ARTICLE

Neonatal Seizures
Alan Hill, MD, PhD*
OBJECTIVES:
After completing this article, readers should be able to:
1. State the most common cause of neonatal seizures in the term infant.
2. Compare and contrast the clinical features of neonatal seizures with
those of epilepsy in older children.
3. Describe the relationship of clinically suspected neonatal seizures with
findings on surface electroencephalography.
4. Delineate the most important determinant of prognosis for neonatal
seizures.
Introduction
Neonatal seizures often are a mani-
festation of significant neurologic
disease and a major predictor of
adverse neurologic outcome in the
newborn. The clinical features and
electroencephalographic (EEG) char-
acteristics of neonatal seizures differ
considerably from those associated
with epilepsy in older infants and
children, an observation that reflects
the immature stage of development
of the newborn brain. Another major
difference relates to the fact that
neonatal seizures rarely are idio-
pathic. Prompt diagnosis, investiga-
tion to establish the underlying etiol-
ogy, and rapid intervention are
essential to minimize the possibility
of associated cardiorespiratory insta-
bility and to correct treatable causes.
Furthermore, experimental data sug-
gest that ongoing or prolonged sei-
zures may cause additional cerebral
injury and have detrimental long-
term effects.
Definition
A seizure is defined generally as an
excessive, synchronous electrical
discharge (ie, depolarization of neu-
rons in the brain). However, this
definition may be too restrictive
when applied to seizures in the new-
born. Neonatal seizures may be
defined more aptly as paroxysmal
alterations in neurologic function
(eg, behavioral, motor, or autonomic
function). This definition encom-
*Professor and Head, Division of Neurology,
Department of Pediatrics, University of
British Columbia, Vancouver, British
Columbia, Canada.
passes both clinical phenomena that
correlate temporally with epilepti-
form EEG abnormalities and stereo-
typical, paroxysmal clinical activities
that are not associated clearly with
EEG alterations.
Epidemiology
The reported incidence of neonatal
seizures varies widely. Based on
clinical observation, they are thought
to occur in approximately 0.5% of
term newborns and 20% of preterm
newborns. However, long-term EEG
recordings in pharmacologically par-
alyzed term newborns suggest that
the incidence may be as high as
40% in some high-risk populations.
Pathogenesis
A detailed discussion of the physio-
logic and metabolic mechanisms
underlying neonatal seizures is
beyond the scope of this article.
However, several concepts that have
important clinical implications
deserve amplification. Generalized
tonic-clonic seizures or an orderly
progression of seizures is uncom-
mon in the newborn because of the
immature organization of the cere-
bral cortex and incomplete myelina-
tion of the interhemispheric connec-
tions. In contrast, oral-buccal-lingual
movements, oculomotor distur-
bances, and autonomic dysfunction
are frequent clinical manifestations
and are considered to reflect the
relatively more advanced develop-
ment of brainstem and diencephalon
in this age group. Alternatively, the
observed lack of correlation of clini-
cal events with epileptiform activity
recorded by surface EEG has raised
the speculation that some of these
clinical events represent “brainstem
release phenomena” rather than true
epileptic seizures (ie, primitive
brainstem and spinal motor patterns
that are dissociated from normal
cortical inhibition).
In addition to the interest sur-
rounding the origins of “seizure-like
activity” in the newborn (which may
determine whether treatment with
conventional anticonvulsant medica-
tions is used), the physiologic and
metabolic consequences of neonatal
seizures are of major clinical signifi-
cance. These include interference
with respiration, alterations in blood
pressure, and cerebral perfusion
(even in the absence of abnormal
motor activity), which in turn may
exacerbate hemorrhagic or ischemic
brain injury. In addition, experimen-
tal data suggest that ongoing neona-
tal seizures may deplete cerebral
glucose levels and impair synthesis
of cerebral DNA and proteins,
which could contribute to the extent
of cerebral injury.
Etiology
Neonatal seizures rarely are idio-
pathic, and immediate attention
should be focused on identifying an
underlying etiology to permit appro-
priate intervention and to enable
accurate decisions regarding progno-
sis. Although there are numerous
possible underlying etiologies of
neonatal seizures, a relatively small
number account for the majority of
cases (Table 1). The time of onset
and characteristics of neonatal sei-
zures may suggest the most probable
cause (Table 2). Clearly, a number
of concomitant etiologic factors may
be operative in the same infant. For
example, hypoglycemia and hypo-
calcemia may occur as a result of
catabolic stress in certain situations,
such as hypoxic-ischemic encepha-
lopathy or meningitis.
HYPOXIC-ISCHEMIC
ENCEPHALOPATHY
Moderate or severe acute hypoxic-
ischemic encephalopathy accounts

