Abstract
Hypoxic-ischemic brain injury is a very important neurological problem of the perinatal period. This importance of hypoxic-ischemic brain injury relates to the general gravity of the lesions and to the relatively large number of affected infants. In this chapter, we review the neuropathology and pathogenesis of neonatal hypoxic-ischemic encephalopathy. The major neuropathological varieties include selective neuronal necrosis, which is the necrosis of neurons in a characteristic, often widespread distribution; it is very unusual to observe this in isolation. The topography of the neuronal injury depends in part on the severity and temporal characteristics of the insult and on the gestational age of the infant. Basic patterns observed best in term infants are diffuse neuronal injury, cerebrocortical–deep nuclear neuronal necrosis, pontosubicular neuronal injury, and cerebellar injury. Parasagittal cerebral injury is a lesion of the cerebral cortex and subcortical white matter with a distribution comprising parasagittal and superomedial aspects of the cerebral convexities; it is characteristic of the full-term infant with perinatal asphyxia. The predominant lesion in infants with hypoxic-ischemic encephalopathy may involve primarily cerebral white matter. Approximately 15% of infants exhibit this pattern of injury as the dominant abnormality. The similarities with periventricular leukomalacia of very premature infants are apparent. Important contributing pathogenetic factors in infants with hypoxic-ischemic encephalopathy are late preterm gestational age, neonatal hypoglycemia, and often chronic hemodynamic instability. The majority of term infants with congenital heart disease dying days after cardiac surgery exhibit at autopsy periventricular leukomalacia as a prominent lesion. Involvement of cerebral white matter is also the dominant neuroimaging feature of infants with complex congenital heart disease both before and after cardiac surgery.
Keywords
selective neuronal necrosis, parasagittal cerebral injury, pontosubicular necrosis, cerebellar injury, congenital heart disease, full-term infants
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 24 ). 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 and pathogenesis of neonatal hypoxic-ischemic encephalopathy. The major lesions are discussed separately, although commonly there is overlap in the occurrence of each lesion. In Chapters 19 and 20 , we review the pathogenesis and clinical features of neonatal hypoxic-ischemic encephalopathy, using 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 the discussion of clinical aspects. The major neuropathological varieties are shown in Table 18.1 . In the context of generalized hypoxemia-ischemia, the focus of this chapter, the first three varieties are most common and discussed next. Stroke occurs in the context of multiple etiologies and is discussed separately in Chapter 21 .
| Selective neuronal necrosis |
| Parasagittal cerebral injury |
| Periventricular leukomalacia |
| Focal (and multifocal) ischemic brain necrosis—stroke |
Brain Swelling and Brain Necrosis
Brain swelling is discussed separately from the recognized neuropathological disorders associated with perinatal hypoxic-ischemic insults because some workers have suggested that brain swelling is a separate and dominant lesion that may lead to additional brain injury. This view is derived principally from experience with adult patients and from experimental data (see later discussion). Indeed, it is well known in standard neuropathological writings concerning adult patients that severe hypoxic-ischemic insults are associated with a major degree of brain swelling and increased intracranial pressure and that the latter may accentuate neurological morbidity. Extrapolation of such data to the neonatal brain cannot be made a priori. Earlier work with neonatal kittens and rats indicated a relative resistance of immature brain to the development of prominent edema produced by hypoxic-ischemic or cold-induced injury; similar insults regularly produce pronounced brain edema in adult animals. Therefore it is reasonable to ask whether brain swelling with hypoxic-ischemic injury is a consistent feature in the human newborn with perinatal asphyxia.
