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Hypoxic-Ischemic Encephalopathy in the Term Infant: Neuropathology
Hypoxic-ischemic brain injury is a very important neurological problem of the perinatal period. This importance relates to the general gravity of the lesions and to the relatively large number of affected infants. In the premature infant, this encephalopathy is often accompanied by intraventricular hemorrhage and its concomitants, which contribute to the neurological morbidity (see Chapter 28 ). Thus it is apparent that a basic understanding of hypoxic-ischemic brain injury provides insight into a major portion of neonatal neurology. The subsequent neurological deficits of concern are, principally, a variety of motor deficits, especially spasticity, but also choreoathetosis, dystonia, and ataxia, often grouped together as “cerebral palsy,” with or without accompanying cognitive deficits and seizures.
In this chapter, we review the neuropathology of neonatal hypoxic-ischemic encephalopathy. The major lesions are discussed separately, although commonly there is overlap in the occurrence of each lesion. In Chapters 23 and 24 , we review the pathogenesis and clinical features of neonatal hypoxic-ischemic encephalopathy and use the same framework of neuropathological lesions discussed in this chapter.
Neuropathology
The neuropathological features of neonatal hypoxic-ischemic encephalopathy vary considerably with the gestational age of the infant, the nature of the insult, the types of interventions, and other factors, most still to be defined. Nevertheless, certain basic lesions can be recognized, and recognition of these lesions provides a useful framework for discussion of clinical aspects. The major neuropathological varieties are shown in Box 22.1 . In the context of generalized hypoxemia-ischemia, the focus of this chapter, the first three varieties are most common and discussed next. Stroke, a focal ischemic lesion, occurs in the context of multiple etiologies and is discussed separately in Chapter 25 .
BOX 22.1
Major Neuropathological Varieties of Neonatal Hypoxic-Ischemic Encephalopathy
Selective neuronal necrosis
Parasagittal cerebral injury
Cerebral white matter injury
Focal (and multifocal) ischemic brain necrosis–stroke
Selective Neuronal Necrosis: Patterns of Injury
Selective neuronal necrosis is the most common variety of injury observed in neonatal hypoxic-ischemic encephalopathy. The term refers to necrosis of neurons in a characteristic, although often widespread, distribution. Neuronal necrosis often coexists with other distinctive manifestations of neonatal hypoxic-ischemic encephalopathy (see later sections), and in fact it is very unusual to observe one of the other varieties of neonatal hypoxic-ischemic encephalopathy without some degree of selective neuronal injury as well. The topography of the neuronal injury depends in considerable part on the severity and temporal characteristics of the insult and on the gestational age of the infant. Three basic patterns derived primarily from correlative clinical and brain imaging findings, and observed best in term infants, can be distinguished ( Table 22.1 ). Diffuse neuronal injury occurs with very severe and very prolonged insults in both term and premature infants. A cerebral cortical–deep nuclear neuronal predominance occurs primarily in term infants with moderate to severe, relatively prolonged insults. The deep nuclear involvement includes basal ganglia (especially putamen) and thalamus. Deep nuclear–brainstem neuronal predominance occurs primarily in term infants with severe, relatively abrupt insults. Two additional patterns, pontosubicular neuronal injury and cerebellar injury, occur particularly in premature infants with a still-to-be-defined temporal pattern of insult (see later discussion), but these patterns are usually accompanied by other features of selective neuronal injury and are discussed in this overall context. In the discussion that follows, we review the cellular aspects of selective neuronal injury and the regions of predilection. Current concepts of pathogenesis (reviewed in detail in Chapters 16 and 23 ) are summarized only briefly.
TABLE 22.1
Major Patterns of Selective Neuronal Injury and Characteristics of Usual Insult in Term Newborns
| PATTERN a | USUAL INSULT |
|---|---|
| Diffuse | Very severe, very prolonged |
| Cerebral cortex–deep nuclear b | Moderate to severe, prolonged |
| Deep nuclear b –brainstem | Severe, abrupt |
a The patterns reflect areas of predominant neuronal injury; considerable overlap is common. Note that two additional patterns of selective neuronal necrosis—that is, pontosubicular and cerebellar, which occur predominantly in premature newborns (see text)—are not listed here because the temporal characteristics of the insult(s) are unknown.
b Deep nuclear: basal ganglia (especially putamen) and thalamus.