Pediatrics in Review Vol. 21 No. 4 April 2000 117

 NEUROLOGY
Neonatal Seizures
TABLE 1. Causes of Neonatal Seizures
ETIOLOGY
Hypoxic-ischemic encephalopathy
Intraventricular hemorrhage (severe)
Subarachnoid hemorrhage (severe)
Hypoglycemia
Hypocalcemia
Intracranial infection
Cerebral dysgenesis
Drug withdrawal
for approximately two thirds of all
cases of neonatal seizures. Such sei-
zures may be of any type, usually
begin at any time during the first
24 hours of life, and frequently are
difficult to control effectively with
anticonvulsant medications. Often
there are associated abnormalities of
brainstem responses and muscle
tone. Hypoxic-ischemic cerebral
injury sustained earlier during gesta-
tion may be asymptomatic in the
newborn period. Consistently unilat-
eral, focal seizures often are indica-
tive of localized brain lesions, espe-
cially focal cerebral infarction.
However, focal or multifocal sei-
zures in the newborn also may occur
in the context of diffuse cerebral
injury.
TABLE 2. Correlation of Timing and Etiology of Neonatal Seizures
ETIOLOGY
Intracranial hemorrhage
Hypoxic-ischemic encephalopathy
Hypoglycemia
Hypocalcemia
Inborn errors of metabolism
Intracranial infection
Cerebral dysgenesis
Anesthetic injection
Drug withdrawal
Neonatal epilepsy syndromes
118
TERM INFANTS PRETERM INFANTS OUTCOME
Most common Common Variable
Uncommon Common Poor
Common Uncommon Good
Common Common Variable
Uncommon Uncommon Good
Common Common Variable
Common Common Poor
Uncommon Uncommon Variable
METABOLIC DERANGEMENTS dependency is a rare, autosomal
The most common metabolic distur- recessive cause of neonatal or even
bances associated with seizures are intrauterine seizures that can be
hypoglycemia, hypocalcemia, and excluded based only on the response
derangements of serum sodium lev- to several weeks of treatment with
els. Early hypoglycemia and hypo- pyridoxine. The response to intrave-
nous pyridoxine during EEG moni-
calcemia occur most commonly
toring no longer is considered to be
following gestational diabetes and in
diagnostic of this disorder. Accord-
infants who are preterm, small for
ingly, it has been recommended that
gestational age, or both. Hypo- or all newborns who have seizures of
hypernatremia may result from unknown etiology receive a trial of
dehydration, inappropriate fluid oral pyridoxine.
administration, or inappropriate
secretion of antidiuretic hormone.
Rarely, inborn errors of metabolism INTRACRANIAL INFECTION
present with seizures and an evolv- In infants who have intracranial bac-
ing, catastrophic neurologic and sys- terial infection, seizures often begin
temic deterioration, usually after during the latter part of the first
several days of age. Pyridoxine week of life, usually in the context
MOST COMMON TIME OF ONSET
DAYS 1 TO 2 DAYS 3 TO 7 DAYS 7 TO 10
X X
X
X
X (early) X (late)
X
X
X X X
X
X
X X
Pediatrics in Review Vol. 21 No. 4 April 2000
 NEUROLOGY
Neonatal Seizures