Pathological Aspects in Human Infants
Pathological studies of neonatal hypoxic-ischemic encephalopathy do not provide decisive support for the occurrence of brain swelling as a separate and dominant lesion without comparable degrees of tissue necrosis. Several older reports do emphasize brain swelling in asphyxiated newborn infants. However, often the definition of swelling is not precise, the degree of associated brain injury is not clearly quantitated, the length of time spent on ventilatory and circulatory support before death is not defined, and the type of management after the insult is not described. These factors have major bearing on the questions of whether edema, in fact, was present, and if so, whether it was simply the consequence of brain necrosis or was a predominant lesion per se. Moreover, because fetal and neonatal human brain contains more water than myelinated, mature brain and the immature brain swells considerably during fixation, Gilles et al. suggested that “much of what has been called edema in the fixed brain may well reflect the initial high water content of this tissue plus the water accumulated during fixation.” The absence of external signs of swelling and of necrosis caused by transtentorial (hippocampal) or transmagnal (cerebellar) herniation in the huge autopsy population of the National Collaborative Perinatal Project has been emphasized.
Several clinical studies also indicated that primary brain swelling (i.e., in the absence of marked brain necrosis) is not a prominent feature of hypoxic-ischemic encephalopathy in the human newborn. In one study, clearly increased intracranial pressure (i.e., >10 mm Hg) was observed in only 22% of 32 asphyxiated term newborns; it did not compromise cerebral perfusion pressure, it reached a maximum at 36 to 72 hours, and it correlated with computed tomography (CT) evidence for early brain necrosis. In a second systematic study, intracranial pressure reached a maximum at a mean age of 29 hours and was not correlated with clinical or electroencephalographic evidence for neurological deterioration. Changes in cerebral perfusion pressure most often reflected decreases in arterial blood pressure rather than increases in intracranial pressure. Moreover, administration of mannitol in a single dose to asphyxiated infants in a controlled study had no beneficial clinical effect. These observations support the conclusion that early brain edema is a consequence rather than a causative factor of hypoxic-ischemic brain injury ( Table 18.2 ).
| Intracranial pressure (ICP) >10 mm Hg is uncommon in asphyxiated term infants |
| When ICP >10 mm Hg occurs, timing is relatively late (i.e., 24–72 h) |
| Marked decreases in cerebral perfusion pressure (CPP) are uncommon, and decreases in CPP that do occur are usually caused by decreases in blood pressure rather than by increases in ICP |
Experimental Aspects in Perinatal Animals
Intrauterine Partial Asphyxia in the Fetal Monkey.
The notion that brain swelling is an important early feature with perinatal hypoxic-ischemic insults and the cause of subsequent tissue necrosis is based on studies with term fetal monkeys by Myers and co-workers. In these experiments, in association with “prolonged partial asphyxia” of the term fetal monkey (produced by a variety of procedures that impair placental gas exchange, such as maternal hypotension, maternal hypoxemia, and umbilical cord compression), a pattern of cerebral injury characterized by necrosis and edema was observed. The topography of the necrosis was typical of the parasagittal cerebral injury observed in the asphyxiated human term infant (see later discussion).
Associated with the cerebral injury in the monkeys was brain swelling , defined primarily by gyral flattening. The edema was considered to be intracellular on the basis of electron microscopic observations in related experiments. In similar experiments, statistically significant changes in brain water content could not be demonstrated. On balance, the brain swelling in these experiments appears most likely to be secondary to the pronounced tissue injury (with cytotoxic edema) rather than a primary event leading to the injury. This possibility would be compatible with conclusions derived from human pathological material (see earlier discussion).
Intrauterine Partial Asphyxia in the Fetal Lamb.
Studies of the fetal lamb subjected to intrauterine partial asphyxia do not support the notion of brain edema, at least of the vasogenic variety, as an important consequence of acute hypoxic-ischemic brain injury in this model. Extravascular plasma volume was quantitated by the iodine-125-labeled albumin method with asphyxia and was found not to be significantly increased in cerebrum, brain stem, or cerebellum. Moreover, the postasphyxial delayed cerebral hypoperfusion observed in this model occurred in the absence of brain edema. In later studies of near-term fetal lambs subjected to hypoxia-ischemia, findings indicative of cytotoxic edema correlated with documented neuronal injury were obtained—a correlation consistent with the observations in human infants (see earlier).
Hypoxic-Ischemic Insult in the Neonatal Rat and Piglet.