Pathogenesis
Current concepts of pathogenesis of hypoxic-ischemic neuronal injury are important to recognize, in part to understand the progression of the cellular neuropathology to be described in the next section. The progression to neuronal death and related cellular changes occur over three major phases in the first several days after the initial insult. Initially, in the primary phase , if the initial insult is severe, severe energy failure develops and neuronal necrosis occurs. More commonly, neurons survive and enter a latent period of 6 to 8 hours characterized by suppressed neural metabolism and activity. This transient recovery then is followed by a secondary phase of progressive failure of oxidative metabolism, seizures, cytotoxic cellular edema, neuroinflammation, and extensive programmed cell death, occurring over 24 to 72 hours. Subsequently, a tertiary phase ensues, characterized by chronic inflammation, with microgliosis (characterized by activated M1 microglia) and astrogliosis (characterized by reactive astrocytes). Potential targets for therapeutic interventions are directed at many of the molecular events accompanying these phases and are discussed in Chapters 16 and 23 .
Cellular Aspects
As the name selective neuronal necrosis implies, the neuron is the primary site of injury. Experimental studies indicate that the first observable change in the neuron is cytoplasmic vacuolation, caused by mitochondrial swelling, occurring within 5 to 30 minutes after the onset of hypoxia. In contrast to the rapid onset of neuronal changes in tissue cultures of neonatal mouse cerebellum exposed to hypoxia, no structural alteration was observed in astrocytes. However, as discussed later, studies of a variety of developing models suggest that differentiating oligodendrocytes exhibit approximately the same sensitivity to glucose and oxygen deprivation as do neurons. On balance, the data suggest that in the immature brain, the order of vulnerability is neuron ≥ oligodendroglia > astrocyte > microglia. In the context of the present discussion, the neuron is the cellular element most vulnerable to hypoxia-ischemia.
The temporal features of neuronal and related changes in neonatal human brain have been well documented ( Table 22.2 ). Affected neurons progress through a series of events that are accompanied by distinct morphological changes (see Table 22.2 ). Neuronal vacuolation, the initial change apparent by specialized techniques within 30 minutes, cannot be fully appreciated in standard histopathology preparations, and the first morphological change that is evident by light microscopy is the so-called red dead neuron. This change is noted 24 to 36 hours after hypoxic-ischemic injury and manifests as cytoplasmic hypereosinophilia accompanied by nuclear changes, such as pyknosis (nuclear condensation) or karyorrhexis (nuclear fragmentation) ( Fig. 22.1 ). Hypereosinophilia is due to the breakup of Nissl substance and, possibly, coagulation of cytoplasmic proteins, and the alterations in nuclear morphology reflect the activation of cell death pathways. At this stage the affected neuron may also increase in size owing to cell swelling as the nuclear and plasma membranes break down, allowing water to pass into the neuron. These early morphological events can be difficult or even impossible to detect in some neuroanatomic structures, owing to the late developmental maturation of neurons in certain structures, including areas of cerebral cortex, where neuronal differentiation and the appearance of Nissl substance are relatively late developmental events. As a result, it is possible for the morphological assessment of neuropathological findings to underestimate the true extent of hypoxic-ischemic injury in newborns. Two additional factors alter the ability to identify such neuronal changes early after perinatal asphyxia: (1) the gestational age of the infant and (2) the nature of the survival period. Thus recognition of neuronal changes in premature infants is difficult because of the close packing of immature cortical neurons and their relative lack of Nissl substance. Moreover, the brain of any infant who has been maintained on a respirator for several days, with compromised ventilation or perfusion, may have undergone enough autolysis to obscure early cellular changes. When these factors are not taken into consideration, the presence and magnitude of neuronal injury may be misjudged and may lead to spurious conclusions about the nature of the neuropathology.
TABLE 22.2
Histopathologic Stages of Hypoxic-Ischemic Injury in Neonatal Hypoxic-Ischemic Encephalopathy
| STAGE | TIMING | HISTOPATHOLOGIC FINDINGS |
|---|---|---|
| Acute | 8–24 hours | Hypereosinophilic neurons characterized by increased cytoplasmic eosin staining as Nissl substance fragments and by nuclear changes consisting of pyknosis or karyorrhexis |
| Subacute | 3–5 days |
|
| Chronic | Weeks to months and beyond | Cavity organizes and may contract to form a glial scar. |
The early neuronal changes are followed in several days by overt signs of cell necrosis ( Fig. 22.2 ). Associated with this cell necrosis is the appearance of microglia and, by 3 to 5 days after the insult, hypertrophic astrocytes. Foamy macrophages consume the necrotic debris, and a glial mat forms over the next several weeks ( Fig. 22.3 ). Severe lesions may result in cavity formation, ( Fig. 22.4 ) especially in the cerebral cortex. Late changes include encrusted, mineralized neurons ( Figs. 22.5 and 22.6 ).