of systemic sepsis. The time of
onset of seizures following congeni-
tal viral infection varies.
INTRACRANIAL HEMORRHAGE
Seizures associated with intracranial
hemorrhage vary considerably,
depending on the type of hemor-
rhage. Germinal matrix-intra-
ventricular hemorrhage, which
occurs most commonly in the pre-
term newborn, may present with
tonic seizures. Seizures associated
with subarachnoid hemorrhage usu-
ally begin during the first day of life
in term newborns. Characteristically,
infants appear healthy between sei-
zures, and the long-term prognosis is
good. Subdural hemorrhage or cere-
bral contusion often presents with
focal or subtle seizures of early
onset.
DEVELOPMENTAL CEREBRAL
ABNORMALITIES
Seizures associated with cerebral
dysgenesis or genetic syndromes
have variable onset. Dysmorphic
features, microcephaly, or cutaneous
lesions may suggest these diagnoses.
DRUG WITHDRAWAL AND
INTOXICATION
Infants who are exposed prenatally
to alcohol and heroin rarely present
with seizures. However, tremors and
irritability, which may be mistaken
for seizures, are a common manifes-
tation. Seizures may occur in the
context of withdrawal from cocaine
or short-acting barbiturates. In addi-
tion, focal seizures may occur in
association with cerebral infarction
following prenatal exposure to
cocaine. Rarely, inadvertant injec-
tion of a local anesthetic agent into
the fetal scalp during delivery may
result in transient seizures during the
first hours of life.
NEONATAL EPILEPSY
SYNDROMES
The most common neonatal epilepsy
syndrome is autosomal dominant
benign familial neonatal seizures,
which usually begin on the third day
of life and resolve after several
months. In contrast, early myoclonic
epileptic encephalopathy and
Ohtahara syndrome are associated
with progressive neurologic
deterioration.
Clinical Aspects
SYMPTOMS AND SIGNS
In most instances, neonatal seizures
are identified by clinical observa-
tion. Any unusual repetitive and ste-
reotypic event may represent a clini-
cal seizure. The relationship between
such abnormal movements and
abnormal electrical/epileptiform
activity on EEG may be inconsis-
tent. Furthermore, neonatal seizures
must be distinguished from nonepi-
leptic movements, which may mimic
seizures. A clinical classification of
neonatal seizures is summarized in
Table 3. It is important to remember
that seizures may manifest as iso-
lated alterations in autonomic func-
tion, especially abnormal heart rate
or change in blood pressure or oxy-
genation. Apnea alone rarely repre-
sents a seizure unless it occurs in
the context of other clinical seizure
activity.
Several common movement dis-
orders may be mistaken for seizures
in the newborn (Table 4). Accurate
diagnosis of nonepileptic movements
is important to avoid the inappropri-
ate use of anticonvulsant medica-
tions and to permit more accurate
prediction of outcome.
EVALUATIONS
Because neonatal seizures rarely are
idiopathic, immediate attention must
be directed toward identifying an
underlying etiology. Clearly, a
detailed history, especially about
maternal risk factors and complica-
tions of pregnancy, labor, and deliv-
ery, and physical examination are of
paramount importance. In addition,
initial screening investigations that
should be considered include mea-
surement of serum glucose, calcium,
magnesium, pH, sodium bicarbonate,
sodium, blood urea nitrogen, and
ammonia. Lumbar puncture should
be performed to determine the pres-
ence of infection or intracranial
hemorrhage. If these investigations
fail to identify a specific etiology,
additional studies may include neu-
roimaging; measurement of serum

TABLE 3. Classification of Neonatal Seizures

SEIZURE TYPE CLINICAL MANIFESTATIONS EEG ABNORMALITIES
Subtle ● Oral-buccal-lingual movements Variable
● Ocular movements
● Stereotypic pedalling, swimming, stepping
● Autonomic dysfunction
Clonic ● Rhythmic, slow jerking Common
● Focal or multifocal
● Involves facial, extremity, or axial structures
Tonic ● Sustained posturing of limbs Focal: common
● Asymmetric position of trunk/neck Generalized: uncommon
● Focal or generalized
Myoclonic ● Rapid, isolated jerks Variable
● Involves limbs or trunk
● Generalized, multifocal, or focal

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 NEUROLOGY
Neonatal Seizures

TABLE 4. Nonepileptic Behaviors of Newborns

MOVEMENT DISORDER
Jitteriness
Benign neonatal sleep myoclonus
Stimulus-evoked myoclonus
Hyperekplexia (“stiff-man syndrome”)
BRIEF DESCRIPTION
● Spontaneous or stimulus-sensitive
● Flexion and extension of equal amplitude
● Diminished by repositioning/flexion of extremity
● No associated abnormal eye movements
● Bilateral or unilateral, synchronous or asynchronous myoclonus
● Occurs during active sleep
● Not stimulus-sensitive
● Occurs with severe central nervous system dysfunction
● Focal or generalized myoclonus
● May have cortical spike-wave discharge on electroencephalography
● Rare familial disorder
● Hyperactive startle, generalized myoclonus
● Severe hypertonia
● May have apnea and bradycardia
● Responds to benzodiazepines