Careful morphological, physiological, and biochemical studies of the neonatal rat and piglet subjected to a combination of ischemia (carotid ligation) and hypoxemia also failed to support the notion of brain edema as a primary or injury-causing result of hypoxic-ischemic insult. In the studies of neonatal rats, although the water content of brain increased, a close correlation was defined between the degree of tissue necrosis and the increase in brain water. No sign of transtentorial or cerebellar herniation was observed, unlike the case in adult animals similarly studied. No inverse correlation of cerebral blood flow (CBF) and brain water content could be identified over the 6 days following the hypoxic-ischemic insult. Moreover, administration of four doses of mannitol over 2 days following the insult did not ameliorate the incidence, distribution, or severity of the extensive tissue injury, despite reduction in the increase in brain water content in the hypoxic-ischemic hemisphere. In addition, the spatial relationships between this increase in brain volume and the tissue injury did not suggest that the apparent edema caused or contributed to the cerebral injury. The conclusion is that the brain edema is a “consequence rather than a cause of major ischemic damage in the immature animal.”
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 18.3 ). Diffuse neuronal injury occurs with very severe and very prolonged insults in both term and premature infants. A cerebrocortical–deep nuclear neuronal predominance occurs in primarily term infants with moderate to severe, relatively prolonged insults. The deep nuclear involvement includes basal ganglia (especially putamen) and thalamus. Deep nuclear–brain-stem neuronal predominance occurs in primarily 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, the regions of predilection, and the current concepts of pathogenesis. Because autopsied newborns have complex clinical problems, it is not possible at postmortem examination to determine with absolute certainty which of the many insults, alone or in combination, are responsible for the neuropathological findings. Indeed, hypoxia-ischemia, hypoglycemia, and hyperbilirubinemia are all characterized by acute neuronal necrosis, neuronal loss, or gliosis, albeit in different topographic distributions, and all share common mechanisms of cell injury, particularly glutamate toxicity.
| PATTERN a | USUAL INSULT |
|---|---|
| Diffuse | Very severe, very prolonged |
| Cerebral cortex–deep nuclear b | Moderate to severe, prolonged |
| Deep nuclear b –brain stem | Severe, abrupt |
a The patterns reflect areas of predominant neuronal injury; considerable overlap is common. Note that two additional patterns of selective neuronal necrosis (i.e., pontosubicular and cerebellar ) that occur predominantly in premature newborns (see text) are not listed here because the temporal characteristics of the insults are unknown.
b Deep nuclear: basal ganglia (especially putamen) and thalamus.
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 and mature 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. The major changes to be seen by classic light microscopy occur after 24 to 36 hours and are characterized by marked eosinophilia of neuronal cytoplasm, loss of Nissl substance (endoplasmic reticulum), condensation (pyknosis) or fragmentation (karyorrhexis) of nuclei, and breakdown of nuclear and plasma membranes, often with observable cell swelling ( Fig. 18.1 ). Two 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 account, the presence and magnitude of neuronal injury may be misjudged and may lead to spurious conclusions about the nature of the neuropathology.
The early neuronal changes are followed in several days by overt signs of cell necrosis ( Fig. 18.2 ). Associated with this 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. Severe lesions may result in cavity formation, especially in the cerebral cortex.
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 (NMDA)–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.
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 18.3 ). 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–brain stem disease, basal ganglia–thalamus–brain stem 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, we discuss diffuse disease first, since all 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 18.4 .
| BRAIN REGION | PREMATURE | TERM NEWBORN |
|---|---|---|
| Cerebral neocortex | + | |
| Hippocampus | ||
| Sommer’s sector | + | |
| Subiculum | + | |
| Deep nuclear structures | ||
| Caudate-putamen | + | + |
| Globus pallidus | + | + |
| Thalamus | + | + |
| Brain stem | ||
| 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) | ± | |
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) in the term newborn and the subiculum of the hippocampus in the premature newborn (see later discussion) are especially prone to injury (see Table 18.4 ). 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 the depths of sulci. Perhaps reflecting the relative immaturity of cerebral cortical neurons in premature infants, involvement of cerebral cortex is uncommon, particularly in comparison with neurons of deep nuclear structures and brain stem (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 Chapter 7 , Chapter 14 , Chapter 16 ). 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 14 ). The important point in this context is that the abnormalities of cerebral cortex may not reflect direct cortical neuronal necrosis, at least as evidenced by histological criteria.
