Hypoxic-Ischemic Encephalopathy

With dramatic advances in neonatal critical care, hypoxic-ischemic encephalopathy (HIE) has emerged as the primary cause of neurologic morbidity in the newborn period. This injury can occur both in premature neonates and term neonates. HIE is a consequence of poor delivery of oxygen to the brain, with hypoperfusion and ischemia likely being the most important mechanism. Much of the injury actually occurs during reperfusion of the ischemic brain. HIE can result from any mechanism that results in poor blood flow to the fetal brain in utero including chorioamnionitis, placental abruption, nuchal cord, and chronic maternal hypertension. It can also occur in the setting of severe postnatal cardiorespiratory compromise, including respiratory or cardiac arrest. In premature neonates, it is often associated with intraventricular hemorrhage (IVH).

Intraventricular Hemorrhage

Although the premature cerebrovasculature has reasonable capacity for autoregulation within the normal range of blood pressure, this mechanism quickly becomes inadequate as blood pressures fluctuate outside the norm, predisposing the brain to ischemic injury during times of hypotension and hemorrhagic injury during times of hypertension. The periventricular germinal matrix of the premature brain is at high risk for hemorrhagic injury because of the presence of a rich but relatively immature capillary network. This region is particularly critical because it harbors the neural stem and progenitor cell population that provides precursors necessary for future myelination and development of the brain. Figure 101-1 demonstrates patterns of hemorrhagic injury that can occur in both premature and term infants.

Figure 101-1 Intracranial hemorrhage in a newborn.

Neonatal Seizures

Neonatal seizures are often a manifestation of underlying neurologic disease or injury (Table 101-1). In each case, the metabolic or structural abnormalities cause disorganized electrical activity that can lead to epileptogenic foci.

Table 101-1 Common Causes of Neonatal Seizures

Neonatal Hypotonia

Hypotonia is a common sign of neurologic disease in newborns that can be caused by dysfunction anywhere along the neuromuscular axis. These may arise from genetic defects causing protein dysfunction in either nerve or muscle cells, loss of cerebral regulation of tone secondary to global central nervous system (CNS) dysfunction as in many chromosomal disorders or injuries, or disturbed signal transmission at the neuromuscular junction. The more common causes of hypotonia can be organized by the location of the primary defect (Figure 101-2).

Figure 101-2 Primary sites of motor disorders.

Hypoxic-Ischemic Encephalopathy

In his classic text, Volpe describes a “neurologic syndrome” that summarizes an infant who has sustained a hypoxic-ischemic insult to the brain. In severe cases, the infant progresses through several clinical phases. During the first 6 to 12 hours, the baby will have depressed consciousness and may even be comatose. This time is often characterized by apnea or periodic breathing and minimal movement, but the patient usually has intact pupillary and oculomotor reflexes. Seizures commonly occur during this initial period. The next 12 to 24 hours are often characterized by apparent clinical improvement. The newborn may appear more alert. Jitteriness is common and may be misinterpreted as seizures, although a considerable number of patients also develop true seizures during this time window. The apparent improvement is likely a consequence of excitatory neurotransmitter cascades that are characteristic of this phase of reperfusion injury. The next 24 to 72 hours often see a return of stupor or coma; respiratory failure; and more significant loss of central reflexes, including oculomotor disturbances.

Intraventricular Hemorrhage

In a premature baby in the first few days of life, acute IVH may be characterized by subtle signs such as new-onset apnea or decreased activity. However, a catastrophic bleed may make itself evident by a dramatic change in mental status along with cardiovascular collapse. If enough blood is lost into the brain, the baby may become anemic and develop severe hypotension and respiratory failure. Metabolic acidosis may become refractory to therapy if systemic perfusion is inadequate because of anemia and hypotension. Hydrocephalus is a common consequence of IVH as the blood obstructs the flow of cerebrospinal fluid (CSF). This manifests clinically as increasing head circumference, which may develop acutely or slowly depending on the size of the hemorrhage.

Neonatal Seizures

The newborn brain remains immature, particularly with regard to myelination. This immature anatomic organization makes neonatal seizures difficult to recognize and classify and often presents problems in selecting therapy and gauging efficacy. The fact that normal newborn infants often exhibit unusual movements confounds the diagnosis of neonatal seizures. With these difficulties, neonatal seizures often experience a paradoxical combination of overdiagnosis and underdiagnosis.

Neonatal seizures have a variety of manifestations and a variety of normal mimics (Box 101-1). Clonic seizures can occur either focally or multifocally and are repetitive high-amplitude, low-frequency jerking movements. Tonic seizures are constant stiffening of a portion of the body and may be focal or generalized. Myoclonic seizures include sudden extension or flexion of part of the body. Subtle seizures encompass other small abnormal movements that do not fit into the previously listed seizure types, including eye deviation, lip smacking, and tongue thrusting, among others. Subtle seizures and generalized tonic seizures often do not have electroencephalographic (EEG) correlates and are thought to emanate from deeper subcortical brain regions, a theory supported by animal studies.

Several other unusual movements frequently seen in newborns must be considered in the differential diagnosis of seizures. These may occur in normal infants or may suggest other underlying disease. Jitteriness is a hypersensitivity to stimulus and may be suggestive of underlying abnormalities such as drug withdrawal; hypoxic-ischemic injury; or metabolic disease, particularly hypoglycemia. Benign myoclonus is a sudden, brief, jerking movement of the extremities that occurs during sleep in many normal infants. Opisthotonus is a tonic stiffening of the body, often resulting in arching of the back and neck. This is a common finding associated with gastroesophageal reflux (Sandifer’s syndrome). Neonatal apnea may or may not be associated with seizures, but it is frequently an independent clinical event in premature infants.