Neonatal Seizures

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.

What have been termed "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, these movements are thought not be epileptic in nature and more commonly are an epi-phenomena of severe encephalopathy.^[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.  These movements are thought to be non-epileptic in nature and a reflection of severe encephalopathy.  

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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.

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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 sodium-potassium 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.

Genetic disorders

"Early-onset epileptic encephalopathy" refers to a syndrome in which seizures are refractory to medications and severe cognitive/developmental issues are present. In those patients in whom structural and metabolic causes have been ruled out, genetic mutations are increasingly recognized. These mutations occur in genes that code for ion channel subunits (such as SCN1A, SCN8A, KCNT1) and other nueronal proteins and enzymes (such as CDKL5, STXBP1).^[5]

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.

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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.^[6]

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.

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Prognosis

Prognosis is determined by the etiology of the neonatal seizures. If the EEG background is normal, the prognosis is excellent for seizures to resolve; normal development is likely.^{[7, 8]}

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 with neonatal seizures who 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.^[9]

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/spasticity
• Cerebral atrophy/Hydrocephalus ex-vacuo
• Epilepsy
• Feeding difficulties

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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.^[10]

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.

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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
• Chromosomal microarray - Chromosomal abnormalities are often associated with neonatal encephalopathy including seizures
• Epilepsy panel/genetic testing - Single gene mutations are frequently identified as causative of neonatal seizures, such as channels for electrolyte or glucuse transport, or genes involved in metabolism (metabolic epilepsies)

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
• Amino acids - To detect nonketotic hyperglycinemia
• 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.^{[11, 12]} Video EEG monitoring may be helpful when infrequent neonatal seizures persist.^[13] (See the images below.)

View Image

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 le....

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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 fr....

View Image

This seizure had focal onset in the right frontal (FP4) region and subsequent buildup of activity in the right frontocentral region. As the seizure ev....

Continuous video-EEG (cEEG)

A recent large cohort of newborns with seizures treated at centers that use cEEG demonstrated that ~50% of those with high seizure burden received ≥2 antiseizure medications, and/or died or had abnormal examination at discharge. Greater seizure burden was associated with increased morbidity and mortality. The authors findings underscore the importance of accurate determination of neonatal seizure frequency and etiology and a potential for improved outcome if seizure burden is to be reduced.^[14]

Neonatal hypothermia for hypoxic ischemic encephalopathy

Infants undergoing brain cooling for hypoxic ischemic encephalopathy via selective head cooling with the Cool-Cap system are unable to undergo continuous video EEG monitoring with a full electrode array for 48 hours or longer following initiation of brain cooling. This renders concern for not recognizing neonatal seizures during a particularly high-risk period. Amplitude-integrated EEG (aEEG) may be useful for monitoring such infants.^{[15, 16]}

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. Hypothermia can also be achieved by whole body colling, which would enable cEEG to be performed.^[17]

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" early intervention program may be indicated. Patients with tone abnormalities must be monitored carefully for development of contractures; strongly consider a physical medicine/physical therapy referral.

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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.^[18] 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.

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Medical Care

Acute neonatal seizures should be treated aggressively, although controversy exists as to the optimal treatment for them.^{[11, 19]}

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.

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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. Since phenobarbital and phenytoin have disadvantages, including long-term side effects and, for phenytoin, difficulty maintaining levels, other medications may be considered. Some options include levetiracetam, oxcarbazepine, and topiramate.

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Medication Summary

Administration of antiepileptic medications should be instituted in an orderly and efficient manner.^[20] 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.

Levetiracetam can be effective for patients who do not respond to trandtional AEDs. In 2010, levetiracetam was designated as an orphan drug for neonatal seizures by the FDA. Levetiracetam can be given intravenously.^[21]

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Phenobarbital

• Dosing, Interactions, etc.

Clinical Context:  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, in order to minimize respiratory distress. Start with the loading dose and continue with the maintenance dosage.

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Phenytoin (Dilantin, Phenytek)

• Dosing, Interactions, etc.

Clinical Context:  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)

• Dosing, Interactions, etc.

Clinical Context:  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.

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Levetiracetam (Keppra)

• Dosing, Interactions, etc.

Clinical Context:  Antiepileptic mechanism unknown. It may inhibit voltage-depedent N-type calcium channels. Levetiracetam may bind to synaptic proteins that modulate neurotransmitter release, and through displacement of negative modulators may facilitate GABA-ergic inhibitory transmission. It is designated as an orphan drug by the FDA for treatment of neonatal seizures.

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Class Summary

These agents prevent seizure recurrence and terminate clinical and electrical seizure activity.

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Pyridoxine (Aminoxin, Pyri-500)

• Dosing, Interactions, etc.

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

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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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