Deep Nuclear Structures.
Involvement of deep nuclear structures, principally thalamus and basal ganglia, is particularly characteristic of hypoxic-ischemic neuronal injury in both preterm and term newborns. With diffuse disease, thalamus is particularly vulnerable. As discussed later, a particular pattern of injury in term newborns involves a combination of affection of neurons of thalamus, basal ganglia, and brain stem, with relative sparing of cerebral cortical neurons. Hypothalamic neurons and those of the lateral geniculate nuclei (thalamus) are also especially vulnerable. In preterm newborns, involvement of deep nuclear structures is a major form of gray matter injury. Injury to thalamus and basal ganglia was apparent in 40% to 50% of one series of 41 premature infants studied at autopsy (see later). Of the basal ganglia, neurons of the caudate, putamen, and globus pallidus are often injured in both term and premature newborns (see Table 18.4 ). Neurons of the putamen (and head of the caudate nucleus) are somewhat more likely to be affected in the term infant, whereas neurons of the globus pallidus are more likely to be affected in the premature infant. This distinction is subtle, however. Neuronal injury to basal ganglia is usually accompanied by thalamic neuronal injury. Indeed, in my experience, the combination of putaminal and thalamic neuronal injury is typical of neonatal hypoxic-ischemic disease, especially in the term infant.
Brain Stem.
Particularly characteristic of hypoxic-ischemic encephalopathy in the newborn is involvement of the brain stem. In general, hypoxic-ischemic injury to brain stem in the term newborn tends to be more or less restricted to neurons. With premature infants, although neurons are involved primarily, injury may be so marked as to result in cystic necrosis. As discussed later, involvement of neurons of brain stem may occur in combination with basal ganglia and thalamic involvement.
In midbrain, the inferior colliculus stands out in terms of vulnerability. This is in keeping with the studies of Ranck, Windle, and Faro of asphyxiated fetal monkeys, particularly with total asphyxia. Neuronal injury is also found frequently in the neurons of the oculomotor and trochlear nuclei, substantia nigra, and reticular formation.
In pons, particularly frequently involved are the motor nuclei of the fifth and seventh cranial nerves, the reticular formation, the dorsal cochlear nuclei, and the pontine nuclei. Striking involvement of the nuclei in ventral pons and of the neurons of the subicular portion of the hippocampus in some cases led Friede to the term pontosubicular neuronal necrosis. This pattern of injury is discussed later.
In medulla, particularly vulnerable are the dorsal nuclei of the vagus, nucleus ambiguus (ninth and tenth cranial nerves), inferior olivary nuclei, and the cuneate and gracilis nuclei. Involvement of neurons of the inferior olivary nuclei is the single most common brain-stem neuronal lesion in both term and preterm infants. In one series of 41 premature infants studied at autopsy, fully 90% had evidence of inferior olivary injury. Important clinical correlates of many of these brain stem lesions are discussed in Chapter 20 .
Cerebellum.
The cerebellum is especially vulnerable to hypoxic-ischemic neuronal injury, and the Purkinje cells in the term infant and the granule cell neurons (of both the internal and external granule cell layers) in both the term and premature infant are the most vulnerable cerebellar neurons (see Table 18.4 ). Neurons of the vermis may be especially easily injured in the term infant. Neurons of the dentate nucleus (and other roof nuclei) are also somewhat susceptible to injury, more so in the preterm newborn than at later ages. In the term infant, a subsequent disturbance of cerebellar growth, especially involving the vermis, has been observed by magnetic resonance imaging (MRI). In this setting, frequent concomitant injury to thalamus and basal ganglia also raises the possibility of transsynaptic effects. Involvement of the cerebellum, especially the cerebellar hemispheres, and subsequently impaired cerebellar growth are particular features of very premature infants and are sufficiently distinctive to be discussed as a separate form of selective neuronal necrosis (see later).
Spinal Cord.
