNQ2/3
mutations (either BFNE or KCNQ2 encephalopathy).103 If car-
bamazepine or oxcarbazepine is not effective, a trial of retiga-
bine, which selectively affects the K+ channel, may be
worthwhile.103
OUTCOMES AFTER NEONATAL SEIZURES
Neonatal seizures are associated with an array of adverse out-
comes, including intellectual disability, cerebral palsy, post-
neonatal epilepsy, and death. Most often in the literature,
cognitive and behavioral outcomes are not reported separately
from cerebral palsy. Instead, outcomes are grouped into
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Neonatal Seizures e327
“favorable” (survival without impairment) or “unfavorable”
(death, or intellectual disability, and/or cerebral palsy, and/or 18
epilepsy). The risk for unfavorable outcomes related to neo-
natal seizures is difficult to isolate from the underlying cause
of the seizures. Additionally, because many infants with neo-
natal seizures are critically ill, they often have multiple comor-
bidities that affect long-term outcomes. As an example, a
newborn whose seizures are caused by HIE is at risk for
impaired neurodevelopment because of the acute brain injury,
as well as the seizures, but might also have neonatal sepsis or
feeding problems that lead to suboptimal nutrition, all of
which may elevate the risk for adverse outcomes.
Mortality After Neonatal Seizures
Despite modern neonatal intensive care, 10% to 30% of new-
borns with seizures die during the neonatal period.5 The risk
of death is higher in certain subgroups (e.g., preterm infants).
Geographic variation in reported mortality may reflect cultural
differences regarding decisions to withdraw intensive care for
neonates with extremely poor prognosis. Among survivors of
neonatal seizures, those with abnormal neurodevelopment
remain at elevated risk of death throughout childhood.
Cognitive Outcomes After Neonatal Seizures
The longest-term follow-up studies for neonatal seizures
included infants with clinically diagnosed seizures.5,104 Among
survivors, 40% to 50% have global developmental delays, and
preterm infants are at higher risk than full-term neo-
nates.5,8,104,105 Among neonates with HIE, a diagnosis of neo-
natal seizures increases the risk for developmental delays and
intellectual disability, after controlling for the degree of
encephalopathy.106 Severe seizure burden increases this risk.
One study reported that HIE survivors with severe clinical
seizure burden, compared with those with HIE who remained
seizure-free, had on average a 30-point (2 standard deviations)
lower full-scale IQ at age 4 years, even after adjusting for MRI-
detected brain injury. On average, HIE survivors with a lower
seizure burden still scored one full standard deviation lower
than their seizure-free peers.8
Cerebral Palsy After Neonatal Seizures
About 25% to 35% of long-term neonatal seizure survivors
develop cerebral palsy.104,105 Most of those with severe cerebral
palsy have comorbid global developmental delays, including
intellectual disability. Among survivors of neonatal seizures,
having cerebral palsy is also a significant risk factor for post-
neonatal epilepsy.107,108
Postneonatal Epilepsy
Postneonatal epilepsy—in which the acute symptomatic
seizures subside, but recurrent unprovoked seizures develop
later in life—affects 20% to 30% of survivors of neonatal
seizures.41,105,109,110 Most often, epilepsy develops in the first few
years of life. Children can have a range of epilepsy syndromes,
depending on the etiology of the neonatal seizures. Most
studies have not been powered to describe details of the epi-
lepsy syndromes, but several groups have reported a 10% to
16% incidence of West syndrome after clinical neonatal
seizures.104,105,109
There are many known risk factors for postneonatal epi-
lepsy. Clinical risk factors include requirement of more than
one medication to control the acute neonatal seizures, moder-
ate or severe neonatal encephalopathy, abnormal neuroimag-
ing, and low birth weight. EEG risk factors include status
e328 PART IV  Perinatal Acquired and Congenital Neurologic Disorders
BOX 18-1  Neonatal Seizure Pearls
• Clinical observation is unreliable for neonatal seizure detection;
EEG is the gold standard for neonatal seizure diagnosis.
• Newborns typically have a high seizure burden—it is rare to
have only one or two seizures.
• Most neonatal seizures have an acute symptomatic cause.
• If seizures persist beyond 96 hours, they are probably not
caused by an acute symptomatic cause.
• Seizure treatment should occur in tandem with an expedited
evaluation for the seizures’ etiology.
• Electroclinical seizures can become subclinical after treatment
is initiated.
• Duration of treatment depends on the etiology.
epilepticus, persistently abnormal interictal EEG background,
multifocal (vs. focal) seizures, and ictal spread to the contra-
lateral hemisphere.5
Among people with chronic epilepsy, a history of clinical
neonatal seizures is a definite risk factor for long-term non-
remission of the epilepsy.111 By extension, because treatment-
resistant epilepsy is associated with cognitive and behavioral
challenges, early life seizures may predispose to long-term
intellectual and behavioral difficulties.
CONCLUSIONS
The immature brain is predisposed to seizures. Neonatal sei-
zures usually reflect acute underlying brain injury, rather than
epilepsy. Thus evaluations to confirm the diagnosis of seizures
(with EEG) and to determine and treat their etiology must
occur simultaneously. There are very few data from clinical
trials to guide treatment decisions. Phenobarbital is the most
commonly prescribed first-line agent. Controversy remains
regarding the ideal duration of treatment. However, it is clear
that neonatal seizures are associated with substantial risk of
mortality and of long-term neurodevelopmental disability
and epilepsy. High-quality research is urgently needed in order
to determine the best treatment algorithms and, ultimately, to
improve long-term outcomes.
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