Neonatal Seizure

Background
The most prominent feature of neurologic dysfunction in the neonatal period is the
occurrence of seizures. Determining the underlying etiology for neonatal seizures is critical.
Etiology determines prognosis and outcome and guides therapeutic strategies.[1] (See
Etiology, Prognosis, Treatment, and Medication.)
The neonatal period is limited to the first 28 days of life in a term infant. For premature
infants, this term usually is applied until gestational age 44 weeks; ie, the age of the infant
from conception to 44 weeks (ie, 4 wk after term).

Seizure characteristics
Most neonatal seizures occur over only a few days, and fewer than half of affected infants
develop seizures later in life. Such neonatal seizures can be considered acute reactive (acute
symptomatic), and therefore the term neonatal epilepsy is not used to describe neonatal
seizures.[2]
Seizures in neonates are relatively common, with variable clinical manifestations. Their
presence is often the first sign of neurologic dysfunction, and they are powerful predictors
of long-term cognitive and developmental impairment. (See Prognosis.)
Most seizures in the neonate are focal, although generalized seizures have been described in
rare instances.
Subtle seizures are more common in full-term than in premature infants. Video
electroencephalogram (EEG) studies have demonstrated that most subtle seizures are not
associated with electrographic seizures. Examples of subtle seizures include chewing,
pedaling, or ocular movements.[3]

Neonatal seizure classification

Clonic seizures
These movements most commonly are associated with electrographic seizures. They often
involve 1 extremity or 1 side of the body. The rhythm of the clonic movements is usually
slow, at 1-3 movements per second.
Tonic seizures

These may involve 1 extremity or the whole body. Focal tonic seizures involving 1
extremity often are associated with electrographic seizures.
Generalized tonic seizures often manifest with tonic extension of the upper and lower limbs
and also may involve the axial musculature in an opisthotonic fashion. Generalized tonic
seizures mimic decorticate posturing; the majority are not associated with electrographic
seizures.
Myoclonic seizures
These may occur focally in 1 extremity or in several body parts (in which case they are
described as multifocal myoclonic seizures).
Focal and multifocal myoclonic seizures typically are not associated with electrographic
correlates. Generalized myoclonic jerks are possibly the clinical equivalent of infantile
spasms.

Pathophysiology
The biochemical effects of neonatal seizures include derangements of energy metabolism.
Energy-dependent ion pumps are compromised, and adenosine diphosphate (ADP) levels
rise. The rise in ADP stimulates glycolysis with the ultimate increase in pyruvate, which
accumulates as a result of compromised mitochondrial function.

Patient education
For patient education information, see the Brain and Nervous System Center, as well as
Seizures in Children and Seizures Emergencies.

Etiology
Seizures occur when a large group of neurons undergo excessive, synchronized
depolarization. Depolarization can result from excessive excitatory amino acid release (eg,
glutamate) or deficient inhibitory neurotransmitter (eg, gamma amino butyric acid
[GABA]).

Hypoxic-ischemic encephalopathy
Another potential cause is disruption of adenosine triphosphate (ATP) dependent resting
membrane potentials, which cause sodium to flow into the neuron and potassium to flow
out of the neuron. Hypoxic-ischemic encephalopathy disrupts the ATP-dependent sodiumpotassium pump and appears to cause excessive depolarization. It is an important cause of
neonatal seizures.[1, 4]

Seizures resulting from hypoxic-ischemic encephalopathy may be seen in term and

premature infants. They frequently present within the first 72 hours of life. Seizures may
include subtle, clonic, or generalized seizures.

Hemorrhage
Intracranial hemorrhage occurs more frequently in premature than in term infants.
Distinguishing infants with pure hypoxic-ischemic encephalopathy from those with
intracranial hemorrhage often is difficult.
Subarachnoid hemorrhage is more common in term infants. This type of hemorrhage occurs
frequently and is not clinically significant. Typically, infants with subarachnoid hemorrhage
appear remarkably well.
Germinal matrix-intraventricular hemorrhage is seen more frequently in premature than in
term infants, particularly in infants born prior to 34 weeks' gestation. Subtle seizures are
seen frequently with this type of hemorrhage.
Subdural hemorrhage is seen in association with cerebral contusion. It is more common in
term infants.

Metabolic disorders
Metabolic disturbances include hypoglycemia, hypocalcemia, and hypomagnesemia. Less
frequent metabolic disorders, such as inborn errors of metabolism, are seen more
commonly in infants who are older than 72 hours. Typically, they may be seen after the
infant starts feeding.

Intracranial infections
Intracranial infections (which should be ruled out vigorously) that are important causes of
neonatal seizures include meningitis, encephalitis (including herpes encephalitis),
toxoplasmosis, and cytomegalovirus (CMV) infections. The common bacterial pathogens
include Escherichia coli and Streptococcus pneumoniae.

