Diagnosis

Seizure manifestations in newborns differ from those in older children in that newborns generally do not have well-organized, tonic-clonic seizures due to the immaturity of synaptic connections (Volpe, 2008). Table 80.1 summarizes the common types of neonatal seizures. The basis for classification should be a combination of clinical and electroencephalographic (EEG) abnormalities (Clancy, 2006). These seizure types are not specific for cause, but some are seen more often with certain underlying conditions. Tonic seizures, which may represent nonepileptic decerebrate posturing, occur in up to 50% of premature newborns with severe intraventricular hemorrhage (IVH). Focal clonic seizures in the term newborn are most commonly associated with focal cerebral infarction or traumatic injury, such as cerebral contusion.

Table 80.1 Types of Neonatal Seizures

Differentiation of Seizures from Nonconvulsive Movements

Simultaneous monitoring with EEG and video display in newborns with movements suggestive of “subtle seizures” have not shown consistent electrographic discharges concomitant with the movement. This suggests that the abnormal movements may represent nonictal brainstem release phenomena rather than seizures. Similarly, epileptiform discharges rarely accompany tonic extensor posturing in newborns with severe IVH, and the posturing responds poorly to anticonvulsant therapy. Myoclonic seizures, which may evolve into infantile spasms, often have a dismal outcome and must be distinguished from benign neonatal sleep myoclonus, which occurs in healthy newborns.

Jitteriness, an exaggerated startle response, is often confused with clonic seizures, especially because both jitteriness and clonic seizures occur in conditions such as hypoxic-ischemic or metabolic encephalopathies and in drug withdrawal. The absence of associated ocular movements and autonomic changes (e.g., tachycardia, increase in blood pressure, apnea) and the presence of stimulus sensitivity distinguish jitteriness and seizures. The predominant movement is tremor that stops when passively flexing the affected limb.

Determination of the Underlying Cause

Diagnosis of the underlying cause allows specific treatment and a more precise prediction of outcome (Glass and Wu, 2009; Tekgul et al., 2006). Table 80.2 summarizes the major causes of neonatal seizures, their usual times of onset, and prognosis. Sometimes, several factors cause seizures (e.g., the combination of intracranial hemorrhage, metabolic derangement, and hypoxic-ischemic injury). Benign genetic epilepsies rarely have their onset in the neonatal period; the only example is benign familial neonatal epilepsy, an autosomal dominant trait for which two gene loci, KCNQ2 and KCNQ3, have been identified, which encode for voltage-gated potassium channels (Bellini et al., 2010).

Table 80.2 Major Causes of Neonatal Seizures: Clinical Features and Outcomes

Electroencephalography

EEG, particularly continuous EEG monitoring when available, is a valuable aid in the diagnosis of neonatal seizures, especially in newborns paralyzed to assist ventilation and in those with suspected subtle seizures. Amplitude-integrated EEG is a more recent technique that may assist in detecting subtle and subclinical electrographic seizures (van Rooij et al., 2010). Concern exists that use of amplitude-integrated EEG criteria alone may lead to an overdiagnosis of neonatal seizures, so confirmation by standard EEG is advisable prior to treatment with anticonvulsants (Koh et al., 2010). EEG correlates of neonatal seizures are focal or multifocal spikes or sharp waves and focal monorhythmic discharges. Sharp transients are normal in premature newborns and should not be confused with seizure activity. Similarly, the trace alternant pattern of quiet sleep in normal term infants, in which normal low-amplitude reactivity is preserved between bursts, must be distinguished from the abnormal burst-suppression pattern, in which long periods of voltage suppression or absence of activity are recorded between bursts of high-voltage spikes and slow waves (Lamblin et al., 2010).

Interictal EEG may have prognostic value. Severe suppression of the background activity, whether or not interrupted by high-amplitude bursts, is associated with an abnormal outcome in more than 90% of patients. In contrast, normal background activity is associated with good outcome.

Management

Neonatal seizures require urgent treatment. Once adequate ventilation and perfusion are established, the blood glucose concentration is measured. If the glucose concentration is low, 10% dextrose should be administered in a dose of 2 mL/kg. In the absence of hypoglycemia, immediate treatment should be started with anticonvulsant medication, as outlined in Table 80.3. Studies for other underlying causes should proceed concurrently and specific treatment initiated whenever possible.

Table 80.3 Treatment of Neonatal Seizures

* Fosphenytoin is an alternate form of phenytoin that may be used.

Phenobarbital alone controls seizures in most newborns after administering adequate dosages (up to a maximum of 40 mg/kg loading dose). Give phenytoin, 20 mg/kg, if seizures continue. Evaluation of fosphenytoin in the newborn, which is converted to phenytoin, is presently unknown, but initial data suggest that the rate of conversion is identical to that shown for older infants. Unfortunately, seizures are often incompletely controlled by phenobarbital and phenytoin (Jensen, 2009). When these drugs fail, other anticonvulsants (benzodiazepines: midazolam, lorazepam, levetiracetam, and topiramate) may be effective. These are not recommended as first-line drugs (Bassan et al., 2008; Jensen, 2009; Rennie and Boylan, 2007).

