Term newborns presenting with neonatal encephalopathy have a number of potential causes for their altered neurologic examination (Box 34.1). The most regarded etiology is hypoxia-ischemia, but stroke, traumatic brain injury, infection, toxin exposure, and genetic or metabolic disorders may be equally prevalent. Premature newborns may not show the same signs of encephalopathy as a term newborn, but they can experience injury to the developing brain through the same mechanisms, resulting in a different pattern of injury due to vulnerability of maturation-dependent populations of neural cells. An understanding of the causes of neonatal encephalopathy is crucial to the concepts of prevention and treatment. Although advances have been made in recognition of the many potential causes, these advances have not led to a reduction in the overall rate of cerebral palsy. Furthermore, the effect of neonatal encephalopathy on cognition has not been adequately studied in large populations.

While many causes of neonatal encephalopathy begin prenatally, the majority of infants with HIE are full-term infants who have had perinatal complications. Recent studies suggest that, although antenatal or genetic factors might predispose some infants to perinatal brain injury, events that occur in the immediate perinatal period are most important in infants presenting with neonatal encephalopathy. Labor imposes both mechanical and hypoxic stress on the fetus and, therefore, if this stress becomes excessive, the newborn is at risk for permanent neurologic sequelae. Intrauterine distress (abnormal fetal heart rate patterns, meconium-stained or infected amniotic fluid, or abnormalities in acid–base balance) or puerperal complications (abruptio placentae, cord prolapse, tight nuchal cord, or mechanically traumatic delivery) can produce the syndrome of HIE. The precise clinical picture and the underlying pathophysiology leading to irreversible neuronal damage vary depending on the severity and duration of the perinatal compromise, as well as on other variables such as gestational age, the presence of maternal factors such as preeclampsia, intrauterine infection, and glycemic status. For example, in acute total asphyxia caused by placental abruption, the clinical picture is that of a severely depressed infant requiring immediate resuscitation. This newborn will remain encephalopathic for many days and have early and refractory seizures and disturbances in multiorgan systems (renal, cardiac, and pulmonary). When the hypoxic-ischemic events occur over a longer duration with less severity, possibly due to an intrauterine inflammatory environment, Apgar scores may be near normal, and severe neurologic depression with multiorgan involvement will not be present. However, the neonate may have poor feeding or subtle abnormalities of the neurologic examination as the only immediate manifestation. Newer technologies such as magnetic resonance spectroscopy (MRS) and diffusion-weighted imaging (DWI), coupled with advanced structural imaging, may be helpful in the early identification of such infants who are at risk for future neurologic handicap.

In the developing brain, metabolic changes and alterations in cerebral blood flow occur during the injury. There is a shift from oxidative to anaerobic metabolism (glycolysis) with an accumulation of lactic acid and a depletion of high-energy phosphate reserves that can be seen in regions of compromise, especially the basal ganglia (Fig. 34.1). At the same time, failure
of energy-dependent ionic pumps results in an early influx of calcium into cells. With alterations in membrane homeostasis, there is a release of the excitatory neurotransmitters, especially glutamate, which activates N-methyl-D-aspartate (NMDA) and non-NMDA receptors that are enriched in particularly vulnerable regions and on targeted cells (neurons and preoligodendrocytes, respectively). This activation results in an increase in the activity of membrane-associated neuronal nitric oxide synthase (NOS) in neurons in the deep gray nuclei, and activation of microglia containing the inducible form of NOS. Increase in NOS activity results in generation of nitric oxide that diffuses over large areas and is both directly and indirectly toxic to vulnerable neurons and preoligodendrocytes with limited antioxidant reserves. These reactive oxygen and nitrogen species will damage membranes, as well as activate injurious genetic programs (transcription factors) that ultimately lead to energy-dependent cell death (Fig. 34.2). The pathologic changes observed in the brain are dependent upon the gestational age at the time of the insult. For example, selective neuronal necrosis of the deep gray nuclei, especially striatum and thalamus, is the most common pathologic finding noted in the term ischemic brain. In the preterm infant, both subplate neurons and preoligodendrocytes are selectively vulnerable, leading to a pattern of early white matter injury, and later diffuse cortical atrophy from disruption of thalamocortical connectivity disturbed by the loss of the subplate population. All of the vulnerable cells are susceptible to oxidative stress; therefore, therapies aimed at reducing the oxidative burden should eventually prove to be neuroprotective.