Malformation syndromes
While most cerebral malformations present with seizures at a later age, major malformation
syndromes are important to consider. Lissencephaly, pachygyria, polymicrogyria, and linear
sebaceous nevus syndrome can present with seizures in the neonatal period.

Benign neonatal seizures

Benign neonatal seizure syndromes can be characterized by familial or idiopathic seizures.

Benign familial neonatal seizures typically occur in the first 48-72 hours of life; the
seizures disappear by age 2-6 months. A family history of seizures is usual. Development is
typically normal in these infants.
Benign idiopathic neonatal seizures typically present at day 5 of life (ie, fifth day fits), with
the vast majority presenting between days 4 and 6 of life. Seizures are often multifocal.
Cerebrospinal fluid (CSF) analysis is usually unremarkable.

Epidemiology
The incidence of neonatal seizures in the United States has not been clearly established,
although an estimated frequency of 80-120 cases per 100,000 neonates per year has been
suggested. The incidence of seizures is higher in the neonatal period (ie, the first 4 wk after
birth) than at any other time of life.[5]

Age-related demographics
Neonatal seizures by definition occur within the first 4 weeks of life in a full-term infant
and up to 44 weeks from conception for premature infants. Seizures are most frequent
during the first 10 days of life.

Prognosis
Prognosis is determined by etiology for neonatal seizures. If the EEG background is
normal, the prognosis is excellent for seizures to resolve; normal development is likely.[6, 7]
Severe EEG background abnormalities indicate poor prognosis; such patients frequently
have cerebral palsy and epilepsy. The presence of spikes on EEG is associated with a 30%
risk of developing future epilepsy.
The prognosis following neonatal seizures that result from isolated subarachnoid
hemorrhage is excellent, with 90% of children not having residual neurologic deficits.

Scoring system
Pisani et al devised a scoring system for early prognostic assessment after neonatal
seizures. Analysis of 106 newborns who had neonatal seizures and were followed
prospectively to 24 months' postconceptional age identified 6 independent risk factors for
adverse outcome: (1) birth weight, (2) Apgar score at 1 minute, (3) neurologic examination
at seizure onset, (4) cerebral ultrasonogram, (5) efficacy of anticonvulsant therapy, and (6)
presence of neonatal status epilepticus.

Each variable was scored from 0 to 3 to represent the range from normal to severely
abnormal; these were then added together to produce a total composite score, ranging from
0 to 12. A cutoff score of 4 or higher provided the greatest sensitivity and specificity for
prediction of adverse neurologic outcome.[8]

Morbidity and mortality

Neonatal seizures are a risk factor that markedly increases rates of long-term morbidity and
neonatal mortality. The presence of neonatal seizures is the best predictor of long-term
physical and cognitive deficits. Complications of neonatal seizures may include the
following:

Cerebral palsy

Cerebral atrophy

Hydrocephalus ex-vacuo

Epilepsy

Spasticity

Feeding difficulties

History

Infants with neonatal seizures are frequently lethargic between seizures and often appear ill.
Findings of the neurologic examination between seizures may be normal. However,
neurologic examination abnormalities may be seen correlating with a focal or generalized
neurologic syndrome. The clinical history provides important clues to the likely etiology of
neonatal seizures.[1]
Family history

A family history of neonatal convulsions may suggest that the infant has a genetic
syndrome. Many of these syndromes are considered benign and frequently disappear within
the neonatal period. In the absence of other etiologies, a family history of neonatal seizures
may suggest a good prognosis.[9]
Pregnancy history

A detailed pregnancy history is important. Search for a history that supports TORCH
(toxoplasmosis, rubella, cytomegalovirus, herpes) infections. The presence of kittens may

suggest toxoplasmosis as an etiology. A history of fetal distress, preeclampsia, or maternal

infection also can provide etiologic clues.
Delivery history

Delivery history is also important. The type of delivery and the antecedent events should be
documented. Apgar scores may offer some guidance concerning etiology, although a low
Apgar score without the need for resuscitation and subsequent neonatal intensive care is
unlikely to be associated with neonatal seizures.
Postnatal history

The postnatal history is also significant. Neonatal seizures in infants with an uneventful
antenatal history and delivery may result from a postnatal cause. A history of tremulousness
may suggest drug withdrawal or neonatal hypocalcemia. Temperature and/or blood pressure
instability may suggest an infection; a sepsis workup may be required.
A history of rubella or the absence of immunization against rubella may offer a diagnostic
clue. In the United States, rubella immunization typically is given during the toddler years
to both sexes and the degree of immunity is high. In countries where only teenage girls are
immunized for rubella, neonatal seizures resulting from central nervous system (CNS)
rubella involvement is a greater threat.