Phenobarbital may suppress seizures caused by hypocalcemia, and a favorable response does not exclude that diagnosis. Approximately 50% of newborns with hypocalcemia also have hypomagnesemia, which requires specific treatment.

Pyridoxine deficiency, a rare cause of neonatal seizures, should be considered whenever no other cause is determined. Most infants have an unusual paroxysmal pattern on EEG, with generalized bursts of synchronous high-voltage activity of 1- to 4-Hz intermixed spikes and sharp waves. The diagnosis of pyridoxine deficiency is not excludable based on lack of response to a single large dose of intravenous (IV) pyridoxine with concurrent EEG recording; rather, large doses (50-100 mg daily) should be given orally for several days (Mills et al., 2010).

Specific metabolic disorders require specific therapeutic considerations with rapid intervention to maximize the chance of a good outcome (Pearl, 2009). Glut-1 deficiency syndrome is another rare cause of seizures and major developmental delay associated with hypoglycorrhachia, which may have implications for treatment in that the ketogenic diet may be most effective for control of seizures (Moers et al., 2002).

Duration of Treatment and Outcome

The optimal duration of maintenance therapy for neonatal seizures is unknown. The duration of maintenance treatment for neonatal seizures depends on the risk for recurrence, underlying cause (see Table 80.3), results of the neurological examination, and EEG findings (Glass and Wirrell, 2009). Phenytoin should be discontinued when stopping IV therapy because adequate serum levels are difficult to maintain with oral phenytoin in the newborn. If seizures have stopped and the neurological examination and EEG are normal, phenobarbital should be discontinued before discharge from the hospital. If continuing phenobarbital after discharge, discontinuation should be considered as early as 1 month later based on the neurological status and EEG. Discontinuing zphenobarbital should be considered in an infant whose examination is not normal if EEG does not show epileptiform activity. The potential deleterious effects of phenobarbital on brain development are a concern. Infants should be treated with phenobarbital for the briefest possible time.

Diagnosis

Because asphyxia is mainly an intrauterine event, careful documentation of maternal risk factors and abnormalities of labor and delivery are important. An accurate history also may provide precise information about the type of insult as well as its severity, duration, and timing, which in turn determines in large part the specific pattern of brain injury. Acute, total, or near-total asphyxia may cause disproportionate injury to thalami, basal ganglia, and brainstem nuclei, whereas prolonged partial asphyxia causes injury principally to the cerebral cortex and subcortical white matter (Miller et al., 2005; Roland et al., 1998).

The initial clinical features of severe hypoxic-ischemic encephalopathy include depressed level of consciousness, periodic breathing (due to bilateral hemisphere dysfunction), hypotonia, and seizures. When the hypoxic-ischemic insult is of the acute/near-total type, brainstem dysfunction may be a prominent feature. Between 24 and 72 hours of age, the level of consciousness, seizures, apnea, and other brainstem abnormalities become more prominent, which also correspond to the timing of maximum intracranial pressure. After 72 hours, infants who survive show continued (although diminishing) stupor, abnormal tone, and brainstem dysfunction, with disturbances of sucking and swallowing. Specific patterns of weakness related to the distribution of neuronal injury may become evident (Table 80.4). Table 80.5 summarizes the temporal profile of clinical features of severe hypoxic-ischemic encephalopathy in the term newborn.

Table 80.4 Neuropathological Patterns of Neonatal Hypoxic-Ischemic Brain Injury and Clinical Correlation

Table 80.5 Clinical Features of Severe Hypoxic-Ischemic Encephalopathy

The classification of hypoxic-ischemic encephalopathy into mild, moderate, and severe is useful for prediction of outcome. Characteristics of mild encephalopathy are increased irritability, exaggerated Moro and tendon reflexes, and sympathetic overreactivity. Recovery is usually complete within 2 days, and long-term sequelae do not occur. Moderate encephalopathy with lethargy, hypotonia, diminished reflexes, and possibly seizures is associated with a 20% to 40% risk for abnormal outcome. Infants with severe encephalopathy with coma, flaccid muscle tone, brainstem and autonomic dysfunction, seizures, and possible increased intracranial pressure either die or survive with severe neurological abnormalities.

Other clinical features that provide corroborative evidence for significant hypoxic-ischemic brain injury include prolonged low Apgar scores, metabolic acidosis, and involvement of other organs.

Electroencephalography and Cortical Evoked Responses

Hypoxic-ischemic encephalopathy is the single most important cause of seizures in term and premature newborns. Seizures associated with moderate or severe encephalopathy most commonly begin during the first 24 hours after the original insult and may be notoriously difficult to control. The pattern of background activity on EEG may have prognostic implications. Thus, infants with normal EEG findings 1 week after the initial insult usually have a favorable outcome.