amino acids, lactate, and urine value often is limited. In an attempt the underlying physiologic and met-
organic acids; investigation for con- to improve diagnostic accuracy, abolic derangements (if present) and
genital viral infections; chromosome some modifications of the EEG controlling ongoing or recurrent sei-
karyotype; and toxic drug screen. technique have been developed, such zures. If necessary, immediate sup-
Assessment of other organ systems as serial or prolonged studies, con- port of ventilation and perfusion
(eg, renal, hematologic, hepatic) tinuous EEG monitoring, cerebral must be ensured. When the cause is
may support a diagnosis of hypoxic- function monitoring, and synchro- not a particular correctable meta-
ischemic encephalopathy or an nized video/EEG recording. EEG bolic derangement (eg, intracranial
inborn error of metabolism. rarely is helpful for identifying a infection, hemorrhage, inborn errors
Confirmation of neonatal seizures specific etiology, but interictal of metabolism), appropriate specific
often depends on the use of EEG, abnormalities, especially the back- treatment should be initiated in con-
especially in infants who are para- ground electrical activity, may have junction with symptomatic treatment
lyzed pharmacologically. Although significant prognostic value. with anticonvulsant medications.
routine interictal EEG is a noninva- A scheme for treatment of neonatal
sive and portable procedure, inter- seizures is outlined in Table 5.
pretation of the findings in this age MANAGEMENT
Serial blood levels of anticonvul-
group is difficult and requires spe- The treatment of neonatal seizures sants (eg, phenobarbital, phenytoin)
cial expertise. Further, its diagnostic should be directed toward correcting often must be obtained to determine
maintenance dosages because of the
variable pharmacokinetics in this
TABLE 5. Acute Treatment of Neonatal Seizures age group. Enteric absorption of
● Ensure respiration phenytoin is especially unpredict-
able. There are anecdotal reports of
● Ensure cardiac support
the use of other anticonvulsants,
● If hypoglycemic: including primidone, lamotrigine,
—Glucose 10% solution: 2 mL/kg IV followed by continuous infusion thiopentone, paraldehyde (no longer
at 5 to 7 mg/kg per minute available in the United States, but
● Other specific treatments (as indicated): available in Canada), and carbamaz-
—Calcium gluconate 5% solution: 4 mL/kg IV epine, for treatment of refractory
—Magnesium sulfate 50% solution: 0.2 mL/kg IM seizures.
—Pyridoxine 50 to 100 mg IV Several major issues remain unre-
solved, including optimal mainte-
● Symptomatic treatment: nance doses of anticonvulsants, the
—Phenobarbital loading dose: 20 mg/kg IV; additional doses: 5 mg/ importance of eliminating electro-
kg IV (10 to 15 min) to maximum of 20 mg/kg graphic seizures, and the optimal
—Phenytoin 20 mg/kg (1 mg/kg per minute) duration of anticonvulsant therapy.
—Lorazepam 0.05 to 0.10 mg/kg IV The duration of therapy must be
IV ⴝ intravenous; IM ⴝ intramuscular. guided by the underlying etiology.
Recent reports suggest that unneces-