Diagnostic Considerations
Benign sleep myoclonus
The clinician should be familiar with this benign condition, in which rhythmic movements
(which occur only during sleep) mimic seizures. The condition can be alarming and may
occur focally during nonrapid eye movement (non-REM) sleep. Video EEG monitoring
shows no electrographic seizures.
Jitteriness
Jitteriness must be differentiated from seizures in neonates. Jitteriness is not associated with
ocular deviation. It is stimulus sensitive (eg, easily stopped with passive movement of the
limb). The movement resembles a tremor, and no autonomic changes are associated with it.
Seizures often are associated with ocular deviation and are not stimulus sensitive.
Autonomic changes frequently accompany them. The movements are clonic, unlike the
tremorlike movements of jitteriness.

Other conditions to consider in the differential diagnosis of neonatal seizures include the
following:

Anoxia

Benign epilepsy syndromes

Mitochondrial cytopathies

Myoclonic epilepsy

Myoclonus

Organic acidurias

Pyridoxine-dependent epilepsy

Subarachnoid hemorrhage

Subdural hematoma

Tuberous sclerosis

Vein of Galen malformation

Viral encephalitis

Viral meningitis

Differential Diagnoses

Abnormal Neonatal EEG

Benign Neonatal Convulsions

Cerebellar Hemorrhage

Early Myoclonic Encephalopathy

Epilepsy and Seizures

Epileptiform Discharges

Herpes Simplex Encephalitis

Neonatal Injuries in Child Abuse

Neonatal Meningitis

Shuddering Attacks

Imaging Studies
Cranial ultrasonography
Cranial ultrasonography is performed readily at the bedside; it is a valuable tool for quickly
ascertaining whether intracranial hemorrhage, particularly intraventricular hemorrhage, has
occurred. A limitation of this study is the poor detection rate of cortical lesions or
subarachnoid blood.

Cranial CT scanning
Cranial computed tomography (CT) scanning is a much more sensitive tool than
ultrasonography in detecting parenchymal abnormalities. The disadvantage is that the sick
neonate must be transported to the imaging site.
A distinct advantage is that with modern CT scan techniques, a study can be obtained in
approximately 10 minutes.
Cranial CT scan can delineate congenital malformations. Subtle malformations may be
missed on CT scan, requiring a magnetic resonance imaging (MRI) study.

MRI
Cranial MRI is the most sensitive imaging study for determining the etiology of neonatal
seizures, particularly when electrolyte imbalance has been excluded as the seizures cause.
[16]
A major disadvantage is that MRI cannot be performed quickly and, in an unstable
infant, it is best deferred until the acute clinical situation resolves.

Echocardiography
This study can rule out cardiac hypomotility as a result of more diffuse hypoxia.

Approach Considerations
Tests to ascertain the cause of neonatal seizures include the following:

Serum glucose and electrolytes - Transient neonatal hypocalcemia is a cause of

neonatal seizures during the first 3 weeks of life; hypocalcemia associated with
chromosome 22q11 deletion syndrome may also be a consideration

TORCH (toxoplasmosis, rubella, CMV, herpes) infection studies

Urine organic acids

Serum amino acid assay

Renal function tests - These tests rule out posthypoxic renal dysfunction; hypoxic
damage to multiple organ systems may also be suggested by elevated liver
transaminase levels.

Cerebrospinal fluid analysis

This should include tests checking for the following:

Pleocytosis

Xanthochromia - Suggestive of blood breakdown products, particularly if jaundice

is not present

Lactic acid and pyruvate - For evidence of mitochondrial cytopathies

Herpes virus - Using a polymerase chain reaction (PCR) assay

Glucose concentration - Low glucose concentration is suggestive of bacterial

meningitis

In the absence of bacterial meningitis, persistently low CSF glucose concentrations may
suggest a glucose transporter defect.

Electroencephalography
Electroencephalography plays a vital role in properly identifying and differentiating
neonatal seizures from nonepileptic events.[10, 11] Video EEG monitoring may be helpful
when infrequent neonatal seizures persist.[12] (See the images below.)

Onset of neonatal seizure demonstrating a focal onset in the

right frontal (FP4) region. At this point, the child had head and eye deviation to the left.