Apoptotic as well as necrotic cell death is observed in hypoxic-ischemic disease in human infants, as in neonatal animal models. In one study of neuronal injury after “birth asphyxia,” the mean fractions of apoptotic and necrotic cells in cerebral cortex were 8.3% and 20.8%, respectively. In a study of the neonatal piglet subjected to hypoxia-ischemia, apoptotic neuronal death predominated among immature neurons and necrotic cell death among mature neurons. A similar susceptibility of immature neurons to apoptosis has been shown in N -methyl- d -aspartate–treated neurons in culture. In one specific form of human neonatal injury, pontosubicular necrosis (see later), the predominant form of cell death, appears to be apoptosis. Multiple forms of cell death along an apoptosis–necrosis continuum have been recognized in recent years. The modes of therapeutic intervention vary somewhat for these forms (see Chapter 23 ).
Regional Aspects (Autopsied Infants)
As noted earlier, three major regional patterns of selective neuronal necrosis can be delineated in the human newborn, especially the term infant (see Table 22.1 ). In diffuse disease, certain neurons at essentially all levels of the neuraxis are affected. In predominantly cerebral–deep nuclear disease, the prominent involvement is of cerebral neocortex, hippocampus, and basal ganglia–thalamus. In predominantly deep nuclear–brainstem disease, basal ganglia–thalamus–brainstem is the topography. A fourth pattern, more commonly observed in the preterm infant, pontosubicular necrosis , is characterized by involvement of neurons of the base of the pons and the subiculum of the hippocampus (see later). A fifth pattern, observed particularly in the small premature infant but to a different degree in the term infant, involves the cerebellum (see later). Given that overlap among these groups is the rule rather than the exception , I discuss diffuse disease first, because all of the vulnerable groups are involved.
Diffuse Neuronal Injury
The major sites of predilection for diffuse neuronal necrosis in the term and preterm newborn infant are shown in Table 22.3 .
TABLE 22.3
Sites of Predilection for the Diffuse Form of Hypoxic-Ischemic Selective Neuronal Injury in Premature and Term Newborns a
| BRAIN REGION | PREMATURE | TERM NEWBORN |
|---|---|---|
| Cerebral neocortex | + | |
| Hippocampus | ||
| Sommer’s sector | + | |
| Subiculum | + | |
| Deep nuclear structures | ||
| Caudate-putamen | + | + |
| Globus pallidus | + | + |
| Thalamus | + | + |
| Brainstem | ||
| Cranial nerve nuclei | + | + |
| Pons (ventral) | + | + |
| Inferior olivary nuclei | + | + |
| Cerebellum | ||
| Purkinje cells | + | |
| Granule cells (internal, external) | ± | ± |
| Spinal cord | ||
| Anterior horn cells (alone) | ± | |
| Anterior horn cells and contiguous cells (? Infarction) | ± |
+ , Common; ± , less common.
Cerebral Cortex
Neurons of the cerebral cortex in the term infant are particularly vulnerable, most notably the hippocampus (pyramidal cells) among the cerebral cortical regions. Sommer’s sector (and contiguous areas) of the hippocampus in the term newborn and the subiculum of the hippocampus in the premature newborn (see later discussion) are especially prone to injury (see Table 22.3 ). With more severe injury in the term infant, the better differentiated neurons of the calcarine (visual) cortex and of the precentral and postcentral cortices (i.e., perirolandic cortex) may be injured. In very severe injury, diffuse involvement of cerebral cortex occurs. Neurons in deeper cortical layers and, particularly, in the depths of sulci are especially affected. A role for patterns of blood flow in the determination of the topography is apparent from the more severe neuronal injury consistently observed in border zones between the major cerebral arteries, especially in the posterior cerebrum, and in depths of sulci. Perhaps reflecting the relative immaturity of cerebral cortical neurons in premature infants, involvement of the cerebral cortex is uncommon, particularly in comparison with neurons of deep nuclear structures and brainstem (see later). However, sophisticated brain imaging studies of premature infants at term equivalent age and later in childhood show impressive abnormalities of cerebral cortex (see Chapters 7 , 18 , and 20 ). Thus diminutions of cerebral cortical volumes and gyral development have been documented. The disturbances may reflect abnormalities of cerebral cortical development and may be related to concomitant cerebral white matter injury (see Chapter 18 ). The important point in this context is that these later abnormalities of cerebral cortex may not reflect direct cortical neuronal necrosis, at least as evidenced by conventional histological criteria.
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