120 Pediatrics in Review Vol. 21 No. 4 April 2000


sary prolongation of therapy for
transient disorders should be
avoided because of unresolved con-
cerns about the possible adverse
effects of anticonvulsants on the
developing nervous system. There is
no evidence that prolongation of
anticonvulsant therapy decreases the
risk for developing epilepsy in later
childhood.
Prognosis
The mortality rate for clinical sei-
zures in term newborns has
decreased considerably in recent
years to approximately 15%. How-
ever, mortality rates in preterm
infants who have seizures remain
high and may be increased as much
as fourfold compared with that of
term infants. In addition, adverse
neurologic sequelae are common
and have been reported in approxi-
mately two thirds of survivors. Men-
tal retardation and motor deficits
(cerebral palsy) are more common
sequelae following neonatal seizures
than epilepsy. In many instances,
these sequelae may be the result of
the underlying cause of the neonatal
seizures.
PIR QUIZ
Quiz also available online at
www.pedsinreview.org.
4. A mother brings her 3-week-old
infant to you because she is
concerned about twitching movements
of the lower extremities that he has
exhibited for 2 weeks. She has
observed these movements when he is
asleep. Physical examination reveals a
sleeping infant who has an occasional
twitching movement in the right leg
similar to what the mother has
observed. Upon arousal the infant
appears vigorous, and findings on the
neurologic examination are normal.
Which of the following is the most
likely diagnosis?
A. Benign neonatal myoclonus.
B. Cerebral palsy.
C. Hyperekplexia.
D. Inborn error of metabolism.
E. Infantile spasm.
Pediatrics in Review Vol. 21 No. 4 April 2000
The most important determinant
of prognosis is the underlying etiol-
ogy. Thus, infants who have cere-
bral dysgenesis have uniformly poor
outcomes, and 50% to 100% of
those who have moderate or severe
hypoxic-ischemic encephalopathy
develop sequelae. In contrast, infants
who have transient metabolic
derangements and are treated
promptly or who have only sub-
arachnoid hemorrhage usually have
a good outcome. Intracranial infec-
tion and inborn errors of metabolism
are associated with a variable
prognosis.
Characteristics of the clinical sei-
zures and the EEG often are useful
predictors. Early-onset seizures and
frequent or prolonged seizures that
are refractory to multiple anticonvul-
sants generally have a poor progno-
sis. In the term newborn, the interic-
tal EEG may be useful for predict-
ing outcome. A normal interictal
EEG is associated with an 85%
chance of normal development com-
pared with isoelectric, low-voltage,
or paroxysmal burst-suppression
background activity, which generally
is associated with a poor outcome.
However, caution must be exercised
5. You are called to examine a
1-day-old infant who exhibits
repeated sucking movements inter-
spersed with facial twitching and
rhythmic horizontal movements of the
eyes. You suspect the infant is having
seizures. Which of the following is a
true statement regarding neonatal
seizures?
A. Electroencephalography is a sensi-
tive and specific method of
detecting seizures.
B. Generalized tonic-clonic activity is
the most common clinical mani-
festation.
C. Most neonatal seizures are idio-
pathic.
D. Subarachnoid hemorrhage is a
more common cause of seizures in
preterm infants than in term
infants.
E. The underlying cause of the
seizure activity is the most impor-
tant determinant of outcome.
NEUROLOGY
Neonatal Seizures
in predicting outcome based on EEG
findings because of technical and
interpretive difficulties with the pro-
cedure. This applies especially to
preterm newborns and term infants
who have mild or moderate abnor-
malities on EEG.
SUGGESTED READING
Clancy RR. The management of neonatal sei-
zures. In: Stevenson KD, Sunshine P, eds.
Fetal and Neonatal Brain Injury: Mecha-
nisms, Management and the Risks of Prac-
tice. Oxford, United Kingdom: Oxford
University Press; 1997:432– 461
Holmes GL. Epilepsy in the developing brain:
lessons from the laboratory and clinic.
Epilepsia. 1997;38:12–30
Holmes GL. Neonatal seizures. Semin Pediatr
Neurol. 1994;1:72– 82
Massingale TW, Buttross S. Survey of treat-
ment practices for neonatal seizures.
J Perinatol. 1993;13:107–110
Mizrahi EM. Consensus and controversy in
the clinical management of neonatal sei-
zures. Clin Perinatol. 1989;16:485–500
Sher MS. Seizures in the newborn infant.
Diagnosis, treatment and outcome. Clin
Perinatol. 1997;24:735–772
Volpe JJ. Neonatal seizures. In: Volpe JJ, ed.
Neurology of the Newborn. 3rd ed. Phila-
delphia, Penn: WB Saunders Co; 1995:
172–207
Volpe JJ. Neonatal seizures: current concepts
and revised classification. Pediatrics.
1989;84:422– 428
6. A 2-day-old girl presents with gener-
alized tonic/clonic movements and
facial twitching lasting for
15 minutes. Respirations appear irreg-
ular. After ensuring the adequacy of
airway and ventilation, 0.1 mg/kg
lorazepam is administered intrave-
nously. Which of the following drugs
should be administered next?
A. Carbamazepine.
B. Clonazepam.
C. Paraldehyde.
D. Phenobarbital.
E. Valproic acid.
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