Twenty seconds into a seizure that had focal onset in the

right frontal (FP4) region, the seizure shows a rhythmic buildup of activity in the right

frontocentral region.
This seizure had focal onset in the right
frontal (FP4) region and subsequent buildup of activity in the right frontocentral region. As
the seizure evolves, the electroencephalogram shows diffuse involvement of both cerebral
hemispheres.
Neonatal brain cooling for hypoxic ischemic encephalopathy [13, 14, 15]
Infants undergoing brain cooling for hypoxic ischemic encephalopathy are unable to
undergo an EEG for 48 hours or longer following initiation of brain cooling. This renders
concern for neonatal seizures. Amplitude-integrated EEG (aEEG) may be useful for
monitoring such infants.
Therapeutic hypothermias (rectal temperature of 34C) in infants older than conceptual age
36 weeks initiated within the first 6 hours following delivery may decrease mortality and
neurodevelopmental disabilities. This period is also one during which neonatal seizures
may occur, rendering diagnosis by EEG inaccessible, specially when cooling is isolated to
the head by means of a Cool Cap". The neonatal EEG can be initiated only after completion
of Cool Cap therapy, when the core temperature has been normalized. Otherwise, the EEG
would assess a brain that is hypothermic and appear more suppressed than actual brain EEG
activity.

Consultations

Neurology consultation is recommended to help with the evaluation of seizures,

electroencephalography, video EEG monitoring, and management of anticonvulsant
medications.

Transfer
Mothers in premature labor ideally should be transferred to a facility with a tertiary
neonatal intensive care unit. This is more desirable than transfer after birth, since later
transfers more commonly result in morbidity.

Monitoring
Neurology outpatient evaluation and follow-up are needed to decide when to discontinue
seizure medications. Orthopedic evaluations may be appropriate in infants with joint
deformities.
Patients require developmental evaluation for early identification of physical or cognitive
deficits. Enrollment in a "birth to 3" program may be indicated. Patients must be monitored
carefully for development of contractures; strongly consider a physical medicine/physical
therapy referral.
Medical Care

Acute neonatal seizures should be treated aggressively, although controversy exists as to

the optimal treatment for them.[10, 17]
When clinical seizures are present, a rigorous workup to determine an underlying etiologic
cause should be initiated quickly. Electrolyte imbalances should be corrected through a
central venous site. Hypocalcemia should be treated cautiously with calcium, since leakage
of calcium into subcutaneous tissue can cause scarring.
When an inborn error of metabolism is suspected, discontinue feeding, since feeding may
exacerbate the seizures and encephalopathy. Institute intravenous solutions.
Once these issues have been addressed, antiepileptic drug (AED) therapy should be
considered. Phenobarbital is the initial drug of choice. If seizures persist, the use of
phenytoin should be considered.
Patients with seizures resulting from intracranial hemorrhage should have head
circumference measurements performed daily. A rapid increase in head circumference may
indicate hydrocephalus.

Seizure Medications

Seizure medication concentrations should be monitored during the acute period. These
drugs often are discontinued between ages 3 and 6 months if further seizures have not
occurred. A trend toward earlier discontinuation has met with good results.
A general recommendation is to use AEDs for 3 months, but electroencephalography may
be helpful in deciding when to stop AEDs.
If the patient remains seizure free, then medications may be tapered gradually. If the patient
is on 2 AEDs, then one should be tapered first before considering withdrawal of the other.
If seizures recur, then the patient should be placed back on AEDs. The patient may be
placed on the original AED, or carbamazepine may be considered.

Medication Summary
Administration of antiepileptic medications should be instituted in an orderly and efficient
manner.[18] Initial treatment with phenobarbital should be considered. If seizures persist,
phenytoin should be added. Persistent seizures may require the use of an intravenous
benzodiazepine, such as lorazepam or midazolam.
As previously stated, seizure medication concentrations should be monitored during the
acute period. These drugs often are discontinued between ages 3 and 6 months if further
seizures have not occurred. A trend toward earlier discontinuation has met with good
results. Hypoglycemia, if present, should be corrected.

Anticonvulsants, Other
Class Summary
These agents prevent seizure recurrence and terminate clinical and electrical seizure
activity.
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Phenobarbital

It is important to use the minimal amount of phenobarbital required and to wait for the
anticonvulsant effect to develop before a second dose is given. Start with the loading dose
and continue with the maintenance dosage.
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Phenytoin (Dilantin, Phenytek)

Phenytoin should be added to phenobarbital if seizures persist. Phenytoin may act in the
motor cortex, where it may inhibit the spread of seizure activity. The activity of brain-stem
centers responsible for the tonic phase of grand mal seizures also may be inhibited.
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Lorazepam (Ativan)

Lorazepam is a benzodiazepine anticonvulsant. It is used in cases refractory to

phenobarbital and phenytoin. By increasing the action of GABA, which is a major
inhibitory neurotransmitter in the brain, lorazepam may depress all levels of the CNS,
including the limbic and reticular formations.

Vitamins, Water-Soluble
Class Summary
Pyridoxine may be effective in seizures that are refractory to the medications already
discussed. It is essential for normal deoxyribonucleic acid (DNA) synthesis and cell
function.
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Pyridoxine (Aminoxin, Pyri-500)

Pyridoxine should be tried in patients not responding to the above regimen. Patients with
pyridoxine-dependent seizures respond immediately to pyridoxine.