INTRODUCTION	Section 2 of 10
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Background: 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 weeks after term).

Most neonatal seizures occur over only a few days, and fewer than half of affected infants develop seizures later in life. Such neonatal seizures could be considered acute reactive (acute symptomatic), thus the term "neonatal epilepsy" is not used to describe neonatal seizures.

Seizures in neonates are relatively common, with variable clinical manifestations. Their presence is often the first sign of neurological dysfunction, and they are powerful predictors of long-term cognitive and developmental impairment.

Pathophysiology: 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]). Another potential cause is disruption of ATP-dependent resting membrane potentials, which causes a flow of sodium into the neuron and potassium 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.

Frequency:

• In the US: The incidence of neonatal seizures has not been established clearly, 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 weeks after birth) than in any other age group.

• Internationally: Incidence is unknown.

Mortality/Morbidity:

• 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.

Race: No racial preponderance is known.

Sex: Sex-based frequency differences have not been described.

Age:

• 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.

	CLINICAL	Section 3 of 10
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History: The clinical history provides important clues to the likely etiology of neonatal seizures.

• 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.

• 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 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.

• 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 CNS rubella involvement is a greater threat.

• Neonatal seizures are classified as follows:

• 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 EEG studies have demonstrated that most subtle seizures are not associated with electrographic seizures. Examples of subtle seizures include chewing, pedaling, or ocular movements.

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

• Tonic seizures: These may involve one extremity or the whole body. Focal tonic seizures involving one extremity often are associated with electrographic seizures.
  • Generalized tonic seizures often manifest with tonic extension of both 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 one 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.

• 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.

Physical:

• 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.

Causes: The differential diagnosis for neonatal seizures is voluminous. Important causes include the following:

• Seizures resulting from hypoxic-ischemic encephalopathy may be seen in both term and premature infants. They frequently present within the first 72 hours of life. Seizures may include subtle, clonic, or generalized seizures.

• 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 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 (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.

• 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 seizure syndromes are characterized by the following:

• 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.

• 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 non-rapid eye movement (REM) sleep. Video EEG monitoring shows no electrographic seizures.