Affection of anterior horn cells by hypoxic-ischemic injury has been identified. This involvement is accompanied clinically by hypotonia and weakness and electrophysiologically by signs of anterior horn cell disturbance; it may underlie at least some cases of so-called atonic cerebral palsy (see Chapter 20 ). The neuronal injury occurs in typical form in the term infant and is similar cytopathologically to that observed in other regions. When present in the premature infant, the lesion, as with hypoxic-ischemic injury to brain stem, often also involves contiguous cellular elements, which may have the histological appearance of infarction and may be accompanied by hemorrhage.
Cerebral–Deep Nuclear Neuronal Injury.
Although systematic data are difficult to gather, MRI studies of asphyxiated term infants suggest that approximately 35% to 85% exhibit predominantly cerebral–deep nuclear neuronal involvement. Among neurons of cerebral cortex, those in the parasagittal areas of perirolandic cortex are especially likely to be affected. Involvement of hippocampus and other neocortical areas was described earlier. The most common additional neuronal lesion affects basal ganglia, especially putamen, and thalamus. The pathogenesis appears usually to involve a moderate or moderate-to-severe insult that evolves in a gradual manner (i.e., a “prolonged, partial” insult; see the section on pathogenesis in Chapter 19 ).
Deep Nuclear–Brain-Stem Neuronal Injury.
Although involvement of neurons of basal ganglia and thalamus occurs in approximately two thirds of asphyxiated term infants, in approximately 15% to 20% of infants with hypoxic-ischemic disease, involvement of deep nuclear structures (i.e., basal ganglia, thalamus, and tegmentum of brain stem) is the predominant lesion. Until the advent of MRI, detection of this deep gray matter predominance in the living infant had not been accomplished readily; thus the relative frequency of this pattern of neuronal injury was not recognized. However, studies based on MRI and careful clinical-pathological correlations have delineated this pattern as a distinct entity. The topography of the neuropathology is illustrated in Fig. 18.3 .
At least some cases of this predominantly deep gray matter form of selective neuronal injury may evolve to status marmoratus, a disorder of basal ganglia and thalamus not seen in its complete form until the latter part of the first year of life, despite the perinatal timing of the insult. The basic initiating role of hypoxia-ischemia is demonstrated not only by clinical data in human infants (see later discussion) but also by the reproduction of the lesion in the newborn rat subjected to hypoxic-ischemic insult as well as in the term fetal monkey subjected to intrauterine asphyxia.
Status marmoratus has three major features: neuronal loss, gliosis, and hypermyelination. Hypermyelination is the characteristic feature of the lesion; this term refers to an apparent increase in amount and an abnormal distribution of myelinated fibers within the affected nuclear structures, especially the putamen ( Fig. 18.4 ). The hypermyelination has been noted at as early as 8 months of life. The abnormal myelin pattern gives a marbled appearance to the basal ganglia, hence the term status marmoratus or état marbré . Previous observations by light microscopy had led to the suggestion that the many myelinated fibers in status marmoratus were axons, and the idea that such apparent overgrowth was a result of aberrant myelination of nerve fibers was accepted for many years. However, electron microscopic techniques were used to show that the abnormal myelinated fibers, at least in part, are astrocytic processes. It appears that the very young brain, at the time of normal myelination, may myelinate fibers that are not axonal in origin. Thus this distinctive response to injury appears to depend on the time of occurrence of the insult as well as the locus of the injury. Nevertheless, the proportion of infants with hypoxic-ischemic involvement of basal ganglia and thalamus who develop status marmoratus and the determinants for the occurrence of this relatively specific pathological response to injury versus that of only gliosis and atrophy remain to be determined. Concerning the sequela of gliosis and atrophy alone, a reasonable speculation is that an injury so severe as to eliminate oligodendrocytes as well as neurons may prevent the occurrence of the typical hypermyelination of status marmoratus. As discussed later (see the section on pathogenesis in Chapter 19 ), the hypoxic-ischemic insult associated with the occurrence of predominant involvement of deep gray matter structures typically is severe and abrupt in evolution (i.e., an “acute, total” insult).