The usefulness of the visual, auditory, and somatosensory evoked responses in the diagnosis and prognosis of hypoxic-ischemic encephalopathy is more limited (see Chapter 32A), although there may be a role for visual evoked responses in the diagnosis of periventricular leukomalacia (PVL) and for auditory evoked responses in the diagnosis of brainstem injury.

Metabolic Biomarkers

Hypoglycemia, hypocalcemia, hyponatremia (inappropriate antidiuretic hormone secretion), and lactic acidosis may contribute to the neurological syndrome of hypoxic-ischemic encephalopathy. Uncorrected metabolic derangements may worsen the cerebral injury (Hanrahan et al., 1998).

Neuroimaging

Neuroimaging has major value for locating and quantifying cerebral injury. MRI in the term newborn and US and MRI in the premature newborn are especially valuable. Although MRI has superseded CT in many instances, CT still has a role in the assessment of acute hypoxic-ischemic brain injury, especially in term newborns unable to tolerate the prolonged scanning time required with MRI (Chau et al., 2009). CT performed between 3 and 5 days of age may show decreased attenuation. More precise anatomical delineation of mild brain injury or selective involvement of thalamus and basal ganglia or cerebellum may be assessed more accurately by MRI (Rutherford et al., 2010) (Fig. 80.1). More advanced MRI techniques may prove especially useful (e.g., diffusion tensor imaging, functional MRI, diffusion tractography) (Counsell et al., 2010; Miller and Ferreiro, 2009).

Fig. 80.1 A composite of computed tomography (CT) and magnetic resonance imaging (MRI) images from a normal term infant and an infant who sustained an episode of acute/near-total asphyxia. Note the density of the thalami in column 3 (acute/near-total insult) is decreased compared to the cerebral cortex and more closely resembles the attenuation of the white matter. Compare this with the normal thalami in column 1. There is marked restricted diffusion on the ADC maps in column 4, showing involvement of the lentiform nuclei and central lateral nuclei of the thalami, as well as the motor strip superiorly.

Several techniques may also provide additional insight into the functional disturbances of newborn hypoxic-ischemic cerebral injury. For example, positron emission tomography, single-photon emission computed tomography, and near-infrared spectroscopy show disturbances of cerebral perfusion, and magnetic resonance spectroscopy shows decreased brain levels of high-energy phosphates in asphyxiated infants (Barkovich et al., 2006).

Management

Optimal management begins in utero by measures to prevent hypoxic-ischemic injury. Fetuses at risk must be identified early, monitored serially (as discussed earlier), and considered for cesarean delivery when signs of fetal distress persist. An asphyxiated newborn requires immediate intervention and resuscitation to prevent additional hypoxic-ischemic cerebral injury. This includes correction of impaired ventilation, perfusion, and blood glucose concentrations; control of seizures; and maintenance of perfusion and function of other affected organs including the heart, liver, kidneys, and gastrointestinal tract.

Maintenance of Adequate Ventilation

Maintenance of adequate ventilation and minimizing additional postnatal hypoxemia and hypercapnia are critical to outcome. The availability of continuous transcutaneous oxygen and carbon dioxide monitoring facilitates the recognition of hypoxemia and hypercapnia. Deleterious effects of hypercapnia include worsening intracellular acidosis and impaired cerebrovascular autoregulation, with development of a pressure-passive cerebral circulation. Experimental and human data do not support the use of hyperventilation in asphyxiated newborns, except perhaps in those with persistent fetal circulation.

Maintenance of Adequate Perfusion

The maintenance of adequate perfusion is critical to prevent further cerebral ischemia. The basis for management of perfusion is knowledge of normal systemic arterial blood pressure levels in the newborn at all gestational ages. Systemic hypotension should be avoided because cerebral blood flow is not autoregulated in asphyxiated newborns and reflects systemic blood pressure in a pressure-passive manner. Transitory myocardial ischemia, a common cause of hypotension in asphyxiated newborns, may respond to inotropic agents such as dopamine. Other important causes of systemic hypotension that may result in decreased cerebral perfusion are patent ductus arteriosus and recurrent apneic spells with bradycardia. Because of the pressure-passive relationship between the systemic and cerebral circulations in some premature and asphyxiated term newborns, systemic hypertension should be avoided, especially in the premature infant, in whom the presence of vulnerable germinal matrix capillaries predisposes to the development of IVH.

Hyperviscosity due to polycythemia (venous hematocrit > 65%) may further impair cerebral perfusion in asphyxiated newborns, especially in those who are small for gestational age. Jitteriness, apnea, poor feeding, and seizures are concomitant neurological features in approximately 40% of these newborns. All symptomatic newborns with polycythemia require partial exchange transfusion with plasma. Those who are asymptomatic may require the same treatment.